NOVEMBER/DECEMBER 2017 VOL 28 NO 6
www.cvja.co.za
CardioVascular Journal of Africa (official journal for PASCAR)
• Review of warfarin toxicity in a tertiary hospital in Cape Town • Medication adherence among cardiac patients in Sudan • Profile, management and outcomes of pulmonary embolism patients • Predictive value of ECG abnormalities in pulmonary hypertension • Survey of non-communicable diseases and their risk factors • Effect of iloprost and sildenafil on myocardial ischaemia • Lifestyle interventions and body composition during pregnancy
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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za PHARMA DYNAMICS CLOPIDOGREL 75 mg. Each tablet contains 75 mg clopidogrel. S3 A42/8.2/0128. NAM NS2 10/7.1/0377. For full prescribing information, refer to the package insert approved by the Medicines Control Council, October 2008. 1) Database of Medicine Prices (14 March 2017). Department of Health website. http://www.mpr.gov.za - Accessed on 30 March 2017. 2) Poponina TM, et al. Current approaches to the prevention of thrombotic complications in patients with acute coronary syndrome without ST-segment elevation. Topical issues of heart and vascular diseases. 2009;4:4-9. (English translation) 3) Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Vascular Medicine 1998;3:257-260. 4) COMMIT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet 2005;366(9497):1607-1621. 5) Sabatine MS, et al. Addition of Clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. New England Journal of Medicine 2005;352:1179-89. 6) The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine 2001;345:494-502. PDCLD395/04/2017.
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689
ISSN 1995-1892 (print) ISSN 1680-0745 (online)
Vol 28, No 6, NOVEMBER/DECEMBER 2017
CONTENTS
Cardiovascular Journal of Africa 343
www.cvja.co.za
FROM THE EDITOR’S DESK P Commerford
EDITORIAL 344
Warfarin: better the devil you know M Blockman
346
A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa A Jacobs • F Bassa • EH Decloedt
350
Medication adherence among cardiac patients in Khartoum State, Sudan: a cross-sectional study A Awad • N Osman • S Altayib
356
Clinical profile, management and outcomes of patients with pulmonary embolism: a retrospective tertiary centre study in Angola A Manuel • A Aufico • R Africano • T Peralta • A Salas • A Silva • J Ricardo • P Sabola • D Baião • C Sotolongo • AD Neto • T Martins • V Sabino • AP Filipe Júnior
362
Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats F Nduhirabandi • B Huisamen • H Strijdom • A Lochner
370
Prevalence and predictive value of electrocardiographic abnormalities in pulmonary hypertension: evidence from the Pan-African Pulmonary Hypertension Cohort (PAPUCO) study I Balieva • A Dzudie • F Thienemann • AO Mocumbi • K Karaye • MU Sani • OS Ogah • A Voors • AP Kengne • K Sliwa
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 28, No 6, NOVEMBER/DECEMBER 2017
377
A survey of non-communicable diseases and their risk factors among university employees: a single institutional study EI Agaba • MO Akanbi • PA Agaba • AN Ocheke • ZM Gimba • S Daniyam • EN Okeke
384
Letter to the editor
385
Relationship between coronary tortuosity and plateletcrit coronary tortuosity and plateletcrit L Cerit • Z Cerit
389
The effect of iloprost and sildenafil, alone and in combination, on myocardial ischaemia, and nitric oxide and irisin levels S Aydin • T Kuloglu • S Aydin • M Yardim • D Azboy • Z Temizturk • AK Kalkan • MN Eren
397
The effect of lifestyle interventions on maternal body composition during pregnancy in developing countries: a systematic review ED Watson • S Macaulay • K Lamont • PJ-L Gradidge • S Pretorius • NJ Crowther • E Libhaber
404
Unusually aggressive immature neo-intimal hyperplasia causing in-stent restenosis K McCutcheon • AS Triantafyllis • J Bennett • T Adriaenssens
406
NT-pro BNP and plasma-soluble ST2 as promising biomarkers for hypertension, hypertensive heart disease and heart failure in sub-Saharan Africa A Dzudie • BS Dzekem • AP Kengne
408
congress NEWS
PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed)
e1
Efficacy of cardiac magnetic resonance imaging in a sub-aortic aneurysm case R Meel • R Nethononda • F Peters • M Essop
e4
Miller–Fisher syndrome after coronary artery bypass surgery M Aldag • S Albeyoglu • U Ciloglu • H Kutlu • L Ceylan
REVIEW ARTICLE
IMAGES IN CARDIOLOGY
LETTER TO THE EDITOR
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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
343
From the Editor’s Desk This issue carries the first of what I hope will become a regular feature. On page 404, McCutcheon and colleagues publish a coronary angiogram with aggressive in-stent restenosis due to neo-intimal hyperplasia a short while after coronary stent implantation. The accompanying optical coherence tomographic images demonstrate the utility of this technology. I encourage readers to submit similar unusual or informative images. The new oral anticoagulants remain expensive and will not be readily available in countries with limited medical resources. Warfarin will probably remain the agent of choice for some time and this almost certainly applies to many countries in Africa. Jacobs and co-workers from Tygerberg Hospital (page 346) conducted a retrospective review of patients admitted with warfarin toxicity. They identified the causes of the toxicity and the human and financial cost. An editorial by Blockman (page 344) points out that warfarin accounts for a significant number of the adverse drug reactions causing admission to hospital. In a similar vein, Awad and colleagues (page 350) report on
an investigation on medication adherence among cardiac patients in Sudan. They determined that the top four barriers to poor medication adherence among the study participants were the high cost of drugs, polypharmacy, and lack of pharmacist and physician communication with patients about their drug therapy. There is not much individual physicians can do about the high cost of drugs and polypharmacy is sometimes necessary, but we should talk to our patients to explain their illnesses and the need for adherence to medication. It is sad that this does not happen. Balieva and co-workers report on the electrocardiographic features found in a sub-group of patients from a larger registry of patients in Africa with pulmonary hypertension, diagnosed by clinical and echocardiographic features. They compared them to ECG features found in a population known to be disease-free following extensive cardiological evaluation (page 370). PJ Commerford, Patrick.Commerford@uct.ac.za Editor-in-Chief
Merry Christmas and a Happy New Year The management and staff of Clinics Cardive Publishing wishes you and your family a wonderful holiday season and a healthy and peaceful 2018. May your holidays be filled with joy, peace and good cheer! We take this opportunity to thank you for your loyal support during 2017 and look forward to being of service during 2018. Please note our offices will close on 15 December and will be open from 08 January 2018.
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Editorial Warfarin: better the devil you know Marc Blockman Long-term anticoagulation with warfarin is recommended for patients with atrial fibrillation (AF), valvular heart disease and pulmonary embolus, as these conditions significantly increase the risk for thromboembolic complications.1 AF for example increases the risk for ischaemic stroke four- to five-fold.¹ Warfarin has high efficacy in the prevention and treatment of thromboembolic disease.2 In AF patients, for example, warfarin reduces stroke risk by 64% compared with placebo or no treatment (absolute risk reduction 2.7% for primary prevention, 8.4% for secondary prevention), and by 38% when compared to aspirin (absolute risk reduction 0.7% primary prevention, 7.0% secondary prevention).3 Importantly, for clinical practice, warfarin has a narrow therapeutic window and requires regular monitoring in the form of routine international normalised ratio (INR) measurements. It has an unpredictable pharmacokinetic/pharmacodynamic (PK/PD) profile, and to optimise efficacy and avoid toxicity, INR monitoring is essential. Sub-therapeutic warfarin doses increase the risk of thrombus formation, while excess anticoagulation will increase the probability of a life-threatening bleed.4 Therefore, meticulous control and monitoring is required throughout treatment. Warfarin causes significant morbidity and is among the top drugs leading to adverse drug reactions.5 The risk of major bleeding depends on the patient group and can range from 0.75 to 10.0% per annum.6-8 In South Africa, bleeding due to warfarin is among the top five adverse drug reactions (ADRs) resulting in hospital admission.9 A multicentre, hospital-based survey in South African medical wards to determine the burden of ADRs resulting in admission and death revealed that ADRs accounted for 8.4% of medical admissions and 2.9% of deaths.10 In this study, haemorrhage was the fourth most common cause, with warfarin accounting for 68% of these bleeds.10 It is difficult to predict who is at increased risk for toxicity. Many factors result in the inconsistent response to warfarin therapy. These include its narrow therapeutic window, unpredictable dose response, numerous drug–drug interactions (importantly, non-steroidal anti-inflammatory drugs, rifampicin and the enzyme-inducing anti-epileptics), diet containing high levels of vitamin K, and patient co-morbid conditions.2,11,12
Department of Medicine, Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Marc Blockman, MB ChB, BPharm, PG Diploma Int Res Ethics, MMed, marc.blockman@uct.ac.za
In a South African black population, genetic modifications in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1 resulted in approximately 45% of warfarin dosage variability.13 Further research is required to establish whether routine genetic testing and dose adjustment will lead to improved outcomes when using warfarin. Patient non-adherence and prescriber fear are important causes of INR variability.4 The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study found that adherence to a standardised warfarin dosing algorithm improved patient control.14 The INR is used as a surrogate for treatment success. Patients’ INRs are routinely measured and used to assess the time in the therapeutic range (TTR). TTR is defined as the duration of time in which the patient’s INR values were within a desired range. TTR strongly associates with bleeding and thromboembolic risk, namely, a high TTR correlates with reduced risk of both thromboembolic complications and major bleeding.4,11,15 A study in patients with AF receiving warfarin found that even a small 7% improvement in TTR reduced major haemorrhage rates by one event per 100 patient years, and a 12% increase in TTR reduced the thromboembolic rate by one event per 100 patient years.16 It is suggested that INR monitoring clinics aim for a TTR between 70 and 80% to optimise benefits and reduce patient harm.16,17 A post hoc analysis of the ACTIVE W study, which assessed dual antiplatelet therapy versus warfarin in patients with AF, found a mean TTR of 63.4%. Despite patients being managed in the controlled environment of this clinical trial, the South Africa cohort had a mean TTR of 46.3%; well below the widely accepted range.17 Countries that achieved a TTR of close to 75% had improved clinical benefits from warfarin therapy.17 Newer agents have been compared to warfarin in patients with AF. The Africa cohort of the RE-LY study had a TTR of 58% compared to the overall population TTR of 64%.15 The South African patient population of the ROCKET-AF study had a TTR of 54.8%.18 Once again, the outcomes of the South African cohort within the ROCKET-AF trial emphasise that despite being evaluated under clinical trial conditions, there are challenges to achieving therapeutic TTRs. Unfortunately, newer warfarin dosing strategies (computer-aided dosing, specialitypharmacy clinics and genotype-guided dosing) have shown only modest improvements in TTR.19 In conclusion, warfarin remains an important agent for the prevention of thrombosis and thromboembolism in highrisk patients. Despite its clinically significant effectiveness, its unpredictable bleeding risk must be respected. Before committing to its prescription, clinicians must recognise and mitigate which factors may contribute to this risk. Regular INR monitoring and patient education can dramatically reduce this risk.
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MJ, et al. Evidence-based management of anticoagulant therapy:
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Thrombol 2013; 35(3): 333–335. Available from: http://www.ncbi.nlm. nih.gov/pubmed/23456572 (Accessed Nov 11th 2017). Hart RG, Pearce L.A, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibril4.
sible for differences in the quality of anticoagulation control between
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MG, et al. Efficacy and safety of dabigatran compared with warfarin
Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et
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prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet
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Yousef ZR, Tandy SC, Tudor V, Jishi F, Trent RJ, Watson DK, et al.
6736(10)61194-4. 16. Wan Y, Heneghan C, Perera R, Roberts N, Hollowell J, Glasziou P, et
district general hospital. Heart 2004; 90: 1259–1262.
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Johnson CE, Lim WK, Workman BS. People aged over 75 in atrial fibril-
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17. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi
Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet
MG, et al; ACTIVE W Investigators. Benefit of oral anticoagulant
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over antiplatelet therapy in atrial fibrillation depends on the quality of
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black population. Pharmacogenomics 2011: 2(7): 953–963. 14. Van Spall HGC Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat R, Yang S, et al. Variation in warfarin dose adjustment practice is respon-
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Singer DE, Albers GW, Dalen, JE, Fang MC, Go AS, Halperin, JL, et
implications, challenges, and strategies for improvement. J Thromb
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M, et al. Adverse drug reactions causing admission to medical wards.
Lokhnygina Y, et al. Impact of global geographic region on time
Medicine (Baltimore) 2016; 95(19): 1–10.
in therapeutic range on warfarin anticoagulant therapy: data from
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the ROCKET AF clinical trial. J Am Heart Assoc 2013; 1: e000067.
et al. Mortality from adverse drug reactions in adult medical inpatients
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at four hospitals in South Africa: a cross-sectional survey. Br J Clin
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19. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess
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the quality of warfarin control in atrial fibrillation patients in the United
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States. J Managed Care Pharm 2009; 15(3): 244–152. Available at: http://
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Cardiovascular Topics A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa Annemarie Jacobs, Fatima Bassa, Eric H Decloedt
Abstract Aim: Warfarin is a widely used anticoagulant for the prevention and treatment of thromboembolism. We conducted a retrospective review to determine the causes and management of warfarin toxicity of patients admitted to Tygerberg hospital between June 2014 and June 2015. Results: We identified and evaluated 126 patients who met the inclusion criteria. The cause of warfarin toxicity was identified and addressed in only 14.3% (18/126) of patients. Where the cause was identified, 56% (10/18) was due to dosing errors and 17% (3/18) drug–drug interaction (DDI). However, 77% (97/126) of patients were retrospectively identified as receiving concomitant medicines known to interact with warfarin at the time of admission. Twenty-eight per cent (35/126) of patients presented with major bleeding, which included seven cases of intracranial haemorrhage. Patients were admitted for a median of eight days at an average treatment cost of R10 578. Conclusion: We found that warfarin toxicity carries significant mortality and cost, but little attention is paid to the causes of toxicity.
Keywords: warfarin, toxicity, bleeding, treatment, cost Submitted 1/3/17, accepted 16/5/17 Published online 21/6/17 Cardiovasc J Afr 2017; 28: 346–349
www.cvja.co.za
DOI: 10.5830/CVJA-2017-029
Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa Annemarie Jacobs, MB ChB, annemariejacobs15@gmail.com
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa Eric H Decloedt, MB ChB, BSc Hons (Pharmacology), MMed (Clin Pharm), FCCP (SA)
Division of Haematology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa Fatima Bassa, MB ChB, FCPath (Haem), MMed (Haem)
Warfarin is a widely used anticoagulant indicated for the prevention and treatment of thromboembolism in patients with atrial fibrillation, prosthetic heart valves and deep-vein thrombosis. However, warfarin therapy is challenging. Sonuga et al.1 reported in a study done at Victoria Hospital, Cape Town, that a therapeutic international normalised ratio (INR) outcome was achieved in only 48.5% of patients. The warfarin dose–response curve is not predictable and requires regular INR monitoring to optimise efficacy and minimise toxicity.2 Cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genetic polymorphisms contribute to clinically significant variability in warfarin exposure and efficacy.2,3 Genetic polymorphisms in the CYP2C9 and VKORC1 enzymes account for 10 to 15% and 20 to 35% of inter-individual variance in warfarin dosing, respectively, with an increase in genetic polymorphisms found in Caucasian populations in comparison to African populations.3,4 Genetic polymorphisms are associated with decreased metabolism of or increased sensitivity to warfarin, as well as increased risk for bleeding events.3 There is a direct relationship between increased INR and risk of bleeding, with an INR > 4.0 associated with a high bleeding risk.5 Various risk factors predispose patients with therapeutic INRs to develop warfarin toxicity: dosing errors, drug–drug interactions, acute illnesses (diarrhoea, cardiac failure, hepatic impairment, fever) and dietary changes influencing vitamin K intake.6,7 Bleeding associated with warfarin toxicity carries a significant rate of morbidity and mortality. Risk factors for warfarin-associated bleeding mortality are advanced age, concomitant antiplatelet use, INR ≥ 4 at presentation, the use of vitamin K during hospitalisation, and intracerebral haemorrhage as a complication.8 Management of warfarin toxicity is determined by the degree of INR elevation with or without bleeding, and in the event of bleeding, the severity. Patients with an elevated INR and no evidence of bleeding can be managed with vitamin K, with or without omission of the next warfarin dose. Minor bleeding can be managed in a similar manner. The presence of major bleeding warrants immediate reversal of coagulopathy with the administration of vitamin K in conjunction with fresh frozen plasma (FFP) or 4-factor prothrombin complex concentrate (PCC). FFP and 4-factor PCC are considered to have a similar efficacy.7 There are no published data evaluating the causes, management and treatment costs of warfarin toxicity in South African healthcare facilities. The aim of this study was to provide an overview of warfarin toxicity, the management thereof and cost implications to treat a patient with warfarin toxicity in an academic hospital in South Africa.
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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
Methods Ethical approval for the study was obtained from the Human Research Ethics Committee of the Faculty of Medicine and Health Sciences of the University of Stellenbosch (U15/09/002). We conducted a retrospective review of adult patients (18 years or older) admitted to Tygerberg hospital (TBH), Cape Town, with warfarin toxicity during a one-year period from June 2014 to June 2015. Only patients known to be on established warfarin therapy were eligible for inclusion. Patients who were initiated on warfarin therapy during admission were excluded. Patients admitted more than once during the study period were recorded separately for each admission. We used National Health Laboratory Service (NHLS) records to identify patients with raised INRs and reviewed clinical notes, laboratory investigations and prescription data. We collected demographic information, admission and discharge dates, INR measurements, the presence or absence of bleeding, sites and complications of bleeding, management, presumed cause of warfarin toxicity as recorded in the clinical notes, and whether it was addressed prior to discharge, as well as concomitant medicine use at time of admission. The cause of warfarin toxicity was recorded as not identified if a cause was not recorded in the clinical records. In the presence of bleeding, we classified it as major or non-major bleeding. Major bleeding was regarded as life- or limb-threatening bleeding, whereas all other cases where regarded as non-major bleeding. We included patients presenting with warfarin toxicity, as defined by an admission INR value greater than 5. Patients
Raised INR measurements identified (n = 474)
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included required at least one additional in-patient INR measurement to capture only in-patients. We excluded patients with an elevated INR who were not using warfarin and presented with elevated INRs due to other pathology such as liver impairment and sepsis. Patients with one elevated INR reading but who died prior to an additional INR measurement being done were not eligible for inclusion. We calculated the warfarin toxicity treatment cost using the procurement cost of blood and blood products from the Western Cape Blood Transfusion Service, procurement cost of medicines from the TBH pharmacy, and cost to the hospital to admit a patient in a general ward in TBH using 2015 financial year costing. The general ward admission cost included personnel cost, clinical consumables, maintenance and engineering, equipment, services and overhead costs. We used DRUG-REAX® Interactive Drug Interactions database (Truven Health Analytics Inc, Micromedex® Healthcare Series)8 to identify possible drug–drug interactions (DDI) between warfarin and drugs used by patients at the time of admission.
Statistical analysis No sample size was calculated and all patients identified during the study period were included. Data were entered into Microsoft Excel® and analysed using Stata version 11.0 (StataCorp, College Station, TX, USA). We assessed the normality of the data visually and using the Shapiro–Wilk test. Normally distributed data are described using the mean and standard deviation (SD) while non-normally distributed data are described using median and interquartile ranges (IQR). We explored statistical significance using appropriate tests for categorical, normal numerical and non-normal numerical data.
Results Excluded due to no records being available (n = 55)
Excluded due to not being admitted (n = 24)
Excluded due to only one INR measured (n = 46)
We identified 474 raised INR measurements (467 patients), of which 126 (122 patients) met our inclusion criteria for warfarintoxicity admissions (Fig. 1). Four patients presented with two admissions for warfarin toxicity during the study period and each admission was recorded. For clarity we will refer to the 126 warfarin-toxicity admissions as patients. Sixty per cent (76/126) of patients were female and 40% (50/126) were male, with a median (IQR) age of 61 (48–70) years. Fifteen per cent (19/126) of patients died before discharge, although we could not attribute with certainty cause of death to warfarin toxicity. Patients were admitted for a median (IQR) of eight (5–16) days. The most common indications for the usage
Excluded as not on warfarin at admission (n = 187) Table 1. Indications for warfarin therapy
Excluded due to not being admitted (n = 24)
Patients eligible for inclusion (n = 126)
Indication AF
48
38
Heart valve replacements
24
19
DVT
21
17
Other
21
17
9
7
3
2
Multiple indications (including, but not limited to AF, heart valve replacements and DVT) Unknown
Fig. 1. Study sample selection.
Number of patients Percentage
Total AF = atrial fibrillation, DVT = deep-vein thrombosis.
126
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Table 2. Causes of warfarin toxicity Causes
No of patients
Table 4. Bleeding versus antiplatelet medicines Percentage
Aspirin
Clopidogrel
Aspirin and clopidogrel
Major bleeding (n)
8
1
0
7.9
Non-major bleeding (n)
4
0
0
7
5.6
No bleeding (n)
20
2
1
Patient
2
1.6
Both
1
0.8
3
2.4
Cause identified
18
14.3
Dosing error
10
Physician
Drug–drug interaction
Bleeding
Table 5. Most frequent interventions given
Acute illness
2
1.6
Intervention
Inability to control INR despite best effort
2
1.6
Vitamin K (oral/IV) (mg)
Other (liver injury)
1
0.8
FFP (IU)
Cause not identified
108
85.7
Total
126
of warfarin were atrial fibrillation (AF) (57 patients), deep-vein thrombosis (DVT) (24 patients) and heart valve replacements (29 patients) (Table 1). The median (IQR) admission INR was 8.49 (6.38–10) with the median (IQR) discharge INR 1.98 (1.28–2.82). The cause of warfarin toxicity was identified and addressed in 14.3% (18/126) of patients. Where the cause was identified, 55.6% (10/18) were due to dosing errors, 16.7% (3/18) DDIs, 11.1% (2/18) acute illnesses and 11.1% (2/18) due to inability to control INR despite best effort. In cases of dosing errors, seven were due to physician error, two were due to patient error, and one was due to both physician and patient error. Physician error was due to a too-aggressive increase in warfarin dosage in response to previously sub-therapeutic episodes, and patient error was ascribed to incorrect and/ or inconsistent usage of warfarin. In 85.7% of patients with warfarin toxicity, the cause was not identified (Table 2). Eighty-five per cent (107/126) of patients were using concomitant medication on admission with 77% (97/126) of patients using one or more medicines with a known DDI with warfarin. The median (IQR) number of possible DDIs was two (one to three) per patient. The potential number of DDIs with warfarin per patient were: one DDI 18% (23/126), two DDIs 25% (31/126), three DDIs 18% (23/126), four DDIs 10% (13/126), five DDIs 4% (5/126), six DDIs 1% (1/126), and seven Table 3. Major DDIs with warfarin Drug
Number of patients Quality of evidence using drug of interaction
Cardiovascular medicines Simvastatin
57
Excellent
Aspirin
33
Fair
Clopidogrel
4
Fair
Amiodarone
3
Excellent
Antimicrobial, including antiretroviral medicines
10 (5–20) 3 (2–4)
Packed RBC (IU)
2.5 (2–5)
4-factor PCC (IU)
1 250 (1 000–2 000)
IQR = interquartile range, IV = intravenous, FFP = fresh frozen plasma, RBC = red blood cells, IU = international units, PCC = prothrombin complex concentrate.
DDIs 1% (1/126). The most frequent drugs used found to have a DDI with warfarin were simvastatin (57 patients), aspirin (33 patients) and atenolol (29 patients). Table 3 reports on all major DDIs with warfarin. Twenty-eight per cent (35/126) of patients presented with major bleeding, 18% (23/126) with non-major bleeding and 54% (68/126) without bleeding. The most frequent sites of bleeding were upper gastrointestinal tract (31%, 18/58), haemoptysis (19%, 11/58) and epistaxis (17%, 10/58). Seven cases (12%, 7/58) of intracranial haemorrhage were reported. The median INRs for the major bleeding, non-major bleeding and non-bleeding groups were not significantly different (p = 0.05) at 10, 7.59 and 7.65, respectively. We found no statistically significant relationship between the presence of DDIs and the occurrence of bleeding. Furthermore, although 36 patients were using concomitant antiplatelet medicines, no statistically significant relationships were found between the concomitant usage of antiplatelet medicines together with warfarin and the occurrence of bleeding (see Table 4). The median number of treatment interventions was two, with 33.3% (42/126) of patients not receiving any interventions and 35.7% (45/126) and 23.8% (30/126) of patients receiving one and two treatment interventions, respectively. Nine (7.14%) patients received three or more interventions. Five per cent (6/126) of patients received three, 2% (2/126) received four and 1% (1/126) received five interventions, respectively. The most frequently used interventions were vitamin K (45 patients), FFP (43 patients) and packed red blood cells (RBC) (34 patients). Factor PCC (Haemosolvex®) was administered in eight patients. Other interventions used were cryoprecipitate (one patient), tranexamic acid (two patients) and platelet products (three patients). See Table 5 for median (IQR) total dose given for the most frequently used interventions.
Efavirenz
6
Fair
Amoxicillin
1
Good
Amoxicillin/clavulanic acid
1
Good
Ciprofloxacin
1
Good
Cotrimoxazole
1
Excellent
Hospital stay
Moxifloxacin
1
Excellent
Vitamin K
Metronidazole
1
Good
Fluoxetine
4
Good
Citalopram
1
Good
Total cost to treat
Mirtazapine
1
Excellent
Valproic acid
1
Good
Central nervous system medicines
Median total dose given (IQR)
Table 6. Calculated treatment cost Component
Cost average R 7 464 R 21
Total range (R 627 – R70 224) (R 1 – R 81)
FFP
R 3 948
(R 1 193 – R 10 737)
Packed RBC
R 4 617
(R 2 434 –R 15 821)
4-factor PCC
R 4 312
(R 1 568 – R 6 273)
R 10 578
(R 627 – R 79 762)
FFP = fresh frozen plasma, RBC = red blood cells, PCC = prothrombin complex concentrate.
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The average cost to treat a patient with warfarin toxicity was calculated at R10 578. The largest contributors to treatment costs were cost to be admitted and the use of blood and blood products when required (see Table 6).
Discussion To the best of our knowledge, this is the first review of warfarin toxicity in South Africa looking at causes, management and treatment cost implications. We found that the cause of warfarin toxicity was not identified in the majority of patients. DDIs were identified to be the cause of warfarin toxicity in only three cases, while we identified that 77% (97/126) of patients were using concomitant medication known to have a DDI with warfarin. The most frequently prescribed interacting medicines were cardiovascular medicines. Major DDIs with antimicrobial, antiretroviral and central nervous system medicines were also identified. Our patients presented with significant morbidity, with nearly half of the patients presenting with bleeding, while 28% presented with major bleeding. Although many unrecorded DDIs with warfarin were identified, we could not prove a statistically significant relationship for the presence of DDIs and the occurrence of bleeding. Furthermore we could not prove a statistically significant relationship between the usage of antiplatelet medicines together with warfarin and the occurrence of bleeding. Patients were admitted for a median of eight days and the average total cost to treat a patient with warfarin toxicity was estimated at R10 578. Of concern is that some patients were treated with high-cost interventions, which do not address the pathophysiology of warfarin toxicity. We also recognised a significant mortality rate associated with warfarin toxicity as 15% of patients died, although the final cause of death could not be attributed with certainty to warfarin toxicity. The low pick-up rate for the cause of warfarin toxicity could be explained by physicians not documenting the cause of warfarin toxicity, however this is unlikely. Furthermore, it could be postulated that physicians are not aware of or unable to determine all the drug interactions with warfarin. Medicines found to have major DDIs with warfarin are used over a variety of disciplines and within a tertiary setting could result in the addition of medications to a patient’s treatment regime without adequate knowledge of already prescribed medication by other disciplines. Difficulty in dose adjustment could be explained by the availability of only 5-mg oral tablets in the public sector, limiting physicians in the degree that they can adjust warfarin dosage. Our study has a number of limitations. Firstly, this was a retrospective study and relied on the availability of clinical records and the quality of available records. We were unable to obtain access to the clinical records of 55 raised INR measurements. Secondly, it is possible that we excluded patients presenting with warfarin toxicity complicated by major bleeding using our inclusion criteria. We identified 19 patients who died with only one INR measurement having been done, but who were excluded from our analysis due to insufficient clinical information and our inclusion criteria.
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Thirdly, we were unable to determine the impact of genetics on warfarin toxicity. However, genotype-guided dosing is only of value when initiating warfarin therapy.10 Fourthly, INR measurements are reported up to 10 with values above 10 being reported as > 10 by the NHLS. For statistical analysis, values greater than 10 were processed as 10, and underestimated the association between INR and bleeding severity of warfarin toxicity. Lastly, we were not able to determine prolonged admission to hospital for concomitant medical or surgical conditions after correction of warfarin toxicity.
Conclusion We found that the cause of warfarin toxicity is frequently not identified by physicians and is therefore rarely addressed. We found that warfarin toxicity carries a significant morbidity rate and significant resources to treat. Future prospective research should study the causes of patients who are stable on warfarin treatment and present with warfarin toxicity, and target interventions to address this.
References 1.
Sonuga BO, Hellenberg DA, Cupido CS, Jaeger C. Profile and anticoagulation outcomes of patients on warfarin therapy in an urban hospital in Cape Town, South Africa. Afr J Prim Health Care Fam Med 2016; 8(1): a1032.
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Rossiter D (ed). South African Medicines Formulary. Cape Town: Health and Medical Publishing Group of the South African Medical Association, 2014: 102–103.
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Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009; 30(7): 375–386.
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Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MM, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010; 115(18): 3827–3834.
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Westaway K, Cruickshank M, Roberts GW, Esterman AJ. Factors influencing over-anticoagulation and bleeding warfarin therapy during the initial five months of treatment. Austr Nursing J 2010; 17(10): 28–31.
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Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med 2000; 109: 481–485.
7.
Hull RD, Garcia DA. Correcting excess anticoagulation after warfarin [Online] 2015 [access 2015, April 23]; Available: http://www.uptodate. com/contents/correcting-excess-anticoagulation-after-warfarin
8.
Mezin J, Hoesche J, Friedman M, Nichols C, Bergman C, Crowther M, et al. Failure to correct international normalized ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. J Thromb Haemostasis 2012; 10: 596–605.
9.
DRUG-REAX®. Interactive Drug Interactions database (Truven Health Analytics Inc. Micromedex® Healthcare Series) 2016. [Online]. Available:
http://www.micromedexsolutions.com/micromedex2/
librarian/CS/C70D18/ND_PR/evidencexpert/ND_P/evidencexpert/ DUPLICATIONSHIELDSYNC/9DCF96/ND_PG/evidencexpert/ ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.FindDrugI [2016, July] 10. Primohamed M, Burnside G, Eriksson N, Jorgensen AL, Hock Toh C, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. New Engl J Med 2013; 369(24): 2294–2303.
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Medication adherence among cardiac patients in Khartoum State, Sudan: a cross-sectional study Abdelmoneim Awad, Nahid Osman, Siham Altayib
Abstract Introduction: Non-adherence to medication among cardiac patients is often the major risk factor for poor clinical outcomes, increased mortality rates and higher healthcare costs. The literature evaluating the prevalence of and reasons for non-adherence in resource-poor settings is extremely limited compared to resource-rich settings. There is a scarcity of data about medication adherence in Sudan hence this study was performed to identify prevalence, predictors and barriers of non-adherence to medication among cardiac patients in Khartoum State. Methods: A descriptive, cross-sectional survey was performed using a pre-tested, self-administered questionnaire on a sample of 433 randomly selected cardiac patients attending the largest three cardiac centres located in Khartoum State. Descriptive and multivariate logistic regression analyses were used for data analysis. Results: The response rate was 89.1%. The mean (± SD) number of chronic diseases among respondents was 2.3 (± 1.3) and that of medication use was 4.2 (± 1.9). The mean (± SD) duration of medication use among participants was 6.4 (± 5.4) years. Optimal adherence was defined as having a score of greater than six on the eight-item Morisky medication adherence scale. Using this cut-off point, 49% (95% CI: 43.9–54.1) of respondents had optimal adherence and 51% (95% CI: 45.9–56.1) had poor adherence. Respondents with a high level of education, low and middle income levels, and those taking five or more medications daily were found to be significantly more non-adherent to medication use than those with low to intermediate education levels (p < 0.001), those with high income levels (p < 0.001), and those taking one to four medications daily (p = 0.039). The top four barriers for poor medication adherence among the study participants were the high cost of drugs, polypharmacy and lack of pharmacist and physician communication with patients about their drug therapy. Conclusions: The current findings highlight the need for urgent, multifaceted interventions, given the burden of cardiovascular diseases and the clinical and economic consequences of medication non-adherence. These interventions include affordable medications, easy-to-use medication regimens with fewer daily doses, ongoing communication between patients and healthcare providers, and improvement of the patient– provider partnership.
Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait Abdelmoneim Awad, PhD, amoneim@hsc.edu.kw
Department of Pharmacy Practice, Faculty of Pharmacy, Qassim University, Saudi Arabia Nahid Osman, PhD
Department of Clinical Pharmacy, Faculty of Pharmacy, National University, Khartoum, Sudan Siham Altayib, MSc
Keywords: non-adherence, adherence, cardiac patients, cardiovascular medications, Khartoum State, Sudan Submitted 23/9/16, accepted 8/3/17 Published online 24/3/17 Cardiovasc J Afr 2017; 28: 350–355
www.cvja.co.za
DOI: 10.5830/CVJA-2017-016
Cardiovascular diseases (CVDs) are the leading cause of deaths in both developed and developing countries. There is a rapid increase in the burden of CVDs in Africa and it is currently a public health concern. In Sudan, CVDs are estimated to cause 12.0% of all mortalities.1 Cardiovascular diseases have been consistently reported as one of the top 10 causes of hospital mortality in Sudan.2 Cardiovascular disease is one of the most preventable causes of death in the world, due to the fact that the majority of its risk factors are preventable or controllable.3 In 2006, a survey of risk factors for coronary heart disease among the population in Khartoum State showed a high prevalence of low physical activity (86.6%), overweight and obesity (53.9%), hypertension (23.6%), dyslipidaemia (19.8%), diabetes (19.2%) and smoking (12%).2 Non-adherence to cardiovascular medications has become increasingly documented across patient populations and cardiovascular drug classes. A meta-analysis of 20 studies involving 376 162 patients illustrates a non-adherence prevalence of 43% throughout multiple drug classes, as measured by pharmacy refill data.4 This is comparable to the average prevalence of non-adherence to both cardiovascular and non-cardiovascular medications in developed countries, 50% as indicated by the World Health Organisation.5 Non-adherence to cardiovascular medications has been associated with poor clinical outcomes, including re-admissions to hospital, subsequent myocardial infarction, increased mortality rates and increased healthcare costs. 6-8 Several studies have been conducted in developed countries to determine adherence to cardiovascular medications, and have shown the prevalence of non-adherence to cardiovascular medications, the association between non-adherence and outcomes, the reasons for non-adherence, and the interventions to improve medication adherence.4,9-13 By contrast, data related to the prevalence of non-adherence to cardiovascular medications from developing countries is limited, even though its prevalence in these regions is increasing at more than twice the rate observed in developed countries.5 A systematic review of studies conducted in developing countries shows that adherence to cardiovascular medications is suboptimal and appears comparable to that observed in developed countries. The overall adherence to cardiovascular medications pooled across studies was 57.5%.14
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The exact prevalence rate of medication non-adherence among cardiac patients in Sudan is not known since there are limited published studies. A study was conducted at Elshaab Hospital in Khartoum to determine the adherence to secondary-prevention medication among 210 patients and it was found to be 66%.15 Another study was performed among 76 patients with heart failure admitted to the Sudan Heart Institute in Khartoum, which indicated that 75% of the respondents were adherent to their medications.16 These previous studies have used limited study populations or a small number of patients in single clinical settings and may not enable meaningful conclusions to be drawn regarding levels of adherence to cardiovascular medications. This highlights the need to expand this area of research to include patients attending multicentre, out-patient cardiovascular clinics and to improve the quality of such research. Therefore, this study was conducted to evaluate prevalence, predictors and barriers of non-adherence to medications among cardiac patients attending the three largest national referral cardiac centres located in Khartoum State.
Methods This was a descriptive, quantitative and cross-sectional study designed to describe the adherence of patients with cardiovascular diseases to their medications. Sudan is one of largest countries in Africa (total area of 1 861 484 km2) with an estimated population of 36 million people as of July 2015 (CIA fact book, 2016). It is a federal nation consisting of 18 states. Khartoum State, the capital of Sudan, covers an area of 28 165 km2 and contains almost 20% of the population, 84% of whom live in urban areas. This study was conducted between September 2014 and March 2015 in Khartoum State, Sudan. The study population consisted of out-patients attending the cardiac clinics in Ahmed Gasim Cardiac Surgery and Renal Transplantation Centre, Elshaab Teaching Hospital and Sudan Heart Institute, because they represent the three largest national referral cardiac centres located in Khartoum State. The study was conducted in accordance with the Declaration of Helsinki and national and institutional standards. Ethical approval for this study was obtained from the Directorate of Research, Ministry of Health, Khartoum State. Inclusion criteria for a patient to enter the study were patients aged 18 years or older diagnosed with cardiovascular disease or its major risk factor, hypertension, who started using a cardiovascular medication for a duration of three months or more. Patients who had psychiatric disorders or cognitive impairment were excluded. The sample size was determined using PS power and sample size calculator V.3.05.17 A sample of 260 patients would be necessary to determine a 20% difference in proportion between two groups; for example, male versus female with 90% power and at 5% significance level. Assuming a response rate of 60%, a sample size of 433 patients was approached to be included in the study. The total number of patients selected from each hospital was proportional to the out-patient population attending the hospital per year. The patients at each hospital were randomly selected, using systematic random sampling from the patients’ registration lists. The content validity of the study questionnaire was established by a research group at Kuwait University. The questionnaire was translated into Arabic and subjected to a
351
process of forward and backward translation. The accuracy and meaning of the translated versions both forward and backward were checked, and recommended amendments where necessary were discussed before being finalised. It was pre-tested for content, design, readability and comprehension on 16 patients with cardiovascular diseases, and modifications were made as necessary so that the questionnaire was simple to understand and answer, yet gave accurate data. The final version of the pre-tested questionnaire was composed of four sections, and it contained both open-ended and closed questions. The first section included items to provide information about the sociodemographic characteristics of the respondents (age, gender, marital status, educational level, residence and monthly income). Section two consisted of questions to provide information about the clinical variables of the study population (type and duration of cardiovascular disease, and type and duration of medications used by the patient). The third section evaluated adherence to medications using the validated eight-item Morisky medication adherence scale (MMAS-8).18 Each item measures a specific medication-taking behaviour; response categories are yes/no for each item with a dichotomous response and a five-point Likert response for the last item (never/rarely, once in a while, sometimes, usually and all the time). The negative response for each item was coded as one, except for the item asking if the patient took the medications yesterday (where a positive response was coded as one). The total score was calculated by summing the values from all eight question items. Optimal adherence was defined as having a MMAS-8 score of greater than six out of a total of eight, according to the methodology used in previous literature.19,20 Section four included questions to explore the reasons for not taking the medications regularly. Data were collected via structured face-to-face interviews of the respondents in the waiting rooms of the cardiac clinics using the pre-tested questionnaire. The interview lasted approximately 15–20 minutes. The selected patients were contacted and given an explanation about the purposes of the research. They were assured of confidentiality and gave verbal consent to participate in the study. Data about clinical variables were checked with the attending physicians from the patients’ medical records.
