CVJA Volume 29 Issue 3 by Clinics Cardive Publishing

MAY/JUNE 2018 VOL 29 NO 3

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CardioVascular Journal of Africa (official journal for PASCAR)

• Cardiovascular magnetic resonance imaging in rheumatic heart disease • Insights from the THESUS-HF registry in Africans • Myocardial fibrosis in chronic rheumatic mitral regurgitation • HIV disease and endothelial dysfunction with long-term ART in Botswana • Atorvastatin vs rosuvastatin on endothelial dysfunction in hyperlipidaemia • Nucleus balloon: an alternative when there is no Inoue balloon • Impact of obesity on the relationship between sodium and blood pressure • Qualitative analysis of ACS care at Kenyatta National Hospital • Cardiovascular risk factors and carotid atherosclerosis in Nigeria • Psoriasis and cardiometabolic disorders

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Cardiovascular Journal of Africa . Vol 29, No 3, May/June 2018

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Cardiovascular Journal of Africa

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ISSN 1995-1892 (print) ISSN 1680-0745 (online)

Vol 29, No 3, MAY/JUNE 2018

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EDITORIAL 135

Cardiovascular magnetic resonance imaging in rheumatic heart disease NAB Ntusi

139

Prevalence, clinical characteristics and outcomes of valvular atrial fibrillation in a cohort of African patients with acute heart failure: insights from the THESUS-HF registry MU Sani • BA Davison • G Cotter • BM Mayosi • C Edwards • OS Ogah • A Damasceno • DB Ojji • A Dzudie • C Mondo • C Kouam Kouam • A Suliman • G Yonga • SA Ba • F Maru • B Alemayehu • K Sliwa

146

Influence of visceral fat and blood pressure on changes in blood flow velocity in non-obese individuals AR Rasyada • M Sha’ban • A Azhim

150

Assessment of myocardial fibrosis by late gadolinium enhancement imaging and biomarkers of collagen metabolism in chronic rheumatic mitral regurgitation R Meel • R Nethononda • E Libhaber • T Dix-Peek • F Peters • M Essop

155

HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana M Mosepele • T Mohammed • L Mupfumi • S Moyo • K Bennett • S Lockman • LC Hemphill • VA Triant

162

The effects of treatment with atorvastatin versus rosuvastatin on endothelial dysfunction in patients with hyperlipidaemia V Demir • MT Doğru • H Ede • S Yılmaz • C Alp • Y Celik • N Yıldırım

167

Percutaneous transmitral balloon commissurotomy using a single balloon with arteriovenous loop stabilisation: an alternative when there is no Inoue balloon E Tefera • M Leye • P Garceau • D Bouchard • J Miró

CARDIOVASCULAR TOPICS

INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 29, No 3, MAY/JUNE 2018

172

Obesity masks the relationship between dietary salt intake and blood pressure in people of African ancestry: the impact of obesity on the relationship between sodium and blood pressure M Maseko • M Mashao • A Bawa-Allah • E Phukubje • B Mlambo • T Nyundu

177

Facilitators, context of, and barriers to acute coronary syndrome care at Kenyatta National Hospital, Nairobi, Kenya: a qualitative analysis E Bahiru • T Temu • J Mwanga • K Ndede • S Vusha • B Gitura • C Farquhar • F Bukachi • MD Huffman

183

Association of traditional cardiovascular risk factors with carotid atherosclerosis among adults at a teaching hospital in south-western Nigeria AD Omisore • OC Famurewa • MA Komolafe • CM Asaleye • MB Fawale • BI Afolabi

189

Double trouble: psoriasis and cardiometabolic disorders NG Mahyoodeen • NJ Crowther • M Tikly

195

Irregular, narrow-complex tachycardia Julian Hövelmann • Charle Viljoen • Ashley Chin

199

Report from Nairobi: towards a 25% reduction in uncontrolled hypertension in Africa M Hudson

PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed)

Levitronix bilateral ventricular assist device, a bridge to recovery in a patient with acute fulminant myocarditis and concomitant cerebellar infarction Y-F Huang • P-S Hsu • C-S Tsai • Y-T Tsai • C-Y Lin • H-Y Ke • Y-C Lin • H-Y Yang

REVIEW ARTICLE

ECG Series

PASCAR News

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Editorial Cardiovascular magnetic resonance imaging in rheumatic heart disease NAB Ntusi Rheumatic heart disease (RHD), a sequela of pharyngeal and skin infection with group A Î˛-haemolytic Streptococcus, affects approximately 33 million persons globally, with low- and middleincome countries (LMICs) disproportionately more affected.1 RHD globally contributes the largest share to cardiovascular mortality in individuals under 50 years old.2 Sub-Saharan Africa (SSA) bears the greatest burden of cardiovascular morbidity and mortality related to RHD.3 In highly endemic parts of SSA, the prevalence of RHD ranges from 4.6 to 21.7 per 1 000 individuals, based on echocardiographic screening.4 Complications secondary to RHD cause disability-adjusted life-years (DALYs) of 142.6 per 100 000 individuals globally, translating to 0.43% of total global DALYs.1 The rate of DALYs attributable to RHD is highest in SSA, where it negatively affects young and economically active members of the population.5 Multiple cardiovascular imaging modalities are important for the assessment of CVD and many are entrenched into the modern practice of cardiovascular medicine (Fig. 1). Cardiovascular magnetic resonance (CMR) is the gold-standard technique for many indications. It permits, in a single examination, comprehensive characterisation of functional, morphological, metabolic, tissue and haemodynamic sequelae of cardiovascular pathologies (Fig. 2).6 The high spatial and temporal resolution of CMR, coupled with excellent tissue contrast enables complete assessment of multiple parameters without exposure to ionising radiation. Further, the ability to obtain images in any tomographic plane regardless of body habitus confers significant advantage in patients with limited sonographic acoustic windows. CMR creates images from atomic nuclei with uneven spin using radiofrequency pulses in the presence of a powerful magnetic field. Hydrogen, which is abundant in fat and water, is the most commonly used atom for MR imaging; and tissue contrast in CMR is accounted for by three important parameters: T1 and T2 relaxation and proton density. CMR is safe, especially when compared with X-ray-based techniques. The main MR contrast agent, gadolinium, has been shown to be safe in millions of patients who have received it over decades, and nephrogenic systemic sclerosis has not been reported with

Division of Cardiology, Department of Medicine, University of Cape Town and Groote Schuur Hospital; Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town; Hatter Institute of Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, South Africa NAB Ntusi, FCP (SA), DPhil, MD, ntobeko.ntusi@uct.ac.za

the newer macrocyclic gadolinium-based agents, which are preferentially used in patients with renal dysfunction due to the high risk posed by iodinated contrast agents.6,7 Characterisation of myocardial tissue is a unique feature of CMR, traditionally achieved through late gadolinium enhancement (LGE) imaging, and based on the relative difference in volume of distribution of intravenously administered gadolinium [and subsequent alteration of longitudinal relaxation (T1) times] between normal and abnormal myocardium.8 Hence, LGE-CMR permits identification of focal fibrosis. More recently, native (pre-contrast) T1 and T2 mapping techniques have allowed direct measurement of myocardial relaxation times on a pixel-wise basis, parameters which have been extensively validated, offering similar diagnostic performance and superior sensitivity for inflammation, infiltration, acute injury and fibrosis, compared with delayed enhancement imaging in detecting myocardial pathology.9 Post-contrast T1 mapping and estimation of the extracellular volume (ECV) allow for the assessment of the degree of diffuse myocardial fibrosis.10 Echocardiographic studies of RHD are established in clinical practice and are indispensable for the comprehensive assessment of valve lesions secondary to RHD, through confirmation of aetiology of the valvular lesion and exclusion of non-rheumatic causes of valve lesions. M-mode and two-dimensional crosssectional echocardiography are important for the assessment of chamber size and function, diastolic dysfunction, valve morphology and function, and both atrial and myocardial remodelling. Colour-flow Doppler evaluates flow across valves and can assess the haemodynamic effects of both stenotic and regurgitant lesions. Furthermore, serial echocardiography is important for monitoring of disease progress as well as efficacy of surgical repair or replacement. The use of strain imaging and threedimensional echocardiography is important for risk stratification and in planning and predicting surgical outcomes.11 Portable echocardiography plays a crucial role in screening for RHD and is important for defining disease burden, clarifying referral pathways and informing policy for scaling up RHD control programmes. The publication of the World Health Federation criteria for the echocardiographic diagnosis of RHD in 2012 has provided standardisation and improved both specificity and utility of echocardiographic screening for RHD.12 CMR has been demonstrated to be capable of performing many of the applications described above.13 Multiparametric CMR has been employed in small case series and case reports in the diagnosis and guidance of management of patients with RHD. In a series of three patients with chronic RHD, CMR was found to be associated with LGE in atrial walls.14 Using

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Fig. 1. D ifferent modalities of cardiovascular imaging.

dated CMR sequences as a comparator, Mutnuru et al. found echocardiography to be a more reliable tool for diagnosis of RHD.15 Our group has recently reported on the role of CMR in unravelling the pathophysiology of heart block and myocarditis in a patient subsequently confirmed to have acute rheumatic fever (Fig. 3).16 Edwards and colleagues reported on a CMR cross-sectional study of 35 patients (mean age 60 years) with asymptomatic moderate and severe primary degenerative mitral regurgitation but impaired VO2 max and found dilated left ventricular (LV) volumes, preserved LV systolic function, evidence of impaired longitudinal and circumferential strain, LGE in 30% of subjects,

and evidence of diffuse myocardial fibrosis from elevated ECV.17 The authors concluded that patients with moderate to severe mitral regurgitation have increased myocardial fibrosis, impaired myocardial strain and reduced exercise capacity. In this issue of the journal (page 150), Meel and colleagues report, similarly, on a study of 22 patients with chronic rheumatic mitral regurgitation and 14 age- and gender-matched controls characterised by echocardiography, LGE-CMR (for assessment of focal fibrosis) and serum biomarkers of collagen turnover.18 The key findings were that 18% of the patients had evidence of LGE, while none was observed in the controls. As expected, on both CMR and echocardiography, patients with rheumatic

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• • • • • • • • • • • •

137

Anatomy Function (global and regional) Vascular assessment (PWV, distensibility) Tissue characterisation (inflammation, oedema) Myocardial deformation (strain) Rest and stress perfusion (inducible ischaemia) Viability Regional fibrosis Diffuse fibrosis Flow/4-D flow Myocardial energetics Myocardial lipidosis

Fig. 2. M ultiparametric capability of CMR.

mitral regurgitation had greater LV dimensions and greater LV mass, though overall LV systolic function was not different. Procollagen IC peptide (PIP) and procollagen III N-terminal pro-peptide (PIIINP) were similar between patients and controls, however, matrix metalloproteinase-1 (MMP-1) activity was increased in the patient group. The authors concluded that chronic rheumatic mitral regurgitation is characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis. RHD is characterised by chronic inflammation which, in many other inflammatory cardiac conditions, 6,8-10 is associated with frequent focal myocardial fibrosis. In this small study, the authors reported the incidence of myocardial fibrosis on LGE-CMR at 18%. It would have been instructive if the

investigators had utilised native T1 mapping or ECV to assess for the presence of diffuse myocardial fibrosis in RHD, which in my experience is found commonly. The authors attribute the infrequent LGE to increased expression of biomarkers of collagen degradation. However, the relationship of serum biomarkers of collagen synthesis, which have low specificity for cardiac fibrosis, has been inconsistently reported in the literature, with a prior publication reporting increased biomarkers of collagen synthesis in RHD.19 In the future, CMR may play an increasingly important and complementary role to echocardiography in the evaluation and management of patients with RHD. An advantage of CMR over echocardiography in RHD is the ability to provide accurate and reproducible information on tissue characteristics, including

Fig. 3. P atient with heart block and acute myocarditis confirmed to be due to acute rheumatic fever. A. balanced steady-state freeprecession image showing a short-axis ciné; B. T1-weighted image showing increased myocardial signal-intensity ratio; C. T2-weighted imaging showing increased myocardial signal-intensity ratio (in keeping with myocardial oedema); D. Ciné tagging imaging of the short axis confirming impaired circumferential strain and strain rate; E. Horizontal long-axis (fourchamber) LGE image showing no myocardial enhancement but evidence of valvulitis, with valvular and atrial enhancement; F. Vertical long-axis (two-chamber) LGE image confirming lack of myocardial LGE, but mitral valve enhancement.

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myocardial fibrosis and oedema, without dependence on the presence of adequate acoustic windows and operator experience.5 CMR may provide additional diagnostic information when echocardiographic imaging is suboptimal. However, the utility of CMR for the evaluation of RHD may be limited by its relative inability to be used in patients with certain types of metallic implants, local artefacts from prosthetic valves, lack of availability, expense of the tests and limited expertise in RHD-endemic countries. Furthermore, data regarding prognostic significance of CMR in RHD are lacking.5

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are common in systemic sclerosis – a clinical study using myocardial T1-mapping and extracellular volume quantification. J Cardiovasc Magnetic Resonance 2014; 16: 21. 9.

Ferreira VM, Piechnik SK, Dall’Armellina E, Karamitsos TD, Francis JM, Ntusi N, et al. T(1) mapping for the diagnosis of acute myocarditis using CMR: comparison to T2-weighted and late gadolinium enhanced imaging. J Am Coll Cardiol Cardiovasc Imag 2013; 6(10): 1048–1058.

10. Ntusi NAB, Piechnik SK, Francis JM, Ferreira VM, Matthews PM, Robson MD, et al. Diffuse myocardial fibrosis and inflammation in rheumatoid arthritis: insights from CMR T1 mapping. J Am Coll Cardiol Cardiovasc Imag 2015; 8(5): 526–536.

I gratefully acknowledge support from the National Research Foundation

11. Lang RM, Mor-Avi V, Sugeng L, Nieman PS, Sahn DJ. Three-

and the Medical Research Council of South Africa, National Heart, Lung

dimensional echocardiography: the bnefits and additional dimension. J

and Blood Institute in the USA, as well as the Harry Crossley Foundation.

Am Coll Cardiol 2006; 48(10): 2053–2069. 12. Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al.

References 1.

Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. New Engl J Med 2017; 377(8): 713–722.

Abubakar II, Tillmann T, Banerjee A, for the GBD 2013 Mortality and

Mocumbi AO. Rheumatic heart disease in Africa: is there a role for

rheumatic heart disease. Texas Heart Inst J 2011; 38(1): 56–60. 15. Mutnuru PC, Singh SN, D’Souza J, Perubhotla LM. Cardiac MR imaging in the evaluation of rheumatic valvular heart diseases. J Clin Diagnost Res 2016; 10(3): TC06–TC09.

Rothenbühler M, O’Sullivan CJ, Stortecky S, Stefanini GG, Spitzer E,

16. Samuels P, Chin A, Ntsekhe M, Ntusi NAB. CMR unravels the

Estill J, et al. Active surveillance for rheumatic heart disease in endemic

pathophysiology of heart block in a young woman. Cardiovasc Magnet

regions: a systematic review and meta-analysis of prevalence among

Resonance Congress S Afr 2017 (abstract). http://www.cubic.uct.ac.za/

children and adolescents. Lancet Global Health 2014; 2(12): e717–e726.

sites/default/files/image_tool/images/217/SCMR%20Abstract%20Petty.

Zühlke LJ, Beaton A, Engel ME, Hugo-Hamman CT, Karthikeyan G,

pdf. Accessed 8 June 2018.

Katzenellenbogen JM, et al. Group A Streptococcus, acute rheumatic

17. Edwards NC, Moody WE, Yuan M, Weale P, Neal D, Townend JN, et

fever and rheumatic heart disease: epidemiology and clinical considera-

al. Quantification of left ventricular interstitial fibrosis in asymptomatic

tions. Curr Treat Options Cardiovasc Med 2017; 19(2): 15.

chronic primary degenerative mitral regurgitation. Circ Cardiovasc Imag

Sood V, Jermy S, Saad H, Samuels P, Moosa S, Ntusi NAB. Review of

2014; 7: 946–953. 18. Meel R, Nethononda R, Libhaber E, Dix-Peek T, Peters F, Essop M.

associated cardiovascular disease. S Afr J Radiol 2017; 21(2): 10.

Assessment of myocardial fibrosis by late gadolinium enhancement

Ntusi NA, Samuels P, Moosa S, Mocumbi AO. Diagnosing cardiac

imaging and biomarkers of collagen metabolism in chronic rheumatic

disease during pregnancy: imaging modalities. Cardiovasc J Afr 2016; 27(2): 96–103. 8.

2009; 119(3): 468–478. linium enhancement in the atrial wall: a novel finding in 3 patients with

cardiovascular magnetic resonance in human immunodeficiency virus7.

imaging for valvular heart disease: technique and validation. Circulation

specific all-cause and cause-specific mortality for 240 causes of death,

genetic studies? Cardiovasc J Afr 2015; 26(2 Suppl 1): S21–S26.

Cardiol 2012; 9(5): 297–309. 13. Cawley PJ, Maki JH, Otto CM. Cardiovascular magnetic resonance

14. Shriki J, Talkin B, Thomas IC, Farvid A, Colletti PM. Delayed gado-

Study 2013. Lancet 2015; 385(9963): 117–171.

rheumatic heart disease – an evidence-based guideline. Nature Rev

Causes of Death Collaborators. Global, regional, and national age-sex 1990–2013: a systematic analysis for the Global Burden of Disease 3.

World Heart Federation criteria for echocardiographic diagnosis of

mitral regurgitation. Cardiovasc J Afr 2018; 29(3): 00–00. 19. Banerjee T, Mukherjee S, Ghosh S, Biswas M, Dutta S, Pattari S, et al.

Ntusi NA, Piechnik SK, Francis JM, Ferreira VM, Rai AB, Matthews

Clinical significance of markers of collagen metabolism in rheumatic

PM, et al. Subclinical myocardial inflammation and diffuse fibrosis

mitral valve disease. PLoS One 2014; 9(3): e90527.

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Cardiovascular Topics Prevalence, clinical characteristics and outcomes of valvular atrial fibrillation in a cohort of African patients with acute heart failure: insights from the THESUS-HF registry Mahmoud U Sani, Beth A Davison, Gad Cotter, Bongani M Mayosi, Christopher Edwards, Okechukwu S Ogah, Albertino Damasceno, Dike B Ojji, Anastase Dzudie, Charles Mondo, Charles Kouam Kouam, Ahmed Suliman, Gerald Yonga, Serigne Abdou Ba, Fikru Maru, Bekele Alemayehu, Karen Sliwa

Abstract Introduction: Rheumatic heart disease (RHD) is the commonest cause of valvular heart disease and a common cause of heart failure in sub-Saharan Africa (SSA). Atrial fibrillation (AF) complicates RHD, precipitates and worsens heart failure and cause unfavourable outcomes. We set out to describe the prevalence, clinical characteristics and outcomes of valvular atrial fibrillation in a cohort of African patients with acute heart failure (AHF). Methods: The sub-Saharan Africa Survey of Heart Failure (THESUS-HF) was a prospective, observational survey of AHF in nine countries. We collected demographic data, medical history and signs and symptoms of HF. Electrocardiograms (ECGs) were done in a standard fashion. AF was defined as either a history of AF or AF on the admission ECG. Using Cox regression models, we examined the associations of AF

with all-cause death over 180 days and a composite endpoint of all-cause death or readmission over 60 days. Results: There were 1 006 patients in the registry. The mean age was 52.3 years and 50.8% were women. AF was present in 209 (20.8%) cases. Those with AF were older (57.1 vs 51.1 years), more likely to be female (57.4 vs 49.1%), had significantly lower systolic (125 vs 132 mmHg) and diastolic (81 vs 85 mmHg) blood pressure (BP), and higher heart rates (109 vs 102 bpm). Ninety-two (44%) AF patients had valvular heart disease. The presence of AF was not associated with the primary endpoints, but having valvular AF predicted death within 180 days. Conclusion: AF was present in one-fifth of African patients with AHF. Almost half of the AF patients had valvular disease (RHD) and were significantly younger and at risk of dying within six months. It is important to identify these high-risk patients and prioritise their management, especially in SSA where resources are limited.

Department of Medicine, Bayero University and Aminu Kano Teaching Hospital, Kano, Nigeria

Department of Internal Medicine, Douala General Hospital and Buea Faculty of Health Sciences, Douala, Cameroon

Mahmoud U Sani, MB BS, FWACP, FACP, FACC, sanimahmoud@ yahoo.com

Anastase Dzudie, MD, PhD Charles Kouam Kouam, MD

Momentum Research, Inc, Durham, North Carolina, United States of America

Uganda Heart Institute, Kampala, Uganda

Beth A Davison, PhD Gad Cotter MD, FACC Christopher Edwards, BSc

Department of Medicine, GF Jooste and Groote Schuur Hospitals, University of Cape Town, Cape Town, South Africa

Charles Mondo, MB ChB, PhD

Faculty of Medicine, University of Khartoum, Khartoum, Sudan Ahmed Suliman, MD

Department of Medicine, Aga Khan University, Nairobi, Kenya

Bongani M Mayosi, DPhil, FCP (SA)

Gerald Yonga, MD, PhD

Department of Medicine, University College Hospital, Ibadan, Nigeria

Service de Cardiologie, Faculty of Medicine, Dakar, Senegal

Okechukwu S Ogah, MB BS, FWACP

Addis Cardiac Hospital, Addis Ababa, Ethiopia

Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique

Fikru Maru, MD Bekele Alemayehu, MD

Albertino Damasceno, MD, PhD

Department of Medicine, University of Abuja Teaching Hospital, Abuja, Nigeria

Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Dike B Ojji, MB BS, PhD

Karen Sliwa, MD, PhD

Abdou Ba, MD, PhD

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Keywords: valvular, atrial fibrillation, heart failure, sub-Saharan Africa Submitted 16/9/16, accepted 19/11/17 Cardiovasc J Afr 2018; 29: 139–145

www.cvja.co.za

DOI: 10.5830/CVJA-2017-051

Rheumatic heart disease (RHD) remains an important cause of heart failure in sub-Saharan Africa (SSA),1,2 and RHD associated with valvular atrial fibrillation (AF) is also common on the continent.3 Among the regions enrolled in the Randomised Evaluation of Long-Term Anticoagulation Therapy in Atrial Fibrillation (RE-LY-AF), a global prospective registry that enrolled patients presenting to an emergency department with AF, RHD was present in 22% of African patients compared with 2% of North American patients.3 The risk of AF increases multiple-fold in the presence of heart failure (HF) and valvular disease.4 The prognostic influence of the presence of AF in HF remains controversial, with some studies illustrating an independent adverse effect on mortality rate.5,6 In a recent meta-analysis of 16 studies comprising more than 50 000 patients with chronic HF, Mamas and colleagues showed that AF was associated with an adverse effect on total mortality rate.7 From a cohort of 1 006 African patients admitted with acute heart failure (AHF) and enrolled in the sub-Saharan Africa Survey of Heart Failure (THESUS-HF) registry, we analysed the burden, clinical characteristics and outcomes of AF in general and valvular AF in particular among acute HF patients in sub-Saharan Africa.

Methods THESUS-HF was a prospective, multicentre, international observational survey of acute HF in 12 cardiology centres from nine countries in sub-Saharan Africa.2 All participating centres had a physician trained in clinical cardiology and echocardiography. Patients, who were older than 12 years, admitted with dyspnoea as the main complaint, and diagnosed with acute HF based on symptoms and signs that were confirmed by echocardiography (de novo or decompensation of previously diagnosed HF), were enrolled consecutively. Patients excluded were those with acute ST-elevation myocardial infarction, severe known renal failure (patients undergoing dialysis or with a creatinine level of > 4 mg/dl), nephrotic syndrome, hepatic failure or another cause of hypoalbuminaemia. Written informed consent was obtained from each subject who was enrolled into the study. Ethical approval was obtained from the ethical review boards of the participating institutions, and the study conformed to the principles outlined in the Declaration of Helsinki. Details of data collection have been previously described.2 In brief, we collected demographic data, detailed medical history, vital signs (blood pressure, heart rate, respiratory rate and temperature), and signs and symptoms of HF (oxygen saturation, intensity of oedema and rales, body weight and levels of orthopnoea). Assessments were done at admission and on days one, two and seven (or discharge if earlier).

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Electrocardiograms were done and read using standard reference ranges. All ECGs were read centrally at the Momentum Research Inc by one cardiologist and reviewed by a second cardiologist. ECGs were analysed for conduction or rhythm disturbances, evidence of myocardial ischaemia/infarction or hypertrophy. AF was defined as either a history of documented AF or a finding of AF on the admission ECG. The information obtained was entered in the database registry together with other clinical data. A detailed echocardiographic assessment of ventricular contractility, valvular structure and function, as well as regional wall abnormalities was performed. All echocardiographic procedures were undertaken by trained physicians, and measurements were made according to the American Society of Echocardiography Guidelines.8 The probable primary cause of HF was provided by the investigators, based on the European Society of Cardiology (ESC) guidelines 9 as recently applied in the chronic HF cohort of the Heart of Soweto Study.10 RHD was defined based on clinical and echocardiographic criteria.11,12 Information on readmissions and death, with respective reasons and cause, was collected over the six-month follow up. Outcomes of interest were readmission or death within 60 days, and death within 180 days. Laboratory evaluations provided by the local institutions and intravenous and oral medications were recorded at admission, and on days one, two and seven (or discharge if earlier). Vital signs (blood pressure, heart rate, respiratory rate and temperature), and signs and symptoms of HF (including oxygen saturation, intensity of oedema and rales, body weight, levels of orthopnoea) were assessed at the same time points. Changes in dyspnoea and well-being relative to admission were assessed on days one, two and seven (or discharge if earlier). Subjects who were discharged after admission were evaluated at one and six months’ follow up. At these time points, patients were evaluated for signs and symptoms of HF, laboratory evaluations were performed, and oral medications recorded. Readmissions and death, with respective reasons and cause, over the six months of follow up were collected.

Statistical analyses All data were processed at the central coordinating centre at Momentum Research, Durham, North Carolina, USA. Data were analysed with the use of SAS version 9.3 (SAS Institute, Cary, North Carolina). Summary statistics (mean, SD, median, and 25th and 75th percentiles) are provided for continuous variables and frequencies for categorical variables. Unless otherwise stated, a chi-squared test was used for categorical variables, the Cochran– Mantel–Haenszel test for ordinal variables, and Wilcoxon test for continuous variables to examine comparisons between groups. AF classification was based on subjects either having a history of AF or the presence of AF on an ECG taken at admission. Baseline characteristics by AF status are presented, as well as characteristics between patients with valvular and non-valvular AF. Comparisons between valvular and non-valvular AF patients are presented to examine differences in the following outcomes: length of index hospitalisation, time to first rehospitalisation within 60 days, all-cause mortality within 180 days, and the composite endpoint of time to all-cause mortality or rehospitalisation within 60 days.

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For length of index hospitalisation, least-square means and the difference between least-square means are presented. For time-to-event outcomes, Cox regression models were used with times for patients without the event of interest being censored at the earlier of the last date the patient was known to be alive or the period of interest for the specific outcome. Kaplan–Meier estimates, hazard ratios and 95% confidence intervals are given, with the log-rank test used for comparison between groups. Two patients who were classified with AF but were missing valvular disease status were excluded from tables comparing valvular disease in only those patients with AF. Imputation for missing values was done only when examining associations after adjustment for potential confounders using multivariable models. For multivariable modelling, these two patients were counted as having neither valvular AF nor non-valvular AF. Anticoagulation use over time is also presented as the frequency of use by AF and by valvular/non-valvular disease in only those patients with AF by time point. The prognostic value of valvular and non-valvular AF was examined in multivariable models for the outcomes all-cause mortality within 180 days and the composite endpoint all-cause mortality or rehospitalisation within 60 days. The multivariable models were adjusted for significant clinical covariates from multivariable prognostic models previously constructed for these outcomes in the overall THESUS-HF registry.13 To account for missing data, multiple imputations were used with seven imputed datasets. Of the 11 baseline variables included in the multivariable model for 180-day mortality, 278 (27.6%) patients were missing one variable, 57 (5.7%) were missing two, nine (0.9%) were missing three, and four (0.4%) were missing four or more. Of the seven baseline variables included in the multivariable model for 60-day death or HF rehospitalisation, 205 (20.4%) patients were missing one variable, 44 (4.4%) were missing two, five (0.5%) were missing three, and none was missing four or more. Rubin’s algorithm was used for averaging parameter estimates across the imputed data-sets.14,15

patients were younger (mean age 52 vs 61 years), had lower systolic blood pressure (120 vs 128 mmHg) and higher left ventricular ejection fraction (LVEF) (47 vs 38%). Fifty-seven per cent had LVEF ≥ 45%. Among patients with non-valvular AF, 61% had hypertensive heart disease. The other baseline characteristics were similar in the two groups (Table 2). Anticoagulation prescription rates were low in this cohort of patients and decreased progressively over time. At six months, only 22% of patients with AF were on oral anticoagulants. For the AF patients, 33% of the patients with valvular AF and 12% of those with non-valvular AF were on anticoagulants at six months’ follow up (Table 3). For aspirin, a greater proportion of patients with AF than without AF were on aspirin one month prior to admission (29 vs 20%), but on and after admission the proportions did not differ significantly. As shown in Table 4, the mean length of the hospital stay was 1.6 days longer in patients with valvular AF than for patients with non-valvular AF, although this was not statistically significant (p = 0.14). Patients were followed for a median of 180 days. Of 151 total deaths over 180 days, 20 occurred among Table 1. Baseline patient clinical characteristics by atrial fibrillation status Variables Age (years) Gender: female, n (%) Black African, n (%)

Atrial fibrillation1 (n = 209)

No atrial fibrillation1 (n = 797)

57.1 (17.73), 60.0 (46.0–70.0)

51.1 (18.26), 52.0 (36.0–65.0)

120 (57.4)

391 (49.1)

0.0328

p-value2 < 0.0001

203 (97.6)

781 (98.7)

0.2291

BMI (kg/m2)

24.94 (5.712), 24.73 (21.02–28.08)

24.85 (5.836), 23.88 (20.83–27.99)

0.4736

SBP (mmHg)

124.5 (29.86), 120.0 (102.0–145.0)

131.9 (34.27), 130.0 (108.0–150.0)

0.0128

DBP (mmHg)

80.6 (19.54), 80.0 (67.0–90.0)

85.3 (21.19), 82.0 (70.0–100.0)

0.0032

109.3 (28.02), 108.0 (90.0–124.0)

102.2 (19.29), 103.0 (90.0–114.0)

0.0021

110 (52.9)

446 (56.2)

0.3959

9 (4.5)

81 (10.4)

0.0109

Heart rate (bpm) History of hypertension, n (%)

Results

Hyperlipidaemia, n (%)

There was a total of 1 006 patients in the THESUS-HF registry. The mean (SD) age of the patients was 52.3 (18.3) years, 511 (50.8%) were women, and the predominant race was black African (98.5%). As reported previously,16 the primary aetiology of heart failure was most commonly hypertension (n = 363, 39.5%), followed by idiopathic dilated cardiomyopathy (n = 136, 14.8%) and rheumatic valvular heart disease (n = 137, 14.9%), with ischaemic HF in only 72 (7.8%) patients. AF was present in 209 (20.8%) of the 1 006 patients. In the previous THESUS-HF publication,2 prevalence was documented to be 18.3% because only those who had AF on the admission ECG were analysed. Table 1 shows the baseline patient characteristics by AF status. In both the AF and non-AF groups, about 80% of the patients were in NYHA class II or III one month prior to admission. Compared to the patients without AF, the patients with AF were older (mean age 57.1 vs 51.1 years) and more likely to be female (57.4 vs 49.1%). They also had significantly lower systolic (125 vs 132 mmHg) and diastolic (81 vs 85 mmHg) blood pressures and higher mean heart rates (109 vs 102 bpm). Ninety-two (44%) of the 207 AF patients had valvular heart disease. Compared with those without valvular disease, these

Stroke, n (%)

7 (3.4)

18 (2.3)

0.3613

Ischaemic heart disease, n (%)

11 (5.3)

71 (8.9)

0.0849

Valvular disease, n (%)

92 (44.4)

180 (22.7)

3 (1.4)

9 (1.1)

0.7072

99 (49.0)

390 (51.0)

0.6183

9 (4.3)

44 (5.6)

0.4815

80 (38.8)

336 (42.6)

0.3243

42.31 (15.721), 41.90 (31.00–52.00)

38.74 (16.623), 37.00 (25.40–50.00)

0.0022

82 (41.6)

405 (55.3)

Peripheral vascular disease, n (%) Anaemia, n (%) Pericardial disease, n (%) Cardiomyopathy, n (%) LVEF (%) LVEF < 40%, n (%) eGFR (ml/min/1.73 m2) Renal dysfunction, n (%)

78.257 (40.114), 84.685 (49.838), 70.782 (49.422–98.271) 77.735 (55.929–104.20) 10 (5.0)

63 (8.4)

< 0.0001

0.0155 0.0522 0.1020

1 Mean (SD), median (first quartile – third quartile) for a continuous variable and frequency (per cent) for a categorical variable. 2 Chi-squared test for a categorical variable, CMH for an ordinal variable and Wilcoxon test for a continuous variable. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate.

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Table 2. Baseline patient clinical characteristics versus valvular and non-valvular AF

Table 3. Anticoagulation and aspirin use versus time

Valvular AF1 (n = 92)

Non-valvular AF1 (n = 115)

p-value2

52.2 (18.98), 52.0 (38.5–65.5)

60.8 (15.74), 64.0 (53.0–72.0)

0.0005

Gender: female, n (%)

59 (64.1)

60 (52.2)

Black African, n (%)

91 (98.9)

111 (97.4)

BMI (kg/m )

24.89 (6.482), 24.76 (20.91–27.91)

24.90 (5.005), 24.52 (21.23–28.11)

SBP (mmHg)

119.9 (24.39), 112.0 (100.0–133.0)

127.9 (33.38), 124.5 (108.0–150.0)

0.0699

78.4 (17.01), 79.0 (65.0–90.0)

82.2 (21.29), 80.0 (68.0–94.0)

0.2521

111.7 (29.68), 109.0 (92.0–127.0)

107.4 (26.86), 107.0 (90.0–120.0)

0.4319

38 (41.8)

70 (60.9)

Variables Age (years)

DBP (mmHg) Heart rate History of hypertension, n (%) Hyperlipidaemia, n (%)

4 (4.6)

4 (3.6)

Stroke, n (%)

3 (3.3)

3 (2.6)

Ischaemic heart disease, n (%)

4 (4.3)

6 (5.2)

Valvular disease, n (%)

92 (100.0)

0 (0.0)

Peripheral vascular disease, n (%) Anaemia, n (%) Pericardial disease, n (%) Cardiomyopathy, n (%) LVEF (%) LVEF < 40%, n (%) eGFR (ml/min/1.73 m2) Renal dysfunction, n (%)

6 months

0.0838

16/136 (11.8) 107/205 (52.2)

31/116 (26.7)

22/101 (21.8)

Aspirin, n (%)

39/135 (28.9)

68/203 (33.5)

67/115 (58.3)

60/102 (58.8)

234/786 (29.8)

66/499 (13.3)

22/326 ( 6.8)

No atrial fibrillation (n = 797) 0.4245 0.7187

19/444 ( 4.3)

Aspirin, n (%)

88/443 (19.9) 283/784 (36.1) 303/499 (60.7) 189/327 (57.8)

p-value1

0.0013

< 0.0001

0.0003

< 0.0001

p-value2

0.0266

0.4905

0.6269

0.8546

Atrial fibrillation Valvular (n = 92) Anticoagulation, n (%)

0.0064

12/63 (19.0)

48/91 (52.8)

20/34 (58.8)

15/45 (33.3)

Aspirin, n (%) 20/63 (31.8)

33/90 (36.7)

13/33 (39.4)

28/46 (60.9)

58/112 (51.8)

10/81 (12.4)

7/56 (12.5)

34/111 (30.6)

54/81 (66.7)

32/56 (57.1)

Non-valvular (n = 115)

0.7244

Anticoagulation, n (%)

0.7706

p-value1

0.0168

0.8915

< 0.0001

0.0117

p-value2

0.4420

0.3667

0.0073

0.7035

Chi-squared test for comparison of anticoagulation use. 2 Chi-squared test for comparison of aspirin use. 1

51 (45.9)

3 (3.3)

6 (5.2)

29 (32.2)

50 (43.5)

47.21 (14.440), 46.00 (40.00–58.00)

38.20 (15.506), 36.50 (27.00–45.70)

< 0.0001

Variable

22 (24.7)

59 (55.7)

< 0.0001

0.4235

4/71 ( 5.6)

Aspirin, n (%) 18/70 (25.7)

0.7719 < 0.0001

Anticoagulation, n (%)

46 (51.7)

6 (5.6)

Day 30

Anticoagulation, n (%)

1 (0.9)

4 (4.3)

Admission

Atrial fibrillation (n = 209)

2 (2.2)

78.731 (39.738), 77.676 (40.914), 74.123 (48.772–92.796) 69.039 (49.709–100.88)

1 month prior to admission

Parameters

0.4196 Table 4. Outcomes versus valvular disease status in patients with atrial fibrillation

0.5030

Valvular atrial fibrillation (n = 92)

Non-valvular atrial fibrillation (n = 115)

Length of index hospitalisation1

11.2

9.6

1.63 (–0.56–3.83)

0.1438

0.7990

Rehospitalisation within 60 days2

6.0

11.3

0.48 (0.15–1.52)

0.2046

0.6961

Death within 180 days2

24.8

13.2

2.11 (1.05–4.24)

0.0320

Death or rehospitalisation within 60 days2

19.1

15.5

1.32 (0.66–2.65)

0.4268

0.1003

Mean (SD), median (first quartile – third quartile) for a continuous variable and frequency (per cent) for a categorical variable. 1 Chi-squared test for a categorical variable, CMH for an ordinal variable and Wilcoxon test for a continuous variable. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate. 1

patients with valvular AF and 13 among those with non-valvular AF. A total of 70 patients, among them two with valvular AF and 10 with non-valvular AF, were lost to follow up within six months but were included in estimated rates as censored observations. Four patients with valvular AF and 11 with non-valvular AF were rehospitalised within 60 days; 16 patients in each group were either rehospitalised or had died by day 60. The unadjusted risk of 180-day mortality rate in patients with valvular AF was twice that in patients with non-valvular AF [hazard ratio (HR) 2.11, 95% CI: 1.05–4.24, p = 0.032], while the unadjusted risks of 60-day rehospitalisation did not differ significantly. Without adjustment for potential confounding factors, neither valvular nor non-valvular AF was associated with 60-day readmission, while valvular but not non-valvular AF was associated with 180-day all-cause mortality (Table 5). Adjustment for clinical characteristics found to be prognostic of the outcomes13 and therefore possible confounders had little effect on these estimated associations. Valvular AF was not a

Effect (95% CI3)

p-value

LS means: difference presented for length of index hospitalisation. Kaplan–Meier event rate. 3 Hazard ratio from Cox regression model presented for rehospitalisation, death, and death/rehospitalisation outcome. 1 2

significant predictor of all-cause death or readmission within 60 days (Fig. 1) (HR 1.39, 95% CI: 0.80–2.42, p = 0.24) but was associated with all-cause death within 180 days (HR 1.61, 95% CI: 0.99–2.62, p = 0.056) (Fig. 2). On the other hand, non-valvular AF was not a significant predictor of either all-cause death or readmission within 60 days (HR 0.99, 95% CI: 0.58–1.68, p = 0.96) (Fig. 1) or the outcome all-cause death within 180 days (HR 0.70, 95% CI: 0.39–1.26, p = 0.23) (Fig. 2).

