CVJA Volume 21, Issue 4

JULY / AUGUST 2010 VOL 21 NO 4

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CardioVascular Journal of Africa (official journal for PASCAR)

• Advance publications • Encouraging patients with chronic atrial fibrillation to use anticoagulation therapy • Concurrent resistance and aerobic training • Microalbuminuria in hypertensive patients

• Right ventricular systolic function using tricuspid annular-plane systolic excursion Cardiovascular Journal of Africa . Vol 21, No 4, July/August 2010

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• Metabolic syndrome indicators in urban black South African men

• Diastolic heart failure • A halo in the heart during coronary angiography

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VOL 21, NO 4. JULY / AUGUST 2010

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial

183 The cost of coping: a cardio-neuro-metabolic risk for black South Africans?

L Malan • NT Malan • A Du Plessis • MP Wissing • JC Potgieter • YK Seedat

From the Editor’s Desk

185 Advance publications AJ Brink

Cardiovascular Topics

186 Assessment of right ventricular systolic function using tricuspid annular-plane systolic excursion in Nigerians with systemic hypertension KM Karaye • AG Habib • S Mohammed • M Rabiu • MN Shehu 190 News from the American Diabetes Association (ADA): Update from Orlando, USA, 25–29 June 2010 J Aalbers 192 Value of trans-oesophageal echocardiography as a method of encouraging patients with chronic atrial fibrillation to use anticoagulation therapy A Bakalli • L Kamberi • G Dragusha • N Zeqiri • F Gashi • L Prekpalaj 196

Concurrent resistance and aerobic training as protection against heart disease I Shaw • BS Shaw • GA Brown • JF Cilliers

200

Prevalence of microalbuminuria in hypertensive patients and its associated cardiovascular risk in clinical cardiology: Moroccan results of the global i-SEARCH survey – a sub-analysis of a survey with 21 050 patients in 26 countries worldwide R Habbal • AR Sekhri • M Volpe • i-Search Investigators

206

Coping and metabolic syndrome indicators in urban black South African men: the SABPA study A Du Plessis • L Malan • NT Malan

INDEXED AT SCISEARCH (SCI), PUBMED AND SABINET Editors Editor-in-Chief (South Africa) PROF AJ BRINK Assistant Editor Prof JAMES KER (JUN) Regional Editor (Cameroon) Prof JC Mbanya Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Editorial Board

prof PA Brink Experimental & Laboratory Cardiology PROF R DELPORT Chemical Pathology PROF MR ESSOP Haemodynamics, Heart Failure & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure PROF J KER (SEN) Hypertension, Cardiomyopathy, Cardiovascular Physiology DR J LAWRENSON Paediatric Heart Disease

PROF A LOCHNER Biochemistry/Laboratory Science PROF BM MAYOSI Chronic Rheumatic Heart Disease DR MT MPE Cardiomyopathy PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society PROF MM SATHEKGE Nuclear Medicine/Society PROF YK SEEDAT Diabetes & Hypertension PROF H DU T THERON Invasive Cardiology

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology) DR ULRICH VON OPPEL Wales (Cardiovascular Surgery) PROF PETER SCHWARTZ Italy (Dysrhythmias) PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

Publishing Consultant Mike Gibbs

Review Article

212 The clinical quandary of left and right ventricular diastolic dysfunction and diastolic heart failure ER Schwarz • R Dashti 220 Letter

to the Editor

CONTENTS

Case Reports

221 A halo in the heart during coronary angiography: calcified left ventricular aneurysm with thrombus formation H Fotbolcu • K Ozden • C Sengul • D Duman • İ Di 223 A coronary artery anomaly: type IV dual left anterior descending artery M Celik • A Iyisoy • T Celik 225 Serotonin and catecholaminergic polymorphic ventricular tachycardia: a possible therapeutic role for SSRIs? S Chen • Q Duan • K Tang • D Zhao • Y Xu

VOL 21, NO 4. JULY / AUGUST 2010

229

Coeur en sabot F Aziz • M Abed

Drug Trends

232 ARBs and possible cancer risk J Aalbers High-risk patients benefit most from nifedipine GITS–telmisartan combination J Aalbers Increased heart rate in high-risk hypertensives related to increased heart failure and sudden death J Aalbers

It's the shell that makes

Cardiovascular and diabetes research in Africa to benefit from Servier sponsorship

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safer.