Statistical analysis Data were entered into the Statistical Package for Social Sciences [IBM SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY, USA)] and descriptive analysis was conducted. The results were reported as percentage (95% confidence interval) and mean (standard deviation). Univariate logistic regression was performed to determine the relationship of each independent variable with adherence to cardiac medications. All variables with p ≤ 0.25 in the univariate analysis were included in the multiple logistic regression analysis to determine the factors that were independently associated with non-adherence to cardiac medications. The excluded variables were gender (p = 0.38), marital status (p = 0.83), residence (p = 0.36), hospitals (p = 0.57) and duration of medication use (p = 0.45). Only the results of multivariate logistic analysis are reported showing odds ratio (OR) and 95% confidence interval (CI). Statistical significance was accepted at p < 0.05.
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For each model, response options for the dependent variable were categorised as either ‘poor adherence’ or ‘optimal adherence’. The predictor variables were categorised as follows: (1) gender: males and females; (2) age: 18–39 years, 40–49 years, 50–59 years, ≥ 60 years; (3) marital status: married and single (includes divorced and widowed); (4) level of education: low– intermediate (0–12 years) for those who completed secondary school or less, and high (> 12 years) for those who had a diploma, bachelor degree or postgraduate degree; (5) residence: Khartoum, Khartoum North, Omdurman and outside Khartoum State; (6) hospitals: Ahmed Gasim Hospital, Elshaab Teaching Hospital and Sudan Heart Institute; (7) monthly income: low < 1 000 Sudanese pounds (SP), middle 1 000–2 000 SP, and high > 2 000 SP; (8) number of chronic diseases: one to two chronic diseases, and ≥ three chronic diseases; (9) number of medications taken: one to four medications, and ≥ five medications); (10) duration of medication use: > three months to one year, > one to five years, > five to 10 years, and > 10 years.
Results Table 1 summarises the sociodemographic characteristics of respondents. A total of 433 Sudanese subjects were approached to be included in the study; 386 agreed to participate, giving a response rate of 89.1%. Of the respondents, 43% were 60 years or over, 57% were females and 81.6% had low–intermediate education. Table 2 shows the clinical characteristics of the study participants. One-half of respondents had hypertension, 30.3%
Table 1. Sociodemographic characteristics of the respondents (n = 386) Characteristic
Frequency (%)
Gender Male
166 (43)
Female
220 (57)
Marital status Single*
239 (61.9)
Married
147 (38.1)
Age (years) 18–39
79 (20.5)
40–59
42 (10.9)
50–59
99 (25.6)
≥ 60
166 (43.0)
Educational level Low–intermediate education High education
315 (81.6) 71 (18.4)
Residence (cities in Khartoum State) Khartoum Khartoum North Omdurman Outside Khartoum State
75 (19.4) 102 (26.4) 92 (23.8) 117 (30.3)
Hospitals
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had dyslipidaemia and 28.5% had ischaemic heart disease. The mean (± SD) number of chronic diseases among the study population was 2.3 (± 1.3) and that of medication use was 4.2 (± 1.9). Two hundred and thirty-six patients (61.1%) were using beta-blockers, and above two-fifths were using loop diuretics (47.2%), statins (47.4%), low-dose aspirin (42.7%) and warfarin (40.7%). The mean (± SD) duration of medication use among participants was 6.4 (± 5.4) years. Table 3 presents the distribution of responses to the MMAS8 among the participants. Seven in 10 participants (n = 274; 71.0%; 95% CI: 66.1–75.4) reported that they never or rarely had difficulty remembering to take all their medications. Half of the respondents indicated that they felt hassled about sticking to their treatment plan (n = 194; 50.3%; 95% CI: 45.2–55.4). Over one-third of the study population reported that they had cut back or stopped their medication without telling their physicians because they felt worse (n = 140; 36.3; 95% CI: 31.5–41.3) and that they sometimes forgot to take their pills (n = 133; 34.5; 95% CI: 29.8–39.5). Optimal adherence was defined as having a score of greater than six on the MMAS-8. Using this cut-off point, 49% (n = 189; 95% CI: 43.9–54.1) of respondents had optimal medication adherence and 51% (n = 197; 95% CI: 45.9–56.1) had poor medication adherence. The mean (± SD) score for the medication
Table 2. Clinical characteristics of the respondents (n = 386) Characteristic
Frequency (%; 95% CI)
Types of chronic diseases Hypertension
195 (50.5; 45.42–55.6)
Dyslipidaemia
117 (30.3; 25.8–35.2)
Ischaemic heart disease
110 (28.5; 24.1–33.3)
Chronic heart failure
85 (22.0; 18.1–26.6)
Arrhythmia
81 (21.0; 17.1–25.5)
Cardiac valve replacement
74 (19.2; 15.4–23.5)
Rheumatic heart disease
71 (18.4; 14.7–22.7)
Cerebrovascular disease
25 (6.5; 4.3–9.5)
Drug class/drug Beta-blockers
236 (61.1; 56.1–66.0)
Statins
183 (47.4; 42.4–52.5)
Furosemide
182 (47.2; 42.1–52.3)
Low-dose aspirin
165 (42.7; 37.8–47.9)
Warfarin
157 (40.7; 35.8–45.8)
Angiotensin converting enzyme inhibitors
147 (38.1; 33.3–43.2)
Potassium-sparing diuretics
115 (29.8; 25.3–34.7)
Calcium-channel blockers
63 (16.3; 12.9–20.5)
Clopidogrel
60 (15.5; 12.2–19.6)
Angiotensin receptor blockers
48 (12.4; 9.4–16.2)
Nitrates
44 (11.4; 8.5–15.1)
Digoxin
31 (8.0; 5.6–11.3)
Thiazide diuretic
15 (3.9; 2.3–6.5)
Number of chronic diseases 1–2
234 (60.6; 55.5–65.5)
≥3
152 (39.4; 34.5–44.5)
Ahmed Gasim Cardiac Surgery and Renal Transplantation Centre
110 (28.5)
Elshaab Teaching Hospital
146 (37.8)
1–4
216 (56.0; 50.8–61.0)
Sudan Heart Institute
130 (33.7)
≥5
170 (44.0; 39.1–49.2)
Number of medications
Duration of medication use (years)
Monthly income Low income
140 (36.3)
≥ 0.25–1
Middle income
136 (35.2)
> 1–5
143 (37.0; 32.3–42.1)
High income
110 (28.5)
> 5–10
95 (24.6; 20.5–29.3)
> 10
73 (18.9; 15.7–23.8)
*Includes divorced and widowed
75 (19.4; 15.7–23.8)
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adherence scale was 6.1 (± 1.8). The item-total correlations were > 0.44 for each of the eight items composing the medication adherence scale. The internal consistency using Cronbach’s alpha was 0.76. Multivariate logistic regression analysis revealed three independent variables had a significant influence on non-adherence to medication use. Respondents with high levels of education, low or middle income levels and those who taking five or more medications daily were found to be more non-adherent to medication use than those with low– intermediate education levels (p < 0.001), those with high income levels (p < 0.001), and those taking one to four medications daily (p = 0.039). Table 4 shows the results of the multivariate analysis for factors associated with high adherence to medication use. The reasons for poor medication adherence among the study participants were found to be the expensive cost of drugs (n = 210; 54.4%; 95% CI: 49.3–59.4), polypharmacy (n = 204; 52.8%; 95% CI: 47.7–57.9), lack of pharmacist’s communication with them regarding the instructions and importance of taking the drug regularly (n = 193; 50.0%; 95% CI: 44.9–55.1), lack of physician’s communication with them regarding their illness and the benefit that the medication will provide (n = 156; 40.4%; 95% CI: 35.5–45.5), bothered by side effects associated with their medications (n = 142; 36.8%; 95% CI: 32.0–41.8), and irregular availability of the drugs in their areas (n = 129; 33.4%; 95% CI: 28.8–38.4).
Discussion This is the first known study to be conducted among patients attending the three largest cardiac centres in Khartoum State to evaluate their level of adherence to cardiovascular medications, and to identify predictors and barriers of non-adherence. These findings would be the first step to provide a better understanding of medication adherence among cardiac patients in Khartoum State, and are valuable for policy makers and clinicians to inform future services. These results could be utilised in designing targeted strategies to improve adherence and to minimise the adverse outcomes associated with non-adherence to medications. A very worrisome finding in this study was the highly prevalent self-reported medication non-adherence among the
study population (51%), compared to that reported in two previous studies (34 and 40.4%, respectively) in Khartoum State.15,16 The current study provides more valid and meaningful results due to the use of an appropriate sample size, sampling strategy, validated MMAS-8, and its inclusion of patients with variant cardiovascular conditions in multicentre out-patient cardiac clinic settings covering the three largest cardiac referral centres in Khartoum State. The present findings are within prevalences reported in developed and developing countries, which ranged between 31 and 60%.4,5,9,14 The high non-adherence rate demonstrated by this study is of particular concern as a potential contributing factor to poor clinical outcomes, including rehospitalisation, increased mortality rates and increased healthcare costs,6-8 and underscores the urgent need for its improvement in order for cardiac patients to derive the maximal benefit of their prescribed medications. In our survey, levels of income and education, and polypharmacy were found to be significant predictors for non-adherence to cardiovascular medications. Medication non-adherence was significantly higher among low- and middleincome groups compared to the high-income group, which is consistent with previous studies.10,14 This finding may be attributed to the precipitous increase in living costs in Sudan during the last three years, which may have led some patients with cardiovascular diseases to consider their medication costs as a lower-priority option. Other possible reasons include the prescribing of expensive, proprietary medications instead of generics, poor health insurance coverage, and bureaucratic processes associated with insurance claims. The current finding highlights the need for the implementation of appropriate tools to determine the patient’s ability to afford the cost of medications since many patients may be embarrassed to admit that they are having trouble affording medications; and the establishment of programmes that involve partnerships between patients, healthcare providers and payers to help patients plan for payment of medication. Also eliminating co-payments and out-of-pocket medication costs for patients with low and middle incomes may be a viable component of future interventions. Table 4. Association between non-adherence and respondents’ characteristics (n = 386) Poor adherence, n (%)
OR (95% CI)
18–39
32 (40.5)
0.8 (0.4–1.4)
Yes, n (%; 95% CI)
40–49
22 (52.4)
1.1 (0.5–2.3)
133 (34.5; 29.8–39.5)
50–59
61 (61.6)
1.6 (0.9–2.8)
≥ 60
82 (49.4)
Reference
152 (48.3)
0.3 (0.2–0.6)
45 (63.4)
Reference
Characteristics Table 3. Distribution of responses to the eight-item Morisky medication adherence scale among the participants (n = 386) Item 1
Do you sometimes forget to take your pills?
2
Over the past two weeks, were there any days when you did not take your medicine?
3
Have you ever cut back or stopped taking your medication without telling your doctor because you felt worse when you took it?
4
When you travel or leave home, do you sometimes forget to bring along your medications?
5
Did you take your medicine yesterday?
6
When you feel better, do you sometimes stop taking your medicine?
75 (19.4; 15.7–23.8)
Age (years)
Low–intermediate High
90 (23.3; 19.3–27.9) 375 (97.2; 94.8–98.5) 58 (15.0; 11.7–19.1)
7
Taking medication every day is a real inconvenience for some people Do you ever feel hassled about sticking to your treatment plan?
194 (50.3; 45.2–55.4)
8
How often do you have difficulty remembering to take all your medication?*
112 (29.0; 24.6–33.9)
*n (%) of once in a while, sometimes, usually, and all the time
p-value 0.25
< 0.001
Educational level 140 (36.3; 31.5–41.3)
353
< 0.001
Monthly income Low
84 (60.0)
6.6 (3.6–12.3)
Middle
88 (64.7)
5.7 (3.1–10.5)
High
25 (22.7)
Reference
1–2
111 (47.4)
1.1 (0.6–1.9)
≥3
86 (56.6)
Reference
1–4
99 (45.8)
0.6 (0.3–0.9)
≥5
98 (57.6)
Reference
Number of diseases
0.79
Number of medications 0.039
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The present study shows that patients with high education levels were more non-adherent compared to those with low– intermediate education levels. This is in contrast with the findings of previous studies, which reported that poor health literacy was associated with medication non-adherence.21,22 There is considerable evidence that those with more years of education tend to have better health and healthier behaviours; however, this is not in agreement with our findings. While the reasons for our apparently contrary findings are unclear, it may be that participants with low–intermediate education levels had better healthcare information to make appropriate health decisions and follow instructions for treatment. This better health information might be gained through health messages, which are delivered through television and/or radio. On the other hand, it is possible that respondents with high education levels are honest to admit that they are human and may not always follow instructions, while those with low–intermediate education levels may not admit that they fail to take their medications to that extent. Also an additional possible reason is that less than one-fifth of the respondents in this survey had high education levels. Hence, this finding highlights the need for further qualitative research to provide better understanding of education level as a predictor of non-adherence among cardiovascular patients in Sudan. The current results revealed that non-adherence was significantly greatest among those taking five or more medications daily, which is consistent with previous studies.11,23 It is evident that reducing the total number of pills per day can improve medication adherence. Hence, an approach needs to be taken to reduce medication complexity through avoiding polypharmacy and using regimens with fewer daily doses. This could be achieved by maximally simplifying cardiovascular medication regimens by combining medications from three or more medication classes (e.g. aspirin, statin and antihypertensives) into a single daily ‘polypill’. The rationale is that the simpler medication regimen leads to improved adherence.24 These findings revealed that gender, co-morbidities and age were not statistically significant predictors for non-adherence, which contrasts with findings in some other studies, where women, elderly individuals and those who had three or more diseases had poorer adherence.12,13 A systematic review of studies conducted in developing countries revealed that patient factors such as age, gender, lifestyle and lack of access to healthcare services were not consistently associated with non-adherence.14 The existence of conflicting information among various studies suggests that assessment of non-adherence cannot be targeted to specific patient populations or characteristics, and the established predictors of adherence are often insufficient to identify individual patients who are likely to be non-adherent, and they should be used cautiously as a means of targeting high-risk populations.25 Another approach to understanding reasons for non-adherence is to identify the barriers. In contrast with predictors of adherence, barriers are restricted to potentially modifiable factors that healthcare providers and/or the healthcare system can attempt in order to reduce medication non-adherence. The top two barriers reported by the study population were the high cost of drugs and polypharmacy. These barriers reported by the patients confirm the results obtained by the Morisky eight-item scale adherence measure. These results underscore the urgent need for the development and implementation of effective strategies to overcome these barriers.
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Lack of pharmacist’s communication regarding instructions and the importance of taking the medication regularly, and lack of physician’s communication regarding the disease and the benefit that the medication will provide were reported as barriers by half and two-fifths of respondents, respectively. These results highlight a call for a more active role that healthcare providers should take in assessment, education and strategic implementation efforts to promote medication adherence. It is evident that the time healthcare providers spend to achieve good patient understanding about the disease and the rationale for medication use fosters a partnership with their patients and improves medication adherence.26 Pharmacists need to develop counselling strategies that help patients form strong habits regarding medication use, educate patients about their medications, and provide regular follow up to ensure that patients are taking medications as directed. The value of pharmacists in adherence to cardiovascular medication was illustrated in two studies, where patients were randomised to intensive pharmacist-led intervention versus usual care. The intervention resulted in significant improvements in adherence and disease control.27,28 Sudanese pharmacists must improve their clinical knowledge and skills, demonstrate their willingness to be responsible for the patient’s drug therapy, and develop a close working relationship with other healthcare professionals. Three in 10 responders indicated that the experienced side effects associated with their medications and irregular availability of the medication in their areas were barriers for adherence. This underscores the need for more dialogue between patients and healthcare providers about medications, including discussions about the possible side effects and management strategies, thus allowing patients to become part of the decision-making process.29 The irregular availability of cardiovascular medications among those resident outside Khartoum State underscores the need for multiple approaches to be used to address challenges within the healthcare system that prevent the reliable availability of essential medications, with a special focus on improving the governance of the drug-delivery system to all states of Sudan. We acknowledge that this type of study has its limitations. It depends very much upon information given by respondents and is open to bias by inaccurate patient recall or by social desirability. The extent of truthful answers or verifying respondents’ claims is not possible in this type of study, and answers were taken at face value. A further limitation of the study is the cross-sectional nature of the data that represented one point in time and therefore does not reflect any changes in respondents’ adherence to cardiovascular medications.
Conclusions The findings of this study provide important information about the prevalence, predicators and barriers of medication non-adherence among out-patient cardiac patients. These results allow for important comparative work with existing and future investigations in Sudan and other developing countries. Our results showed that the use of a validated self-report instrument can provide immediate feedback to help healthcare providers identify non-adherent patients. Such brief, inexpensive tools should be more widely implemented as part of the daily care plan in the out-patient clinics. The study findings underscore the urgent need to establish
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multifaceted and personalised interventions. These should incorporate affordable medications with favourable side-effect profiles, easy-to-use medication regimens with fewer daily doses, ongoing communication among patients and healthcare providers, improvement of the patient–provider partnership, and an expanding role of pharmacists through implementation of pharmaceutical care.
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Am J Hypertens 2009; 22(4): 392–396. Doi: 10.1038/ajh.2008.367. 14. Bowry AD, Shrank WH, Lee JL, Stedman M, Choudhry NK. A systematic review of adherence to cardiovascular medications in resource-limited settings. J Gen Intern Med 2011; 26(12): 1479–1491. Doi: 10.1007/ s11606-011-1825-3. 15. Elhassan OBM, Ibnouf MAM. Adherence of Sudanese coronary artery disease patients to secondary prevention medications at Elshaab Teaching Hospital, Sudan. Sudan J Med Sci 2014; 9(2): 111–116.
We gratefully acknowledge all the medical staff in the three sites for their
16. AL-khadher Mugahed A F-EI, Ahmed W. Compliance to treatment and
assistance and collaboration in carrying out the study, and all patients who
quality of life of Sudanese patients with heart failure. Int J Pharmaceut
agreed to participate in this study for their co-operation.
Medicinal Res 2015; 1(2): 40–44. 17. Dupont WD, Plummer WD Jr. Power and sample size calculations, 2014.
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Clinical profile, management and outcomes of patients with pulmonary embolism: a retrospective tertiary centre study in Angola Ana Manuel, Adelina Aufico, Rui Africano, Tomáz Peralta, Abel Salas, Adelaide Silva, José Ricardo, Pedro Sabola, Domingas Baião, Carlos Sotolongo, António Dias Neto, Telmo Martins, Vasco Sabino, Joaquim van Dúnem, António Pedro Filipe Júnior
Abstract Objective: Pulmonary embolism (PE) is a potentially fatal disease. In Angola, few data are available on its occurrence. The aim of the study was to characterise the clinical profile, management and outcomes of patients with PE. Methods: A retrospective observational study was conducted at the Girassol Clinic in Luanda, Angola. The medical records of patients admitted to the intensive care unit were analysed from 2011 to 2015. Results: Fifty patients were included and the median age was 50.5 ± 17.8 years. Dyspnoea and immobilisation for more than 72 hours were the most frequently seen risk factors at admission; 28% of the patients had massive PE, 36% sub-massive PE, 28% were haemodynamically unstable at admission and 30% had a very high risk of mortality. The in-hospital mortality rate was 20%. Conclusions: The clinical characteristics of our patients were similar to those described in the literature. The high prevalence of patients with very high risk at admisson highlights the need to investigate the cause of worst cardiovascular disease outcomes in Africans. Keywords: pulmonary embolism, pulmonary CT angiography, anticoagulation, cardiovascular disease, Angola, Africa
Cardiothoracic Center, Girassol Clinic, Luanda, Angola Ana Manuel, MD, mosalina@live.com.pt Tomáz Peralta, MD Abel Salas, MD José Ricardo, MD Pedro Sabola, MD Domingas Baião, MD Telmo Martins, MD António Pedro Filipe Júnior, MD
Intensive Care Unit, Girassol Clinic, Luanda, Angola Adelina Aufico, MD Rui Africano, MD Adelaide Silva, MD Carlos Sotolongo, MD António Dias Neto, MD, PhD
Imaging Department, Girassol Clinic, Luanda, Angola Vasco Sabino, MD
Studies Office, Girassol Clinic, Luanda, Angola Joaquim van Dúnem, MD, PhD
Submitted 10/4/16, accepted 4/4/17 Published online 17/5/17 Cardiovasc J Afr 2017; 28: 356–361
www.cvja.co.za
DOI: 10.5830/CVJA-2017-017
Pulmonary embolism (PE) is characterised by obstruction of the pulmonary arteries by thrombus. It is a potentially fatal disease in the absence of timely diagnosis and treatment. Venous thromboembolism is the third most frequent cardiovascular disease in some Western countries.1,2 In Africa, the available data relate to retrospective in-hospital and cohort studies, describing the mortality rate between 9.2 and 64%.3-6 The Virchow triad describes the main factors associated with thrombus formation: blood stasis, hypercoagulable states and endothelial injury. Despite sharing risk factors, deep-vein thrombosis is three times more frequent than PE, and both diseases can co-exist or occur alone.1,7,8 In Angola, few data are available on the occurrence and treatment of PE. Considering the need to improve knowledge about cardiovascular diseases, this study presents the clinical profile, management and outcomes of patients with PE.
Methods A retrospective, single-centre, observational study was conducted at the Girassol Clinic in Luanda, Angola. The study was approved by the clinical studies ethics committee of the Girassol clinic polyvalent intensive care unit (ICU). The manuscript is in accordance with the Helsinki Declaration and with ethical guidelines from our studies committee. The medical records of patients admitted to our ICU were analysed from September 2011 to September 2015. Clinical suspicion was defined by the physician based on symptoms, signs and risk factors. Patients with clinical suspicion were included in the study if PE was confirmed by one of the following diagnostic tests: pulmonary computed tomography (CT) angiography, transthoracic echocardiography and Doppler ultrasound of the limbs. Demographic variables and the presence of symptoms and clinical signs of PE were analysed (Fig. 1, Table 1). The presence of risk factors and co-morbidities is described in Table 2. Patients were also stratified according to PE risk scores (modified Wells and Geneva revised scoring systems). The following diagnostic tests were analysed regarding the frequency of realisation and positivity rates: • Laboratory tests: D-dimer, troponins, B-type natriuretic peptide (BNP), increased white blood cell count, increased
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erythrocyte sedimentation rate and lactate dehydrogenase enzyme (LDH) levels. • Arterial gasometry: presence of hypoxaemia, acute respiratory alkalosis and changes not related to PE. • Chest X-ray: presence of atelectasis, parenchymal infiltrates, pleural effusion, pneumothorax, cardiomegaly, Westmark and Hampton signs and changes not related to PE. • ECG: presence of sinus tachycardia, S1Q3T3 pattern, pulmonary P wave, right bundle branch block, right ventricular hypertrophy, right cardiac axis deviation, reversal of T wave in V1–V3 leads and unspecific alterations of repolarisation. • Echocardiogram: presence of enlargement or thrombus in the right chambers, right ventricle (RV) hypokinesia, McConnell sign, persistent pulmonary hypertension, patent foramen ovale and changes not related to PE. • Doppler ultrasound of limbs: presence of thrombi or decreased venous compressibility. • Pulmonary computed tomography angiography (PCTA): the lesions were classified as massive PE if the thrombosis was in a central location (main and lobar branches); patients with thrombosis in the segmental and sub-segmental branches were classified as sub-massive PE if RV dysfunction was present; and they were classified as low-risk PE on the absence of thrombus. Patients were also classified as haemodynamically unstable if their systolic blood pressure was under 90 mmHg, or there was
7
No of patients
5
357
poor peripheral perfusion or cardiogenic shock, and according to the pulmonary embolism severity index (PESI).9 The treatment type and duration was analysed. The following complications were considered: death; reversed cardiorespiratory arrest; heart failure; respiratory failure requiring mechanical ventilation; major bleeding, cardiogenic shock, acute myocardial infarction, acute kidney injury (AKI) or chronic kidney disease agudisation, sepsis originating in the respiratory tract, hyperglycaemia > 200 mg/dl (11.1 mmol/l) in non-diabetic patients, and peripheral embolisation. Data are presented using tables with absolute and relative frequencies, average arithmetic values and standard deviations. Statistical analysis was performed as two-sided significance tests. The non-parametric chi-squared test was used to test heterogeneity of proportions.
Results A total of 50 patients were included and the median age was 50.5 ± 17.8 years. The age groups 35 to 44 years and 55 to 64 years were the most affected (Fig. 1), 72% of patients were over the age of 40 years, 52% were male and 86% were black. Respiratory symptoms, including dyspnoea (68%), chest pain (40%) and cough (18%) were the most frequent. Only 4% of patients were asymptomatic and one patient presented with cardiorespiratory arrest (Table 1). Risk factors and more prevalent co-morbidities were immobilisation for more than 72 hours (48%), hospitalisation or recent surgery (28%), and hypertension (36%). In three patients (6%) there were no identified risk factors or co-morbidities (Table 2). The estimated pre-test probability of PE was analysed according to the Wells and Geneva criteria. Fifty-six and 58%
4
Table 2. Risk factors and co-morbidities of patients with pulmonary embolism Risk factors and co-morbidities
2 Male Female 0
<18
18–24 25–34 35–44 45–54 55–64 65–74 75–84 Age
Fig. 1. A ge and gender of the patients with pulmonary embolism.
Table 1. Prevalence of symptoms and signs of patients with pulmonary embolism at admission Symptoms and signs
Number (%)
Dyspnoea
34 (68)
Chest pain
20 (40)
Cough
9 (18)
Lower-limb pain
7 (14)
Tachycardia
6 (12)
Altered consciousness
5 (10)
Anxiety
3 (6)
Cyanosis
1 (2)
Syncope
1 (2)
Cardiorespiratory arrest
1 (2)
Other symptoms Asymptomatic
15 (30) 2 (4)
PE, n (%)
Immobilisation > 72 hours
24 (48)
Hospitalisation/surgery < 3 months
14 (28)
Arterial hypertension
18 (36)
Recent trauma
8 (16)
Diabetes mellitus
6 (12)
Obesity
6 (12)
Cancer
5 (10)
Previous known coagulations disorders
4 (8)
Smoking
4 (8)
Coronary artery disease/previous AMI
3 (6)
Hormonal treatment
3 (6)
Deep-vein thrombosis
3 (6)
Dyslipidaemia
2 (4)
Heart failure
2 (4)
COPD
1 (2)
Previous PE < 3 months
1 (2)
Stroke
1 (2)
Sickle cell disease
1 (2)
Pregnancy
1 (2)
Central venous catheter
1 (2)
Atrial fibrilation
1 (2)
Chronic kidney disease
1 (2)
No risk factors or co-morbidities
3 (6)
AMI, acute myocardial infarction; COPD, chronic obstructive pulmonary disease.
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Table 3. Pulmonary embolism risk stratification according to the modified Wells and Geneva revised scoring systems Wells scoring system n (%)
Geneva scoring system n (%)
Low
7 (14)
5 (10)
Moderate
28 (56)
PE probability
Intermediate
29 (58)
High
15 (30)
16 (32)
Total
50
50
Table 4. Frequency and positivity of the auxiliary diagnostic tests in patients with pulmonary embolism Diagnostic tests
Discussion The study results characterise the clinical profile of patients with PE admitted at our hospital. The presented data refer to the current clinical practice without any interference in medical procedures. The high clinical suspicion associated with the
Number (%)
Laboratory tests White blood cells (> 10 × 109 cells/l)
14 (28)
LDH (> 400 U/l)
10 (20)
D-dimers (> 500 μg/l)
4 (8)
Troponins (> 0.1 ng/ml)
4 (8)
ESR (> 10 mm in men, > 20 mm in women)
3 (6)
BNP (> 500 pg/ml)
of patients had moderate and intermediate PE probability, respectively (Table 3). Laboratory tests deviated from normal in 68% of patients; their positivity rates and cut-off values are shown in Table 4. D-dimer, troponin and BNP levels were positive in all tests with available results. More than half of the patients (54%) had abnormal results in their arterial blood gasometry (ABG), namely hypoxaemia in 34% and acute respiratory alkalosis in 20% of patients. About a quarter of patients (13 patients) had normal chest radiography. The electrocardiogram was normal in only 22% of patients and the classic S1Q3T3 pattern was found in only 18%. RV enlargement (20%) and RV hypokinesia (8%) were the main echocardiographic findings in our study. We documented the presence of deep-vein thrombosis by Doppler ultrasound in 20% of patients. PCTA changes were correlated with haemodynamic stability at admission in all patients; 28% had massive PE, of whom 20% were haemodynamically unstable; 36% had sub-massive PE and showed a statistically significant rate of haemodynamic stability at admission (28 vs 8%, p = 0.018). In 36% of patients there was low-risk PE (Table 5). All patients were stratified according to the pulmonary embolism severity index and 30% of the patients had a very high risk of mortality (Table 6). Heparins were the most common form of in-hospital anticoagulation. Unfractionated heparin was used in 32% of patients for 5.4 ± 2.1 days. Low-molecular-weight heparins were used in 44% of patients for 6.2 ± 3.7 days. Among these patients, 70% used oral anticoagulation with warfarin and 6% used new oral anticoagulants (NOAC) (Table 7). Thrombolytic therapy was used in 18% of the patients. In 12 patients, it was not possible to determine the type of anticoagulant used or whether they used thrombolytic therapy, due to the unavailability of data. There were complications in 38% of the patients; 15 had respiratory failure requiring mechanical ventilation and seven had cardiogenic shock (Table 8). The 24-hour and in-hospital mortality rates were 2.5 and 20%, respectively. There were 15 deaths, of which five occurred in the first 24 hours after admission. Considering the study criteria, three patients had a fatal outcome and were not included (no imaging confirmation of PE). However, they showed a high clinical probability for PE and alternative diagnoses were less likely.
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Normal
1 (2) 16 (32)
Arterial blood gasometry (ABG) Hypoxaemia
17 (34)
Acute respiratory alkalosis
10 (20)
Normal
13 (26)
Absent ABG
13 (26)
Chest radiography Pulmonary parenchymal infiltrates
7 (14)
Hampton sign
6 (12)
Pleural effusion
4 (8)
Cardiomegaly
2 (4)
Pneumothorax
1 (2)
Westmark sign
1 (2)
Changes not related to PE
5 (10)
Normal
13 (26)
Absent chest radiography
12 (24)
Electrocardiogram S1Q3T3 pattern
9 (18)
Non-specific repolarisation changes
6 (12)
Right bundle branch block
4 (8)
Right ventricular hypertrophy
1 (2)
Right cardiac axis deviation
1 (2)
Sinus tachycardia
1 (2)
Changes not related to PE
6 (12)
Normal
11 (22)
Absent ECG
11 (22)
Echocardiogram Enlarged right heart chambers with or without thrombus
10 (20)
Right ventricular hypokinesis
4 (8)
Pulmonary hypertension
3 (6)
Persistent foramen ovale
2 (4)
McConnel sign
2 (4)
Changes not related to PE
4 (8)
Normal
9 (18)
Absent echocardiogram
17 (34)
Limb Doppler ultrasound Deep-vein thrombosis
10 (20)
Normal
33 (66)
Absent Doppler ultrasound
7 (14)
LDH, lactate dehydrogenase enzyme; ESR, erythrocyte sedimentation rate; BNP, B-type natriuretic peptide.
immediate availability of pulmonary CT angiography and other diagnostic tests allowed us to confirm PE cases and exclude other differential diagnoses. This context has added greater consistency to the study results. According to Tambe and colleagues in Cameroon,10 it was found that PE is not a rare disease in sub-Saharan African populations. Institutional unavailability of CT angiography may favour sub-detection of the disease in some geographic areas.10 The median age observed in our study was 50.5 ± 17.8 years, similar to that described in the EMPEROR study11 (56.5 ± 18.1 years), and lower than some observational studies describing
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Table 5. Pulmonary embolism classification according to pulmonary computed tomography angiography and correlation with haemodynamic stability at admission CT angiography classification
Haemodynamically Haemodynamically stable patients, unstable patients, n (%) n (%) Sub-total
Massive PE
p-value
10 (20)
14 (28)
0.109
Sub-massive PE
14 (28)
4 (8)
18 (36)
0.018
Low-risk PE
18 (36)
–
18 (36)
–
Total
36 (72)
14 (28)
50
median ages between 60 and 68.9 years.7,12-14 According to Memtsoudis,15 in a retrospective and multicentre study of patients with PE after arthroplasty, the regressive multivariate analysis suggested that there is a higher risk of PE in the age group 45 to 64 years, but age alone was not identified consistently as a risk factor. Black patients were predominant (86.9%) in our study. The fact that the study was conducted in an African country may have contributed to this result. In the EMPEROR study,11 conducted in a population with multiple ethnic groups, they found a prevalence of 25.6% Afro-American patients with PE. Evidence suggested that non-Caucasian origin could be predictive of worse clinical outcomes for acute cardiovascular disease.11,16 The most common symptoms in our study were dyspnoea, chest pain and cough. These results are similar to those found in the JASPER study.12 However tachypnoea and tachycardia have been reported at higher prevalences compared to our results.7,14,17 The clinical manifestations of PE are often unspecific, which represents a diagnostic challenge. Dyspnoea and chest pain are symptoms that may constitute the sole or first manifestation of a broad spectrum of diseases. The observation of sudden dyspnoea may suggest PE. However, few studies describe a correlation between the degree of dyspnoea perceived by the patient and the degree observed by physicians.18 Chest pain associated with PE may have pleuritic or anginal characteristics in cases of RV ischaemia.14 In a cohort study conducted in primary healthcare, the most common differential diagnoses in patients referred for suspected PE were chest pain/non-specific dyspnoea, pneumonia, myalgia, asthma/COPD, hyperventilation anxiety disorders, heart failure, pericarditis and lung cancer. In these patients, although PE was excluded, there was a greater probability of clinically relevant illness in the presence of sudden dyspnoea, tachycardia, cough and haemoptysis.18 The most prevalent risk factor in our study was immobilisation for more than 72 hours in 48% of patients. Similar results were found in the ICOPER7 and EMEP14 studies in 28 and 38.5% of patients, respectively. The effect of the muscle pump in maintaining venous return is considered one of the main Table 6. Stratification of patients according to the pulmonary embolism severity index 30-day mortality risk classes
Number (%)
Table 7. Treatment of pulmonary embolism Treatment
Number (%)
Thrombolytic therapy Unfractionated heparin
4 (8)
Median duration (days) ± SD
9 (18)
–
16 (32)
5.4 ± 2.1
Low-molecular-weight heparins
22 (44)
6.2 ± 3.7
Warfarin
35 (70)
Continuous use after discharge
New oral anticoagulants
3 (6)
Continuous use after discharge
Elastic compression bandage
3 (6)
Continuous use after discharge
12 (24)
–
Unavaible treatment information
promotional mechanisms of blood stasis in immobilised patients.14 The prevalence of patients over 40 years of age was 72% in our study. The incidence of venous thromboembolic events increases after 40 years and it is estimated that the risk doubles with each subsequent decade.19 The prevalence of patients with cancer (10%) was lower than the range of 24.3 to 18.3% reported in other studies.7,12,14,20 This result may have been influenced by the prevalence of cancer in the different populations studied. In a retrospective study in cancer patients, PE was an accidental imaging found in 69.4% of patients. Cancer increases the risk of venous thromboembolism, mainly by activation of the coagulation system. Some authors suggest a systematic investigation for cancer in patients with PE of undetermined aetiology, and the prevention of thrombosis in patients with cancer.21 In the RIETE registry,22 predictors for PE were found to be increased mortality rate, type of venous thromboembolism, advanced age, cancer and immobilisation due to neurological disease.22 In 6% of our patients, no risk factors or co-morbidity were identified. It was recognised that in some patients, aetiology of PE may not be determined, suggesting the existence of unknown risk factors associated with the heterogeneity of individual susceptibility.23,24 The majority of patients in our study had moderate/ intermediate PE probability. Although the Wells score includes subjective criteria, overall accuracy as a clinical prediction rule is similar to the Geneva score, as previously reported.8 In our study, the frequency of intermediate and high-probability PE groups was similar for both scoring systems. Of note, only 10 to 14% of the patients had a low probability. Since requesting D-dimer blood tests is less likely in patients with higher PE probability, there was a low frequency of realisation and positivity rates of D-dimer blood tests. It is Table 8. Complicating events in patients with pulmonary embolism Complications Respiratory failure requiring mechanical ventilation
Massive Sub-massive PE PE
–
15 (37)
Cardiogenic shock
4
3
–
7 (18)
Sepsis and pulmonary infection
2
2
1
5 (13)
Cardiorespiratory arrest (reversed)
3
1
–
4 (10)
AKI or chronic kidney disease agudisation
3
1
–
4 (10)
–
2 (5)
17 (34)
Acute myocardial infaction
2
–
10 (20)
Heart failure
1
1
Hyperglycaemia > 200 mg/dl (11.1 mmol/l) in non-diabetic patients
–
–
IV: High risk (4.0–11.4%)
3 (6)
Number (%)
3
II: Low risk (1.7–3.5%)
5 (10)
Lowrisk PE
12
I: Very low risk (0–1.6%) III: Moderate risk (3.2–7.1%)
359
V: Very high risk (10.0–24.5%)
15 (30)
Sub-total
Total
50
AKI, acute kidney injury.