Discussion We found AF to be present in 20.8% of AHF patients. Fortyfour per cent of the patients with AF had valvular heart disease. Sixty-one per cent of the patients with non-valvular AF had hypertension. The presence of AF was not associated with the primary endpoints, but having valvular AF predicted death within 180 days. To the best of our knowledge, this is the first sub-Saharan African study to assess the prevalence and clinical characteristics

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Table 5. Associations of valvular and non-valvular atrial fibrillation with all-cause death within 180 days HR for a change of

Unadjusted hazard ratio

Multivariable adjusted hazard ratio

(95% CI1)

p-value

(95% CI1)

Valvular atrial fibrillation

Yes vs no

1.61 (1.00–2.58)

0.0475

1.61 (0.99–2.62)

0.0563

Non-valvular atrial fibrillation

Yes vs no

0.69 (0.39–1.21)

0.1949

0.70 (0.39–1.26)

0.2331

Male gender

Yes vs no

–

1.36 (0.96–1.92)

0.0859

Haemoglobin (g/dl)

1 unit increase

–

0.93 (0.87–1.00)

0.0551

HIV positive

Yes vs no

–

1.82 (1.08–3.06)

0.0239

Current or former smoker

Yes vs no

–

0.49 (0.24–0.99)

0.0479

Malignancy

Yes vs no

–

3.05 (1.24–7.54)

0.0157

Hx of cor pulmonale

Yes vs no

–

2.04 (1.26–3.30)

0.0038

SBP (mmHg)

10 units increase

–

0.85 (0.80–0.90)

< 0.0001

Orthopnoea

(2/3 vs 0/1)

–

2.32 (1.06–5.10)

0.0360

Peripheral oedema

(2/3 vs 0/1)

–

1.76 (1.15–2.69)

0.0094

Rales

(2/3 vs 0/1)

–

1.71 (1.11–2.63)

0.0155

Creatinine (mg/dl)2

1.55 vs 0.90

–

1.37 (1.06–1.77)

0.0239

Variable

p-value

Hazard ratio from Cox regression model. Appropriate transformation used due to the non-linear relationship between predictor and outcome.

1 2

RHD was the third commonest cause of HF in the THESUS-HF study after hypertension and idiopathic dilated cardiomyopathy.2 Almost half of all those with AF in this study had valvular disease compared to 23% in those without AF. Valvular heart disease has long been associated with the development of AF. Populationbased estimates from the Framingham data revealed that valvular disease was associated with a 1.8-fold increase of risk of AF in men and a 3.4-fold increased risk in women.27 Although any valvular pathology can be related to AF, stenotic left-sided valvular lesions (and in particular RHD) have the highest prevalence rates. Severity of the obstruction follows a dose–response relationship: prevalence of AF was 9.1% in patients with mild-to-moderate aortic stenosis and 33.7% among those with severe stenosis.28,29 Likewise, the prevalence of AF varies with the complexity of RHD: from 16% with isolated mitral regurgitation to 29% with isolated mitral stenosis, to 52% with coexisting mitral regurgitation and stenosis, and to 70% with mixed mitral and tricuspid valve disease. 30 We found low rates of anticoagulation in this cohort. In a prospective study of AF patients in Cameroon, only 34% of patients with an indication for oral anticoagulation received it;31 similar to the 33% of patients with AF who received warfarin in the Heart of Soweto study.17 In this study 52% of our patients with AF received oral anticoagulants. By contrast, a much higher percentage of patients received an anticoagulant in Senegal, where in a retrospective hospital-based study, anticoagulation with warfarin was established in 62% of cases.32 In the REMEDY registry,18 40.7% of patients had indications for oral anticoagulants and they were prescribed in 69.5% of patients. The use of oral anticoagulants was high in patients with mechanical heart valves (91.6%) and AF (68.6%), but low in those with mitral stenosis in sinus rhythm with either dilated left atrium or left atrial thrombus (20.3%). A study at a private urban referral teaching hospital in Nairobi, Kenya, found that 80% of patients with AF and a CHADS2 score of 2 received anticoagulation.33 Similarly, a recent observational multicentre national registry in South Africa indicated that 75% of patients with AF were on warfarin for stroke prevention.34 We did not collect data on the quality of anticoagulation control in this study. The presence of AF was not associated with all-cause death or readmission within 60 days, but having valvular AF predicted

1.00

0.95

0.90 0.85 0.80 No AF Valvular AF Non-valvular AF

0.70 0.65

Log-rank p-value vs no AF: Valvular AF: 0.24 Non-valvular AF: 0.96

30 40 Study day

Fig. 1. K aplan–Meir plot: death or rehospitalisation up to day 60 based on presence and type of AF.

Survival probability

of AF in patients hospitalised for AHF. Significantly, this study describes an important sub-population of patients with AF, namely AF due to valvular (mostly rheumatic) heart disease, which is still relatively prevalent in sub-Saharan Africa.17-21 The prevalence of AF was 21%, which is generally lower than that reported in previous studies, ranging between 23 and 41%.22-25 Among acutely decompensated HF patients, 20 to 35% will be in AF at presentation.26 This difference may be due to the fact that in sub-Saharan Africa, patients with AHF are younger and have less incidence of ischaemic heart disease. Indeed in the Heart of Soweto HF cohort, AF occurred in only 6.6% of all 2 393 HF cases within the entire study cohort.17 This however was not in the acute decompensated HF setting.

0.75

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0.90 0.85 0.80 0.75

No AF Valvular AF Non-valvular AF

0.70 0.65

Log-rank p-value vs no AF: Valvular AF: 0.06 Non-valvular AF: 0.23

80 100 120 Study day

140

160

180

Fig. 2. Kaplan–Meir plot: death up to day 180 based on presence and type of AF.

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death within 180 days. Eapen and colleagues35 investigated the associations between AF and early outcomes of patients with HF. They found AF to be associated with 30-day mortality in patients with preserved ejection fraction but not in those with reduced ejection fraction. Our data should be interpreted in the context of their limitations. The variable timing of the ECG may have affected the specific results obtained, given that the ECGs were accepted if they were recorded within two weeks of admission. Secondly, our results are drawn from a population of young AHF patients predominantly with systolic dysfunction. Consequently, these findings may not apply to older patients or to those with preserved LVEF. Finally, the study was conducted in selected specialised centres, and only patients who consented to the study were enrolled; therefore not all patients admitted with AHF were represented and the study’s generalisability may be limited. However, we have increased our understanding of the growing importance of cardiovascular disease in this population, who now suffer from the double burden of communicable and non-communicable diseases.

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lation in chronic heart failure. Eur J Heart Fail 2009; 11(7): 676–683. 8.

Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010; 23(7): 685–713; quiz 786–788.

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012; 14(8): 803–869.

10. Stewart S, Wilkinson D, Hansen C, et al. Predominance of heart failure in the Heart of Soweto study cohort: Emerging challenges for urban African communities. Circulation 2008; 118(23): 2360–2367. 11. Remenyi B, Wilson N, Steer A, et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease – an evidencebased guideline. Nat Rev Cardiol 2012; 9(5): 297–309. 12. Rheumatic fever and rheumatic heart disease: Report of a WHO expert consultation. World Health Organ Tech Rep Ser. Geneva, 29 October – 1

Conclusion AF is present in one-fifth of sub-Saharan African patients with AHF. Almost half of the AF patients have valvular disease (RHD) and are significantly younger. Valvular AF was associated with all-cause death within 180 days but was not a significant predictor of all-cause death or readmission within 60 days. The prescription rates of anticoagulation with warfarin were low in this cohort.

November 2001: 923. 13. Sliwa K, Davison BA, Mayosi BM, et al. Readmission and death after an acute heart failure event: Predictors and outcomes in sub-Saharan Africa: Results from the THESUS-HF registry. Eur Heart J 2013; 34(40): 3151–3159. 14. Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons, 1987. 15. Schafer JL. Analysis of Incomplete Multivariate Data. New York: Chapman & Hall, 1997. 16. Sani MU, Davison BA, Cotter G, et al. Renal dysfunction in african

THESUS-HF was funded by Momentum Research Inc, Durham, North Carolina, United States of America

patients with acute heart failure. Eur J Heart Fail 2014; 16(7): 718–728. 17. Sliwa K, Carrington MJ, Klug E, et al. Predisposing factors and incidence of newly diagnosed atrial fibrillation in an urban African

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Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and Intern Med 2012; 172(18): 1386–1394. Oldgren J, Healey JS, Ezekowitz M, et al. Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: The RE-LY atrial fibrillation registry. Circulation 2014; 129(15): 1568–1576.

Darby AE, DiMarco JP. Management of atrial fibrillation in patients with structural heart disease. Circulation 2012; 125: 945–957.

Rivero-Ayerza M, Scholte O, Reimer W, Lenzen M, et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: Results of the EuroHeart failure survey. Eur Heart J 2008; 29(13): 1618–1624.

Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA,

study). Eur Heart J 2015; 36(18): 1115–1122a. 19. Sani MU, Karaye KM, Borodo MM. Prevalence and pattern of rheumatic heart disease in the Nigerian savannah: An echocardiographic study. Cardiovasc J Afr 2007; 18(5): 295–299. 20. Sliwa K Mocumbi AO. Forgotten cardiovascular diseases in Africa. Clin Res Cardiol 2010; 99: 65–74. 21. Ferrieri P, for the Jones Criteria Working Group. Proceedings of the Jones Criteria workshop. Circulation 2002; 106: 2521–2523. 22. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: Treatment considerations for a dual epidemic. Circulation 2009; 119(18): 2516–2525. 23. Latado AL, Passos LC, Braga JC, et al. Predictors of in-hospital lethality in patients with advanced heart failure. Arq Bras Cardiol 2006; 87(2): 185–192.

Stevenson LW. Atrial fibrillation is associated with an increased risk for

24. VillaCorta H, Mesquita ET, Cardoso R, et al. Emergency department

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Cameroon. Europace 2010; 12(4): 482–487. 32. Mbaye A, Pessinaba S, Bodian M, et al. La fibrillation atriale, fréquence, facteurs étiologiques, évolution et traitement dans un service de cardi-

27. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence,

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28. Greve AM, Gerdts E, Boman K, et al. Prognostic importance of

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atrial fibrillation in asymptomatic aortic stenosis: The simvastatin and

characteristics and outcomes of atrial fibrillation and flutter at the Aga

ezetimibe in aortic stenosis study. Int J Cardiol 2013; 166(1): 72–76. 29. Stortecky S, Buellesfeld L, Wenaweser P, et al. Atrial fibrillation and aortic stenosis: Impact on clinical outcomes among patients undergoing transcatheter aortic valve implantation. Circ Cardiovasc Interv 2013; 6(1): 77–84. 30. Diker E, Aydogdu S, Ozdemir M, et al. Prevalence and predictors of

Khan University Hospital, Nairobi. Cardiovasc J Afr 2013; 24(2): 6–9. 34. Jardine RM, Fine J, Obel IW. A survey on the treatment of atrial fibrillation in south africa. S Afr Med J 2014; 104(9): 623–627. 35. Eapen ZJ, Greiner MA, Fonarow GC, et al. Associations between atrial fibrillation and early outcomes of patients with heart failure and reduced or preserved ejection fraction. Am Heart J 2014; 167(3): 369–375.e2.

In Memoriam Sonja van Wyk, 4 May 1990 – 1 June 2018 Sonja lost her battle against cancer on Friday 1 June 2018 at Tygerberg Hospital at the age of 28 years. She had worked at Clinics Cardive Publishing & Design Connection as a personal assistant since October 2014. She was an efficient and well-loved colleague with a good sense of humour and warm gracious manner. Her welcoming and compassionate nature made her a pleasure to have around the office. Sonja’s untimely death has been a shock to all. She is survived by her parents, her life partner of the past 12 years, Jaco, and her two daughters Carli 11 and Mieke 4 years old. Sonja was a friend to all and a devoted mother to her daughters. She will be deeply missed by her family, friends, colleagues and all who knew her.

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Influence of visceral fat and blood pressure on changes in blood flow velocity in non-obese individuals A Rahman Rasyada, Munirah Sha’ban, Azran Azhim

Abstract Introduction: The aim of this study was to evaluate the impact of different visceral fat (VF) and blood pressure (BP) levels on changes in blood flow velocity (BFV) among non-obese subjects, using a cross-sectional study approach. Methods: A total of 110 putatively healthy and non-obese subjects were divided into three groups according to their level of VF and BP. Common carotid artery BFV was measured using a developed portable Doppler ultrasound measurement system. Results: The most pronounced peak systolic velocity (S1) was lower (p < 0.05) in the hypertensive group and the peak diastolic velocity (D) was significantly lower in the pre-hypertensive group than in the normotensive group. There were differences in velocity reflection and resistive indices between the hypertensive and other two BP groups. The higher VF group had significantly lower S1 and D velocities and resistive and vascular elasticity indices. By contrast, the velocity reflection index was larger in the higher VF group. Conclusion: We confirmed that there were significant differences in the BFV among non-obese subjects who differed in level of VF and BP. This study confirms that a putatively increasing VF and BP level is associated with the development of hypertension. Keywords: Doppler ultrasound, hypertension, visceral fat, nonobese, blood flow velocity

increasingly recognised that fat distribution in specific areas can have more detrimental effects than total body fat.2,3 In particular, visceral fat (VF) is associated with hypertension, compared to other fat distributions, including lower body fat and subcutaneous fat.2 Previous studies have demonstrated that VF is associated with vascular disease.4-6 Increased VF accumulation contributed to the development of arteriosclerosis in a normal healthy population7 and coronary artery disease in non-obese patients.6 Numerous studies have demonstrated that Doppler spectral analysis of blood flow changes with vascular disease.8-10 Rutherhold et al. described the discriminant analysis of peak systolic (S1), peak diastolic (D) and end-diastolic (d) velocities in the diagnosis of carotid occlusive disease.8 The accumulation of high levels of VF contribute to greater aortic stiffness in older adults as measured by pulse-wave velocity (PWV).10 Furthermore, cholesterol level was found to have a correlation with mean blood flow velocity (BFV) and S1 velocity.9,11 It was suggested that patients with greater common carotid artery (CCA) plaque and intimal–medial thickness had a high velocity ratio and increased prevalence of coronary artery disease.12 Despite the acknowledgment that VF is associated with some haemodynamic functions, including BP and arterial PWV, the extent to which VF accumulation has an influence on BFV in CCA is not well described. Therefore, to clarify the significance of different VF levels on CCA velocities, non-obese subjects needed to be studied. In this study, we evaluated the role of the level of VF and BP on changes in BFV among non-obese subjects using a cross-sectional study approach.

Submitted 29/7/16, accepted 19/12/17 Cardiovasc J Afr 2018; 29: 146–149

www.cvja.co.za

DOI: 10.5830/CVJA-2018-001

Obesity is one of the well-recognised cardiovascular risk factors for hypertension, dyslipidaemia and the metabolic syndrome.1-3 Body mass index (BMI) of 30 kg/m2 as an indicator of obese status is used as an important indicator of overall body fat.4 However, it is now

Department of Biotechnology, Kulliyyah of Science, International Islamic University Malaysia, Kuantan, Malaysia A Rahman Rasyada, MSc (Mol Med)

Department of Physical Rehabilitation Sciences, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, Kuantan, Malaysia Munirah Sha’ban, PhD

Department of Biomedical Sciences,Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, Kuantan, Malaysia Azran Azhim, Dr Eng, PhD (Med Sci), MIEM, azranazhim@iium.edu.my

Methods The study was performed in 110 (58 males, 52 females) putatively healthy and non-obese volunteers aged from 18 to 64 years. Overweight individuals with a body mass index (BMI) of 25 kg/ m2 and obese individuals with a BMI of 30 kg/m2, according to the World Health Organisation, were excluded from the study.4 The subjects had no overt chronic diseases and did not take any antihypertensive drugs, as assessed by medical history. A written informed consent was obtained from all participants. This study was approved by the research ethics committee of the International Islamic University of Malaysia. Three designated VF groups were based on their VF level, according to the Tanita body composition monitor: lower VF group (less than level 4), middle VF group (from level 4 to 6) and higher VF group (level 7 and above). The manual standard of the Tanita body composition monitor can track visceral fat in the body ranging from 1 to 59. A rating between 1 and 12 indicates a healthy level of visceral fat. A rating between 13 and 59 indicates an excessive level of visceral fat.13 For BP analysis, all subjects were further classified into three groups based on their systolic (SBP) and diastolic blood pressure (DBP) measurements: normotensive (SBP < 120 and DBP ≤ 80

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mmHg), pre-hypertensive (120 ≤ SBP < 140 mmHg or 80 < DBP ≤ 89 mmHg) and hypertensive (SBP ≥ 140 and DBP > 90 mmHg).14 The level of VF was measured using InnerScan body composition monitors (Tanita, Japan). BMI was calculated by dividing measured body weight by the square of height (kg/ m2). Height and waist circumference (WC) were measured in the standing position using a stadiometer (THP-DA, Japan) and measuring tape, respectively. The CardioChek® PA cholesterol test system was used to determine total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels. This device was approved by the United States Food and Drug Administration and Cholesterol Reference Method Laboratory Network. SBP and DBP from the left brachial artery were measured in the seated position using an automatic BP monitor (Tango, SunTech Medical, USA). Mean blood pressure (MBP) was calculated from DBP + (SBP – DBP)/3. The BFV measurement system was based on an application of the Doppler ultrasound technique. The portable system

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consisted of a probe, a Doppler signal discriminator (DSD), a transmitter at the main unit, a receiver, an analog–digital converter (A/D converter) and a computer for real-time monitoring and analysis.15 BFV was measured simultaneously with electrocardiogram (ECG) and BP as illustrated in Fig. 1. Measurements of ECG and BP were used as reference data. The flow velocity (Vd) was determined from the Doppler-shift frequency (fd): c fd

Vd =  _______      (2f cosθ) 0

where c = 1 540 m/s, the speed of acoustic waves in human tissue, f0 = 2.0 MHz, an irradiated ultrasound frequency, and θ is the Doppler insonation angle at 50 degrees. From the Doppler shift frequency of reflected signals, low-frequency signals and harmonic noise were filtered by a band-pass filter of 0.1 to 5.0 kHz that was installed in the DSD. From the same range of frequency, BFV could be extracted. Signal data were transmitted to the receiver at a transmission rate of 28.8 kbps and an output of ~0.5 mV/m. The data were converted into a digital signal with a sampling frequency of

Synchronised measurement system

Real-time monitor and analysis

Fig. 1. B lood flow velocity (BFV) measurement system, synchronised with electrocardiogram (ECG) and blood pressure (BP), using real-time monitoring (left). Feature points on waveform: S1: peak systolic (maximum velocity), S2: second systolic, I: incisura between systole and diastole, D: peak diastolic, and d: end-diastolic velocities (right).

Table 1. Subjects’ characteristics for each visceral fat and blood pressure category in the cross-sectional study Variable

Lower VF

Middle VF

Higher VF

Normotensive

Pre-hypertensive

Hypertensive

28 ± 1

32 ± 2

49 ± 2‡§

27 ± 1

35 ± 2*

50 ± 3*†

Height (cm)

161.9 ± 1.1

164.2 ± 1.3

169.5 ± 1.1‡§

162.9 ± 1.2

164.9 ± 1.1

166.5 ± 2.1

Weight (kg)

51.2 ± 0.8

60.0 ± 0.9

64.9 ± 1.2‡§

53.6 ± 0.9

58.0 ± 1.2*

62.9 ± 2.3*

Age (years) Body mass data

‡

BMI (kg/m²)

19.5 ± 0.2

22.2 ± 0.2‡

22.6 ± 0.2‡

20.2 ± 0.3

21.2 ± 0.2*

22.6 ± 0.4*†

WC (cm)

69.7 ± 0.6

77.2 ± 0.6‡

82.2 ± 0.9‡§

71.4 ± 0.7

75.7 ± 0.9*

81.8 ± 1.6*†

Metabolic variables (mg/dl) Glucose (mmol/l)

77.1 ± 1.9

78.5 ± 2.9

89.9 ± 3.6‡§

77.8 ± 2.1

80.3 ± 2.2

91.9 ± 5.8*†

TC (mmol/l)

195.4 ± 7.5

189.5 ± 7.0

205.8 ± 9.6

187.4 ± 6.5

206.9 ± 8.5

195.9 ± 8.9

HDL (mmol/l)

78.4 ± 3.6

80.1 ± 9.3

53.9 ± 2.9‡§

75.7 ± 3.8

72.0 ± 6.5

59.8 ± 5.5

TG (mmol/l)

62.6 ± 4.8

79.8 ± 6.3

123.9 ± 15.3‡§

63.7 ± 5.9

98.5 ± 10.6*

102.7 ± 18.9

LDL (mmol/l)

101.0 ± 4.9

95.0 ± 11.9

117.5 ± 6.1

100.3 ± 5.2

103.8 ± 9.2

115.6 ± 9.2

The data are presented as mean and SEM. Tukey significances: *p < 0.05 versus normotensive, †p < 0.05 versus pre-hypertensive, ‡p < 0.05 versus lower VF and §p < 0.05 versus middle VF. VF: visceral fat, BP: blood pressure; BMI: body mass index; TC: total cholesterol; HDL: high-density lipoprotein cholesterol; TG: triglycerides; LDL: low-density lipoprotein cholesterol.

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10 kHz using an A/D converter, and then transferred into a computer for real-time monitoring and signal analysis.15 BFV spectra were measured in the relaxed seated posture for one minute. After real-time monitoring, 30 consecutive cardiac cycles were selected from one-minute spectra to characterise the feature points of velocity waveform and calculate its indices. The waveform was extracted using a threshold method and computed using an ensemble averaging technique. The averaged BFV waveform was used to identify velocity feature points, as shown in Fig. 1 (right side). BFV in CCA were characterised into five components: peak systolic (S1), second systolic (S2), insicura between systole and diastole (I), peak diastolic (D) and end-diastolic (d) velocities.7 These values were used to calculate the following velocity indices: resistive index (RI = 1 – d/S1), velocity reflection index (VRI = S2/S1 – 1) and vascular elasticity index (VEI = 1 – I/D), which were originally used by Azhim et al.16

Statistical analysis Data are expressed as mean and standard error of mean (SEM). The differences between VF groups as well as BP groups were analysed by one-way ANOVA. A p-value less than 0.05 was considered statistically significant. Statistical analyses were performed using the statistical package for the social sciences software (SPSS 21.0, USA).

Results Table 1 represents the differences in body mass and metabolic variables in the VF and BP groups. We found the same pattern of differences in the three designated groups of VF and BP, respectively. Participants who were older had higher VF and BP levels and greater height and weight than younger participants. BMI, WC and glucose levels were significantly greater in the higher VF and hypertensive groups. However, there were no significant differences for height, TC, HDL and LDL in all three BP groups. As shown in Table 2, hypertensive subjects had higher VF levels compared to normotensive and pre-hypertensive subjects (p < 0.05). It is to be expected that SBP, DBP and mean BP were significantly higher in the higher VF group than in other two

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groups (Table 3). The most pronounced, S1 velocity, was lower (p < 0.05) in the hypertensive than the normotensive group. The D velocity was lower (p < 0.05) in the pre-hypertensive than the normotensive group. There were differences noted in the VRI between the hypertensive and other two groups. Resistive index was significantly lower in the hypertensive than in the normotensive and pre-hypertensive groups. The other BFV waveforms, S2, d and I, showed no significant differences between the BP groups. We also found that S1, D velocities, RI and VEI indices were significantly lower in the higher VF group (p < 0.05), as shown in Table 3. By contrast, VRI was larger in the higher VF group.

Discussion This study highlights the association between BFV changes and high VF accumulation and the development of hypertension in non-obese individuals. It is suggested that lowering VF level could reduce the incidence of hypertension as an early diseaseprevention step to improve haemodynamic function. Fat distribution has been receiving increasing attention when evaluating the development of hypertension.2,17 Visceral fat has been demonstrated to have an association with hypertension, but not other factors, including BMI, subcutaneous fat and lower-body fat.2 Our study extends this analysis to emphasise the relationship between visceral hypertension and BFV of non-obese individuals. Similar to our study, a previous study reported that individuals with essential hypertension suffered from significant accumulation of VF in the abdominal region.2 Our study also showed that elevated VF level leads to a significant increase in SBP, DBP and MBP (Table 3). Significant differences in S1, D, RI, VRI and VEI were observed between the lower VF group and the other two groups. We found that S1 and D velocities decreased with increasing VF. It is to be expected that VEI in the higher VF group was significantly lower due to the significant decrease in D velocity. D is peak diastolic velocity, which increases due to vascular elastic Table 3. Effect of different levels of visceral fat on blood pressure readings and blood flow velocities Variable

Lower VF

Middle VF

Higher VF

p-value

BP data (mmHg) Table 2. Changes in blood flow velocities and visceral fat in normotensive, pre-hypertensive and hypertensive subjects Variable VF (level)

Normotensive

Pre-hypertensive

Hypertensive

p-value

2.4 ± 0.2

5.3 ± 0.5*

8.5 ± 1*†

< 0.01

Blood flow velocities (cm/s) d

20.6 ± 0.7

20.3 ± 0.7

22 ± 1.4

100.6 ± 2.2

93.9 ± 3.4

79.4 ± 4.6*

< 0.01

54.4 ± 1.9

52.6 ± 2.1

60.9 ± 2.2

32 ± 1.3

29.7 ± 1.1

31.3 ± 1.9

I D

44.9 ± 1.1

41.0 ± 1.0*

39.7 ± 2.2

< 0.05

0.794 ± 0.008

0.776 ± 0.009

0.719 ± 0.016*†

< 0.01

VRI

–0.453 ± 0.021

–0.412 ± 0.030

–0.215 ± 0.037*†

< 0.01

VEI

0.295 ± 0.017

0.277 ± 0.019

0.212 ± 0.021

Data are presented as mean ± SEM. Significantly different: *p < 0.05 vs normotensive group; †p < 0.05 vs pre-hypertensive group. NS: not significant. VF: visceral fat; d: end-diastolic velocity; S1: peak systolic velocity; S2: second systolic velocity; I: insicura between systole and diastole; D: peak diastolic velocity; RI; VRI: velocity reflection index; VEI: vascular elasticity index.

SBP

113.1 ± 1.5

123.6 ± 2.7*

134.9 ± 3.2*†

< 0.01

DBP

68.6 ± 1.2

75.3 ± 1.8*

87.2 ± 2.6*†

< 0.01

MBP

83.5 ± 1.2

91.4 ± 1.9*

103.1 ± 2.7*†

< 0.01

Blood flow velocities (cm/s) d

20.5 ± 0.7

20.5 ± 1.1

20.6 ± 0.8

99.3 ± 2.2

98.6 ± 4.7

80.7 ± 3.2*†

< 0.01

53.5 ± 1.7

54.0 ± 3.1

56.9 ± 1.7

31.5 ± 1.2

30.3 ± 1.7

30.5 ± 1.1

44.4 ± 1.0

42.1 ± 1.6

38.9 ± 1.2*

< 0.05

0.789 ± 0.008

0.786 ± 0.012

0.740 ± 0.011*†

< 0.01

VRI

–0.449 ± 0.021

–0.426 ± 0.041

–0.278 ± 0.027*†

< 0.01

VEI

0.297 ± 0.016

0.286 ± 0.024

0.215 ± 0.014*

< 0.05

Data are presented as mean ± SEM. Significantly different: *p < 0.05 vs lower VF group; †p < 0.05 vs middle VF group. NS: not significant, VF: visceral fat, BP: blood pressure, SBP: systolic blood pressure; DBP: diastolic blood pressure; d: end-diastolic velocity; S1: peak systolic velocity; S2: second systolic velocity; I: insicura between systole and diastole; D: peak diastolic velocity; RI; VRI: velocity reflection index; VEI: vascular elasticity index.

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recoil at a maximum rate.18 It has been reported that higher VF contributes to increased values of plaque score and β-stiffness, an index representing the stiffness of the vascular wall, which accelerates atherosclerosis.5 Stiffness of the artery is indicated by its elastic properties. This observation is consistent with our finding in which the higher VF group had significantly lower D and VEI values than those of the lower VF group. Similar to the higher VF group, the S1 and D velocity peaks declined in the hypertensive group (Table 2). This might have been due to the fact that arteries stiffen with age,14,19 since both groups were older and had VF. Furthermore, the thickening of the arterial wall, which is caused by VF, could induce high blood pressure.20 VRI has been demonstrated to be a good index of cardiovascular risk in hypertensive patients compared to control subjects.10,21 VRI is linked to reflection characteristics of velocity.14 This study showed that there were significant differences between the hypertensive and normotensive groups in both VRI and RI values. The RI is a well-recognised index for quantifying changes in CCA.20,22 This index is widely used as an indicator of peripheral vascular resistance.20 A previous study reported that RI was higher in severe internal carotid artery stenosis, compared to a normal carotid artery of patients.22 Limitations of this study are that we used a cross-sectional approach only, and the three designated VF groups did not consider gender and age differences. In our current setting, it was difficult to find a large number of subjects of the same age with different levels of VF. Further interventional studies on welldiscriminated groups are required to show a distinction between cause and effect among non-obese subjects.

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Yamauchi T, Kuno T, Takada H, Nagura Y, Kanmatsuse K, Takahashi S. The impact of visceral fat on multiple risk factors and carotid atherosclerosis in chronic haemodialysis patients. Nephrol Dialysis Transpl 2003; 18(9): 1842–1847.

Nakamura T, Tokunaga K, Shimomura I, Nishida M, Yoshida S, Kotani K, et al. Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men. Atherosclerosis 1994; 107: 239–246.

World Health Organization (WHO). Obesity and overweight, 2015, http://www.who.int/mediacentre/factsheets/fs311/en/

Rutherford RB, William RH, Erik WK. The use of velocity wave form analysis in the diagnosis of carotid artery occlusive. Surgery 1977; 82(5): 695–702.

Yang Y, Zhang X, Li R, Ren H, Wang Z, Li Z, et al. Evaluation of coronary flow velocity reserve in homozygous familial hypercholesterolemia by transthoracic Doppler echocardiography and dual-source computed tomography. Ultrasound Med Biol 2010; 36(10): 1756–1761.

10. Saleh M, Azhim A, Zulaika H, Bagherpour P, Kinouchi Y, Ibrahim F. Evaluation of blood velocity waveform features in common carotid artery for healthy and cardiovascular patients. The 15th International Conference on Biomedical Engineering, Singapore, December 4–7, 2013. 11. Farhoudi M, Mehrvar K, Aslanabadi N, Ghabili K, Baghmishe NR, Ilkhchoei F. Doppler study of cerebral arteries in hypercholesterolemia. J Vasc Health Risk Manage 2011; 7: 203–210. 12. Nakano H, Okazaki K, Ajiro Y, Suzuki T, Oba K. Clinical usefulness of the common carotid artery blood flow velocity ratio as measured by an ultrasonic quantitative flow measurement system: Evaluation with respect to prevalence of ischemic heart disease. J Nippon Med School 2001; 68(6): 482–489. 13. Tanita. Instruction manual for InnerScan V segmental body composi-

Conclusion We found significant differences in BFV among non-obese subjects with different levels of VF and BP. The study also supports the alleged association between increasing VF and BP levels and the development of hypertension.

tion monitor, BC-601, Tanita publication, Japan. 14. National Institutes of Health (NIH). The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC VI), NIH publication, 2004. 15. Azhim A, Ueno A, Tanaka M, Masatake A, Kinouchi Y. Evaluation of blood flow velocity envelope in common carotid artery for reference data. Biomed Signal Process Control 2011; 6(2): 209–215.

This study was partly supported by Mediprotech Co, Ltd, Korea, under an

16. Azhim A, Katai M, Akutagawa M, Hirao Y, Yoshizaki K, Obara S, et al.

internationally sponsored research grant (SP15-079-0201), and the Ministry

Exercise improved age-associated changes in the carotid blood velocity

of Higher Education, Malaysia under the fundamental research grant scheme (FRGS15-204-0445, FRGS17-026-0592), and MyBrain15 postgraduate scholarship programme.

waveforms. J Biomed Pharmaceut Engineer 2007; 1(1): 17–26. 17. Sutton-Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, Lakatta E, et al. Aortic stiffness is associated with visceral adiposity in older adults enrolled in the study of health, aging and body composi-

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Assessment of myocardial fibrosis by late gadolinium enhancement imaging and biomarkers of collagen metabolism in chronic rheumatic mitral regurgitation Ruchika Meel, Richard Nethononda, Elena Libhaber, Therese Dix-Peek, Ferande Peters, Mohammed Essop

Abstract Background: In chronic rheumatic mitral regurgitation (CRMR), involvement of the myocardium in the rheumatic process has been controversial. Therefore, we sought to study the presence of fibrosis using late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) and biomarkers of collagen turnover in CRMR. Methods: Twenty-two patients with CRMR underwent CMR and echocardiography. Serum concentrations of matrix metalloproteinase-1 (MMP-1), tissue inhibitor of MMP-1 (TIMP1), MMP-1-to-TIMP-1 ratio, procollagen III N-terminal pro-peptide (PIIINP) and procollagen type IC peptide (PIP) were measured. Results: Four patients had fibrosis on LGE-CMR. PIP and PIIINP concentrations were similar to those of the controls, however MMP-1 concentration was increased compared to that of the controls (log MMP-1 3.5 ± 0.7 vs 2.7 ± 0.9, p = 0.02). There was increased MMP-1 activity as the MMP-1-toTIMP-1 ratio was higher in CRMR patients compared to the controls (–1.2 ± 0.6 vs –2.1 ± 0.89, p = 0.002). Conclusion: Myocardial fibrosis was rare in CRMR patients. CRMR is likely a disease characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis. Keywords: chronic rheumatic mitral regurgitation, cardiac magnetic resonance, late gadolinium enhancement, biomarkers Submitted 21/1/17, accepted 19/12/17 Published online 6/2/18 Cardiovasc J Afr 2018; 29: 150–154

www.cvja.co.za

various cardiac conditions, irrespective of aetiology and denotes adverse outcomes.3 Limited recent studies have shown the value of CMR in valvular heart disease, such as degenerative MR and aortic stenosis, in predicting the prognosis based on the presence of fibrosis.2,4,5 Studies pertaining to the possible involvement of the left ventricle (LV) in the rheumatic process have yielded equivocal results.6 In chronic rheumatic mitral regurgitation (CRMR) there may be involvement of the LV in the rheumatic process, especially in the posterobasal region of the LV.7-9 Sepulveda et al. reported diffuse, mesocardial and heterogenous enhancement of the myocardium in acute rheumatic fever using LGE.10 The possible resultant fibrosis may therefore be studied by LGE and have prognostic value similar to that in degenerative MR. Furthermore, data concerning biomarkers of collagen degradation and formation in MR are limited and mostly comprise animal studies in degenerative MR.11,12 In a recent study in rheumatic MR, an increase in biomarkers of collagen synthesis and degradation was reported.13 Biomarkers of collagen turnover may serve as non-invasive tools for identification of myocardial remodelling and add an incremental value in risk stratification for surgery or institution of aggressive medical treatment at an early stage.14-16 Procollagen III N-terminal pro-peptide (PIIINP) and procollagen IC peptide (PIP) are released into the circulation during collagen synthesis, while the turnover of collagen is controlled by matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).14 These markers are therefore an excellent model to study collagen turnover. Therefore we sought to assess the presence of LV fibrosis in CRMR using cardiac MRI and biomarkers of collagen degradation and synthesis.

DOI: 10.5830/CVJA-2018-002

Myocardial fibrosis can be reliably detected non-invasively using late gadolinium enhancement (LGE-CMR) or contrast enhancement cardiac magnetic resonance (CE-CMR) imaging.1 CE-CMR is a useful non-invasive correlate of myocardial fibrosis on histology.2 Fibrosis represents an end-stage process in

Division of Cardiology, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa Ruchika Meel, PhD, ruchikameel@gmail.com Richard Nethononda, DPhil Elena Libhaber, PhD Therese Dix-Peek, MSc Ferande Peters, MD Mohammed Essop, MD

Methods This study was part of a prospective, cross-sectional study at Chris Hani Baragwanath Academic Hospital. Patients were enrolled from January to October 2014. All patients were screened and those deemed to have moderate or severe CRMR were referred for possible inclusion in the study. The inclusion criteria were patients aged 18 years or older with echocardiographic features of moderate or severe CRMR. Patients were excluded if they had co-morbidities, significant aortic valve disease, concurrent mitral stenosis with a valve area of less than 2.0 cm2, documented ischaemic heart disease, pre-existing non-valvular cardiomyopathy, prior cardiac surgery, congenital or pericardial disease, pregnancy, severe anaemia (haemoglobin < 10 g/dl), presence of a pacemaker or defibrillator, claustrophobia, renal dysfunction (estimated glomerular filtration rate, eGFR < 60 ml/min), or refusal to undergo CMR.

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A final number of 91 patients with presumed CRMR underwent clinical evaluation, resting electrocardiogram and detailed echocardiographic assessments according to a pre-determined protocol. Of these 91 patients with CRMR, 69 were excluded due to the following: co-morbidities (human immunodeficiency virus: n = 22; hypertension: n = 44; diabetes mellitus: n = 3; atrial fibrillation: n = 4; anaemia: n = 3; renal dysfunction: n = 3; and inadequate image quality: n = 5). The final sample comprised 22 patients. Fourteen age- and gender-matched controls were also enrolled for the biomarker arm of the study. A tolerance of five years was allowed for age matching.The baseline clinical characteristics of these individuals were recorded and they subsequently underwent comprehensive echocardiography and CMR imaging. The study was approved by the University of the Witwatersrand ethics committee. It was conducted in accordance with the principles outlined in the Declaration of Helsinki. Transthoracic echocardiography was performed on all patients in the left lateral position by experienced sonographers using a S5-1 transducer on a Philips iE33 system (Amsterdam, the Netherlands). Images were obtained according to a standardised protocol. The data were transferred and analysed off-line using the Xcelera workstation. All linear chamber measurements were performed according to the American Society of Echocardiography (ASE) chamber guidelines.17 Measurements relating to LV diastolic function were performed in accordance with the ASE guidelines on diastolic function, and included pulse-wave Doppler at the mitral tips and tissue Doppler of both medial and lateral mitral annuli.18 MR was considered rheumatic in aetiology when the morphology of the valve satisfied the World Heart Federation (WHF) criteria for the diagnosis of chronic rheumatic heart disease (RHD).19 MR severity was assessed using qualitative, semi-quantitative and quantitative methods as per the ASE and European Society of Cardiology.20,21 In equivocal cases, the echocardiographic data were integrated with the clinical evaluation by an experienced cardiologist to distinguish moderate from severe MR. For biomarker analysis, peripheral venous blood samples were drawn from 14 controls and 22 chronic rheumatic heart disease subjects at the time of echocardiographic examination. Samples were collected in a serum separator tube and allowed a clotting time of 30 min before centrifuging for 15 min at 1 000 g and the serum was stored at –80°C before analysis in a single batch. Enzyme-linked immunosorbent assays (ELISA) were used to determine the serum concentration of PIIINP (USCN Life Science Inc/Cloud-Clone Corp, Wuhan, China), and PIP (Clontech,Takara Bio Inc, Japan) was determined by ELISA using the USCN kit according to the manufacturer’s instructions. The minimum detectable dose of PIIINP is typically less than 25.9 pg/ml and the minimum detectable dose of PIP is typically less than 10 ng/ml. Optical density of the analytes was measured at 450 nm on a microplate reader (Elx800, Biotek, USA) and concentrations were determined using a 5-PL algorithm. Multi-analyte analysis of the matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP1) was performed using the magnetic luminex screening assay (RnD systems, Minneapolis, USA) on a Bio-Plex 200 (Bio-Rad, CA, USA) according to the manufacturer’s instructions. The minimum detectable dose of MMP-1 is typically less than 2.7

151

pg/ml, and for TIMP-1, less than 3.42 pg/ml. Since the actual activity of MMP-1 depends on the balance between active enzyme and inhibitor (i.e. TIMP-1), the serum MMP-1/TIMP-1 ratio was considered an index of MMP-1 activity. CMR studies were performed on a 1.5-Tesla scanner (Siemens Healthcare, Erlagen, Germany) using a six-channel phasedarray body coil. The images were obtained during patient expiratory breath-hold for approximately eight seconds and were prospectively ECG gated.22 LV volumes and mass were acquired in line with standard cardiovascular MRI protocols (1.5-T magnetom Avanto; Siemens Healthcare, Erlangen, Germany). Steady-state free-precession imaging (echo times 1.5/3.0 ms, flip angle 60°, temporal resolution 45 ms, slice thickness 7 mm, 3-mm gap, matrix size 256 × 256 mm, field of view 380 × 309 mm) were performed to obtain long-axis cinés and a contiguous stack of short-axis cinés for assessment of LV volumes, mass and ejection fraction, as previously described.23 Ten minutes after the injection of 0.2 mmol/kg gadoliniumbased contrast agent (Magnevist, Schering, Berlin, Germany), LGE-CMR images were acquired in the same long- and shortaxis position, and used in the ciné imaging.5 Inversion recovery times varying from 200–350 ms were used to null the signal from the intact myocardium. Images were analysed by an independent experienced reader (RN), blinded to the echocardiographic results, with Argus software (version 2002B, Siemens Medical Solutions, Erlangen), as previously described.24 The assessment of cardiac function and chamber sizes were performed in standard views in the longaxis (horizontal and vertical) and short-axis planes. Ejection fraction for the LV was assessed with the following formula: end-diastolic volume – end-systolic volume

_________________________________       Ejection fraction =        end-diastolic volume

LV volumes and EF were obtained by semi-automatic tracing of contours on the short-axis images in end-diastole and end-systole, with manual corrections when required.25 Myocardial fibrosis was defined as a region of LGE with signal enhancement greater than the signal intensity of non-enhanced myocardium.1

Statistical analysis Statistical analysis was performed with Statistica version 12.5, series 0414 for Windows. Continuous variables are expressed as means ± SD or medians (IQRs). Categorical data are expressed as a percentage. The differences for continuous variables were calculated using the Student’s t-test or Mann–Whitney U-test when the distribution was non-normal. Chi-squared and Fisher’s exact tests were used to calculate the difference for categorical data for independent samples. Pearson’s and Spearman’s correlation coefficient were used to calculate correlations depending on whether data were normally or non-normally distributed. Biomarker levels (TIMP-1, MMP-1 and MMP-1/TIMP-1 ratio) were log transformed before analysis when distribution was not normal. A p-value < 0.05 was considered statistically significant.