Amlodipine + atorvastatin single pill is the most effective choice for primary prevention J Aalbers 244

Safety-Coated R

81mg

Book Review

The ORIGINAL low dose aspirin for optimum cardio-protection

The Sinatra Solution. Metabolic Cardiology J Straughan

Assistant Editor Special Assignments julia aalbers Tel: 021 976 4378 Fax: 086 610 3395 e-mail: jaalbers@icon.co.za

Production Editor SHAUNA GERMISHUIZEN Tel: 021 785 7178 Fax: 086 628 1197 e-mail: shaunag@xsinet.co.za

Editorial Assistant & Circulation ELSABÉ BURMEISTER Tel: 021 976 8129 e-mail: elsabe@cvja.co.za

Production Co-ordinator

WENDY WEGENER Tel: (021) 976-4378 e-mail: wendy.icon@wol.co.za

GAUTENG CONTRIBUTOR

PETER WAGENAAR Cell 082 413 9954 e-mail : skylark65@myconnection.co.za

Editorial BOARD

The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published six times a year, the deemed publication date being the seventh day of the second designated month, i.e. 7 February, 7 April, 7 June, 7 August and 7 October.

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Postal address: PO Box 1013, Durbanville, 7551 Tel/Fax: 021 976 8129 Int.: +27 21 976 8129 e-mail: info@cvja.co.za Electronic abstracts available on Pubmed Audited circulation

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Subscriptions for six issues: South Africa: R300 (excl VAT) Other African countries: $30 Overseas: Institutions: R845 ($82) Individuals: R1 080 ($105) The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

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183

Editorial The cost of coping: a cardio-neuro-metabolic risk for black South Africans?

Psychosocial stress is a contributing factor to cardiovascular disease.1 An important way of investigating the mechanisms underlying this association is acute psycho-physiological stress testing, involving measurement of physiological responses to laboratory-induced stress. Psycho-physiological stress testing allows individual differences in responses to standardised stress to be evaluated and related to psychosocial and cardiovascular risk factors. Accumulating evidence has demonstrated associations of disturbed psycho-physiological responses with subclinical measures of atherosclerosis, hypertension and metabolic risk.2-11 The complex pattern of responding to stress is influenced by individual differences, such as coping style, race and ethnicity, genetic make-up, background stress, and lifestyle habits, which should be taken into account when interpreting results.

For example, a unique interplay between cardiac and vascular responses in urban black Africans2 is thought to contribute towards a heightened risk of hypertension in this group. Whether or not psycho-physiological risk markers provide prognostic information over and above that of established risk markers is not clear but adapting to or appraisal of an urban environment could add to heightened responses.

There are, however, marked ethnic differences in cardiovascular responses or reactivity (CVR) that may in part be explained by psychosocial factors. Black Africans7,8 and AfricanAmericans4 normally and when exposed to stressful situations exhibit exaggerated CVR and a higher risk for the development of hypertension1 in comparison to Caucasians. In three separate regions, including rural and urban black South Africans, results demonstrated increased vascular responses on exposure to the handgrip and cold pressor tests in urban participants compared to their rural counterparts. It is suggested that in urban Africans the physiological adaptation process is inclined to shift towards increased vascular responses and prevalence of hypertension. We might speculate that the individual who experiences emotional– social–cultural disruption in an urban environment is in a continuous state of hyper-vigilant coping and vascular sympathetic hyperactivity/overdrive through exaggerated CVR. Mental and chronic psychosocial stress triggers sympathetic nervous system (SNS) hyperactivity and has been shown to be associated with increased vascular responsiveness, pressure overload, hypertension and myocardial ischaemic risk.5,7 Also, increased vascular and plasma renin responses seen in black African men further increase sympathetic activity through peripheral vascular hyper-responsiveness and higher blood pressure.6,7,9 This change to a high vascular resistance pattern accompanying hypertension predisposes to the development of left ventricular hypertrophy. In fact, studies show that African-Americans have greater left ventricular wall thickness than Caucasians, suggest-

ing that increased peripheral vascular resistance may be due to structural changes in the vasculature. However, it is not certain whether this is also true for black Africans.

The concept of coping style or strategies implies that humans have a differential capacity to adapt to the same environmental conditions. When attended to and appraised in certain ways, a coordinated set of responses involving behavioural and physiological systems is triggered.3 Mainly, two different appraisals or stress coping responses may be distinguished: firstly, defensive problem-solving active coping (high AC), seeking social support and being-in-control responses, which elicit fight-or-flight b-adrenergic central cardiac responses. Secondly, avoidance coping (low AC) and loss-of-control responses which elicit defeat α-adrenergic vascular responses and are associated with pathology.3 If a coping strategy fails, stress pathology may develop because of an over-arousal of the sympathetic nervous system, thereby increasing the risk for related cardiovascular diseases (CVD).4 It is difficult to fully elucidate if an enhanced stress response is dependent on the appraisal of the stressor, and if mental stress evokes the same stress response pattern in groups of different ethnicity. What is however evident from animal studies is that stress and re-exposure illicit different mono-aminergic (nor-adrenaline, dopamine and serotonin) responses in cortical and sub-cortical (e.g. hippocampus) brain regions, resulting in behavioural changes, and which have their origin in altered functioning of the hypothalamic–pituitary–adrenal stress axis. Appraisal or detection of stressful stimuli at conscious and subconscious levels involves the thalamus, sensory and prefrontal cortex. Reciprocal connections exist with several sub-cortical pathways, determining autonomic and emotional responses through the hypothalamus and amygdala.5 Defensive high active coping responses are generated in a reward centre, i.e. the paraventricular nuclei of the hypothalamus, secreting vasopressin, involving sub-cortical pathways via central cardiac b-adrenergic response patterns.5 Animal studies indicate that while acute stress significantly elevates nor-adrenalin levels, especially in the hippocampus, a significant attenuation is experienced following re-experience.