27 (67)
11 (28)
2 (5) 1 2 (5)
1 (2) 40
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notable that D-dimer, troponin and BNP tests were positive in all our patients with available results. However, there were no D-dimers and cardiac biomarkers measured in more than 50% of our patients, a higher percentage than that found in the SWIVTER register,25 in which 30% of patients with PE had no cardiac biomarkers or echocardiograms done.25 This result may reflect under-utilisation of these tests, or it may just be unavailability of records of the laboratory tests performed. The ABG, chest radiography, electrocardiogram, echocardiogram and Doppler ultrasound of the limbs were performed in more than 75% of our patients. In 54% of these patients, there were deviations from normal in the ABG, and the most frequent was hypoxaemia. Bova et al. described hypoxaemia as an independent predictor of PE mortality at three months.26 Abnormal chest radiography was documented in 50% of our patients. These results are similar to those found in the EMEP study (45.8%).14 According to these authors, interobserver variability and subjectivity in the interpretation of chest radiography may have influenced the results. Electrocardiographic (ECG) changes were identified in 56% of patients; however, isolated use of ECG has low sensitivity and specificity to exclude PE. ECG is an important test for the evaluation of diseases with similar presentation to that of PE in the acute phase and can be included in some risk-stratification strategies.27 In the 48% of patients with abnormalities on the echocardiogram, changes in the right chambers were the most frequent. This examination is often used in the evaluation of patients with PE and has the advantage of not being invasive or expensive. Although there is inter-observer variability and different evaluation criteria, the echocardiogram allows identification of RV dysfunction, which is described as one of the main predictors of early mortality in patients with sub-massive PE. It is estimated that about 30 to 40% of normotensive PE patients at admission have RV dysfunction, identifiable by echocardiography. These patients have in-hospital mortality rates between 11.8 and 23%, substantially higher than the rates of normotensive patients without RV dysfunction (0â&#x20AC;&#x201C;9.6%).28 Lower-limb Doppler ultrasound in symptomatic patients with deep-vein thrombosis (DVT) has a sensitivity of 96% and specificity of 99%. It is an important examination considering that about 70% of patients with PE have lower-limb DVT.29 In our study, 20% of the patients presented with DVT. The inter-observer variability and limitations of ultrasound in identifying thrombi in the pelvis and in small vessels of the leg may have influenced this result. PCTA is the imaging test of choice for diagnosis and exclusion of PE, considering its high sensitivity and specificity.30 The correlation of its changes with haemodynamic stability at admission showed that most of our patients with massive PE had haemodynamic instability, as previously described.31 Additionally, we found a statistically significant rate of haemodynamic stability at admission for patients with sub-massive PE. A meta-analysis to assess the prognostic value of the embolic load for short-term mortality showed that the presence of emboli centrally located in a pulmonary artery was associated with twice the risk of mortality within 30 days.32 On the other hand, assessment of RV function by pulmonary CT angiography has diagnostic and prognostic value in PE.30,33
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In this study, 28% of patients presented with sub-massive PE, despite haemodynamic stability at admission. The presence of RV dysfunction and centrally located pulmonary artery thrombus predicts a higher mortality rate in normotensive patients.30 Low-risk 30-day-mortality PE was identified in 36% of patients and all were stable at admission. Studies show that these patients have a lower risk of adverse events and may be candidates for home treatment.34,35 The treatment of PE in the acute phase, based on anticoagulation with heparin or NOAC, prevents the extension of thrombi and recurrence of thromboembolic events. We found that most of our patients received low-molecular-weight heparins and warfarin. Out-patient anticoagulation depends on the clinical context and existing risk factors, and its duration in PE is still controversial. In our study, thrombolytic therapy was used in 18% of patients, however 28% presented with haemodynamic instability. These results may suggest an underuse of thrombolytic therapy. Similar results were found in the EMEP study14 in which 20% of the patients were hypotensive but thrombolytic therapy was used in only 15% of them. Thrombolysis allows early pulmonary reperfusion, and despite increasing the risk of major bleeding, is indicated in unstable patients. Furthermore, it benefits normotensive patients with sub-massive PE, preventing haemodynamic instability, as demonstrated in the PEITHO study.35 The in-hospital mortality rate of 20% in our study was similar to that described in the EMEP study (22%) and higher than the rate described in other PE studies.7,14,22,36 Conducting the study in the ICU on more severely ill patients with a rate of 38% complications may have contributed to the higher mortality rate. Moreover, we found that 67% of the complicating events occurred in the PCTA sub-group of massive PE; 30% of patients had a very high risk of 30-day mortality, according to the admission PESI score; and a third of the deaths occurred within the first 24 hours of hospitalisation, which may reflect the severity of PE since admission. Some limitations of this study relate to its retrospective nature and the lack of data. In addition, using health professionals from different schools may have favoured some variability in clinical practice during the study period.
Conclusions Our results confirm that PE does not seem to be a rare disease in African populations. The clinical characteristics of the study sample were similar to those described in the literature, although black patients were more prevalent. In diagnostic examinations, the use of pulmonary CT angiography in all patients allowed consistent diagnosis and assessment of the prognosis. Most patients were treated with low-molecular-weight heparin and warfarin. The intra-hospital mortality rate was relatively higher than that described in other studies. The high prevalence of patients with very high risk of mortality at admission highlights the need to investigate the cause of worst cardiovascular disease outcomes in Africans. The authors acknowledge the Studies Office and Arquive Staff of Girassol Clinic for general support and technical assistance.
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Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats Frederic Nduhirabandi, Barbara Huisamen, Hans Strijdom, Amanda Lochner
Abstract Aim: Melatonin supplementation reduces insulin resistance and protects the heart in obese rats. However, its role in myocardial glucose uptake remains unknown. This study investigated the effect of short-term melatonin treatment on glucose uptake by cardiomyocytes isolated from obese and insulin-resistant rats. Methods: Cardiomyocytes were isolated from obese rats fed a high-calorie diet for 16 to 23 weeks, their age-matched controls, as well as young control rats aged four to eight weeks. After incubation with melatonin with or without insulin, glucose uptake was initiated by the addition of 2-deoxy-D-[3H] glucose and measured after 30 minutes. Additional control and obese rats received melatonin in the drinking water (4 mg/kg/day) for the last six weeks of feeding (20 weeks) and glucose uptake was determined in isolated cardiomyocytes after incubation with insulin. Intraperitoneal glucose tolerance and biometric parameters were also measured. Results: Obese rats (fed for more than 20 weeks) developed glucose intolerance. Cardiomyocytes isolated from these obese rats had a reduced response to insulin-stimulated glucose uptake (ISGU) (p < 0.05). Melatonin administration in vitro had no effect on glucose uptake per se. However, it increased ISGU by cardiomyocytes from the young rats (p < 0.05), while having no effect on ISGU by cardiomyocytes from the older control and obese groups. Melatonin in vivo had no significant effect on glucose tolerance, but it increased basal (p < 0.05) and ISGU by cardiomyocytes from the obese rats (50.1 ± 1.7 vs 32.1 ± 5.1 pmol/mg protein/30 min, p < 0.01). Conclusion: These data suggest that short-term melatonin treatment in vivo but not in vitro improved glucose uptake and insulin responsiveness of cardiomyocytes in obesity and insulin-resistance states.
Keywords: cardiomyocytes, glucose homeostasis, glucose uptake, insulin resistance, melatonin, obesity
Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa Frederic Nduhirabandi, MSc, PhD, frederndu@gmail.com Barbara Huisamen, MSc, PhD Hans Strijdom, MD, PhD Amanda Lochner, PhD, DSc
Biotechnology, Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa Barbara Huisamen, MSc, PhD
Submitted 24/5/16, accepted 4/4/17 Published online 17/5/17 Cardiovasc J Afr 2017; 28: 362–369
www.cvja.co.za
DOI: 10.5830/CVJA-2017-018
Although food shortage and malnutrition are still endemic in low- and middle-income countries,1 excessive food intake and reduced physical activity associated with modern lifestyles, as well as night shift-work have led to a dramatic increase in the worldwide prevalence of obesity.2,3 This is accompanied by various metabolic disorders including, among others, type 2 diabetes and cardiovascular diseases.4,5 The major basis for this association is the well-known insulin resistance, which is a fundamental aspect in the development of type 2 diabetes and a common pathological link between obesity and cardiac diseases.6-8 In this condition, the body produces insulin but does not use it properly due to decreased cellular sensitivity to its effect on uptake, metabolism and storage of glucose.9 Melatonin or N-acetyl-5-methoxytryptamine is the hormone secreted mainly by the pineal gland during the night. Its role in metabolic diseases has recently attracted many investigators.10 Several animal11-15 and epidemiological16-20 studies support the role of melatonin in the regulation of glucose homeostasis. Low melatonin secretion levels are associated with elevated risk for hyperglycaemia and type 2 diabetes.12,18 Importantly, removal of the melatonin receptor (MT1) significantly impairs the ability of mice to metabolise glucose and induces insulin resistance in these animals,14 while melatonin administration improves glucose homeostasis in insulin-resistant animals.11,13,21-24 However, the mechanism underlying the role of melatonin in glucose homeostasis is complex and not well understood.25 Impairment of insulin-stimulated glucose uptake is considered the most consistent change that develops early in the hearts of animal models of insulin resistance.26 This change occurs as a consequence of both reduced glucose transporter 4 (GLUT4) protein expression and impaired translocation.27 In this regard, while melatonin’s effects have been extensively reported in other insulin-sensitive organs, such as the hypothalamus, skeletal muscle, liver and adipose tissue,25,28-30 it is unclear whether melatonin affects cardiac glucose uptake in the insulin-resistant state. A previous study showed that melatonin treatment was able to protect the heart against oxidative damage and restore the expression of the GLUT4 gene as well as glucose uptake of cardiomyocytes isolated from hyperthyroid rats,31 supporting the ability of melatonin to improve changes in glucose uptake. Chronic melatonin administration given from the onset of the obesity-inducing diet was recently shown to prevent the harmful effects of obesity, such as insulin resistance and dyslipidaemia and to protect the hearts of obese rats against myocardial ischaemia–reperfusion injury.32 In addition, we observed that
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short-term melatonin consumption also reduced systemic insulin resistance and conferred cardioprotection.33 However, whether melatonin treatment affects myocardial insulin sensitivity and glucose uptake remains unknown. The aim of this study was therefore to investigate the effect of melatonin treatment on myocardial glucose uptake using cardiomyocytes isolated from insulin-resistant rats and their aged-matched controls. To investigate whether melatonin has a direct effect on myocardial glucose uptake, melatonin was administered in vitro to isolated cardiomyocytes and in vivo for the measurement of glucose uptake. To evaluate the effect of ageing, cardiomyocytes isolated from normal control rats (seven to eight weeks old) were also included.
Methods Sixty male Wistar rats were obtained from the University of Stellenbosch Central Research Facility. They were housed with free access to water and food and a 12-hour dark/light cycle (light from 06:00 to 18:00) with temperature and humidity kept constant at 22ºC and 40%, respectively. The experimental procedure was assessed and approved by the Committee for Ethical Animal Research of the Faculty of Medicine and Health Sciences, University of Stellenbosch (ethical clearance no P08/05/008). Animals were treated according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No 85–23, revised 1985) and the revised South African National Standard for the Care and Use of Animals for Scientific Purposes (South African Bureau of Standards, SANS 10386, 2008). For evaluation of insulin responsiveness and sensitivity, cardiomyocytes were isolated from (1) normal rats (225−250 g) (n = 12) or (2) diet-induced obese rats (group D) (n = 24) and their age-matched controls (group C) (n = 24) fed a high-calorie diet and standard rat chow, respectively. The high-calorie diet consisted of 65% carbohydrates, 19% protein and 16% fat, while the standard rat chow consisted of 60% carbohydrate, 30% protein and 10% fat.32 The diet-induced obese and age-matched control rats were seven to eight weeks old at the onset of the experimental programme, which was continued for a period of 16 to 23 weeks. To evaluate the progressive changes in insulin sensitivity, the feeding regime of our existing model of dietinduced obesity and insulin resistance32 was varied from 16 to 23 weeks to exacerbate the effects of obesity, as previously reported.33 To determine whether short-term melatonin administration in vitro had a direct effect on myocardial glucose uptake, melatonin was administered to the cardiomyocytes after isolation (see below for cardiomyocyte preparation). Briefly, isolated cardiomyocytes were incubated with phloretin (glucose-uptake inhibitor, 400 μM), and melatonin (100 nM) with or without insulin (1–100 nM). Fresh melatonin (Sigma-Aldrich, St Louis, MO, USA) solution was used; melatonin was dissolved in a small quantity of ethanol and then in medium buffer to yield a final concentration of 1 nM, 10 nM, 100 nM, 1 μM or 10 μM (with < 0.005% ethanol). Ethanol at that concentration had no effect on glucose uptake by the cardiomyocytes (results not shown). Phloretin (Sigma-Aldrich, St Louis, MO, USA) was dissolved in dimethyl sulfoxide (DMSO), stored at −80°C as stock, and diluted with medium buffer immediately before use.
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To evaluate the effect of in vivo melatonin treatment on myocardial glucose uptake, only rats fed for 20 weeks were used. While studying the effect of in vitro melatonin treatment, we observed that compared to their age-matched control rats, only cardiomyocytes isolated from obese rats fed for more than 20 weeks showed a significant decrease in insulin-stimulated glucose uptake (Fig. 3). Four groups were studied including: (1) untreated control (C), (2) treated control (CM), (3) untreated diet (D), and (4) treated diet (DM). Melatonin was orally administered in the drinking water (4 mg/ kg/day) for six weeks starting from the 14th week of feeding, as described previously.32,33 This is the lowest concentration to have a significant effect in our model of diet-induced obesity.33 Drinking water with or without melatonin was replaced every day one hour before lights off (18:00) and was available throughout the light and dark cycles.33 In contrast to humans, rats are active during the night, when their blood melatonin levels are high. A period of six weeks has been shown as the shortest to elicit marked effects of melatonin on the hearts from diet-induced obese rats and to reverse several of the harmful effects of obesity.33 Animals were anaesthetised with sodium pentobarbitone (160 mg/kg, intraperitoneally). The hearts were immediately removed and perfused for isolation of cardiomyocytes, as described previously.34 The body weight and visceral fat mass were recorded. Adiposity index was calculated as the ratio of visceral fat mass to body weight, multiplied by 100.33 Blood glucose levels were determined in the fasting state, as described previously,35 at the same time (10:00–12:00). Blood was obtained via a tail prick and levels were determined using a conventional glucometer (Cipla MedPro, Bellville, South Africa). Intraperitoneal glucose tolerance (IPGT) curves were generated in animals after an overnight fasting period. Animals were injected with 1 g/kg of a 50% sucrose solution and blood glucose levels were recorded over a two-hour period. Calcium-tolerant adult ventricular myocytes were isolated from the different animal groups, as previously reported.34 After isolation, the myocytes were suspended in a medium buffer containing (in mM): HEPES 10, KCL 6, NaH2PO4 0.2, Na2HPO4 1, MgSO4 1.4, NaCl 128, pyruvate 2, glucose 5.5, and 2% BSA (fraction V, fatty acid free) plus calcium 1.25 mM, at pH 7.4. The cells were left for one to two hours under an oxygen atmosphere on a gently shaking platform to recover from the trauma of isolation. After recovery, the cells were allowed to settle into a loose pellet and the supernatant was removed. This procedure routinely rendered in excess of 80% viable cells, as measured by trypan blue exclusion. They were additionally washed twice with and suspended in a suitable volume of the above medium buffer but without glucose and pyruvate for subsequent glucose uptake determinations. Cardiomyocyte glucose uptake was measured essentially as described previously34 in a final assay volume of 750 μl. Cells prepared from the different groups of animals were incubated with or without one, 10 or 100 nM insulin for 30 minutes. After a total incubation period of 45 minutes, glucose uptake was initiated by addition of 2-deoxy-D-[3H] glucose (2DG) (1.5 μCi/ ml; final concentration 1.8 μM) (Perkin Elmer, Boston, USA). Glucose uptake was allowed to progress for 30 minutes before stopping the reaction by adding phloretin (final concentration 400 μM). Thereafter, the cells were centrifuged at 1 000 g for one minute and the supernatant containing radiolabelled 2DG was
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aspirated. The subsequent pellet was washed twice with medium buffer without substrate and then dissolved in 0.5 M NaOH; 50 μl of this solution was used for the determination of the protein content by the method of Lowry et al.,36 while the rest was counted for radioactivity using a scintillation counter (Beckman). The Western blot technique was performed as previously reported, using the whole heart tissue33 and isolated cardiomyocytes.34 Cell lysates were made after 30 minutes’ incubation with or without insulin or melatonin (before the addition of 2DG). Thereafter the cells were put on ice, transferred to Eppendorf tubes, quickly centrifuged and washed three times with ice-cold medium buffer without substrate. The resultant cell pellet was then lysed in 100 μl of lysis buffer.34 At this point the cells were sonicated on ice (three times, intervals of three-second pulses with one-second break) and centrifuged for 20 minutes. The subsequent pellet was discarded and the supernatant used as cell lysate for Western blotting. Total and phospho PKB/Akt (Ser-473) expressions were evaluated in the cardiomyocytes after incubation with melatonin with or without insulin, as previously described.34 In addition, GLUT4 expression was evaluated in whole heart lysates after six weeks of melatonin treatment, as previously described.33 All antibodies were purchased from Cell Signaling (USA). Betatubulin was used as a loading control. Protein activation is expressed in arbitrary densitometry units as phospho/total ratios.
Statistical analysis Data are expressed as mean ± standard error of the mean (SEM). When comparisons between two groups (treated and untreated) were made, an unpaired Student’s t-test was performed. For multiple comparisons, the ANOVA (two-way when appropriate), followed by the Bonferroni correction was applied. Statistical significance was considered for a p-value < 0.05.
A
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Results Effect of melatonin treatment in vitro on glucose uptake by cardiomyocytes Compared to basal levels, melatonin treatment (10 and 100 nM, 10 and 50 μM) had no significant effect on glucose uptake by the cardiomyocytes isolated from normal rats (Fig. 1A). Insulin (1 nM) administration alone caused a 2.3-fold increase in glucose uptake compared to basal levels (Fig. 1B). However, when insulin was added to cells treated with melatonin (100 nM), there was a further stimulation of glucose uptake (3.4 ± 0.5- vs 2.5 ± 0.2-fold increase, p < 0.05) (Fig. 1B). As melatonin at other concentrations (10 nM) did not influence the levels of insulinstimulated glucose uptake (Fig. 1B) when compared to insulin alone, only 100 nM was used in subsequent experiments. Cardiomyocytes isolated from the control (C) and obese (D) rats after 16 to 19 weeks of feeding, exhibited no significant difference in basal as well as insulin-stimulated glucose uptake between the two groups (Table 1, Fig. 2). As was observed in cardiomyocytes isolated from normal rats (Fig. 1A), melatonin administration (100 nM) also had no significant effect on basal glucose uptake in group C and D rats fed for 16 to 19 weeks (Table 1). However, it enhanced the insulin-stimulated glucose uptake in group C compared to group D rats (C: 73.9 ± 4.1 vs D: 47.5 ± 4.9 pmol/mg protein/30 min, p < 0.05) (Table 1, Fig. 2). After 20 to 23 weeks of feeding, although the diet had no significant effect on basal glucose uptake by isolated cardiomyocytes (Table 2), insulin-stimulated glucose uptake was significantly lower in group D rats compared with the control group (C: 35.3 ± 6.3 vs D: 25.9 ± 1.6 pmol/mg protein/30 min, p < 0.05) (Fig. 3), while melatonin treatment had no effect on insulinstimulated glucose uptake in both group C and D rats (Fig. 3).
B 4
*
** 2DG (fold stimulation)
2DG (pmol/mg protein/30 min)
60
40
20
0
Basal
Ins
Mel 1
Mel 2
Mel 3
Mel 4
3
2
1
0
**
Basal
Ins
Ins + Mel 1
Ins + Mel 2
Fig. 1. E ffect of in vitro melatonin treatment on basal and insulin-stimulated glucose uptake by cardiomyocytes from young control rats (dose response). Cardiomyocytes were isolated and incubated with melatonin and/or insulin for a period of 30 minutes. The accumulated radiolabelled 2 deoxyglucose (2DG) was measured using a scintillation counter and expressed as pmol/ mg protein/30 min. A: Effect on basal glucose uptake. Ins: insulin (1 nM), Mel: melatonin (Mel 1: 10 nM, Mel 2: 100 nM, Mel 3: 10 μM, Mel4: 50 μM), **p < 0.01 (vs basal or melatonin), n (individual preparations): n = 12 (basal), 11 (Ins), three (Mel 1), eight (Mel 2), four (Mel 3), three (Mel 4); analysed in duplicate. B: Effect on insulin-stimulated glucose uptake (fold stimulation). Ins: insulin (1 nM), Mel: melatonin (Mel 1: 10 nM, Mel2: 100 nM); *p < 0.05 (Ins vs Ins + Mel 2); **p < 0.05 (basal vs Ins or Ins + Mel 1 or 2); n = 12 (basal), 11 (Ins), five (Ins + Mel 1), six (Ins + Mel 2) individual preparations/group; analysed in duplicate.
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Table 1. Body weight and visceral mass of rats fed for 16 to 19 weeks and their corresponding glucose uptake by the cardiomyocytes Body weight and visceral fat mass Group
Body weight (g)
Visceral fat (g)
C
435 ± 21
17.0 ± 1.4
D
517 ± 11###
33.3 ± 1.3###
6
n
Glucose uptake (pmol/mg protein/30 min)
Adiposity index
Basal
Insulin
3.8 ± 0.18
25.6 ± 2.8
49.3 ± 5.6*
73.9 ± 4.1***#
25.5 ± 4.4
6.39 ± 0.3###
20.8 ± 3.1
40.8 ± 3.8*
47.5 ± 4.9*
20.0 ± 3.4
6
6
4
6
6
6
Ins + Mel
Mel
C: control, D: high-calorie diet, adiposity index = [(visceral fat/body weight) × 100], Ins: insulin (1 nM), Mel: melatonin (100 nM), *p < 0.05 (vs basal), ***p < 0.001 (vs basal), #p < 0.05 (vs D), ###p < 0.001 (vs C), n = four to six individual preparations per group, uptake determined in duplicate for each preparation.
3
* 2DG (fold stimulation)
2DG (fold stimulation)
3
#
2
1
0
**
**
Effect of melatonin treatment in vivo on glucose uptake by insulin-resistant cardiomyocytes After 20 to 23 weeks, rats fed a high-calorie diet exhibited significantly increased body weight (C: 433 ± 25 vs D: 538 ± 43 g, p < 0.05), visceral fat mass (C: 17.7 ± 1.8 vs D: 37.5 ± 7.5 g, p < 0.001) as well as adiposity index (Table 3). Melatonin treatment for six weeks reduced body weight and adiposity index values in group D rats (p < 0.05) (Table 3). To evaluate the glucose uptake by cardiomyocytes from control and obese rats, a dose response with increasing concentrations of insulin was performed (Fig. 4). The diet had no effect on basal glucose uptake by cardiomyocytes isolated from both group C and D rats (Fig. 4). However it reduced insulin-stimulated glucose uptake in group D rats (Fig. 4, Table 2). Oral melatonin treatment in vivo for six weeks increased the basal glucose uptake by cardiomyocytes from group D rats (DM: 26.4 ± 2.1 vs D: 19.8 ± 3.4 pmol/mg protein/30 min, p < 0.05) while having no effect in
* **
**
1
0
Basal Ins C Ins + Mel C Basal Ins D Ins + Mel D C Mel C D Mel D
Fig. 2. E ffect of in vitro melatonin treatment on insulin-stimulated glucose uptake of cardiomyocytes isolated from control (C) and high-calorie diet (diet-induced obesity) (D) groups after 16 to 19 weeks. 2DG: 2 deoxyglucose, Ins: insulin (1 nM), Mel: melatonin (100 nM); *p < 0.05 (Ins C vs Ins + Mel C), **p < 0.01(basal vs Ins or Ins + Mel; Ins C vs Ins D), #p < 0.05 (Ins + Mel D vs Ins + Mel C), n = four to six individual preparations/group; analysed in duplicate.
2
Basal Ins C Ins + Mel C Basal Ins D Ins + Mel D C Mel C D Mel D
Fig. 3. Effect of in vitro melatonin treatment on insulin-stimulated glucose uptake of cardiomyocytes isolated from control (C) and high-calorie diet (diet-induced obesity) (D) groups after 20 to 23 weeks. 2DG: 2 deoxyglucose, Ins: insulin (1 nM), Mel: melatonin (100 nM); *p < 0.05 (Ins C vs Ins D), **p < 0.01 (basal vs Ins or Ins + Mel), n = four to six individual preparations/group; analysed in duplicate.
group C rats (CM: 22.6 ± 3.7 vs C: 21.1 ± 3.5 pmol/mg protein/30 min, p > 0.05) (Fig. 4). Additionally, compared to their respective untreated group, cardiomyocytes isolated from the control treatment group (CM) had elevated insulin-stimulated glucose uptake (p < 0.05) (Fig. 4). Furthermore, cardiomyocytes from the D treatment group (DM) also showed a further elevation of insulin-stimulated glucose uptake with insulin administration Table 3 Body weight, visceral fat mass and IPGT after 20 weeks of feeding Parameters
C
CM
D
Body weight (g)
433 ± 25
411 ± 17
538 ± 43***
Visceral fat (g)
17.7 ± 1.8
14.33 ± 1.9*
37.50 ± 7.5***
Adiposity index
4.1 ± 0.2
AUC for IPGT
6.9 ± 0.23***
761.5 ± 27.7 760.2 ± 38.8 6
n
3.4 ± 0.16*
870.7 ± 25.2*
6
DM 488 ± 21# 28 ± 4# 5.7 ± 0.3# 826.7 ± 32.5
6
6
C: control, D: high-calorie diet, CM and DM: control and diet receiving melatonin for six weeks, adiposity index [(visceral fat/body weight) × 100], AUC: area under the curve, IPGT: intraperitoneal glucose tolerance, *p < 0.05 (vs C), ***p < 0.001(vs C), #p < 0.05 (vs D), n = six per group.
Table 2. Body weight and visceral mass of rats fed for 20 to 23 weeks and their corresponding glucose uptake by the cardiomyocytes Body weight and visceral fat mass Group
Glucose uptake (pmol/mg protein/30 min)
Body weight (g)
Visceral fat (g)
Insulin
Ins + Mel
Mel
C
457 ± 14
18.4 ± 10.9
4 ± 0.2
19.9 ± 2.6**
35.3 ± 6.3#
33.5 ± 5.9
19.2 ± 1.7
D
575 ± 61###
38.7 ± 2.6###
6.7 ± 0.6###
18.1 ± 1.6**
25.9 ± 1.6
27.8 ± 1.1
18.4 ± 2.3
6
5
6
n
6
6
Adiposity index
6
Basal
6
C: control, D: high-calorie diet, adiposity index [(visceral fat/body weight) × 100], Ins: insulin (1 nM), Mel: melatonin (100 nM), **p < 0.01 (vs Ins or Ins + Mel), #p < 0.05 (vs D), ###p < 0.001 (vs C), n = five to six individual preparations per group, uptake determined in duplicate for each preparation.
366
12
60
C
CM
D
DM
++ ###
**
* ##
##
**
40 *
++ ###
### ##
##
##
# &
#
20
0
Basal
Ins (1 nM)
Ins (10 nM)
Ins (100 nM)
2DG (pmol/mg protein/30 mins)
80 2DG (pmol/mg protein/30 mins)
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C
11
D
10
CM6
#
*
9
DM6
8 7
*
6
*
5 4
0
30
60
90
120
Time (min)
Fig. 4. E ffect of in vivo melatonin treatment (for the last six weeks of feeding) on insulin-stimulated glucose uptake by cardiomyocytes isolated from rats fed a high-calorie diet (20 weeks). Cardiomyocytes were isolated and stimulated with increasing concentrations of insulin for a period of 30 minutes. The accumulated radiolabelled 2DG was measured and expressed as pmol/mg protein/ 30 min. Ins: insulin, C: control, CM: control with melatonin, D: high-calorie diet (dietinduced obesity), DM: diet with melatonin. Treated vs untreated (same dose of insulin or basal): *p < 0.05 (DM vs D), **p < 0.01 (CM vs C). Different doses of insulin vs basal (same group of treatment): #p < 0.05 vs basal, ##p < 0.01 vs basal, ###p < 0.001 vs basal. C vs D (same dose of insulin): and p < 0.05 (D vs C). Comparison between different doses of insulin (same group of treatment): ++p < 0.01 vs 1 nM Ins, n = four to six individual preparations/group; analysed in duplicate.
(100 nM), compared to the untreated group (DM: 50.1 ± 1.7 vs D: 32.1 ± 5.1 pmol/mg protein/30 min, p < 0.01) (Fig. 4).
Effect of melatonin treatment in vivo on IPGT test in insulin-resistant rats A high-calorie diet increased basal fasting blood glucose levels compared to the control diet (5.2 ± 0.28 vs 6.4 ± 0.17 mM, p < 0.05). Similarly, at the end of the test, group D rats continued to have elevated glucose levels (4.5 ± 0.2 vs 5.2 ± 0.1 mM, p < 0.05), compared to the control group (Fig. 5). The area under the curve was also elevated in group D rats, compared to the controls (870.7 ± 25.6 vs 761.8 ± 27.7, p < 0.05) (Table 3). However, despite a significant decrease in blood glucose levels in the melatonin-treated D rats observed between 15 and 25 minutes of the test, we noted that melatonin treatment had no significant effect on basal glucose levels and the overall area under curve in both groups (Fig. 5).
Discussion Our aim was to investigate the effect of melatonin treatment on basal glucose uptake and insulin responsiveness as indicated by glucose uptake, using cardiomyocytes isolated from young control rats, age-matched controls and obese, insulin-resistant rats. The results indicated that (1) melatonin treatment in vitro had no effect on glucose uptake but increased insulin-stimulated
Fig. 5. Effect of in vivo melatonin treatment (for the last six weeks of feeding) on intraperitoneal glucose tolerance. C: control, CM6: control with six weeks’ melatonin treatment, D: high-calorie diet (diet-induced obesity), DM6: high-calorie diet with six weeks’ melatonin treatment, *p < 0.05 (D vs C), #p < 0.05 (D vs DM6), n = six per group.
glucose uptake by cardiomyocytes from only the young and age-matched control rats (Fig. 1B, Table 1); (2) melatonin treatment in vivo increased basal and insulin-stimulated glucose uptake by cardiomyocytes isolated from the hearts of obese, insulin-resistant rats. During the basal state, glucose transport is commonly considered the rate-limiting step for muscle glucose metabolism.37 The involvement of melatonin in glucose uptake was supported by the observation that pinealectomised animals develop insulin resistance associated with a decrease in glucose uptake by adipose tissue.15,38 Accordingly, administration of melatonin reversed pinealectomy-induced insulin resistance and improved glucose uptake by isolated adipose tissue.15,38 In contrast to this, our data show that melatonin per se had no significant effect on in vitro glucose uptake by cardiomyocytes isolated from young normal or obese rats and their age-matched controls (Fig. 1A, Tables 1, 2). A similar observation was previously reported in rat skeletal muscle cells39 and chick brain,40 as well as in adipose tissue from a female fruit bat.41 Of interest was our finding that acute melatonin administration in vitro enhanced insulin-stimulated glucose uptake by cardiomyocytes from normal young rats (Fig 1B) as well as the control rats fed for 16 to 19 weeks (Fig. 2). The enhanced insulin responsiveness of glucose uptake may be related to a synergistic interaction between melatonin and insulin action, supporting the insulin-sensitising effect by melatonin, as previously demonstrated.39,41,42 The in vitro melatonin-enhancing effect on insulin-stimulated glucose uptake was not observed in cardiomyocytes isolated from either the control or obese groups fed for more than 20 weeks (Fig. 3), indicating a progressive loss of the synergistic interaction between melatonin and insulin action. Although this is difficult to explain, it may have resulted from ageing in the control group, as previously demonstrated.43 On the other hand, cardiomyocytes from obese animals fed for 16 to 19 weeks were almost as insulinresponsive as the control cardiac myocytes, but did not exhibit the potentiating effect of melatonin compared to the control group.
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GLUT4
GLUT4
β-tubulin
β-tubulin
100000 * 80000 60000 40000 20000 0
C
CM3
CM6
GLUT4 expression (arbitrary units)
GLUT4 expression (arbitrary units)
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100000 80000 * 60000 40000 20000 0
D
DM3
DM6
Fig. 6. T he effects of melatonin treatment on GLUT4 expression after three and six weeks of treatment. Hearts were isolated from rats fed a high-calorie diet for 20 weeks and their age-matched controls. Both control and obese groups received drinking water with/without melatonin (4 mg/kg/day) for three or six weeks starting after 14 weeks of feeding. C: control group, D: highcalorie diet (obesity) group; CM3, DM3, CM6 and DM6: group C and D rats receiving melatonin treatment for three weeks (M3) or six weeks (M6); beta-tubulin was used as a loading control. C and D performed on the different blot (p > 0.05 C vs D), *p < 0.05 (CM6 vs C) or DM6 vs D, n = four hearts/group.
Various physiological factors such as an effect on adiponectin and leptin may have contributed to the overall effect of in vivo melatonin on glucose uptake, as previously discussed.10 In a preventative-treatment setting, 16 weeks of melatonin consumption, starting before the establishment of obesity, reduced hypertriglyceridaemia and increased high-density lipoprotein cholesterol levels in rats fed the same high-calorie diet.32 However, the exact mechanism whereby in vivo melatonin treatment affects glucose homeostasis and enhances insulin responsiveness is complex and not fully elucidated. Melatonin induced a significant reduction in body weight, associated with a concomitant increase in basal glucose uptake by isolated cardiomyocytes from the obese rats. This effect is consistent with previous observations that chronic melatonin treatment reduced body weight gain and insulin resistance in mice11 and rats21 fed a high-fat diet, as well as in old obese28 and young Zucker diabetic fatty13 rats. Therefore, melatonin action may involve melatonin receptors and various indirect effects on the liver, pancreas and other peripheral insulin-sensitive organs, such as adipose tissue and skeletal muscle.25 A recent report shows that the removal of melatonin receptors (MT1 or MT2) in mice abolished the daily rhythm in blood glucose levels,44 confirming the role of melatonin signalling in the control of glucose homeostasis. Contrary to the in vitro situation, melatonin administered in vivo increased basal glucose uptake by cardiomyocytes isolated from obese rats. Mechanistically, this may involve glucose transporter 1 (GLUT1), which is usually associated with basal glucose uptake by cardiomyocytes, and its expression would give more insight.45 Therefore, it may be that there was an increase in the expression or membrane translocation of GLUT1 in these cardiomyocytes from obese rats treated with melatonin. In addition, insulin was able to elicit a significant response in untreated control animals, while this was not the case in the obese animals after 20 to 23 weeks. This observation could be explained by the insulin-resistant state of the cells from the obese animals compared to their controls. Interestingly,
cardiomyocytes prepared from control as well as obese animals treated with melatonin showed a significantly higher response to insulin than the untreated counterparts (Fig. 4). With regard to the effect of melatonin on glucose tolerance, the present data show that obese rats developed glucose intolerance, and melatonin had no effect on basal glucose levels (10:00–12:00). While data on nocturnal glucose levels may be different, six-week melatonin treatment also reduced systemic insulin resistance in obese rats without affecting basal fasting blood glucose levels.33 These results are consistent with previous findings:46 between 15 and 25 minutes following glucose injection, obese melatonin-treated rats had a significant decrease in blood glucose levels compared to the untreated obese group, somehow indicating their increased ability to absorb glucose. The reduction in insulin resistance or improved glucose uptake and utilisation may involve changes in the metabolic profile, such as increasing adiponectin levels after long-13,23 and short-term33 melatonin administration. Melatonin-induced beneficial changes in adipose tissue41,47 may in turn additionally contribute to improved whole-body insulin sensitivity. Moreover, as indicated above, melatonin may improve glucose homeostasis via its actions in the hypothalamus and liver.48 Impairment of insulin-stimulated glucose transport is considered the most consistent change that develops early in the hearts of animal models of insulin resistance.26 Since GLUT4 is the most prominent glucose transporter in differentiated cardiomyocytes,49 our data underscore the importance of further investigation analysing the expression of intermediates of insulin signal transduction and the effects of melatonin treatment thereupon in cardiomyocytes isolated from treated control and obese hearts. The effect of six weeks of melatonin treatment on the basal expression and activation of a number of intermediates in myocardial tissue from control and obese rats has been studied previously in our laboratory: baseline activation of PKB/ Akt, extracellular signal-regulated kinase (ERK) p42/p44 and glycogen synthase kinase 3 beta (GSK3β) were found to be significantly upregulated by melatonin treatment in both control
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p-PKB/Akt (Ser-473) Total PKB/Akt β-tubulin 1.5 p-/total PKB/Akt (ser-473) ratio (arbitrary units)
p-/total PKB/Akt (ser-473) ratio (arbitrary units)
p-PKB/Akt (Ser-473) Total PKB/Akt β-tubulin 1.5
1.0 &
* 0.5
0.0
Basal
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Ins
Ins+Mel
Mel
1.0
#
0.5
0.0
Mel+Luz
*
Basal
Ins
Ins+Mel
Mel
Mel+Luz
Fig. 7. E ffects of in vitro melatonin administration to isolated cardiomyocytes on PKB/Akt expression and phosphorylation (rats fed for 20 weeks). Cardiomyocytes were isolated and incubated with melatonin with or without insulin stimulation. C: control, D: high-calorie diet. 1: basal, 2: Ins (insulin), 3: Insulin + melatonin, 4: Mel (melatonin), 5: luzindole + melatonin, Luz (luzindole), C: *p < 0.05 (Ins or Ins + Mel vs basal), and p < 0.05 (Mel vs basal or Mel + Luz), D: *p < 0.05 (Ins or Ins + Mel vs basal), #p < 0.05 (D vs C), n = three individual preparations/group. Blots are representative. Beta-tubulin was used as a loading control. C and D performed on the same blot.
and obese rats.33 However, it will be also important to determine whether these observed beneficial changes were secondary to the improved whole-body insulin sensitivity or whether there were changes in cardiomyocyte protein expression and activation per se elicited by melatonin treatment. In this regard, a marginal increase in GLUT4 expression was previously reported to be associated with an increase in glucose uptake by melatonin-treated adipose tissue.41 Our additional observations showed significant increases in GLUT4 expression in the whole heart tissue of obese rats after six weeks of in vivo melatonin treatment (Fig. 6). Interestingly, as expected, the significant lowering in glucose uptake by cardiomyocytes from obese rats was also reflected in the reduction in PKB/Akt activation when compared with their age-matched controls (Fig. 7).