Results The mean age of patients was 36.3 ± 13.9 years, with 81% female (Table 1). All the patients had isolated moderate or severe CRMR and no co-morbidities. Ten patients were in New York heart association (NYHA) functional class I, the remainder

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Discussion

Table 1. Clinical and echocardiographic characteristics of the study patients and controls Study group (n = 22)

Variable

Control (n = 14)

p-value

Clinical parameters Age (years)

36.3 ± 13.9

40.3 ± 14.2

0.40

Gender (F:M)

18:4

10:4

0.36

SBP (mmHg)

123.2 ± 9.5

122.9 ± 5.1

0.91

DBP (mmHg)

77.2 ± 6.4

74.6 ± 12.3

0.34

Pulse (beats/min)

74.6 ± 13.1

75.5 ± 13.3

0.55

Body mass index (kg/m2)

24.8 ± 4.7

28 ± 5.7

0.06

1.6 ± 0.2

1.7 ± 0.2

0.24 < 0.001

Body surface area (m2) Echocardiographic parameters LVEDD (mm)

56.2 ± 7.4

42.2 ± 6.1

LVESD (mm)

41.5 ± 8.6

26.7 ± 4.0

< 0.001

EDVi (ml/m2)†

90.4 (71.5–103.8)

43.2 (35.2–43.2)

< 0.001

ESVi (ml/m2)†

39.6 ± 19.6

15.3 ± 4.6

0.001

LVEF (%)

59.8 ± 10.6

60.6 ± 17.1

0.5

100.1 ± 33.8

61.4 ± 18.7

0.004

LV mass index (g/m2)†

Data are presented as median (interquartile range), mean ± SD or %. Values are indexed to BSA. DBP: diastolic blood pressure; SBP: systolic blood pressure; LV: left ventricle; EDD: end-diastolic diameter; ESD: end-systolic diameter; EDVi: end-diastolic volume indexed; ESVi: end-systolic volume indexed; LVEF: left ventricular ejection fraction.

†

were NYHA functional class II. Four patients were on medical treatment with diuretics (furosemide) and anti-remodelling therapy (spironolactone, carvedilol, enalapril) for previous heart failure secondary to MR. Eight patients were on diuretics alone. In this study, LGE was present in four (18%) patients with CRMR (Table 2). A varied pattern of LGE of the LV myocardium was noted. These included (1) transmural LGE in the lateral wall, (2) patchy areas of LGE in the basal septum, mid-septum and basal inferior wall, (3) transmural fibrosis of the inferior wall, and (4) sub-epicardial LGE in one patient. The two patients with transmural involvement had normal coronary angiograms (done as part of their surgical work-up). PIIINP and PIP were not elevated in patients compared to controls. PIIINP concentrations were 11.8 (6.9–21.6) vs 15.7 (13.6–18.5) ng/ml (p = 0.09), while PIP levels were 780.4 (727.3–1263.7) vs 1065.1 (589.2–1252.0) µg/ml (p = 0.13) (Table 3). Log MMP-1 was elevated in patients with CRMR compared to the controls (3.45 ± 0.7 vs 2.7 ± 0.9, p = 0.02). There was no difference in log TIMP-1 between CRMR patients and controls (4.6 ± 0.39 vs 4.8 ± 0.30, p = 0.15). The ratio of log MMP-1 to TIMP-1 was increased (–1.2 ± 0.6 vs –2.1 ± 0.89, p = 0.002) in the study patients compared to the controls.

The main findings of this study were: fibrosis, as assessed by LGE was uncommon in CRMR; and biomarkers suggestive of collagen degradation (MMP-1, MMP-1/TIMP-1 ratio) were increased in CRMR, but no changes in biomarkers of collagen synthesis (PIP and PIIINP) were noted. In this study, the majority of patients with CRMR did not have LV myocardial fibrosis on LGE. There are no studies on CRMR to draw comparisons from, but the limited studies done in degenerative MR have shown the presence of fibrosis on LGE in about 30% of patients compared to only 18% in the current study.4,26 In contrast with our study, biological factors such as advanced age, and co-morbidities such as hypertension and diabetes may have contributed to the higher prevalence of fibrosis in these studies.4,26 Furthermore, one study used T1 mapping in addition to LGE, and was able to report on microvascular fibrosis, increasing the detection rate of fibrosis in their study.4 An alternative explanation for a lack of fibrosis in the majority of patients in this study may be the presence of diffuse fibrosis, which is missed by the LGE technique, as it compares regions of normal myocardium to abnormal myocardium.1 Conversely, fibrosis may indeed have been absent, and this is supported by the normal markers of collagen synthesis in this study. The above hypothesis is further supported on the basis of a study done by Ho et al. in hypertrophic cardiomyopathy patients, where it was noted that a pro-fibrotic state (as assessed by increased biomarkers of synthesis) preceded the development of fibrosis visible on MRI.27 The sample size in our study was too small to draw comparisons based on the presence or absence of LGE, or to comment on patterns of enhancement in detail. Interestingly though, LV fibrosis in the four patients was not confined to the posterobasal region, an area noted to be affected more commonly by rheumatic fever.7 A higher prevalence of fibrosis is observed commonly in pressure-overload states such as aortic stenosis.2 The exact mechanism of greater fibrosis in pressure-overload states compared to volume-overload states remains speculative.28 The following reasons have been proposed: (1) a greater supply/ demand mismatch in pressure-overload states resulting in ischaemia and fibrosis; (2) data from animal studies have shown that pro-fibrotic pathways are activated to a larger extent in pressure-overload states compared to volume-overload states; (3) the predominant pathology in MR may be extracellular volume Table 3. Biomarkers in the study patients compared to controls Study group (n = 22)

Control (n = 14)

p-value

11.8 (6.9-21.6)

15.7 (13.6-18.5)

0.09

Log PIIINP

2.5 ± 0.7

2.7 ± 2.6

0.18

PIP (µg/ml)

780.4 (727.3–1263.7)

1065.1 (589.2–1252.5)

0.13

Biomarkers PIIINP (ng/ml)

Table 2. CMR characteristics of the study patients CMR characteristics

Values

Regurgitant volume (ml)

47.0 ± 19.9

Regurgitant fraction (%)

49.2 (31.7–56.2)

EDVi (ml/m2)†

98.5 (81–111.1)

ESVi (ml/m2)†

49.1 ± 36.7

LVEF (%)

58.8 ± 15.1

Moderate MR, n (%)

9 (41)

Severe MR, n (%)

13 (55)

Data are presented as median (interquartile range), mean ± SD or %. Values are indexed to BSA. EDVi: end-diastolic volume indexed; ESVi: end-systolic volume indexed; LVEF: left ventricular ejection fraction; MR: mitral regurgitation.

†

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Log PIP MMP-1 (ng/ml) Log MMP-1 TIMP-1 (ng/ml) Log TIMP-1

6.79 ± 0.57

6.8 ± 0.47

0.29

37.5 (19.9–59.7)

16.2 (6.53–37.9)

0.3

3.45 ± 0.7

2.7 ± 0.9

0.02

95.4 (90.4–140.1)

139.2 (110.3–155.5)

0.1

4.6 ± 0.4

4.8 ± 0.30

0.15

MMP-1/TIMP-1 ratio

0.26 (0.21–0.43)

0.11 (0.07–0.26)

0.08

Log MMP-1/TIMP-1 ratio

–1.2 ± 0.6

–2.05 ± 0.89

0.002

Data are presented as median (interquartile range), mean ± SD or %. PIIINP: procollagen III N-terminal pro-peptide; PIP: procollagen type IC peptide; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of matrix metalloproteinase.

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loss, rather than excessive collagen deposition secondary to activation of Kallikrin–Kinin system, and thereby, of bradykinin, which increases MMP activity, causing loss of collagen, and LV dysfunction, as shown in an animal model.29 The predominance of degradation over synthesis results in loss and disruption of the myocardial collagen scaffold and an associated decline in matrix tensile strength, resulting in ventricular dilatation, systolic dysfunction and ultimately death.14 In this study, patients with CRMR had increased collagen degradation, as suggested by increase in MMP activity and normal levels of TIMPs and markers of collagen synthesis. This finding supports the lack of myocardial fibrosis observed in our study. These findings differ from the study by Banerjee et al. in 30 patients with CRMR, where they found an increased level of biomarkers of synthesis and degradation.13 The discrepancy may be explained by: younger patients than in this study (mean age 29.6 ± 2 years), possible ongoing rheumatic activity, and the inclusion of patients with atrial fibrillation, therefore resulting in increased biomarker levels.13 The use of anti-remodelling therapy was similar in our study to that of Banerjee et al.13 Thirty to 40% of their patients were on anti-remodelling therapy with spironolactone and ACE inhibitors, respectively, and 10% were on beta-blockers. In their study, only biopsies of the leaflets were performed, not the LV to assess the absence or presence of fibrosis. Furthermore, they reported increased thickness of the leaflets and collagen deposition in eight patients who underwent surgery. It is unclear, however, as to whether the primary lesion was mitral stenosis or MR in this subset of patients. Moreover, there was increased MMP activity in their MR patients compared to mitral stenosis, as well as increased MMP-to-TIMP ratio. They acknowledge that the elevation in PIP levels was lower than anticipated in their MR cohort, and that markers of collagen degradation exceeded markers of synthesis in their patients with CRMR. The main limitation of this study was the small sample size. A larger sample size would have reduced the probability of chance accounting for the absence or presence of fibrosis. A study with a larger sample size with isolated MR and one with co-morbidities and MR may be required to account for the finding of fibrosis secondary to isolated MR. T1 mapping was not used to exclude the presence of microscopic fibrosis and LV biopsies were not performed.

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e40110. DOI: 10.1371/journal.pone.0040110.

Next-generation cardiac pump improves outcomes, cuts costs In a presentation at the annual meeting of the Heart Failure Association of the European Society of Cardiology, investigators from Brigham and Women’s Hospital recently presented evidence that a next-generation cardiac pump device not only improves long-term outcomes but may also decrease cost of care over time for heart failure patients. The research team analysed results from the MOMENTUM 3 trial, which compared two devices: the HeartMate II (current generation) and HeartMate 3 (a novel, centrifugal-flow pump), both manufactured by Abbott Inc, which sponsored the study. ‘The HeartMate 3 left-ventricular assist device (LVAD) is a more forgiving pump in terms of clinical adverse events, and now we can confirm that its increased effectiveness is associated with decreased costs,’ said Dr Mandeep Mehra, executive director of the Centre for Advanced Heart Disease and medical director of the Heart & Vascular Centre at Brigham and Women’s Hospital. ‘In medicine, most often, a therapy that demonstrates increased effectiveness usually comes at a higher price, and we are able to show that this new technology actually decreases costs to payers and patients over time.’ Mehra and colleagues found that the newer device reduced costs due to re-hospitalisation by 51%, largely driven

by a decrease in stroke and pump malfunction requiring re-operation due to pump thrombosis. Patients who received the HeartMate 3 experienced fewer hospitalisations and, on average, spent 8.3 fewer days in the hospital per year than those who received the HeartMate II. The authors note that it may be possible to further reduce costs by decreasing outlier complications and reducing hospital length of stay and decrease early complications by improving patient selection criteria and considering this therapy before patients get too sick. In April, Abbott Inc issued a field safety notice regarding HeartMate 3 outflow graft twist complications with an incidence rate of 0.72%. The US Food and Drug Administration (FDA) issued a Class I recall but did not recommend the return of LVADs or avoidance of use in new patients. The current study re-reviewed 20 hospitalisations (five in the HeartMate 3 and 15 in the HeartMate II populations) and in a conservative analysis, classified them as being device-related for the purposes of this analysis. Nonetheless, the data still demonstrated a reduction in re-hospitalisation-related hospital days and significant cost savings for the HeartMate 3 compared to the HeartMate II. Source: Medical Brief 2018

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HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana Mosepele Mosepele, Terence Mohammed, Lucy Mupfumi, Sikhulile Moyo, Kara Bennett, Shahin Lockman, Linda C Hemphill, Virginia A Triant

Abstract Background: Untreated HIV infection is associated with increased biomarkers of endothelial dysfunction. However, the predictors and degree of endothelial dysfunction among virally suppressed HIV-infected adults on long-term antiretroviral therapy (ART) have not been well studied in subSaharan Africa (SSA). Methods: We enrolled 112 HIV-infected adults with virological suppression on long-term ART and 84 HIV-uninfected controls in Botswana. We measured plasma levels of markers of endothelial injury [soluble vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-selectin] and plasma levels of biomarkers of inflammation [interleukin 6 (IL-6)] and monocyte activation (sCD163). Baseline traditional cardiovascular disease (CVD) risk factors and bilateral common carotid intima–media thickness (cIMT) were also available for all participants. We assessed whether HIV status (despite virological suppression on ART) was associated with biomarkers of endothelial dysfunction after controlling for traditional CVD risk factors in linear regression

models. We additionally assessed the association between IL-6, sCD163 and cIMT with endothelial dysfunction in separate multivariate linear regression models, controlling for cIMT, among virally suppressed HIV-infected participants only. Results: In multivariate analysis, HIV infection was significantly associated with increased VCAM-1 (p < 0.01) and ICAM-1 (p = 0.03) but not E-selectin (p = 0.74) levels. Within the HIV-positive group, higher sCD163 levels were associated with decreased ICAM-1 and E-selectin (p < 0.01 and p = 0.01, respectively) but not VCAM-1 (p = 0.13) levels. IL-6 was not associated with any of the biomarkers of endothelial dysfunction. Conclusion: HIV disease was associated with biomarkers of endothelial dysfunction among virally suppressed adults in Botswana on long-term ART after controlling for traditional CVD risk factors. Future work should explore the clinical impact of persistent endothelial dysfunction following longterm HIV viral suppression on the risk of CVD clinical endpoints among HIV-infected patients in this setting.

Mosepele Mosepele, MD, MSc, mosepelem@ub.ac.bw

Keywords: human immune deficiency virus, endothelial dysfunction, inflammation, monocyte activation, atherosclerosis, Africa, cardiovascular disease

Botswana–Harvard AIDS Institute Partnership, Gaborone, Botswana

Submitted 12/1/17, accepted 14/1/18

Department of Medicine, Faculty of Medicine, University of Botswana, Gaborone, Botswana

Mosepele Mosepele, MD, MSc Terence Mohammed, MSc Lucy Mupfumi, MSc Sikhulile Moyo, PhD Shahin Lockman, MD, MSc

Bennett Statistical Consulting Inc, Ballston Lake, New York, USA Kara Bennett, MSc

Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, USA Shahin Lockman, MD, MSc

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA Shahin Lockman, MD, MSc

Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Linda C Hemphill, MD

Division of General Internal Medicine and Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Virginia A Triant, MD, MPH

Published online 14/5/18 Cardiovasc J Afr 2018; 29: 155–161

www.cvja.co.za

DOI: 10.5830/CVJA-2018-003

Biomarkers of endothelial dysfunction are elevated among untreated HIV-infected patients in Africa,1-4 and have been noted to be persistently elevated among non-African HIV-infected patients after initiating antiretroviral therapy (ART).5-8 However, little is known about endothelial dysfunction among virally suppressed HIV-infected patients following long-term ART versus controls in the African setting. Similarly, the independent effects of chronic inflammation and monocyte activation on endothelial dysfunction have not been widely assessed among African patients following sustained viral suppression. Increased expression of endothelial adhesion molecules is a marker of endothelial dysfunction. Commonly studied endothelial adhesion molecules that predict atherosclerotic disease in the general population include intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and selectins (P- or E-selectin).9-11 These molecules

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work in concert to promote development of atherosclerotic disease, with selectins facilitating activated leukocyte rolling and the adhesion molecules permitting adhesion and passage of leukocytes into the sub-endothelial space (site for atheroma formation).12 Expression of these molecules among virally suppressed HIV-infected patients has been linked to both systemic and arterial inflammation as well as immune activation. HIV-infected patients experience excess arterial inflammation,13-16 which has been linked to an increase in cardiovascular events.17 One of the main drivers of arterial inflammation is activated monocyte production of interleukin 6 (IL-6).18,19 IL-6 has been strongly associated with atherosclerotic disease20-22 and all-cause mortality among HIV-infected persons in Botswana and elsewhere.22,23 Similarly, soluble CD163, a haemoglobin scavenger protein released from activated monocytes, has been linked to arterial inflammation and all-cause mortality among HIV-infected persons.24,25 More recently, activated non-classical monocytes and VCAM-1 were significantly associated with degree of carotid intima thickness in a cohort of virally suppressed patients in the United States of America.26 Exactly how these markers of inflammation and monocyte activation impact on endothelial function in sub-Saharan Africa (SSA) is not widely known. We therefore sought to compare the degree of endothelial dysfunction among virally suppressed HIV-infected participants on ART in Botswana with that of HIV-uninfected controls, who had similar age and gender distributions, after controlling for traditional cardiovascular risk factors. Within the same setting, we sought to further assess whether biomarkers of inflammation (IL-6) and monocyte activation (sCD163) or carotid intima– media thickness (cIMT) were associated with biomarkers of endothelial dysfunction among virally suppressed HIV-infected participants. We hypothesised that HIV-infected participants have elevated biomarkers of endothelial dysfunction when compared with an HIV-uninfected control group. Additionally, we hypothesised that both IL-6 and sCD163 independently drive excess endothelial dysfunction among HIV-infected participants.

Methods Participants were randomly selected from a larger crosssectional study whose main aim was to assess sub-clinical carotid atherosclerosis and immune activation among adult HIV-infected patients compared to HIV-uninfected controls in Gaborone, Botswana. All participants self-identified as black Africans and were enrolled between February 2014 and April 2015. HIV-infected participants between 30 and 50 years of age (roughly balanced by gender) were recruited from Princess Marina Hospital Infectious Disease Care Clinic (PMH-IDCC). All HIV-infected patients were required to have documented dual-positive HIV enzyme-linked immunosorbent assay (ELISA) testing or pre-treatment HIV RNA > 400 copies/ml, a minimum six months of documented use of ART, no change in antiretroviral regimen in the six weeks preceding enrolment, and documented HIV RNA < 400 copies/ml throughout the six months prior to enrolment. ART in all participants consisted of two nucleoside/tide reverse transcriptase inhibitors (NRTI) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI). Patients

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on national salvage regimen consisting of two NRTIs plus combination of a ritonavir-boosted PI and an integrase inhibitor were eligible to participate. We also recorded the lowest CD4 count prior to ART initiation (nadir CD4) and the last recorded CD4 count prior to ART initiation (baseline CD4 count). All HIV RNA results were available from laboratory testing during routine clinic visits. HIV-uninfected participants were enrolled at the main Gaborone voluntary HIV testing centre and were required to have documented same-day dual-negative HIV ELISA testing. At enrolment, all participants provided written, informed consent to participate. Each participant had all study-related procedures completed on the day of enrolment. A targeted interview and review of medical records were performed to obtain CVD risk history, including prior CVD events, family history of CVD, diabetes mellitus or use of antidiabetic medications, hypertension or use of antihypertensive agents, statin use, cigarette smoking, and chronic kidney disease. Medical records were also reviewed to obtain complete HIV disease history, including diagnoses, pre-antiretroviral therapy and enrolment HIV-associated laboratory results, and complete anti-retroviral treatment history. Furthermore, a focused physical examination was done to obtain resting bilateral arm blood pressures and calculate body mass index (BMI). Non-fasting plasma samples previously obtained and frozen on the day of enrolment were used to measure levels of biomarkers of endothelial dysfunction, inflammation and monocyte activation. Non-fasting lipid profiles and glycosylated haemoglobin levels were available from prior analysis of samples drawn on the same day as the enrolment, when all study-related procedures were completed (including storage of plasma that was thawed for the current analysis). The study protocol was approved by the Botswana Ministry of Health Human Research Ethics Committee, Princess Marina Hospital Ethics Committee and Partners Human Research Committee in Boston, MA, USA. The degree of endothelial injury was assessed using ELISA commercially available kits from R&D systems© products supplied by Bio-techne©, Abingdon, United Kingdom. The ELISA kit manufacturer’s instructions were followed to ascertain levels of the following biomarkers: human soluble E-selectin (CD62E) quantikine ELISA [lower limit of detection (LOD) 0.1 ng/ml, upper LOD 8 ng/ml], human soluble vascular cell adhesion molecule 1 (sVCAM-1)/(CD106) quantikine ELISA (lower LOD 6.3 ng/ml, upper LOD 200 ng/ml) and human intercellular adhesion molecule 1 (sICAM-1)/(CD54) non-specific allele quantikine ELISA (lower LOD 0.6 ng/ml, upper LOD 40 ng/ ml) kits. Soluble CD163 and IL-6 levels were measured using ELISA (Trillium Diagnostics, Bangor, ME, USA & R&D systems© products) according to the manufacturer’s instructions. All participants had VCAM-1 and ICAM-1 results above the LOD. All participants had E-selectin levels above the LOD, however, E-selectin was available in only 90% of the HIV-infected participants and 58% of the HIV-uninfected controls due to limited access to testing reagents. All testing was done on thawed EDTA plasma samples at the Botswana–Harvard HIV Reference Laboratory, Gaborone, Botswana. We used mean common cIMT as a summary measure

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of observed degree of atherosclerosis among HIV-infected participants. Briefly, mean cIMT was ascertained at the distal 1 cm of the common carotid arteries on images obtained in B-mode along the lateral, anterior and posterior longitudinal sections of the common carotid artery bilaterally (right and left common carotid) as per the 2008 American Society of Echocardiography Carotid Intima–Media Thickness Task Force protocol.27 A Sonosite M-turbo© ultrasound machine (FUJIFILM Sonosite Inc, Bothell, WA, USA) connected to an 8–12-MHz linear probe was used to obtain still images at the beginning of the R wave, and sonocal© (version 5 of 2011) was used to measure cIMT in auto-mode as per the manufacturer’s instructions.

Results Among the participants, 112 were HIV infected with HIV-1 RNA < 400 copies/ml (51% were female, mean age 40 ± 5 years) and 84 were HIV-uninfected controls (45% female, mean age 38 ± 5 years). HIV-infected participants had a mean HIV disease duration of 9.8 ± 3.1 years and had been on ART for 8.5 ± 2.7 years, with the majority (73%) still on first-line NNRTI-based ART as per the Botswana national ART guidelines. In addition

Table 1. Demographics and clinical characteristics of HIV-infected participants and HIV-uninfected controls HIVinfected, n = 112a

HIVuninfected, n = 84a

p-value

Statistical analysis

Variables Age (years)

40 ± 5

38 ± 5

0.02

Baseline characteristics were compared using the two-samples t-test for continuous variables and Fisher’s exact test for categorical variables. All biomarkers and cIMT were initially compared between HIV-infected versus HIV-uninfected participants. The association between HIV status and level of each biomarker of endothelial dysfunction was assessed in univariate and multivariate linear regression, with the following variables selected a priori in the multivariate model: age, gender, BMI, mean arterial pressure (MAP), total cholesterol and glycosylated haemoglobin levels, smoking status (current non-smoker vs smoker) and statin use. Both the biomarkers of endothelial dysfunction and sCD163 and IL-6 levels were assessed for deviations from the normal distribution and if noted to be skewed, data were log transformed. During initial model building to assess the association between HIV status and endothelial dysfunction, observed associations were assessed both visually in graphical plot and formally (the latter by including a quadratic term in the model and testing for significance). These additional assessments are not reported for ICAM-1 and VCAM-1 because the overall level of significance of the association was unchanged, and similarly it was not reported for E-selectin due to high rates of missing data. Finally, among HIV-infected participants only, IL-6 and sCD163 were assessed for associations with endothelial dysfunction in univariate models, and then in multivariate models adjusted for each other (IL-6 vs sCD163) and cIMT (as a composite surrogate marker of observed burden of atherosclerosis). If any outliers were noted during preliminary data review (which occurred for IL-6 and log sCD163), sensitivity analyses were performed excluding these observations, and findings were reported if they were different. Furthermore, the three covariates (IL-6, sCD163 and cIMT) were assessed for collinearity and any detected high correlation (> 0.3) was considered to not impact on the analyses if model estimates remained similar between univariate and multivariate models (i.e. estimates were in the same direction and with similar significance level). As in the initial model building above, the association between predictors (IL-6, sCD163 and cIMT) for individual models (ICAM-1, VCAM-1, E-selectin) was assessed both visually in graphical plot and formally (the latter by including a quadratic term in the model and testing for significance). A p-value < 0.05 was considered significant in all analyses. All analysis was done in SAS©, version 9.4 (SAS Institute, Cary, North Carolina, USA).

Female, n (%)

57 (51)

38 (45)

0.47

Never

70 (63)

56 (67)

< 0.01

Prior smoker

36 (32)

12 (14)

6 (5)

16 (19)

Cigarette smoking, n (%)

Current smoker Family history Myocardial infarction, n (%)

1 (1)

4 (5)

0.17

Stroke, n (%)

8 (7)

18 (21)

0.01

Personal history Diabetes mellitus, n (%)

1 (1)

0 (0)

1.00

15 (13)

10 (12)

0.83

Chronic kidney disease, n (%)

4 (3)

0 (0)

0.14

Dyslipidaemia, n (%)

9 (8)

2 (2)

0.12

15 (13)

9 (11)

0.66

6 (5)

1 (1)

0.24

Systolic blood pressure (mmHg)

129.7 ± 15.1

130.4 ± 17.0

0.75

Diastolic blood pressure (mmHg)

84.6 ± 11.5

84.6 ± 13.3

0.97 0.98

Hypertension, n (%)

Medications (current) Anti-hypertensives, n (%) Statins, n (%) Anthropometric data

Body mass index (kg/m2) Underweight (< 18.5), n (%)

10 (9)

8 (10)

Normal weight (18.5–< 25), n (%)

58 (52)

43 (51)

Overweight (25–< 30), n (%)

28 (25)

23 (27)

Obese (≥ 30), n (%)

15 (14)

10 (12)

Total cholesterol (mmol/l)

4.8 ± 1.2

4.5 ± 1.2

0.06

LDL cholesterol (mmol/l)

2.9 ± 1.0

2.6 ± 1.0

0.02

HDL cholesterol (mmol/l)

1.4 ± 0.5

1.4 ± 0.4

0.87

Triglycerides (mmol/l)

1.4 ± 0.8

1.2 ± 1.5

0.41

5.3 ± 0.4

5.5 ± 1.0

0.01

CVD risk laboratory tests

Glycosylated haemoglobin (g/dl) HIV parameters HIV disease duration (years)

9.8 ± 3.1

Duration on ART (years)

8.5 ± 2.7

Nadir CD4 count (cells/μl)

113 ± 74

Baseline CD4 countc (cells/μl)

117 ± 72

Current CD4 count (cells/μl)

553 ± 251

Proportion with undetectable VL, n (%)

100

Time since most recent VL (months)

3.2 ± 2.0

NNRTI-based ART, n (%)

82 (73)

PI-based ART, n (%)

29 (26)

HIV, human immunodeficiency virus; ACE, angiotensin converting enzyme; HMG-Co A, 3-hydroxy-3-methylglutaryl-coenzyme A; CVD, cardiovascular disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein; baseline CD4 count, pre-ART CD4 count; VL, viral load; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor a Means (standard deviations) for continuous measures; counts (percentages) for categorical measures. b Continuous variables were compared using the two-samples t-test and categorical variables were compared using Fischer’s exact test. c Baseline CD4 count indicates pre-ART CD4 count.

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to an NNRTI (73%) or protease inhibitor (PI) (26%), each participant ART regimen also contained Tenofovir/Lamivudine (49%), Zidovudine/Lamivudine (47%), Abacavir/Lamivudine (2%) or Lamivudine (2%) (data not shown in table). Table 1

provides baseline characteristics including CVD risk factors. Among the biomarkers of endothelial dysfunction in unadjusted analysis, only VCAM-1 was elevated among HIV-infected participants when compared to HIV-uninfected

p = 0.42

p = 0.10

8 IL-6 (ng/ml)

Log sCD163 (log ng/ml)

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10 4 0

HIV-uninfected controls HIV-infected on ART Log sCD163 by HIV status

HIV-uninfected controls HIV-infected on ART IL-6 by HIV status

p = 0.09 8.0

p < 0.01

800

600

7.0

I-CAM (ng/ml)

Log VCAM-1 (log ng/ml)

7.5

6.5 6.0 5.5 5.0

200 HIV-uninfected controls HIV-infected on ART Log VCAM-1 by HIV status

HIV-uninfected controls HIV-infected on ART I-CAM by HIV status

p = 0.09

1.0

125

Mean cIMT (ng/ml)

100 E-selection (ng/ml)

400

p = 0.52

0.8

0. 6

0. 4 25 HIV-uninfected controls HIV-infected on ART E-selection by HIV status

HIV-uninfected controls HIV-infected on ART cIMT by HIV status

Fig. 1. C omparison of biomarkers and cIMT between the study groups. The horizontal bars of the whiskers represent the 10th and 90th percentile, while the upper and lower boundaries of the boxes represent the first and third quartiles. All comparisons are between HIV-infected patients on ART and HIV-uninfected controls. From left to right for each pair of box plots, the top depicts sCD163 (ng/ml) and IL-6 (ng/ml), the middle depicts log VCAM-1 (ng/ml) and ICAM-1 (ng/ml), and the bottom depicts E-selectin (ng/ml) and cIMT (mm). VCAM-1, vascular cell adhesion molecule; ICAM-1, intercellular adhesion molecule; cIMT, carotid intimaâ&#x20AC;&#x201C;media thickness.

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Table 2. Association between VCAM-1, ICAM-1, E-selectin levels and HIV-status in multivariate models (among HIV-infected participants only) Log VCAM-1 (ng/ml)

ICAM-1 (ng/ml)

E-selectin (ng/ml)

Estimate (95% CI)

p-value

Estimate (95% CI)

p-value

Estimate (95% CI)

p-value

HIV status (ref = controls)

0.14 (0.04, 0.25)

0.01

55.17 (5.87, 104.46)

0.03

1.19 (–6.15, 8.52)

0.75

Age (per 5-year increase)

0.08 (0.03, 0.13)

< 0.01

9.03 (–14.62, 32.68)

0.45

–1.59 (–5.07, 1.89)

Gender (ref = female)

–0.18 (–0.30, –0.06)

< 0.01

–18.62 (–72.85, 35.61)

0.50

Body mass indexa (kg/m2)

–0.02 (–0.03, –0.01)

< 0.01

1.81 (–3.52, 7.14)

0.50

0.22 (–0.58, 1.01)

0.59

0.44

–0.08 (–1.99, 1.83)

0.93

0.20 (–0.09, 0.49)

0.17

CVD risk factor

Mean arterial pressureb

0.002 (–0.002, 0.006)

Cholesterol (mmol/dl) Glycosylated haemoglobin (%) Previous smoker (not current) vs never Current smoker vs never Statin use (ref = on statin)

2.49 (–5.72, 10.70)

0.37 0.55

–0.001 (–0.003, 0)

0.01

–0.15 (–0.68, 0.38)

0.58

0.01 (–0.08, 0.10)

0.82

0.01 (–0.06, 0.09)

0.75

20.30 (–14.29, 54.88)

0.25

6.16 (1.43, 10.10)

0.01

4.31 (–4.2, 12.93)

0.33

–0.001 (–0.123, 0.121)

0.99

25.02 (–33.28, 83.33)

0.40

0.07 (–0.10, 0.23)

0.45

123.93 (44.47, 203.40)

< 0.01

–0.21 (–0.47, 0.05)

0.12

5.25 (–119.28, 129.78)

0.93

10.72 (–0.47, 21.90)

0.06

–5.85 (–26.56, 14.85)

0.58

VCAM-1, vascular cell adhesion molecule; ICAM-1, intercellular adhesion molecule. # Significant interaction not reported because of high rates of missing data. a Body mass index calculated as body weight (kg) divided by height2 (m). b Mean arterial pressure calculated as one-third systolic blood pressure (mmHg) plus two-thirds diastolic pressure (mmHg).

participants (p < 0.01), while ICAM-1 and E-selectin did not differ by HIV status, as shown in Fig. 1. Similarly, sCD163, IL6 and cIMT did not differ by HIV status. The reported p-value for IL-6 includes five HIV-infected outliers; exclusion of these did not alter the direction of the association. In adjusted analysis, controlling for demographic factors and traditional CVD risk factors, HIV infection was associated with increased log VCAM-1 and ICAM-1 but not with E-selectin levels (p = 0.01, p = 0.03 and p = 0.75, respectively), as shown in Table 2. More traditional risk factors were more significantly associated with VCAM-1 than with ICAM-1 or E-selectin (significant p-values in bold in Table 2). In unadjusted analysis, higher log sCD163 was associated with decreased ICAM-1 and E-selectin levels (p < 0.01 and p = 0.01) but not log VCAM-1 (p = 0.07), as shown in Table 3. These associations were linear based on graphical plot. Inclusion of a quadratic term for log sCD163 in each of the ICAM-1, VCAM1 and E-selectin models did not alter the reported association (data not shown). In preliminary diagnostics prior to performing adjusted analysis, there was a statistically significant negative correlation between sCD163 and IL-6 (r = –0.27, p < 0.01); however, the estimates were similar between the univariate and adjusted models so both were retained in the final models. Table 3. Association between sCD163, IL-6 levels, cIMT and biomarkers of endothelial dysfunction among HIV-infected participants models Univariate models Estimate

p-value

Log sCD163* cIMT

–0.0008

0.14

0.08

0.07

0.08 (–0.02, 0.18)

0.13

–0.23

0.54

–0.33 (–1.07, 0.40)

–0.0006 (–0.002, 0.0005)

0.27 0.37

Adj R2 = 0.05

ICAM-1 IL-6

p-value

Adj R2 = 0.02

Log VCAM-1* IL-6

Multivariable models Estimate (95% CI)

0.19

0.40

0.02 (–0.43, 0.47)

0.93

Log sCD163*

–61.7

< 0.01

–61.5 (–105.4, –17.6)

< 0.01

cIMT

–45.1

0.78

1.27 (–309.8, 312.4)

0.99

Adj R2 = 0.05

E-selectin IL-6

0.66

0.15 (–0.86, 1.15)

0.77

Log sCD163*

–7.8

0.23

0.01

–8.56 (–15.30, –1.82)

0.01

cIMT

–2.5

0.93

5.64 (–51.2, 62.5)

0.84

VCAM-1, vascular cell adhesion molecule; ICAM-1, intercellular adhesion molecule *Data log transformed for univariate linear regression analysis for VCAM-1 and sCD163.

Final multivariate models for each marker of endothelial dysfunction demonstrated sCD163 to be associated with decreased ICAM-1 (–61.5, 95% CI: –105.4, 17.6, p < 0.01), and E-selectin levels (–8.56, 95% CI: –15.30, –1.82, p = 0.01) but not log VCAM-1 (0.08, 95% CI: –0.02, 0.18, p = 0.13), as shown in Table 3. These associations were linear. Neither IL-6 nor cIMT was associated with any biomarker of endothelial function.

Discussion We found that HIV-infected adults in SSA who had attained viral suppression on ART had biomarkers consistent with greater endothelial dysfunction when compared to HIV-uninfected controls, even after adjusting for traditional CVD risk factors. In this small cross-sectional study of adults between 30 and 50 years, endothelial dysfunction was associated with sCD163 but not IL-6 or cIMT. This evidence of ongoing endothelial dysfunction despite chronic viral suppression among HIV-infected patients when compared to HIV-uninfected controls indicates that endothelial dysfunction, first observed prior to ART initiation in this setting,2 persists following ART initiation, similar to what has been observed in other settings.5-7 Specifically, persistently elevated ICAM-1 levels following viral suppression were observed among black South Africans,28 Kenyan women29 and a predominantly male Danish cohort7 following mean ART duration of approximately three, one and 12 years, respectively. This aligns well with our findings following a mean of nine years of ART exposure. Furthermore, our finding of elevated VCAM-1 levels following prolonged ART was previously observed in the same black South African cohort studied by Fourie et al.,28 but not in the Danish cohort.7 To the best of our knowledge, our findings support those of Fourie et al. in a mixed male and female cohort and expand on these findings by providing ascertainment of date of ART initiation.28 Taken together, our findings in relation to ICAM-1 and VCAM-1 build on those of Fourie et al.28 and Graham et al.1 in SSA and also highlight the strong effect of HIV disease on endothelial dysfunction, even after prolonged viral suppression and controlling for multiple traditional CVD risk factors and the use of statin therapy. We did not observe an association between HIV status and elevated E-selectin level, in keeping with a similar report in a

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Danish cohort of virally suppressed HIV-patients versus controls.7 In the Graham report among Kenyan women, E-selectin levels were unchanged at 12 months compared to baseline.1 We believe our report of a lack of difference in E-selectin levels by HIV status to be the first in SSA. The Graham and Danish cohort reports suggest that HIV may not be as strongly associated with E-selectin, compared to VCAM-1 or ICAM-1 levels. Our findings of a lack of association between IL-6 level and cIMT with endothelial dysfunction are similar to those of Fourie et al. in their study among virally suppressed black South African patients.28 Our findings and those of Fourie et al. in this context do not align with the observation among non-African patients that IL-6 level and cIMT were associated with endothelial injury.8,26,30 Our small sample size may have precluded our ability to detect these associations in our setting. Of note, observations of this association in non-African cohorts have not always been consistent. In a recent prospective study of ART-naïve HIV-infected adults in the USA, ICAM-1 level was not associated with progression in cIMT.31 More studies are required to establish the contribution of traditional CVD risk factors to endothelial dysfunction among virally suppressed HIV-infected patients in SSA, and to explore novel markers that may explain the proportion of risk not conferred by traditional CVD risk factors. The relationship between sCD163 level and biomarkers of endothelial dysfunction has not been reported in SSA. Our results of a lack of association between sCD163 and VCAM-1 have been reported by some,32 but not all33 studies in non-SSA settings among patients on ART. We had expected a positive association between sCD163 and VCAM-1 in our study because sCD163 induces arterial inflammation, which may lead to increased shedding of VCAM-1.26 We observed an unexpected negative association between sCD163 with I-CAM and E-selectin levels. We are cautious in interpreting the negative associations observed between sCD163 with ICAM-1 and E-selectin levels in our study pending assessment of these associations in similar cohorts.