Interestingly, this does not occur in the frontal cortex, suggesting that subsequent behavioural changes following re-stress are driven by adrenergic-mediated changes in the hippocampus, such as deficits in cognition. The latter will compromise stress coping and stress responsiveness and in this way ultimately compromise central and peripheral cardiovascular response mechanisms. Hence a sensitisation of defensive pathways may occur, with α-adrenergic vascular pathways gaining influence.

Consequently, the risk for established essential hypertension in high-demand situations may increase.5

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It has also been shown that peripheral vascular adrenergic hyperactivity contributes to human hypertension8 and is characterised by (1) down-regulation of α-adrenergic receptors, (2) an impairment in the neuronal uptake of nor-epinephrine from sympathetic nerve terminals, and (3) an altered functional interaction at the level of the vascular wall between nor-epinephrine, epinephrine, and other humoral (such as angiotensin II), metabolic (including insulin and leptin), or endothelium-derived substances, e.g. asymmetrical dimethylarginine (ADMA).8 Altogether, the above proposed mechanisms coupled to lowrenin hypertension,6 salt sensitivity1 and increased vascular responses in Africans2,6,7,9 and African-Americans may contribute to an increase in peripheral vasoconstrictor tone, as well as an abnormal vasomotor responsiveness to adrenergic stimuli in hypertension.

Overall, subjects maintain their characteristic response tendencies (central or vascular) across mental tasks but it was also shown that when the task was long enough, certain individuals shifted from cardiac to vascular responders. This could support the findings of Malan et al.7,9 where β-adrenergic responses on exposure to acute mental stress were elicited in high AC Africans in a rural environment opposed to α-adrenergic responses in high AC Africans in an urban environment. Therefore, we might propose that if a hyperkinetic–hyperactive peripheral adrenergic sympathetic drive is elicited during acute/chronic stress, coupled to dissociation between a behavioural and a physiological defensive high AC β-adrenergic coping style, it could imply uncontrollable stress.2 A resultant high vascular resistance pattern emerges, augmenting possible inward eutrophic vascular remodelling and inflammation, a hallmark of hypertension.5 Implementing Fig. 1, these data suggest a physiological adaptation process of black Africans associated with an urban environment or chronic psychosocial stress. Moving from a traditional rural African setting (a collectivistic cultural context with support networks) to an urban area (an individualistic cultural environment without social support) is likely to exacerbate stress. Over time, the combined effects of stress, enhanced vascular reactivity, associated with α-adrenergic stimulation and synergistic effects on cortisol may further impact on depression/stress via the hypothalamus–pituitary–adrenal cortex axis (submitted to Biol Psych 2010) and predispose these individuals to greater cardiovascular risk. Clearly, our understanding of these interactions is critical for the development of recommendations for early prevention of hypertension and the metabolic syndrome in urbanised Africans.

Future studies are, however, required to establish if stress responses to behaviourally induced stressors could prospectively predict hard clinical CVD endpoints, such as myocardial infarction and cardiovascular death. Laboratory-induced responses are relatively stable within an individual and consistent across time, although the responses might not always be reflective of everyday life. Therefore, future work is required that examines not only a battery of laboratory measures but also the associations of ambulatory responses to real-life stress in relation to risk of CVD. The first well-controlled psycho-physiological study in Africa, the SABPA I study (Sympathetic activity and Ambulatory Blood Pressure study on Africans) was conducted in 2008/2009. It is an example of such a study where genetic polymorphisms, adrenergic, pro-inflammatory, prothrombic, blood pressure,

1 ALARM REACTION Urban environment 3 2

EXHAUSTION STAGE

RESISTANCE STAGE

Dissociation between behavioural and physiological AC cardioneuro-metabolic responses: ↑lifestyle diseases (HT, IFG, sensitized defensive pathway, loss of control, chronic stress)

↑vascular responses, ↑HT, ↑glucose, ↑stress (↑Prolactin, ↓Testosterone, ↑Cortisol:Testosterone, ↑Cortisol:Prolactin)