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Conclusion To our knowledge, this is the first study on the role of melatonin in cardiac glucose uptake in an insulin-resistant state. The cardiovascular benefits of melatonin supplementation are supported by the fact that circulating melatonin levels are decreased in cardiovascular diseases.50,51 Convincing evidence exists for the benefits of increasing glucose uptake as an important therapeutic goal in the management of left ventricular systolic dysfunction.52 Although its role in melatonin-induced cardioprotection needs further investigation, present data suggest that short-term melatonin treatment in vivo, but not in vitro, improved basal glucose uptake and insulin responsiveness in insulin-resistant cardiomyocytes isolated from obese rats.
Diabetes Endocrinol 2014; 2: 911–922. 6.
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Benito M. Tissue specificity on insulin action and resistance: Past to recent mechanisms. Acta Physiol (Oxf) 2011; 201: 297–312.
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Riehle C, Abel ED. Insulin signaling and heart failure. Circ Res 2016;
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Hardy OT, Czech MP, Corvera S. What causes the insulin resistance
118: 1151–1169. underlying obesity? Curr Opin Endocrinol Diabetes Obes 2012; 19: 81–87. 10. Nduhirabandi F, du Toit EF, Lochner A. Melatonin and the metabolic syndrome: A tool for effective therapy in obesity-associated abnormalities? Acta Physiol (Oxf) 2012; 205: 209–223. 11. Sartori C, Dessen P, Mathieu C, et al. Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice. Endocrinology 2009; 150: 5311–5317.
This study was supported by the South African National Research Foundation, the Harry Crossley Foundation and Stellenbosch University.
12. Peschke E, Frese T, Chankiewitz E, et al. Diabetic goto kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J
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14. Contreras-Alcantara S, Baba K, Tosini G. Removal of melatonin receptor type 1 induces insulin resistance in the mouse. Obesity (Silver Spring) 2010; 18: 1861–1863. 15. Lima FB, Machado UF, Bartol I, et al. Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am J Physiol Endocrinol Metab 1998; 275: E934–941. 16. Xia Q, Chen ZX, Wang YC, et al. Association between the melatonin receptor 1B gene polymorphism on the risk of type 2 diabetes, impaired glucose regulation: A meta-analysis. PLoS One 2012; 7(11): e50107. 17. Ronn T, Wen J, Yang Z, et al. A common variant in MTNR1B, encoding melatonin receptor 1B, is associated with type 2 diabetes and fasting plasma glucose in han chinese individuals. Diabetologia 2009; 52: 830–833. 18. McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin secretion and the incidence of type 2 diabetes. J Am Med Assoc 2013; 309: 1388–1396. 19. McMullan CJ, Curhan GC, Schernhammer ES, Forman JP. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am J Epidemiol 2013; 178: 231–238. 20. Prokopenko I, Langenberg C, Florez JC, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet 2009; 41: 77–81.
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24. She M, Deng X, Guo Z, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/highsucrose-fed rats. Pharmacol Res 2009; 59: 248–253. 25. Karamitri A, Renault N, Clement N, Guillaume J, Jockers R.
Biochimie 2013; 95: 1650–1654. 43. Carroll R, Carley AN, Dyck JR, Severson DL. Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts. Am J Physiol Endocrinol Metab 2005; 288: E900–E906.
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44. Owino S, Contreras-Alcantara S, Baba K, Tosini G. Melatonin signaling
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29. Anhe GF, Caperuto LC, Pereira-Da-Silva M, et al. In vivo activation of
48. Faria JA, Kinote A, Ignacio-Souza LM, et al. Melatonin acts through
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15: E230–242. 49. Montessuit C, Lerch R. Regulation and dysregulation of glucose transport in cardiomyocytes. Biochim Biophys Acta 2013; 1833: 848–856.
31. Ghosh G, De K, Maity S, et al. Melatonin protects against oxidative
50. Dominguez-Rodriguez A, Abreu-Gonzalez P, Arroyo-Ucar E, Reiter
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Prevalence and predictive value of electrocardiographic abnormalities in pulmonary hypertension: evidence from the Pan-African Pulmonary Hypertension Cohort (PAPUCO) study Irina Balieva, Anastase Dzudie, Friedrich Thienemann, Ana O Mocumbi, Kamilu Karaye, Mahmoud U Sani, Okechukwu S Ogah, Adriaan A Voors, Andre Pascal Kengne, Karen Sliwa
Abstract Background: Pulmonary hypertension (PH) is prevalent in Africa and is still often diagnosed only at an advanced stage, therefore it is associated with poor quality of life and survival rates. In resource-limited settings, we assessed the diagnostic utility of standard 12-lead electrocardiograms (ECG) to detect abnormalities indicating PH. Methods: Sixty-five patients diagnosed with PH were compared with 285 heart disease-free subjects. The prevalence and diagnostic performance of ECG features indicative of PH and right heart strain were calculated. Results: Compared to the control group, all abnormalities were more frequent in the PH cohort where no patient had a completely normal ECG. The most prevalent (cases vs control) ECG abnormalities were: pathological Q wave in at least two contiguous peripheral leads (47.7 vs 6.7%), left ventricular hypertrophy (38.5 vs 9.8%) and p-pulmonale (36.9 vs 20.7%) (all p < 0.05). The sensitivity of ECG criteria for right heart strain ranged between 6.2 and 47.7%, while specificity ranged between 79.3 and 100%. Negative predictive value ranged between 81.5 and 88.9% and positive predictive value between 25 and 100%. Positive predictive value was lowest (25%) for right bundle branch block and QRS right-
Hatter Institute for Cardiovascular Research in Africa, SAMRC Cape Heart Centre, IDM, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Irina Balieva, BSc (med), irinabalieva@gmail.com Anastase Dzudie, MD, PhD, FESC Friedrich Thienemann, MD, PhD Mahmoud U Sani, MB BS, PhD, FWACP, FACC Andre Pascal Kengne, MD, PhD Karen Sliwa, MD, PhD, FESC, FACC
University of Groningen, Groningen, the Netherlands Irina Balieva, BSc (med), irinabalieva@gmail.com Adriaan A Voors, MD, PhD
Department of Internal Medicine, Douala General Hospital, Douala, Cameroon; NIH Millennium Fogarty Chronic Disease Leadership Programme Anastase Dzudie, MD, PhD, FESC
Soweto Cardiovascular Research Heart Unit (SOCRU), Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa Anastase Dzudie, MD, PhD, FESC Karen Sliwa, MD, PhD, FESC, FACC
axis deviation (≥ 100°), and highest (100%) for QRS axis ≥ +100° combined with R/S ratio in V1 ≥ 1 or R in V1 > 7 mm. Conclusion: When present, signs of PH on ECG strongly indicated disease, but a normal ECG cannot rule out disease. ECG patterns focusing on the R and S amplitude in V1 and right-axis deviation had good specificity and negative predictive values for PH, and warrant further investigation with echocardiography. Keywords: pulmonary hypertension, electrocardiogram, subSaharan Africa, screening Submitted 27/5/16, accepted 4/4/17 Published online 11/10/17 Cardiovasc J Afr 2017; 28: 370–376
www.cvja.co.za
DOI: 10.5830/CVJA-2017-020
Pulmonary hypertension (PH) is a worldwide public health challenge with an estimated population of affected people in resource-limited countries of 20 to 25 million in 2008.1,2 Based on shared pathophysiology and disease mechanisms, the World Health Organisation (WHO) and the 5th World Symposium on Pulmonary Hypertension distinguish five groups of PH: arterial
Clinical Infectious Diseases Research Initiative, IDM, University of Cape Town; Integerafrica Research and Development, Cape Town; Wellcome Centre Infectious Diseases Research in Africa, Institue of Infectious Diseases and Molecular Medicine, Cape Town; and Department of Medicine, Groote Schuur Hospital, Faculty of Health Sciences, University of Cape Town, South Africa Friedrich Thienemann, MD, PhD
Instituto Nacional de Saúde; Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique Ana O Mocumbi, MD, PhD, FESC
Department of Medicine, Bayero University, Kano, Nigeria Kamilu Karaye, BM BCh, PhD, FACC, FESC Mahmoud U Sani, MB BS, PhD, FWACP, FACC
Department of Medicine, University College Hospital, Ibadan; Ministry of Health, Umuahia, Nigeria Okechukwu S Ogah, MB BS, PhD, FWACP, FESC, FACC
Non-Communicable Diseases Unit, South African Medical Research Council, Cape Town, South Africa Andre Pascal Kengne, MD, PhD
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(PAH), venous, hypoxic, thromboembolic and miscellaneous3 (Fig. 1). Overall, PH results from varying combinations of increases in pulmonary vascular resistance, pulmonary blood flow and pulmonary venous pressure. Sustained pressure overload secondary to chronic PH leads to right ventricular (RV) changes, including hypertrophy, dilatation and RV failure, which are detectable using non-invasive tests such as electrocardiogram (ECG), echocardiography, cardiac magnetic resonance or at best, the gold standard but invasive right heart catheterisation (RHC). Despite improvements in the understanding of PH and the development of novel therapies, the condition is still diagnosed at an advanced stage in a significant proportion of patients, due to the paucity of symptoms in the early stages of the disease. This has a negative impact on the quality of life and survival rate of patients.4 The American College of Cardiology/American Heart Association5 and the European Society of Cardiology/European Respiratory Society4 guidelines recommend the ECG as an initial tool in diagnosing patients with suspected PH, based on studies done predominantly in patients with PAH. However, these guidelines consider ECG to be an inadequate tool for screening and emphasise the advantage of Doppler echocardiography. In sub-Saharan Africa (SSA) where chronic and endemic precursors of PH, including chronic infectious diseases, hypertensive heart disease, cardiomyopathy and rheumatic heart disease are highly prevalent,6 early diagnosis of PH is of particular relevance. The high cost and low availability of, and need for expertise in echocardiography limit its utility in this part of the world and justify the interest in alternative tests such as ECG. ECG abnormalities in patients with PH have been predominantly described in other populations.7-11 The Pan-African Pulmonary Hypertension Cohort (PAPUCO) was established to map out the epidemiology of PH in SSA. In this sub-study, we aimed to assess the predictive value of an affordable, widely available, objective and reproducible test such as ECG to diagnose PH in resource-limited settings.
Methods As previously described,12 the PAPUCO study was a prospective, registry-type cohort study of PH in Africa. The registry aimed to recruit consecutive patients with newly diagnosed PH based on clinical and echocardiographic criteria, who would be able or likely to return for a six-month follow up, who were at least 18 years old (except for those in paediatric centres in Mozambique and Nigeria), and who consented in writing to participate in the registry.
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Centre eligibility included availability of echocardiography, training in assessing right heart function, experience in diagnosing PH according to the WHO classification, experience in clinical management of patients with right heart failure (RHF), and resources to review patients at six-month follow up. Participating centres were invited to join the registry at African cardiac meetings and conferences.12 The Heart of Soweto study was a study of 387 urban South Africans of predominantly African descent, determined to be heart disease free (using the Minnesota code) following advanced cardiological assessment, including echocardiography.13 PH was diagnosed by specialist cardiologists using the non-invasive definition of PH. The standard is a pathological condition with an increase in mean pulmonary arterial pressure (PAP) beyond 25 mmHg at rest, as assessed by RHC.14 Because RHC is seldom available in our setting, PH was diagnosed in patients with a documented elevation in right ventricular systolic pressure (RVSP) above 35 mmHg on transthoracic echocardiography in the absence of pulmonary stenosis and acute RHF, usually accompanied by shortness of breath, fatigue, peripheral oedema and other cardiovascular symptoms, and possibly ECG and chest X-ray changes in keeping with PH, as per the European Society of Cardiology and European Respiratory Society (ESC/ERS) guidelines on PH.4 We searched ECGs from the PAPUCO registry to identify all patients who had had both Doppler echocardiography and 12-lead ECG performed within 48 hours of their baseline inclusion. We excluded all patients with pacemakers (due to inapplicability of standard ECG criteria), poor-quality ECGs and those without measurable RVSP. Controls were non-smokers and asymptomatic subjects with normal Doppler echocardiography (and RVSP less than 35 mmHg) who all underwent ECG recordings during their baseline inclusion in the Heart of Soweto study.15 This study represents urban South African men and women, all free of any heart disease and other major forms of cardiovascular disease. All ECGs were reviewed and interpreted by two independent clinical cardiologists who were blinded to the echocardiography results. If consensus could not be reached, a third opinion (AD, FT or KS) was requested. We electively studied pre-specified ECG patterns classified into minor or major abnormalities, as previously described in a large African cohort of heart disease-free Africans.13 Minor abnormalities included sinus tachycardia (> 100 beats per min), minor T-wave changes (T-wave flattening) or early repolarisation, definitive right ventricular hypertrophy (QRS axis ≥ +100° or R/S ratio in V1 ≥ 1, or R in V1 > 7 mm or a combination of a right bundle branch block and QRS axis ≥ +100°).
Pulmonary hypertension (PH)
Group 1: Pulmonary arterial hypertension (PAH) e.g. human immunodeficiency virusassociated PAH
Group 2: PH due to left heart disease e.g. mitral stenosis due to rheumatic heart disease
Group 3: PH due to lung diseases and/or hypoxaemia e.g. chronic obstructive pulmonary disease
Group 4: Chronic thromboembolic CPH e.g. chronic pulmonary embolism
Group 5: PH with unclear or multifactorial mechanisms e.g. endomyocardial fibrosis
Fig. 1. W orld Health Organisation classification for PH adapted from the 5th World Symposium on Pulmonary Hypertension.3
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Major abnormalities included: • arrhythmias (supraventricular as premature supraventricular tachycardia, atrial flutter, atrial fibrillation, multifocal atrial tachycardia, paroxysmal atrial tachycardia or ventricular-like premature ventricular complex, ventricular fibrillation, accelerated idioventricular rhythm, Torsades de pointes) • major T-wave abnormalities (T-wave inversion) • left ventricular hypertrophy defined by the Cornell voltage criteria [(S in V3 + R in aVL > 24 mm (men) or > 20 mm (women)] • pathological Q waves • prolonged QTc (> 470 ms as calculated by Bazett’s formula) • left bundle branch block or other conduction delay • p-pulmonale defined as a P wave in lead II > 2 mm or > 1.5 mm in lead V1/V2.
Prevalence, Se, Sp, PPV and NPV are presented as percentages, while continuous variables are presented as means and standard deviation (SD), or median (25th to 75th percentiles). We used χ² to compare proportions of categorical variables and the Student’s t-test to compare mean differences for continuous variables. A p-value < 0.05 was considered statistically significant.
Results Fig. 2 shows how we obtained our cohort of 65 adult patients with ECGs indicating PH from the overall 254 PAPUCO patients. The patients were young (mean age 47 ± 14 years), 21 (32%) were men, and all except four were of black African origin. These four patients were coloured or of mixed race. In Fig. 3, showing a sample ECG, chest X-ray and echocardiographic images of a A
Statistical analysis All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) 20.0, Chicago, Illinois. Prevalence, sensitivity (Se), specificity (Sp), and positive (PPV) or negative predictive values (NPV) were calculated by the following formulae:16,17 Prevalence of an ECG abnormality = total with the abnormality of interest/total number of patients in the group of interest. Considering echocardiography as our reference diagnostic test in this study (PH present or not), we assessed the diagnostic capability of ECG (ECG criteria positive or negative) in a 2 × 2 contingency table, and calculations were done using the above equation, in which true (false) positive represented our patients (PH group) with (without) ECG abnormalities, while true (false) negative represented controls without (with) ECG abnormalities. • Se = [true positive/(true positive + false negative)] × 100 • Sp = [true negative/(true negative + false positive)] × 100 • PPV = [sensitivity × prevalence] ÷ [sensitivity × prevalence + (1 – specificity) × (1 – prevalence)] • NPV = [specificity × (1 – prevalence)] ÷ [specificity × (1 – prevalence) + (1 – sensitivity) × prevalence]
Patients admitted with PH n = 254 45 patients did not fulfill inclusion criteria: • Newly diagnosed PH – based on clinical and echocardiographic criteria • Able or likely to return for a 6-month follow up • At least 18 years old • Consented in writing to participate in the registry Patients enrolled in the study n = 209 144 patients excluded because of: • Missing ECG (118) • Poor-quality ECG (17) • Missing echocardiographic diagnosis (9) ECGs analysed n = 65
Fig. 2. Flow chart of inclusion for the study.
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B
C
D
Fig. 3. ECG of a 38-year-old HIV-positive woman from the PAPUCO cohort. The patient had been on highly active antiretroviral therapy for three years and presented with palpitations and WHO functional class stage III shortness of breath. The chest X-ray (A) shows mild right heart enlargement and borderline raised cardiothoracic ratio. Doppler echocardiographic images (B, C) confirm the diagnosis of severe PH with both severely enlarged right atrium and ventricle with estimated RVSP of 63 mmHg. The ECG (D) shows a normal heart rate and sinus rhythm, right heart enlargement indicated by right-axis deviation of the QRS complex and by a R/S ratio in lead V1 of > 1 with poor R-wave progression. Right ventricular function was altered with a tricuspid annular plane systolic excursion (TAPSE) of 9 mm. Left ventricular ejection fraction was preserved, there was no valvular heart disease and the pericardium was normal.
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
Profile
All Male Female (n = 65) (n = 21) (n = 44) mean ± 2SD, mean ± 2SD, mean ± 2SD, n (%) n (%) n (%) p-value
Sociodemographic profile 43 ± 15
47 ± 14
41 ± 15
44 (67.7)
9 (42.9)
35 (79.5)
Ex-smoker
8 (12.3)
8 (38.1)
0 (0)
Current smoker
5 (7.7)
2 (9.5)
3 (6.8)
21 (32.3)
7 (33.3)
13 (29.5)
Mean age (years)
< 0.001
Smoking Never smoked
Previous or current pulmonary tuberculosis
0.133
0.536
Clinical presentation Dizziness
22 (33.8)
4 (19)
18 (40.9)
0.120
Shortness of breath
56 (86.2)
19 (90.5)
37 (84.1)
0.473
23.7 ± 5.8
24.1 ± 6.5
23.5 ± 5.5
0.690
93 ± 19
91.6 ± 10.2
94.7 ± 5.8
0.195
Pulse oximetry at rest (%)
93.8 ± 7.5
94.7 ± 5.8
91.6 ± 10.2
0.156
Abnormal respiration at rest, n (%)
15 (23.1)
5 (23.8)
10 (22.7)
0.861
Systolic BP (mmHg)
117 ± 22
123 ± 27
114 ± 14
0.186
Diastolic BP (mmHg)
78 ± 16
82 ± 19
77 ± 14
0.238
WHO functional class III or IV
36 (55.4)
13 (61.9)
23 (52.3)
0.323
67 ± 17
69 ± 15
67 ± 18
0.717
Distance walked in 6-min walking test (m)
280 ± 138
352 ± 97
254 ± 142
0.017
Jugular venous distension
56 (86.2)
19 (90.5)
37 (84.1)
0.591
Peripheral oedema
40 (61.5)
13 (61.9)
27 (61.4)
0.594
Body mass index (kg/m2) Heart rate (bpm)
Karnofsky performance score (%)
Main echocardiography characteristics Right ventricular systolic pressure (mmHg)
61.4 ± 19.8
60.5 ± 24.6
61.8 ± 17.2
0.797
Tricuspid annular plane systolic excursion (mm)
14.9 ± 5
14.7 ± 5.8
15 ± 4.5
0.844
Left ventricular ejection fraction (%)
51.6 ± 20
53.2 ± 21
0.357
Mean left ventricular end-diastolic diameter (mm)
49.6 ± 12.3
52.4 ± 9.9
48.1 ± 13.2
0.210
Right ventricular enlargement
56 (86.2)
18 (85.7)
38 (86.4)
0.335
Right atrial enlargement
57 (87.7)
19 (90.5)
38 (86.7)
0.830
48 ± 17.5
Data are % or mean ± SD; p-values based on the t-test, chi-squared or Fisher’s exact test as appropriate; statistical significance is based on p < 0.05. BP, blood pressure; WHO, World Health Organisation.
patient with PH, we describe the clinical context of presentation and confirmation of PH. The control subjects were younger with a mean age of 36 ± 10 years and 48 (16%) were men. Table 1 summarises the demographic, clinical and echocardiographic profile comparing men and women in the patient group. Significant gender differences were seen, with a higher prevalence of male smokers (47.6 vs 6.8%; p < 0.001) and better performance in the males during the six-minute walking test (352 ± 97 vs 254 ± 142 m, p = 0.017). Based on the WHO classification of PH, group 2 (venous PH) was the most prevalent (46%), followed by group 1 (PAH) (31%), group 3 (hypoxic PH) (22%) and group 5 (miscellaneous PH) (3%). In all, 55.4% of patients presented in the WHO functional class III or IV and the mean Karnofsky performance score was 67 ± 17%. Compared to the control group, nearly all abnormalities were much more frequent in our PH cohort. As shown in Fig. 4A, the most prevalent (case vs control) major abnormalities were:
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A Proportion of patients with major abnormalities (%)
Table 1. Demographic, clinical and echocardiographic profile of patients with PH in the PAPUCO registry
90 80 70 60 50 40 30 20 10 0
ArrhythMajor T-wave mia*** abnormality
LVH***
PH group
Patho- Prolonged LBBB p-pulmological Q QTc inter- or other nale** wave*** val*** conduction delay***
control group
B Proportion of patients with minor abnormalities (%)
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45 40 35 30 25 20 15 10 5 0
Tachycardia Bradycardia *** PH group
QRS rightRBBB and Right ventricaxis devia- QRS right- ular hypertion*** axis deviation trophy*** control group
Fig. 4. Prevalence of major (A) and minor (B) ECG abnormalities in 65 patients with pulmonary hypertension in the PAPUCO registry compared to 285 controls with normal Doppler echocardiography and right ventricular systolic pressure. RBBB; right bundle branch block, QRS right-axis deviation = QRS axis > 100°. *p < 0.05, **p < 0.01, ***p < 0.001.
pathological Q wave (47.7 vs 6.7%), followed by left ventricular hypertrophy (LVH) (38.5 vs 9.8%) and p-pulmonale (36.9 vs 20.7%). None of the patients had a completely normal ECG, as opposed to 15% in the control group. Of the minor ECG abnormalities (Fig. 4B), tachycardia (40 vs 12.6%) and QRS axis ≥ 100° (38.5 vs 5.3%) were the most prevalent. In all, 58.5% of the PH group vs 76.5% of the controls were in sinus rhythm. Bradycardia (1.5 vs 4.9%) and right bundle branch block (RBBB) with QRS right-axis deviation (1.5 vs 1.1%) were the least prevalent. Overall, in the PH group, 32.3% had at least three or four major abnormalities and 24.6% had three or four minor abnormalities. The respective numbers in the control group were 4.2 and 0%.
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Table 2. Predictive values of ECG patterns suggestive of right ventricular hypertrophy or right atrial enlargement for the diagnosis of PH in the PAPUCO registry (RSVP > 35 mmHg) Positive Negative predictive predictive Sensitivity Specificity values values (%) (%) (%) (%)
ECG criterion QRS axis ≥ 100° Extreme axis deviation (QRS > 190°)
38.5
94.7
62.5
87.1
6.2
100.0
100.0
82.4
R/S ratio in V1 > 1 or R in V1 > 7 mm
47.7
95.8
72.1
88.9
Definite right ventricular hypertrophy
30.8
100.0
100.0
86.4
Right bundle branch block and QRS right-axis deviation (≥ 100°)
1.5
99.0
25.0
81.5
P > 2.0 mm in lead II or > 1.5 mm in lead V1/V2, unchanged duration
36.9
79.3
28.9
84.6
• QRS axis ≥ +100°; and • R/S ratio in V1 ≥ 1 or R in V1 > 7 mm
We calculated the predictive values of the ECG patterns suggestive of right ventricular hypertrophy (RVH) or right atrial enlargement (RAE) for the diagnosis of PH. Table 2 shows the sensitivity, specificity and positive and negative predictive values for the occurrence of PH. Sensitivity ranged between 6.2 and 47.7% while specificity ranged between 79.3 and 100%. The NPV ranged between 81.5 and 88.9%. The PPV was lowest at 25% for RBBB and QRS right-axis deviation (≥ 100°), and highest at 100% for QRS axis ≥ 100° combined with R/S ratio in V1 ≥ 1 or R in V1 > 7 mm. We calculated the predictive values of the ECG patterns for the diagnosis of indirect signs of PH (RVH or RAE) in patients with PH. The sensitivity for predicting RVH and RAE were relatively similar for all parameters, ranging from 2.1 to 56.3% and 2.6 to 57.9%, respectively (Table 3). The specificity was higher for both RVH and RAE for all parameters (all > 60%). The PPV was found to be higher for RVH than for RAE, for which all parameters had values above 90%. The NPV was higher for RAE than for RVH, but for both, it was relatively low (all < 50%).
Discussion The main findings from this study of the predictive value of ECG abnormalities in patients with PH in SSA are the following. A strictly normal ECG was exceptional, with the most prevalent abnormalities being pathological Q wave, tachycardia, QRS right-axis deviation and left ventricular hypertrophy. The specificity of ECG abnormalities suggestive of PH was generally high, but prevalence of those relating to right heart strain were
rather less frequent. Altogether, our findings suggest that on their own, ECG abnormalities cannot discriminate patients who are more likely to be diagnosed with PH via costly and technically demanding examinations, nor can they reliably rule out patients for whom such examinations should be withheld. Previous studies of heart failure in SSA have reported that a completely normal ECG is very rare in the presence of heart disease.18,19 In general, the ECG abnormalities have higher specificity than sensitivity. The low sensitivity in our study precludes the ECG from being sufficient for screening without complementary tests, but the ECG is a simple, non-invasive and inexpensive test to perform. It could be implemented in screening protocols as a supplement to physical examination, signs and symptoms, exercise test, chest X-ray and medical history of predisposing factors such as chronic infections, chronic obstructive pulmonary disease and congenital heart disease. The specificity, as well as the NPV, was high for the parameters indicating PH. Positive findings on an ECG could therefore warrant further investigation with more advanced diagnostics. The most useful parameters seemed to be QRS right-axis deviation of more than 100° and R/S ratio in V1 > 1 or R wave in V1 > 7 mm, especially when both were present. Overall, the indirect ECG features of PH, namely RVH and RAE, had high specificity and high PPV. Both were higher for RVH than for RAE, possibly explained by the fact that RAE was seen only in more advanced disease. Sensitivity and NPV were lower, and the absence of ECG abnormalities indicating RVH or RAE could not exclude their presence. The sensitivity of indirect ECG features was, however, superior to direct ECG indication of PH, suggesting that a positive ECG can point to RVH or RAE better than to PH directly. Previous studies have assessed the role of ECG in predicting right ventricular dysfunction but not PH directly, therefore offering less opportunity for comparison with our findings. A study conducted in Canada showed that ECG abnormalities suggestive of RVH were rare in patients with normal RVSP, and had a high positive predictive value.20 Although Henkens et al. showed that ECG-derived ventricular gradient was superior to conventional ECG parameters, QRS right-axis deviation, suggesting chronically increased RV pressure load, was shown to have a sensitivity and specificity of 84 and 96%, respectively.21 Increased R/S ratio in V1 or increased R wave in V1 was the best predictor for RVH and RAE, which is in agreement with the results of Nagai et al.,22 who found that increased R/S ratio in V1 indicated right ventricular systolic dysfunction. Also
Table 3. Predictive values of ECG patterns for the diagnosis of indirect signs of pulmonary hypertension (right ventricular hypertrophy or right atrial enlargement) in patients with pulmonary hypertension from the PAPUCO registry Sensitivity (%)
Specificity (%)
Positive predictive values (%) Negative predictive values (%)
ECG criterion
RVH
RAE
RVH
RAE
RVH
RAE
RVH
RAE
QRS axis ≥ 100°
45.8
47.4
85.7
73.9
91.7
75.0
31.6
46.0
Extreme axis deviation (QRS > 190°)
8.3
7.9
100.0
95.7
100.0
75.0
24.2
38.6
R/S ratio in V1 > 1 or R in V1 > 7 mm
56.3
57.9
78.6
65.2
90.0
73.3
34.4
48.4
Definite right ventricular hypertrophy
37.5
42.1
92.9
87.0
94.7
84.2
30.2
47.6
Right bundle branch block and QRS right-axis deviation (≥ 100°)
2.1
2.6
100.0
100.0
100.0
100.0
23.0
38.3
P > 2 mm in lead II or > 1.5 mm in lead V1/V2, unchanged duration
45.8
39.5
85.7
60.9
91.7
62.5
31.6
37.8
• QRS axis ≥ +100°; and • R/S ratio in V1 ≥ 1 or R in V1 > 7 mm
RVH, right ventricular hypertrophy; RAE, right atrial enlargement.
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Al-Naamani et al.20 showed that ECG abnormalities in V1 were superior to abnormalities in V5 and V6, possibly due to lower LV influence in the left precordial leads. Ahearn et al.23 found that an ECG was not sufficient for diagnosing PH, although, from all the parameters, QRS ≥ 100° was the best discriminator and was highly suggestive of RV enlargement. This was, however, a study on PAH in particular, therefore not to be extrapolated without caution to PH of other causes. This emphasises the need to analyse the predictive values of ECG according to the aetiology of PH. In our cohort, left heart disease was the aetiology of PH in 46% of the cases. This could also have influenced the ECG results by possibly concealing mild right ventricular involvement.
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diagnosis of PH without exposing patients to unnecessary and costly right heart catheterisation in resource-limited settings. Our sincere appreciation goes to the entire PAPUCO study investigators for their efforts in creating and keeping the PH registry. We are grateful to the patients who participated. The study and the publication were partly funded by the Pulmonary Vascular Research Institute, Bayer Healthcare, and the Maurice Hatter Foundation and the Non-Communicable Disease Research and Leadership programme of the National Institute of Health, University of the Witwatersrand, Johannesburg, South Africa.
References
Limitations
1.
Our study has some limitations. First, we acknowledge that the gold standard for diagnosing PH is right heart catheterisation. However it is not always accessible or affordable in our setting and it also has a non-negligible procedure-related mortality rate and serious-events risk, even in an expert’s hands.24 Doppler echocardiography is a good alternative as it is safe and non-invasive. Furthermore, the study by Janda et al.25 showed a good correlation between right ventricular systolic pressure on echocardiography and pulmonary artery systolic pressure on RHC at baseline. Second, other useful ECG parameters for our calculations were not recorded. These are R in V1 ≥ 7 mm, R in V5 ≤ 5 mm, R in lead I ≤ 1 mm, S in V1 ≤ 2 mm, R/S in V5 ≤ 1 mm and R in V1 + S in V5 ≥ 10 mm. These have previously been shown to have a good positive predictive value,20 and including them in a future study may add to the value of an ECG for screening. Other studies on PH from China and America26,27 found that prolonged QRS and QTc durations were associated with impaired right ventricular function and the prediction of adverse outcomes in PAH. Third, the small number of participants with PH most likely affected our capacity to detect significant findings. Lastly, the cardiac disease-free sub-group in this study was an external cohort in whom the echocardiographic assessment ruled out only cardiac disease and PH. This, in turn, could have resulted in differences in case-mix and affected the diagnostic performance of ECG abnormalities for PH. The strengths of this study include the rigorous approach to ECG interpretation and data analysis, and that the data were derived from the first multicentre study of PH across Africa, where the burden of the condition is increasing.
2.
Gidwani S, Nair A. The burden of pulmonary hypertension in resourcelimited settings. Glob Heart 2014; 9(3): 297–310. Mocumbi AO, Thienemann F, Sliwa K. A global perspective on the epidemiology of pulmonary hypertension. Can J Cardiol 2015; 31(4): 375–381.
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Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D34–41.
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Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30(20): 2493–2537.
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McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53(17): 1573–1619.
6.
Sliwa K, Wilkinson D, Hansen C, Ntyintyane L, Tibazarwa K, Becker A, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study. Lancet 2008; 371(9616): 915–922.
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Pancholy SB, Palamaner Subash Shantha G, Patel NK, Boruah P, Nanavaty S, Chandran S, et al. Electrocardiogram-based scoring system for predicting secondary pulmonary hypertension: A cross-sectional study. J Roy Soc Med Cardiovasc Dis 2014; 3: 2048004014547599.
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Lau KC, Frank DB, Hanna BD, Patel AR. Utility of electrocardiogram in the assessment and monitoring of pulmonary hypertension (idiopathic or secondary to pulmonary developmental abnormalities) in patients ≤ 18 years of age. Am J Cardiol 2014; 114(2): 294–299.
Conclusion ECG abnormalities are common in African patients with PH, but those relating to RV strain specifically are less frequent. When present, ECG features suggestive of PH strongly indicate the disease, but a normal ECG does not rule out disease. The presence of QRS right-axis deviation of ≥ 100° and/or R/S ratio in V1 > 1 or R wave in V1 > 7 mm had good specificity and therefore warrants further investigation with echocardiography. Innovative measures in electrocardiography are required to improve the diagnosis of PH in SSA. This could include studies combining ECG with echocardiography, clinical criteria and cardiac biomarkers to better define the criteria for early
9.
Scherptong RW, Henkens IR, Kapel GF, Swenne CA, van Kralingen KW, Huisman MV, et al. Diagnosis and mortality prediction in pulmonary hypertension: the value of the electrocardiogram-derived ventricular gradient. J Electrocardiol 2012; 45(3): 312–318.
10. Goncalvesova E, Luknar M, Lesny P. ECG signs of right ventricular hypertrophy may help distinguish pulmonary arterial hypertension and pulmonary hypertension due to left ventricular diastolic dysfunction. Bratisl Lek Listy 2011; 112(11): 614–618. 11. Henkens IR, Scherptong RW, van Kralingen KW, Said SA, Vliegen HW. Pulmonary hypertension: the role of the electrocardiogram. Neth Heart J 2008; 16(7–8): 250–254. 12. Thienemann F, Dzudie A, Mocumbi AO, Blauwet L, Sani MU, Karaye KM, et al. Rationale and design of the Pan African Pulmonary hyperten-
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sion Cohort (PAPUCO) study: implementing a contemporary registry on
CA, Maan AC, et al. Improved ECG detection of presence and severity of
pulmonary hypertension in Africa. Br Med J Open 2014; 4(10): e005950.
right ventricular pressure load validated with cardiac magnetic resonance
13. Sliwa K, Lee GA, Carrington MJ, Obel P, Okreglicki A, Stewart S. Redefining the ECG in urban South Africans: electrocardiographic findings in heart disease-free Africans. Int J Cardiol 2013; 167(5): 2204–2209. 14. Lau EMT, Tamura Y, McGoon MD, Sitbon O. The 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: a practical chronicle of progress. Eur Respir J 2015; 46(4): 879–882.
imaging. Am J Physiol Heart Circ Physiol 2008; 294(5): H2150–157. 22. Nagai T, Kohsaka S, Murata M, Okuda S, Anzai T, Fukuda K, et al. Significance of electrocardiographic right ventricular hypertrophy in patients with pulmonary hypertension with or without right ventricular systolic dysfunction. Intern Med 2012; 51(17): 2277–2283. 23. Ahearn GS, Tapson VF, Rebeiz A, Greenfield JC, Jr. Electrocardiography
15. Stewart S, Wilkinson D, Becker A, Askew D, Ntyintyane L, McMurray JJ,
to define clinical status in primary pulmonary hypertension and pulmo-
et al. Mapping the emergence of heart disease in a black, urban population
nary arterial hypertension secondary to collagen vascular disease. Chest
in Africa: the Heart of Soweto Study. Int J Cardiol 2006; 108(1): 101–108. 16. Altman DG, Bland JM. Diagnostic tests 2: Predictive values. Br Med J 1994; 309(6947): 102. 17. Altman DG, Bland JM. Diagnostic tests. 1: Sensitivity and specificity. Br Med J 1994; 308(6943): 1552. 18. Karaye KM, Sani MU. Electrocardiographic abnormalities in patients with heart failure. Cardiovasc J Afr 2008; 19(1): 22–25. 19. Dzudie A, Milo O, Edwards C, Cotter G, Davison BA, Damasceno A,
2002; 122(2): 524–527. 24. Hoeper MM, Lee SH, Voswinckel R, Palazzini M, Jais X, Marinelli A, et al. Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol 2006; 48(12): 2546–2552. 25. Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and metaanalysis. Heart 2011; 97(8): 612–622.
et al. Prognostic significance of ECG abnormalities for mortality risk in
26. Sun PY, Jiang X, Gomberg-Maitland M, Zhao QH, He J, Yuan P, et
acute heart failure: insight from the Sub-Saharan Africa Survey of Heart
al. Prolonged QRS duration: a new predictor of adverse outcome in
Failure (THESUS-HF). J Card Fail 2014; 20(1): 45–52.
idiopathic pulmonary arterial hypertension. Chest 2012; 141(2): 374–380.
20. Al-Naamani K, Hijal T, Nguyen V, Andrew S, Nguyen T, Huynh T.
27. Rich JD, Thenappan T, Freed B, Patel AR, Thisted RA, Childers R, et al.
Predictive values of the electrocardiogram in diagnosing pulmonary hyper-
QTc prolongation is associated with impaired right ventricular function
tension. Int J Cardiol 2008; 127(2): 214–218.
and predicts mortality in pulmonary hypertension. Int J Cardiol 2013;
21. Henkens IR, Mouchaers KT, Vonk-Noordegraaf A, Boonstra A, Swenne
167(3): 669–676.