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Botswana on long-term ART after controlling for traditional CVD risk factors. Unexpectedly, we observed a modest inverse relationship between sCD163 level (a marker of monocyte activation) and some biomarkers of endothelial dysfunction. Our study is the first to report on markers of endothelial dysfunction following prolonged ART among virally suppressed black Africans. We also report a lack of association between sCD163 and VCAM-1 for the first time in a SSA clinical cohort, replicating what has been observed in non-African cohorts, and we corroborate a previously demonstrated lack of association between IL-6 and cIMT with endothelial dysfunction in this setting. Future work should explore the impact of persistent endothelial dysfunction following long-term HIV viral suppression on the risk of CVD clinical endpoints among HIV-infected patients in this setting. The study was funded by the National Institutes of Health (NIH), grant NIH/NIAID 5P30AI060354-0 through Harvard University Centre for AIDS Research (HU-CFAR), Harvard Global Health Institute (HGHI), grant BWH#2013D002079, International Fogarty Training grant (PI-Max Essex DVM, Botswana–Harvard AIDS partnership) and NIH/NHLBI R01HL132786 (to VAT).

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Graham SM, Rajwans N, Jaoko W, Estambale BB, McClelland RS, Overbaugh J, Liles WC. Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression. AIDS 2013; 27(11): 1803–1813.

Fourie C, van Rooyen J, Schutte A, Pieters M, Conradie K, Hoekstra T. Is HIV-1 infection associated with endothelial dysfunction in a population of African ancestry in South Africa? Cardiovasc J Afr 2011; 22(3): 134–140.

Royal W III, Cherner M, Burdo TH, Umlauf A, Letendre SL, Jumare J, et al. Associations between cognition, gender and monocyte activation among HIV infected individuals in Nigeria. PLoS One 2016; 11(2): e0147182.

Limitations The main limitations of our study are the cross-sectional design, small sample size and limited number of biomarkers that were studied. The cross-sectional design precludes the ability to arrive at a temporal association between our predictors and outcomes. Furthermore, studying activated peripheral blood mononuclear cells and human endothelial cells would provide a more robust understanding of pathways involved in the development of endothelial dysfunction. Because we relied on standard-ofcare HIV RNA results that were measured within an average of three months prior to time of enrolment, it is possible that some patients may have been viraemic. We believe that this potential effect would have been minimal, given the high viral suppression rates of 96.5% observed among patients on ART in routine HIV care in Botswana.34 A strength of our study was the ascertainment of traditional CVD risk factors, which allowed for robust assessment of confounding.

Bestawros M, Chidumayo T, Blevins M, Canipe A, Bala J, Kelly P, et al. Increased systemic inflammation is associated with cardiac and vascular dysfunction over the first 12 weeks of antiretroviral therapy among undernourished, HIV-infected adults in Southern Africa. J AIDS Clin Res 2015; 6(3): 431.

De Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis 2004; 4(4): 213–222.

Gresele P, Falcinelli E, Sebastiano M, Baldelli F. Endothelial and platelet function alterations in HIV-infected patients. Thromb Res 2012; 129(3): 301–308.

Rȍnsholt FF, Ullum H, Katzenstein TL, Gerstoft J, Ostrowski SR. Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy. PLoS One 2013; 8(6): e65182.

Ross AC, Rizk N, O’Riordan MA, Dogra V, El-Bejjani D, Storer N, Harrill D, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima–media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis 2009; 49(7):

Conclusion We observed that HIV disease was associated with biomarkers of endothelial dysfunction among virally suppressed adults in

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Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res 2001; 89(9): 763–771.

10. Baker JV, Duprez D. Biomarkers and HIV-associated cardiovascular

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disease. Curr Opin HIV AIDS 2010; 5(6): 511–516. 11. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr 2012; 23(4): 222–231. 12. Sundd P, Pospieszalska MK, Cheung LS, Konstantopoulos K, Ley K. Biomechanics of leukocyte rolling. Biorheology 2011; 48(1): 1–35. 13. Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in patients with HIV. J Am Med Assoc 2012; 308(4): 379–386. 14. Stein JH, Currier JS, Hsue PY. Arterial disease in patients with human immunodeficiency virus infection: what has imaging taught us? J Am Coll Cardiol Cardiovasc Imaging 2014; 7(5): 515–525.

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among adults receiving combination antiretroviral therapy in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses 2013; 29(7): 993–999. 24. Knudsen TB, Ertner G, Petersen J, Møller HJ, Moestrup SK, EugenOlsen J, et al. Plasma soluble CD163 level independently predicts allcause mortality in HIV-1-infected individuals. J Infect Dis 2016; 214(8): 1198–1204. 25. Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, et al. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after antiretroviral therapy. J Infect Dis 2011; 204(1): 154–163. 26. Barbour JD, Jalbert EC, Chow DC, Gangcuangco LMA, Norris PJ,

15. Tawakol A, Lo J, Zanni M, Marmarelis M, Ihenachor E, MacNabb M, et

Keating SM, et al. Reduced CD14 expression on classical monocytes

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statin therapy on coronary artery plaque volume and high-risk plaque

27. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER,

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randomised, double-blind, placebo-controlled trial. Lancet HIV 2015;

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the American Society of Echocardiography Carotid Intima–Media

17. Figueroa AL, Takx RA, MacNabb MH, Abdelbaky A, Lavender ZR, Kaplan RS, et al. Relationship between measures of adiposity, arterial inflammation, and subsequent cardiovascular events. Circ Cardiovasc Imaging 2016; 9(4): e004043. 18. De Pablo-Bernal RS, Ramos R, Genebat M, Cañizares J, Rafii-El-Idrissi

Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008; 21(2): 93–111; quiz 189–190. 28. Fourie CM, Schutte AE, Smith W, Kruger A, van Rooyen JM. Endothelial activation and cardiometabolic profiles of treated and nevertreated HIV infected Africans. Atherosclerosis 2015; 240(1): 154–160.

Benhnia M, Muñoz-Fernández MA, et al. Phenotype and polyfunc-

29. Graham SM, Rajwans N, Tapia KA, Jaoko W, Estambale BBA, Scott R,

tional deregulation involving interleukin 6 (il-6)- and il-10-producing

et al. A prospective study of endothelial activation biomarkers, including

monocytes in HIV-infected patients receiving combination antiretroviral

plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating

therapy differ from those in healthy older individuals. J Infect Dis 2016; 213(6): 999–1007.

antiretroviral therapy. BMC Infect Dis 2013; 13: 263. 30. Longenecker CT, Funderburg NT, Jiang Y, Debanne S, Storer N,

19. Jalbert E, Crawford TQ, D’Antoni ML, Keating SM, Norris PJ,

Labbato DE, et al. Markers of inflammation and CD8 T-cell activa-

BNakamoto BK, et al. IL-1-beta enriched monocytes mount massive

tion, but not monocyte activation, are associated with subclinical

IL-6 responses to common inflammatory triggers among chronically

carotid artery disease in HIV-infected individuals. HIV Med 2013; 14(6):

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385–390.

vascular disease. PLoS One 2013; 8(9): e75500.

31. Hileman CO, Longenecker CT, Carman TL, McComsey GA. C-reactive

20. Bahrami H, Budoff M, Haberlen SA, Rezaeian P, Ketlogetswe K, Tracy

protein predicts 96-week carotid intima media thickness progression in

R, et al. Inflammatory markers associated with subclinical coronary

HIV-infected adults naive to antiretroviral therapy. J Acquir Immune

artery disease: the Multicenter AIDS Cohort Study. J Am Heart Assoc 2016; 5(6): e003371.

Defic Syndr 2014; 65(3): 340–344. 32. Beltran LM, Hernández RM, de Pablo Bernal RS, Morillo JSG, Egido

21. Hsu DC, Ma YF, Hur S, Li D, Rupert A, Scherzer R, et al. Plasma IL-6

J, Noval ML, et al. Reduced sTWEAK and increased sCD163 levels in

levels are independently associated with atherosclerosis and mortality

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in HIV-infected individuals on suppressive antiretroviral therapy. AIDS 2016; 30(13): 2065–2074. 22. Borges AH, O’Connor JL, Phillips AN, Neaton JD, Grund B, Neuhaus J, et al. Interleukin 6 Is a stronger predictor of clinical events than highsensitivity C-reactive protein or D-dimer during HIV infection. J Infect Dis 2016; 214(3): 408–416. 23. McDonald B, Moyo S, Gabaitiri L, Gaseitsiwe S, Bussmann H, Koethe JR, et al. Persistently elevated serum interleukin-6 predicts mortality

cation and HCV co-infection. PLoS One 2014; 9(3): e90541. 33. Grome HN, Barnett L, Hagar CC, Harrison DG, Kalams SA, Koethe JR. Association of T cell and macrophage activation with arterial vascular health in HIV. AIDS Res Hum Retroviruses 2017; 33(2): 181–186. 34. Gaolathe T, Wirth KE, Holme MP, Makhema J, Moyo S, Chakalisa U, et al. Botswana’s progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a populationbased survey. Lancet HIV 2016; 3(5): e221–230.

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The effects of treatment with atorvastatin versus rosuvastatin on endothelial dysfunction in patients with hyperlipidaemia Vahit Demir, Mehmet Tolga Doğru, Hüseyin Ede, Samet Yılmaz, Cağlar Alp, Yunus Celik, Nesligül Yıldırım

Abstract Introduction: Statins can reduce cardiovascular events and improve endothelial function. However, differences in the effect of statins on endothelial dysfunction have not been researched sufficiently. Here, we aimed to compare the effects of atorvastatin versus rosuvastatin on endothelial function via flow-mediated and endothelial-independent dilation. Methods: Hyperlipidaemic subjects on treatment with statins for one year (either 20 mg/day atorvastatin or 10 mg/day rosuvastatin) were enrolled in the study. In accordance with the literature, flow-mediated dilation (FMD) and nitrate-mediated endothelium-independent dilation (EID) were measured by ultrasonography on the right brachial artery of each subject. Baseline and final measurements were compared in each group and between the groups. Results: One hundred and four subjects (50 atorvastatin and 54 rosuvastatin users) were enrolled in the study. Fifty-eight subjects were female. The groups were statistically similar in terms of age and body mass index, and haemoglobin, creatinine, total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein cholesterol levels. In each group, the mean final FMD and EID values were higher compared to their respective baseline values, but the mean changes in FMD and EID were statistically similar in both groups (p = 0.958 for FMD and 0.827 for EID). There was no statistically significant difference between the atorvastatin and rosuvastatin groups in terms of final FMD and EID values (p = 0.122 and 0.115, respectively). Conclusion: This study demonstrated that both one-year atorvastatin and rosuvastatin treatments significantly improved endothelial function, when assessed with FMD and EID and measured by ultrasonography. However, the amount of improvement in endothelial dysfunction was similar in the two treatments.

Cardiology Department, Faculty of Medicine, Bozok University, Yozgat, Turkey Vahit Demir, MD, dr.vdemir@hotmail.com Hüseyin Ede, MD

Cardiology Department, Faculty of Medicine, Kırıkkale University, Kırıkkale, Turkey Mehmet Tolga Doğru, MD Cağlar Alp, MD Yunus Celik, MD Nesligül Yıldırım, MD

Cardiology Department, Yozgat State Hospital, Yozgat, Turkey Samet Yılmaz, MD

Keywords: atorvastatin, endothelial function, flow-mediated vasodilatation, rosuvastatin Submitted 31/8/17, accepted 14/1/18 Published online 8/3/18 Cardiovasc J Afr 2018; 29: 162–166

www.cvja.co.za

DOI: 10.5830/CVJA-2018-008

Hyperlipidaemia is an important risk factor for the development of atherosclerosis. Statins may reduce the risk of cardiovascular events and improve endothelial function.1,2 The positive effect of statins on endothelial dysfunction is carried out via endothelial nitric oxide enzyme activation.3 Pleiotropic effects of statins include improvement in endothelial function, anti-thrombosis, plaque stabilisation and anti-oxidative effects, and decreasing the duration of vascular inflammation.4 However, differences in the effect of statins on endothelial dysfunction has not been researched sufficiently. Earlier studies demonstrated that improved endothelial dysfunction in different vascular beds started after a few days of treatment with statins.5-8 Endothelial dysfunction is the early sign of atherosclerosis and enhances the risk of cardiovascular events.9 Flow-mediated dilation (FMD) is a well-known method used for predicting the extent of atherosclerosis. FMD is measured on the brachial arteries and reflects the ability of an artery to enlarge after being compressed for a certain time. Nitric oxide (NO) is the most important vascular vasodilator and is produced by the endothelium in response to certain factors such as shear stress. Its production is impaired in the case of endothelial dysfunction. Increased production of NO after increased vascular blood flow is the underlying mechanism of FMD.10 Studies on primary and secondary prevention of cardiovascular disease and its complications by statins revealed that their effect occurs not only due to their lipid-lowering effect but also due to pleiotropic effects, the mechanism of which remains unclear. In this study we aimed to compare the effect of one-year rosuvastatin versus atorvastatin therapy on endothelial function in hyperlipidaemic patients, using FMD and endotheliumindependent dilation (EID), measured ultrasonographically on the brachial artery.

Methods A total of 112 patients diagnosed with hyperlipidaemia and without a history of previous lipid-lowering medication for at least the previous two months, and with an indication for medical treatment despite a first-line, four-week, lipid-lowering diet, applied to the cardiology out-patient unit and were enrolled

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in the study between May 2010 and August 2011. Approval of the local ethics committee and informed consents of the participants were obtained accordingly. A subject was considered treatment adherent when he/she took her/his prescribed statin regularly on a daily basis. A subject was considered complient if his/her baseline and post-treatment measurements were obtained as per the study protocol. Eight cases (four with compliance problems with follow up, one with lung cancer and three with non-adherence to medication) were excluded from the study. The study was completed with 104 hyperlipidaemic patients, of whom 50 were assigned to atorvastatin 20 mg per day and 54 to rosuvastatin 10 mg per day. Patients under the age of 18 and over the age of 80 years, those with heart failure, uncontrolled hypertension, endocrine diseases, previous coronary artery disease, frequent and permanent cardiac dysrhythmia, malignancy, chronic obstructive pulmonary disease, and chronic liver, kidney, neurological or psychiatric diseases, which were likely to produce a compliance problem, were not included in the study. Baseline demographic characteristics of the patients were recorded. Body mass index (BMI) was calculated as body weight (kg)/height2 (m). Levels of fasting blood glucose, serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides (TG), urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), creatinine phosphokinase (CPK) and complete blood counts were measured in all patients after a 12-hour fasting period. In addition, the patients underwent transthoracic echocardiography. Lipid levels indicated eligible patients, who were randomly assigned to receive either rosuvastatin 10 mg/day or atorvastatin 20 mg/day. The patients were followed for one year. Baseline measurements were repeated at the end of the 12-month treatment period. Change in LDL level (ΔLDL) was defined as the difference between baseline and post-treatment LDL values. Endothelial function was measured ultrasonographically over the brachial artery using echocardiography (Ge-Vivid 7 Pro, General Electric, Florida, USA) with a 12-L probe. All measurements were performed according to the method described elsewhere in the literature.11 Brachial artery basal Doppler velocity (DV), basal diameter (BD), brachial artery hyperaemia velocity (HV), and post-flow brachial artery lumen diameter (hyperaemia diameter = HD flow-mediated dilation response = FMDR) were recorded. FMD was calculated from the following equation: FMDR – BD

___________   × 100 % FMD =      BD

Baseline endothelium-independent dilation (EID) was measured 10 minutes after deflation of the cuff to obtain baseline conditions and was labelled as pre-nitrate BD. Thereafter, the patients received 400 μg of nitroglycerin sublingually; three to five minutes later, post-nitrate Doppler, post-nitrate velocity (NTGV) and post-nitrate arterial diameter (NTGD) were measured. Lumen diameter was measured three times and the arithmetic mean was calculated. Post-nitrate arterial diameter was named nitrate-mediated dilation response (NMDR). EID was calculated using the following equation: NMDR – pre-nitrate BD

____________________    × 100 % EBG =      Pre-nitrate BD

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ΔFMD and ΔEID were defined as the difference between baseline and post-treatment FMD and EID values, respectively.

Statistical analyses The SPSS (SPSS, Inc, Chicago, IL, USA) program was used to analyse the data. Mean and standard deviations (SD) were used for descriptive data. Student’s t-test was used to compare normally distributed quantitative variables, whereas the Mann– Whitney U-test was used to compare independent non-normally distributed quantitative variables. Moreover, statistical comparison between continuous dependent variables was done by paired-samples t-test for normally distributed variables, whereas the Wilcoxon test was used for non-normally distributed variables. Relationships between the parameters were assessed with Pearson’s correlation analysis for parametric variables and by Spearman’s correlation analysis for non-parametric variables. The results were evaluated with a 95% confidence interval and at the significance level of p < 0.05.

Results A total of 104 hyperlipidaemic cases were included in the study. The patients were randomly assigned to either atorvastatin (group 1, n = 50, 48.1%) or rosuvastatin (group 2, n = 54, 51.9%) therapy. Of the overall patients, 46 were male (53.7 ± 9.7 years) and 58 were female (54.3 ± 10.1 years). There was no statistically significant difference between the two groups in terms of baseline anthropometric characteristics of the subjects, haemoglobin, haematocrit, white blood cell count, thrombocyte count, and urea, creatinine, AST, ALT, CPK, total cholesterol, TG, HDL and LDL levels. Mean ΔLDL at the end of 12 months was 71.0 ± 29.7 mg/ dl (1.84 ± 0.77 mmol/l) and percentage ΔLDL was 42.2 ± 17.6% (n = 104) in the study population. ΔLDL was significantly correlated with ΔFMD (r = 0.367, p < 0.005) and ΔEID (r = 0.523, p < 0.001). Percentage ΔLDL was statistically correlated with ΔFMD (r = 0.412, p < 0.005) and ΔEID (r = 523, p < 0.001). In the atorvastatin group, a statistically significant reduction was shown in total cholesterol, LDL and TG levels compared to baseline values. LDL level showed a 52.5% decrease after 12 months compared to baseline value, whereas no decrease was observed in HDL level. FMD showed a statistically significant increase (Table 1). In the rosuvastatin group, a statistically significant decrease was found in total cholesterol, LDL and TG levels compared to baseline values. LDL level showed a 58.5% decrease at the end of the 12 months compared to baseline value, whereas no change was observed in HDL levels. While a statistically significant increase was observed in the brachial artery basal diameter and hyperaemia diameter compared to baseline values, no change was observed in the post-nitrate diameter and EID values. FMD showed a statistically significant increase compared to baseline (Table 2). No statistically significant difference was found between the atorvastatin and rosuvastatin groups in respect of baseline transthoracic echocardiographic and brachial artery endothelial function measurements (Table 3). Comparison between the two groups in terms of their effects on non-invasive ultrasonographic brachial artery measurements after one year revealed no

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Table 1. Post-treatment versus baseline values in the atorvastatin group Atorvastatin

Baseline mean ± (SD)

12-month mean ± (SD)

p-value*

Basal diameter (mm)

4.0 ± 0.6

4.1 ± 0.6

0.045

Hyperaemia diameter (mm)

4.2 ± 0.6

4.3 ± 0.6

0.436

NTG diameter (mm)

4.5 ± 0.6

4.7 ± 0.6

0.002

FMD (%)

8.5 ± 3.3

10.4 ± 4.1

< 0.001

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Table 3. Statistical comparison between atorvastatin and rosuvastatin groups in terms of baseline brachial artery measurements Baseline brachial artery measurements

Atorvastatin group

Rosuvastatin group

p-value*

BA basal diameter (mm)

4.01 ± 0.6

4.02 ± 0.5

0.850

BA basal velocity (cm/s )

71.95 ± 14.8

79.32 ± 16.9

0.240

BA hyperaemia diameter (mm)

4.34 ± 0.6

4.43 ± 0.5

0.404

BA hyperaemia velocity (cm/s)

72.21 ± 15.9

73.4 ± 16.3

0.713

15.5 ± 5.1

16.3 ± 4.8

TC (mg/dl) (mmol/l)

261.3 ± 28.3 (6.77 ± 0.73)

174.3 ± 38.9 (4.51 ± 1.01)

< 0.001

BA NTG diameter (mm)

4.6 ± 0.6

4.69 ± 0.5

0.451

BA NTG velocity (cm/s)

68.92 ± 15.4

68.23 ± 15.5

0.833

TG (mg/dl) (mmol/l)

161.8 ± 66 (1.83 ± 0.75)

131.9 ± 50 (1.49 ± 0.57)

< 0.001

BA FMD (%)

8.52 ± 3.3

9.71 ± 3.4

0.750

LDL-C (mg/dl) (mmol/l)

176.8 ± 23.5 (4.58 ± 0.61)

92.9 ± 28.1 (2.41 ± 0.73)

< 0.001

15.31 ± 5.1

16.84 ± 5.8

0.159

HDL-C (mg/dl) (mmol/l)

54.7 ± 12.1 (1.42 ± 0.31)

54.4 ± 12.4 (1.41 ± 0.32)

0.145

AST (U/l)

23.8 ± 9.1

21.9 ± 5.6

0.068

ALT (U/l)

23.6 ± 12.8

24.1 ± 13.1

0.746

EID (%)

CPK (U/l)

136.8 ± 74

113.4 ± 67

0.143

0.427

*Student’s t-test, p < 0.05. SD: standard deviation; NTG: post-nitrate; FMD: flow-mediated dilation; EID: endothelium-independent dilation; AST: aspartate transaminase; ALT: alanine transaminase; CPK: creatinine phosphokinase; TG: triglycerides; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.

statistically significant difference. However, a significant difference was observed in hyperaemia diameter in favour of rosuvastatin (Table 4). Percentage changes in non-invasive brachial artery measurements after 12 months of treatment were compared between the two groups. A statistically significant difference was found in percentage change in the rosuvastatin group’s brachial artery post-nitrate diameter (p < 0.05). Non-significant changes were found in the basal diameter and hyperaemia velocity in favour of the rosuvastatin group (p = 0.089 and p = 0.088, respectively) (Table 5).

BA EID (%)

*Student’s t-test, p < 0.05. SD: standard deviation; BA: brachial artery; NTG: post-nitrate; FMD: flowmediated dilation; EID: endothelium-independent dilation.

an effect on baseline lipid values, brachial artery basal diameter and hyperaemia diameter, and FMD and EID measurements. Comparing 12-month non-invasive measurements of atorvastatin and rosuvastatin groups, it was found that the statins had similar effects on endothelial function in the subjects with hyperlipidaemia. Post-nitrate diameter in the rosuvastatin group was significantly improved at the end of the 12-month treatment compared to baseline values. Endothelial dysfunction is one of the early functional markers of atherosclerosis.11,12 Preventative measurements should be taken before clinical manifestation of atherosclerotic events. For this reason, detection of early atherosclerotic changes is of great importance in reducing risk factors. Endothelial dysfunction can be detected via FMD, a Table 4. Rosuvastatin versus atorvastatin in terms of non-invasive test results after 12 months of statin therapy Atorvastatin group (n = 50)

Rosuvastatin group (n = 54)

p-value*

BA basal diameter (mm)

3.87 ± 0.59

4.17 ± 0.54

0.09

Discussion

BA basal velocity (cm/s)

78.82 ± 13.40

72.55 ± 22.3

0.743

This study revealed that both atorvastatin and rosuvastatin had

BA hyperaemia diameter (mm)

4.29 ± 0.60

4.60 ± 0.52

0.006

BA hyperaemia velocity (cm/s)

80.03 ± 16.8

71.12 ± 18.5

0.017

BA NTG diameter (mm)

4.78 ± 0.60

4.75 ± 0.52

0.757

BA NTG velocity (cm/s)

71.2 ± 19.45

61.1 ± 16.32

0.323

Table 2. Post-treatment versus baseline values in the rosuvastatin group 12 months

p-value*

4.0 ± 0.5

4.2 ± 0.5

0.003

Hyperaemia diameter (mm)

4.4 ± 0.5

4.6 ± 0.5

< 0.001

NTG diameter (mm)

4.6 ± 0.5

4.7 ± 0.5

0.687

FMD (%)

9.7 ± 3.4

12.7 ± 3.7

< 0.001

Rosuvastatin

Baseline

Basal diameter (mm)

16.8 ± 5.8

18.2 ± 5.8

TC (mg/dl) (mmol/l)

271.2 ± 35.7 (7.02 ± 0.92)

188.4 ± 44.8 (4.88 ± 1.16)

< 0.001

TG (mg/dl) (mmol/l)

173.5 ± 55.2 (1.96 ± 0.62)

143 ± 54.1 (1.62 ± 0.61)

< 0.001

LDL-C (mg/dl) (mmol/l)

180.5 ± 26.1 (4.67 ± 0.68)

105 ± 39.2 (2.72 ± 1.02)

< 0.001

HDL-C (mg/dl) (mmol/l)

56.8 ± 13.6 (1.47 ± 0.35)

54 ± 11.5 (1.40 ± 0.30)

0.093

AST (U/l)

22.8 ± 6.7

23.3 ± 6.5

0.819

ALT (U/l)

22.8 ± 9.7

23.6 ± 9.3

0.759

116 ± 73.8

0.007

EID (%)

CPK (U/l)

94 ± 31.3

Brachial artery measurements after therapy

BA FMD (%) BA EID (%)

10.42 ± 3.3 16.3 ± 4.83

11.75 ± 3.7 18.2 ± 5.83

0.122 0.115

*Student’s t-test, p < 0.05. SD: standard deviation; BA: brachial artery; NTG: post-nitrate; FMD: flowmediated dilation, EID: endothelium-independent dilation.

0.105

Table 5. Changes in brachial artery measurements after 12 months of treatment in the atorvastatin versus rosuvastatin group Change in brachial artery measurements after therapy

Atorvastatin group (n = 50) Median (25–75%)

Rosuvastatin group (n = 54) Median (25–75%)

p-value*

BA basal diameter (mm)

0.011 (–0.041–0.031) 0.010 (–0.007–0.045)

BA basal velocity (cm/s)

0.001 (–0.119–0.157) –0.043 (–0.206–0.378) 0.120

BA hyperaemia diameter (mm) 0.018 (–0.034–0.060)

0.021 (0.011–0.048)

0.089 0.644

BA hyperaemia velocity (cm/s) 0.056 (–0.087–0.0347) –0.012 (–0.168–0.116) 0.088 BA NTG diameter (mm) BA NTG velocity (cm/s)

0.028 (0.008–0.045)

0.020 (–0.028–0.036)

0.045

–0.004 (–0.167–0.113) –0.020 (0.0113–0.088) 0.982

BA FMD (%)

0.203 (0.008–0.441)

0.193 (0.049–0.0433)

0.958

BA EID (%)

0.110 (–0.115–0.225) 0.037 (–0.460–0.347)

0.827

*Mann–Whitney U-test, p < 0.05. BA: brachial artery; NTG: post-nitrate; FMD: flow-mediated dilation; EID: endothelium-independent dilation.

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non-invasive, easily applicable and repeatable method. Studies have demonstrated that FMD was correlated with endothelial function, making it a good marker of endothelial function.13,14 In the MERCURY I trial, eight-week atorvastatin 20 mg/ day and rosuvastinin 10 mg/day therapies were compared in terms of achieving target LDL-C values of NCEP ATPIII; 80% of the patients in the rosuvastatin group and 74% of those in the atorvastatin group achieved target LDL-C values.15 In the SOLAR trial, either atorvastatin 10 mg/day, rosuvastatin 10 mg/ day or simvastatin 20 mg/day was administered as the initial dose for six weeks in 1 634 high-risk patients. The dose was doubled in patients who failed to achieve target value at the end of six weeks. At the end of 12 weeks, target values were achieved with rosuvastatin in 76% of patients, with atorvastatin in 58%, and with simvastatin in 53%.16 It is known that atorvastatin 20 mg is pharmacokinetically the same as rosuvastatin 10 mg.17 In the present study, LDL cholesterol level decreased with both statins at the end of the 12th month versus baseline, but no statistically significant difference was found between the groups. The effect of different doses of atorvastatin and rosuvastatin on HDL levels varies according to clinical setting and patient characteristics. The size of the increase is generally more signifcant with lower baseline values. Additionally, the effect is moderate compared to niacin or fibrates. The elevation of HDL level ranges from five to 13%.18 In our study, the amount of elevation was not significant, which could have been due to low-dose statin usage or the relatively higher baseline HDL levels of the subjects. Cardiovascular risk factors such as hyperlipidaemia contribute to endothelial dysfunction, which is the first step in atherogenesis. Although the concurrent presence of hyperlipidaemia and endothelial dysfunction is frequently encountered, the mechanism is unclear. However, oxidised LDL cholesterol is thought to cause endothelial injury. Many studies have demonstrated that endothelium-dependent (flowmediated) dilation is enhanced with increased duration of the endothelium’s exposure to oxidised LDL.19-21 Kawano et al. demonstrated impaired flow-mediated dilation in an experimental model of acute hyperglycaemia in healthy adults on a fatty diet.22 Harrison et al. reported improvement in endothelial function due to decreased cholesterol in the diet.23 In studies on statins, the time for endothelial function to improve ranged from hours to months. In earlier studies, improvement in endothelial function with increased NO levels due to statin therapy was observed at the end of a six-month treatment period.24,25 On the other hand, Marchesi et al. observed remarkable improvement in endothelial function after a two-week atorvastatin therapy in postmenopausal women with hyperlipidaemia.26 In the present study, a 22.3 and 30.9% (p = 0.122) increase in FMD was observed in both atorvastatin and rosuvastatin groups, respectively, after 12 months of statin therapy. Improvement in FMD showed no correlation with post-treatment LDL levels. We found however that percentage ΔLDL was well correlated with ΔFMD and ΔEID, which may suggest that statins have a pleiotropic effect independent of their cholesterol-lowering effects. Similarly, ΔLDL was also found to be well correlated with ΔFMD and ΔEID values. In other words, endothelial function was statistically significantly improved at the end of 12-month statin therapy, in parallel with ΔLDL, among patients with hyperlipidaemia.

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Although endothelium-independent dilation increased in both groups, the increase was not statistically significantly different. Increased brachial artery basal diameter after 12 months of treatment, which was more pronounced in the rosuvastatin group, reached a value close to the diameter obtained for baseline FMD, due probably to increased NO levels. More prominent increases in FMD and basal diameter in the rosuvastatin group suggest that the NO-secreting effect from the endothelium induced by rosuvastatin was more significant than that by atorvastatin. There are some limitations of the present study, such as limited patient numbers, as well as not measuring blood NO and asymmetric di-methyl arginine levels due to technical issues. In addition, the technique for measuring FMD depends on the experience of the person carrying it out.

Conclusion In this study, both atorvastatin 20 mg/day and rosuvastatin 10 mg/day therapies given to hyperlipidaemic patients for one year provided significant benefits on endothelial function. The data from non-invasive evaluations found that although the favourable effects of rosuvastatin on the endothelium may have been relatively more prominent compared to those of atorvastatin, there was no statistically significant difference.

References 1.

Forte L, Cimmino G, Loffredo F, De Palma R, Abbate G, Calabrò P, et al. C-reactive protein is released in the coronary circulation and causes endothelial dysfunction in patients with acute coronary syndromes. Int J Cardiol 2011; 152(1): 7–12.

Marzilli M. Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs 2010; 10(Suppl 1): 3–9.

Hermida N, Balligand JL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal 2014; 20(8): 1216–1237.

Waters DD. Exploring new indications for statins beyond atherosclerosis: Successes and setbacks. J Cardiol 2010; 55(2): 155–162

Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999; 99(25): 3227–3233.

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360(9326): 7–22.

The HOPE (Heart Outcomes Prevention Evaluation) study: the design of a large, simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. The HOPE study investigators. Can J Cardiol 1996; 12(2): 127–137.

Hecker M, Bara AT, Busse R. Relaxation of isolated coronary arteries by angiotensin-converting enzyme inhibitors: role of endotheliumderived kinins. J Vasc Res 1993; 30(5): 257–262.

Xu Y, Arora RC, Hiebert BM, Lerner B, Szwajcer A, McDonald K, et al. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging 2014; 15: 736–746.

10. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J 2003; 145(6):

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943–951. 11. Gori T, Muxel S, Damaske A, Radmacher MC, Fasola F, Schaefer S, et al. Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease. Eur Heart J 2012; 33(3): 363–371.

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tion inhibitory factor in hypertension-hyperlipidemia patients correlates with impaired endothelial function. Medicine (Baltimore) 2016; 95(43): e5207. 20. Sawada T, Tsubata H, Hashimoto N, Takabe M, Miyata T, Aoki K, et al. Effects of 6-month eicosapentaenoic acid treatment on postprandial

12. Manganaro A, Ciracì L, Andrè L, Trio O, Manganaro R, Saporito F,

hyperglycemia, hyperlipidemia, insulin secretion ability, and concomi-

et al. Endothelial dysfunction in patients with coronary artery disease:

tant endothelial dysfunction among newly-diagnosed impaired glucose

insights from a flow-mediated dilation study. Clin Appl Thromb Hemost

metabolism patients with coronary artery disease. An open label, single

2014; 20(6): 583–588.

blinded, prospective randomized controlled trial. Cardiovasc Diabetol

13. Liu Z, Zhao Y, Lu F, Zhang H, Diao Y. Day-by-day variability in self-

2016; 15(1): 121.

measured blood pressure at home: effects on carotid artery atheroscle-

21. Higashi Y, Sanada M, Sasaki S, Nakagawa K, Goto C, Matsuura H,

rosis, brachial flow-mediated dilation, and endothelin-1 in normotensive

et al. Effect of estrogen replacement therapy on endothelial function

and mild-moderate hypertensive individuals. Blood Press Monit 2013;

in peripheral resistance arteries in normotensive and hypertensive post-

18: 316–325.

menopausal women. Hypertension 2001; 37(2 Part 2): 651–657.

14. Beyer AM, Zinkevich N, Miller B, Liu Y, Wittenburg AL, Mitchell M,

22. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto

et al. Transition in the mechanism of flow-mediated dilation with aging

T, et al. Hyperglycemia rapidly suppresses flow-mediated endothelium-

and development of coronary artery disease. Basic Res Cardiol 2017;

dependent vasodilation of brachial artery. J Am Coll Cardiol 1999;

112(1): 5.

34(1): 146–154.

15. Schuster H, Barter PJ, Stender S, Cheung RC, Bonnet J, Morrell

23. Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration

JM, et al. Effects of switching statins on achievement of lipid goals:

of endothelium-dependent relaxation by dietary treatment of athero-

Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J 2004; 147(4): 705–713.

sclerosis. J Clin Invest 1987; 80(6): 1808–1811. 24. John S, Schlaich M, Langenfeld M, Weihprecht H, Schmitz G, Weidinger

16. Insull W Jr, Ghali JK, Hassman DR, Y As JW, Gandhi SK, Miller E.

G, et al. Increased bioavailability of nitric oxide after lipid-lowering

Achieving low-density lipoprotein cholesterol goals in high-risk patients

therapy in hypercholesterolemic patients: a randomized, placebo-

in managed care: comparison of rosuvastatin, atorvastatin, and simvastatin in the SOLAR trial. Mayo Clin Proc 2007; 82(5): 543–550.

controlled, double-blind study. Circulation 1998; 98(3): 211–216. 25. Baspınar O, Bayram F, Korkmaz S, Aksu M, Kocer D, Dizdar OS, et al.

17. Meor Anuar Shuhaili MFR, Samsudin IN, Stanslas J, Hasan S,

The effects of statin treatment on adrenal and sexual function and nitric

Thambiah SC. Effects of different types of statins on lipid profile: a

oxide levels in hypercholesterolemic male patients treated with a statin.

perspective on Asians. Int J Endocrinol Metab 2017; 15(2): e43319.

J Clin Lipidol 2016; 10(6): 1452–1461.

18. McTaggart F, Jones P. Effects of statins on high-density lipoproteins: a

26. Marchesi S, Lupattelli G, Siepi D, Schillaci G, Vaudo G, Roscini AR,

potential contribution to cardiovascular benefit. Cardiovasc Drugs Ther

et al. Short-term atorvastatin treatment improves endothelial function

2008; 22(4): 321–338.

in hypercholesterolemic women. J Cardiovasc Pharmacol 2000; 36(5):

19. Zhou B, Ren C, Zu L, Zheng L, Guo L, Gao W. Elevated plasma migra-

617–621.

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Percutaneous transmitral balloon commissurotomy using a single balloon with arteriovenous loop stabilisation: an alternative when there is no Inoue balloon Endale Tefera, Mohamed Leye, Patrick Garceau, Denis Bouchard, Joaquim Miró

Abstract Background: The Inoue balloon technique is the standard technique for mitral valve balloon commissurotomy at this stage. However, the hardware for this technique is expensive and may not always be available in resource-limited settings. Objectives: This article reports our experience with percutaneous transmitral balloon commissurotomy using a single balloon (Nucleus) with arteriovenous loop stabilisation. Methods: Eleven young patients, aged 12–26 years and weighing 23–48 kg, underwent transmitral balloon commissurotomy using the described technique at our centre from April to May 2014. Results: Mean fluoroscopy time was 22.6 ± 6.4 min (18.5– 30.0). Mean transmitral gradient decreased from 24.1 ± 5.9 (16–35) to 6.6 ± 3.8 (3–14) mmHg, as measured on transoesophageal echocardiography. Mean mitral valve area increased from 0.69 ± 0.13 cm2 (range 0.5–0.9) before dilation to 1.44 ± 0.25 cm2 (1.1–1.9) after dilation (p < 0.001). Mean estimated pulmonary artery systolic pressure decreased from 110.0 ± 35 mmHg (75–170) before dilation to 28.0 ± 14.4 mmHg (range 10–60) after dilation. Conclusion: Our modified Nucleus balloon technique for mitral valve dilation in young patients with mitral stenosis is effective and safe. The technique differs from other over-thewire techniques in that it avoids placing stiff wire in the left ventricle. It also offers better balloon stability and control owing to the arteriovenous loop. This technique may be easier for use by paediatric interventionists who might not be familiar with the Inoue balloon technique. Keywords: arteriovenous loop stabilisation, balloon mitral commissurotomy, modified Nucleus balloon technique, mitral valvotomy in resource-limited settings

Department of Paediatrics and Child Health, Cardiology Division, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia Endale Tefera, MD, endalet2008@gmail.com

Division of Paediatric Cardiology, CHU Sainte-Justine, Université de Montréal, QC, Canada Mohamed Leye, MD Joaquim Miró, MD

Department of Medicine, Montréal Heart Institute, Université de Montréal, QC, Canada Patrick Garceau, MD

Division of Cardiovascular Surgery, Montreal Institute of Cardiology, Université de Montréal, QC, Canada Denis Bouchard, MD

Submitted 9/12/16, accepted 29/1/18 Published online 19/2/18 Cardiovasc J Afr 2018; 29: 167–171

www.cvja.co.za

DOI: 10.5830/CVJA-2018-010

Although it has become exceedingly rare in the developed world, rheumatic heart disease continues to be a serious health problem in developing nations.1 Unlike other valvular lesions, which might be attributed to multiple aetiologies, mitral stenosis alone or in combination with other valvular lesions is the only lesion almost exclusively attributed to rheumatic heart disease.2,3 Studies from developing countries have shown that mitral stenosis progresses rapidly and may lead to serious disability early in life.4-7 Commissural fusion, leaflet thickening and alteration of the subvalvular apparatus are the dominant mechanisms causing clinically important mitral stenosis of rheumatic origin.8 As mitral stenosis is a mechanical obstruction to forward flow, the only definitive treatment is mechanical relief of the obstruction. Such invasive treatments include closed mitral commissurotomy, open mitral valve repair, mitral valve replacement, or percutaneous transmitral balloon commissurotomy.9-11 Percutaneous transmitral commissurotomy is associated with significant changes in mitral valve morphology in terms of splitting of the fused mitral commissures, increased mitral valve area, improved leaflet excursion and splitting of the sub-valvular structures.12 A variety of hardware and techniques has been described. These include the Inoue balloon technique, single-balloon over-the-wire techniques, double-balloon technique, multi-track system, metallic valvotome and other similar techniques.13-17 Currently, the Inoue balloon is the standard technique. However, the hardware for this technique is expensive and may not always be available in resource-limited settings. In this article, we describe a technique for balloon mitral commissurotomy using a single Nucleus balloon, with arteriovenous loop stabilisation.

Methods This technique is a modification of the regular single-balloon, over-the-wire technique described previously,18 and adapted by subsequent workers.19 It was modified according to the available materials at our centre during that period, and to adapt to the relatively small size of our patients. A total of 11 patients, all teenagers or young adults, underwent transmitral balloon commissurotomy using the described technique in our centre from April to May 2014. Eight patients (72.7%) were female. In all patients, diagnosis of mitral stenosis was made on the first presentation to medical attention.