Fig. 1. Implementing the general adaptation syndrome10 to interpret the dissociation between behavioural and physiological AC cardio-neuro-metabolic responses in urban black Africans. HT = hypertension; AC = active coping; IFG = impaired fasting glucose.

heart rate variability (HRV), ischaemic events, oxidative stress, and stress hormone responses to acute mental stress were evaluated in urban teachers from South Africa. In addition, the study will incorporate ambulatory measures during the normal working day. Preliminary findings from SABPA I indicated that the prevalence of HIV/AIDS in the black SABPA teachers was only 9%, opposed to the overwhelmingly increased hypertension prevalence rates in the black teachers [males (79%), females (45%)]. This implies that CVD risk attributable to other risk factors apart from the inflammatory status contributed to their overall health profile, and risk factors should be broadened without concentrating on only the HIV/AIDS factor. Data from the SABPA I and SABPA II follow-up (2011/2012) studies will therefore provide an estimate of the health/disease burden attributable to established and emerging risk factors for CVD, metabolic syndrome, psychological distress and progression of subclinical atherosclerosis.

Future studies should examine whether non-pharmacological interventions that reduce SNS hyper-responsiveness, such as physical activity and/or active relaxation breathing techniques could lessen sympathetic drive and increase vagal outflow.

LEONÉ MALAN, NT MALAN, A DU PLESSIS Hypertension in Africa Research Team (HART), School for Physiology, Nutrition and Consumer Sciences, North-West University, Potchefstroom Campus, Potchefstroom, South Africa MP WISSING, JC POTGIETER Psychosocial Behavioural Sciences, North-West University, Potchefstroom Campus, Potchefstroom, South Africa YK SEEDAT The Renal Hypertension Unit, Nelson Mandela School of Medicine, University of Kwa-Zulu Natal, Durban, South Africa

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References 1. Opie L, Seedat YK. Hypertension in Sub-Saharan African populations.

Circulation 2005; 112: 3562–3568.

2. Hamer M, Malan L. Psychophysiological risk markers of cardiovascular disease. In: Psychophysiological Biomarkers of Health. Special Edition: Neurosc Biobehav Rev 2010 (in press).

3. Lazarus RS. Coping theory and research: past, present, and future.

Psychosom Med 1993; 55: 234–247.

4. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87: 873–904.

5. Korner PI. Essential Hypertension and its Causes: Neural and Non-Neural Mechanisms. New York: Oxford University Press, 2007: 347–358.

6. Hamer M, Malan L, Schutte AE, Huisman HW, van Rooyen JM, Schutte R, et al. Plasma renin responses to mental stress and carotid intima

media thickness in black Africans: The SABPA Study. J Hum Hypertens 2010 (in press).

7. Malan L, Schutte AE, Malan NT, et al. Specific coping styles of Africans during urbanization: comparing cardiovascular responses and perception of health data. Biol Psych 2006; 72: 305–310.

8. Grassi G, Arenare F, Quarti-Trevano F, Seravelle G, Mancia G. Heart rate, Sympathetic Cardiovascular Influences, and The Metabolic Syndrome. Prog Cardiovasc Dis 2009; 52: 31–37.

9. Malan L, Malan NT, Wissing MP, Seedat YK. Coping with urbanization: a cardiometabolic risk? The THUSA study. Biol Psychol 2008; 79: 323–328.

10. Selye H. The Stress of Life. London: Longmans Green, 1956.

11. Du Plessis A, Malan L, Malan NT. Coping and metabolic syndrome indicators in urban black South African men: the SABPA study. Cardiovasc J Afr 2010; 21(4): 206–211.

From the Editor’s Desk Advance publications

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The office of the Cardiovascular Journal of Africa has recently experienced a dramatic increase in the number of articles submitted to this journal. The articles emanate from authors in many diverse countries. As a consequence of the volume of articles, we are experiencing delays in the length of time to publish them.

To obviate this, we have now made available an additional option for authors to advance publish their articles online. We must charge for this option as it involves additional expense.

Local authors in Africa will pay R1 000 and those overseas R2 500. This amount could be budgeted for in the research grant if one knows beforehand that the article needs to be advance published.

Authors will now have the immediate benefit of having their article appear online on PubMed, but will have to wait as usual for the article to appear in the printed journal. We trust that this will be of help in getting your important research to the immediate attention of other interested researchers and readers.

Please contact Elsabé Burmeister at elsabe@cvja.co.za for more information.

160

Articles received Articles rejected

140 Number of articles

120 100 6 months

80 60 40 20 0

2007

2008

Year

2009

2010

Fig. 1. The ratio of articles received and rejected for the Cardiovascular Journal of Africa from January 2007 to July 2010.