Confidence Through Clinical and Real World Experience1-3 #1 Scripted Non-VKA Oral Anticoagulant by Cardiologists* Millions of Patients Treated Worldwide Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fi brillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales January 2017. S4 Xarelto 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia NS2 : 12/8.2/0006; S2 Botswana: BOT1302296; Zimbabwe: PP10 Reg. 2017/10.2/5363 S4 Xarelto 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112;Namibia NS2 : 12/8.2/0007; S2 Botswana: BOT1302297; Zimbabwe: PP10 Reg. 2017/10.2/5364 PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM 06.2017.1808 © Bayer June 2017 *Impact RX Data 2016 NOAC: Non Vitamin K Oral Anticoagulant
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A survey of non-communicable diseases and their risk factors among university employees: a single institutional study Emmanuel I Agaba, Maxwell O Akanbi, Patricia A Agaba, Amaka N Ocheke, Zumnan M Gimba, Steve Daniyam, Edith N Okeke
Abstract Background: The incidence of non-communicable diseases (NCDs) is rising globally, with its attendant morbidity and mortality, especially in developing countries. This study evaluated the prevalence of NCDs and their risk factors among members of a university community. Methods: All employees of the university were invited to the University health clinic for screening, using the World Health Organisation’s STEPwise approach to NCDs. Results: A total of 883 (521; 59.0% males) employees with a mean age of 44 ± 10 years were studied. The median (IQR) number of NCD risk factors was three (two to three) per participant. The most common NCD risk factors were inadequate intake of fruit and vegetables (94.6%; 95% CI: 92.8–95.9), physical inactivity (77.8%; 95% CI: 74.9–80.5%) and dyslipidaemia (51.8%; 95% CI: 48.4–51.6%). Others included obesity (26.7%; 95% CI: 23.9–29.8%), alcohol use (24.0%; 95% CI: 21.3–27.0%) and cigarette smoking (2.9%; 95% CI: 2.0–4.3). Hypertension was the most common NCD (48.5%; 95% CI: 45.1–51.8%), followed by chronic kidney disease (13.6%; 95% CI: 11.4–16.1) and diabetes mellitus (8.0%; 95% CI: 6.4–10.1). There was no gender-specific difference in the prevalence of NCDs. Conclusion: This study identified that NCDs and their modifiable risk factors are highly prevalent in this community. Workplace policy to support the adoption of healthy living is needed. Keywords: diabetes mellitus, hypertension, non-communicable disease, obesity, physical inactivity
Department of Medicine, University of Jos, Nigeria Emmanuel I Agaba, BM BCh, FWACP, FRCP, eiagaba@gmail.com Maxwell O Akanbi, MB BS, FMCP, MSCI Edith N Okeke, BM BCh, FWACP, FRCP
Department of Family Medicine, University of Jos, Nigeria Patricia A Agaba, BM BCh, FWACP, FMCFM
Department of Obstetrics and Gynaecology, University of Jos, Nigeria Amaka N Ocheke, MB BS, FWACS
Submitted 18/7/16, accepted 4/4/17 Published online 15/8/17 Cardiovasc J Afr 2017; 28: 377–384
www.cvja.co.za
DOI: 10.5830/CVJA-2017-021
The incidence of non-communicable diseases (NCDs) is rising globally, with its attendant morbidity and mortality. NCDs (particularly cardiovascular disease, diabetes and cancers) were responsible for 38 million (68%) of the world’s 56 million deaths in 2012.1 Studies have shown that early detection and timely intervention can prevent further morbidity and ultimately prolong life. Additionally, some risk factors for these diseases, when identified, can be modified, thus preventing their onset and progression. Developing countries are currently witnessing an epidemic transition from communicable diseases to non-communicable diseases.1 Many individuals in these countries are caught in this ‘epidemic transition of illnesses’ as a result of lifestyle changes. In Nigeria, the common NCDs include cardiovascular disease, hypertension, diabetes and cancers.2 Many studies have documented the rising prevalence of NCDs among the general population in Nigeria. Hypertension is said to affect 25 to 48% of the adult population, while nearly 10% are diabetic,1,6 and the incidence of cancer is on the increase.3,4 Recently, attention has focused on special populations, such as healthcare providers, civil servants and bankers, as they are thought to be among the relatively affluent in the community.5-7 University employees over time have also become affluent (personal communication) and therefore are also likely to be at risk of NCDs due to changes in lifestyle and increasing urbanisation. However, very few studies have addressed NCDs among university employees in Nigeria.8,9 The magnitude of NCDs and their risk factors in this subset of the population therefore largely remains unknown. We embarked on this cross-sectional study to describe the prevalence of selected NCDs and their risk factors among the staff members of a university in north-central Nigeria. We also used this project to sensitise the participants on NCDs, as workplace interventions have been found to lead to health promotion.10
Department of Medicine, Jos University Teaching Hospital, Nigeria
Methods
Zumnan M Gimba, MB BS, FWACP
A cross-sectional study of adults, aged 18 years and over employed in the University of Jos, was conducted over a fourmonth period (February to June 2014). The study was resident at the university health centre.
University Health Centre, University of Jos, Nigeria Steve Daniyam, BM BCh
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At the end of July 2010, the University workforce comprised a total of 2 603 people (1 793 senior and 810 junior staff). The minimum sample size (380) was calculated from the Kish formula,11 using the prevalence of hypertension (as this is the NCD with the highest prevalence) and a precision of 5%. Sensitisation of the university staff members was carried out using invitation letters through the various directorate heads, announcements on the university FM radio station, and banners placed at strategic places such as the entrances and exits of the university and the health clinic two months prior to and during the study period. All employees of the university who subsequently presented to the university health clinic during the study period were recruited into the study. Pregnant and menstruating women were excluded from the study as anthropometric measurements and urine testing for abnormalities would not be useable. The Human Research and Ethics Committee of the Jos University Teaching Hospital approved the study. All participants gave written informed consent before participation. All participants had the opportunity to be counselled on healthy lifestyles, and participants found to have NCDs were referred for appropriate care. All the participants were evaluated using a modified version of the World Health Organisation (WHO) STEPwise approach to non-communicable disease.12 STEP 1 entailed history taking, looking particularly for risk factors for NCDs and the lifestyle of the subjects. STEP 2 involved a physical examination in which the height and weight were measured using an electronic weighing scale, stadiometer and non-stretch tape measure, respectively. The body mass index (BMI) was calculated from the Quetelet index.13 Blood pressure was measured using the OMRON digital sphygmomanometer. STEP 3 involved obtaining blood samples for casual plasma glucose, serum creatinine, total cholesterol and high-density lipoprotein cholesterol levels, and urine testing for proteinuria and haematuria. Casual plasma glucose (CPG) level was estimated using the glucose oxidase method. Serum creatinine was assayed using the kinetic enzymatic method, and estimated glomerular filtration rate (eGFR) from the measured serum creatinine level using the CKD-EPI calculator.14 The laboratory analyses of the tests were carried out at the commercial laboratory of APIN, Jos University Teaching Hospital, Jos. Generalised obesity, hypertension, diabetes mellitus and dyslipidaemia were defined according to internationally accepted guidelines.13,15-17 Chronic kidney disease (CKD) was regarded as the presence of proteinuria using urine dipsticks and/or eGFR < 60 ml/min/1.73 m2.18
distributed continuous variables. A p-value < 0.05 was considered significant.
Results A total of 883 (521; 59.0% males) employees with a slight predominance of junior-cadre workers participated in the study (Table 1). The majority were between 31 and 60 years old with a mean age of 44 ± 10 years. Women were older than the men and half had completed tertiary level education. The majority (80.5%) were married, with a median monthly household income of US$400 equivalent (US$1:00 exchanged for N150:00 as at the time of the study). The median (IQR) number of NCD risk factors was three (two to three) per participant. The most common NCD risk factors were inadequate intake of fruit and vegetables (94.6%; 95% CI: 92.8–95.9), physical inactivity (77.8%; 95% CI: 74.9– 80.5%) and dyslipidaemia (51.8%; 95% CI: 48.4–51.6%). Details of NCD risk factors by sociodemographic variables are shown in Table 2. No participant admitted to passive (second-hand) smoking at home or in the work environment and none used smokeless tobacco. As shown in Fig. 1, tobacco use (Fig. 1A), obesity and dyslipidaemia (Fig. 1B) increased with age. A low intake of fruit and vegetables was common in participants with a formal education (Fig. 1C), as were physical inactivity, obesity and dyslipidaemia (Fig. 1D), compared to those without Table 1. Characteristics of 883 staff members of the University of Jos evaluated for select non-communicable diseases between February and June 2014 Variable Mean age, years
Data obtained were analysed using the Epi Info 7 statistical software (CDC, Atlanta, GA). Means ± SD were used to describe normally distributed continuous variables, and proportions for categorical variables. Median with range was used to describe non-normally distributed continuous variables. The Student’s t-test was used to compare group means and the chi-squared test to compare proportions. The Fisher exact test was used when cells contained less than five observations. The non-parametric Mann–Whitney U-test was used to compare non-normally
Total (n = 883)
Males (n = 521)
Females (n = 362)
p-value
44 ± 10
43 ± 10
45 ± 9
0.002 < 0.0001
Age group, years, n (%)* < 20
3 (0.3)
2 (0.4)
1 (0.3)
21–30
83 (9.4)
61 (11.7)
22 (6.1)
31–40
257 (29.1)
166 (31.9)
91 (25.1)
41–50
294 (33.3)
155 (29.8)
139 (38.4)
51–60
215 (24.3)
115 (22.1)
100 (27.6)
> 60
31 (3.5)
22 (4.2)
9 (2.5)
Married (n = 878); n (%)
707 (80.5)
437 (84.2)
270 (75.2)
< 0.0001
Tertiary education completed (n = 876); n (%)
440 (50.2)
243 (46.9)
197 (55.0)
0.02
Junior staff (n = 843); n (%)
466 (55.3)
319 (63.0)
147 (43.6)
< 0.0001
400
333.33
466.66
< 0.0001
BMI (kg/m2)
27.2 ± 5.1
25.1 ± 3.5
30.2 ± 5.7
< 0.0001
SBP (mmHg)
129 ± 19
130 ± 19
127 ± 20
0.06
DBP (mmHg)
79 ± 12
79 ± 12
80 ± 11
0.4
85.0
85.0
86.0
0.10
Monthly income, USD, median
CPG, median (mg/dl) [mmol/l]
Statistical analysis
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[4.72]
[4.72]
[4.77]
Proteinuria (n = 883) (%)
116 (13.2)
72 (13.8)
44 (12.2)
1.15
Serum creatinine (mmol/l)
74.5 ± 19.3
81.8 ± 19.7
64.0 ± 13.1
< 0.0001
eGFR (ml/min/1.73m2)
114.2 ± 20.5
115.1 ± 20.7
113.1 ± 20.2
0.15
4 (0.4)
2 (0.4)
2 (0.5)
0.69
TC (mg/dl)
193.4 ± 43.9
201.4 ± 46.2
[mmol/l]
[5.01 ± 1.14] [5.22 ± 1.20] [4.87 ± 1.07]
Reduced eGFR
60.7 ± 16.5
187.9 ± 41.4 < 0.0001
HDL-C (mg/dl)
56.6 ± 16.4
[mmol/l]
[1.47 ± 0.42] [1.57 ± 0.43] [1.39 ± 0.41]
53.8 ± 15.7
< 0.0001
*Fisher exact test; USD: United States Dollars; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; CPG: casual plasma glucose; eGFR: estimated glomerular filtration rate; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol.
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Table 2. Sociodemographic characteristics and distribution of non-communicable diseases and their risk factors among 883 staff members of the University of Jos, Nigeria Alcohol % (95% CI)
Diet % (95% CI)
Physical inactivity % (95% CI)
Variable
Tobacco % (95% CI)
Obesity % (95% CI)
Dyslipidaemia % (95% CI)
HPTN % (95% CI)
All
2.9 (2.0–4.3)
24.0 (21.3–27.0) 94.6 (92.8–95.9) 77.8 (74.9–80.5) 26.7 (23.9–29.8) 51.8 (48.4–51.6) 48.5 (45.1–51.8)
Male
4.8 (3.2–7.1)
33.8 (29.8–38.0) 94.6 (92.2–96.3) 72.9 (68.9–76.7) 10.6 (8.1–13.6) 48.8 (44.4–53.1) 43.0 (38.7–47.4)
Female
0.3 (0.0–1.8)
DM % (95% CI)
CKD % (95% CI)
8.0 (6.4–10.1)
13.6 (11.4–16.1)
Gender 9.9 (7.2–13.6)
6.9 (5.0–9.5)
14.2 (11.4–17.6)
94.5 (91.5–96.5) 84.8 (80.7–88.3) 50.0 (44.7–55.3) 55.0 (39.8–50.3) 56.4 (51.1–61.5)
9.7 (6.9–13.3)
12.7 (9.5–16.7)
Marital status Married
3.0 (1.9-4.6)
24.3 (21.2-27.7) 94.6 (92.6-96.1) 79.5 (76.3-82.4) 27.0 (23.8-30.5) 53.2 (49.4-56.9) 49.4 (45.6-53.1)
8.8 (6.8-11.2)
13.0 (10.7-15.8)
Unmarried
2.8 (0.9–6.5)
22.7 (16.8–29.6) 94.3 (89.8–97.2) 71.0 (63.7–77.6) 25.6 (19.3–32.7) 46.0 (38.5–53.7) 44.9 (37.4–52.6)
5.1 (2.4–9.5)
15.9 (10.8–22.2)
Age group, years < 20
0.0 (0.0–70.8)
0.0 (0.0–70.8)
100.0 (0.0–29.2) 100.0 (0.0–29.2)
0.0 (0.0–70.8)
33.3 (0.8–90.6)
33.3 (0.8–90.6)
0.0 (0.0–70.8)
0.0 (0.0–70.8)
21–30
7.2 (2.7–15.1)
7.2 (2.7–15.1)
88.0 (79.0–94.1) 73.5 (62.7–82.6)
7.2 (2.7–15.1)
36.1 (25.9–47.7) 14.5 (7.7–23.9)
2.4 (0.3–8.4)
7.2 (2.7–15.1)
31–40
3.1 (1.4–6.0)
22.2 (17.3–27.8) 94.9 (91.5–97.3) 69.3 (63.2–74.8) 22.2 (17.3–27.8) 42.4 (36.3–48.7) 36.2 (30.3–42.4)
3.9 (1.9–7.0)
15.6 (11.4–20.6)
41–50
2.0 (0.8–4.4)
29.9 (24.8–35.3) 96.9 (93.8–98.4) 80.6 (75.6–85.0) 29.9 (24.8–35.5) 53.4 (40.8–52.5) 49.0 (43.1–54.8)
5.8 (3.4–9.1)
12.6 (9.0–16.9)
51–60
2.3 (0.8–5.3)
34.9 (28.5–41.7) 93.5 (89.3–96.4) 85.6 (80.2–90.0) 34.9 (28.9–41.7) 65.1 (58.3–71.5) 71.2 (64.6–77.1) 16.7 (12.0–22.4) 14.4 (10.0–19.8)
61–70
3.2 (0.1–16.7)
32.3 (16.7–51.4) 96.8 (83.3–99.9) 77.4 (58.9–90.4) 32.3 (16.7–51.4) 64.5 (45.4–80.8) 80.6 (62.5–92.5) 19.4 (7.5–37.5)
19.4 (7.5–37.5)
Education, years None
0.0 (0.0–60.2)
< 7 years
6.3 (2.1–14.0)
0.0 (0.0–60.2)
0.0 (0.0–60.2)
31.3 (21.3–42.6) 97.5 (91.3–99.7) 85.0 (75.3–92.0) 32.5 (22.4–43.9) 52.5 (41.0–63.8) 63.8 (52.2–74.2) 17.5 (9.9–27.6)
0.0 (0.0–60.2)
0.0 (0.0–60.2)
0.0 (0.0–60.2)
0.0 (0.0–60.2)
25.0 (0.6–80.6) 75.0 (19.4–99.4)
13.8 (7.1–23.3)
8–11 years
3.3 (0.7–9.2)
29.3 (20.3–39.8) 95.7 (89.2–98.8) 84.8 (75.8–91.4) 23.9 (15.6–33.9) 46.7 (36.3–57.4) 48.9 (38.3–59.6)
7.6 (3.1–15.1)
8.7 (3.8–16.4)
> 12 years
2.7 (1.6–4.3)
22.0 (18.9–25.5) 94.0 (91.8–95.7) 76.3 (72.7–79.5) 26.4 (23.1–30.1) 52.7 (48.7–56.6) 45.8 (41.8–49.7)
6.6 (4.9–8.9)
14.3 (11.7–17.3)
5.7 (3.9–8.2)
12.9 (10.2–16.3)
Staff cadre Junior
4.4 (2.9–6.8)
25.9 (22.1–30.0) 94.5 (92.1–96.3) 77.2 (73.2–80.7) 20.8 (17.4–24.7) 57.7 (52.4–62.4) 43.2 (38.8–47.7)
Senior
1.0 (0.3–2.8)
21.6 (17.7–26.2) 94.6 (91.7–96.5) 78.6 (74.2–82.6) 34.3 (29.6–39.3) 47.3 (42.8–51.8) 55.2 (50.1–60.2) 11.1 (8.2–14.7) 14.4 (11.2–18.4)
Lowest
3.4 (1.1-7.9)
28.4 (21.2-36.5) 93.0 (87.6-96.6) 75.0 (67.1-81.8) 20.1 (13.9-27.6) 43.1 (34.8-51.6) 38.1 (30.2-46.6)
4.9 (2.0-9.8)
10.4 (5.9-16.6)
Second
6.1 (2.9-10.9)
28.6 (21.8-36.2) 93.2 (88.3-96.6) 81.7 (74.9-87.3) 20.1 (14.2-27.0) 48.8 (40.9-56.7) 40.2 (32.6-48.1)
4.9 (2.1-9.4)
15.8 (10.6-22.3)
Third
0.0 (0.0-100.0)
22.3 (15.8-30.1) 94.4 (89.2-97.5) 81.1 (73.7-87.1) 33.5 (25.8-41.9) 53.8 (45.3-62.2) 52.4 (43.9-60.8)
9.1 (4.9-15.0)
13.9 (8.7-20.7)
Fourth
3.0 (1.0-6.9)
18.2 (12.7-25.0) 95.7 (91.4-33.0) 82.9 (76.2-88.3) 25.6 (19.1-33.0) 57.3 (49.4-65.0) 56.1 (48.1-63.8)
11.6 (7.1-17.5)
11.5 (7.1-17.5)
Fifth
0.6 (0.02-3.5)
22.7 (16.3-30.1) 95.4 (90.8-98.1) 76.6 (90.8-98.1) 35.0 (27.5-43.1) 59.7 (51.5-67.6) 55.1 (46.9-63.2)
11.0 (6.6-17.1)
13.6 (8.6-20.0)
Income quintile
HPTN = hypertension; DM = diabetes mellitus; CKD = chronic kidney disease.
formal education. Fig. 1F shows that physical inactivity and dyslipidaemia increased with increasing household income. Hypertension was the most common NCD, being present in nearly half the participants (48.5%; 95% CI: 45.1–51.8%), as indicated in Table 2. Its prevalence rose with increasing age (Fig. 2A) and household income (Fig. 2B) but decreased with increasing level of education (Fig. 2C). Similar trends were noticed for diabetes mellitus (DM) with regard to age and household income (Fig. 2A, B). CKD also increased with increasing age (Fig. 2A). The prevalence of DM and CKD by sociodemographic characteristics is shown in Table 2.
Discussion The main findings of our study were that: (1) the most prevalent NCD risk factors were low intake of fruit and vegetables, physical inactivity and dyslipidaemia, with the majority of participants having multiple factors; (2) nearly half (48.5%) of the participants were hypertensive, and CKD and DM occurred in 13.6 and 8.0%, respectively; and (3) the sociodemographic characteristics of age, income and education impacted on the prevalence of the common NCDs and their risk factors. Inadequate consumption of fruit and vegetables was the most prevalent risk factor in this study, followed by physical inactivity and obesity. This is in accord with the findings of many researchers. Sufficient consumption of fruit and vegetables was lacking in 96.6% of respondents in a Nepalese community.19
Zaman and co-workers20 reported that 92% of participants in a nationally representative sample in Bangladesh reported inadequate intake of fruit and vegetables (median serving of 1.6 portions/day). In a study of university employees in western Nigeria, 96% of participants had inadequate consumption of fruit and vegetables.8 Similarly, a high prevalence (90%) has been reported from northern Nigeria.6 However, in a community survey in eastern Nigeria, a slightly lower proportion (70.4%) of respondents had inadequate intake of fruit and vegetables.21 Nonetheless, a high prevalence of inadequate intake of fruit and vegetables exists in the general population and that needs to be addressed. Physical inactivity has been found to contribute significantly to NCD-related mortality.22 Three-quarters of the participants in our study were physically inactive. This is in accord with the findings of Oladimeji and co-workers,6 who reported that 91% of workers in the public sector were physically inactive. Likewise, nearly 80% of hospital workers in Nigeria have been reported to be physically inactive.23 However, a lower prevalence of physical inactivity has been reported in earlier studies. Of the 2 000 persons studied in Togo, 41% were sedentary, while 35% was reported from Bangladesh.24,25 In a study among workers at a medical college in Ghana, only 25% were physically inactive.26 The reason for the disparity between our findings and those of prior studies reporting low prevalence of physical inactivity may be related to the highly selective nature of our
380
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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
A
B 90 80
100
Prevalence of risk factors (%)
Prevalence of risk factors (%)
120
80 60 40 20 0
70 60 50 40 30 20 10
21–30 Alcohol
31–40 41–50 51–60 Age group (years) Tobacco
0
61–70
Unhealthy diet
C
21–30
31–40 41–50 51–60 Age group (years)
Physical inactivity
Obesity
61–70 Dyslipidaemia
D 90 80
100
Prevalence of risk factors (%)
Prevalence of risk factors (%)
120
80 60 40 20 0
70 60 50 40 30 20 10
A Alcohol
B C Number of years educated Tobacco
0
D Unhealthy diet
B C Number of years educated
Physical inactivity
A: no formal education, B: 1–7 years of education, C: 8–11 years of education, D: ≥ 12 years of education
E
A
Obesity
D Dyslipidaemia
A: no formal education, B: 1–7 years of education, C: 8–11 years of education, D: ≥ 12 years of education
F 90 80
100
Prevalence of risk factors (%)
Prevalence of risk factors (%)
120
80 60 40 20 0
70 60 50 40 30 20 10
Lowest Alcohol
Second Third Fourth Income quintiles Tobacco
Fifth
Unhealthy diet
0
Lowest
Second Third Fourth Income quintiles
Physical inactivity
Obesity
Fifth
Dyslipidaemia
Fig. 1. P revalence of non-communicable disease risk factors in relation to some sociodemographic characteristics in 883 staff members of the University of Jos.
study participants. We noted the rarity of both active and passive cigarette
smoking in our participants. This is in keeping with previous reports that document a paucity of smoking among Nigerians.8,6,27
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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
A 90 Prevalence of risk factors (%)
80 70 60 50 40 30 20 10 0
21–30
31–40 41–50 51–60 61–70 Age group (years) Chronic kidney Diabetes Hypertension disease mellitus
B
Prevalence of risk factors (%)
60 50 40 30 20 10 0
Lowest
Second Third Fourth Income quintiles
Hypertension
Diabetes mellitus
Fifth
Chronic kidney disease
C
Prevalence of risk factors (%)
80 70 60 50 40 30 20 10 0
A
B C Number of years educated
Hypertension
Diabetes mellitus
D
Chronic kidney disease
A: no formal education, B: 1–7 years of education, C: 8–11 years of education, D: ≥ 12 years of education
Fig. 2. P revalence of non-communicable diseases in relation to some sociodemographic characteristics among 883 staff members of the University of Jos.
381
Generally, this finding is in contrast to the findings in southern Africa, Asia20,28 and the Western world,29-31 where smoking constitutes a major public health hazard. Clustering of risk factors was prevalent in this study, with the median number of risk factors being three (IQR 2–3) per participant. This finding corroborates the findings of previous studies. In a study of over 3 800 South African adults aged 50 years and above, Phaswana-Mafuya and associates32 reported a mean incidence of risk factors of three. In a recent German survey, 45.1% of participants had multiple risk factors.33 Similar clustering has been reported by the SAGE wave 1 study that evaluated older adults across six countries.34 A study among Senegalese private sector workers revealed that more than half of the participants had two or more cardiovascular risk factors.35 Villegas and co-workers36 reported that 67.6% of men and women sampled across 17 general practice settings in Ireland had more than one cardiovascular risk factor. This scenario is the typical clustering in patients and deserves attention to reverse or limit their contribution to NCD and its related mortality. The prevalence of the selected NCDs parallels that obtained in the literature from the Western world and the African region. Hypertension was present in nearly half of the participants; CKD was present in a little over a 10th of the population, and DM in nearly a 10th. In the SAGE wave 1 study, the prevalence of hypertension ranged from as low as 17.9% in Bangladesh to as high as 78% in South Africa among older persons.34 A prevalence of 47.2% was reported among Irish hospital attendees in a study that evaluated over 1 000 patients recruited from several general practices. Oluyombo and colleagues,37 working in south-west Nigeria, reported a prevalence of 47.2% among residents of a semi-urban community. A slightly lower prevalence of 31.4% was recently reported from south-east Nigeria.21 In a large community survey that evaluated 5 206 adults in Malawi, Msyamboza and associates38 reported a prevalence of 33% among persons aged 25 to 64 years. A recent review by Bosu7 demonstrated that the prevalence of hypertension among workers in the West African sub-region has steadily increased from 12.9% in the 1980s to 37.5% in 2014, while figures up to 51.6% (95% CI: 49.8–53.4) and 43% (95% CI: 42.1–43.9) have been recently reported in Nigeria among urban and rural populations, respectively.4 CKD, an emerging NCD, has gained attention in recent times as it is both an end-point of communicable and non-communicable diseases and a strong cardiovascular risk factor. It has become a pandemic, affecting both developed and developing countries. CKD was present in a significant proportion of the participants in our study. Similar reports exist regarding the prevalence of CKD from the Western world and Asia.39-41, However, varying reports from the African region exist. In a recent community survey from Senegal that studied 1 037 adults, CKD was present in 4.9% of the participants.42 In a similar study from Cameroun, the prevalence of CKD ranged from 11.0 to 14.2%, depending on the prediction equation used.43 In a study that evaluated 402 private sector IT workers in Dakar, Senegal in late 2010, 22.4% had CKD.35 The prevalence of CKD in Nigeria in various subsets of the population has been reported to range from 7.8% among public sector employees,44 to 11.4% in the community45 and 43.5% among retirees,46 depending on the criteria used.
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The prevalence of DM in this study parallels the estimated global prevalence of 9%, the WHO estimated prevalence of 7.9% in Nigeria in 2014,1 and the 9.7% recently reported from Senegal.35 It is however slightly lower than the 11% obtained among university employees in south-western Nigeria.8 However, our study differed from theirs as they relied on selfreported diagnosis, which is subject to recall bias. Oluyombo and associates37 recently reported that 6.8% of 750 respondents had DM. Our finding together with the foregoing support the assertion that the prevalence of DM is on the increase in Nigeria. However, the prevalence of DM in our study was higher than the 2.5% reported by Oladapo and co-workers47 in south-west Nigeria, and the 3.6% by Okpechi and colleagues21 in southeastern Nigeria. That sociodemographic characteristics impact on NCDs and their risk factors was confirmed by the findings of our study. The prevalence of hypertension, CKD and DM rose with increasing age, as expected. Their prevalence also increased with increasing income, as a result of the concomitant rise in the prevalence of some of the risk factors with increasing income. It is noteworthy that hypertension decreased with increasing educational level. This confirms the results of prior studies that reported an inverse relationship between educational level and hypertension.19,48 This provides an opportunity for intervention in order to halt the rising trends in NCD. Together with the existing literature, our study has implications for the subset of employees at this university and the general population at large, as large numbers of these individuals are at an elevated risk of NCD-related events. In a recent review of national policies addressing NCDs in low- and middle-income countries, Lachat and colleagues22 demonstrated the disconnect that exists between the burden of NCDs and the response of the respective governments, including Nigeria. Concerted efforts are needed to stem the high prevalence of NCDs and their risk factors in our environment, so as to achieve the 2025 voluntary global targets of the Global NCD Action Plan.1
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employees in Nigeria to date. Our study therefore provides the fulcrum for further studies of this nature to elucidate the burden of NCDs in this category of workers.
Conclusion This study identified that the most prevalent NCD risk factors among employees of a university are behavioural and therefore modifiable. We also demonstrated that the NCDs and their risk factors are impacted upon by sociodemographic characteristics. Given the burden of NCDs and their risk factors among this subset of the general population, there is a need for workplace policies aimed at health promotion to be put in place in order to stem the rising trend of NCDs. Multicentre studies addressing the burden of NCDs among university employees are imperative. This study was funded in part by the Tertiary Education Trust Fund of the Federal Government of Nigeria. The authors acknowledge the contribution of the management of the University health centre and the leaders and members of the various associations at the University of Jos for participating in the study. We also appreciate the efforts of the physicians who participated in data collection, and Mr Chime of the Jos University Teaching Hospital for data entry.
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Prevalence of cardiovascular risk factors in an urban area of Togo: a
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WHO STEPS-wise approach in Lome, Togo. Cardiovasc J Afr 2012;
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population. Korean J Intern Med 2016; 31(6): 1120–1130.
25. Zaman MM, Bhuiyan MR, Karim MN, et al. Clustering of non-
42. Seck SM, Doupa D, Guéye L, Dia CA. Epidemiology of chronic kidney
communicable diseases risk factors in Bangladeshi adults: An analysis
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CIRCULATIONAHA.108.777334.
Letter to the Editor Dear Sir We read the article titled ‘Relationship between coronary tortuosity and plateletcrit coronary tortuosity and plateletcrit’ by Cerit et al., published online in the Cardiovascular Journal of Africa on 25 April 2017, with great interest (see page 385 in this issue). However, we have some comments regarding this study. Although it is a relatively common finding in coronary angiography, little is known about the importance of coronary tortuosity (CorT). As mentioned in the article, clinical studies have demonstrated that CorT may be related to aging, hypertension, atherosclerosis and diabetes mellitus.1,2 In this study, there was a significant difference between the groups regarding hypertension, diabetes mellitus and aging. For this reason, it was to be expected that CorT would be higher in the group with these risk factors. High blood pressure itself initiates a chain of events in vessel walls in the form of oxidative stress, inflammation and endothelial dysfunction.3
Similarly, in diabetes, Herder et al. found an increased level of inflammatory reactions and their components, including inflammatory parameters.4 In previous studies, PCT, MPV, NLR and PLR were found to be markers of inflammatory status. In conclusion, we would have expected higher PCT, MPV, NLR and PLR values in the CorT group. It would have been preferable if there were no differences between the two groups in terms of hypertension, diabetes mellitus and aging. Then PCT, MPV, NLR and PLR would have provided more accurate information about the ability of CorT to predict disease. Future studies should be directed towards larger randomised trials with more emphasis on long-term clinical endpoints.
References 1.
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2.
Li Y, Shen C, Ji Y, Feng Y, Ma G, Liu N. Clinical implication of coronary tortuosity in patients with coronary artery disease. PLoS One 2011;
Training and Research Hospital, Sakarya University, Sakarya, Turkey Kahraman Cosansu, MD, kahraman141@gmail.com Mustafa Gokhan Vural, MD Mehmet Akif Cakar, MD
6: 24232. doi: 10.1371/journal.pone.0024232. 3.
Mittal BV, Singh AK. Hypertension in the developing world: challenges and opportunities. Am J Kidney Dis 2010; 55(3): 590–598. doi: 10.1053/j. ajkd.2009.06.044.
4.
Herder C, Carstensen M, Ouwens DM. Anti-inflammatory cytokines and risk of type 2 diabetes. Diabetes Obes Metab 2013; 15: 39–50.
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Relationship between coronary tortuosity and plateletcrit coronary tortuosity and plateletcrit Levent Cerit, Zeynep Cerit
Abstract Background: Coronary tortuosity (CorT) is a common angiographic finding and may be associated with myocardial ischaemia, even without coronary artery disease. Platelets play a crucial role in inflammatory and thrombotic processes and the physiopathology of cardiovascular disease. Larger platelets are more active enzymatically and have higher thrombotic ability compared to smaller platelets. Plateletcrit (PCT) provides complete information on total platelet mass. We aimed to evaluate the relationship between CorT and PCT in patients with chronic stable angina. Methods: The medical records of consecutive patients who underwent coronary angiography from January 2013 to January 2016 were retrospectively reviewed for CorT. CorT and clinical, echocardiographic, haematological and biochemical parameters were evaluated. Taking into consideration the inclusion criteria, 106 patients with CorT and 108 with normal coronary angiographies (control group) were included in the study. CorT was defined as three fixed bends during both systole and diastole, with each bend ≥ 45°. Results: The median PCT, mean platelet volume (MPV), platelet:large-cell ratio (P-LCR), neutrophil:lymphocyte ratio (NLR) and platelet:lymphocyte ratio (PLR) of the CorT group were significantly higher than those of the control group (0.26 ± 0.02 vs 0.2 ± 0.03%, p < 0.001; 10.6 ± 0.14 vs 9.6 ± 0.65 fl, p < 0.001; 29.3 ± 6.7 vs 23.4 ± 5.1, p < 0.001; 2.3 ± 1 vs 1.47 ± 0.48, p < 0.001; 1.28 ± 0.5 vs 0.82 ± 0.23, p < 0.001, respectively). The incidence of diabetes mellitus, hypertension and female gender were significantly higher in the CorT group (18.9 vs 1.9%, p < 0.001, 90.6 vs 50%, p < 0.001, 70.8 vs 44.4%, p < 0.001, respectively). Multivariate logistic regression analysis revealed age, hypertension, diabetes mellitus and plateletcrit were independently associated with CorT. Conclusion: CorT was associated with increased PCT, MPV, P-LCR, NLR and PLR, even in the absence of coronary artery disease. Age, hypertension, diabetes mellitus and plateletcrit were independently associated with CorT.
Keywords: coronary angiography, plateletcrit, mean platelet volume Submitted 2/6/16, accepted 11/4/17 Published online 26/4/17 Cardiovasc J Afr 2017; 28: 385–388 DOI: 10.5830/CVJA-2017-023
Near East University Hospital, Nicosia, Cyprus Levent Cerit, MD, drcerit@hotmail.com Zeynep Cerit, MD
www.cvja.co.za
Coronary tortuosity (CorT) is a common coronary angiographic finding. CorT is defined as three fixed bends during both systole and diastole in at least one epicardial artery, with each bend showing a 45° change in vessel direction.1 The aetiology, clinical implications and long-term prognosis are not well clarified. Clinical studies have demonstrated that CorT may be related to aging, hypertension, atherosclerosis and diabetes mellitus.2,3 CorT is associated with reversible myocardial perfusion defects and chronic stable angina.4,5 Zegers et al.6 demonstrated three cases of patients with CorT and hypothesised that CorT may lead to ischaemia. Patients with CorT may suffer from effortinduced chest pain and pain at rest.6 The relationship between CorT and coronary atherosclerosis is unclear. Platelets play a key role in the genesis of thrombosis. Platelets, the amount of which in the blood is indicated with plateletcrit (PCT), are important for inflammation, thrombosis and cardiovascular pathophysiology. Increased mean platelet volume (MPV) has been found to be associated not only with coronary artery disease but also with carotid artery disease, deep-vein thrombosis and pulmonary embolism.7-9 Platelets with larger volumes are more active and vulnerable and therefore are a topic of interest in the development of atherosclerosis.10 PCT provides more comprehensive data about total platelet mass because it is equivalent to MPV and platelet count (PLT), where PCT = PLT × MPV/107. To the best of our knowledge, PCT and its association with CorT has not been previously reported. In this study, we investigated the relationship between all platelet markers and CorT.
Methods A retrospective evaluation was performed of consecutive patients undergoing coronary angiography due to stable angina pectoris. Stable angina was defined as discomfort in the chest, back, jaw, shoulder or arms, typically elicited by exertion or emotional stress, and relieved by rest or nitroglycerin. All patients enrolled in the study underwent coronary angiography as a result of chest pain and objective signs of ischaemia during treadmill exercises. Routine laboratory and clinical parameters (hypertension, hypercholesterolaemia, diabetes mellitus and tobacco use) were obtained from the patient medical records. Study exclusion criteria included acute or chronic hepatic and renal failure, chronic obstructive pulmonary disease, peripheral and cerebral arterial disease, inflammatory diseases, congenital heart disease, restrictive cardiomyopathy, dilated cardiomyopathy, hypothyroidism, hyperthyroidism, malignancies, autoimmune diseases, acute or chronic infectious disease, coronary ectasia, severe coronary artery disease, coronary slow flow, mild-to-severe valvular disease, heart failure, anaemia and patients on anti-aggregation therapy. All patients underwent coronary angiography according to the Judkins technique. Angiograms were reviewed by at least two blinded reviewing cardiologists. The left anterior descending
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coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) were observed in various angulations. CorT was evaluated on special angulations, the LAD was assessed in the right anterior oblique view with cranial angulations, and the LCX in the left anterior oblique with caudal angulations, while the RCA was assessed in the right anterior oblique view. CorT was identified by three or more bends (defined as ≥ 45° change in vessel direction) along the main trunk of at least one artery, present both in systole and diastole.1 Prior to coronary angiography, eight-hour postprandial venous blood was collected from all patients for routine laboratory testing. Haematological parameters, including haemoglobin, haematocrit and white blood cell count were analysed using an automated CBC device (Abbott Cell Dyn; Abbott Laboratories, Effingham, Illinois, USA). Biochemical parameters were measured using an Olympus AU 600 autoanalyser (Olympus Optical Co, Ltd, Schimatsu-Mishima, Japan). All study parameters were reviewed and approved by the local ethics committee.
Statistical analysis Statistical analysis was performed using the SPSS (version 20.0, SPSS Inc, Chicago, Illinois) software package. Continuous variables are expressed as mean ± standard deviation (mean ± SD) and categorical variables as percentages (%). The Kolmogorov– Smirnov test was used to evaluate the distribution of variables. The Student’s t-test was used to evaluate continuous variables showing normal distribution and the Mann–Whitney U-test was used to evaluate variables that did not show normal distribution. A p-value < 0.05 was considered statistically significant. To identify predictors of CorT, the following variables were initially assessed in a univariate model: age, hypertension, female gender, diabetes, hyperlipidaemia, current smoking and haematological parameters. Significant variables in univariate analysis were then entered into a multivariate logistic regression analysis using backward stepwise selection.