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Mean mitral valve area, measured by planimetry on transoesophageal echocardiography (TEE), was 0.69 ± 0.13 cm2 (range 0.5–0.9). Mean transmitral diastolic gradient was 24.1 ± 5.9 mmHg (range 16–35) and mean estimated pulmonary artery systolic pressure was 110.0 ± 35 mmHg (75–170). Other baseline characteristics of the patients are shown in Table 1. Under general anaesthesia, right femoral vein access was taken with a 7F short sheath. A 0.025-inch regular wire was advanced up the superior caval vein and a 7F long sheath was advanced to the left innominate vein. The wire was withdrawn and a Brockenbrough needle (Medtronic Inc, Minneapolis, MN, USA) was introduced. After sliding the system down to the oval fossa, transseptal puncture was performed under TEE and single-plane fluoroscopy guidance. The needle was withdrawn into the dilator and the sheath–dilator assembly was advanced into the left atrium. Once in the left atrium, the dilator was removed. A 6F 110-cm-long wedge balloon catheter (Arrow Int, Inc, Bernville Rd, Reading PA, USA) was advanced into the left atrium. The pre-formed stiff end of a regular wire (Fig. 1) was used as a stylet to guide the inflated wedge balloon across the mitral valve. Once the balloon was at the apex of the left ventricle, its position at the centre of the mitral apparatus (and not through the chordae) was confirmed by TEE. The wedge balloon catheter was then advanced up the

septal curve

Mitral valve curve

Fig. 1. P re-shaped stiff end of a regular guide wire with septal and mitral valve cuves for guiding the wedge balloon across the mitral valve A

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Table 1. Baseline characteristics of patients treated for severe rheumatic mitral stenosis using a modified Nucleus balloon technique Mean ± SD (range)

Variables

14.3 ± 4.2 (12–26)

Age (years) Weight (kg)

30.3 ± 7.4 (23–48)

Height (cm)

146.6 ± 9.9 (133–163)

Spontaneous echo contrast in the left atrium (number of patients)

NYHA functional class Class I

–

Class II

Class III

Class IV

–

ascending aorta, using the pre-shaped end of the stiff wire, if necessary. A 0.035-in × 260-cm Terumo wire (Terumo Medical Corporation, Cottontail Lane, Somerset, New Jersey, USA) was advanced through the wedge catheter and the wire was snared to the descending aorta from the arterial side to establish an arteriovenous loop (Fig. 2A). Then the inflated wedge catheter was again withdrawn into the left ventricle and pushed and pulled gently through the mitral valve apparatus to ascertain that there was no entrapment within the mitral valve chordae. The wedge balloon and the long sheath were then removed. A 12F to 14F short sheath was introduced into the femoral vein. The septal puncture was dilated with a 6- or 8-mm balloon (Fig. 2A). Finally, a Nucleus balloon (NuMED Canada Inc, Second Street West Cornwall, ON, Canada) of appropriate size, according to the patient’s size and TEE measurement of the mitral annulus, was introduced and placed across the mitral valve. We did not encounter any difficulty with passing the balloon through the septal puncture in any of our patients. A 20-cm3 syringe with 25% contrast and 75% saline combination was attached using a three-way stopcock. An inflation device filled with a similar combination of contrast and saline was attached. The desired inflation pressure was decided based on the table provided with the balloon (Table 2), in order to achieve the exact target diameter. Both ends of the arteriovenous loop were pulled to stabilise the balloon in a good position and the balloon was inflated using fluoroscopic and TEE guidance. C

A 6-mm balloon across septal puncture

Fig. 2. A . Establishment of arteriovenous loop and dilation of the septal puncture. B. Nucleus balloon inflated across a severely stenotic mitral valve. C. Full inflation of the Nucleus balloon across the mitral valve showing near-disappearance of the waist.

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Maximum precautions were taken not to inflate the balloon in the left ventricular outflow tract. Inflation was first with the syringe and then with the inflation device, since the total volume frequently exceeded the capacity of the inflation device. A waist formed and then disappeared (Fig. 2B, C). Inflations at increased pressure were repeated if needed, with control for degree of mitral regurgitation, mean transmitral diastolic gradient and post-dilation mitral valve area on TEE.

Results Mean fluoroscopy time was 22.6 ± 6.4 min (18.5–30.0). Mean transmitral gradient decreased from 24.1 ± 5.9 (16–35) to 6.6 ± 3.8 (3–14) mmHg, as measured on TEE. Mean mitral valve area increased from 0.69 ± 0.13 cm2 (range 0.5–0.9) before dilation to 1.44 ± 0.25 cm2 (range 1.1–1.9) after dilation (p < .001). Mean estimated pulmonary artery systolic pressure decreased from 110.0 ± 35 mmHg (range 75–170) before dilation to 28.0 ± 14.4 mmHg (range 10–60) immediately after dilation on TEE. Outcome variables after balloon dilation are shown in Table 3. One patient developed severe mitral regurgitation due to a tear on the anterior mitral valve leaflet and she underwent semiurgent valve replacement surgery. Another patient developed moderate mitral regurgitation, which was well tolerated. No complications were noted in the other patients either immediately after the procedure or on subsequent follow up. At the follow up, up to 20 months later, all the patients were in NYHA functional class I–II. Mean mitral valve area remained stable at 1.43 ± 0.32 cm2 (range 1.1–1.9). Transmitral mean diastolic pressure gradient was 5.4 ± 2.7 mmHg (range 2–7). Estimated mean of the systolic pulmonary artery pressure was 40.1 ± 8.4 mmHg (range 25–45). Mitral regurgitation was mild in three patients while it was trivial or none in the rest. Tricuspid regurgitation was graded as mild in four patients and minimal in the rest. All the patients were on monthly benzathine penicillin prophylaxis against recurrence of rheumatic fever. None was on diuretics or any other cardiac medications or has needed further intervention.

Discussion

Table 2. Nominal balloon diameter versus inflation pressures and corresponding effective balloon diameters obtained

16.7

19.0

After dilation mean ± SD (range)

Mitral valve area (cm2) by planimetry

0.69 ± 0.13 (0.5–0.9)

1.44 ± 0.25 (1.1–1.9)

< 0.001

Mean transmitral gradient (mmHg)

24.1 ± 5.9 (16–35)

6.6 ± 3.8 (3–14)

< 0.001

Average estimated pulmonary artery systolic pressure (mmHg)

110.0 ± 35 (75–170)

28.0 ± 14.4 (10–60)

< 0.001

Variables

Mitral regurgitation Severe

–

Moderate

–

Mild

Trivial

None

Severe

–

21.8

24.4

25.9

Moderate

–

27.4

29.7

Mild

Trivial

None

–

18.0 mm 20.0 mm 22.0 mm 25.0 mm 28.0 mm 30.0 mm 15.5

Before dilation mean ± SD (range)

Tricuspid regurgitation

Balloon diameters Applied pressure

Our technique is actually a modification of older singleballoon techniques used for the treatment of mitral stenosis.20,21 Compared to other single-balloon techniques, the Nucleus balloon offers the advantage of asymmetric inflation of both extremities before the central part of the balloon, thus ensuring some degree of stabilisation over the stenotic orifice. Our technique is significantly different from that in which the Nucleus balloon has been used, in that it avoids placing a stiff wire in the left ventricle, decreasing the risk of ventricular arrhythmia, or hypotension from mitral interference. The use of a very floppy Terumo wire in our technique preserves mitral valve function until the arteriovenous loop is pulled for some seconds during balloon inflation. Furthermore, the risk of apical left ventricular rupture associated with the double balloon and other similar techniques is less likely to be a problem with our technique. Establishment of an arteriovenous loop offers better balloon stability and can potentially be used with any other type of balloon available, especially in resource-limited settings. We felt that stabilising the balloon in that manner would be a particular advantage in our relatively young and small population of patients. Indeed the procedure was adopted in our first patient, after initial inflation of the Nucleus balloon over a stiff wire placed at the left ventricular apex proved unsuccessful, the balloon being pushed back to the left atrium. The concern that applying tension on both ends of the Terumo wire may result in aortic injury may be overcome by placing a catheter over the wire, although we have not done this in the patients treated thus far. We used small balloons to dilate the septal puncture. Although there may be a theoretical risk of creating an iatrogenic atrial septal defect through the hole, this did not occur in any of our patients. In initial publications describing single-balloon over-thewire procedures,18 Lock et al. positioned the exchange wire in the descending aorta, thus increasing support and stability for the balloon. The addition of the arteriovenous loop increases stability by pulling both ends of the wire, while using a softer Table 3. Outcome variables in patients treated for severe rheumatic mitral stenosis using the modified Nucleus balloon technique

Currently the Inoue balloon technique is the standard technique for mitral valve dilation for treatment of mitral stenosis due to rheumatic heart disease or calcific mitral stenosis. The technique we describe here does not compare to the Inoue balloon technique in terms of ease and safety of operation. We do not imply that this technique is an alternative to the Inoue balloon under circumstances where the Inoue balloon is available and the operator is well versed with the technique. There is no doubt that the Inoue balloon is superior, if it is available and the operator is experienced with it.

1 atm

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2 atm

16.1

17.3

19.6

22.9

3 atm

16.9

17.3

19.6

22.9

4 atm

17.9

19.9

p-value

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guide wire. Although techniques using arteriovenous loops have been described previously,19,22 they never gained widespread acceptance, either because the wire was snared inside the left ventricle,19 or because the balloon was advanced through the arterial end of the loop.22 With the current catheters, guide wires and snares available, our technique is definitely much more straightforward than the originally proposed variants. This technique may be considered a good option in resourcelimited settings where the Inoue balloon is not always an available option. Compared with the Inoue balloon, the total cost of the Nucleus balloon and its associated hardware is significantly less. Besides, the Nucleus balloon is easier to clean and resterilise as it has a single layer, compared to cleaning the Inoue balloon. It can be reused multiple times, offering a significant cost advantage in resource-limited settings such as ours. This technique may also be easier for use in children by paediatric interventionists who may not be familiar with the Inoue balloon technique but frequently use arteriovenous loops for other interventions. One of our patients developed a tear in the anterior mitral valve leaflet and underwent valve replacement surgery. This complication may not be associated specifically with the described technique and could potentially occur with the Inoue balloon and other techniques. In fact, when inspected by the surgeon, the valve appeared too dysplastic to attempt repair. However, our technique carries a potential complication of inflating the balloon partially in the left ventricular outflow tract, thus avulsing the sub-valvar mitral apparatus. Great care has to be taken to not fully inflate the balloon if it seems to engage partially in the outflow tract during gentle initial inflation. Although our patient population was small, the outcomes achieved in terms of increase in mitral valve area and reduction of mean transmitral diastolic gradient were comparable to those obtained with the Inoue balloon and other techniques.21,23 Estimated pulmonary artery pressure also dropped significantly. These outcomes were maintained on follow up at close to two years. Except for one patient who had an anterior leaflet tear leading to severe mitral regurgitation, the degree of mitral regurgitation was mild or less in all cases at the last follow up. A limitation is that the number of patients in our study was relatively small. Furthermore, we did not compare our technique head to head with other techniques; it was based rather on a literature review.

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Thakur JS, Negi PC, Ahluwalia SK, Vaidya NK. Epidemiological survey of rheumatic heart disease among school children in the Shimla Hills of northern India: prevalence and risk factors. J Epidemiol Commun Health 1996; 50: 62–67.

Padamavati S. Rheumatic fever and rheumatic heart disease in developing countries. Bull World Health Org 1978; 56: 543–550.

Rick AR, Gregory JE. Experimental evidence that lesions with basic characteristics of rheumatic carditis can result from anaphylactic hypersensitivity. Bull Johns Hopkins Hosp 1943; 73: 239.

Al-Bahrani IR, Thamer MA, Al-Omeri MM, Al-Namaan YD. Rheumatic heart disease in the young in Iraq. Br Heart J 1966; 28: 824.

Borman JB, Stern S, Shapira T, Milvidsky H, Braun K. Mitral valvotomy in children. Am Heart J 1961; 61: 763.

Shrivastava S, Tandon R. Severity of rheumatic mitral stenosis in children. Int J Cardiol 1991; 30: 163–167.

Tadele H, Mekonnen W, Tefera E. Rheumatic mitral stenosis in children: more accelerated course in sub-Saharan patients. BMC Cardiovasc Disord 2013; 13: 95.

Horstkotte D, Niehues R, Strauer BE. Pathomorphological aspects, aetiology and natural history of acquired mitral stenosis. Eur Heart J 1991; 12: 55–60.

Cardoso LF, Grinberg M, Rati MA, et al. Comparison between percutaneous balloon valvuloplasty and open commissurotomy for mitral stenosis: a prospective and randomized study. Cardiology 2002; 98: 186–190.

10. Ben Farhat M, Ayari M, Maatouk F, et al. Percutaneous balloon versus surgical closed and open mitral commissurotomy: seven-year follow-up results of a randomized trial. Circulation 1998; 97: 245–250. 11. Reyes VP, Raju BS, Wynne J, et al. Percutaneous balloon valvuloplasty compared with open surgical commissurotomy for mitral stenosis N Engl J Med 1994; 331: 961–967. 12. Hasan-Ali H, Shams-Eddin H, Abd-Elsayed AA, Maghraby MH. Echocardiographic assessment of mitral valve morphology after percutaneous transvenous mitral commissurotomy (PTMC). Cardiovasc Ultasound 2007; 5: 48. 13. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984; 87: 394–402. 14. Ribeiro PA, al Zaibag M, Rajendran V, et al. Mechanism of mitral valve area increase by in vitro single and double balloon mitral valvotomy. Am J Cardiol 1988; 62: 264–269. 15. Reid CL, Otto CM, Davis KB, Labovitz A, Kisslo KB, McKay CR.

Conclusion The Inoue balloon is not usually available in our centre as we get most of our consumables on donation. Our modified Nucleus balloon technique for mitral valve dilation in patients with mitral stenosis is effective and safe. The technique differs from other over-the-wire balloon techniques described in the past in that it avoids placing a stiff wire in the left ventricle, avoiding the risk of ventricular arrhythmia. It also offers better balloon stability and control owing to the arteriovenous loop. This technique can potentially be used with any other balloon available and may be easier for use by paediatric interventionists who might not be familiar with the Inoue balloon technique. TEE guidance is very useful to avoid the potential risk of inflating the balloon in the left ventricular outflow tract or through the sub-valvar apparatus. The Nucleus balloon can also be resterilised and used multiple times.

Influence of mitral valve morphology on mitral balloon commissurotomy: immediate and six-month results from the NHLBI Balloon Valvuloplasty Registry. Am Heart J 1992; 124: 657–665. 16. Bonhoeffer P, Esteves C, Casal U, et al. Percutaneous mitral valve dilatation with the multi-track system. Catheter Cardiovasc Interv 1999; 48: 173–183. 17. Cribier A, Eltchaninoff H, Koning R, et al. Percutaneous mechanical mitral commissurotomy with a newly designed metallic valvulotome: immediate results of the initial experience in 153 patients. Circulation 1999; 99: 793–799. 18. Lock JE, Khalilullah M, Shrivastava S, Bahl V, Keane JF. Percutaneous catheter commissurotomy in rheumatic mitral stenosis. N Engl J Med 1985; 313: 1515–1518. 19. Commeau PGG, Huret B, Foucault JP, Potier JC, Commeau P, Grollier G, et al. Percutaneous mitral valvotomy in rheumatic mitral stenosis: a new approach. Br Heart J 1987; 58: 142–147. 20. Uruchurtu Chavarin E, Sanchez A, Solis H, et al. Immediate results

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in percutaneous mitral valvoplasty with the nucleus balloon. Arch Inst Cardiol Mex 2000; 70: 486–491.

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transarterial balloon valvuloplasty for mitral valve stenosis. Am J Cardiol 1986; 57: 1101–1104.

21. Angeles-Valdes J, Uruchurtu Chavarin E, Gomez Cruz A. Mitral valvo-

23. Fawzy ME, Hassan W, Stefadouros M, Moursi M, El Shaer F,

plasty: The double balloon technique compared with ‘Nucleus’ single

Chaudhary MA. Prevalence and fate of severe pulmonary hypertension

balloon technique (abstract). Arch Cardiol Mex 2002; 72: 290–296.

in 559 consecutive patients with severe rheumatic mitral stenosis under-

22. Babic UU, Pejcic P, Djurisic Z, Vucinic M, Grujicic SM. Percutaneous

going mitral balloon valvotomy. J Heart Valve Dis 2004; 13: 942–948.

Large nuclear cardiology laboratory slashes radiation dose by 60% in eight years A large nuclear cardiology laboratory has slashed its average radiation dose by 60% in eight years, according to new research presented recentlyat the International Conference on Nuclear Cardiology (ICNC) 2017 and published in J Am Coll Cardiol: Cardiovasc Imaging. The study in over 18 000 patients shows dose reductions were achieved despite a large number of obese patients. ‘There has been concern among the medical community and the public that the radiation from medical diagnostic tests could increase the risk of cancer, said Professor Randall Thompson, a cardiologist at the Mid-America Heart Institute, Kansas City, Missouri, US. He continued: ‘Although the risk of harm from an individual nuclear cardiology test is very low – even very conservative estimates suggest only one in 1 000 extra patients would develop cancer 20 years later – the cumulative dose from multiple medical diagnostic tests may be a concern.’ Medical societies advocate getting radiation doses as low as is reasonably achievable. There are ways to do this but surveys show that adoption of new technologies, which cost money, and new testing algorithms, which take more physician time, has been slow. This study assessed the impact on radiation dose of modifying protocols and introducing new hardware (cameras) and post-processing software in a large nuclear cardiology laboratory network in Kansas City. The study included the 18 162 single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) studies performed at all four of the Saint Luke’s Mid-America Heart Institute nuclear cardiology laboratories from 1 January 2009 to 30 September 2016. SPECT MPI shows how well blood flows through the muscle of the heart and is primarily performed to diagnose the cause of chest pain or to help manage patients with known coronary artery disease. Protocols were modified by performing stress-only tests where possible, which saves the radiotracer dose from the rest scan. Stress and rest scans are still required in some patients since shadowing from body parts can look like a lack of blood flow and two scans can clarify the findings. Technetium tracers are now used instead of thallium 100%

of the time at one-third of the radiation dose. Small field-of-view cameras, which have advanced post processing, and a new generation of camera systems, which are more sensitive and need less radiotracer injected into the body, have both been introduced. These camera systems are equipped with advanced processing which enhances the nuclear pictures and need less radiation or shorter image acquisition times. Professor Thompson’s laboratory focused primarily on reducing the radiation dose. The average radiation dose fell from 17.9 mSv in 2009 to 7.2 mSv in 2016 and the median dose (the 50th percentile) dropped from 10.2 to 2.5 mSv. Professor Thompson said: ‘There was a dramatic lowering of the radiation dose with all of these concerted efforts. The average dose fell by 60% and the median dropped by 75%.’ ‘The average dose had fallen to 5.4 mSv in 2012 but crept up as we’ve had more obese patients referred in whom we have to use the higher dose protocols,’ he added. ‘But more than half of patients now are tested with a low-dose, stressonly test using the new technology, which is why the median dose of radiation has fallen so dramatically.’ The average background dose for people living in Europe and North America from radon underground and cosmic background sources is about 3 mSv a year. Medical societies consider higher- and lower-dose tests to be above 10 mSv and below 3 mSv, respectively. In 2010 the American Society of Nuclear Cardiology set a target of 9 mSv or less for the majority of tests. Professor Thompson said: ‘The majority of studies were in the high-dose range back in 2009 and now most tests have a radiation dose that is about a third of the target. This is despite being referred a larger number of obese patients. In the last 2.5 years, 17% of patients have needed the large fieldof-view camera as their average body mass index was 46 kg/ m2 and they were simply too big for the small cameras.’ He concluded: ‘By adopting contemporary protocols and technologies it is feasible to substantially lower radiation doses in nuclear cardiology in very large numbers of patients in real world clinical practice.’ Source: European Society of Cardiology Press Office

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Obesity masks the relationship between dietary salt intake and blood pressure in people of African ancestry: the impact of obesity on the relationship between sodium and blood pressure Muzi Maseko, Mercy Mashao, Abdulraheem Bawa-Allah, Edgar Phukubje, Bongubuhle Mlambo, Thamsanqa Nyundu

Abstract Previous studies conducted to investigate the relationship between sodium intake and blood pressure in our African population have yielded contradictory results. With the high prevalence of obesity in this population, it is possible that these contradictory findings are due to the masking effects of obesity on this relationship. We measured 24-hour ambulatory blood pressure and 24-hour urine excretion on 547 South Africans of African ancestry. A multivariate regression analysis revealed no independent relationship between 24-hour sodium excretion and blood pressure in the total population sample, but when participants were stratified according to body mass index (BMI) status, there was a significant association between 24-hour sodium excretion and blood pressure in the normal-BMI participants but not in the overweight/obese participants. We concluded that dietary salt intake, indexed by 24-hour urinary sodium excretion, was associated with increased ambulatory blood pressure but this relationship was masked because of a high proportion of overweight/obese individuals in this population. Keywords: dietary salt intake, obesity, hypertension, salt retention, body mass index Submitted 24/3/17, accepted 29/1/18 Published online 12/2/18 Cardiovasc J Afr 2018; 29: 172â&#x20AC;&#x201C;176

www.cvja.co.za

DOI: 10.5830/CVJA-2018-011

Cardiovascular diseases (CVD) are presently a leading cause of death in South Africa and sub-Saharan Africa (SSA).1,2 Hypertension remains the commonest risk factor for CVD.3,4 A number of studies have associated an increased dietary sodium (Na+) intake and obesity with hypertension and target-organ damage.5

School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Muzi Maseko, PhD, muzi.maseko@wits.ac.za Mercy Mashao, MSc Abdulraheem Bawa-Allah, MSc Edgar Phukubje, BSc Bongubuhle Mlambo, BSc Thamsanqa Nyundu, MSc

In an effort to lessen the worldwide prevalence of hypertension, global strategies and population-based intervention studies, including Dietary Approaches to Stop Hypertension (DASH), have focused particularly on reduction of Na+ intake as a means of lowering blood pressure (BP) in a population.6-8 This could be of benefit to people of African descent because a number of studies have shown that the incidence of hypertension is increasing in black communities.9-11 However there is a gap in our knowledge on the role of dietary sodium on blood pressure in this community. Even though previous studies conducted in this population have revealed a high prevalence of hypertension,12,13 the relationship between dietary salt intake and BP is still not well understood because studies have revealed contradictory findings on this relationship.14,15 One study showed a modest association,16 while others showed no association.17,8 In one study, the investigators showed an association between BP and the sodium-to-potassium ratio, which is also an index of dietary sodium intake, but they could not show any direct relationship between BP and dietary sodium.18 The contradictory findings of these studies are indicative of the complex relationship between BP and dietary sodium. In this population, the complexity of this relationship could be compounded by the high prevalence of obesity,19 as body mass index (BMI) has been shown to have a direct association with BP.20-23 A possibility exists that obesity masks the relationship between BP and dietary sodium intake in this population. The biggest contributor to the masking effect could be the high proportion of overweight or obese individuals, especially women. Therefore, in this study, in order to investigate whether the relationship between dietary salt intake (indexed by 24-hour urinary sodium excretion) and blood pressure is masked by obesity, we stratified participants according to BMI status.

Methods Informed consent was obtained from the participants, and the principles of the Declaration of Helsinki were adhered to. The study was approved by the University of the Witwatersrand Committee for Research in Human Subjects (approval number: M15-06-44) and forms part of the South African Hypertension and Diet Study (SAHDS), which is part of the ongoing African Project on Genes in Hypertension. The study design has been briefly described in other publications.24,25 We randomly recruited 1 219 South Africans of African ancestry from a metropolitan area of Johannesburg (Soweto). Of these participants, 547 (346 women and 201 men) were selected

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because they had complete 24-hour ambulatory BP (ABP) and 24-hour urine samples. The minimum age for the study participants was 18 years, and there was no upper age limit. A standardised questionnaire was administered to each participant to obtain demographic data, medical history such as the presence of hypertension, and use of medication. Height and weight measurements were recorded with the participants wearing indoor clothes with no shoes. BMI was calculated as weight in kilograms divided by the square of height in metres. Twenty-four-hour ambulatory BP monitoring was performed using oscillometric monitors (Spacelabs, model 90207). Standard cuffs with an inflatable bladder suitable for the participant’s arm circumference were used. The monitors were programmed to measure BP at 15-minute intervals from 06:00 to 22:00 and then at 30-minute intervals from 22:00 to 06:00. Participants kept a diary card for the duration of the recordings to note the time of going to bed in the evening and time of waking up in the morning. These times were used to determine the wake and sleeping periods. Participants also recorded the time when they took medication, smoked, drank caffeine or alcohol, depending on which was applicable to each participant. On completion of the recordings, data were transferred to a computer for analysis. Ambulatory blood pressure data were expressed as 24-hour average systolic and diastolic BP. Timed urine samples were collected over a 24-hour period. Each participant was issued with a urine collection bottle and the bottles were then collected from each participant after 24 hours. Twenty-four-hour urine Na+ excretion rate was calculated from the product of urine volume and urine electrolyte concentration. Creatinine clearance was determined from the product of urine volume and urine creatinine concentrations divided by plasma creatinine concentration. The quality of urine samples was determined by constructing regression relations between 24-hour urine creatinine and body weight, and 24-hour urine volume and age in gender-specific groups. Based upon the 95% confidence intervals for each group, a 24-hour urine sample was considered acceptable if 24-hour urine creatinine (mmol) was > 3.5 and < 35 for males and > 3.5 and < 30 for females. Samples with urine volumes < 500 ml/day were also assumed to be incomplete urine collections. These are standard approaches and have been published on numerous occasions by other groups.

Statistical analysis For statistical analysis the SAS software, version 9.4 (SAS Institute Inc, Cary, NC), was used. Data are shown as mean ± SD and p < 0.05 was considered significant. To determine the independent relationship between 24-hour urinary excretion and 24-hour systolic and diastolic BP, a multivariate regression analysis was used. Confounders such as age, gender, BMI (as a continuous variable), alcohol consumption, smoking, the presence of diabetes and treatment of hypertension were included in the regression model.

Results Table 1 gives a description of the demographic, anthropometric, haemodynamic and general clinical characteristics of the participants in this study. They were divided into three groups: total sample, men and women. The characteristics include age, BMI, 24-hour ambulatory BP, 24-hour urinary Na+ excretion rates, alcohol consumption, smoking, diabetes status and hormone concentrations. The mean age of the total population sample was 45.3 ± 18.5 years. There was no age difference between males and females (men 45.5 ± 19.9 and women 45.1 ± 17.7 years) with 63.2% of participants being women. The mean BMI of the group was 29.1 ± 7.8 and 71% of participants were either overweight or obese. When BMI was calculated according to gender, more women were in the overweight/obese category (75%) compared to men (47%). Thirty-five per cent (35%) of the total sample population was hypertensive, 23.0% consumed alcohol regularly, 15% smoked, and 14% had diabetes mellitus or an HbA1c > 6.1%. There was no significant difference in urinary sodium excretion in the total sample and in men; however the overweight/ obese women had significantly lower urinary sodium excretion rates. Both insulin and leptin levels were significantly higher in the overweight/obese individuals compared to the normalweight participants. Gender differences were observed in leptin concentrations. Compared to men, leptin concentrations were significantly higher in women. Table 2 gives the haemodynamic characteristics of the population. Both systolic and diastolic BP values were higher in the overweight/obese participants compared to the normal-weight participants. Table 3 shows the relationship between 24-hour urinary sodium excretion and 24-hour systolic and diastolic BP. There was no

Table 1. General and clinical characteristics of the study population according to gender and BMI status Total sample

Men

Women

Normal

Overweight/ Obese

All

Normal

Overweight/ Obese

Parameters

All

Normala

Overweightb/ Obesec

Age (years)

45.3 ± 18.5

36.3 ± 18.3

50.4 ± 15.2

45.5 ± 19.9

38.2 ± 18.9

53.5 ± 18.0

45.1 ± 17.7

33.7 ± 17.4

48.9 ± 16.1

BMI (kg/m2)

29.1 ± 7.8

21.6 ± 2.1

34.4 ± 1.4

24.9 ± 5.0

21.2 ± 2.0

29.1 ± 4.1

31.5 ± 8.1

21.9 ± 2.2

34.6 ± 6.7

Hypertensive (%)

35.1

17.6

43.8

24.4

19.8

30.2

39.3

14.9

47.5

Diabetic (%)

14.3

7.2

16.9

12.9

9.4

16.8

13.9

4.6

16.9 11.1

All

Alcohol intake (%)

23.6

33.1

18.0

41.8

46.7

36.8

12.7

17.2

Smokers (%)

15.2

26.4

9.1

33.8

43.4

23.0

4.3

5.7

105.6 ± 78.4

108.9 ± 89.8

103.8 ± 72.1

106.5 ± 74.7

115.7 ± 71.1

105.0 ± 80.55

121.5 ± 99.4

Na+ (mmol/day)

98.5 ± 77.9

3.9 99.5±68.6*

6.2 ± 1.5

5.8 ± 1.0

6.3 ± 1.6

6.1 ± 1.7

5.8 ± 1.4

6.5 ± 1.9

6.2 ± 1.3

5.7 ± 0.3

6.3 ± 1.5

36.4 ± 73.8

35.9 ± 75.8

34.8 ± 35.7

35.2 ± 52.2

33.1 ± 51.6

37.5 ± 53.0

37.0 ± 84.1

39.5 ± 98.4

31.0 ± 5.0

Insulin (mmol/l)

14.4 ± 16.6

10.8 ± 13.8

16.8 ± 18.9*

13.8 ± 19.3

9.8 ± 13.3

18.9 ± 23.1*

14.8 ± 14.8

13.1 ± 14.1

15.5 ± 15.0

Leptin (ng/ml)

24.2 ± 25.3

9.9 ± 12.4

43.0 ± 29.4*

8.5 ± 8.7

4.3 ± 6.9

12.2 ± 8.4*

35.0 ± 27.2

17.6 ± 13.9

40.5 ± 28.1*

HbA1c (%) Renin (ng/dl)

HbA1c, glycated haemoglobin; BMI, body mass index; Na+, 24-hour urinary sodium excretion rate. a Normal BMI is defined as < 25 kg/m2, boverweight is defined as BMI ≥ 25 < 30 kg/m2 and cobese is defined as BMI ≥ 30 kg/m2.

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All participants

Normal BMIa

Overweightb/Obesec

SBP24 (mmHg)

118.6 ± 14.9

114.9 ± 12.3

121.6 ± 16.1*

DBP24 (mmHg)

72.2 ± 8.5

71.3 ± 9.1

74.4 ± 10.6*

SBP24 (mmHg)

116.9 ± 98.1

109.6 ± 9.8

116.6 ± 15.1*

DBP24 (mmHg)

71.9 ± 9.9

68.4 ± 7.3

71.3 ± 9.9*

SBP24 (mmHg)

123.2 ± 18.1

119.8 ± 12.15

125.4 ± 15.7*

DBP24 (mmHg)

64.4 ± 11.6

63.2 ± 11.1

66.8 ± 12.6*

Total sample

Women

Men

BMI, body mass index; SBP24, 24-hour ambulatory systolic blood pressure; DBP24, 24-hour ambulatory diastolic blood pressure. a Normal weight is defined as < 25 kg/m2, boverweight is defined as BMI ≥ 25 < 30 kg/m2 and cobese is defined as BMI ≥ 30 kg/m2. *p < 0.05 vs normal BMI.

significant relationship between 24-hour sodium excretion rate and BP in the total sample but when participants were stratified according to BMI status, the relationship reached statistical significance in the normal-weight individuals, even though it remained insignificant in the overweight/obese participants. When participants were divided according to gender, there was a significant association between urinary sodium excretion rate and BP in the total sample of men and in the normal-weight men but not in overweight men. In women there was no relationship between 24-hour urine excretion and BP, irrespective of BMI status. Fig. 1 compares the slopes of the relationship between 24-hour urinary sodium excretion and BP in the total population. The slope (β-coefficient) of the normal-BMI participants was significantly higher than that of the overweight/obese group.

Discussion To determine the masking effects of an increased BMI, we first investigated the relationship between 24-hour urinary sodium excretion and BP in the total population sample. Consistent with previous studies in this population4-6 and in other population groups,29,30 we found no relationship. In spite of the inconclusive results in this population, the relationship between sodium level and BP has been well established in a number of studies,31-34 therefore our current findings require thorough scrutiny. The limitations of previous studies conducted in this population could be that they did not take into consideration the high prevalence of obesity. So in order to account for the high incidence of obesity, in this study we stratified participants according to BMI status.

In a multivariate regression analysis, there was a statistically significant relationship between 24-hour urinary sodium excretion and both systolic and diastolic BP. However sodium level was not related to BP in the overweight/obese group. This difference was further demonstrated when the slopes of this relationship were compared between the two groups. The β-coefficients of the normal-BMI participants were significantly higher than those of the overweight/obese groups. This is indicative of a stronger relationship in the normal-weight group compared to the overweight/obese individuals. The differences in the relationship between the two groups are indicative of the masking effects of obesity. These masking effects were further confirmed when the participants were divided according to gender. In men, the relationship was present in the total sample of men and in the lean group but not in the overweight/obese group. In the women, no relationship was observed irrespective of BMI status. The gender differences are due to dissimilarities in the degree of obesity in the two groups. In men the average BMI was 24.9 ± 5.0 kg/m2 and only 47% were overweight or obese. On the other hand the average BMI in women was 31.5 ± 8.1 kg/m2 with 75% of the women in the overweight/obese category. Due to the lower BMI and lower proportion of overweight/obese men, the relationship between sodium and BP was not masked. On the

4 β-Coefficient of urinary Na+ (mmol/day) vs BP (mmHg)

Table 2. Haemodynamic characteristics of the study population according to BMI status

2 1 0

SBP24 Total population

DBPD Normal BMI

Overweight/obese

Fig. 1. Multi-adjusted slopes (β-coefficients) of 24-hour urinary sodium excretion versus 24-hour systolic and diastolic blood pressure in the total sample, normal-weight and overweight/obese participants. Adjustments were made for age, gender, smoking, alcohol intake, diabetes and hypertension. BMI, body mass index; BP, blood pressure; SBP24, 24-hour systolic blood pressure; DBP24, 24-hour systolic blood pressure.

Table 3. Relationship between dietary sodium intake and 24-hour ambulatory BP according to gender and BMI status Total sample All participants

Men

Partial r2

95% CI

p-value

Partial r2

SBP24 (mmHg)

0.08

–0.01–0.16

0.0872

DBP24 (mmHg)

0.06

0.02–0.14

SBP24 (mmHg)

0.11

DBP24 (mmHg)

0.10

SBP24 (mmHg) DBP24 (mmHg)

Women

95% CI

p-value

Partial r2

95% CI

0.23

0.02–0.40

p-value

0.0252*

0.05

–0.06–0.15

0.1469

0.21

0.4095

0.02–0.40

0.0299*

0.07

0.03–0.18

0.1747

0.02–0.19

0.0146*

0.01–0.18

0.0193*

0.25

0.05–0.43

0.0122*

0.07

–0.14–0.29

0.5016

0.29

0.10–0.47

0.0030*

0.06

–0.14–0.29

0.5016

0.06

–0.04–0.17

0.2448

0.01

0.07

–0.04–0.17

0.2551

0.01

–0.2–0.19

0.9091

0.08

–0.05–0.21

0.2058

–0.2–0.21

0.9751

0.09

–0.02–0.22

0.1281

Normal BMIa

Overweightb/obesec

CI, confidence intervals; SBP24, 24-hour systolic blood pressure; DBP24, 24-hour diastolic blood pressure; BMI, body mass index. a Normal BMI is defined as < 25 kg/m2, boverweight is defined as BMI ≥ 25 < 30 kg/m2 and cobese is defined as BMI ≥ 30 kg/m2. Adjustments were made for age, gender (in the total population), BMI (as a continuous variable), hypertension, diabetes, smoking and alcohol intake.

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other hand, the significantly higher BMI and higher proportion of overweight/obese women resulted in the masking of the relationship in the female group. Since women made up 63% of the total population sample, the masking effects of this female group are imputed to the whole population sample. Mechanisms responsible for the masking effects seem to be mediated by leptin. Plasma renin and insulin levels were similar between the different groups but leptin was significantly higher in the overweight/obese group, especially in women. This could account for the significantly lower urinary sodium excretion rate in the overweight/obese women compared to normal-weight women. As explained earlier, women made up 63% of this population and 75% of them were overweight or obese, therefore they were responsible for the significantly lower urinary sodium excretion rate (106 mmol/day) in this population compared to other population groups. In a study conducted in 45 countries with a total of 69 011 participants, the average 24-hour urinary sodium excretion rate was 159.4 mmol/day.35 In a Chinese study, the average 24-hour urinary sodium excretion was 235 mmol/day,3 which is more than double that of our population. A low sodium excretion rate of 104 mmol/day was observed in the trials of the Hypertension Prevention Collaborative Research Group.36 However in this study, the participants were on a low-sodium diet. The relatively low urinary sodium excretion rate is unique to our population sample and it may account for the leptin-mediated masking effects. The significantly higher leptin concentrations in the overweight/obese groups, especially in women where it was more than three times higher than that of the overweight/obese males, mediated the masking effects. Normally sodium intake results in a slight increase in BP due to volume expansion. This causes an increased sodium excretion rate through pressure natriuresis. A steady state is reached where sodium intake is equal to sodium excretion. However in the presence of high leptin concentrations the steady state is not achieved. Although leptin stimulates the sympathetic nervous system, it also increases nitric oxide concentration.37 Therefore, the pressor effects of the sympathetic nervous system are counteracted by the depressor effects of nitric oxide. Consequently there is no net change in BP. Without an increase in BP, pressure natriuresis is suppressed, resulting in a reduced urinary sodium excretion rate. This explains the significantly lower urinary sodium excretion rates in overweight/obese women and in the total population sample since women constituted 63% of this sample. The low urinary sodium concentration leads to a narrow range of urinary sodium concentration. As a consequence, the relationship between 24-hour urinary sodium excretion and BP is blunted. The masking of a relationship due to low concentrations is called a regression dilution.3 To the best of our knowledge, this is the first study to show that increased BMI masks the relationship between 24-hour urinary sodium excretion and BP, and that leptin mediates the mechanisms responsible for the masking effect. Potential limitations of our study are as follows; firstly, we collected once-off 24-hour urine samples and this does not account for the daily variation in dietary sodium intake. Although 24-hour urinary sodium excretion is an acceptable index of dietary sodium intake, the once-off 24-hour urine sample does not take into account the within- and betweenperson sodium intake variations. Secondly, the covariates

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such as alcohol intake and smoking were obtained through a self-reported questionnaire and therefore may not have been accurate. Thirdly, we did not use a dietary recall questionnaire to assess sodium intake. This could have been a useful tool for assessing the accuracy of 24-hour urinary sodium excretion as an index of dietary sodium intake. Finally, this was a cross-sectional study, therefore conclusions regarding cause and effect must be drawn with caution.

Conclusion This study indicates that dietary sodium intake influenced BP in this population, however this relationship could only be observed in lean participants, since increased BMI masked this relationship. These data suggest that future studies must take into account the high prevalence of obesity in this population before any conclusions are drawn on the relationship between sodium intake and BP.

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He FJ, MacGregor GA. Reducing population salt intake worldwide: from evidence to implementation. Prog cardiovasc Dis 2010; 52: 363–382.

Charlton KE, Steyn K, Levitt NS, Zulu JV, Jonathan D, Veldman FJ, et al. Diet and blood pressure in South Africa: intake of foods containing sodium, potassium, calcium, and magnesium in three ethnic groups. Nutrition 2005; 21: 39–50.

Akpan EE, Ekripo UE, Udo AA, Bassey BE. Prevalence of hypertension in Akwa Ibom State, South-South Nigeria: Rural versus urban communities study. Int J Hypertens 2015. http://dx.doi.org/10.1155/2015/975819.