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Cardiovascular Topics Assessment of right ventricular systolic function using tricuspid annular-plane systolic excursion in Nigerians with systemic hypertension KM KARAYE, AG HABIB, S MOHAMMED, M RABIU, MN SHEHU

Summary

Cardiovasc J Afr 2010; 21: 186–190

Aim: Right ventricular (RV) systolic function in patients with hypertensive heart disease (HHD) is not well characterised.

The primary aim of this study was to assess the systolic function of the right ventricle in patients with HHD using tricuspid annular-plane systolic excursion (TAPSE).

Methods: The study was cross-sectional in design and carried out in Kano, Nigeria. Patients were recruited if they had HHD on echocardiography and were at least 15 years of age.

Patients with other cardiac pathologies such as ischaemic and valvular heart diseases were excluded. Patients were considered to have abnormal RV systolic function if they had reduced values of TAPSE (< 15 mm). A p-value of < 0.05 was considered statistically significant.

Results: A total of 186 patients were serially recruited over seven months. Of these, 131 (70.4%) had normal RV systolic function (group 1) and 55 patients (29.6%) had abnormal function (group 2). Group 2 patients were older (p = 0.002) and had a higher prevalence of peripheral oedema (p = 0.002), moderate to severe dyspnoea, higher heart rate and lower left ventricular ejection fraction (p < 0.001). Atrial arrhythmias were also more prevalent among group 2 patients (p < 0.05).

The best correlate to TAPSE was the septal mitral annularplane systolic excursion (r = +0.541, p < 0.001). Several variables such as age predicted the presence of reduced TAPSE. Conclusion: The study found that almost one-third of patients with HHD in Kano had RV systolic dysfunction as defined by reduced TAPSE, and these patients had a greater prevalence of factors associated with morbidity and mortality.

DOI: CVJ-21.011

Keywords: right ventricular systolic function, hypertension, TAPSE Submitted 25/12/09, accepted 10/3/10

www.cvja.co.za

The right ventricle has a complex three-dimensional structure with a crescent-shaped cavity when viewed in cross section. It consists of three parts: the inflow tract, the apical ‘trabecular’ portion (which is basically immobile) and the outflow tract.1 The inflow and outflow portions contract perpendicularly to each other: the proximal part longitudinally and the distal part circumferentially, in the orientation of their respective muscle fibres.1 Although the right ventricle can now be imaged and studied in several ways, two-dimensional (2D) guided M-mode echocardiography is an attractive tool due to its simplicity. Right ventricular (RV) long-axis movement represented by tricuspid annularplane systolic excursion (TAPSE) is an index that correlates excellently with RV ejection fraction obtained with radionuclide angiography and is independent of any geometric assumption.2 TAPSE provides a simple method for global RV functional assessment and is a strong predictor of prognosis in heart failure.3 For many years the right ventricle was grossly undervalued and considered to function mainly as a conduit, while its contractile performance was considered haemodynamically unimportant. Since the early 1950s, however, the relevance of the chamber in the maintenance of normal cardiac physiology was recognised in several cardiovascular disorders.4 Studies on RV function among patients with hypertensive heart disease (HHD) are rather few and have focused mainly on the diastolic function of the chamber.5,6 The primary aim of this study was to assess the systolic function of the right ventricle in patients with HHD, using TAPSE. A secondary aim was to compare the characteristics of patients found to have normal RV systolic function with those with abnormal function, as well as determine the correlates of TAPSE among the patients.

Methods Department of Medicine, Bayero University, Kano, Nigeria KM KARAYE, FWACP, kkaraye@yahoo.co.uk AG HABIB, FWACP

Department of Medicine, Aminu Kano Teaching Hospital, Kano, Nigeria KM KARAYE, FWACP, kkaraye@yahoo.co.uk AG HABIB, FWACP S MOHAMMED, MWACP M RABIU, MB BS MN SHEHU, MWACP

The study was carried out in three echocardiography laboratories within the city of Kano in Nigeria: Aminu Kano Teaching Hospital (AKTH), Murtala Muhammad Specialist Hospital (MMSH) and a private centre (PC). Kano is a state in the north-western geopolitical zone of Nigeria and was previously reported to have the highest prevalence of systemic hypertension in the country.7 The research ethics committees of the study centres reviewed and approved the study protocol. All recruited patients gave informed written consent to participate in the study. The study conformed to the principles outlined in the Declaration of

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Helsinki, on the ethical principles for medical research involving human subjects.8 The study was cross sectional in design and patients were recruited serially from October 2008 to May 2009. After computing a minimum sample size using a validated formula,9 applying a prevalence of HHD in Kano of 56.7% (among patients referred for echocardiography),10 and a sample error of 10%, 186 patients were eventually recruited to improve the power of the study.