0.79 vs 5.34 ± 0.82 mmol/l), p = 0.478; 48 ± 13.6 vs 43.3 ± 5.6 mg/ dl (1.24 ± 0.35 vs 1.12 ± 0.12 mmol.l), p = 0.075; 152.4 ± 27.4 vs 163.1 ± 48.5 mg/dl (1.72 ± 0.31 vs 1.84 ± 0.55 mmol/l), p = 0.517; 13.3 ± 1.5 vs 14.4 ± 1.2 g/dl, p = 0.527; 6.96 ± 2.12 vs 7.0 ± 1.3 103/µl, p = 0.683; 4.35 ± 1.6 vs 3.97 ± 0.99 103/µl, p = 0.408; 0.48 ± 0,14 vs 0.44 ± 0.18 mg/dl, p = 0.267; 35.0 ± 10.5 vs 38.7 ± 5.8 mg/ dl, p = 0.428; 0.79 ± 0.18 vs 0.83 ± 0.12 mg/dl; p = 0.367; 60.4 ± 2.5 vs 61.6 ± 3.2%, p = 0.751, respectively] (Table 2). However, there was a significant difference between the groups regarding hypertension, with more hypertensive patients in the CorT group (90.6 vs 50%, p < 0.001) (Table 1). There were also significant differences between the groups regarding age, female gender, diabetes mellitus and low-density lipoprotein cholesterol levels [61.8 ± 8.7 vs 52.9 ± 8.1 years, p < 0.001; 70.8 vs 44.4%, p < 0.001; 18.9 vs 1.9%, p < 0.001; 139.9 ± 24.7 vs 132.7 ± 27.4 mg/dl (3.62 ± 0.64 vs 3.44 ± 0.71 mmol/l), p = 0.02, respectively]. The median PCT, MPV, P-LCR, NLR and PLR values of the CorT group were significantly higher than those of the control group (0.26 ± 0.02 vs 0.2 ± 0.03%, p < 0.001; 10.6 ± 0.14 vs 9.6 ± 0.65 fl, p < 0.001; 29.3 ± 6.7 vs 23.4 ± 5.1, p < 0.001; 2.3 ± 1 vs 1.47 ± 0.48, p < 0.001; 1.28 ± 0.5 vs 0.82 ± 0.23, p < 0.001, respectively) (Table 2). The results of univariate analyses are presented in Table 3. On univariate analysis, age, diabetes mellitus, hypertension, female gender, PCT and NLR were associated with CorT (Table 3). On multivariate analysis age, hypertension, diabetes mellitus and PCR were independent predictors for CorT (OR 1.826; 95% CI: 1.354–2.167; p < 0.001, OR 2.158; 95% CI: 1.462–2.937; p < 0.001, OR 1.583; 95% CI: 1.362–2.835; p < 0.001, OR 1.634; 95% CI: 1.345–2.724; p < 0.001, respectively) (Table 4).
Table 2. Laboratory and echocardiographic parameters Laboratory and echocardiographic variables Haemoglobin (g/dl) Platelets (103/µl)
Results The coronary tortuosity and normal coronary groups comprised 106 and 108 patients, respectively. The demographic characteristics of both groups are summarised in Table 1. There was no significant difference between the groups regarding current smoking (28.3 vs 20.4% p = 0.176) (Table 1). There was no significant difference between the groups regarding total cholesterol, high-density lipoprotein cholesterol and triglyceride levels, haemoglobin, white blood cell and neutrophil counts, C-reactive protein, urea and creatinine levels, and ejection fraction [209.9 ± 30.5 vs 206.3 ± 31.8 mg/dl (5.44 ± Table 1. General characteristics of the patients Coronary tortuosity
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Coronary tortuosity + (n = 106)
– (n = 108)
13.3 ± 1.5 (13.9)
14.4 ± 1.2 (14.1)
236.5 ± 57.1 (229.0) 218.5 ± 32.1 (219.0)
p-value 0.527 0.009
White blood cells (103/µl)
6.96 ± 2.12 (6.84)
7.0 ± 1.3 (6.9)
Mean platelet volume (fl)
10.6 ± 1.4 (10.5)
9.5 ± 0.65 (9.5)
Neutrophils (103/µl)
4.35 ± 1.6 (4.1)
3.97 ± 0.99 (4.39)
0.408
Lymphocytes (103/µl)
1.99 ± 1 (1.96)
2.77 ± 0.58 (2.65)
< 0.001
Neutrophil:lymphocyte ratio
2.3 ± 1 (2.06)
1.47 ± 0.48 (1.45)
< 0.001
Platelet:large-cell ratio
29.3 ± 6.7 (29)
23.4 ± 5.1 (23.1)
< 0.001
Platelet:lymphocyte ratio
1.28 ± 0.5 (1.1)
0.82 ± 0.23 (0.8)
< 0.001
Plateletcrit (%)
0.26 ± 0.16 (0.24)
0.21 ± 0.03 (0.20)
< 0.001
C-reactive protein (mg/dl)
0.48 ± 0.14 (0.45)
0.44 ± 0.18 (0.41)
0.267
Total cholesterol (mg/dl)
209.9 ± 30.5 (210)
206.3 ± 31.8 (204)
0.478
[mmol/l]
[5.44 ± 0.79 (5.44)]
[5.34 ± 0.82 (5.28)]
High-density lipoprotein cholesterol (mg/dl)
48 ± 13.6 (45)
43.3 ± 5.9 (43)
[mmol/l]
[1.24 ± 0.35 (1.17)]
[1.12 ± 0.15 (1.11)]
Low-density lipoprotein cholesterol (mg/dl)
139.9 ± 24.7 (148)
132.7 ± 27.4 (134)
0.683 < 0.001
0.075
0.02
+ (n = 106)
– (n = 108)
p-value
[mmol/l]
[3.62 ± 0.64 (3.83)]
[3.44 ± 0.71 (3.47)]
61.8 ± 6.1 (61)
52.9 ± 8.1 (51)
< 0.001
Triglycerides (mg/dl)
152.4 ± 27.4 (134)
163.1 ± 48.5 (154.5)
Female gender, n (%)
75 (70.8)
48 (44.4)
< 0.001
[mmol/l]
[1.72 ± 0.31 (1.51)]
[1.84 ± 0.55 (1.75)]
Hypertension, n (%)
96 (90.6)
54 (50)
< 0.001
Urea (mg/dl)
35.0 ± 10.5 (36)
38.7 ± 5.8 (38)
0.428
Diabetes mellitus, n (%)
20 (18.9)
2 (1.9)
< 0.001
Creatinine (mg/dl)
0.79 ± 0.18 (0.76)
0.83 ± 0.12 (0.80)
0.367
Current smoking, n (%)
30 (28.3)
22 (20.4)
Ejection fraction (%)
60.4 ± 2.5 (61.1)
61.6 ± 3.2 (62.4)
0.751
Patient characteristics Age, years
0.176
0.517
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Table 4. Multivariate analysis of predictors for coronary tortuosity
Table 3. Univariate analysis of predictors for coronary tortuosity OR (95% CI)
p-value
Predictor variables
OR (95% CI)
p-value
Age, years
3.275 (1.943–5.627)
< 0.001
Age, years
1.826 (1.354–2.167)
< 0.001
Diabetes mellitus, n (%)
2.539 (1.675–3.592)
< 0.001
Hypertension, n (%)
2.158 (1.462–2.937)
< 0.001
Hypertension, n (%)
2.856 (1.345–3.863)
< 0.001
Diabetes mellitus, n (%)
1.583 (1.362–2.835)
< 0.001
Female gender, n (%)
2.348 (1.857–4.362)
< 0.001
Plateletcrit
1.634 (1.345–2.724)
< 0.001
Plateletcrit
2.896 (1.964–4.857)
< 0.001
Neutrophil:lymphocyte ratio
1.854 (1.376–2.827)
0.001
Predictor variables
Discussion In this study, we investigated the association between CorT and PCT. Our results reveal that PCT, MPV, P-LCR, NLR and PLR of patients with CorT were higher than those of the control group consisting of patients with a normal coronary artery. Age, hypertension, diabetes mellitus and PCT were independently associated with CorT. CorT is a common coronary angiographic finding. In the study by Li, et al., the prevalence of CorT was 39.1% in patients with stable angina pectoris.3 To date the aetiology of CorT is unclear. There are several possible mechanisms implicated in the development of CorT. Some authors claim that degeneration of the elastin layer of the vessel may be the cause of coronary tortuosity.11 CorT may be associated with age, hypertension and atherosclerosis.12-14 In our study, CorT was independently associated with hypertension, diabetes mellitus, age and PCT. Li et al.3 found that CorT was positively correlated with essential hypertension. They hypothesised that the arteries may become tortuous due to reduced axial strain and hypertensive pressure in an elastic cylindrical arterial model. Therefore CorT may be one of the forms of artery remodelling induced by hypertension due to increased coronary pressure and blood flow. This is consistent with the findings of our study. We found a highly significant difference between the CorT and non-CorT groups regarding the presence of hypertension. However, some authors suggest that CorT is a common finding seen with aging and hypertension due to elongation and dilatation of the arteries associated with left ventricular hypertrophy.13,15 CorT may be related to typical anginal pain with angiographic evidence of objective ischaemia without significant coronary lesions. This could be due to compression of the vessel during heart contraction.14 CorT has a minor influence on coronary blood supply at rest, whereas during exercise, patients with CorT may lack the ability to adjust distal resistance sufficiently to compensate for the extra resistances generated by tortuosity, and this may further lead to an ineffective regulation of the blood supply.16 Li et al.17 found that CorT can result in decreased coronary blood pressure depending on the severity of tortuosity, and therefore severe CorT may cause myocardial ischaemia. In another study, Li et al.5 found that CorT was associated with reversible myocardial perfusion defects in patients with chronic stable angina and normal coronary angiograms. CorT is associated with coronary atherosclerotic changes regardless of the presence of actual coronary stenosis. CorT may induce subclinical atherosclerosis in the absence of significant obstructive lesions.18 Severe tortuosity in the coronary arteries simplifies atherosclerosis.19 Therefore atherosclerosis is more common in patients with coronary artery tortuosity, as greater curvature has more areas of low-shear wall stress. Shear stress is an essential causal factor in the development of atherosclerosis20
and in vulnerable plaque rupture.21 Davutoglu et al.22 found that CorT was strongly associated with subclinical atherosclerosis indicated by carotid intima–media thickness and retinal artery tortuosity. On the other hand, some studies found that CorT was negatively correlated with significant coronary artery disease detected by coronary angiography.3,23 Esfahani et al.24 showed that the mean Gensini index of the tortuous group was significantly lower than that of the non-tortuous group. Platelet activation plays a significant role in the initiation and progression of atherosclerosis.25,26 Platelets release many mediators such as thromboxanes, and interleukin (IL)-1, IL-3 and IL-6 that may lead to increased inflammation.27 PCT is part of the routine CBC haematology and provides more comprehensive data about total platelet mass because the PCT is the product of the platelet count and the MPV.28 Ekici et al.29 reported a strong association between MPV and angiographic severity of coronary artery disease. Several studies have shown that there was a strong relationship between PCT and saphenous vein disease and slow coronary flow.30,31 The association between haematological parameters and adverse cardiovascular outcomes has been shown in previous studies.32-35 In this study, we found that PCT, MPV, NLR and PLR of the CorT group were significantly higher than those of the control group. Hypertension, diabetes mellitus, age and PCT were independently associated with CorT. Our study has some limitations. First was the small sample size. Second, coronary angiography, which we used, only shows the arterial lumen, whereas cardiac computed tomography (CT) angiography and intravascular ultrasound (IVUS) allow visualisation of the lumen as well as the vascular wall. Cardiac CT and IVUS allow detection and characterisation of coronary atherosclerotic plaques. Accordingly, cardiac CT helps in the evaluation of atherosclerotic plaques that are undetected by conventional coronary angiography.
Conclusions This is the first study to evaluate the relationship between CorT and PCT. Hypertension, diabetes mellitus, age and PCT were independently associated with CorT. We concluded that CorT is associated with increased pro-inflammatory processes related to coronary artery disease. Long-term follow up of PCT levels in patients with CorT with regard to the development of coronary artery disease may be useful.
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et al. Platelet activation in patients after an acute coronary syndrome:
dial infarction. Clin Invest Med 2011; 34: 330.
results from the TIMI-12 trial: thrombolysis in myocardial infarction. J
11. Jakob M, Spasojevic D, Krogmann ON, Wiher H, Hug R, Hess OM. Tortuosity of coronary arteries in chronic pressure and volume overload. Cathet Cardiovasc Diagn 1996; 38: 25–31. 12. Pancera P, Ribul M, Presciuttini B, Lechi A. Prevalence of carotid artery kinking in 590 consecutive subjects evaluated by Echocolordoppler. Is there a correlation with arterial hypertension? J Intern Med 2000; 248: 7–12. 13. Del Corso L, Moruzzo D, Conte B, Agelli M, Romanelli AM, Pastine F, et al. Tortuosity, kinking, and coiling of the carotid artery: expression of atherosclerosis or aging? Angiology 1998; 49: 361–371. 14. Satish G, Nampoothiri S, Kappanayil M. Images in cardiovascular medicine. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations. Circulation 2008; 117: 477–478. 15. Hutchins GM, Bulkley BH, Miner MM, Boitnott JK. Correlation of age and heart weight with tortuosity and caliber of normal human coronary arteries. Am Heart J 1977; 94: 196–202. 16. Xie X, Wang Y, Zhu H, Zhou H, Zhou J. Impact of coronary tortuosity on coronary blood supply: a patient-specific study. PLoS One 2013; 8: e64564. doi: 10.1371/journal.pone.0064564. 17. Li Y, Shi Z, Cai Y, Feng Y, Ma G, Shen C, et al. Impact of coronary tortuosity on coronary pressure: numerical simulation study. PLoS One 2012; 7: e42558. doi: 10.1371/journal.pone.0042558.
Am Coll Cardiol 1999; 33: 634–639 27. Klinger MH, Jelkmann W. Role of blood platelets in infection and inflammation. J Interferon Cytokine Res 2002; 22: 913–922. 28. Ergelen M, Uyarel H. Plateletcrit: a novel prognostic marker for acute coronary syndrome. Int J Cardiol 2014; 177: 161. 29. Ekici B, Erkan AF, Alhan A, Sayın I, Aylı M, Töre HF. Is mean platelet volume associated with the angiographic severity of coronary artery disease? Kardiol Pol 2013; 71: 832–838. 30. Akpinar I, Sayin MR, Gursoy YC, Aktop Z, Karabag T, Kucuk E, et al. Plateletcrit and red cell distribution width are independent predictors of the slow coronary flow phenomeno. J Cardiol 2014; 63: 112–118. 31. Akpinar I, Sayin MR, Gursoy YC, Karabag T, Kucuk E, Buyukuysal MC, et al. Plateletcrit: a platelet marker associated with saphenous vein graft diseas. Herz 2014; 39: 142–148. doi: 10.1007/s00059-013-3798-y. 32. Aydınlı B, Demir A, Güçlü ÇY, Bölükbaşı D, Ünal EU, Koçulu R, et al. Hematological predictors and clinical outcomes in cardiac surgery. J Anesth 2016; 30: 770–778. doi: 10.1007/s00540-016-2197-y. 33. Durukan AB, Gurbuz HA, Unal EU, Tavlasoglu M, Durukan E, Salman N, et al. Role of neutrophil/lymphocyte ratio in assessing the risk of postoperative atrial fibrillation. J Cardiovasc Surg (Torino) 2014; 55: 287–293. 34. Unal EU, Ozen A, Kocabeyoglu S, Durukan AB, Tak S, Songur M,
18. El Tahlawi M, Sakrana A, Elmurr A, Gouda M, Tharwat M. The
et al. Mean platelet volume may predict early clinical outcome after
relation between coronary tortuosity and calcium score in patients
coronary artery bypass grafting. J Cardiothorac Surg 2013; 8: 91. doi:
with chronic stable angina and normal coronaries by CT angiography. Atherosclerosis 2016; 246: 334–337. doi: 10.1016/j.atherosclerosis.2016.01.029. 19. Cunningham KS, Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 2005; 85: 9–23.
10.1186/1749-8090-8-91. 35. Unal EU, Durukan AB, Ozen A, Kubat E, Kocabeyoğlu SS, Yurdakok O, et al. Neutrophil/lymphocyte ratio as a mortality predictor following coronary artery bypass surgery. Turk Gogus Kalp Dama 2013; 21: 588–593. doi: 10.5606/tgkdc.dergisi.2013.8210.
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The effect of iloprost and sildenafil, alone and in combination, on myocardial ischaemia and nitric oxide and irisin levels Suna Aydin, Tuncay Kuloglu, Suleyman Aydin, Meltem Yardim, Davut Azboy, Zeki Temizturk, Ali Kemal Kalkan, Mehmet Nesimi Eren
Abstract Aim: Insufficient oxygen supply to organs and tissues due to reduced arterial or venous blood flow results in ischaemia, during which, although ATP production stops, AMP and adenosine continue to be produced from ATP. The fate of irisin, which causes the production of heat instead of ATP during ischaemia, is unknown. Iloprost and sildenafil are two pharmaceutical agents that mediate the resumption of reperfusion (blood supply) via vasodilatation during ischaemic conditions. Our study aimed to explore the effects of iloprost and sildenafil on irisin levels in the heart, liver and kidney tissues and whether these pharmaceutical agents had any impact on serum irisin and nitric oxide levels in rats with induced experimental myocardial ischaemia. Methods: The study included adult male Sprague-Dawley rats aged 10 months and weighing between 250 and 280 g. The animals were randomly allocated to eight groups, with five rats in each group. The groups were: sham (control), iloprost (ILO), sildenafil (SIL), ILO + SIL, myocardial ischaemia (MI), MI + ILO, MI + SIL and MI + ILO + SIL. The treatment protocols were implemented before inducing ischaemia, which was done by occluding the left coronary artery with a plastic ligature for 30 minutes. Following the reperfusion procedure, all rats were
Department of Cardiovascular Surgery, Elazig Education and Research Hospital, Health Science University, Elazig, Turkey
sacrificed after 24 hours, and their heart, liver and kidney tissues and blood samples were collected for analyses. An immunohistochemical method was used to measure the change in irisin levels, the ELISA method to quantify blood irisin levels, and Griess’ assay to determine nitric oxide (NO) levels in the serum and tissue. Myocardial ischaemia was confirmed based on the results of Masson’s trichrome staining, as well as levels of troponin and creatine kinase MB. Results: Irisin levels in biological tissue and serum dropped statistically significantly in the ischaemic group (MI), but were restored with ILO and SIL administration. Individual SIL administration was more potently restorative than individual ILO administration or the combined administration of the two agents. NO level, on the other hand, showed the opposite tendency, reaching the highest level in the MI group, and falling with the use of pharmaceutical agents. Conclusions: Individual or combined administration of ILO and SIL reduced myocardial ischaemia and NO levels, and increased irisin levels. Elevated levels of irisin obtained by drug administration could possibly contribute to accelerated wound recovery by local heat production. Sildenafil was more effective than iloprost in eliminating ischaemia and may be the first choice in offsetting the effects of ischaemia in the future. Keywords: iloprost, sildenafil, nitric oxide, irisin, myocardial ischaemia–reperfusion Submitted 2/11/16, accepted 25/4/17
Suna Aydin, MD, cerrah52@hotmail.com Davut Azboy, MD Zeki Temizturk, MD
Published online 31/8/17
Department of Anatomy, School of Medicine, Firat University, Elazig, Turkey
DOI: 10.5830/CVJA-2017-025
Suna Aydin, MD
Myocardial ischaemia impairs the function and survival of cardiac myocytes. Current treatment for this condition is elimination of ischaemia.1 Although the use of coronary dilator anti-aggregatory medications to various degrees is the treatment of choice in the elimination of ischaemia,2,3 surgical coronary bypass methods are also used, as laid down in treatment guidelines.4-6 Additionally, iloprost is the first line of treatment in occlusions seen in peripheral artery disease.7 Iloprost (ILO) is an eicosanoid pharmaceutical agent from the prostacyclin group.8 Currently, it is clinically used to unblock occluded vessels.9,10 ILO exercises its vasodilatory effect by preventing platelet aggregation.8,11 Another vasodilatory agent that acts via nitric oxide (NO) is sildenafil (SIL).12 NO levels increase during ischaemia.13 During reperfusion, NO levels are elevated,13 caused by the vasodilator effect of SIL.14 The increased NO levels combine with a superoxide radical (O2-) to
Department of Histology and Embryology, School of Medicine, Firat University, Elazig, Turkey Tuncay Kuloglu, MD
Department of Medical Biochemistry (Firat Hormones Research Group), School of Medicine, Firat University, Elazig, Turkey Suleyman Aydin, PhD Meltem Yardim, MD
Department of Cardiology, Education and Research Hospital, Istanbul, Turkey Ali Kemal Kalkan, MD
Department of Cardiovascular Surgery, School of Medicine, Dicle University, Diyarbakir, Turkey Mehmet Nesimi Eren, MD
Cardiovasc J Afr 2017; 28: 389–396
www.cvja.co.za
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form a toxic oxygen metabolite, peroxynitrite (ONOO-), which causes damage in the tissues.15,16 Therefore, elucidation of the changes in NO levels caused by the administration of ILO and SIL, which were used for the reperfusion of tissues, could help explain the mechanisms underlying this process. At present, sildenafil is employed to correct erectile dysfunction.12 Since it acts as a vasodilator, it can serve as a therapeutic agent during ischaemia.14 Vasodilatation enhances oxygenation and therefore mediates in the elimination of ischaemia and increases adenosine triphosphate (ATP) formation. It is established that aerobic ATP formation is blocked in hypoxic states. Therefore, ischaemia leads to a decrease in ATP production.17 Another molecule that causes a reduction in ATP levels is irisin.18,19 By increasing the amount of uncoupling proteins, this molecule leads to the release of heat rather than ATP from molecules.18 Since ILO,7 used in ischaemic peripheral artery disease, and SIL,12 used in erectile dysfunction, increase oxygenation through vasodilatation, the tissues recovered from ischaemia would theoretically be expected to have elevated ATP levels. On the other hand, in the presence of irisin, heat production would increase through uncoupling of proteins and cause a decrease in ATP production.18,19 Therefore there seems to be an obvious correlation between the treatment of ischaemic tissue with ILO and SIL, and irisin levels. Furthermore, myocardial ischaemia does not only affect heart tissue. It was reported in previous studies that myocardial ischaemia could directly impact on kidney tissue,20 which is an excretory organ, and the liver,21 where glycogenesis takes place. In addition, there is an increased need for energy (glucose) during ischaemic conditions. It was reported that irisin inhibited glycogenesis, or impeded the production of glucose.22 Therefore the aim of this study was to determine the change in irisin level in tissues with increased energy needs under ischaemic conditions. Our principal objectives were to explore (1) whether ILO and SIL played a part in recovery after myocardial injury and how they changed irisin expression in experimentally induced myocardial ischaemia–reperfusion; (2) whether ILO, SIL, or a combination of both were more efficient in the treatment of ischaemic injury; (3) how NO levels were altered in response to these therapeutic agents; (4) whether irisin, which causes metabolisation of ATP, was down- or upregulated in tissues with an increased need for ATP, as in the case of ischaemia; and (5) how ILO and SIL treatment affected irisin expression in heart, liver and kidney tissues under ischaemic conditions.
Methods All protocols of the animal experiments were approved (date 5.2.2014, decision no: 35) by the Animal Ethics Committee (FUAEC) in accordance with the policy of the European convention for the protection of vertebrate animals. The study included adult male Sprague-Dawley rats aged 10 months and weighing between 250 and 280 g. The rats were randomly divided into the following groups: control group (sham: no procedure to be applied, only physiological serum administered), ILO, SIL, ILO + SIL, myocardial ischaemia (MI), MI + ILO, MI + SIL and MI + ILO + SIL. Each group contained five rats. Ischaemia was induced by left coronary artery ligation, as described previously.23 In rat experiments, sildenafil citrate (Viagra) is usually used in the 1–2.5-mg/kg dose range,24,25 and
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ILO in the 0.2–2-μg/kg range.26,27 In this study, 2 mg/kg sildenafil citrate was administered to the SIL group and 1 μg/kg to the ILO group via the intraperitoneal route before the induction of ischaemia–reperfusion, as described previously by Harada et al.28 A 30-minute occlusion was then induced using a plastic ligature, as described previously.29 After the ligature was released, blood flow was visually confirmed. All rats were sacrificed at 24 hours following the reperfusion procedure. Blood samples were collected as described for previous experiments,30 centrifuged at 4 000 rpm and stored at –80°C until the irisin analysis. Glucose, creatine kinase (CK), creatine kinase MB (CKMB) and troponin I on the other hand, were analysed without delay on an auto-analyser. Heart, liver and kidney tissue was fixed in 10% formaldehyde solution and stored for immunohistochemical analysis. The remaining heart, liver and kidney tissue, after the wet weight was determined, were homogenised and the supernatants were stored at –80°C for NO analysis. As its half life is short, it is difficult to directly analyse NO. For NO measurements, its stable end-products, nitrite and nitrate, are quantified in tissues with a spectrophotometric method. This method is based on the principle of measuring the absorbance at 545 nm of the complex formed when nitrate is reduced to nitrite in the presence of nitrate reductase enzyme, and the resulting nitrite reacts with sulfanylamide and N-ethylendiamin.31 Serum irisin levels were determined using the ELISA method, following the catalogue guidelines provided by the manufacturing firm.32 The kit was reported to have a minimum irisin detection limit of 1.29 ng/ml and minimal cross-reactivity (~9%) with fibronectin type III domain-containing protein 5 (FNDC5). In our laboratory results, we found an intra-assay value of 8% and inter-assay value of 10%. Histopathological examinations were carried out using the triphenyl tetrazolium chloride method to identify the damage to the myocardium and other tissues, as described previously.23 Myocardial injury was assessed according to the semi-quantitative method of Miller et al.33 The Abc immunohistochemical method of Hsu et al.34 was used to determine the distribution of irisin expression in the myocardium and other tissues.34
Statistical analysis The extent of the damage in the myocardium and other tissues was determined using the Student’s t-test. SPSS 22 software was employed in all statistical analyses. Level of statistical significance was determined at a p-value of 0.05.
Results Masson’s trichrome staining results under light microscopy showed that the heart tissue of the control group had a normal appearance (Fig. 1A). The MI group, however, showed an increase in inflammatory cells (black arrow), congestion (red arrow), impairment of tissue integrity and oedema (Fig. 1B). Data from the statistical analysis of histopathological changes in the MI group are given in Table 1. Evaluation under the light microscope of immunohistochemical staining revealed irisin immunoreactivity in the muscle cells of the cardiac tissue (black arrow). The control (Fig. 2A), ILO (Fig. 2B), SIL (Fig. 2C) and ILO + SIL (Fig. 2D) groups had similar irisin immunoreactivity. Compared to the control group,
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A
391
B
Fig. 1. I schaemic and control heart tissues after Masson’s trichrome staining. The ischaemic group shows an increase in inflammatory cells (black arrow), congestion (red arrow), impairment of tissue integrity and oedema (black asterisk).
A
B
C
D
E
F
G
H
I
Fig. 2. I risin immunoreactivity in the heart tissues with iloprost (ILO) and sildenafil (SIL) administration in cardiac ischaemia (MI) induced by left coronary artery ligation. Control (A), ILO (B), SIL (C), ILO + SIL (D), MI + ILO (F), MI + SIL (G), MI + ILO + SIL (H), and negative control; no irisin immunoreactivity (I).
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the MI group (Fig. 2E) had statistically significantly reduced irisin immunoreactivity (p < 0.05). Relative to the MI group, MI + ILO (Fig. 2F), MI + SIL (Fig. 2G) and MI + ILO + SIL (Fig. 2H) all showed elevated irisin immunoreactivity, similar to that of the control group. Irisin immunoreactivity (black arrow) was also observed in the hepatocytes of the liver tissue in all groups. Irisin immunoreactivity was similar in the control (Fig. 3A), ILO (Fig. 3B), SIL (Fig. 3C) and ILO + SIL (Fig. 3D) groups. However, relative to the control group, the MI group had statistically significantly reduced irisin immunoreactivity (p < 0.05), while the MI + ILO (Fig. 3F), MI + SIL (Fig. 3G) and MI Table 1. Histological scores in the heart tissue of rats with induced cardiac ischaemia Inflammatory cells Control MI
0 ± 00
Congestion Fibrosis 0 ± 00
0 ± 00
Oedema
Tissue integrity
0 ± 00
0 ± 00
2.33 ± 0.51a 2.50 ± 0.83a 0 ± 00 3.16 ± 0.40a 2.83 ± 0.98a
Necrosis 0 ± 00 0 ± 00
MI: myocardial ischaemia–reperfusion; aIn comparison with the control group, p < 0.05.
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+ ILO + SIL (Fig. 3H) groups had significantly increased irisin immunoreactivity, similar to that in the control group. Examination under the light microscope of immunohistochemical staining to detect irisin immunoreactivity showed that the tubule cells in the renal cortex of the kidney of all groups had irisin immunoreactivity (black arrow). Irisin immunoreactivity was similar in the control (Fig 4A), ILO (Fig. 4B), SIL (Fig. 4C) and ILO + SIL (Fig. 4D) groups. In comparison with the control group, the MI (Fig. 4E) group had a statistically significant decrease in irisin immunoreactivity (p < 0.05). However, the MI + ILO (Fig. 4F), MI + SIL (Fig. 4G), MI + ILO + SIL (Fig. 4H) had a significantly higher irisin immunoreactivity. Table 2 summarises the histological scores of irisin immunoreactivity in all tissues and groups. When serum irisin levels in the ischaemic group were compared to those of the control group, they were found to be significantly lower than the controls. However, the groups to which ILO and SIL were administered, either individually or in combination, had elevated serum irisin levels. Serum irisin levels of the control group and the groups administered ILO and SIL before MI induction were statistically similar.
A
B
C
D
E
F
G
H
I
Fig. 3. I risin immunoreactivity after iloprost (ILO) and sildenafil (SIL) administration to hepatic tissues with cardiac ischaemia. Control (A), ILO (B), SIL (C), ILO + SIL (D), MI + ILO (F), MI + SIL (G), MI + ILO + SIL (H) and negative control; no irisin immunoreactivity (I).
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Furthermore, CK, CKMB, troponin I and NO values measured in the study increased with ischaemia. In addition to the histological findings presented above, elevated CK, CKMB and troponin I levels provided further confirmation of the induction of ischaemia with left coronary artery ligation in this animal experiment (Table 3). A comparison of serum and heart tissue NO levels between the ischaemic and control groups demonstrated that the
former had statistically significantly higher NO levels (Table 3). However, groups to which ILO and SIL were administered, either individually or in combination after the induction of ischaemia, had lower serum and heart tissue irisin levels. NO levels in the serum and heart tissue of the control group and groups administered ILO and SIL before MI induction were statistically similar. Table 3. Changes in the levels of CK, CKMB, troponin I, NO and irisin in serum of rats administered iloprost (ILO) and sildenafil (SIL) for cardiac ischaemia
Table 2. The histological scores pertinent to irisin immunoreactivity in all tissues and groups
CK (IU/l)
CKMB (IU/l)
Troponin 1 (ng/ml)
NO (μmol)
Irisin (ng/ml)
Heart
Liver
Kidney
Groups
Control
0.83 ± 0.12
0.69 ± 0.15
0.72 ± 0.15
Control
ILO
0.78 ± 0.09
0.82 ± 0.24
0.75 ± 0.17
ILO
SIL
0.74 ± 0.13
0.78 ± 0.18
0.76 ± 0.15
SIL
6.9 ± 1
0.00 ± 0
ILO + SIL
0.75 ± 0.12
0.61 ± 0.12
0.65 ± 0.15
ILO + SIL
7.1 ± 2
0.00 ± 0
MI
0.24 ± 0.05a
0.28 ± 0.07a
0.26 ± 0.05a
MI
648 ± 146a
118 ± 54
4.8 ± 9a
135 ± 26
9 ± 2.6a
MI + ILO
0.76 ± 0.15b
0.77 ± 0.12b
0.61 ± 0.17b
MI + ILO
594 ± 116b
82 ± 18b
3.9 ± 8b
96 ± 24
7.6 ± 2.6b
MI + SIL
0.85 ± 0.05b
0.68 ± 0.10b
0.82 ± 0.13b
MI + SIL
416 ± 119b
64 ± 17b
3.1 ± 8b
62 ± 11
6.3 ± 2.4
MI + ILO + SIL
0.73 ± 0.15b
0.70 ± 0.14b
0.64 ± 0.08b
MI + ILO + SIL
577 ± 133b
77 ± 17b
3.4 ± 9b
69 ± 12
6.9 ± 2.6b
In comparison with the control group, bin comparison with the MI group, p < 0.05.
a
6±1
0.00 ± 0
0.01 ± 0
34 ± 7
16.1 ± 1.7
6.5 ± 1
0.02 ± 0
0.01 ± 0
41 ± 9
14.9 ± 2.9
0.00 ± 0
29 ± 6
15.8 ± 2.7
0.00 ± 0
31 ± 6
16.2 ± 08
In comparison with the control group, bin comparison with the MI group, p < 0.05
a
A
B
C
D
E
F
G
H
I
Fig. 4. I risin immunoreactivity after iloprost (ILO) and sildenafil (SIL) administration to renal tissues with cardiac ischaemia. Control (A), ILO (B), SIL (C), ILO + SIL (D), MI + ILO (F), MI + SIL (G), MI + ILO + SIL (H) and negative control; no irisin immunoreactivity (I).
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Table 4. Nitric oxide (μmol/g wet weight) changes in the heart, hepatic and kidney tissue supernatants of rats administered iloprost (ILO) and sildenafil (SIL) in myocardial ischaemia–reperfusion (MI) Heart
Liver
Kidney
Control
76 ± 17
54 ± 11
24 ± 7
ILO
85 ± 16
61 ± 13
32 ± 8
SIL
69 ± 14
48 ± 9
19 ± 6
ILO + SIL
71 ± 12
56 ± 10
22 ± 5
MI
248 ± 46a
125 ± 29a
106 ± 19a
MI + ILO
186 ± 32b
82 ± 18b
73 ± 18b
MI + SIL
106 ± 18b
64 ± 17b
41 ± 9b
MI + ILO + SIL
119 ± 21
77 ± 17
59 ± 10b
b
b
In comparison with the control group, bin comparison with the MI group, p < 0.05.
a
Table 4 summarises NO changes in the heart, liver and kidney tissue supernatants of rats administered ILO and SIL in myocardial ischaemia–reperfusion. There was a negative correlation between serum NO (r = –0.73; p < 0.005) and serum irisin levels (r = –0.52; p < 0.005) of the groups, and positive correlations between the serum and tissue NO levels (r = 0.64; p < 0.005) and myocardial infarct markers [CK (r = 0.49; p < 0.005), CKMB (r = 0.56; p < 0.005) and troponin I (r = 0.66; p < 0.005)]. These correlations either disappeared or were reversed with the administration of ILO and SIL.