10. Lindhorst J, Alexander N, Blignout J, Rayner B. Differences in hypertension between blacks and whites: An overview. Cardiovasc J Afr 2007; 18(4): 241–247. 11. Mbokazi AJ. Hypertension: common patient presentations in the developing world. Common Presentations 2006; 24(5): 232–236. 12. Ntuli ST, Maimela E, Alberts M, Choma S, Dikotope S. Prevalence and associated risk factors of hypertension amongst adults in a rural community of Limpopo Province, South Africa. Afr J Primary Health Care Family Med 2015; 7(1): 847. 13. Peer N, Steyn K, Lombard C, Gwebushe N, Levitt N. A high burden of

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hypertension in the black population of Cape Town: The cardiovascular risk in black South Africans (CRIBSA) study. PLoS ONE 2013; 8(11): e78567 doi:10.1371/journal.pone.0078567. 14. Oparil S. Low sodium intake – cardiovascular health benefit or risk. New Engl J Med 2014; 371: 677–679.

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Gros M. High salt diet and hypertension: focus on the renin-angiotensin system. Kidney Blood Pressure Res 2011; 34: 1–11. 27. Apel IJ, Dietary approaches to lower blood pressure. J Clin Hypertens 2009; 11: 358–368. 28. Gu J, Bailey AP, Tan W, Shparago M, Young E. Long-term high salt

15. O’Donnell MJ, Mente A, Smyth A, Yusuf, S. Salt intake and cardiovas-

diet causes hypertension and decreases renal expression of vascular

cular disease: why are the data inconsistent? Nutr Cardiovasc Dis 2013;

endothelial growth factor in Sprague Dawley rats. J Am Soc Hypertens

34: 1034–1040.

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16. Intersalt Cooperative Research Group. Intersalt: an international study

29. Shin J, Xu E, Lim YH, Choi BY, Kim BK, Lee YG, et al. Relationship

of electrolyte excretion and blood pressure. Results for 24 hour urinary

between nocturnal blood pressure and 24-hour sodium excretion

sodium and potassium excretion. Br Med J 1988; 297: 319–328.

in a rural population in Korea. Clin Hypertens 2014; 20: 9. doi:

17. Hoosen S, Seedat YK, Bhigjee AI, Neerahoo RM. A study of urinary sodium and potassium excretion rates among urban and rural Zulus and Indians. J Hypertens 1985; 3: 351–358.

10.1186/2056-5909-1-3. 30. Staessen JA, Birkenhager W, Bulpit CJ, Fagard R, Fletcher AE, Lijnen P, et al. The relationship between blood pressure and sodium and potas-

18. Redelinghuys M, Norton GR, Scott L, Maseko MJ, Brooksbank R,

sium excretion during the day and night. J Hypertens 1993; 11: 443–447.

Majane OHI, et al. Relationship between urinary salt excretion and

31. Suckling RJ, He FJ, Markundu ND, MacGregor GA. Dietary salt influ-

pulse pressure and central aortic haemodynamics independent of steady

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pressure. Kidney Int. 2012; 81: 407–411.

19. Smyth A, O’Donnell MJ, Yusuf S, Clase CM, Teo KK, Canavan M,

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Plasma sodium, ignored and underestimated. Hypertension 2005; 45:

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33. Dyer AR, Elliot P, Shipley M, Stamler R, Stamler J. Body mass index

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and associations of sodium and potassium with blood pressure in

blood pressure in children. Paediat Nephrol 2016; 26: 279–288.

INTERSALT. Hypertension 1994; 23: 729–736.

21. Grimes CA, Riddell LJ, Campbell KJ, He FJ, Nowson CA. Twenty-four

34. Ndanuko NR, Tapsel LC, Charlton KE, Neale EP, O’Donnell KM,

hour sodium excretion is associated with obesity in a cross-sectional

Batterham MJ. Relationship between sodium and potassium intake

sample of Australian children. Br J Nutr 2016; 115(6): 1071–1079.

and blood pressure in a sample of overweight adults. Nutrition 2017;

22. Yi SS, Kansagra SM. Association of sodium intake with obesity, body mass index, waist circumference and weight. Am J Prevent Med 2014; 45(6): 53–55. 23. Gelber RP, Gaziano M, Manson JE, Buring JE, Sesso HD. A prospective study of body mass index and the risk of developing hypertension in men. Am J Hypertens 2007; 20: 370–377.

33: 285–290. 35. Mc Carron AD, Kazaks AG, Greeling JC, Stern JS, Graudal NA. Normal range of human dietary sodium intake: A perspective based on 24-hour urinary sodium excretion worldwide. Am J Hypertens 2013; 26(10): 1218–1223. 36. Trials of Hypertension Prevention Collaborative Research Group.

24. Maseko MJ, Majane HO, Milne J, Norton GR, Woodiwiss AJ. Salt

Effects of weight loss and sodium reduction intervention on blood pres-

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sure and hypertension incidence in overweight people with high normal

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blood pressure. The Trials of Hypertension Prevention phase II. Arch

25. Shiburi CP, Staessen JA, Maseko M, Wojciechowska W, Thijs L, van Bortel LM, et al. Reference values for SphygmoCor measurements in South Africans of African ancestry. Am J Hypertens 2006; 19: 40–46. 26. Drenjancevic-Peric I, Jelakovic B, Lombard JH, Kunert MP, Kibel A,

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Facilitators, context of and barriers to acute coronary syndrome care at Kenyatta National Hospital, Nairobi, Kenya: a qualitative analysis Ehete Bahiru, Tecla Temu, Julia Mwanga, Kevin Ndede, Sophie Vusha, Bernard Gitura, Carey Farquhar, Frederick Bukachi, Mark D Huffman

Abstract Background: The prevalence of ischaemic heart disease and its acute manifestation, acute coronary syndrome (ACS), is growing throughout sub-Saharan Africa, including Kenya. To address this increasing problem, we sought to understand the facilitators, context of and barriers to ACS care at Kenyatta National Hospital, with the aim of improving the quality of care of ACS. Methods: We conducted in-depth interviews with healthcare providers involved in the management of ACS patients from January to February 2017 at Kenyatta National Hospital in Nairobi, Kenya. We selected an initial sample of key participants for interviewing and used a snowballing technique to identify additional participants until we achieved saturation. After transcription of audio recordings of the interviews, two authors conducted data coding and analysis using a framework approach.

Northern Pacific Global Health Research Fellowship Training Consortium, University of Washington, Seattle, WA; and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA

Results: We conducted 16 interviews with healthcare providers. Major themes included the need to improve the diagnostic and therapeutic capabilities of the hospital, including increasing the number of ECG machines and access to thrombolytics. Participants highlighted an overall wide availability of other guideline-directed medical therapies, including antiplatelets, beta-blockers, statins, anticoagulants and ACE inhibitors. All participants also stated the need for and openness to accepting future interventions for improvement of quality of care, including checklists and audits to improve ACS care at Kenyatta National Hospital. Conclusion: Major barriers to ACS care at Kenyatta National Hospital include inadequate diagnostic and therapeutic capabilities, lack of hospital-wide ACS guidelines, undertraining of healthcare providers and delayed presentation of patients seeking care. We also identified potential targets, including checklists and audits for future improvements in quality of care from the perspective of healthcare providers. Keywords: acute coronary syndrome, sub-Saharan Africa, global health, qualitative research Submitted 20/6/17, accepted 15/2/18 Published online 17/4/18

Ehete Bahiru, MD, ebahiru@ucla.edu

Cardiovasc J Afr 2018; 29: 177â&#x20AC;&#x201C;182

Department of Preventive Medicine, Northwestern University, Chicago, IL, USA

DOI: 10.5830/CVJA-2018-013

Mark D Huffman, MD, MPH

Department of Global Health, University of Washington, Seattle, WA, USA Tecla Temu, MD, PhD

Department of Medicine, University of Nairobi, Nairobi, Kenya Julia Mwanga, MB ChB Kevin Ndede, MB ChB

Organization International Centre for Reproductive Health Kenya (ICRHK), Kenya Sophie Vusha

Division of Cardiology, Department of Medicine, Kenyatta National Hospital, Nairobi, Kenya Bernard Gitura, MB ChB

Departments of Global Health, Epidemiology and Medicine, University of Washington, Seattle, WA, USA Carey Farquhar, MD, MPH

Department of Medical Physiology, University of Nairobi, Nairobi, Kenya Frederick Bukachi, MB ChB, MMed, PhD

www.cvja.co.za

Sub-Saharan African countries, including Kenya, are experiencing a rapid rise in the prevalence of ischaemic heart disease and its risk factors, including aging, hypertension, diabetes, obesity, physical inactivity and dyslipidaemia in the context of urbanisation and globalisation. The need to strengthen the health system in sub-Saharan Africa to adequately respond to the growing trends of non-communicable chronic diseases (NCDs), including ischaemic heart disease, is recognised by the World Health Organisation (WHO).1 Local cardiology societies such as the Pan-African Society of Cardiology (PASCAR) and the Kenyan Cardiac Society (KCS) advocate and support efforts to increase understanding of the burden of ischaemic heart disease and its acute manifestations such as acute coronary syndrome (ACS) in this region, with the goal of building upon and improving current management trends.2 To increase the understanding of ACS care in Kenya, our team conducted a retrospective evaluation of the presentation, management and outcomes of ACS patients managed at Kenyatta National Hospital between 2013 and 2016.3 The study has helped to describe current ACS management trends to identify important areas for future improvement of quality

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of care. To complement our quantitative evaluation of current ACS care at Kenyatta National Hospital, we also conducted a prospective qualitative analysis to understand facilitators of, barriers to and the context of in-hospital ACS care. We sought to identify knowledge, attitude and behaviour about interventions for improvement of quality of healthcare through in-depth interviews with healthcare providers involved in the management of ACS patients at Kenyatta National Hospital. This qualitative evaluation will provide informative data for future activities to improve quality of care in the hospital and region.

Methods This qualitative study included in-depth interviews of key participants who were healthcare providers involved in the management of ACS patients at Kenyatta National Hospital, which is one of the two main public referral centres in Kenya. The hospital has Kenya’s most advanced diagnostic and management capabilities for ACS care, including having the only public cardiac catheterisation laboratory in the country. We developed interview guides to explore facilitators of, barriers to and context of in-hospital ACS care at Kenyatta National Hospital. We modelled this qualitative study based on our team’s prior research in India, which has led to the development of a theoretical model that viewed ACS care through a patient-orientated process map including five stages: (1) prior to first medical contact, (2) at the point of first medical contact, (3) early hospitalisation, (4) mid-to-late hospitalisation, and (5) at the point of discharge.4 Starting in January 2017, we selected an initial sample of hospital leaders for interviewing and used a snowballing technique to identify additional participants during February 2017. We used the principle of maximal variability sampling to seek new participants to achieve a diverse sample. We continued our recruitment until we achieved saturation of major themes identified during our analysis. All interviews with audio recordings were conducted by one interviewer (EB) in English and lasted between 36 and 65 minutes. Audio transcripts and interview field notes of the first three Table 1. Participants’ characteristics Participants

transcripts were independently coded by two individuals (EB, SV) to develop a comprehensive codebook. The same coders used Dedoose version 7.5.275 to code the remaining transcripts and field notes using the codebook. We also developed and implemented a brief survey to capture demographic data and open-ended responses regarding facilitators of, barriers to and context of ACS care, which were further explored in the in-depth interviews. The study was approved by the University of Washington institutional review board, the Kenyatta National Hospital/ University of Nairobi ethics and research committee and Northwestern University institutional review board. Written informed consent was obtained from all participants.

Results We conducted 16 interviews during the study period, including with one cardiologist, two accident and emergency (A&E) attending physicians, two medical officers in the casualty department, three A&E nurses, and eight medical registrars (Table 1). More than half (56%) of the interviewees were women. We also provide a summary of the major facilitators of and barriers to ACS care at Kenyatta National Hospital that were highlighted by most participants in Tables 2 and 3, respectively.

Theme 1: There is a significant delay from onset of patient symptoms to presentation at Kenyatta National Hospital All participants explained that there is a significant delay from symptom onset to presentation at Kenyatta National Hospital, which seems largely driven by a lack of patient understanding of ACS symptoms that warrant emergent medical attention. This delay is further exacerbated by the inter-hospital transfer system from district hospitals to Kenyatta National Hospital. ‘Of course, from the patient side, delay is a big problem and therefore once they come late we end up doing heart-failure management post MI, many of our people do not have the knowledge that if I have a chest pain, I need to rush to hospital…So, knowledge in our community is an area that we need to educate the community about chest pain’

Number = 16 (%)

Type of ACS provider Cardiologist

1 (6)

A&E room attendants

2 (13)

A&E room medical officers

2 (13)

Nurses

3 (19)

Medical residents

8 (50)

Female

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9 (56)

Other respondents described patients seeking care at pharmacies rather than hospitals, for initial management. ‘Significant delay in presentation from symptom onset because most of the time most Kenyans usually try and buy over-the-counter medications and don’t present unless the pain is severe.’

Table 2. Facilitators of in-hospital ACS management at Kenyatta National Hospital Hospital level

Provider level

• The hospital is one of a few institutions that has diagnostics including ECG and echocardiography, and is the only • Availability of expert staff including cardipublic hospital with a cardiac catheterisation laboratory, although availability of some of these diagnostic services ologists, well-trained critical-care nursing are limited and could be improved staff and medical registrars • Guideline-directed in-patient and discharge. Medical therapy, specifically antiplatelet agents, beta-blockers, statins, • Well-trained echocardiography technicians anticoagulants and ACE inhibitors are largely available • Providers that participated in this qualita• Hospital-fee waiver for certain services is available for patients who are unable to afford emergency medical treatment tive research displayed great interest in • The hospital has critical care units, both in the casualty department and medical wards, to take care of critically ill improving existing ACS care, including patients, including ACS patients potential quality improvement • Structured follow-up mechanism post discharge through the cardiology clinic • Continuing medical education programmes that cover current ACS treatment guidelines

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Table 3. Barriers to in-hospital acute ACS management at Kenyatta National Hospital Hospital level • • • • • • • • •

Provider level

No standardised triaging system for patients with chest pain or suspected ACS • Low level of training Inadequate number of ECG machines or lack of routine maintenance if malfunctioning on the management Occasional inadequate availability of essential ACS diagnostic tests, such as cardiac biomarkers of ACS Lack of availability of some medicines such as nitroglycerine • Inadequate number Thrombolytics are not consistently stocked or are not available most of the time of staff with high There is a lack of standardised protocol or hospital guidelines for ACS management patient-to-nurse ratio, There is no dedicated coronary care unit and very limited availability of ICU beds and resuscitation rooms. especially in the mediCardiac catheterisation laboratory is available but currently no primary PCI service cal wards No hospital-organised specific training for ACS or other cardiac emergencies

Patient level • Low level of knowledge about symptoms of ACS • Inability to afford medical treatment • Self-medication using over-the-counter medications • Language barriers

PCI, percutaneous coronary intervention.

Inter-hospital transfer delays are also driven by delays in diagnosis at district-level hospitals as well as limited access to ambulances for rapid transport. ‘Our hospital, of course, is a national hospital, so many times we get patients who have been referred and therefore they would have passed one or two other hospitals, being managed for either pneumonia or for an abdominal problem, so they tend to come late.’

Theme 2: Diagnostic, management and treatment capabilities of the hospital are sub-optimal Theme 2.1: Availability of electrocardiogram (ECG) and cardiac biomarkers Respondents all agreed that the limited availability of functioning ECG machines in the hospital creates a significant barrier to rapid ACS diagnosis. Some patients are referred from the A&E department to the out-patient cardiology department for acute ECG monitoring, whereas other patients do not receive an ECG during their hospitalisation. This assessment parallels findings from our study that retrospectively evaluated current ACS management trends at Kenyatta National Hospital, which showed the rate of ECG acquisition within 24 hours of presentation among non-transferred cases was 71%; a small minority (5%) of patients admitted and managed for ACS did not get an ECG during their entire hospitalisation.3 ‘Right now, we are not able to do ECG for our patients because our ECG machine broke down a few months ago. We are in the process of getting one….at the moment what we are doing, we are sending the patients to the cardiology unit…to get their ECG done.’ Participants reported that cardiac biomarkers are generally but not always available. ‘At times, also if the reagents for…the cardiac enzymes, troponin, if they don’t have it in the lab that is a challenge. We usually send, take the samples outside, we tell the relatives to take it outside.’

Theme 2.2: Availability of reperfusion therapy While Kenyatta National Hospital has a cardiac catheterisation laboratory, primary percutaneous coronary intervention is not available at all times. In-hospital cardiac catheterisation is also not part of the routine management of ACS patients admitted to the hospital, often because of late patient presentation for ST-segment elevation myocardial infarction.

‘The hospital has (a) catheterisation lab but again we are not doing primary PCI at the moment…so most of the patients are being managed medically.’ ‘Why are they being managed medically?’ ‘Cause (sic) many times they will come late.’ All participants mentioned that thrombolysis for reperfusion therapy for eligible ACS patients is currently not available at the hospital and attributed cost as the primary reason the hospital does not consistently stock thrombolysis medications. However, the lack of in-hospital thrombolytic availability further limits its use. ‘Currently this hospital does not stock [thrombolysis medicines] in the hospital and therefore even if these patients came on time and could benefit from lysis the relatives have to be given the prescription to go out there and purchase this medicine. So, you can imagine by the time all that is done, the patient came late, by the time the relatives go and buy these medicine, it is never going to be on time.’ Respondents also acknowledged that many providers do not have adequate training to administer thrombolytic therapy. ‘…if we were to get a patient who comes on time and residents make that decision to thrombolyse this patient, are they comfortable with the thrombolysis?’ ‘I would say no.’ Cost of cardiac catheterisation and intervention is another significant barrier. Patients or their relatives need to purchase coronary stents, which is not feasible during the acute treatment period. ‘Of course, the patients have to pay for this angiogram … it is always economically easier for the relatives if [the patients] are discharged through the cardiology clinic, they come and book for that angiogram, and they source for the money…. So, we do tend to do angiogram usually in the course of one week to a month.’

Theme 3: Guideline-directed in-hospital and discharge medical therapy such as antiplatelets, beta-blockers, statins and anticoagulants are largely available Participants reported that other guideline-directed medicines recommended by the current international ACS guidelines such as the American College of Cardiology/American Heart Association or the European Society of Cardiology are available

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at Kenyatta National Hospital, including aspirin, clopidogrel, nitrates, beta-blockers, statins, ACE inhibitors, oxygen, morphine and anticoagulants. Stock-outs are rare. ‘We have definitely the oxygen points and the oxygen supplies. We have the analgesics, the operators are there. Nitroglycerin would be there. Aspirin, clopidogrel would be there. If maybe (there) was hypertensive emergency, the drugs would be there. There would be the beta-blockers, and ACE inhibitors are available.’

Theme 5: Most staff feel inexperienced managing ACS patients Most participants highlighted that they generally feel inexperienced in managing patients with ACS. Participants stated most of their knowledge on management of ACS cases came from self-initiated review of international guidelines,6 peers or experiences from working in other institutions. ‘We follow guidelines, most of them are British or American guidelines. European Society for Cardiology, American Cardiac Society, but we only do what is available. And also, sometimes the norms if you are a new resident, like when I started working here, you find what other residents have been doing. So that is what you do, or when you get an ACS patient you consult, you have a resident who can tell you this is usually done.’

Similarly, guideline-directed medicines are available for prescription at the time of discharge. ‘…of course they will be discharged with all the drugs which are useful for coronary artery disease; then they will be followed up in the cardiology clinic.’ However, participants acknowledged that even if these medicines are available, many patients have limited or delayed access, largely due to cost, which influences long-term adherence. Patients may have to pay for these medications prior to administration, especially in the casualty department. ‘The bad thing is that they have to dig deep into their pockets to take care of [treatment]… the good thing also is that the hospital allows us, especially in emergency set up, allows us to waive all the cost.’

Theme 4: Lack of awareness and use of standardised hospital protocol to guide ACS management Most participants stated that they were not aware whether there is a standardised hospital-wide ACS protocol to guide management of patients. Two participants acknowledged that there is a guideline for ACS management in the casualty department, drafted by the emergency medical services of Kenya, although it is currently not widely distributed to healthcare providers. ‘We don’t have any pinned-up protocols on the wall yet, but there are some protocols we are using from the emergency medical services of Kenya. We are able to disseminate them to the doctors, right now we are in the process of printing, we want to make them into small notebooks and give the nurses and the doctors.’

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Theme 6: Acceptability of interventions for improvement of quality, including checklists, audits and feedback reports All participants made several suggestions on how to improve existing ACS care at Kenyatta National Hospital. Table 4 summarises these recommendations, which are primarily targeted at hospitallevel infrastructure, provider-level ACS training, and communitylevel awareness of ACS management. At the hospital level, recommendations focused on increasing current diagnostic and therapeutic capabilities, such as ECG machines and thrombolytics and implementing a hospital-wide standardised ACS protocol. At the provider level, the most common recommendation focused on improving current training on ACS management. We also assessed the acceptability of initiatives to improve quality of care of ACS, such as checklists, audits and feedback reports, which have been shown to improve processes of care in ACS management.7,8 ‘A checklist would definitely be very useful because a lot of the times as residents we manage all sorts of different case presentations... So I think having a checklist just reminds you that there might be an important step that I skipped so you can easily go back to it before it’s too late.’ Most participants described the use of other checklists at the hospital for intensive care unit (ICU), tuberculosis (TB) and trauma services.

However, awareness and use of any existing ACS protocol was not universal. ‘We don’t have (a) protocol. When you get in, you do what you see everyone else do.’

‘ICU and TB and chest wards have existing checklists that are standard across public hospitals, especially the TB checklist that has standardised the care for TB patients in the hospital. If there is a specific checklist for ACS patients, that could improve the care.’

Table 4. Participants’ suggestions for future improvement in quality of ACS care Hospital level

Provider level

• Increase diagnostic capabilities, primarily increased number of ECGs in the hospital • Have a dedicated ECG machine at triaging point in the accident and emergency room • Ensure consistent availability of thrombolysis medicines • Improve other laboratory capabilities, such as point-of-care cardiac markers • Implement a standardised protocol or hospital guidelines for chest pain triaging and ACS management • Build a dedicated coronary care unit

• Improve knowledge of health- • Public health initiative to improve care providers on ACS managepatient knowledge on recognition of ment guidelines ACS symptoms and need for emergent • Training and protocol on safe medical evaluation administration of thrombo• Evaluate mechanisms to cover medical lytics costs for ACS care, including expan• Hospital-sponsored advanced sion of the national health insurance cardiac life-support training fund to cover essential treatments

Patient level

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Discussion This qualitative research study describes facilitators of, barriers to and context of ACS care at Kenyatta National Hospital. The most prominent facilitators mentioned by the majority of participants highlighted that Kenyatta National Hospital is one of two main public referral and teaching centres with the highest capability for ACS diagnostics and therapeutics, including the only public hospital with a cardiac catheterisation laboratory, expert consultants such as cardiologists, and cardiac surgery. However, all participants highlighted that there are several facility-, provider- and patient-level barriers to optimal ACS management. At the facility level, sub-optimal diagnostic capabilities, especially the very limited number of ECG machines in the hospital, was listed as one of the most significant barriers to making prompt diagnosis when ACS is suspected. A limited supply of thrombolysis medications and adaptation of standardised ACS protocols were listed as additional barriers. All participants had positive attitudes towards both checklists and audit and feedback systems as key tools to improve ACS care. Some participants described existing checklists such as ICU, tuberculosis or trauma care checklists as examples that a toolkit for improvement of quality of ACS care that included checklists could be feasibly incorporated at the hospital. We know of no other studies from sub-Saharan Africa that have evaluated facilitators of, barriers to and context of ACS care, using qualitative research methods. There are similar studies from high-income and other low- and middle-income countries that have used qualitative research as a tool to guide future targets and tailor solutions to improvement of quality of care. For example, a 2001 qualitative study at eight US hospitals explored initiatives, strategies and approaches to improvement of care for patients with acute myocardial infarction. This study showed that shared goals for improvement, substantial administrative support, strong physician leadership, and use of credible feedback data were mechanisms used in hospitals that improved their processes of care, such as medication use, compared to those that did not.9 Themes from a 2010 study in Egypt, which assessed barriers and opportunities to implement an ACS registry included the need to build a culture of applied research, the importance of modelling a blame-free culture, and the potential of clinical registries as cost-effective investments to support improvement in quality of care for ACS in low- and middle-income countries. Limited human resources and technical infrastructure were two key constraints identified.10 A 2016 qualitative study from Kerala, India, evaluating pre-hospital ACS care has been useful in identifying areas for improvement of quality in pre-hospital ACS care.4 The study found lack of recognition of ACS symptoms that warrant emergent evaluation, high cost of ACS treatment, specifically cardiac catheterisation, insufficient transport systems, and infrequent use of medical emergency services by the public as contributors to pre-hospital delays.4 The framework of the WHO’s health system building blocks consists of service delivery, health workforce, health information systems, access to essential medicines, financing and leadership as key target components of improving access to quality healthcare.2 This framework can be used to place our results into context. For example, service delivery requires accurate diagnosis for appropriate management, which highlights the primacy

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of functioning ECG machines for improving ACS care. The WHO includes ECGs as an essential diagnostic technology in its package of essential non-communicable disease interventions (PEN), and therefore they should be a priority for improving ACS care.11 Another example is the need for a health information system to build the evidence base and plan for appropriate and timely allocation of healthcare providers and treatment. An audit and feedback system for ACS and other acute cardiovascular conditions would be one potential mechanism to strengthen the Kenyan health system for better ACS performance and outcomes. The WHO also recommends a comprehensive human resources information system to monitor the health workforce to assess needs and guide appropriate training and utilisation of the health workforce. Notably, these interviews were conducted during a period when there was a nationwide physician strike in Kenya that lasted 100 days and affected public institutions, including Kenyatta National Hospital.12 A physician strike shows the potential fragility of low- and middle-income country health systems and the challenges in improving quality and safety. In terms of financing, Kenya spends 6.4% of its gross domestic product on healthcare, which is relatively low compared with global peers.13 However, 40% of this spending comes from government sources. Future expansion of Kenya’s healthcare expenditures, particularly in the context of achieving universal access to healthcare, will need to account for the growing disease burden of ischaemic heart disease, its acute manifestations such as ACS, and underlying risk factors, to create a sustainable, responsive, high-quality health system that offers financial protection to its citizens. Our study has some limitations, including being a single location at a public referral hospital; however, ours is the first study of its kind in the region. Another major limitation of this study is that we did not include patients among those interviewed, which is an area of future research for our team. We plan to explore patients’ perspectives in areas of pre-hospital delay, patients’ knowledge about ACS, experiences in receiving ACS-related care and patients’ medical costs.

Conclusions This qualitative research assessed facilitators of, barriers to and context of ACS care at Kenyatta National Hospital. These results provide the novel perspectives of healthcare providers on the current trends of ACS management, and potential areas of limitations and opportunities to improve ACS care and outcomes. MDH receives grant support from the World Heart Federation to serve as its senior programme advisor for the Emerging Leaders programme. This programme is supported by unrestricted educational grants from Boehringer Ingelheim and Novartis, with previous support from AstraZeneca and Bupa. Funding was provided by Fogarty International Center TW R25TW009345 and the Tibar Fabian award from the University of California, Los Angeles.

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syndrome. A registry study from Kenyatta National Hospital in Nairobi, 4.

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Berwanger O, Guimaraes HP, Laranjeira LN, Cavalcanti AB, Kodama

13. Dieleman JL, Campbell M, Chapin A, Eldrenkamp E, Fan VY,

AA, Zazula AD, et al. Effect of a multifaceted intervention on use of

Haakenstad A, et al. Future and potential spending on health 2015–40:

evidence-based therapies in patients with acute coronary syndromes in

development assistance for health, and government, prepaid private,

Brazil: the BRIDGE-ACS randomized trial. J Am Med Assoc 2012;

and out-of-pocket health spending in 184 countries. Lancet 2017;

307(19): 2041–2049.

389(10083): 2005–2030.

An egg a day could significantly reduce CVD risk People who consume an egg a day could significantly reduce their risk of cardiovascular disease (CVD) compared with eating no eggs, suggests a study carried out in China. CVD is the leading cause of death and disability worldwide, including China, mostly due to ischaemic heart disease and stroke (including both haemorrhagic and ischaemic stroke). Unlike ischaemic heart disease, which is the leading cause of premature death in most Western countries, stroke is the most responsible cause in China, followed by heart disease. Although ischaemic stroke accounted for the majority of strokes, the proportion of haemorrhagic stroke in China is still higher than that in high-income countries. Eggs are a prominent source of dietary cholesterol, but they also contain high-quality protein, many vitamins and bioactive components such as phospholipids and carotenoids. Previous studies looking at associations between eating eggs and impact on health have been inconsistent, and most of them found insignificant associations between egg consumption and coronary heart disease or stroke. Therefore, a team of researchers from China and the UK led by Prof Liming Li and Dr Canqing Yu from the School of Public Health, Peking University Health Science Centre, set out to examine the associations between egg consumption and cardiovascular disease, ischaemic heart disease, major coronary events, haemorrhagic stroke and ischaemic stroke. They used data from the China Kadoorie Biobank (CKB) study, an ongoing prospective study of around half a million (512 891) adults aged 30 to 79 years from 10 different geographical areas in China. The participants were recruited between 2004 and 2008 and were asked about the frequency of their egg consumption. They were followed up

to determine their morbidity and mortality. For the new study, the researchers focused on 416 213 participants who were free of prior cancer, CVD and diabetes. From that group at a median follow up of 8.9 years, a total of 83 977 cases of CVD and 9 985 CVD deaths were documented, as well as 5 103 major coronary events. At the start of the study period, 13.1% of participants reported daily consumption of eggs (usual amount 0.76 eggs/day) and 9.1% reported never or very rare consumption of eggs (usual amount 0.29 eggs/day). Analysis of the results showed that compared with people not consuming eggs, daily egg consumption was associated with a lower risk of CVD overall. In particular, daily egg consumers (up to one egg/day) had a 26% lower risk of haemorrhagic stroke, a 28% lower risk of haemorrhagic stroke death and an 18% lower risk of CVD death. In addition, there was a 12% reduction in risk of ischaemic heart disease observed for people consuming eggs daily (estimated amount 5.32 eggs/week), when compared with the ‘never/rarely’ consumption category (2.03 eggs/week). This was an observational study, so no firm conclusions can be drawn about cause and effect, but the authors said their study had a large sample size and took into account established and potential risk factors for CVD. The authors concluded: ‘The present study finds that there is an association between moderate level of egg consumption (up to 1 egg/day) and a lower cardiac event rate. Our findings contribute scientific evidence to the dietary guidelines with regard to egg consumption for the healthy Chinese adult.’ Source: Medical Brief 2018

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Association of traditional cardiovascular risk factors with carotid atherosclerosis among adults at a teaching hospital in south-western Nigeria Adeleye Dorcas Omisore, Olusola Comfort Famurewa, Morenikeji Adeyoyin Komolafe, Christiana Mopelola Asaleye, Michael Bimbola Fawale, Babalola Ishmael Afolabi

Abstract Background: Traditional cardiovascular risk factors (CVRFs), which include age, gender, hypertension, diabetes mellitus, dyslipidaemia, smoking, alcohol consumption, chronic kidney disease and obesity, have been shown to be associated with atherosclerosis. We aimed to evaluate the impact of traditional CVRFs on carotid atherosclerosis (CA) in a sample of Nigerian adults. Methods: We examined 162 subjects with traditional CVRFs in a cross-sectional study. Demographic and clinical data, including history of hypertension, diabetes mellitus, smoking, alcohol intake and chronic kidney disease, as well as systolic and diastolic blood pressure, weight and height were collected. Serum creatinine, fasting blood glucose and lipid profiles were also determined. Carotid intima–media thickness (CIMT) and presence of carotid plaque (CP) were evaluated by high-frequency B-mode ultrasound. Chi-squared and regression analyses were carried out to determine associations between variables of CIMT and CVRF. Results: Increased CIMT was associated with all CVRFs (p < 0.05) except gender (p > 0.05), while CP was associated with older age, obesity, hypertension and dyslipidaemia (p < 0.05). We found prevalence of increased CIMT was 53.7%, while that of CP was 16.1%. The prevalence of CA (increased CIMT and CP) also increased with increasing number of CVRFs in the subjects. Age ≥ 50 years, hypertension, dyslipidaemia, obesity and alcohol intake explained 78.7% of variance in CIMT, while age ≥ 50 years and hypertension explained 38.0% of variance in CP. Conclusions: CA was associated with presence and increasing number of traditional CVRFs. A significant percentage of variance in CA was, however, unexplained by traditional CVRFs.

Department of Radiology, Obafemi Awolowo University and Obafemi Awolowo University teaching hospitals complex, Ile-Ife, Nigeria Adeleye Dorcas Omisore, MB BS, FWACS, FMCR, omisoreadeleye@yahoo.com Olusola Comfort Famurewa, MB ChB, FWACS Christiana Mopelola Asaleye, MB ChB, FWACS

Department of Medicine, Obafemi Awolowo University, Ile-Ife, Nigeria Morenikeji Adeyoyin Komolafe, MB BS, FWACP Michael Bimbola Fawale, MB BS, MSc, FMCP

Department of Radiology, Obafemi Awolowo University teaching hospitals complex, Ile-Ife, Nigeria Babalola Ishmael Afolabi, MB ChB, FWACS, FMCR

Keywords: atherosclerosis, cardiovascular, carotid, Nigerian, risk factors Submitted 1/8/16, accepted 19/2/18 Published online 28/2/18 Cardiovasc J Afr 2018; 29: 183–188

www.cvja.co.za

DOI: 10.5830/CVJA-2018-014

Atherosclerosis is the primary cause of morbidity and mortality in cardiovascular disease.1 It develops silently over decades, long before symptoms occur.1 Carotid intima–media thickness (CIMT) is a measure of subclinical atherosclerosis associated with cardiovascular risk factors (CVRFs) and is predictive of cardiovascular diseases such as myocardial infarction and stroke.2 Conventionally, CVRFs are divided into traditional and non-traditional factors.3 Traditional CVRFs, including age, gender, obesity, diet, hypertension, diabetes mellitus, dyslipidaemia, smoking, alcohol consumption and chronic kidney disease have been shown to account for most of the populationattributable risks for cardiovascular events.3-5 Existing evidence suggests an association between these individual traditional CVRFs and CIMT.6 Studies have gone further to establish the greater impact of multiple risk factors on CIMT compared with individual risk factors in different population groups.6,7 Traditional CVRFs, however, account for < 50% of the variance of atherosclerotic plaque burden and may not explain a large proportion of the variance in CIMT, especially when measured in plaque-free locations.8 Intima–media thickness is widely accepted as a valid marker for the process of atherosclerosis and has been applied in the study of cardiovascular disease for more than two decades.1 Carotid ultrasonography is a non-invasive means of identifying early-stage atherosclerotic changes in the arterial wall with the measurement of intima–media thickness and detection of plaque.1 Combined CIMT and plaque assessment is considered better than either measure alone in the assessment of atherosclerotic risk.9 Early detection of predictors of CIMT and their early modification may have a significant impact on the prevention of atherosclerotic disease.1 Therefore, to reduce the mortality rate associated with cardiovascular diseases such as stroke, it is clinically important to study the effects of CVRFs on carotid atherosclerosis. In this study, we aimed to evaluate the association of individual traditional CVRFs and the cumulative effect of multiple CVRFs with carotid atherosclerosis (CA) in a sample of Nigerian adults with established CVRFs.

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Methods Adults aged 18 years and older were consecutively recruited from individuals who visited the medical out-patient, cardiology, neurology, hypertension and diabetes clinics of Obafemi Awolowo University teaching hospitals complex (OAUTHC), Ile-Ife, Nigeria, between January and December 2013. A total of 162 subjects were enrolled. Ethical approval was obtained from the Ethics and Research Committee of OAUTHC, Ile-Ife, and written informed consent was obtained from every study participant. Demographic and clinical data such as age, gender, history of hypertension, diabetes mellitus, chronic kidney disease, smoking and alcohol intake were obtained by means of a structured data sheet. Blood pressure was measured in line with practice guidelines after 15 minutes of rest in the examination room, before ultrasound of the carotid artery was done. With patients seated comfortably, back supported, legs uncrossed, left upper arm bare and supported at heart level, an appropriate bladder cuff of an analogue mercury sphygmomanometer was applied to the left upper arm to encircled 80% or more of the arm circumference. After inflation, the mercury column was deflated at 2 to 3 mm/s. The first and last audible sounds were taken as systolic and diastolic blood pressure, respectively, and their measurements were given to the nearest 2 mmHg. Neither the patient nor the doctor taking the measurement talked during the procedure. Two readings at one-minute intervals were taken, and the average was recorded. Weight and height were measured using a mechanical physician’s weighing scale attached to a stadiometer (model ZT-160, China). Body mass index (BMI) was calculated as weight (kilograms) divided by height (metres) squared. Venous blood samples were taken from each participant between 07:00 and 08:00, after an overnight fast of eight hours. Samples were centrifuged within two hours of collection at 3 000 g for five minutes in a swing-bucket centrifuge, after which the serum was separated into plain plastic screw-capped containers and stored frozen at –20°C until analysis. Samples were analysed in the chemical pathology department of the hospital. Plasma samples were analysed for glucose concentration (based on the glucose oxidase method) on the day of collection, while serum samples were analysed for other biochemical markers within one week of collection. Creatinine (Cr) level was estimated in the serum with picric acid (Jaffe’s reaction); total cholesterol (TC) was determined with the cholesterol oxidase method; triglycerides (TG) were assayed with the glycerol phosphate oxidase/peroxidase method; and high-density lipoprotein cholesterol (HDL-C) was determined with the precipitation method. Assay kits for lipid profiles were purchased from Randox Laboratory Ltd, UK. Low-density lipoprotein cholesterol (LDL-C) was calculated using the empirical relationship of Friedewald’s formula:10 LDL = total cholesterol – HDL-C – TG/5 All components of the lipid profile are given in mmol/l. Normal values were taken as TC ≤ 5.2 mmol/l, HDL-C ≥ 1.03 mmol/l in men, ≥ 1.30 mmol/l in women, LDL-C ≤ 3.4 mmol/l, and TG ≤ 1.7 mmol/l, based on the National Cholesterol Education Program Adult Treatment Panel III (ATP III).10 Serum creatinine level is expressed in µmol/l, and values between 80 and 115 µmol/l in males and 53 and 97 µmol/l in females were considered normal.10 Fasting blood sugar levels of 4.1–5.6 mmol/l were considered normal.10 These laboratory

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assessments were done in collaboration with the chemical pathologists. Definition of risk factors was guided by the ATP III guidelines.10 Hypertension was defined as resting systolic blood pressure (SBP) ≥ 140 mmHg, and/or diastolic blood pressure (DBP) ≥ 90 mmHg,10 or use of antihypertensive drugs. Dyslipidaemia was defined as use of antilipaemic drugs or having one or more of the following: TC ≥ 5.2 mmol/l, LDL-C ≥ 3.4 mmol/l, HDL-C ≤ 1.0 mmol/l, or TG ≥ 1.70 mmol/l.10 Diabetes mellitus (DM) was defined as fasting blood glucose (FBG) ≥ 7.0 mmol/l, or use of antidiabetes medication.10 A smoker was defined as a person who had smoked at least 100 cigarettes over his/her lifetime, including both current smoker (a person who continued to smoke daily or occasionally at the time of study) and past smoker (a person who had not smoked in the past 12 months).11 An alcohol consumer was defined as a person who imbibed alcohol, including current consumer (a person who had consumed alcohol in the past 12 months) and past consumer (a person who had consumed alcohol in the past, but not in the past 12 months).11 A history of peripheral artery disease, myocardial infarction, angioplasty, stroke or coronary artery bypass surgery was not recorded in our study participants. Carotid ultrasonography was performed using a Mind-ray DC 7 ultrasound machine, equipped with a 7.5–12-MHz highresolution linear-array transducer. The common carotid artery was scanned for CIMT and measurements were taken 10 mm from the carotid bulb. Intima–media thickness was defined as the distance between the leading edge of the lumen–intima and the leading edge of the media–adventitia echo.12 An average of the right and left common carotid arteries (CCA) was taken for the study. CA was defined as the presence of increased CIMT with or without carotid plaque (CP). CIMT ≥ 0.9 mm was taken as increased CIMT.12,13 Carotid plaques were recorded as present or absent if seen or not, respectively. Plaque was defined as focal thickening of at least 50% greater than that of the surrounding vessel wall, with a minimal thickness of at least 1.5 mm.12,13

Statistical analysis All analyses were performed using the Statistical Package for the Social Sciences (SPSS) statistical software (Version 20.0), SPSS Inc. Continuous variables are represented as mean ± standard deviation (SD) while categorical variables are represented as percentages. Group means of subjects with and without CVRFs were compared using the Student’s t-test, while proportions were compared using the chi-squared test. Bivariate logistic regression was used to compare associations of subjects with CVRFs with carotid atherosclerosis (increased CIMT or plaque presence) and those without (normal CIMT or plaque absence). Only variables with statistically significant associations on bivariate analysis were included in the final multivariate logistic regression model with the odds ratio and 95% CI presented. Significance was taken at p < 0.5.