Information obtained from all recruited patients included relevant history, and findings from a physical examination, echocardiogram and electrocardiogram (ECG). Additional information obtained included recent (tested within the previous eight weeks) serum levels of creatinine and urea, and packed-cell volume (PCV) in venous blood.

Transthoracic echocardiography was performed using the Aloka cardiac ultrasound system (model SSD 4000 PHD) in AKTH, the Toshiba diagnostic ultrasound machine (model SSA 325A) in MMSH and the ATL Ultramark 9 ultrasound machine at the private centre, with 3.75-MHz sector transducers. The procedure was performed according to the recommendations of the American Society of Echocardiography,11,12 and by the same person (KMK) in all cases to avoid inter-observer variability.

Patients were examined in the left lateral decubitus position.

Right ventricular long-axis function (TAPSE) was recorded from the apical four-chamber view with the M-mode cursor positioned at the free wall angle of the tricuspid valve annulus.

Right ventricular long-axis excursion amplitude (TAPSE) was taken from end-systole to end-diastole.13 Reduced TAPSE was defined as a value of < 15 mm, which has been found to be a strong predictor of death or emergency heart transplantation among heart failure patients.3 Normal RV systolic function was therefore defined as TAPSE of ≥ 15 mm (patients categorised as group 1), while values below 15 mm were considered abnormal (patients categorised as group 2).

Evidence of raised pulmonary vascular resistance, suggestive of pulmonary hypertension, was defined as pulmonary valve (PV) acceleration time of < 100 ms.

Among the recruited hypertensive patients, a diagnosis of hypertensive heart disease was made if an abnormality was detected on the echocardiogram, which was causally related to hypertension and without an alternative explanation. These abnormalities included any of the three abnormal LV geometric patterns of HHD as defined by Ganau et al.,14 increased left atrial (LA) size and volume, and diastolic or systolic left ventricular dysfunctions.

Systemic hypertension was defined according to the recommendation of the World Health Organisation/International Society of Hypertension (WHO/ISH), using the cut-off values of systolic/diastolic blood pressures (SBP/DBP) of ≥ 140/90 mmHg.15 Renal failure was simply defined as the presence of a serum creatinine concentration of ≥ 176 µmol/l (≥ 2 mg/dl).15 Anaemia was defined as packed-cell volume of < 39% in men and < 36% in women. History of tobacco smoking was considered a risk factor if smoking was daily, regardless of the dose. Excessive alcohol intake was defined as a weekly intake of more than 21 units for men and 14 units for women.16 The diagnosis of diabetes mellitus (DM) was based on WHO criteria.17 Cardiac rhythm disturbances were defined according to the recommendations of the American College of Cardiology/American Heart Association task force on clinical data standards.18 Ischaemic heart disease was excluded by the presence of all of the following: no history of angina,

187

no ECG changes suggestive of myocardial infarction,18 and no regional wall motion abnormalities on echocardiography.

Data were analysed with SPSS version 11.5. Means and standard deviations were computed and presented for quantitative variables. The Student’s t-test, Wilcoxon rank-sum (z), Fisher’s exact and Chi-square (χ2) tests and measures of effect were used for comparison between groups as appropriate, with p < 0.05 regarded as significant. Pearson’s correlation (r) coefficient and the binary logistic regression model were used to analyse the associations between TAPSE and a number of variables.

Results A total of 186 patients were serially recruited and studied from the three centres over seven months (October 2008 to May 2009), comprising 89 males (47.85%) and 97 females (51.15%). The mean age of all patients was 55.94 ± 17.00 years.

Table 1 describes the baseline characteristics of the patients and compares patients with normal RV systolic function (group 1) with those with abnormal function (group 2). The table shows that compared with patients in group 2, group 1 patients were significantly younger and tended to have a shorter duration of hypertension. Group 1 patients also had a lower prevalence of features of heart failure (dyspnoea and peripheral oedema) and anaemia, and lower mean heart rate.

The mean TAPSE in all patients was 18.30 ± 5.82 mm. Table 2 compares the echocardiographic features of the two groups.

Patients in group 2 had a significantly larger right ventricle, left ventricle and left atrium, and lower mean TAPSE. Indices of LV long-axis function (LV lateral and septal APSE) were also significantly lower among group 2 patients.

Table 3 shows the findings in the resting ECG of the patients.

Atrial arrhythmias were more prevalent among group 2 patients, and the most frequent were atrial fibrillation or flutter. Group 2 patients also had statistically significant shorter PR and longer QTc intervals.

Table 4 describes the correlates of TAPSE. The strongest correlates of TAPSE were its corresponding indices of long-axis function of the left ventricle [lateral and septal annular-plane systolic excursion (APSE)].