Discussion Disruption of the arterial or venous blood flow in biological systems (hypoxia) causes inadequate perfusion of the organ or tissues, resulting in generalised cell injury or cell death.5 Ischaemia–reperfusion injury in the heart tissue causes myocardial stunning, reperfusion arrhythmias, necrosis in the myocytes, as well as coronary endothelial and microvascular dysfunction.29 Ischaemia–reperfusion injury in the heart also affects the renal tissues,20 and the hepatic tissues where gluconeogenesis takes place.21 In this study, ischaemia was induced by left coronary artery ligation, and the roles of ILO and SIL in tissue reperfusion, and their effect on the fate of irisin, which functions in heat regulation, were examined. The induction of ischaemia by left coronary artery ligation was confirmed by Masson’s trichrome staining of the heart tissue. Light microscopy of the cells showed that the control heart tissues had a normal appearance, while the MI group was characterised by an increase in inflammatory cells, congestion, impairment of tissue integrity and oedema. This resulted from the interruption of ATP production. However, since ATP catabolism continues, AMP and adenosine were formed from ATP. The depletion of cellular energy reserves and the accumulation of toxic metabolites due to ischaemia led to an increase in inflammatory cells, congestion, and finally cell death.35 The presence of ischaemia was also confirmed by the levels of CK, CKMB and troponin I, which increased dramatically during myocardial ischaemia, compared to the control levels. The levels of CK, CKMB and troponin I in our study were similar to those found in previous animal studies, where myocardial ischaemia was induced with isoproterenol.35 When irisin levels in the ischaemic groups were compared to those in the control group, irisin was statistically significantly lower in the serum, and individual or combined administration of ILO and SIL restored irisin serum concentrations. The ischaemia-associated decrease in irisin concentrations in
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biological systems may be attributed to increased demand for ATP in the tissues, as irisin elevates the levels of uncoupling proteins, which in turn causes increased heat production in the cells, rather than increased ATP production.18,19,36 However, there is a need for much greater amounts of ATP to reduce the amount of cell injury and death resulting from hypoxia.17 Therefore the heart, liver and kidney tissues may have limited their irisin production for the purposes of encouraging cells to produce ATP instead of heat. The decrease in ATP levels during this period indicates that the increase in inflammatory cells, congestion, impairment of tissue integrity and oedema provoked the development of rigor-type contracture.35 In the case of ischaemia-associated coronary endothelial dysfunction, the vasodilator response is reduced because the increase in endothelin-1 level, a potent vasoconstrictor, which is formed in the process, causes vasoconstriction and leads to a decrease in blood flow.37 In this context, administration of ILO and SIL to the rats individually or in combination enhanced the blood flow by vasodilatation, ensuring re-oxygenation of the cells, and hence increased irisin synthesis. Energy production of the cells during re-oxygenation is probably kept under strict control by irisin (considered as the decisive molecule at the stage of heat or ATP production) via regulation of the flow of oxygen in the electron transport chain in the mitochondrial organ, depending on the need for ATP. Otherwise, the entry of high doses of molecular oxygen into the cell would increase free oxygen radical (FOR) derivatives and cause reperfusion damage.38 This is because about 1–4% of the oxygen intake is used for superoxide anion production and about 20% of the produced superoxide anions is channelled to the cells. This is believed to be directly related to the production of energy molecules or ATP by the cells. Limited irisin production in biological tissues causes a reduction in serum irisin levels. Given that the source of serum irisin is biological tissue, the decrease in irisin synthesis by the tissues is reflected in serum irisin levels. These data not only support the finding of reduced irisin levels in MI induced by ISO,35 but also are consistent with the MI results provided by Aydin et al. in saliva, and by Emanuele et al.39,40 In our study, ischaemia induced by left coronary artery ligation caused ischaemia–reperfusion injury, not only in the heart, but also in the liver and kidneys. Ischaemic damage inflicted on the liver and kidneys, as in damage to the heart tissue, was reduced by the administration of ILO or SIL, or their combination, relative to the group not administered any drug, and the administration of these drugs also elevated the irisin levels in these tissues. ILO is thought to restore ischaemic injury in the liver and kidneys via its anti-platelet, cytoprotective and fibrinolytic action, and vasodilator effect, while SIL, a specific phosphodiesterase type 5 (PDE 5) inhibitor, is believed to reduce ischaemic injury via its vasodilator effect mediated by NO.41 Administration of SIL alone was found to be more effective in reducing ischaemic injury than ILO alone or the combination of both agents. The possible mechanism underlying the potency of SIL is that since it uses NO, the NO produced during ischaemia is reduced in the presence of SIL. Had NO not been depleted or reduced, it would have combined with the superoxide (O2-) radical produced during reperfusion to form peroxynitrite (ONOO-), a toxic oxygen metabolite, and the resulting ONOO- could have caused damage to the tissues.15,16 Therefore, a possible reason why
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SIL was slightly superior to ILO in treating ischaemic injury was that it reduced or depleted the NO formed during ischaemia, as SIL enhances NO-mediated vasodilatation. In our study, individual administration of SIL (resulting in the lowest NO levels) and combined administration of ILO and SIL were observed to cause a decrease in NO levels in comparison to that found in the ILO alone and ischaemic groups (which had the highest NO levels). Therefore, we believe that this biochemical feature of SIL could be used to eliminate ischaemia–reperfusion injury in the future. Irisin may contribute to the acceleration of wound recovery, since heat speeds up chemical reactions and enables rapid production of the proteins involved in wound healing, thus promoting rapid recovery. It has recently been reported that wound healing of human umbilical vein endothelial cells (HUVEC) was gradually accelerated in groups treated with 10 and 20 nM irisin at both 12 and 24 hours, via increasing migration and tube formation.42 The administration of both drugs in combination did not prove more effective than the individual administration of each. However, when individual administrations of ILO and SIL were compared to one another, SIL was found to be more potent in circumventing ischaemia. One explanation why SIL was more efficient in ischaemia treatment may be that since it is an NO-dependent agent, it can deplete NO arising from ischaemia and therefore reduce the amount of peroxinitrite originating from NO and causing tissue injury.43
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Aydin S, Aydin S, Nesimi Eren M, Sahin I, Yilmaz M, Kalayci M, et al. The cardiovascular system and the biochemistry of grafts used in heart surgery. Springerplus 2013; 2: 612.
7.
Smith FC, Tsang GM, Watson HR, Shearman CP. Iloprost reduces peripheral resistance during femoro-distal reconstruction. Eur J Vasc Surg 1992; 6(2): 194–198.
8.
Pace-Asciak CR. Novel eicosanoid pathways: the discovery of prostacyclin/6-keto prostaglandin F1alpha and the hepoxilins. Mol Neurobiol 2005; 32(1): 196.
9.
Kecskér A, Blitstein-Willinger E. Pharmacological activity and local and systemic tolerance of topically applied iloprost. Arzneimittelforschung 1993; 43(4): 450–454.
10. Roy S, Brosstad F, Sakariassen KS. Selective thrombolysis in acute deep vein thrombosis: evaluation of adjuvant therapy in vivo. Cardiovasc Intervent Radiol 1999; 22 (5): 403–410. 11. Arslan M, Donmez T, Erer D, Tatar T, Comu FM, Alkan M. Effect of iloprost on erythrocyte deformability in rat’s lower extremity undergoing an ischemia reperfusion injury. Bratisl Lek Listy 2013; 114(4): 189–191. 12. Lagoda G, Jin L, Lehrfeld TJ, Liu T, Burnett AL. FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms. J Sex Med 2007; 4(4 Pt 1): 908–916. 13. Liu K, Yan M, Zheng X, Yang Y. The dynamic detection of NO during
Conclusion
the ischemic postconditioning against global cerebralischemia/reperfusion injury. Nitric Oxide 2014; 38: 17–25.
In this experimentally induced animal myocardial ischaemia model, administration of ILO and SIL reduced both ischaemia and the release of NO, while elevating irisin levels. Our study showed that even though SIL and ILO have not been routinely used in the management of myocardial ischaemia–reperfusion, both drugs are critical pharmaceutical agents in eliminating tissue ischaemia. Further clinical studies are necessary on patients to elucidate this phenomenon.
14. Beck-Broichsitter M, Hecker A, Kosanovic D, Schmehl T, Gessler T,
This project was supported by the protocol number TF-1508 of the scientific
17. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of
Weissmann N, et al. Prolonged vasodilatory response to nanoencapsulated sildenafil in pulmonary hypertension. Nanomedicine 2016; 12(1): 63–68. 15. Ronson RS, Nakamura M, Vinten-Johansen J. The cardiovascular effects and implications of peroxynitrite. Cardiovasc Res 1999; 44(1): 47–59. 16. Beckman JS. -OONO: rebounding from nitric oxide. Circ Res 2001; 89(4): 295–297.
research unit of Fırat University, to whom we would like to extend out thanks
ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012; 298: 229–317.
for their support. This study was orally presented at the 14th Congress of the
18. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A
Turkish Society of Cardiovascular Surgery held in Antalya, Turkey, from 3–6
PGC1-α-dependent myokine that drives brown-fat-like development of
November 2016.
white fat and thermogenesis. Nature 2012; 11(7382): 463–468. 19. Aydin S. Three new players in energy regulation: preptin, adropin and
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969–985. 39. Aydin S, Aydin S, Kobat MA, Kalayci M, Eren MN, Yilmaz M, et al. Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology. Peptides 2014; 56: 141–145. 40. Emanuele E, Minoretti P, Pareja-Galeano H, Sanchis-Gomar F,
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(Abc) in immunoperoxidase techniques – a comparison between Abc
Joint congress in Khartoum, Sudan
Prof Fausto Pinto (Portugal) former European Society of Cardiology president front left with Prof Elijah Ogola (Kenia)
There are more pyramids in Sudan than in Egypt! Please refer to the congress text on page 408
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Review Article The effect of lifestyle interventions on maternal body composition during pregnancy in developing countries: a systematic review Estelle D Watson, Shelley Macaulay, Kim Lamont, Philippe J-L Gradidge, Sandra Pretorius, Nigel J Crowther, Elena Libhaber
Abstract Optimal maternal body composition during pregnancy is a public health priority due to its implications on maternal health and infant development. We therefore aimed to conduct a systematic review of randomised, controlled trials, and case–control and cohort studies using lifestyle interventions to improve body composition in developing countries. Of the 1 708 articles that were searched, seven studies, representing three countries (Brazil, Iran and Argentina), were included in the review. Two articles suggested that intervention with physical activity during pregnancy may significantly
reduce maternal weight gain, and five studies were scored as being of poor quality. This systematic review highlights the lack of research within developing countries on lifestyle interventions for the management of excessive weight gain during pregnancy. Similar reviews from developed countries demonstrate the efficacy of such interventions, which should be confirmed using well-designed studies with appropriate intervention methods in resource-limited environments. Keywords: diet, physical activity, pregnancy, obesity, gestational weight gain Submitted 29/9/16, accepted 2/1/17 Published online 24/8/17 Cardiovasc J Afr 2017; 28: 397–403
Centre for Exercise Science and Sports Medicine, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Estelle D Watson, PhD, estelle.watson@wits.ac.za Philippe J-L Gradidge, PhD, MSc (Med)
MRC/Wits Developmental Pathways of Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Estelle D Watson, PhD Shelley Macaulay, MSc (Med) (Human Genetics), MSc (Med) (Genetic Couselling), BSc (Hons)
Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa Shelley Macaulay, MSc (Med) (Human Genetics), MSc (Med) (Genetic Couselling), BSc (Hons)
Soweto Cardiovascular Research Unit, University of the Witwatersrand, Johannesburg, South Africa Kim Lamont, PhD, MSc (Med), MPhil (Med) (IP Law) Sandra Pretorius, PhD
Department of Chemical Pathology, National Heath Laboratory Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Nigel J Crowther, PhD
School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Elena Libhaber, PhD
www.cvja.co.za
DOI: 10.5830/CVJA-2017-003
Both developed and developing countries are experiencing a rapid increase in the prevalence of obesity, which places affected individuals at an increased risk for a number of different diseases, including hypertension, diabetes, heart disease, asthma and cancer.1,2 The World Health Organisation (WHO) estimated that in 2005 there were approximately 1.6 billion adults (aged 15 years and over) globally who were overweight and at least 400 million adults who were obese.3 Especially alarming is the high prevalence of overweight and obesity among women of childbearing age in both developed and developing countries. Around 12 to 38% of pregnant women in developed countries,5 and 8 to 26% of pregnant women in developing countries4,6 are reported to be overweight or obese. Obesity during pregnancy is associated with an increased risk for maternal and neonatal complications. The associated adverse maternal effects of obesity during pregnancy include miscarriage, pre-eclampsia, gestational diabetes mellitus, infection, venous thromboembolism and haemorrhage.7 The foetal risks associated with maternal obesity include stillbirths and neonatal deaths, preterm births, congenital abnormalities and macrosomia.8 Long-term effects of maternal obesity on the offspring have also been observed and include increased risks of childhood and adolescent obesity, and diabetes and cardiovascular disease in adult life.9
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Both under- and overweight pose a risk to the mother and child during and after birth.10 It is therefore important to carefully manage weight gain during pregnancy with dietary intake of a sufficient level to ensure proper foetal nutrition,11 but avoiding excessive maternal weight gain. The use of lifestyle interventions to attenuate such weight gain during pregnancy has been the focus of many studies in the developed world, with a recent systematic review of 88 studies, involving 182 139 women, showing that maternal weight control during pregnancy via diet, exercise or a mix of these methods is safe and improves both maternal and foetal outcomes.12 However, no similar analysis of such data from the developing world is currently available. The health risks of maternal obesity and excessive gestational weight gain to the mother and baby pose significant demands on the healthcare system, with an increased need for additional resources in both primary and secondary care settings.11,13 This is particularly true in developing countries where insufficient resources exist to meet these extra demands on the public health system, and where obesity is already prevalent. It is therefore important to develop cost-effective interventions to reduce maternal obesity in such environments. In an attempt to determine the effectiveness of maternal lifestyle interventions in resource-limited environments, we conducted a systematic review of the literature on weight-management protocols for pregnant females, undertaken in developing countries. Table 1. Search terms Search 1
Pregnancy AND obesity AND diet AND developing countries
Search 2
Pregnancy AND obesity AND nutrition AND developing countries
Search 3
Pregnancy AND obesity AND physical activity AND developing countries
Search 4
Pregnancy AND obesity AND exercise AND developing countries
Search 5
Pregnancy AND overweight AND diet AND developing countries
Search 6
Pregnancy AND overweight AND nutrition AND developing countries
Search 7
Pregnancy AND overweight AND physical activity AND developing countries
Search 8
Pregnancy AND overweight AND exercise AND developing countries
Search 9
Pregnancy AND obesity AND diet AND middle-income countries
Search 10 Pregnancy AND obesity AND nutrition AND middle-income countries Search 11 Pregnancy AND obesity AND physical activity AND middle-income countries Search 12 Pregnancy AND obesity AND exercise AND middle-income countries Search 13 Pregnancy AND overweight AND diet AND middle-income countries Search 14 Pregnancy AND overweight AND nutrition AND middle-income countries Search 15 Pregnancy AND overweight AND physical activity AND middleincome countries Search 16 Pregnancy AND overweight AND exercise AND middle-income countries Search 17 Pregnancy AND obesity AND diet AND low-income countries Search 18 Pregnancy AND obesity AND nutrition AND low-income countries Search 19 Pregnancy AND obesity AND physical activity AND low-income countries Search 20 Pregnancy AND obesity AND exercise AND low-income countries Search 21 Pregnancy AND overweight AND diet AND low-income countries Search 22 Pregnancy AND overweight AND nutrition AND low-income countries Search 23 Pregnancy AND overweight AND physical activity AND low-income countries Search 24 Pregnancy AND overweight AND exercise AND low-income countries
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Methods Five electronic databases were searched; these included Public/ Publisher MEDLINE (PubMed), SCOPUS, a bibliographic database containing abstracts and citations for academic journal articles, Biomed Central, the Cochrane Library and the Cumulative Index to Nursing and Allied Health (CINHAL). Twenty-four search terms, with varying combinations, encompassing pregnancy, obesity/overweight, diet/nutrition, physical activity and developing countries (Table 1), were used. The search included all articles published up to 4 December 2013. No filters were set, in order to obtain articles in all languages and all types of documents. Randomised, controlled trials (RCTs), caseâ&#x20AC;&#x201C;control studies and cohort studies that were performed in developing countries and which investigated overweight/obesity in pregnant women and/or lifestyle interventions during pregnancy were considered eligible. Investigations performed in developing countries and the following types of studies were not eligible for inclusion: reviews, position statements/guidelines, reports, epidemiological studies, observational studies and prevalence studies. The literature search was performed independently by two authors, Shelley Macaulay (SM) and Estelle Watson (EW). The search results obtained from each of the five electronic databases were pooled and duplicates were removed. At the first step, titles were screened for eligibility. Following this, the abstracts of those that were considered eligible were then obtained and read. Fulltext articles of the abstracts that fulfilled the inclusion criteria were then obtained and read. In addition, the reference lists of appropriate full-text articles were hand-searched for further relevant articles. Data were extracted from the full-text articles by four of the reviewers: Phillipe Gradidge (PG), Elena Libhaber (EL), EW and SM. For each included article, data were extracted for country, region, sample size, gestational age, BMI, intervention details and outcomes. The quality of each included article was assessed by three authors (EW, PG and EL) using the Cochrane Risk of Bias Tool (Cochrane, 2011). In accordance with the risk-assessment checklist, each study was assessed on: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other threats to validity. The studies were classified as being good, average or poor quality based on how many of the above criteria were met. Good-quality articles met five or more of the above criteria, average-quality articles met three to four of the above criteria, and poor-quality ones met less than three of the above criteria.
Results A total of 6 988 records were identified from the five databases, after which 5 280 duplicates were removed. The title screen therefore involved 1 708 articles, of which 73 were considered appropriate, and their abstracts were obtained and reviewed. After reviewing the abstracts, 23 full-text articles were obtained and read. In addition, the bibliography of the full-text articles were hand-searched for further appropriate articles. Six additional articles were obtained through hand-searching. Together with the hand-searched articles, a final total of seven articles were considered eligible for this systematic review. Articles that were excluded at this stage were those conducted in high-income
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Identification
Records through Pubmed (n = 155)
Records through Scopus (n = 5253)
Records through BioMed Central (n = 1113)
Records through Cochrane Library (n = 445)
Records through Cinhal (n = 22)
Total records identified (n = 6988)
Screening
Duplicates removed (n = 5280)
Titles excluded (n = 1635) • systematic reviews, literature reviews, summaries • management guidelines, policies • domestic violence • TB, HIV, influenza, cancer • adolescents healthy eating • developed countries • schizophrenia, depression • undernutrition, micronutrient deficiency, diabetes • unable to find full text
Titles screened (n = 1708)
Eligibility
Abstracts screened (n = 73)
Abstracts excluded (n = 50)
Full text articles excluded (n = 22) • review studies/position statements/ guidelines/reports • epidemiological/prevalence studies • studies performed in high-income countries
Full-text articles screened (n = 23)
Included
Abstracts of titles identified by hand-searching whose full-text articles were read (n = 6) Full-text articles included in systematic review (n = 7)
Fig. 1. F low diagram illustrating the number of included and excluded studies in the systematic review on lifestyle interventions for obesity/overweight during pregnancy in developing countries
countries and articles involving women post delivery of their babies (Fig. 1). The results of the Cochrane Risk of Bias Tool are displayed in Table 2, highlighting the criteria for assessing quality and risk of bias. Two of the included six articles displayed adequate sequence
generation, allocation concealment, and addressed incomplete outcome data.14,15 However, only one of these reported a low risk of bias for ‘blinding’ of participants.14 The final outcome of the quality assessment showed that five out of the seven articles (71%) were of poor quality.
Table 2. Reporting quality and risk-of-bias assessment Cochrane tool for assessing bias Sequence generation
Allocation concealment
Blinding
Incomplete outcome data
Selective outcome reporting
Other threats to validity
Final outcome
Santos et al., 200514
Yes
Yes
Yes
Yes
Unclear
Yes
Good
Sedaghati et al., 200716
No
No
No
Yes
Unclear
No
Poor
Garshasbi et al., 200519
Unclear
Unclear
No
Yes
Unclear
Yes
Poor
Prevedel et al., 200317
Unclear
Unclear
No
No
Yes
Yes
Poor
Cavalcante et al., 200918
Yes
Yes
No
Yes
Yes
Yes
Good
Malpeli et al., 201311
No
No
No
Yes
Yes
No
Poor
Ghodsi & Asltoghiri, 201215
No
No
No
Yes
Unclear
Yes
Poor
Author
400
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Table 3. Details and characteristics of the final studies included in the systematic review Type of study
Country
Region
Age (years)
Gestational age (weeks)
Santos et al., 200514
RCT
Brazil
Porto Alegre
Public health clinic (not specified)
Healthy, non-smoking, Control 35 ≥ 20 years, gestational Exercise 37 age < 20 weeks; BMI 26–31 kg/m2
Control 28.6 ± 5.9 Exercise 26.0 ± 3.4
Control 18.4 ± 3.9 Exercise 17.5 ± 3.3
Garshasbi et al., 200519
RCT
Iran
Tehran
Hospital
Primi-gravid, 20–28 Control 105 years old, 17–22 weeks’ Exercise 107 gestation, housewives, high-school graduated
Control 26.48 ± 4.43 Exercise 26.27 ± 4.87
Not specified
Malpeli et al., 201311
Nonrandomised
Argentina
Buenos Aires
Urban
Sample from lowincome families, pregnant women, without chronic or infectious diseases
Control 164 Experimental 108
Control 25.8 ± 6.4 Control 23.6 ± 9.3 Intervention 26.3 ± 7.1 Intervention 24.3 ± 8.00
Sedaghati et al., 200716
Nonrandomised
Iran
Qom Pre-natal clinics province
Exclusion: history of orthopaedic diseases or surgery, history of exercise before pregnancy
Control 50 Experimental 40
Control 23.36 ± 4.237 Exercise 23.28 ± 2.522
Control 38.884 ± 1.232 Exercise 39.195 ± 0.921
Prevedel et al., 200317
RCT
Brazil
Sao Paulo
Pre-natal clinic of the Faculty of Medicine de Botucatu (urban)
Primi-gravid or adolescents, singleton pregnancies, no co-morbidities
Intervention 22 Control 19
Mean: 20 years
16–20
Cavalcante et al., 200918
RCT
Brazil
Sao Paulo
Pre-natal outpatient clinic of the University of Campinas and the neighbouring basic healthcare centre
Low-risk, sedentary Intervention 34 pregnant women who Control 34 had not had more than 1 C-section and were able to participate in physical exercise
Not specified
16–20
Ghodsi & Asltoghiri, 201215
RCT
Iran
Unspec- Pre-natal clinics ified and hospitals
BMI 19.8–26 kg/m2; lack of specific disease, willingness to participate, correct address for follow up; ability to read and write; nulliand primi-gravid
Control 25.86 ± 4.90 Training 25.43 ± 4.52
20–26
Author
Study setting (urban/rural)
Inclusion criteria
Sample size
Total sample 250; unclear on specific numbers in each group
RCT = randomised, control trial; BMI = body mass index.
The articles comprised five RCTs from Brazil and Iran and two non-RCTs from Argentina and Iran, as shown in Table 3.11,14-19 Characteristics of the interventions across the seven studies are detailed in Table 4. Six of the trials studied the impact of exercise alone on maternal and birth outcomes, and one study investigated using fortified food to enhance micronutrient nutritional status. A study by Prevedel et al.17 was one of two that used aquatic physical activity as an intervention. The relative body fat percentage of the experimental group remained at 29%, however, the control group increased by 1.9%. A study by Cavalcante et al.18 also used an intervention of aquatic exercise during pregnancy to determine its effectiveness on maternal outcomes. No differences were noted between control and intervention groups for weight gain during pregnancy, body fat percentage, fat-free mass or body mass index (BMI). The effects of supervised aerobic exercise on the maternal outcomes of overweight pregnant women were evaluated by Santos et al.14 Although oxygen consumption of the exercise group at anaerobic threshold was higher post intervention, neither groups showed any differences in weight change after the intervention. Two Iranian interventions16,19 evaluated the effect of landbased exercise on low-back pain during pregnancy. The typical exercise programme for these studies included a combination of midwife-supervised anaerobic and aerobic exercise performed three days per week at a moderate intensity. In the study by Garshabi et al.,19 lordosis was reduced in the exercise group after the intervention, but weight gain was similar between the study
groups. In addition, spinal flexibility was significantly lower in the exercise group post intervention, and this was correlated with BMI. Weight gain was lower in the control group, and body weight of the neonate was higher than in the exercise group. Although Sedaghati et al.16 showed intensity of low-back pain was higher in the control group, weight gain during pregnancy was higher in the exercise group. The intervention that aimed to determine the possibility of improving maternal outcomes using fortified foods11 found that the prevalence of folic acid and serum retinol deficiency decreased, while vitamin A deficiency remained the same post intervention. No differences were noted for body composition, and the proportions of overweight and obesity in the groups were at a moderate level of 20 and 26.3%, respectively, post intervention.
Discussion Pregnancy appears to be a pivotal time for both maternal and foetal health. Emerging research has highlighted the profound effects of the in utero environment on the lifelong health of the baby. More specifically, both underweight and overweight babies are at risk of obesity later on in life.20 The perinatal period has been cited by Lawlor and Chaturvedi21 as one of the three critical periods in life for the prevention of obesity. Maternal obesity is perhaps one of the major causes of intrauterine over-nutrition during pregnancy, and can lead to largefor-gestational-age deliveries. In addition, excessive gestational
Mixed aerobic and flexibility exercise
RCT
Ghodsi & Asltoghiri, 201215
Mixed exercise regime including stretching and flexibility and aerobic exercises (swimming, cycling, walking) three times a week
Water aerobics for 50 min three times a week. Moderate intensity, 24.6 sessions per woman
Hydrotherapy three times a week. Moderate intensity for 1 hour at a time.
15 min warm-up and cool-down, 30 min cycling (55–65% MHR), 3 days/week, RPE 12–13,
The nutritional intervention consisted of the monthly supply of a basic food basket containing 1 kg fortified wheat flour (30 mg iron, 2 200 μg folic acid, 6.3 mg thiamine, 1.3 mg riboflavin, 13 mg niacin per kg), 2 kg soy-enriched maize flour fortified with micronutrients (1 500 μg RE vitamin A, 8 mg thiamine, 8 mg riboflavin, 100 mg niacin, 1,000 μg folic acid, 40 mg iron, 30 mg zinc per kg), 1 kg sugar, and 1 kg rice. It also contained a nutritional supplement (powder soup, 2 daily servings) equivalent to 250 Kcal daily, 270 μg retinol, 12 μg vitamin D, 20 mg vitamin C, 0.7 mg vitamin B1, 0.7 mg vitamin B2, 0.9 mg vitamin B6, 0.9 μg vitamin B12, 6.8 mg niacin, 200 μg folic acid, 240 mg calcium, 35 mg magnesium, 6 mg iron, 4 mg zinc and 29 mg selenium.
3 days/week, 60 min, 5 min slow walking, 5 min extension movements, 10 min general warm-up, 15 min anaerobic, 20 min specific exercise, 5 min return to first position, HR ≤ 140 bpm
60 min, 3 days/week, 5–10 warm up, 30 min heart rate-monitored aerobic, 10–15 min upper- and lowerlimb exercise, 10 min relaxation. Aerobic: 50–60% max HR ≤ 140 bpm
Intervention (details)
20–26th week until delivery
Until 36 weeks’ gestation
Until 36–40 weeks
Not specified
1 year
12 weeks
12 weeks
Intervention (duration)
Neonatal weight; 1st and 5th APGAR scale
Weight (kg), body fat (%), fat-free mass (%), BMI, % vaginal deliveries, % preterm, neonatal weight
Lean body weight (kg), total fat (kg), relative fat (%), VO2 max (ml/kg/min), systolic volume (ml), cardiac output (l/min), full-term/preterm birth, baby’s weight (g)
Intensity of low-back pain, maternal weight gain
Weight per trimester, BMI per trimester, low weight, normal weight, overweight, obese, ferritin, iron deficiency (prevalence), folate, prevalence of folate deficiency, zinc, prevalence of zinc deficiency, retinol, prevalence of vitamin A deficiency
Primary: intensity of lowback pain, lordosis, flexibility, maternal weight gain, pregnancy length, neonatal weight
Primary: O2 consumption, Secondary: respiratory exchange ratio, CO2 output, HR, RHR, low birth weight, prematurity, small for gestational age
Outcome measure
Not specified
Intervention 63.8 ± 12.7, control 60.8 ± 10.2
Not specified
Not specified
Not specified
19.8–26 kg/m2 Mean BMI for training group was 23.4 ± 1.9 and 23.3 ± 2.1 for the control group
Not specified
Mean: 58 kg; height: 159–161 cm
Baseline BMI: control 24.30 ± 1.289, exercise 24.10 ± 1.134 Baseline weight: control 61.04 ± 3.681 kg, exercise 60.78 ± 3.577 kg; Weight gain: exercise group 13.55 ± 1.131 kg, control 15.10 ± 2.102 kg, p < 0.0001
At baseline 27.5% were underweight; 25.4% normal weight; 22.4% overweight; 24.7% obese. There was a significant decrease in folate deficiency in the intervention group compared to the control group. The risk of vitamin A deficiency decreased significantly in the intervention group.
Baseline weight: control 55.42 ± 12.90, exercise 67.08 ± 12.8 BMI baseline: control 25.58 ± 5.12, exercise 25.98 ± 4.82 Weight gain during pregnancy: control 13.8 ± 5.2, exercise 14.1 ± 3.8, p = 0.63 Weight of neonate: control 3 500 ± 431 g, exercise 3 426 ± 675 g
Control: 27.5 ± 2.1, Exercise: 28.0 ± 2.1 (BMI); Baseline weight: control 71.2 ± 7.4, exercise 71.5 ± 7.9 Post-intervention weight: control 77.6 ± 8.3, exercise 77.2 ± 9.1
Pre-pregnancy BMI/weight Weight/BMI
Table 4. Details and characteristics of the interventions in the studies
PA = physical activity; min = minutes; RCT = randomised controlled trial; BMI= body mass index; HT = heart rate; RHR = relative heart rate.
Aquatic exercise
Nonrandomised
Sedaghati et al., 200716
RCT
Midwife supervised exercise
Nonrandomised
Malpeli et al., 201311
Cavalcante et al., 200918
Nutritional intervention
RCT
Garshasbi et al., 200519
Aquatic exercise
Midwifesupervised exercise
RCT
Santos et al., 200514
Prevedel et al., RCT 200317
Supervised PA
Type of study
Author
Intervention (type)
No significant difference in neonatal weight between the training and control group (3 204 g vs 3 216 g, respectively). No significant differences in APGAR scale between the two groups. No reporting on maternal weight as an outcome
No significant difference seen between the two groups for any of the outcome measures.
No difference in babies’ weight between the two groups (3 175 g control group, 3 110 g intervention group). Significant findings were: the mother’s relative fat percentage increased in the control group but remained the same in the intervention group. Systolic volume and cardiac output increased in the intervention group suggesting better cardiometabolic maternal adaptation.
Greater increase in weight gain was also seen in the control group
No significant differences recorded between intervention and control for anthropometric measurements. Energy and nutrient intake was significantly increased in the intervention group.
No significant difference between two groups according to maternal weight gain and neonatal birth weight. Exercise group gained 0.3 kg more weight
Exercise group gained approximately 0.5 kg less over 12 weeks, but not statistically significant (p = 0.62). Exercise sessions during pregnancy were not associated with low birth weight 3.363 ± 504 kg (exercise) versus 3.368 ± 518 kg (control), p = 0.97.
Conclusion
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weight gain in both overweight and normal-weight women has been shown to increase obesity in the offspring in both childhood22 and adolescence.23 For the mother, obesity-related complications and gestational diabetes mellitus may predispose her to the risk of metabolic and vascular diseases later on in life.24 Therefore, with the current epidemic of obesity, maternal obesity has serious implications on the health of both current and future generations. Due to the potential health consequences of maternal obesity, pregnancy is a pivotal period to implement health interventions,25 however, little research exists on health promotion during this period.24 A previous systematic review by Thangaratinam et al.12 found 44 randomised, controlled trials, conducted in developed countries, which implemented dietary or physical activity interventions to influence maternal weight during pregnancy. In their review, 14 studies implemented physical activity interventions, while 10 looked at dietary interventions and 10 addressed a mixed approach. Similarly, in our study, the majority of interventions focused on physical activity over dietary programmes. It is interesting to note that Thangaratinam et al.12 found that diet was more cost effective than physical activity in the management of weight in this population. The type of interventions used to limit weight gain during pregnancy appears to vary widely between studies. In their systematic review of lifestyle interventions in pregnancy, Oteng-Ntim et al.26 found a variety of individual, group and seminar interventions, while in the review by Thangaratinam et al.,12 interventions varied from a balanced diet and exercise prescription to counselling and educational sessions. In our study, six out of the seven interventions focused on physical activity, while only one used a nutritional intervention. Although previous systematic reviews have analysed the literature dealing with interventions during pregnancy for limiting excessive weight gain,12,26,27 ours is the first review of such studies performed solely in developing countries. Changes in diet and activity levels resulting from globalisation and movement of populations from rural to urban environments have led to a rapid rise in the prevalence of obesity in developing countries,28 and have caused this disease to move to the top of the public health agenda in many of these countries.29 Although there have been calls to focus interventions on maternal nutrition in order to reduce the risk of obesity later on in life,30 our review found only seven articles covering maternal obesity interventional studies, with only one specifically addressing nutrition. In addition, although the rate of obesity is high and affects many developing countries, our study showed that only three countries (Brazil, Iran and Argentina) have reported on interventions to curb obesity during pregnancy. Despite the growing prevalence of obesity in developing countries and the well-recognised detrimental effects of maternal obesity on both maternal and foetal outcomes, this review demonstrates the lack of pertinent research in this area within developing countries. Two of the studies in our review found an increase in weight16 and fat percentage17 in their control groups, and weight or weight gain was often a secondary outcome measure within the studies reviewed, the majority of which (six of seven studies) were not targeted to overweight women. Other reviews have demonstrated the effectiveness and safety of lifestyle interventions for reducing gestational weight gain,12 but this was not strongly demonstrated in the current study.
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Key messages: • Lifestyle interventions may be a cost-effective and useful way to manage maternal overweight and obesity as well as gestational weight gain • Few good-quality studies assessing the efficacy of lifestyle interventions on maternal body composition have been conducted in developing countries • In this systematic review of seven studies, two suggested that a physical activity intervention during pregnancy may significantly reduce maternal weight gain; and five were scored as being of poor quality. • Future, well-designed lifestyle-intervention studies aimed at managing maternal body composition are much needed in developing countries
Very few studies exist to address the issues of intervention for obesity and weight gain during pregnancy in developing countries. This review summarises the existing literature, of which 71% were of poor quality. Although our review focused on lifestyle interventions for overweight and obesity during pregnancy, the search yielded only one study that aimed the intervention at overweight women, and 50% of the studies were not primarily measuring weight gain as an outcome. In addition, the studies varied significantly from type of intervention to outcome measure, and additionally, the methodology was often poorly described, making comparative and accumulative analysis difficult.
Conclusion Dietary and lifestyle interventions during pregnancy may well be the key to addressing the prevention of obesity in future generations.28 Physical activity29 and dietary12 interventions have been shown to play an effective role in maternal weight management in the developed world. To our knowledge, this review is the first to address interventions for weight gain and obesity in developing countries, and few articles appear to have addressed this important issue. Lifestyle interventions may be a cost-effective and useful way to curb the growing epidemic of nutrition-related non-communicable diseases. Despite maternal health and obesity being a public health priority, few robust studies have addressed this critical area. This review has highlighted the need for further research, and in particular, carefully designed randomised, controlled trials, addressing primarily the issues of weight gain and obesity in pregnancy. Such studies are essential to determine the effectiveness and safety of appropriate lifestyle interventions during pregnancy in resource-limited settings. KL and SP were funded by Wits/NIH Non-Communicable Diseases Leadership Programme, funded through the Fogarty International Centre of the NIH Millennium Promise Awards: Non-communicable Chronic Diseases Research Training Programme (NCoD) (D43), grant number: 1D43TW008330-01A1. KL was also funded by the NRF Scarce Skills Awards. EW is supported in part by the National Research Foundation of South Africa for the grant no: 87944. Any opinion, finding and conclusion or recommendation expressed in this material is that of the author(s) and the NRF does not accept any liability in this regard.
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2009; 6: 1.doi: 10.1186/1742-4755-6-1. 19. Garshasbi A, Zadeh SF. The effect of exercise on the intensity of low back pain in pregnant women. Int J Gynaecol Obstet 2005; 88(3): 271–275. doi: 10.1016/j.ijgo.2004.12.001. 20. Oken E, Gillman MW. Fetal origins of obesity. Obes Res 2003; 11(4): 496–506. doi: 10.1038/oby.2003.69. 21. Lawlor DA, Chaturvedi N. Treatment and prevention of obesity – Are there critical periods for intervention? Int J Epidemiol 2006; 35(1): 3–9. doi: 10.1093/ije/dyi309. 22. Olson CM, Strawderman MS, Dennison BA. Maternal weight gain during pregnancy and child weight at age 3 years. Matern Child Health J 2009; 13(6): 839–846. doi: 10.1007/s10995-008-0413-6.
pre-pregnancy body mass index categories on obstetrical and neonatal
23. Oken E, Rifas-Shiman SL, Field AE, Frazier AL, Gillman MW. Maternal
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26. Oteng-Ntim E, Varma R, Croker H, Poston L, Doyle PC. Lifestyle
M, et al. Short-term evaluation of the impact of a fortified food aid
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Kries RC. Physical activity and gestational weight gain: a meta-analysis
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weight and obstetric outcomes: meta-analysis of randomised evidence. Br Med J 2012; 344: e2088. doi: 10.1136/bmj.e2088. 13. World Health Organisation 2006. Working Together for Health. WHO Global Report, Geneva, Switzerland, 2006: 1–237. 14. Santos IA, Stein R, Fuchs SC, Duncan BB, Ribeiro JP, Kroeff LR, et al. Aerobic exercise and submaximal functional capacity in overweight pregnant women: a randomized trial. Obstet Gynaecol 2005; 106(2): 243–249. doi: 10.1097/01.AOG.0000171113.36624.86. 15. Ghodsi Z, Asltoghiri M. Maternal exercise during pregnancy and
doi: 10.1111/j.1471-0528.2010.02801.x. 28. Popkin BM, Adair LS, Ng SWC. Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev 2012; 70(1): 3–21. doi: 10.1111/j.1753-4887.2011.00456.x. 29. Prentice AM. The emerging epidemic of obesity in developing countries. Int J Epidemiol 2006; 35(1): 93–99. doi: 10.1093/ije/dyi272. 30. Yang Z, Huffman SLC. Nutrition in pregnancy and early childhood and associations with obesity in developing countries. Matern Child Nutr 2013; 9(S1): 105–119. doi: 10.1111/mcn.12010.
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Images in Cardiology Unusually aggressive immature neo-intimal hyperplasia causing in-stent restenosis Keir McCutcheon, Andreas S Triantafyllis, Johan Bennett, Tom Adriaenssens
Abstract This image illustrates a very unusual pattern of early and aggressive immature neo-intimal hyperplasia in a 52-year-old man with unstable angina, two months after deployment of a drug-eluting stent in the proximal left anterior descending artery. A
Department of Cardiovascular Medicine, University Hospitals Leuven, Leuven, Belgium Keir McCutcheon, BSc (Hons), MSc, MB BCh, FCP (SA), Cert Cardiol (SA), keir.mccutcheon@uzleuven.be Andreas S Triantafyllis, MD, PhD Johan Bennett MB BCh, MD Tom Adriaenssens, MD, PhD
C
F E D
D
*
C
E
F
B C D E F
Fig. 1. A : Still frame of left coronary angiography showing restenosis in the proximal LAD. Letters in black correspond with the optical coherence tomography (OCT) images that follow. Bâ&#x20AC;&#x201C;F: OCT from distal to proximal left anterior descending (LAD) and left mainstem demonstrating mature neo-intimal hyperplasia in mid-LAD stent (C, asterisk), aggressive immature neo-intimal hyperplasia in the proximal LAD stent (D, double arrowhead line) with tissue protrusion (E, arrowheads) and stent edge vascular response (F).