Results Clinical, laboratory and anthropometric characteristics of the subjects are shown in Table 1. The mean age of the study participants was 51.96 ± 15.09 years and 49.4% were male. The

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mean values of Cr, BMI, SBP, DBP, TC, TG, HDL-C, LDL-C and prevalence of CVRFs are shown in Table 1. The prevalence of carotid plaque among the study participants was 16.1%, and 87 (53.7%) of the subjects had increased CIMT (≥ 0.9 mm). Mean values of CIMT were significantly increased with advancing age and in subjects with individual CVRFs compared with subjects without CVRFs (p < 0.05) (Table 2). CIMT was however not significantly different between male and female subjects. There was a significant association between increased CIMT and other traditional CVRFs (Table 3). However, age ≥ 50 years, hypertension, obesity, dyslipidaemia and alcohol intake remained independently associated with increased odds of increased CIMT (Table 3). CP was associated with age ≥ 50 years (p < 0.001), obesity (p = 0.002), hypertension (p < 0.001) and dyslipidaemia (p = 0.001) (Table 4). Age ≥ 50 years and hypertension were the independent predictors of increased odds of CP (Table 4). Mean values of CIMT increased with increasing number of CVRFs, as shown in Fig 1.

Discussion The commonest traditional CVRFs besides age (51.2% of study sample were ≥ 50 years in age) in this study were dyslipidaemia (68.5%), hypertension (49.4%) and obesity (34.2%). Previous studies in Nigeria have sought to describe the prevalence of CVRFs in different populations, such as hypertensives, diabetics, and elderly and apparently healthy adult Nigerians. Similar to our results, Akintunde et al.,14 in a cross-sectional study in the south-western region of Nigeria among apparently healthy university staff aged 27 to 73 years, with a mean age of Table 1. Clinical, laboratory and anthropometric characteristics of the study sample Variables

Statistics

45.27 ± 7.87 years, found dyslipidaemia (49.5%), generalised obesity (44.7%) and hypertension (40.8%) to be the most prevalent CVRFs in their study population. Another populationbased cross-sectional study by Sani et al.15 in the north-western region of Nigeria among 300 apparently healthy Nigerians between 18 and 75 years, with mean age of 37.6 ± 10.6 years, found dyslipidaemia (28.3%), hypertension (25.7%) and generalised obesity (21.3%) most prevalent. Despite our study being hospital-based among subjects with CVRFs, the commonest traditional risk factors in our study are similar to these two non-hospital-based studies among apparently healthy adult Nigerians. From these reports and ours, it appears that dyslipidaemia, hypertension and obesity rank highest in frequency among traditional CVRFs in Nigeria. This requires confirmation in larger population studies. The differences in CVRF frequencies between our study and other Nigerian studies may be due to age differences, lifestyle and environmental factors, as well as differences in clinical characteristics. In our study, more than half of the subjects (53.7%) had increased CIMT (≥ 0.9 mm) and one in six (16.1%) had CP. Even though each of our study subjects had at least one CVRF, 46.3% of them still had CIMT within normal limits. A possible explanation for this finding is that the subjects with normal CIMT values probably had had risk factors for a shorter time, since CIMT has been shown to worsen with longer exposure to CVRFs.16 Table 2. Mean CIMT by CVRFs No of cases, total = 162

CIMT (mean ± SD) (mm)

p-value

< 40

0.75 ± 0.23

< 0.001

41–50

1.08 ± 0.43

51–60

1.20 ± 0.34

61–70

1.23 ± 0.33

1.10 ± 0.32

Risk factors Age (years)

Age (years) (mean ± SD)

51.96 ± 15.09

> 70

BMI (kg/m2) (mean ± SD)

27.98 ± 5.59

Gender

80 (49.4)

Male

1.12 ± 0.40

SBP (mmHg) (mean ± SD)

141.27 ± 29.95

Female

1.08 ± 0.42

DBP (mmHg) (mean ± SD)

89.49 ± 21.00

Smoking Present

1.26 ± 0.30

Absent

137

1.07 ± 0.43

Gender (male), n (%)

FBS (mmol/l) (median (Q1–Q3)

4.00 (3.80–5.53)

Cr (µmol/l) (mean ± SD)

100.13 ± 24.26

TC (mmol/l) (mean ± SD)

5.34 ± 1.25

TG (mmol/l) (median (Q1–Q3)

1.96 (1.50–3.61)

Present

1.34 ± 0.32

HDL-C (mmol/l) (mean ± SD)

1.23 ± 0.31

Absent

0.87 ± 0.36

LDL-C (mmol/l) (mean ± SD)

3.59 ± 1.03

Diabetes

83 (51.2)

Present

1.26 ± 0.36

80 (49.4)

Absent

116

1.04 ± 0.42

Age ≥ 50 years, n (%) Hypertension, n (%) Diabetes mellitus, n (%)

45 (27.8)

111

1.23 ± 0.41

Obesity, n (%)

56 (34.6)

Absent

0.81 ± 0.24

Alcohol, n (%)

45 (27.8)

Smoking, n (%)

25 (15.4)

Present

1.31 ± 0.37

Chronic kidney disease n (%)

32 (19.8)

Absent

117

1.02 ± 0.40

1.10 (0.70–1.40)

0.003

< 0.001

Alcohol < 0.001

CKD

Increased CIMT, n (%)

87 (53.7)

Present

130

1.25 ± 0.40

Presence of plaque, n (%)

26 (16.1)

Absent

1.07 ± 0.41

Present

1.34 ± 0.39

Absent

106

0.98 ± 0.37

BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, FBS: fasting blood sugar, Cr: serum creatinine, TC: serum total cholesterol, TG: serum triglycerides, HDL-C: serum high-density lipoprotein cholesterol, LDL-C: serum low-density lipoprotein cholesterol, CIMT: carotid intima–media thickness, SD: standard deviation, CVRFs: cardiovascular risk factors.

< 0.001

Dyslipidaemia Present

CIMT (mm) (median (Q1–Q3)

0.038

Hypertension

111 (68.5)

Dyslipidaemia, n (%)

0.574

0.027

Obesity < 0.001

CIMT: carotid intima–media thickness, CVRFs: cardiovascular risk factors, CKD: chronic kidney disease.

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Table 3. Association between risk factor variables and increased CIMT

Variable Age ≥ 50 years

Logistic regression model Nagelkerke R2 = 0.787

Bivariate model

Normal CIMT (%)

Increased CIMT (%)

UOR

95% CI

p-value

AOR

95% CI

p-value

21 (28.0)

62 (71.3)

6.38

3.2– 12.66

< 0.001

0.048

0.01–0.23

< 0.001

Gender (male)

36 (48.0)

44 (50.6)

1.11

0.598–2.056

0.744

Obesity

10 (13.3)

46 (52.9)

7.293

3.317–16.032

< 0.001

0.163

0.03–0.77

0.022

Hypertension

10 (13.3)

70 (80.5)

26.77

11.43–62.68

< 0.001

0.035

0.008–0.149

Diabetes mellitus

10 (13.3)

36 (41.4)

4.59

2.08–10.12

< 0.001

0.20

0.037–1.07

< 0.001 0.060

Dyslipidaemia

32 (42.7)

79 (90.8)

13.27

5.62–31.32

< 0.001

0.03

0.02–0.428

0.009

Abnormal TC

15 (20.0)

48 (55.2)

4.92

2.43–9.98

< 0.001

0.99

0.17–5.60

0.987

Abnormal TG

23 (30.7)

66 (75.9)

7.11

3.55–14.23

< 0.001

11.68

1.12–122.1

0.040

Abnormal LDL-C

24 (32.0)

57 (65.5)

4.04

2.09–7.78

< 0.001

3.92

0.51–30.12

0.190

Abnormal HDL-C

3 (4.0)

17 (19.5)

5.83

1.64–20.77

0.003

0.83

0.11–6.39

0.859

Smoking

4 (5.3)

21 (24.1)

5.65

1.84–17.32

0.001

0.146

0.02–1.08

0.059

Alcohol

7 (9.3)

38 (43.7)

7.53

3.11–18.30

< 0.001

0.067

0.01–0.36

0.002

Chronic kidney disease

8 (10.7)

24 (27.6)

3.19

1.34–7.62

0.007

0.729

0.14–3.71

0.703

CIMT: carotid intima–media thickness, CI: confidence interval, TC: total cholesterol, TG: triglycerides, LDL-C: low-density lipoprotein cholesterol, HDL-C: highdensity lipoprotein cholesterol, UOR: unadjusted odds ratio, AOR: adjusted odds ratio.

In a Nigerian study by Okeahialam et al.17 in 70 hypertensives, 70 diabetics and 71 non-diabetic non-hypertensive controls aged 30 years and older at a teaching hospital in north-central

Average CCA IMT

2.50

2.00

1.50

1.00

0.50

1.00

2.00

3.00 4.00 5.00 CV risk burden

6.00

7.00

Fig 1. B ox plots showing the relationship between CIMT and the number of CVRFs.

Nigeria, the prevalence of CA in their population was 47.5% for diabetics, 48.9% for hypertensives and 36.5% for the controls. They did not find any significant difference in CIMT between the subjects with hypertension and DM and the controls, although they found a reasonable degree of CA in their controls. Therefore they suggested that there is a need to evaluate for other traditional risk factors other than hypertension and DM, and for novel emerging risk factors. In our cross-sectional study, we evaluated for more traditional risk factors than just hypertension and DM, and our subjects had at least one CVRF. Comparing our subjects to controls who had no traditional CVRFs may have shown significant differences in CIMT between the two groups, as has been demonstrated by other researchers.6,7 In the present study, CIMT increased with advancing age until the seventh decade, after which it decreased. However, the difference between CIMT in the seventh and eighth decades was not statistically significant on post hoc analysis (p > 0.05). Also, 70.1 and 84.6% of subjects with increased CIMT and CP, respectively, were ≥ 50 years of age. Ayoola et al.,18 in a previous study in the same location as ours in 200 hypertensives with a mean age of 58.8 ± 11.6 years and 100 controls with a mean age of

Table 4. Association between risk factor variables and presence of plaques Logistic regression model Nagelkerke R2 = 0.380

Bivariate model

Plaque (–) (%)

Plaque (+) (%)

UOR

95% CI

p-value

AOR

95% CI

p-value

Age ≥ 50 years

61 (44.9)

22 (84.6)

6.76

2.21– 20.67

<0.001

0.21

0.06–0.73

0.014

Gender (male)

67 (49.3)

13 (50.0)

1.03

0.45–2.38

0.945

Obesity

40 (29.4)

16 (61.5)

3.84

1.61–9.18

0.002

0.50

0.18–1.41

0.191 0.041

Variable

Hypertension

57 (41.9)

23 (88.5)

10.63

3.04–37.10

< 0.001

0.30

0.008–1.21

Diabetes mellitus

35 (25.7)

11 (42.3)

2.12

0.89–5.04

0.086

Dyslipidaemia

86 (63.2)

25 (96.2)

14.54

1.92–110.55

0.001

0.18

0.01–2.81

0.220

Abnormal TC

44 (32.4)

19 (73.1)

5.68

2.22–14.50

< 0.001

0.22

0.05–1.08

0.063

Abnormal TG

67 (49.3)

22 (84.6)

5.66

1.85–17.30

0.001

1.42

0.27–7.60

0.681

Abnormal LDL-C

63 (46.3)

18 (69.2)

2.61

1.06–6.40

0.032

2.57

0.52–12.70

0.248

Abnormal HDL-C

13 (9.6)

7 (26.9)

3.49

1.23–9.84

0.014

0.64

0.19–2.13

0.468

Smoking

20 (14.7)

5 (19.2)

1.38

0.47–4.09

0.558

Alcohol

34 (25.0)

11 (42.3)

2.20

0.92–5.25

0.071

Chronic kidney disease

24 (17.6)

8 (30.8)

2.07

0.81–5.32

0.124

Plaque (–): plaque absent, plaque (+): plaque present, CI: confidence interval, TC: total cholesterol, TG: triglyceride, LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, UOR: unadjusted odds ratio, AOR: adjusted odds ratio.

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54.9 ± 10.9 years, found age to be an important predictor of CCA IMT in both groups of subjects. Similarly, Ibinaiye et al.19 found among hypertensives that CCA IMT increased with age from 21 to 70 years in a study population sample drawn from northern Nigeria. Ren et al.6 also showed that middle-aged and older adults with CVRFs displayed increased CIMT and higher grades of severity than the younger age groups in Chinese subjects. We found a relationship between traditional CVRFs and CA in this study. Increased CIMT was independently predicted by age ≥ 50 years (six times the unadjusted odds and 0.05 times the adjusted odds in those under 50 years), hypertension (26 times the unadjusted odds and 0.04 times the adjusted odds in those without hypertension), intake of > 2 g/day of alcohol (7.5 times the unadjusted odds and 0.07 times the adjusted odds in those who had never drunk or not taken in the past year), obesity (seven times the unadjusted odds and 0.2 times the adjusted odds in the non-obese) and dyslipidaemia (13 times the unadjusted odds and 0.03 times the adjusted odds in the non-obese). A Brazilian study by Baroncici et al.20 among 533 CVRF subjects with a mean age of 67.06 ± 12.44 years found male gender in addition to hypertension and age to be risk factors that increased CIMT. Gender was however not associated with increased CIMT in our study. The differences in CVRFs associated with CA in these studies could be due to ethnoracial differences, which should be confirmed in larger multiracial studies. Another key finding of this study was that CIMT increased as the number or burden of CVRFs increased. Clustering of CVRFs was seen in our sample population and the value of CIMT paralleled the number of CVRFs in a linear, dose-dependent fashion. The risk of atherosclerosis increases with increasing burden of CVRFs. Previous studies6,21,22 have confirmed the greater impact of multiple risk factors on CIMT than individual CVRFs in different population groups despite differences in age, number of risk factors and race of the subjects and the carotid segments studied. The prevalence of CP in this study was 16.1%. The prevalence of CP reported from other studies varies quite widely, despite comparability in sonographic methods. This may be explained by differences in sample characteristics, prominent among which are racial and environmental differences. Umeh et al.,13 in a study of normotensive and hypertensive subjects, found an overall prevalence of CP of 25.8% (29.2 and 22.5% in the hypertensive and normotensive subjects, respectively), which is higher than our prevalence despite similarities in the segment of carotid vessel where CIMT and CP were measured and the location of the studies. The older age of their sample compared to ours may partly explain the differences in CP prevalence. Interestingly, we found in our study that the presence of carotid plaque was independently predicted by age ≥ 50 years (seven times the unadjusted odds and 0.2 times the adjusted odds in those < 50 years) and hypertension (11 times the unadjusted odds and 0.3 times the adjusted odds in people without hypertension). In support of our finding, a study in northern Nigeria,19 which measured CIMT and CP in the CCA, similar to our study, but in a slightly younger sample of hypertensive patients (mean age of 50.62 ± 10.46 years) than ours, expectedly found a lower CP prevalence of 10%. A hospital-based study similar to ours and the other two Nigerian studies,13,19 done among Brazilians,20 with a mean age of 67.06 ± 12.44 years, found the prevalence of CP to be 23.8% in their study, which is not unexpected, as the

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mean age of the subjects in their study was higher than in the three Nigerian studies. Much higher prevalence of CP has been reported in the literature in population-based studies such as the Northern Manhattan Cohort Study (NOMAS),8 with a unique race/ ethnic distribution of community residents aged ≥ 39 years, which reported CP prevalence of 58% overall, 70% in Caucasian participants, 52% in Hispanics and 58% in blacks. Also, in Beijing, China,23 the prevalence of CP was 60.3% among urban residents aged 43–81 years, almost 70% in subjects ≥ 60 years, and 80% in those ≥ 70 years. The population-based study setting, which would have eliminated selection bias, in addition to the lower age range of the participants in our study (23–81 years) and the other three hospital-based studies by Umeh et al.,13 Ibinaiye et al.19 and Baroncici et al.,20 compared to the NOMAS (65–74 years) and Beijing studies (≥ 75 years) might explain the lower prevalence of CP found in our study and the three hospital-based studies. From our study, age ≥ 50 years, hypertension, dyslipidaemia, obesity and alcohol intake > 20 g/day explained 78.7% of the variance in CIMT, while age ≥ 50 years and hypertension explained 38.0% of the variance in CP. This finding suggests that CIMT and CP may be influenced by different CVRFs, although age and hypertension influenced both. The relationships between CVRFs and carotid atherosclerosis could be properly evaluated in a longitudinal study. It is not surprising that age and hypertension rank high in the prediction of CIMT and CP because they happen to be the most important risk factors for stroke. Age is the most important non-modifiable risk factor for stroke, while hypertension is the most important modifiable risk factor. Santos et al.,24 in a multicentre Brazilian study, found traditional CVRFs explained 14.1 to 37.3% of the CIMT variance. Kuo et al.,8 in the NOMAS study, found age, SBP, DBP, blood pressure- and lipid-lowering medications and diabetes to be the traditional risk factors that predicted CP and they explained 19.5% of variance in CP burden. This difference can most likely be attributed to different characteristics of the study populations (race, age), the carotid segments measured, and study designs. Kuo et al.8 measured near and far walls of the CCA, the bulb and internal carotid artery (ICA) on both sides, while Santos et al.24 measured the far wall of the CCA, similar to us. Our study was a hospital-based study, in contrast to the population-based studies by Kuo et al.8 and Santos et al.24 Another hospital-based study like ours found age, gender, pack-years of smoking, SBP, DBP, DM, HDL-C, and blood pressure- and lipid-lowering medications to be the most significant determinants of carotid plaque area, explaining 52% of the variance in total plaque area (TPA).25 Apart from the difference in the predictors of CP between our study and this hospital-based study, the difference in the measurement of plaque considered (plaque thickness in our study versus total plaque area in theirs) may explain the higher percentage of variance in CP in that study.

Limitations The evidence from this study is limited by its cross-sectional design and hospital-based setting. The analysis was also limited to the CCA, which might not have detected the presence of atherosclerosis in other vascular beds or the more distal segments

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of the carotid artery. However, while prospective studies, which will generate IMT data in the carotid bulb and ICA are pending, our findings provide important insights into the determinants of subclinical CA in this population. Most of the subjects in the present study presented with more than one risk factor and received more than one medical therapy. However, assessment of the effects of each medication on each risk factor, as well as the effects of the prescribed medication on CIMT was not performed.

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Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2497. 11. Bonita R, Courten M, Dwyer T, Jamrozik K, Winkelmann R. Surveillance of risk factors for noncommunicable disease: The WHO STEP wise approach. Summary. Geneva: WHO; 2001. 12. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima–media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004,

Conclusion This study provides evidence that a linear, graded and independent association exists between CVRFs and CIMT and that the risk of CP increases with increasing number of CVRFs. Age ≥ 50 years, hypertension, obesity and alcohol intake > 20 g/day were independent contributors to CIMT variance, while age ≥ 50 years and hypertension were the contributors to CP variance. About 21.3% of CCA IMT and 62.0% of CP could not be explained by traditional CVRFs in this study. This observation represents strong evidence to encourage future studies focusing on the influence of novel CVRFs on CIMT and CP.

Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 2012; 34: 290–296. 13. Umeh EO, Agunloye AM, Adekanmi AJ, Adeyinka AO. Ultrasound evaluation of intima–media thickness of carotid arteries in adults with primary hypertension at Ibadan, Nigeria. West Afr J Med 2013; 32(1): 62–67. 14. Akintunde AA, Salawu AA, Opadijo OG. Prevalence of traditional cardiovascular risk factors among staff of Ladoke Akintola University of technology, Ogbomoso, Nigeria. Niger J Clin Pract 2014; 14: 750–755. 15. Sani MU, Wahab KW, Yusuf BO, Gbadamosi M, Johnson OV, Gbadamosi A. Modifiable cardiovascular risk factors among apparently healthy adult Nigerian population – A cross sectional study. BMC Res

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lipid profile with carotid intima media thickness and plaque. BMC

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with type 1 diabetes mellitus. Cardiovasc Diabetol 2011; 10: 53. Doi:

Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu

17. Okeahialam BN, Alonge BA, Pam SD, Puepet FH. Carotid intima

a decade: the multi-ethnic study of atherosclerosis. Stroke 2014; 45:

media thickness as a measure of cardiovascular disease burden in

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McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease

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in the 21st century: implications of the Pathobiological Determinants

18. Ayoola OO, Onuwaje AM, Akintomide AO. Sonographic assessment

of Atherosclerosis in Youth (PDAY) Study. Circulation 2008; 117:

of the carotid intima-media thickness on B-mode ultrasonography in a 19. Ibinaiye PO, Kolade-Yinusa HO, Abdukadir A, Yinusa T. Relationship

of potentially modifiable risk factors associated with myocardial infarc-

of carotid artery intima media thickness to blood pressure, age and body

2004; 364: 937–952.

O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, et

cardiovascular risk factors. Int J Cardiol Heart Vasc 2015; 9: 48–51. 21. Urbina EM, Kimball TR, McCoy CE, Khoury PR, Daniels SR, Dolan

376: 112–123.

LM. Youth with obesity and obesity-related type 2 diabetes mellitus

Ren L, Cai J, Liang J, Li W, Sun Z. Impact of cardiovascular risk

demonstrate abnormalities in carotid structure and function. Circulation 2009; 119: 2913–2919. 22. Niu L, Zhang Y, Qian M, Meng L, Xiao Y, Wang Y, et al. Impact of

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Zhang F, Feng L, Chen Y, Geng Z, Xu X. Relationship between

ness and elasticity. PLoS One 2013; 8: e67809. doi: 10.1371/journal.

carotid artery intima–media thickness and cardiovascular risk factors in Chinese Uygur population. Int J Clin Exp Med 2014; 7: 5412–5420. Kuo F, Gardener H, Dong C, Cabral D, Della-Morte D, Blanton SH, et al. Traditional cardiovascular risk factors explain the minority of the variability in carotid plaque. Stroke 2012; 43: 1755–1760. 9.

and carotid plaque represent different adaptive responses to traditional

22 countries (the interstroke study): A case- control study. Lancet 2010;

cross-sectional study. PLoS One 2015; 10(12): e0144182. doi: 10.1371/

mass index of hypertensive adult patients. Arch Int Surg 2015; 5: 63–68. 20. Baroncici LAV, Sylvestre LC, Filho RP. Carotid intima–media thickness

al. Risk factors for ischemic and intracerebral haemorrhagic stroke in

factors on carotid intima–media thickness and degree of severity: a

Nigerian population. Niger Med J 2015; 56(5): 357–361.

Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, et al. Effect tion in 52 countries (the interheart study): Case-control study. Lancet

10.1186/1475-2840-10-53.

KJ, et al. Predictors of carotid thickness and plaque progression during

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Notes 2010; 3:11. Doi: 10.1186/1756-0500-3-11. 16. Pozza RD, Beyerlein A, Thilmany C, Weissenbacher C, Netz H, Schmidt

pone.0067809. 23. Wang W, Wu YF, Zhao D, Yang Y, Lang LR, Wang M, et al. Distribution characteristics and risk factors of carotid atherosclerosis in middle-aged and elderly Chinese. Chin J Cardiol 2010; 38: 553–557. 24. Santos IS, Alencar AP, Rundek T, Goulart AC, Barreto SM, Pereira AC,

Naqvi TZ, Lee MS. Carotid intima–media thickness and plaque in

et al. Low impact of traditional risk factors on carotid intima-media

cardiovascular risk assessment. J Am Coll Cardiol Cardiovasc Imaging

thickness: the ELSA–Brasil cohort. Arterioscler Thromb Vasc Biol 2015;

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25. Lanktree MB, Hegele RA, Schork, Spence JD. Extremes of unexplained

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Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult

3(2): 215–221.

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Review Article Double trouble: psoriasis and cardiometabolic disorders Nasrin Goolam Mahyoodeen, Nigel J Crowther, Mohammed Tikly

Abstract Psoriasis (PsO) is a chronic immune-mediated inflammatory skin disorder associated with numerous co-morbidities. This descriptive review focuses on the cardiometabolic co-morbidities of PsO with reference to the epidemiology and pathogenetic mechanisms linking PsO and cardiometabolic disease (CMD). Registry-based studies have shown PsO to be associated with an increased risk of cardiovascular morbidity and mortality. Factors linking PsO and CMD include: chronic inflammation, obesity, classic cardiovascular risk factors, and the effects of systemic therapy used to treat PsO. Chronic inflammation is associated with PsO itself, and with obesity. Adipose tissue is responsible for the secretion of various adipokines, which together with pro-inflammatory cytokines arising from the psoriatic plaque, contribute to the proinflammatory and pro-atherogenic environment. Systemic therapy aimed at decreasing inflammation has been shown to improve CMD in PsO. Screening for and treating CMD and initiating lifestyle modifications will remain the most important interventions until further data emerge regarding the effect of systemic therapy on CMD progression.

Keywords: psoriasis, cardiovascular disease, cardiometabolic disease, co-morbidities, metabolic syndrome, obesity Submitted 26/6/17, accepted 6/12/17 Published online 13/12/17 Cardiovasc J Afr 2018; 29: 189–194

exceeds that observed in several chronic conditions including malignancy and heart failure.3 A wide range of co-morbidities are associated with PsO, ranging from chronic inflammatory disorders such as inflammatory arthritis, [often referred to as psoriatic arthritis (PsA)],4 Crohn’s disease,4 neuropsychiatric disorders such as Parkinsonism,5 psychiatric disease,6,7 malignancies,4,8 as well as cardiometabolic diseases9-13 (Table 1). In this descriptive review, we examine the epidemiological and pathological evidence linking PsO and cardiometabolic disorders, with a particular focus on cardiovascular disease (CVD). We conducted a PubMed search using the term ‘psoriasis’ in combination with the terms ‘cardiovascular disease’, ‘co-morbidities’, ‘diabetes’, ‘metabolic syndrome’, ‘obesity’, ‘hypertension’, ‘dyslipidaemia’, ‘non-alcoholic fatty liver disease’ and ‘inflammation’. Our search was limited to articles published in English.

Immunopathogenesis of psoriasis The interplay between genetic factors and environmental triggers results in the classic psoriatic plaque, characterised histologically by epidermal hyperplasia, vascular hyperproliferation and chronic inflammation.4 Common triggers for the disease are local skin trauma (Koebner phenomenon), stress, Streptococcus pyogenes, infection and smoking.4 About a third of patients have a family history of PsO and genome-wide analysis studies have shown the PSORS1 gene, located on chromosome 6p, accounts for between 35 and 50% of the heritability of PsO.24

www.cvja.co.za

DOI: 10.5830/CVJA-2017-055

Table 1. Co-morbidities associated with psoriasis • Psoriatic arthritis4

Psoriasis (PsO) is a complex, chronic, immune-mediated inflammatory skin disorder, which has a global prevalence ranging between 0.91 and 8.5%.1 It is recognised by the World Health Organisation as a major global health challenge,2 and is associated with impaired psychological quality of life, which

• Crohn’s disease4 • Parkinson’s disease5 • Psychiatric disease –– Major depression6 –– Alcohol abuse7 • Malignancy4,8 • Chronic kidney disease14

Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Nasrin Goolam Mahyoodeen, MB ChB, FCP (SA), Cert Endocrinol Metab (SA), mahyoodeen@yahoo.com Mohammed Tikly, FRCP, PhD

Department of Chemical Pathology, National Health Laboratory Services and University of the Witwatersrand, Johannesburg, South Africa Nigel J Crowther, PhD

• Cardiometabolic diseases –– Obesity15 –– Metabolic syndrome13,16 »» Type 2 diabetes17 »» Hypertension17 »» Dyslipidaemia18 –– Myocardial Infarction10 –– Stroke19,20 –– Abdominal aortic aneurysms 21 –– Non-alcoholic fatty liver disease22 • Hyperuricaemia and gout 23

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A complex cross-talk between keratinocytes and dendritic cells (DCs) in the skin, and T lymphocytes, mediated by a variety of cytokines, results in keratinocyte hyperplasia, the characteristic histological feature of PsO.25 Initially, keratinocytes recruit DCs to produce IL-23 and IL-12, which in turn activate mostly T helper (Th) 1 and Th17 cells, resulting in further up-regulation of cytokine secretion, especially IL-17, interferon-γ (IFNγ), tumour necrosis factor (TNF) and IL-22.12 These cytokines amplify psoriatic inflammation and keratinocyte hyperplasia.4 Moreover, pro-angiogenic factors produced by keratinocytes such as vascular endothelial growth factor drive abnormal vascular proliferation within the psoriatic plaque.4,25

Psoriasis and cardiometabolic disorders Recent interest has focused on the wide spectrum of cardiometabolic co-morbidities observed in subjects with PsO. These include obesity,15 the metabolic syndrome (MetS) and its components,13,16 non-alcoholic fatty liver disease (NAFLD)22 and CVD10,19,20,26-28 (Table 1). The dual burden of PsO and associated co-morbidities impacts negatively on health-related quality of life and is associated with an increased risk of premature death.8,29 There is now a large body of evidence linking chronic inflammation to accelerated atherosclerosis.30,31 Rheumatoid arthritis (RA) was the first chronic inflammatory condition to be associated with an increased risk of premature cardiovascular death, by as much as 50%.32 The traditional Framingham risk factors such as type 2 diabetes mellitus (T2DM), hypertension and smoking have been shown to only partly account for the increased cardiometabolic risk in RA.33 Mechanistically, the pro-inflammatory state of RA leads to cytokine-mediated accelerated atherosclerosis.34,35 The epidemiological evidence supporting the notion that PsO is associated with a similar increased CMD risk is less wellestablished and the precise pathobiology driving atherosclerosis in PsO is complex and not fully elucidated. One hypothesis is that the chronic inflammatory state of PsO triggers a ‘psoriatic march’ where the pro-inflammatory milieu leads to insulin

resistance and endothelial cell dysfunction, predisposing to accelerated atherosclerosis, finally manifesting as clinical CMD.36

Epidemiology of cardiometabolic disease in psoriasis The association of PsO with cardiovascular disease (CVD) was first proposed by McDonald and Calabresi in 1973 in a letter published in the New England Journal of Medicine.37 In a subsequent retrospective record review comparing 323 PsO and 325 non-psoriatic dermatology patients, they reported an increased prevalence of ‘occlusive vascular disease’, which included myocardial infarction (MI), stroke, thrombophlebitis and pulmonary embolism in PsO patients.38 Several recent registry-based studies, mainly from the United Kingdom (UK) and Denmark have supported these initial observations (Tables 2, 3). In a prospective study of 130 000 PsO patients and more than 500 000 control subjects in the UK General Practice Research Database (UKGPRD), PsO was found to be a risk factor for MI, with hazard ratios (HR) of 1.54 (95% CI: 1.24–1.91) and 7.08 (95% CI: 3.06–16.36) in mild and severe cutaneous PsO, respectively.10 The increased risk remained even after controlling for major cardiovascular risk factors such as age, gender, smoking, T2DM, hypertension, prior MI, dyslipidaemia and body mass index (BMI). In the Danish studies of more than 36 000 PsO patients, PsO was associated with an increased risk of adverse CV events and all-cause mortality.26 Younger patients and those with severe cutaneous disease appeared to have the greatest risk, a finding that was similar to that for the UKGPRD cohort.24 Two metaanalyses, comprising 14 cohorts of patients from Europe and the United States have shown that the risk for CVD is greatest in patients with severe PsO.27,28 A major limitation of many studies included in the meta-analyses was the lack of adjustment for traditional cardiovascular (CV) risk factors. Some smaller studies have failed to show the association between PsO and CVD. A prospective study of 1 380 PsO patients, followed up for 10 years, showed no increase in

Table 2. Longitudinal studies arising from the UK General Practice Research database Reference

Sample size

Control group size

HR mild PsO

HR severe PsO

Gelfand et al.10

Mild: 127 139 Severe: 3 837

PsO may confer an independent risk of MI

1.54 (1.24–1.91)

7.08 (3.06–16.36)

Gelfand et al.20

Age, gender, HT, DM, cholesterol, smoking, cerebrovascular disease

Both mild and severe PsO were independent risk factors for stroke

1.06 (1.0–1.1)

1.43 (1.1–1.9)

14 330

Age, gender, smoking, DM, HT, hyperlipidaemia

Severe PsO was an independent risk factor for cardiovascular mortality

–

1.57 (1.26–1.96)

14 330

Age, gender

Patients with severe PsO were at increased risk for death from CVD

–

1.57 (1.26–1.96)

Variables in multivariate models

Main outcomes

556 995

Age. gender, HT, DM, BMI, previous MI, cholesterol, smoking

Mild: 129 143 Severe: 3 603

Mild: 496 666 Severe: 14 330

Mehta et al.51

Severe: 3 603

Abubara et al.52

Severe: 3 603

HT, hypertension; DM, diabetes mellitus; BMI, body mass index; MI, myocardial infarction.

Table 3. Longitudinal studies arising from the Danish Nationwide cohort Reference

Sample size

Control group size

Variables in multivariate models

Main outcomes

RR mild PsO

RR severe PsO

Ahlehoff et al.26

Mild: 34 371 Severe: 2 621

4 003 625

Age, gender, co-morbidities, medication

Cardiovascular mortality was increased in patients with PsO

1.14 (1.06–1.22)

1.57 (1.27–1.94)

Ahlehoff et al.26

Mild: 34 371 Severe: 2 621

4 003 625

Age, gender, co-morbidities, medication

MI was increased in patients with PsO

1.22 (1.12–1.33)

1.45 (1.10–1.90)

Ahlehoff et al.19

Mild: 36 765 Severe: 2 793

4 478 926

Age, gender, co-morbidities, medication

PsO was associated with an increased risk of ischaemic stroke

1.25 (1.17–-1.64)

1.65 (1.33–2.05)

MI, myocardial infarction.

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cardiovascular mortality (standard mortality ratio: 0.83, 90% CI: 0.7–1.0).39 In another study comparing over 15 000 patients and over 27 000 controls, PsO was found to be an equivocal risk factor for admission for ischaemic heart disease (IHD), after controlling for age and gender (HR = 1.10, 95% CI: 0.99–1.23).40 Moreover, age- and gender-matched survival analysis revealed no difference in the risk of acute MI. A recent Dutch study of 262 ambulatory PsO patients over 55 years of age showed no increase in CV morbidity and mortality.41 The strength of this study was that CV events were identified using clinical data and specialised investigations, including CT scans, and electro- and echocardiography to minimise classification bias (all previous studies had used diagnostic codes). However, the limitations of this study were the small sample size, older age of the cohort (mean = 64 years), and that most patients had mild cutaneous PsO. Overall, the balance of evidence suggests that PsO, especially severe cutaneous disease, is associated with an increased risk of CVD. Other metabolic disorders shown to occur more frequently in PsO are the MetS (and its components), hyperuricaemia, and non-alcoholic fatty liver disease (NAFLD). In a UK study, the MetS was more prevalent in PsO patients compared to the general population, more so in patients with severe than with mild cutaneous disease (OR for mild PsO = 1.22, 95% CI: 1.11–1.35; severe PsO = 1.98, 95% CI: 1.62–2.43).13 Furthermore, systematic reviews suggest that individual components of the MetS (dysglycaemia, obesity and hypertension) occur more frequently in PsO patients15,42,43 (Table 4). A meta-analysis of 16 observational studies found that PsO patients were more likely to be obese (pooled OR = 1.66, 95% CI: 1.17–1.82).15 A combined mean BMI of 30.6 kg/m2 has been observed in a review of clinical trials where biologics have been tested for the treatment of moderate to severe cutaneous PsO.44 Studies have also shown that PsO is associated with abdominal obesity, which is a proxy measure of visceral adipose tissue, and is a well-recognised risk factor for T2DM, hypertension, coronary artery disease and decreased life expectancy.45 The prospective Nurses’ Health Study II identified 809 incident cases of PsO and observed that it was more common in subjects with an increased waist circumference, a surrogate marker for abdominal visceral fat.46 In a cross-sectional case–control study, subjects with PsO were shown to have higher levels of visceral fat measured by computed tomography (CT) compared to controls.47 The role of visceral fat in chronic inflammation is discussed below. Several studies have shown an increased prevalence of hypertriglyceridaemia in PsO patients.13,16,18 Comparisons of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) between patients and controls have yielded conflicting results. Some studies show an increase in TC and LDL-C levels in PsO patients compared to controls,18 whereas others show no significant differences or decreased levels.48 Asymptomatic hyperuricaemia is more common in PsO, even after correcting Table 4. Systematic reviews showing association of type 2 diabetes, hypertension and obesity with psoriasis Odds ratio

No of studies

Overall

Mild PsO

Severe PsO

Type 2 diabetes42

1.59 (1.38–1.83)

1.53 (1.16–2.04)

1.97 (1.48–2.62)

Hypertension43

1.58 (1.42–1.76)

1.30 (1.15–1.47)

1.49 (1.20–1.86)

Obesity15

1.66 (1.49–1.89)

1.46 (1.17–1.82)

2.23 (1.63–2.05)

Risk factor

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for confounders (age, gender and features of the MetS).23 Likewise, the risk of gout is also increased in PsO and PsA (HR = 1.71, 95% CI: 1.36–2.15).49 Several studies have demonstrated an increased prevalence of NAFLD in subjects with PsO.22 The diagnostic methods used in these studies included ultrasonography, biochemistry, transient elastography, liver biopsy, or combinations thereof. The prevalence of NAFLD was 65.6 versus 35% in matched controls (p < 0.001) when measured by ultrasonography.50

Pathophysiological basis linking psoriasis with cardiometabolic disease Inflammation: the common denominator There is now overwhelming evidence that chronic sub-clinical systemic inflammation accelerates atherosclerosis,29 including histological studies demonstrating the presence of inflammation in atherosclerotic lesions.53 Both innate and adaptive immunity are known to play a role in this process.30 This has been welldocumented in type 2 diabetes,54 and also in RA34 and systemic lupus erythematosus.55 Further evidence linking inflammation to atheroslcerosis is that C-reactive protein (CRP), a wellrecognised biomarker of inflammation, is also associated with atherothrombotic disease, as well as the MetS and its components.56 As PsO is a systemic disease, the prevailing pro-inflammatory milieu is considered to contribute to the increased CMD risk.57 A meta-analysis of 78 studies found significantly elevated levels of pro-inflammatory cytokines, namely IL-6, TNF, CRP, E-selectin and ICAM 1, in PsO patients compared to controls.58 Obesity, which, as discussed previously, is prevalent in subjects with PsO, is a further source of inflammation. White adipose tissue (WAT), which is the primary component of visceral fat, is composed of both adipocytes and other immunologically active cells such as macrophages.59 Hence it is both metabolically and immunologically active. Adipocytes secrete adipokines, which are mainly pro-inflammatory, such as leptin, visfatin and resistin; as well adiponectin, which has anti-inflammatory properties.59 Other pro-inflammatory factors that are produced by WAT include TNF, IL-1, IL-6 and plasminogen activator inhibitor type 1 (PAI-1), all of which have been shown to directly or indirectly affect endothelial cell function and insulin sensitivity.60

Possible genetic links Epidemiological studies suggest a common genetic link between PsO, T2DM and obesity. In a 2016 cross-sectional, populationbased twin study in 33 588 Danish subjects, a significant association between PsO, T2DM and obesity was observed.61 Analysing data from twins discordant for PsO and including both monozygotic and dizygotic twin pairs, the study observed evidence for a shared genetic aetiology of obesity and PsO. Moreover, there is evidence indicating that the strongest predictor of major adverse cardiovascular events (MACE) in patients with PsO is a family history of CVD.62 In a study of more than 25 000 mainly young Danes with mild PsO, and over 4 000 patients with severe disease, approximately two-thirds of patients in each group had a family history of CVD. The adjusted incidence rate ratios of MACE (with 95% CI) in patients with a family history of cardiovascular events were 1.28 (1.12–1.46) in those with mild PsO, and 1.62 (1.14–2.30) in

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subjects with severe PsO. There was no increased risk for MACE in PsO patients without a family history of CVD.