In the logistic regression model controlling for other confounding factors, independent predictors of reduced TAPSE were age [odds ratio (OR) = 1.035; confidence interval (CI) = 1.012–1.058 years; p = 0.002], peripheral oedema (OR = 2.921; CI = 1.036– 8.239; p = 0.043), LA diameter (OR = 1.061; CI = 1.001–1.125 mm; p = 0.046), LV end-diastolic diameter (LVEDD) (OR = 0.882; CI = 0.811–0.959 mm; p = 0.003), LV end-systolic diameter (LVESD) (OR = 1.133; CI = 1.058–1.214 mm; p < 0.001), LV out-flow tract (LVOT) diameter (OR = 0.855; CI = 0.754–0.970 mm; p = 0.015), and septal APSE (OR = 0.777; CI = 0.641–0.943 mm; p = 0.011).

Discussion Although systemic hypertension is one of the most researched subjects in medicine, the literature on right ventricular systolic function among hypertensives is quite scanty,6 especially among Africans. This study showed that almost one-third of patients with HHD (29.6%) on echocardiography in Kano had RV systolic dysfunction in the form of reduced RV long-axis excursion (TAPSE).

In a sample population of patients with heart failure of vari-

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TABLE 1. BASELINE CHARACTERISTICS Group 1 Group 2 n = 131 (70.4%) n = 55 (29.6%) p-value All patients Males/females 67/64 22/33 0.199 89/97 Mean age (years) 53.50 ± 17.10 61.78 ± 15.38 0.002* 55.94 ± 17.00 Urban residence 112 (85.5%) 42 (76.4%) 0.141 154 (82.8%) Duration of hypertension (years) 5.57 ± 6.62 7.87 ± 8.83 0.054 6.24 ± 7.21 Dyspnoea (NYHA III or IV) 46 (35.1%) 33 (60.0%) 0.002* 79 (42.5%) Peripheral oedema 34 (26.0%) 30 (54.6%) < 0.001* 64 (34.4%) Smoking 6 (4.6%) 1 (1.8%) 0.676 7 (3.8%) Alcohol 13 (9.9%) 4 (7.3%) 0.681 17 (9.1%) Diabetes mellitus 11 (8.4%) 5 (9.1%) 0.878 16 (8.6%) Stroke/TIA 15 (11.5%) 2 (3.6%) 0.103 17 (9.1%) Anaemia 19 (14.5%) 18 (32.7%) 0.016* 37 (19.1%) Renal failure 20 (15.3%) 15 (27.3%) 0.101 35 (18.8%) Systolic BP (mmHg) 156.61 ± 30.50 149.25 ± 28.16 0.150 154.54 ± 29.97 Diastolic BP (mmHg) 95.11 ± 20.26 93.19 ± 18.51 0.570 100.88 ± 86.80 Pulse pressure (mmHg) 61.54 ± 22.95 56.06 ± 18.35 0.141 60.00 ± 21.85 Heart rate 88.52 ± 16.45 102.58 ± 19.45 < 0.001* 92.47 ± 18.41 PCV (%) 28.67 ± 10.67 30.46 ± 8.61 0.534 29.57 ± 9.63 Serum urea (mmol/l) 14.30 ± 11.21 14.16 ± 10.98 0.963 14.24 ± 11.00 Serum creatinine (µmol/l) 585.72 ± 789.49 333.33 ± 383.36 0.155 477.55 ± 654.72 *p-value statistically significant; PCV: packed-cell volume. All values are expressed as means ± standard deviations, or as proportions, or as numbers with percentages in parentheses.

TABLE 2. ECHOCARDIOGRAPHIC FEATURES Group 1 Group 2 n = 131 n = 55 (70.4%) (29.6%) p-value RVOTd (mm) 28.83 ± 5.50 31.02 ± 7.03 0.024* TAPSE (mm) 21.00 ± 4.60 11.82 ± 2.24 < 0.001* Left atrium (mm) 38.31 ± 7.50 43.04 ± 7.76 < 0.001* IVSd (mm) 11.25 ± 3.85 10.65 ± 4.43 0.358 LVPWd (mm) 9.64 ± 3.02 9.22 ± 2.99 0.383 LVEDD (mm) 51.69 ± 11.45 57.07 ± 13.51 0.006* LVEF (%) 57.88 ± 16.82 42.42 ± 19.00 < 0.001* PV acceleration time (ms) 119.71 ± 39.54 86.41 ± 27.10 < 0.001* LV lateral APSE (mm) 12.38 ± 4.11 8.80 ± 2.52 < 0.001* Septal APSE (mm) 11.50 ± 3.99 7.06 ± 4.04 < 0.001* *p-value statistically significant; LVEF: left ventricular ejection fraction; RVOTd: right ventricular out-flow tract dimension at end-diastole; TAPSE: tricuspid annular plane systolic excursion; IVSd: interventricular septal thickness at end-diastole; LVPWd: left ventricular posterior wall thickness at end-diastole; LVEDD: left ventricular enddiastolic dimension; PV: pulmonary valve. All values are expressed as means ± standard deviations.