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Keywords: in-stent restenosis, neo-intimal hyperplasia, optical coherence tomography Submitted 2/2/17, accepted 19/4/17 Published online 10/10/17 Cardiovasc J Afr 2017; 28: 404–405
www.cvja.co.za
DOI: 10.5830/CVJA-2017-024
A 52-year old man was admitted with unstable angina two months after deployment of a drug-eluting stent (DES) in the proximal left anterior descending (LAD) artery. Five months prior to the current admission he had undergone percutaneous coronary intervention (PCI) with a DES to his proximal right, proximal circumflex and mid-LAD coronary arteries. The patient had no cardiovascular risk factors apart from a family history of premature coronary artery disease. Coronary angiography demonstrated in-stent restenosis of the proximal LAD stent (Fig. 1A). Optical coherence tomography (OCT) demonstrated various tissue responses to stent implantation (Fig. 1B). High-signal, smooth muscle-rich
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mature neo-intimal hyperplasia was present within the stent in the mid-LAD (Fig. 1C; asterisk) whereas signal-poor homogeneous aggressive immature neo-intimal hyperplasia was present at the level of the proximal stent edge, causing sub-total occlusion (Fig. 1D; double arrowhead line), with tissue protrusion clearly visible below the immature neo-intimal hyperplasia in certain frames (Fig. 1E; arrowheads). Proximal to the stent, an inhomogeneousedge vascular response was observed (Fig. 1F). The focal restenosis in the proximal stent segment was treated with another DES and post-dilated with a non-compliant balloon with a good angiographic result (not shown). This image illustrates a very unusual pattern of early and aggressive immature neo-intimal hyperplasia. Although immature neo-intimal hyperplasia has been described,1 to our knowledge this is the first image of such aggressive immature neo-intimal hyperplasia.
Reference 1.
Malle C, Tada T, Steigerwald K, et al. Tissue characterization after drug-eluting stent implantation using optical coherence tomography. Arterscler Thromb Vasc Biol 2013; 33: 1376–1383.
Treatment of heart attack patients depends on history of cancer Treatment of heart attack patients depends on their history of cancer, according to research published recently in European Heart Journal: Acute Cardiovascular Care. The study in more than 35 000 heart attack patients found they were less likely to receive recommended drugs and interventions and more likely to die in hospital if they had cancer than if they did not. ‘It is well known that cancer patients may have an increased risk of cardiovascular disease as a result of their treatment’, said senior author Dr Dragana Radovanovic, head of the AMIS Plus Data Centre in Zurich, Switzerland. ‘However, on the other hand, little is known about the treatment and outcomes of cancer patients who have an acute myocardial infarction.’ This study investigated whether acute myocardial infarction patients with a history of cancer received the same guideline-recommended treatment and had the same in-hospital outcomes as those without cancer. The study included 35 249 patients enrolled in the Acute Myocardial Infarction in Switzerland (AMIS Plus) registry between 2002 and mid-2015. Of those, 1 981 (5.6%) had a history of cancer. Propensity score matching was used to create two groups of 1 981 patients each – one with a cancer history and one without – that were matched for age, gender and cardiovascular risk factors. The researchers compared the proportions of patients in each group who received specific immediate drug therapies for acute myocardial infarction, and percutaneous coronary intervention (PCI) to open blocked arteries. They also compared the rates of in-hospital
complications and death between the two groups. The researchers found that cancer patients underwent PCI less frequently [odds ratio (OR) 0.76; 95% confidence interval (CI): 0.67–0.88) and received P2Y12 blockers (OR 0.82; 95% CI: 0.71–0.94) and statins (OR 0.87; 95% CI: 0.76–0.99) less frequently. In-hospital mortality rate was significantly higher in patients with cancer than those without (10.7 vs 7.6%; OR 1.45; 95% CI: 1.17–1.81). Patients with a history of cancer were more likely to have complications while in hospital. They had 44% higher odds of cardiogenic shock, 47% higher chance of bleeding and 67% greater odds of developing heart failure than those with no history of cancer. Dr Radovanovic said: ‘Patients with a history of cancer were less likely to receive evidence-based treatments for myocardial infarction. They were 24% less likely to undergo PCI, 18% less likely to receive P2Y12 antagonists and 13% less likely to receive statins. They also had more complications and were 45% more likely to die while in hospital.’ ‘More research is needed to find out why cancer patients receive suboptimal treatment for myocardial infarction and have poorer outcomes’, continued Dr Radovanovic. ‘Possible reasons could be the type and stage of cancer, or severe co-morbidities. Some cancer patients may have a very limited life expectancy and refuse treatment for myocardial infarction’, she added. Source: European Society of Cardiology Press Office
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Letter to the Editor NT-pro BNP and plasma-soluble ST2 as promising biomarkers for hypertension, hypertensive heart disease and heart failure in sub-Saharan Africa Dear Sir In three recent publications,1-3 Ojji and colleagues reported on the role of two novel biomarkers, NT-pro-BNP and plasma soluble ST2, for differentiating sub-Saharan African people with hypertension (HT) without left ventricular hypertrophy (LVH) and without heart failure (HF) from hypertensive people with LVH (HTLVH) and those with HF (HTHF). The authors clinically and echocardiographically evaluated a group of 210 patients with hypertension residing in Abuja, the capital city of Nigeria. All these patients had measurements done for the cardiac neurohormone NT-pro-BNP and for soluble ST2, which is a novel cardiac biomarker of mechanical strain. In the first publication,1 in which they investigated the effect of LV remodelling on the concentration of soluble ST2, the authors found that subjects with HTHF had higher plasma ST2 concentrations compared to those with HTLVH and those with HT (134.7 ± 57.3 vs 23.0 ± 8.3 vs 14.5 ± 4.9 ng/ml, all p < 0.0001). Soluble ST2 also had a strong correlation with clinical and echocardiographic parameters. The authors concluded that ‘Plasma ST2 is a useful biomarker in not only differentiating HTHF from HT with or without LVH, but also distinguishes hypertensive LVH from HT without LVH’. In the second publication,2 the authors investigated the relationship between soluble ST2 levels and LV geometric patterns in the same cohort of patients with HT and found that patients with concentric LVH had higher soluble ST2 levels compared with patients with normal LV geometry (20.4 ± 8.4 vs 14.3 ± 5.4 ng/ml, p < 0.002). This also led to the conclusion that ‘soluble ST2 level is not only affected by hypertensive LVH, but may be a future biomarker in differentiating concentric hypertrophy from normal geometry in hypertension’. Department of Medicine, University of Cape Town, Cape Town, South Africa; Douala General Hospital and Clinical Research Education Networking and Consultancy, Douala, Cameroon; Faculty of Health Sciences, University of Buea, Buea, Cameroon Anastase Dzudie, MD, aitdzudie@yahoo.com
Douala General Hospital, and Clinical Research Education Networking and Consultancy, Douala, Cameroon; Faculty of Health Sciences, University of Buea, Buea, Cameroon Bonaventure Suiru Dzekem, MD
Department of Medicine, University of Cape Town, and Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa Andre Pascal Kengne, MD
In the third study,3 the authors examined the effect of NT-proBNP on LV and RV remodelling in this same hypertensive African cohort. Participants with HTHF had significantly higher NT-pro-BNP levels compared to those with HTLVH. Based on these results, the authors proposed that NT-pro-BNP could be a useful biomarker for differentiating HT with or without LVH from HTHF in black hypertensive subjects. The conclusions drawn by these authors are valid exclusively in the study context for a number of reasons. First, it is important to remember that hypertension and hypertensive heart disease, which are potentially preventable diseases, are the main contributors of the growing burden of heart failure in SSA.4 Second, echocardiography is globally the cornerstone of the routine assessment of various types of hypertensive heart disease as it allows for the detection of normal left ventricular concentric remodelling, concentric versus eccentric LVH, and HF with the possible differentiation between HF with reduced ejection fraction and HF with preserved ejection fraction using tissue Doppler imaging, as well as the measurement of pulmonary artery pressure, another prognostic marker in this population.5 However, echocardiography remains expensive, less available in most SSA settings, and requires experts both for its performance and interpretation. For these reasons, requesting cardiac echocardiography in most settings in SSA is like searching for the goose that lays the golden egg. There is value therefore in using circulating biomarkers, which could be useful as surrogate markers of the heart disease process in resource-poor settings. Natriuretic peptide (BNP and NT-proBNP) levels have been shown to accurately reflect left ventricular pressure, and studies have found that peptide levels are sensitive and specific for diagnosing heart failure and also relevant for risk stratification.6,7 There is no doubt that the third study by Ojji et al.3 is a confirmation of the usefulness of the diagnostic role of NT-pro BNP in the SSA setting and it has immediate relevance for clinicians. Contrary to NT-pro BNP measurement, which is already an established gold standard for HF, soluble ST2 as a biomarker has been less investigated. Just as with other novel biomarkers, such as mid-regional pro-atrial natriuretic peptide (MR-proANP) and galectin-3, which are promising diagnostic and prognostic biomarkers beyond established natriuretic peptides, the role of soluble ST2 in the clinical care of patients is yet to be established beyond any doubt. It is very encouraging to note that, as suggested by Ojji and co-workers, soluble ST2 can help differentiate HT, HTLVH and HTHF, as well as concentric LVH from normal LV geometry. The relevance of these three studies by Ojji and co-workers in this particular context should however not completely
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overshadow the shortcomings. First, this was a single-centre study with a limited number of participants. Second, heart disease and especially heart failure in this population may have included cases of different severity and chronicity, especially ischaemic causes, which could limit the generalisability of their findings to all hypertensive patients. Finally, further research is required to determine the optimal cut-off points for diagnosis, the relevance of serial measurements, changes following treatment, and the prognostic role in Africans, before they can be widely recommended for clinical decision making.
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15(12): 899–904. 3.
Ojji DB, Opie, LH, Lecour S, Lacerda L, Adeyemi OM, Sliwa K. The proposed role of plasma NT pro-brain natriuretic peptide in assessing cardiac remodelling in hypertensive African subjects. Cardiovasc J Afr 2014; 25(5): 233–238.
4.
Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012; 172(18): 1386–1394.
5.
Bursi F, McNallan SM, Redfield MM, Nkomo VT, Lam CSP, Weston SA, et al. Pulmonary pressures and death in heart failure: a community study. J Am Coll Cardiol 2012; 59(3): 222–231.
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Hill SA, et al. BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review. Heart Fail
Ojji DB, Opie LH, Lecour S, Lacerda L, Adeyemi OM, Sliwa K. The
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effect of left ventricular remodelling on soluble ST2 in a cohort of hypertensive subjects. J Hum Hypertens 2014; 28(7): 432–437. 2.
Santaguida PL, Don-Wauchope AC, Oremus M, McKelvie R, Ali U,
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Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead
Ojji DB, Opie LH, Lecour S, Lacerda L, Adeyemi O, Sliwa K.
A, et al. Plasma B-type natriuretic peptide levels in systolic heart failure:
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importance of left ventricular diastolic function and right ventricular
cohort of hypertensive patients. J Clin Hypertens (Greenwich) 2013;
systolic function. J Am Coll Cardiol 2004; 43(3): 416–422.
Statins associated with improved heart structure and function Statins are associated with improved heart structure and function, according to research presented recently at EuroCMR 2017. The benefits were above and beyond the cholesterol-lowering effect of statins. ‘Statins are primarily used to lower cholesterol’, said lead author Dr Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. ‘They are highly effective in preventing cardiovascular events in patients who have had a heart attack or are at risk of heart disease.’ He continued: ‘Statins have other beneficial, non-cholesterollowering, effects. They can improve the function of the blood vessels, reduce inflammation, and stabilise fatty plaques in the blood vessels. Studies in mice and small studies in humans have shown that statins also reduce the thickness of heart muscle but this needed to be confirmed in a larger study.’ This study investigated the association between statins and heart structure and function. The study included 4 622 people without cardiovascular disease from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was used to measure left and right ventricular volumes and left ventricular mass. Information on statin use was obtained from medical records and a selfreporting questionnaire. The relationship between statin use and heart structure and function was assessed using a statistical technique called multiple regression, which adjusts for potential confounders that can have an effect on the heart, such as ethnicity, gender, age, and body mass index (BMI). Nearly 17% of participants were taking statins. Those taking statins were older, had higher BMI and blood pressure, and were more likely to have diabetes and hypertension. ‘This was not surprising because we prescribe statins to patients at high risk of heart disease and these are all known risk factors’, said Dr Aung. Patients taking statins had a 2.4% lower left ventricular mass and lower left and right ventricular volumes. Dr Aung
said: ‘People using statins were less likely to have a thickened heart muscle (left ventricular hypertrophy) and less likely to have a large heart chamber. Having a thick, large heart is a strong predictor of future heart attack, heart failure or stroke and taking statins appears to reverse the negative changes in the heart which, in turn, could lower the risk of adverse outcomes.’ ‘It is important to note that in our study, the people taking statins were at higher risk of having heart problems than those not using statins yet they still had positive heart remodelling compared to the healthier control group’, added Dr Aung. In terms of how statins might reduce the thickness and volume of the heart, Dr Aung said several studies have demonstrated that statins reduce oxidative stress and dampen the production of growth factors that stimulate cell growth. Statins also increase the production of nitric oxide by the cells lining the blood vessels, leading to vasodilatation, improved blood flow, lower blood pressure, and lower stress on the heart, which is less likely to become hypertrophied. The findings raise the issue of extending statin prescriptions to anyone above the age of 40 years, but Dr Aung said that was probably not the way to go. ‘There are clear guidelines on who should receive statins’, he said. ‘There is debate about whether we should lower the bar and the question is when do you stop. What we found is that for patients already taking statins, there are beneficial effects beyond cholesterol lowering and that’s a good thing. But instead of a blanket prescription, we need to identify people most likely to benefit, that is, personalised medicine.’ Dr Aung said: ‘A dual approach should be considered to identify people who will benefit most from statins. That means looking at not only clinical risk factors, such as smoking and high blood pressure, but also genetic (hereditary) factors, which can predict individuals’ response to statins. This is an area of growing interest and one that we are also investigating in our lab with our collaborators.’ Source: European Society of Cardiology Press Office
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Congress News Khartoum, what a location for the joint congress of PASCAR, the Sudan Heart Society and the Pan-African Interventional Cardiology Course (PAFCIC)! The PAFCIC (http://pafcic.org/) took place alongside the main congress and presented the practicalities of interventional procedures. The African summit of the World Heart Federation was also held in proximity to the congress (proceedings documented at https://www.world-heart-federation.org/whf-african-summit/). The joint congress was housed in the Friendship Hall, in Khartoum, next to the Blue Nile, a kilometre or so from the confluence of the two Nile rivers. The opening by General Bakris Hassan Saleh, first vice-president of the republic and national prime minister of Sudan was magnificent. Proceedings were in Arabic, but one could follow a translation into English on small headsets. After a few words from Prof Bongani Mayosi, president of PASCAR, delegates were introduced to the guest speaker, Prof AA Gehani from the Heart Centre, Cornell Medical Centre, Qatar. Prof Gehani advanced a well-supported hypothesis that Ibn-Nafis, a 13th century Arabic scholar, described the pulmonary circulatory system about four centuries before William Harvey did. He also explained how Harvey may have read this, having had access to Arabic sources that had been translated into Latin. This theory is not new and appears in a letter to the Cardiovascular Journal of Africa in 2009; 20(5): 299. The main themes of the congress were around diseases endemic to Africa: rheumatic heart disease, hypertension and heart failure, but a fair share of the programme revolved around ischaemic heart disease and related interventions. Some space was also allotted to congenital and arrhythmic heart disease. Presentations were almost along the lines of taking stock: ‘What cardiovascular disease do we see? How frequent is it? What is available to diagnose and manage it? How do we compare among each other and compared to developed countries, and is what we do appropriate for Africa?’ For example, Bongani Mayosi, stated that rheumatic heart disease is still endemic in all parts of Africa, major parts of Asia and in some pockets elsewhere in the world. He explained how some countries have managed to decrease its prevalence through increasing awareness and prevention. Eighty per cent of premature cardiovascular disease and death occurs in developing countries, a very significant proportion of which is Africa. Karen Sliwa addressed the issue of whether Africa can meet the 25 × 25 goal of the United Nations to achieve a 25% reduction in premature mortality from cardiovascular disease by 2025. Others speakers, Ibtisam Ali, Anastase Dzudie, Albertino Damasceno, Elijah, Salim Yusuf and Gerald Yonga talked about how to address the major risk factors, such as hypertension, smoking and others. A major issue is the cost and quality
of medication and the payment thereof. Three ministers of health, who are important for formulating and implementing public health policies with regard to smoking, sugar consumption, hypertension and more, unfortunately did not put in an appearance. The work of Salim Yusuf from Canada is fascinating. His group has been studying cardiovascular disease on a global scale by asking simple questions such as: ‘Is the incidence and prevalence of events the same? If a myocardial infarction or stroke occurred, are the “risk” factors the same? Are the outcomes of events the same or different in different settings?’ On this last question, Yusuf asked, ‘If one finds oneself having chest pain in an area where primary percutaneous coronary intervention (PPCI) is not timeously available, if at all, and even appropriately given thrombolysis may not be available, what should one do?’ He ventured an idea for self-treatment; to carry an emergency ‘cocktail’ of aspirin, an ACE inhibitor, a β-blocker and a statin. This makes sense, even in Khartoum. Ahmed Suliman gave an overview of the situation in Sudan. Even in Khartoum, with many private and some public cardiac catheterisation laboratories (CCL), you are likely to get timely PPCI only if you pay privately. In the public system, at primary care facilities, after first dealing with issues of payment, the window of opportunity will have passed, and even thrombolysis will not be done. According to Toure, in Niger there is no CCL. Some other countries are in a similar situation and Habib Gamra has compiled a very useful interventional map for Africa. The cardiac surgery situation in Sudan is interesting. Besides the Sudanese facilities, elaborated on by Kamal Khoghali, there is also a major centre, the Salam Centre, funded by an NGO and expounded on by Alessandro Salvati, which undertakes surgery and follow up at no cost. Representatives of both the Cardiovascular Journal of Africa and the Sudan Heart Journal (SHJ) had the opportunity of giving an overview. Siddiq Khalil, the editor of SHJ, gave an excellent review on the origin of the journal in 2011, its policies, growth and aims. He also spoke about the history of Sudan and the conquering of Sudan by General Horatio Kitchener in 1898. This is a name we in South Africa can identify with, thinking of the role Kitchener played in the Anglo–Boer war two years later. The foreign delegates were well treated by a number of friendly young doctors who helped us into and out of Sudan, as well as getting us to where we needed to be. The evening outings to some excellent restaurants were very enjoyable despite the absence of alcohol.
Opening of congress: General Bakri Saleh in white turban sitting on stage
Left to right: Anastase Dzudie (Cameroon), Paul Brink (South Africa), Ahmed Suliman (Sudan), George Nel (South Africa)
PA Brink
Additional photos on page 396
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Case Report Efficacy of cardiac magnetic resonance imaging in a sub-aortic aneurysm case Ruchika Meel, Richard Nethononda, Ferande Peters, Mohammed Essop Case report
Abstract Sub-aortic (SA) aneurysms are a rare entity of variable aetiology. We report the first case of a SA aneurysm assessed using cardiac magnetic resonance imaging (MRI). A 33-year-old female with human immunodeficiency virus and on highly active antiretroviral treatment presented with syncope and dyspnoea. Clinical examination suggested moderate to severe aortic regurgitation (AR) confirmed by transthoracic and transoesophageal echocardiograms. However, echocardiography was suboptimal in defining the precise mechanism and severity of AR. A cardiac MRI was done to elucidate the aetiology, severity and mechanism of regurgitation. It confirmed the presence of a SA aneurysm below the left coronary cusp and its retraction, resulting in an eccentric AR jet. An assessment of moderate AR, based on regurgitant volume, was made. Furthermore, the anatomical relationships of the aneurysm were clearly defined. Cardiac MRI allowed comprehensive assessment of this SA aneurysm. Keywords: cardiac magnetic resonance imaging, sub-aortic aneurysm, aortic regurgitation Submitted 25/1/17, accepted 1/5/17 Published online 29/6/17 Cardiovasc J Afr 2017; 28: e1–e3
www.cvja.co.za
DOI: 10.5830/CVJA-2017-027
Sub-aortic (SA) aneurysms are a rare entity with variable aetiology. Most cases are congenital and result from a defect between the ventricular wall and valvular annuli.1 Earlier reports were mostly from Africa. Between 1957 and 1993, only 22 cases had been reported.2 Since then, isolated reports on various aspects of this rare condition have been published. There have been no reports in the literature on adult patients, using cardiac magnetic resonance imaging (MRI), to investigate SA aneurysms.
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 Ferande Peters, MD Mohammed Essop, MD
The patient was a 33-year-old human immunodeficiency virus (HIV)-positive woman on highly active antiretroviral treatment (HAART), with a current CD4 count of 1 000 cells/µl. She was referred from a peripheral hospital, with a history of a single syncopal episode. She also admitted to a two-week history of progressive dyspnoea and fatigue (New York Heart Association functional class II). No further relevant past medical or family history was obtained. On examination, the blood pressure was 102/52 mmHg with a pulse of 106 beats/min. No dysmorphic features were noted. She had large volume and collapsing peripheral arterial pulses, with a wide pulse pressure (50 mmHg). The apex beat was in the fifth intercostal space and displaced slightly to the left of the midclavicular line. The second heart sound was loud. There was a grade 3/4 early decrescendo diastolic murmur in the left parasternal border, characteristic of aortic regurgitation (AR). There were no peripheral stigmata of infective endocarditis. She had been treated with diuretics and there were no signs of congestive cardiac failure. An electrocardiogram showed left ventricular (LV) hypertrophy with strain pattern in the lateral leads and left atrial (LA) enlargement. The chest X-ray was normal. The blood count was normal and the serology for syphilis and connective tissue disease was negative. A transthoracic echocardiogram (TTE) revealed a dilated LV with an ejection fraction of 56% and moderate-to-severe eccentric aortic regurgitation secondary to leaflet malcoaptation (Fig. 1). There was compression of the LA by an outpouching with calcified walls adjacent to the aortic root, the exact origin and location of which was difficult to define on TTE. There was flow into and out of this structure in diastole.
Fig. 1. Parasternal short-axis view of the sub-aortic (SA) aneurysm (white arrow, left). Apical three-chamber views depicting the SA aneurysm (white arrow, middle), and an eccentric aortic regurgitation jet on colour flow, with flow into the SA aneurysm (right).
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Fig. 2. L eft ventricular outflow tract views showing the subaortic aneurysm (blue arrow) compressing the left atrium (red arrow, left) and sparing the left coronary artery (right).
A two- and three-dimensional transoesophageal echocardiogram (2D/3D TEE) was done to further define this lesion. In this patient, poor transoesophageal views prevented a full assessment of the pathology. There was a likely SA aneurysm with orifice located below the non-coronary and left coronary cusps (NCC/ LCC). The aortic leaflets and the root were normal. There was retraction of the aortic leaflets and impingement of the LA, the right pulmonary artery, and possibly the right ventricular outflow tract (RVOT) by the aneurysm. There were no associated thrombi, vegetations or other congenital lesions. Due to suboptimal imaging on TTE and TEE, a cardiac MRI was requested to confirm the SA aneurysm and to define with certainty its relationship to the surrounding structures (Fig. 2). A 30 Ă&#x2014; 14-mm aneurysm with a 12-mm neck was noted below the aortic valve, which extended to the LA roof (Fig. 3). The communication point was just below the LCC. AR of moderate severity was noted (Fig. 4).
Discussion SA aneurysms are rare and postulated to be the result of a defect of congenital origin between the valvular annuli and the ventricular wall.1 Other possible aetiologies, although not
Fig. 3. L eft ventricular outflow tract (left) and short-axis views (right) depicting compression of the left atrium (blue arrow) by the sub-aortic aneurysm (red arrow).
Fig. 4. Left ventricular outflow tract MRI image showing an aortic regurgitant jet (arrow) secondary to retraction of the left coronary cusp by the sub-aortic aneurysm.
confirmed, include tuberculosis, syphilis, rheumatic fever and infective endocarditis.3,4 Whether HIV has a causal connection also remains to be proven. These infections may merely represent an association, given their high prevalence, and causality cannot be inferred.5 SA aneurysms are rarer than sub-mitral aneurysms and the diagnosis is more challenging.1,2,6 They are mostly not suspected clinically and are found coincidentally on imaging.7 The chest X-ray was normal in this patient, unlike with sub-mitral aneurysms where an enlarged cardiac silhouette is often noted.3 SA aneurysms need to be differentiated from more commonly occurring aneurysms such as sinus of Valsalva aneurysms, which are located above the aortic valve.6 SA aneurysms mostly occur in young Africans.6 The origin is usually below the left coronary cusp, as in our patient.2,6 Clinical presentation varies, ranging from cardiac failure and systemic emboli (due to aneurysmal thrombi) to angina (due to coronary artery compression or emboli), and dysrhythmias such as ventricular tachycardia.1 A lack of aortic cusp support and distortion of the annulus is responsible for AR and subsequent cardiac failure.3 The most widely available imaging tool is TTE but this may be inadequate, as smaller aneurysms may be missed, especially in patients with suboptimal imaging windows. The diagnosis is also dependent on the skill and knowledge of the operator.7 Cardiac MRI is increasingly becoming a complimentary tool to echocardiography in assessing valves and congenital lesions.8 In patients with inadequate echocardiographic imaging, cardiac MRI allows a detailed assessment of the anatomy of congenital lesions such as SA aneurysms, and their relationship to the surrounding structures. Additionally, MRI allows accurate quantification of AR severity. Cardiac MRI in our case allowed the precise localisation of the lesion below the LCC, which proved difficult on TTE and 2D TEE. Furthermore, involvement of the RVOT, which was
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suspected on 2D TEE, was excluded with certainty. Cardiac MRI is able to accurately quantify the severity of regurgitant lesions, which may not always be possible by echocardiography alone. For example, an eccentric AR jet, as in our patient, is more accurately assessed on cardiac MRI using volumetric analysis, as opposed to less-validated echocardiographic quantification, such as the proximal isovelocity surface-area method.8 Two-dimensional TEE offers higher temporal resolution compared to cardiac MRI but its use is limited by angle dependence, image quality and acquisition. Cardiac MRI does not have these limitations and is able to provide improved spatial resolution.9 It also has a greater range of imaging techniques, therefore offering more anatomical and functional information. This enables enhanced clinical assessment and management. Three-dimensional echocardiography has been used for the detection and assessment of anatomical defects in the context of congenital heart disease.10 It has been used to image a SA aneurysm complicating infective endocarditis.11 3D TEE allowed us to define the anatomy of the SA aneurysm at the bedside but was limited by suboptimal views. The shortcomings are that it is angle dependent, the spatial and temporal resolution is still suboptimal and it is highly reliant on 2D image quality. MRI therefore proved to be an indispensable tool in this patient.
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References 1.
Chesler E, Mitha A, Edwards J. Congenital aneurysms adjacent to the anuli of the aortic and/or mitral valves. Chest 1982; 82: 334–337.
2.
Head H, Jue K, Askren C. Aortic subannular ventricular aneurysms. Ann Thorac Surg 1993; 55: 1268–1272.
3.
Chesler E, Joffe N, Schamroth l, Meyers A. Annular subvalvular left ventricular aneurysms in the South African Bantu. Circulation 1965; 32: 43–51.
4.
Poltera A, Jones A. Subvalvular left ventricular aneurysms. A report of 5 Ugandan cases. Br Heart J I973; 35: IO85–IO9I.
5.
Takawira F, Joshi J, Du Plessis D. Development of a subaortic aneurysm secondary to disseminated tuberculosis in a child. Ann Thorac surgery 2010; 90: 644–647.
6.
Normann S. Annular subaortic aneurysm resulting in sudden death. Clin Cardiol 1991; 14: 68–72.
7.
Cho S, Mun S. Congenital subaortic left ventricular aneurysm diagnosed by 64-slice multidetector-row computed tomography. J Thorac Imag 2010; 25: W75–W76.
8.
Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33: 2451–2496.
9.
Myerson S, Francis J, Neubauer S. Cardiovascular Magnetic Resonance. New York: Oxford University, 2013.
10. Hung J, Lang R, Flachskampf F ,Shernan SK, McCulloch ML, Adams DB, et al. 3D echocardiography: a review of the current status and
Conclusion Cardiac MRI is a useful adjunctive tool to echocardiography in the comprehensive assessment of SA aneurysms.
future directions. J Am Soc Echocardiogr 2007; 20: 213–233. 11. Müllera H, Cikirikcioglub M, Lercha R. Subaortic aneurysm caused by Paecilomyces lilacinus endocarditis. Arch Cardiovasc Dis 2008; 101: 803–804.
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Case Report Miller–Fisher syndrome after coronary artery bypass surgery Mustafa Aldag, Sebnem Albeyoglu, Ufuk Ciloglu, Hakan Kutlu, Levent Ceylan
Abstract Miller–Fisher syndrome (MFS) is an uncommon neurological disorder that is considered a variant of the Guillain–Barre syndrome (GBS). It is clinically defined by a triad of symptoms, namely ataxia, areflexia and ophthalmoplegia. These acute inflammatory polyradiculopathic syndromes can be triggered by viral infections, major surgery, pregnancy or vaccination. While the overall incidence of GBS is 1.2–2.3 per 100 000 per year, MFS is a relatively rare disorder. Only six cases of GBS after cardiac surgery have been reported, and to our knowledge, we describe the first case of MFS after coronary artery bypass surgery. Although cardiac surgery with cardiopulmonary bypass may increase the incidence of MFS and GBS, the pathological mechanism is unclear. Cardiac surgery may be a trigger for the immune-mediated response and may cause devastating complications. It is also important to be alert to de novo autoimmune and unexpected neurological disorders such as MFS after coronary bypass surgery.
Keywords: Miller–Fisher syndrome, Guillain–Barre syndrome, coronary artery bypass grafting, cardiopulmonary bypass Submitted 1/10/16, accepted 13/7/17 Cardiovasc J Afr 2017; 28: e4–e5
www.cvja.co.za
DOI: 10.5830/CVJA-2017-033
Miller–Fisher syndrome (MFS) is an uncommon neurological disorder that is considered a variant of Guillain–Barre syndrome (GBS).1 MFS is clinically defined by a triad of symptoms, namely ataxia, areflexia and ophthalmoplegia. Both syndromes usually occur after viral infections, mostly by Campylobacter jenuni, cytomegalovirus, and Epstein–Barr and influenza viruses. These acute inflammatory polyradiculopathic syndromes can also be
Department of Cardiovascular Surgery, Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey Mustafa Aldag, MD, mustafa.aldag@saglik.gov.tr Sebnem Albeyoglu, MD Ufuk Ciloglu, MD Hakan Kutlu, MD Levent Ceylan, MD
triggered by major surgery, pregnancy or vaccination.2 While the overall incidence of GBS is 1.2–2.3 per 100 000 persons per year,3 MFS is a relatively rare disorder, accounting for approximately 5% of patients with GBS.4 GBS is rare among post-surgical inflammatory neuropathies. Only six cases of GBS after cardiac surgery have been reported,5 and to our knowledge, we have described the first case of MFS after coronary artery bypass surgery.
Case report A 50-year-old man was admitted to the emergency department with a four-hour history of angina pectoris. Anterior ST-segment elevation myocardial infarction was confirmed and the patient underwent coronary angiography. Triple-vessel coronary artery disease was demonstrated on catheterisation, requiring urgent coronary bypass surgery. A successful emergency coronary artery bypass procedure (left internal thoracic artery to the left anterior descending artery, and saphenous vein graft to the circumflex and diagonal arteries) was performed using cardiopulmonary bypass (CPB) with 30°C hypothermia. Alhough the pre- and intra-operative periods remained uneventful, the patient noticed ataxia, left-sided ptosis, weakness and paresthaseia of his legs, which progressed rapidly on the fifth postoperative day. Ataxia was prominent in the lower extremities during standing and walking. There was no history of viral infection, fever or other neurological diseases. On neurogical examination, unilateral ptosis, gait ataxia and areflexia were noted. After neurology consultation, cranial computerised tomography (CT) revealed nothing unusual. Brain CT and cerebrospinal fluid (CSF) analysis yielded normal results. CSF viral serology and gram stain culture were negative. Additional laboratory work-up, including tests for connective tissue disorders, anti-thyroid peroxidase and anti-thyroglobulin antibodies were within normal limits. Electromyography and brain magnetic resonance imaging (MRI) were performed and a possible diagnosis of Miller–Fisher syndrome was considered. Urgent plasmapheresis treatment was planned but within 24 hours the patient had serious dysphagia and rapidly developed dyspnoea. After elective intubation, the patient was transfered to the neurology intensive care unit. Treatment with plasmapheres and intravenous immunoglobulin (0.4 g/kg/daily) was started immediately. Although inotropic support and medications were given to the patient, cardiopulmonary arrest occured on the ninth postoperative day and he died inauspiciously.
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Discussion Although GBS has occasionally been reported after cardiac surgery, there is no case report in the literature of MFS after coronary artery bypass surgery.5 To our knowledge, we describe the first case of MFS after coronary bypass surgery. Although cardiac surgery with CPB may increase the incidence of MFS and GBS, the pathological mechanism is unclear.6 A humoral immune response with deposition of complements and immunoglobulins and a cellular response of infiltrating macrophages and T cells are the most common hypotheses on the underlying mechanism of these syndromes.7 After cardiac surgery, several factors may be triggered to initiate an inflammatory response. These include cardiopulmonary bypass (extracorporeal circulation), ischaemia and reperfusion injury. When patients present with rapidly progressive paralysis, a diagnosis of GBS and variants such as MFS need to be made as soon as possible. The diagnosis is largely based on clinical patterns because radiological and diagnostic markers are not available for most variants of the syndrome. MFS is a clinical diagnosis, but additional investigations may be helpful or even necessary for confirmation. Examination of CSF is important, especially to exclude other causes of weakness associated with an increase in CSF cell count.8 Nerve conduction studies may help support the diagnosis, to discriminate between axonal and demyelinating subtypes, but nerve conduction abnormalities are most pronounced two weeks after the start of weakness.9 Severe, generalised manifestations of GBS and MFS with respiratory failure affect 20 to 30% of cases.10 Treatment with intravenous immunoglobulin or plasma exchange is the optimal management approach, alongside supportive care. Intravenous administration of high-dose immunoglobulin was found to be as effective as plasma exchange.11
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autoimmune and unexpected neurological disorders such as MFS after coronary bypass surgery.
References 1.
Wakerly BR, Uncini A, Yuki N, et al. Guillain–Barre and Miller–Fisher syndromes – new diagnostic classification. Nat Rev Neurol 2014; 10(9): 537–544.
2.
Mori M, Kuwabara S, Yuki N. Fisher syndrome: clinical features, immunopathogenesis and management. Expert Rev Neurother 2012; 12(1): 39–51.
3.
Sejvar JJ, Baughman AL, Wise M, et al. Population incidence of Guillain–Barre syndrome: a systematic review and meta-analysis. Neuroepidemiology 2011; 36(2): 123–133.
4.
Dagklis IE, Papagiannopoulos S, Theodoridou V, Kazis D, Argyropoulou O, Bostantiopoulou S. Miller–Fisher syndrome: Are antiGAD antibodies implicated in its pathophysiology? Case Rep Neurol Med 2016; 2016: 3431849.
5.
Hekmat M, Ghaderi H, Foroughi M, Mirjafari A. Guillain–Barre syndrome after coronary bypass graft surgery: A case report. Acta Med Iran 2016; 54(1): 76–78.
6.
Cingoz F, Tavlasoglu M, Kurkluoglu M, Sahin MA. Guillain–Barre syndrome after coronary artery bypass surgery. Interact Cardiovasc Thorac Surg 2012: 15(5): 918–919.
7.
Hartung HP, Willison HJ, Kieseier BC. Acute immunoinflammatory neuropathy: Update on Guillain–Barre syndrome. Curr Opin Neurol 2002; 15: 571–577.
8.
Van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, Van doorn PA. Guillain–Barre syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol 2014; 10: 469–482.
9.
Hadden RD, Cornblath DR, Hugbes RA, et al., for the plasma exchange/sandoglobulin
Guillain–Barre
syndrome
trial
group.
Electrophysiological classification of Guillain–Barre syndrome: Clinical associations and oucome. Ann Neurol 1998; 44: 780–788. 10. Fokke C, Van den Berg B, Drenthen J, Walgaard C, Van Doorn PA,
Conclusion MFS, which is a variant of GBS, is a rare but severe neurological complication after cardiac surgery. Cardiac surgery may be a trigger for immune-mediated responses and may cause devastating complications. It is important to be alert to de novo
Jacobs BC. Diagnosis of Guillain–Barre syndrome and validation of Brighton criteria. Brain 2014; 137: 33–43. 11. Van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain–Barre syndrome. Dutch Guillain–Barre study group. N Eng J Med 1992; 326: 1123–1129.
ECG rhythms CPD CPD developed by Prof Rob Scott Millar, Cardiac Clinic, UCT/Groote Schuur Hospital CPD overview: Following the introductory “Approach to Rhythms”, this online educational CPD quiz will consist of a series of ECGs with a variety of important cardiac rhythms. Each will be accompanied by a series of questions, followed by a detailed analysis and explanation. Target audience: Cardiologists, physicians, emergency unit doctors and anaesthetists. Including those studying for FCP and certificate in cardiology. Total time commitment: ± 30 to 60 minutes. Assessment information: A pass mark of 70% is required. A candidate has 60 days to complete the CPD after registration. CPD certificate: A PDF certificate of completion will be issued on successful completion the CPD. CPD enrollment fee: Free / no charge. Important notice: The CPD was made possible by an unrestricted educational sponsorship from Bayer Pharmaceuticals South Africa, which had no control over the content. Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.
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Shown to reduce the risk of atherosclerotic events in a wide range of patients with a history of: • • • •
Stroke3,4,6 PAD3 STEMI4,5 Unstable Angina/NSTEMI6
For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za PHARMA DYNAMICS CLOPIDOGREL 75 mg. Each tablet contains 75 mg clopidogrel. S3 A42/8.2/0128. NAM NS2 10/7.1/0377. For full prescribing information, refer to the package insert approved by the Medicines Control Council, October 2008. 1) Database of Medicine Prices (14 March 2017). Department of Health website. http://www.mpr.gov.za - Accessed on 30 March 2017. 2) Poponina TM, et al. Current approaches to the prevention of thrombotic complications in patients with acute coronary syndrome without ST-segment elevation. Topical issues of heart and vascular diseases. 2009;4:4-9. (English translation) 3) Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Vascular Medicine 1998;3:257-260. 4) COMMIT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet 2005;366(9497):1607-1621. 5) Sabatine MS, et al. Addition of Clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. New England Journal of Medicine 2005;352:1179-89. 6) The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine 2001;345:494-502. PDCLD395/04/2017.
Cardiovascular Journal of Africa . Vol 28, No 6, November/December 2017
cost effective1, clinically proven2 reduction of atherosclerotic events
• Images in Cardiology
Published online: • Efficacy of cardiac MRI in sub-aortic aneurysm case