Conventional cardiovascular risk factors Patients with PsO have a higher burden of classic CV risk factors compared to the general population.11,63 In particular, and as discussed previously, there are higher prevalences of T2DM, dyslipidaemia, hypertension and obesity in subjects with PsO. Furthermore, it is known that patients with PsO have a higher prevalence of smoking than those who do not have PsO.64

Drug therapy Several drugs used to treat cutaneous PsO and PsA potentially increase the risk of cardiometabolic disorders. These include oral corticosteroids, cyclosporine and acitretrin, which may precipitate weight gain and unmask hypertension, T2DM and dyslipidaemia.8,65 Non-steroidal anti-inflammatory drugs, used in the treatment of PsA, increase the risk of hypertension and CVD.66

Strategies to reduce cardiovascular risk in psoriasis Psoriasis management guidelines highlight the importance of addressing cardiometabolic risk factors in PsO.67 There is a need for further research to address whether systemic therapy for PsO may potentially ameliorate CV risk.67,68

General measures Several expert groups recommend clinical and biochemical screening of PsO patients for early detection and management of co-morbidities such as hypertension, dysglycaemia and lipid abnormalities.69,70 The cessation of smoking, which is common in PsO,71,72 is critical in the management of this group of patients.68 Weight reduction not only reduces CV risk but has also been shown to attenuate the severity of PsO. A randomised, control study investigating the impact of hypocaloric dietary intervention and physical activity over 20 weeks in 303 overweight/obese patients with moderate to severe plaque PsO demonstrated a 48% reduction in PsO area and severity index score in the interventional arm, compared to only 25.5% in the informationonly arm (p = 0.02).73 The weight loss target of ≥ 5% was achieved in 29.8% of the interventional arm compared with 14.5% in the information-only arm (p = 0.001). There are also anecdotal case reports of improvement in PsO following bariatric surgery.74,75

mortality rate in RA.76 The cardioprotective effect of MTX is mediated by increased adenosine levels that bind to adenosine A2 receptors on macrophages and block foam cell formation.77,78 In PsO, MTX and biologics such as the TNF inhibitors have been shown to lower the risk for CVD.79 Use of these agents in a Danish study have shown lower incidence rates of death, MI and stroke than patients on other therapies, with incidence (95% CI) rates of 6.0 (2.7–13.4) and 17.3 (12.3–24.3) for biologics and MTX, respectively, compared to 44.5 (34.6–57.0) for other therapies. Data from a small, prospective study and retrospective analyses suggest that systemic anti-inflammatory therapies (such as MTX or TNF blockers) in subjects with PsO or PsA may have the potential to ameliorate cardiovascular disease.79,80 While these have generated considerable interest, no conclusive data from randomised clinical trials are available to date.

Impact of therapies for co-morbidities The anti-diabetic drugs pioglitazone81 and glucagon-like peptide 1 (GLP 1) agonists82 have been shown to improve PsO. Pioglitazone is a well-known insulin-sensitising agent, hence its efficacy may support the role of insulin resistance in the pathogenesis of PsO. The GLP 1 agonists are thought to be effective as a result of their extra-pancreatic effects, particularly their anti-inflammatory action.83 However, they may also exert indirect effects as their use is also associated with weight loss.

Conclusions A growing body of evidence supports the association between cardiometabolic diseases and PsO. The risk for CMD appears to be greatest with moderate–severe PsO and PsA. A complex interaction seems to exist between body adiposity, chronic inflammation and the psoriatic plaque, which leads to increased CVD risk.57 Screening and appropriate intervention, including lifestyle modification, to reduce the burden of cardiometabolic disease are important in the overall management and healthrelated quality of life of patients with PsO. N Goolam Mahyoodeen has received a grant from the Carnegie Corporation of New York, NY, USA (Grant Number: B 8749.RO1) and the Astra Zeneca Research Trust.

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Given the earlier discussion on chronic systemic inflammation as a risk factor for CMD, there is emerging evidence that controlling inflammation reduces the risk of CMD. There are several lines of clinical and biochemical evidence suggesting that methotrexate (MTX), a drug widely used for the treatment of moderate–severe cutaneous PsO and PsA, has anti-inflammatory and cardioprotective properties. MTX was found to provide a substantial survival benefit, mainly by reducing cardiovascular

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ECG Series Irregular, narrow-complex tachycardia Julian Hoevelmann, Charle Viljoen, Ashley Chin

A 54-year-old lady with longstanding hypertension and a recent diagnosis of atrial fibrillation presented to the emergency unit The correct differentiation of an irregular, narrow-complex with a two-day history of palpitations and mild dizziness. This tachycardia has crucial implications for the therapeutic was preceded by a few weeks of pedal oedema, with progressively management of these conditions. In this article we present worsening dyspnoea and effort intolerance. Clinically, she was a differential diagnostic and treatment approach to irregular, mildly distressed with peripheral oedema, a respiratory rate of 24 narrow-complex tachycardias. breaths a minute and blood pressure of 129/84 mmHg. She had a low-volume pulse that was irregularly irregular, with a rate of Keywords: ECG, atrial fibrillation, atrial flutter, multifocal atrial around 120 beats per minute. The jugular venous pressure was not tachycardia elevated, but her apex beat was diffuse and minimally displaced. On auscultation she had heart sounds of variable intensity, but no Cardiovasc J Afr 2018; 29: 195–198 www.cvja.co.za murmurs. Her chest had soft crackles in the bases. Echocardiography revealed a non-dilated left ventricle with signs of concentric left ventricular hypertrophy (LVH) and impaired left ventricular (LV) function [LV ejection fraction Hatter Institute for Cardiovascular Research in Africa, (LVEF) of 40%]. The left atrium was dilated and there was mild University of Cape Town, South Africa, and Hannover mitral regurgitation (MR). She had normal pulmonary artery Medical School, Department of Cardiology and Angiology, pressures and right ventricular (RV) function. Hannover, Germany dollie, shireen ID:026928135 22-JAN-2018 10:20:40 Her ECG (Fig. 1) showed an irregular, GROOTE SCHUUR HOSPITAL narrow-complex Julian Hoevelmann Vent. rate 117 BPM Atrial fibrillation tachycardia. with rapid ventricularVery responserapid, with premature ventricular or aberrantly conducted complexes continuous and variable atrial activity Female of Caucasian PR intervalSchuur Hospital * ms & T wave abnormality, consider inferior ischemia or digitalis effect Division Cardiology, Groote and ST QRS duration 102 ms Abnormal ECG was seen. The question was raised whether this ECG could be Room: ms University of Cape Town,QT/QTc South Africa 364/507 Loc:34 P-R-T axes * 4 -58 in keeping with ‘course’ atrial fibrillation or atrial flutter with Charle Viljoen, MB ChB, MMed, FCP (SA), charle.viljoen@uct.ac.za variable block (Fig. 2). Careful inspection of the atrial activity Ashley Chin, MB ChB, FCP (SA), MPhil Technician: revealed that there was subtle variation in rate, amplitude and Test ind:

Abstract

Referred by:

Confirmed By: DOC UNCONFIRMED

aVR

aVL

III

aVF

V1 25mm/s

10mm/mV

150Hz

7.1.1

12SL 239

CID: 1

EID:9 EDT: 14:52 24-JAN-2018 ORDER: Page 1 of 1

Fig. 1. T he 12-lead ECG with coarse atrial fibrillation, which could easily be mistaken for atrial flutter.

Atrial ﬁbrillation

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Atrial ﬁbrillation Atrial fibrillation

Note ﬁbrillatory waves have constantly changing morphologies

Atrialwaves ﬂutter with a variable block Note ﬁbrillatory have constantly changing morphologies Note fibrillatory waves have constantly changing morphologies Atrial flutter with a variable block

Atrial ﬂutter with a variable block

V1 Note flutter waves have an identical morphology throughout Note ﬂutter waves have an identical morphology throughout

Fig. 2. C omparison of coarse atrial fibrillation (fibrillatory wave morphology is not regular and uniform) and atrial flutter (flutter-wave morphology is regular and uniform).

In atrial fibrillation there is chaotic, asynchronous atrial morphology. Also, there is no pattern to the irregularity of the Note ﬂutter waves have an identical morphology throughout impulse propagation, with multiple wavelets that course RR intervals. Based on these findings, the diagnosis of atrial irregularly through the atria and reach the AV node at irregular fibrillation was made. intervals, which cause irregular AV nodal conduction. On the The patient’s heart failure therapy was optimised with ECG (Fig. 3), atrial fibrillation is recognised by an irregular diuretics. She was initially treated with a rate-control strategy and RR interval with no pattern to the irregularity and the absence oral anticoagulation in accordance with standard international of distinct P waves. Very rapid, continuous, irregular ‘chaotic’ guidelines.1,2 She will be seen in the rhythm clinic for consideration of a cardioversion and a future rhythm-control strategy with activity (called fibrillatory waves) can be seen. These are best catheter ablation. seen in V1 and can be coarse or fine. Fibrillatory waves can be as fast as 400–600 per minute. The ventricular rate, however, can be fast, normal or slow, depending on AV nodal conduction.9 Causes of irregular, narrow-complex tachycardia Atrial flutter (AFL), the second most common pathological The differential diagnosis of an irregular, narrow-complex supraventricular tachyarrhythmia, shares many risk factors with tachycardia includes atrial fibrillation, atrial flutter with variable atrial fibrillation.10 In contrast to AF, AFL is caused by rapid, continuous atrial activity around a fixed re-entry circuit, usually atrio-ventricular (AV) block and multifocal atrial tachycardia. an anti-clockwise circuit in the right atrium. Flutter waves have Table 1 shows the differentiating electrocardiographic features. a saw-tooth pattern and are best appreciated in standard lead Atrial fibrillation (AF) is the most common cause of an II and lead V1 (Fig. 4). It can be difficult to differentiate atrial irregular, narrow-complex tachycardia, affecting approximately flutter with variable block from coarse atrial fibrillation. 33 million people worldwide.3 Patients of older age are at increased risk of developing AF, as well as patients with In contrast to AF, flutter waves are regular and discrete, hypertensive, valvular and ischaemic heart disease.4 AF can be uniform in morphology (in keeping with the organised re-entry triggered by acute alcohol intoxication, thyrotoxicosis, sepsis or circuit) with a fixed atrial rate usually around 300 per minute dehydration.5 More recently, AF has been shown to be associated (can range between 240 and 360). The ventricular rate depends with obesity and obstructive sleep apnoea.6-8 on the degree of AV block (e.g. QRS rate of approximately 150 Table 1. Diagnostic approach to irregular, narrow-complex tachycardia Key features

Atrial fibrillation

Atrial flutter

Atrial wave morphology

Fibrillatory waves (f waves, irregular in morphology and amplitude)

Flutter waves At least three different P-wave morpholo(F waves, regular in morphology and amplitude) gies in same lead

Multifocal atrial tachycardia

Atrial wave timing

Variable

Identical

Variable

Atrial wave cycle length

400–600 per min

240–360 per min

Usually < 130 per min

PR interval

No obvious PR interval

Variable PR intervals

Ventricular (QRS) response

Usually narrow QRS complexes, often vary in amplitude, constantly irregular RR intervals

Usually narrow QRS complexes, constant F/R ratios

Usually narrow QRS complexes, random and constantly irregular RR intervals

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have aavariable morphology waveswaves have variable morphology V1 Fibrillatory Fibrillatory

No pattern to theirregularity irregularity of the RRof interval No pattern to the the RR interval

Fig. 3. I n atrial fibrillation, the chaotic atrial activity translates to irregular fibrillatory waves.

Regular and uniformmorphology morphology of flutter waves Regular and uniform of ďŹ&#x201A;utter waves

Regular atrial activity

300

3:1

Variable AV conduction

2:1

Variable AV conduction conduction Variable AV

Fig. 4. I n atrial flutter with a variable block, the re-entry circuit results in uniform flutter waves.

Variable P-wavemorphologies morphologies Variable P wave

Variable intervals Variable PRPRintervals

Fig. 5. I n multifocal atrial tachycardia, there are recognisable P waves with at least three different morphologies.

in 2:1 block, approximately 100 in 3:1 block, and approximately 75 in 4:1 block). In patients with AV node disease or who take drugs that slow AV conduction, the ventricular response to atrial flutter may be irregular, though less erratic than in atrial fibrillation.9,10 Multifocal atrial tachycardia (MAT) is a rare condition that occurs in patients with advanced pulmonary disease or who are receiving theophylline treatment.11 In multifocal atrial tachycardia there is random firing of different atrial ectopic foci. MAT is defined as a rhythm with an atrial rate > 100 beats per

minute with at least three morphologically distinct P waves (Fig. 5), irregular P-P intervals, and an isoelectric baseline between P waves (distinguishing MAT from AF and AFL).9,10

The correct treatment depends on the correct diagnosis The correct distinction between AF, AFL and MAT is of paramount importance, since the three conditions require different therapeutic approaches.

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To reduce the risk of thromboembolism, appropriate oral anticoagulation should be offered to patients with AF and AFL and who do not have any contra-indications to vitamin K antagonists (VKAs) or non-vitamin K oral anticoagulants (NOACs).2 On the other hand, patients with MAT do not require anticoagulation. Uncontrolled tachyarrhythmia due to atrial fibrillation or flutter can result in acute cardiac decompensation as well as tachycardia-induced cardiomyopathy (TIC) in the long term.12 Rate control is therefore an essential part in the treatment of AF and AFL.13 In atrial fibrillation, rhythm control was not found to be superior to rate control in the AFFIRM and RACE trials.14,15 Rhythm-control strategies were often associated with drug toxicity of anti-arrhythmic drugs and failure to maintain sinus rhythm in atrial fibrillation. Pulmonary vein isolation (PVI) is another rhythm-control strategy that may not require additional anti-arrhythmic drugs. Catheter ablation (pulmonary vein isolation) can improve LV systolic function in patients with AF and reduced LVEF and may improve survival.16 In atrial flutter, a rhythm-control strategy is often preferred over a rate-control strategy. Radiofrequency ablation is a highly effective treatment of typical atrial flutter involving the right atrial cavotricuspid isthmus. For these reasons, rate control of atrial flutter is usually not a long-term option, especially if patients are symptomatic, if the ventricular rate is difficult to control (which is not uncommon) and if there is an associated tachycardia-induced cardiomyopathy.17 Previous studies have found an improvement in LV systolic function after RFA in patients with AFL and a reduced LVEF.18,19 MAT is treated by treating the underlying lung disease.20 Betablockers are often not well tolerated in this population.

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lation (Framingham Heart Study): a community-based cohort study. Lancet 2009; 373: 739–-745. 5.

Sibley S, Muscedere J. New-onset atrial fibrillation in critically ill patients. Can Respir J 2015; 22: 179–182.

Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. J Am Med Assoc 2013; 310: 2050–2060.

Pathak RK, Middeldorp ME, Meredith M, Mehta AB, Mahajan R, Wong CX, et al. Long-term Effect of Goal-directed weight management in an Atrial fibrillation Cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol 2015; 65: 2159–2169.

Vizzardi E, Sciatti E, Bonadei I, D’Aloia A, Curnis A, Metra M. Obstructive sleep apnoea–hypopnoea and arrhythmias: new updates. J Cardiovasc Med (Hagerstown) 2017; 18: 490–500.

Millar RS. The ECG Atlas of Cardiac Rhythms. Cape Town: Clinics Cardive, 2015.

10. Link MS. Clinical practice. Evaluation and initial treatment of supraventricular tachycardia. N Engl J Med 2012; 367: 1438–1448. 11. Schwartz M, Rodman D, Lowenstein SR. Recognition and treatment of multifocal atrial tachycardia: A critical review. J Emergency Med 1994; 12: 353–-360. 12. Gupta S, Figueredo VM. Tachycardia mediated cardiomyopathy: pathophysiology, mechanisms, clinical features and management. Int J Cardiol 2014; 17: 40–46. 13. Dorian P. Rate control in atrial fibrillation. N Engl J Med 2010; 362: 1439–1441. 14. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825–1833.

The images used for this ECG series are from ECG APPtitude and are used

15. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma

with permission. The authors thank Professor Rob Scott Millar for the ECG

T, et al. for the Rate Control versus Electrical Cardioversion for

examples used in Figs 2–5, from the Rob Scott Millar ECG Library at the

Persistent Atrial Fibrillation study group. A comparison of rate control

Groote Schuur Cardiac Clinic.

and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347: 1834–1840.

References 1.

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats the diagnosis and treatment of acute and chronic heart failure: The

Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009; 104: 671–677.

failure of the European Society of Cardiology (ESC). Developed with

18. Pizzale S, Lemery R, Green MS, Gollob MH, Tang ASL, Birnie DH.

the special contribution of the Heart Failure Association (HFA) of the

Frequency and predictors of tachycardia-induced cardiomyopathy in

Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893–2962.

atrial fibrillation with heart failure. N Engl J Med 2018; 378: 417–427. 17. Spector P, Reynolds MR, Calkins H, Sondhi M, Xu Y, Martin A, et al.

ESC. Eur Heart J 2016; 37: 2129–2200.

Jordaens L, et al., CASTLE-AF investigators. Catheter ablation for

AJS, et al.; ESC Scientific Document Group. 2016 ESC guidelines for Task Force for the diagnosis and treatment of acute and chronic heart

16. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L,

patients with persistent atrial flutter. Can J Cardiol 2009; 25: 469–472. 19. Luchsinger JA, Steinberg JS. Resolution of cardiomyopathy after ablation of atrial flutter. J Am Coll Cardiol 1998; 32: 205–210. 20. Page RL, Joglar JA, Caldwell MA, Calkins H, Conti JB, Deal BJ, et al.;

Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M,

Evidence Review Committee Chair. 2015 ACC/AHA/HRS guideline

Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a

for the management of adult patients with supraventricular tachycar-

global burden of disease 2010 study. Circulation 2014; 129: 837–847.

dia: a report of the American College of Cardiology/American Heart

Schnabel RB, Sullivan LM, Levy D, Pencina MJ, Massaro JM,

Association Task Force on Clinical Practice Guidelines and the Heart

D’Agostino RB Sr, et al. Development of a risk score for atrial fibril-

Rhythm Society. Circulation 2016; 133: e506–574.

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PASCAR News Report from Nairobi: towards a 25% reduction in uncontrolled hypertension in Africa ‘The first step in an ambitious, long-term, intercontinental project to save millions of lives in Africa by reducing the unacceptably high stroke morbidity and mortality rates and other devastating but preventable consequences of undiagnosed and uncontrolled hypertension in Africa. Indeed an important step towards the ultimate goal: a 25% reduction in cases of uncontrolled hypertension on this continent by 2025, as set out in the PASCAR Roadmap on Hypertension.’1 This is how the outcome can be described of the first continental meeting in Nairobi, where a delegation of more than 30 key opinion leaders in hypertension and cardiology from Britain, Ireland, India and Africa deliberated for two days to review and Africanise the successful and relevant Indian Certificate Course in the Management of Hypertension (ICCMH*). This emerged during a media conference held at the meeting. Representatives of the Public Health Foundation of India (PHFI) in New Delhi, the International Society of Hypertension (ISH), the British and Irish Hypertension Society (BIHS), the Centre for Chronic Disease Control (CCDC) in New Delhi and the Pan-African Society of Cardiology (PASCAR) gathered in Nairobi to discuss the expansion and customisation of the ICCMH to the African region. The main objective of the course is to train doctors, nurses and community healthcare workers on the continent to diagnose and manage hypertension as effectively as possible at the primary care level, by early diagnosis and better hypertension control, based on guidelines adapted for the African continent and different ethnic groups. This will free the few hypertension specialists on the continent to manage complicated hypertension cases at a tertiary level. The following key aspects were highlighted at the media conference.

Undiagnosed and uncontrolled hypertension is the number one killer in the world In excess of 10 million people around the world die each year of hypertension-related diseases, mainly cardiovascular diseases, including stroke. It kills more people in the world than any other communicable disease, said Prof Francesco P Cappuccio, president of the BIHS.

The World Health Organisation has declared Africa the region of the world with the highest incidence of hypertension The African Union considers hypertension the most important challenge on the continent after HIV/AIDS, but up to now, experts have not succeeded in translating these political decisions into important actions that could change cardiovascular health

on the continent, explained Prof Saad Subahi, cardiologist and president of PASCAR’s National Council. This is where PASCAR entered four years ago and initiated the PASCAR Roadmap on Hypertension. A recent situation analysis revealed that hypertension affects one-third (150 million) of the adult population in Africa, but only one-tenth (about 15 million) of these people are aware of the disease, and when they are aware, only one in five people (about three million) is treated. When they are treated, only one in 14 (about 215 000) is treated to such an extent that their risk for renal disease, heart disease or stroke, or dying from hypertension are reduced. This is a dire situation, Prof Subahi said.

Increased awareness among health professionals and society was identified as the highest priority towards a 25% reduction in uncontrolled hypertension by 2025 In the first attempt to increase awareness, more than 20 African countries took part in a huge global initiative in 2017 to screen people for hypertension. This will now be followed by the Africanisation, translation and roll out of the Indian hypertension-education programme in Africa over the next two years, said Prof Neil Poulter, president of the ISH.

International hypertension experts from the ISH, BHIS and India are keen and commited to assist Africa in its fight against hypertension ‘It is our duty to fill a gap. A 25% reduction in undiagnosed, uncontrolled hypertension will mean saving the lives of millions of people every year. It will also reduce morbidity by millions,’ Cappucino reiterated.

The next steps Following the meeting in Nairobi, the priority actions, as identified in the PASCAR Roadmap on Hypertension, will be implemented to overcome the identified roadblocks. These key elements were highlighted at the media conference: • Training and education to increase awareness: PASCAR will roll out the adapted training programme to train the trainers across the African region in the coming months; to ultimately train 250 000 community health workers, 50 000 nurses and 25 000 certified general physicians. • Create and customise easy-to-use treatment protocols for different ethnic groups within a proper referral linkage pattern. Poulter shed more light on the possible treatment protocols: ‘The CREOLE trial2 in six sub-Saharan African countries, to indicate which antihypertensive drugs and

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combination drugs will be best for African patients and even for different ethnic groups, will be completed in June 2018. The results, as well as the availability and cost effectiveness of drugs, will be taken into account when drafting the treatment protocols.’ ‘We expect the CREOLE trial to show that a diuretic and a calcium channel blocker (CCB) will be the most effective anti-hypertensive drugs for black patients, but we don’t know yet what combination will be best: a CCB and a diuretic, or a CCB plus angiotensin converting enzyme inhibitor (ACEI), or a diuretic plus an ACEI. If we get this information, it will be a big leap forward. We would like to reproduce the CREOLE trial in South Asia and the Far East, to determine which two drugs are the best for each ethnic group.’ • High-quality generic anti-hypertensive drugs will be produced and delivered cost effectively by non-profit-making companies. These efforts will hopefully lead to more countries in Africa joining the initiative. Currently only 25% of countries in Africa have a government policy and guidelines to treat and reduce the burden of hypertension,’ Poulter said.

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*Certificate Course in Management of Hypertension (CCMH) is a joint certification programme currently being run in India. It is offered by the Public Health Foundation of India (PHFI), International Society of Hypertension (ISH), British and Irish Hypertension Society (BIHS) and Centre for Chronic Disease Control (CCDC). CCMH is a 10-month course, which is currently being offered at 40 regional training centres across India.

Marí Hudson

References 1.

Dzudie A, Rayner B, Ojji D, Schutte AE, Twagirumukiza M, Damasceno A, et al., on behalf of the PASCAR task force on hypertensiom. Roadmap to achieve 25% hypertension control in Africa by 2025. Cardiovasc J Afr 2017; 28(4): 261–272.

Barasa FA. CREOLE trial (Comparison of Three Combination Therapies in Lowering Blood Pressure in Black Africans. http://www. kenyacardiacs.org/downloads/02%20CREOLE%20-%20Is%20all%20 hypertension%20the%20same%20-%20Felix%20BARASA.pdf.

New high-sensitivity troponin test reduces heart attack risk The newer high-sensitivity troponin test discovers smaller amounts of heart-specific proteins, troponins, than the older troponin test and therefore identifies more myocardial infarction patients than before. A study from Karolinska Institutet in Sweden now reports that the risk of a future heart attack is lower in patients diagnosed with the new test. A blood test that measures the presence of heart-specific proteins called troponins is used by emergency clinics to diagnose myocardial infarction in patients with chest pain. For the past few years a newer laboratory method has been used at most hospitals in Sweden that is 10n times more sensitive than the conventional troponin test. The high-sensitivity troponin test can discover heart attacks earlier so that treatment can commence, which is thought to improve the patient’s prognosis. ‘But there is a lack of larger studies examining whether the high-sensitivity troponin test is of any significance for patients with newly diagnosed myocardial infarction in terms of survival or the risk of another heart attack,’ says study leader Dr Martin Holzmann, associate professor of epidemiology at Karolinska Institutet’s Department of Medicine in Solna and physician at Karolinska University Hospital. The study included all patients in Sweden who had had their first heart attack between 2009 and 2013. This gave a study population of almost 88 000 patients, 40 000 of whom had been diagnosed using the high-sensitivity troponin test and just over 47 000 using the conventional troponin test. The researchers found that 5% more myocardial infarctions were being diagnosed in hospitals that used the

high-sensitivity troponin test. A year after the heart attack was registered there was no difference in mortality rate between the two groups, although the number of new heart attacks was lower in the group that had been diagnosed using the high-sensitivity troponin test. ‘This surprised us,’ says Holzmann. ‘We didn’t think that the more sensitive test would affect the risk of future heart attacks.’ The use of coronary angiography and balloon angioplasty was 16 and 13% more common, respectively, in the patients diagnosed with the high-sensitivity troponin test. In the USA, where the new test was not approved until 2017, there are fears that the more sensitive methods can entail a large increase in the number of examinations with no benefit to the patients. ‘The increase we observed in our study was less than expected, which means that the high-sensitivity troponin test has enabled doctors to single out the patients who benefit from such intervention. We found no differences in medication between the two groups, so the differences in prognosis with fewer new heart attacks could be attributed to the fact that more coronary angiography and balloon dilation procedures have been performed on the right patients,’ says Holzmann, who also believes that the study supports the idea that the handful of hospitals in Sweden that still do not use the high-sensitivity troponin test should start to do so. Source: Medical Brief 2018

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Case Report Levitronix bilateral ventricular assist device, a bridge to recovery in a patient with acute fulminant myocarditis and concomitant cerebellar infarction Yi-Fan Huang, Po-Shun Hsu, Chien-Sung Tsai, Yi-Ting Tsai, Chih-Yuan Lin, Hong-Yan Ke, Yi-Chang Lin, Hsiang-Yu Yang

Abstract We report on the case of a 27-year-old male who presented to our emergency room with chest tightness, dyspnoea and cold sweats. The 12-lead electrocardiogram showed diffuse ventricular tachycardia with wide QRS complexes. Troponin-I level was elevated to 100 ng/ml. The coronary angiogram showed good patency of all three coronary vessels, and acute fulminant myocarditis was suspected. The patient underwent cardiopulmonary resuscitation in the catheter room and high-dose inotropic support was initiated to stabilise his haemodynamic status. After resuscitation, the patient was in a coma and acute stroke was highly suspected. In addition, deteriorating cardiogenic shock with acute renal failure and pulmonary oedema were also detected. Due to haemodynamic compromise despite high-dose inotropic support, a Levitronix® bilateral ventricular assist device (Bi-VAD) was implanted on an emergency basis for circulatory support. Postoperative brain computed tomography revealed acute left cerebellar infarction. Because the patient had left cerebellar infarction with right hemiplegia, heart transplantation was contraindicated. Eventually, cardiac systolic function recovered well and the patient underwent successful Bi-VAD removal after a total of 18 days on Levitronix® haemodynamic support. He was weaned from the ventilator two weeks later and was discharged 10 days later. Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan, Republic of China Yi-Fan Huang, MD Po-Shun Hsu, MD, hsuposhun@yahoo.com.tw Chien-Sung Tsai, MD Yi-Ting Tsai, MD Chih-Yuan Lin, MD Hong-Yan Ke, MD Yi-Chang Lin, MD Hsiang-Yu Yang, MD

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan, Republic of China Yi-Fan Huang, MD

Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taipei, Taiwan, Republic of China Chien-Sung Tsai, MD

Keywords: ventricular assist device, acute myocarditis, cerebellar infarction Submitted 1/1/17, accepted 22/1/18 Published online 7/2/18 Cardiovasc J Afr 2018; 29: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2018-009

In the past two decades, intra-aortic balloon pump and extra-corporeal membrane oxygenation (ECMO) have been predominantly used at our centre as a bridge, either to cardiac transplantation or to recovery in patients with decompensated heart failure.1,2 However, most patients die because of either ECMO-related morbidity or systemic malperfusion if cardiac function does not recover in time and cardiac transplantation is contraindicated in this period.2 In such patients, Levitronix® bilateral ventricular assist device (Bi-VAD) could provide temporary cardiac support for a much longer period than ECMO.3 Our experience with this case indicates that timely implantation of Bi-VAD can function as a bridge to recovery in patients with acute fulminant myocarditis, particularly when heart transplantation is contraindicated.

Case report A 27-year-old man was brought to our emergency room with a history of chest tightness, dyspnoea and cold sweats that had manifested a few hours earlier. However, the symptoms did not ameliorate with rest. He denied any systemic disease, except a common cold one week earlier. The 12-lead electrocardiogram (ECG) showed diffuse ventricular tachycardia with wide QRS complexes. Troponin-I levels were elevated to 100 ng/ml. An emergency coronary angiogram showed good patency of all three coronary vessels, and acute fulminant myocarditis was suspected. His haemodynamic status suddenly deteriorated because of ventricular fibrillation shortly after the angiogram, and cardiopulmonary resuscitation was performed for 30 minutes. His vital signs were restored after initiation of high-dose inotropic support with multiple inotropic agents (dopamine: 15 mcg/kg/min, dobutamine: 15 mcg/kg/min, norepinephrine: 32 mcg/min and epinephrine: 1 mcg/min). Because his vital signs were unstable during the coronary angiogram, we did not

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 3, May/June 2018

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Fig. 1. ( A) Photograph of the cardiac operation and (B) a chest X-ray showing the left heart venous drainage tube (white arrow), the arterial perfusion tube (white dotted arrow), the right heart venous drainage tube (black arrow), and the arterial perfusion tube (black dotted arrow).

perform a routine myocardial biopsy, which was necessary for the pathological diagnosis of myocarditis. We had no choice but to send the patient back to the intensive care unit for stabilisation of the haemodynamic status. However, his level of consciousness did not improve (Glasgow coma scale score 3). Emergency brain computed tomography (CT) showed no intracranial haemorrhage, and magnetic resonance imaging (MRI) was contraindicated because infusion pumps were implanted. We were therefore unable to rule out acute stroke. Meanwhile, 24-hour hypothermia therapy (HT) at approximately 34°C was employed for neurological protection in post-resuscitation circulatory shock. Transthoracic echocardiogram showed general hypokinesia of both ventricles (left ventricular ejection fraction 15–20%). Despite these interventions, acute pulmonary oedema and deteriorating liver and renal function with progressive oliguria ensued. To avoid multiple organ dysfunction syndrome, a continuousflow Levitronix® CentriMag Bi-VAD (Levitronix®, Waltham, MA) was implanted via a median sternotomy under the guidance of transoesophageal echocardiography. First, the left heart vent tube was inserted from the right superior pulmonary vein into the left ventricular apex, and the arterial cannula was inserted into the ascending aorta. Second, the right heart vent tube was inserted into the right atrium, and the arterial cannula was inserted into the pulmonary artery (Fig. 1). Then pursestring sutures with non-absorbable retention sutures secured with tourniquets and spigots were tied around all the cannulae. The vital signs immediately stabilised with Bi-VAD support and the high-dose inotropic support was tapered off the next day (dopamine: 5 mcg/kg/min, dobutamine: 5 mcg/kg/min and norepinephrine: 3.7 mcg/min). Because a Bi-VAD was inserted, systemic heparinisation therapy was administered through a peripheral line to maintain an activated clotting time (ACT) at 160–180 s using the Hemochron® Response ACT point-of-care testing system. Unfortunately, CT the following day showed an acute left cerebellar infarction (Fig. 2),

which resulted in right hemiplegia. We assumed that the cerebellar infarction was caused by the cardiopulmonary resuscitation rather than VAD-related thrombus formation. To prevent post-infarct haemorrhage, we tapered the ACT to 140–160 s. Three days later, the patient fully recovered from the coma, and his muscle power also improved. Daily echocardiography examinations showed progressive improvement of the cardiac systolic function. When the left ventricular ejection fraction was approximately 50%, the Bi-VAD was weaned (right-VAD: 0.5 l/min; left-VAD: 0.8 l/min). The patient underwent successful Bi-VAD removal,

Fig. 2. Hypodense defect indicates acute left cerebellar infarction (white arrow).

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Discussion Before the use of VADs became popular, ECMO played an important role in the haemodynamic support for decompensation in cases of acute heart failure at our centre.1,2 VADs provide substantially longer durability and considerably fewer complications than ECMO.3-5 According to the 2016 guidelines recommended by the International Society for Heart and Lung Transplantation, clinically severe symptomatic cerebrovascular disease may be considered a contraindication to transplantation.6 Our policy was to use VADs as a bridge, either to recovery or transplantation if the patient was able to recover from left cerebellar infarction with right hemiplegia. After starting VAD, high-dose inotropic support could be tapered immediately (Table 1) to prevent vasoconstriction in the vital visceral organs. During the period with VAD support, both troponin-I levels and liver function progressively returned to normal ranges. In time, cardiac function improved and the VAD was successfully removed. Although renal function did not recover promptly and haemodialysis was necessary during the VAD period, the renal function did recover completely, albeit two weeks later after VAD removal. This means that timely VAD support could provide immediate circulatory support, enabling cessation of high-dose inotrope administration, which would cause vasoconstriction in the visceral organs, sequential ischaemia of the visceral organs, and consequent multiple organ failure. Currently, VADs can be categorised into two major types: pulsatile-flow and continuous-flow VADs. We chose the Levitronix® VAD for the following reasons. First, recent studies showed better outcomes with continuous-flow VADs than with pulsatile-flow ones. In addition, complications associated with continuous-flow VADs, especially bleeding and thromboembolism, are lower.7,8

Fig. 3. T he initial hypodense lesion progressed to chronic encephalomalacia of the left cerebellum (white arrow).

after a total of 18 days on Levitronix® haemodynamic support. One week later, a tracheostomy was performed, and the patient was weaned from the ventilator a week later. The follow-up CT showed chronic encephalomalacia of the left cerebellum (Fig. 3). The patient was discharged home 10 days later, after a total hospital stay of 42 days. During out-patient follow up, no signs of heart failure or device-related complications were noted.

Table 1. Clinical time course Before VAD

POD1

POD2

POD3

POD6

POD9

POD12

POD15

POD18 VAD removal

Cardiac enzyme BNP (pg/ml)

350

518

553

2219

1974

584

590

405

363

CK (U/l)

1743

2609

3098

3245

800

219

CKMB (U/l)

136.6

67.8

–

Troponin-I (ng/ml)

90.06

94.02

60.70

33.65

6.31

0.68

0.22

0.11

0.05 121

Renal function BUN (mg/dl)

108

114

Creatinine (mg/dl)

3.4

3.6

4.6

4.7

7.7

5.3

3.8

3.6

3.1

128

250

545

1540

1120

1160

2550

2240

Daily urine amount (ml) Liver function GOT (U/l)

214

722

1191

795

133

GPT (U/l)

416

633

706

372

200

Total bilirubin (mg/dl)

4.0

2.7

3.6

3.2

2.5

1.4

1.8

2.5

2.0

Inotropic agent Dopamine (mcg/kg/min)

15.0

5.1

3.0

1.8

2.9

4.7

4.4

7.6

Dobutamine (mcg/kg/min)

15.0

5.1

3.0

1.8

2.9

3.1

7.6

Epinephrine (mcg/min)

1.0

–

Norepinephrine (mcg/min)

3.7

–

2.0

1.6

1.2

–

VAD flow Right (l/min)

2.7

3.5

3.2

3.0

2.8

1.6

Left (l/min)

4.5

5.0

4.8

2.6

VAD revolutions per minute Right (/min)

3000

2900

2700

1700

Left (/min)

4100

4000

3700

3500

2000

POD = post-operative day; VAD = left ventricular assist device; BUN = blood urea nitrogen; CK = creatinine kinase; CKMB = creatinine kinase MB coenzyme; GOT = glutamic-oxaloacetic transaminase; GPT = glutamic-pyruvic transaminase.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 3, May/June 2018

Second, we expected recovery of the stunned myocardium after the acute myocardial infarction. Therefore, we abandoned use of the most advanced VADs, such as the HeartMate II9 or HeartWare,10 in which cannulation of the ventricular apex for drainage is necessary. We rather used the Levitronix® because we could cannulate the vent tube on the right superior pulmonary vein (Fig. 1) instead of the ventricular apex. The apical location would make surgical repair much more difficult, assuming that the viable but stunned myocardium could recover and the VAD could be withdrawn. We used a Snell-tie retention suture to securely fix both the vent and perfusion tubes. This also enabled a simple and quick closure of the cannulation wounds, which would facilitate the withdrawal procedure. Third, although various kinds of VADs are available in Taiwan, not all are reimbursed by the National Health Insurance. In Taiwan, the Levitronix® costs approximately US$12 000, while the HeartMate II or HeartWare costs over US$170 000. Only the Levitronix® is covered by the National Health Insurance. Therefore, we opted to use Levitronix® instead of the HeartMate II or HeartWare because of economic considerations. However, complications such as coagulopathy, thromboembolisation and mechanical failure are common with VAD use. Thromboembolisation after VAD implantation resulting in cerebrovascular events is devastating.11 There is no optimal treatment for stroke in patients implanted with a VAD. Supportive anticoagulation therapy rather than thrombolytic therapy, which is potentially associated with greater risk of haemorrhagic events after major surgery, is obviously essential treatment in this population.12 In our current protocol for heparinisation therapy, we prefer to maintain the ACT at approximately 160 s to avoid major, spontaneous bleeding disasters. If there are complications such as surgical bleeding or symptoms of coagulopathy (e.g. bloody sputum, massive gastrointestinal bleeding and large subcutaneous ecchymoses), we taper the heparin dose and maintain the ACT at approximately 140 s. If VAD-related thrombosis is suspected, we aim to prolong the ACT at 180–250 s. In the present case, the pre-VAD CT scan showed no cerebral ischaemia, but the post-VAD CT scan showed acute left cerebellar infarction (Fig. 2). Judging by the chronology of events, the stroke event was suspected to be due to cardiopulmonary resuscitation rather than VAD-related embolisation. This is because a stroke event cannot usually be detected in the acute stage (especially within 24 hours) on CT. The only imaging examination to confirm acute-stage stroke is MRI, which was not practicable for this patient. Therefore we maintained the ACT at 140–160 s rather than > 180 s. Of course, post-infarct haemorrhage is another big concern. Eventually, we did not maintain the ACT at < 140 s because the CT scan showed no post-infarct haemorrhage. In this case, the patient suffered from concomitant fulminant myocarditis and acute cerebellar infarction. It is useful to stabilise the infarct without ischaemic expansion or haemorrhagic transformation by maintaining the ACT at 140–160 s throughout the course. Our experience in this case indicates that short-term VAD use would be the first choice for mechanical circulatory

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support, not only because of much shorter surgery time but also cost-effectiveness, especially in patients with unconfirmed brain damage.

Conclusion Levitronix® VAD provides excellent short-term cardiac mechanical support for patients with severe symptomatic cerebrovascular disease. It offers patients an option, a bridge to recovery, that is not only cost-effective but also decreases cardiac trauma during potential removal.

References 1.

Magovern GJ, Simpson KA. Extracorporeal membrane oxygenation for adult cardiac support: the Allegheny experience. Ann Thorac Surg 1999; 68: 655–661.

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Published online: • Levitronix bilateral ventricular assist device for circulatory support