ous aetiologies, including systemic hypertension, Puwanant et al. recently reported that 58% of the patients had reduced TAPSE (< 15 mm), in contrast to our finding of 29.6%.19 However, our study was exclusively on patients with HHD, and a history of diabetes mellitus (DM) was found in only 8.6%. In comparison, 51% of the patients in the series by Puwanant et al. had coronary artery disease, 37% had DM and 32.5% had cardiomyopathies.

In addition, the patients in the latter study were older than ours (mean age of 72 ± 14 vs 55.94 ± 17.00 years), and we have shown that older age predicted reduced TAPSE. Furthermore, differences in the aetiology of heart disease in the two studies could have amplified the disparities in TAPSE.19

TABLE 3. FINDINGS IN THE RESTING ELECTROCARDIOGRAMS Group 1 Group 2 Characteristic n = 30 (16.1%) n = 156 (83.9%) p-value PR interval (ms) 165.09 ± 30.96 136.15 ± 42.41 < 0.001* QRS duration (ms) 94.91 ± 18.99 99.84 ± 23.59 0.218 432.17 ± 47.31 455.97 ± 42.71 0.009* QTc interval (ms) Atrial fibrillation/ flutter 4 (3.1%) 11 (20.0%) < 0.001* Other SVT 1 (0.8%) 3 (5.5%) 0.043* Complete heart block 2 (1.5%) 0 – Complete LBBB 4 (3.1%) 4 (7.3%) 0.196 Complete RBBB 4 (3.1%) 1 (1.8%) 0.635 1st degree heart block 8 (6.1%) 1 (1.8%) 0.214 SVT: supraventricular tachycardias; LBBB and RBBB: left and right bundle branch block respectively. All values are expressed as means ± standard deviations or as numbers with percentages in parentheses.

It is possible that RV disease develops in parallel with a similar process on the left side in hypertensive patients, likely as a result of ventricular interdependence. This is supported by the close correlation we found between the TAPSE and the indices of LV long-axis function, lateral and septal APSE (r = +0.534 and +0.541, respectively, p < 0.001 for both). Ventricular interdependence is defined as the forces that are transmitted directly from one ventricle to the other through the myocardium and pericardium, independent of neural, humoral or circulatory effects. It is a consequence of the close anatomical association between the ventricles, which are encircled by common muscle fibres, they share a septal wall, and are enclosed within the pericardium.20 Future studies are however needed to corroborate our finding and to explore other explanations.

To the best of our knowledge, our study is the first, at least in Africans, to group and compare hypertensives based on normal

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TABLE 4. CORRELATES OF TAPSE TAPSE (mm) Variable r p-value* Age (years) +0.385 < 0.001 Duration of hypertension (years) –0.202 0.007 Heart rate –0.263 0.001 PR interval (ms) +0.216 0.025 QTc interval (ms) –0.256 0.004 RVOTd (mm) –0.223 0.002 Left atrium (mm) –0.232 0.001 LVEDD (mm) –0.207 0.004 LVESD (mm) –0.354 < 0.001 LVEF (%) +0.462 < 0.001 PV acceleration time (ms) +0.440 < 0.001 LV lateral APSE (mm) +0.534 < 0.001 Septal APSE (mm) +0.541 < 0.001 *p-value statistically significant; LVEF: left ventricular ejection fraction; RVOTd: right ventricular out-flow tract dimension at enddiastole; TAPSE: tricuspid annular plane systolic excursion; LVEDD: left ventricular end-diastolic dimension; PV: pulmonary valve.

or reduced TAPSE. We have shown that patients in group 2 with reduced TAPSE were older (p = 0.002), had longer duration of hypertension (p = 0.054) and higher prevalence rates of other indices associated with a poor prognosis. These indices include higher prevalence rates of moderate to severe dyspnoea (p = 0.002), peripheral oedema (p < 0.001) and anaemia (0.016). In addition, group 2 patients also had a shorter PR interval (p < 0.001), a longer QTc interval (p = 0.009), and a higher prevalence of supraventricular tachycardias (p = 0.043), including atrial fibrillation and flutter (p < 0.001).

Previous studies have shown that atrial tachyarrhythmias are the most common arrhythmias encountered in patients with RV failure. In the setting of acute RV failure or severe RV dysfunction, atrial tachyarrhythmias often lead to haemodynamic instability. Other studies have demonstrated that atrial flutter or atrial fibrillation is associated with an increased risk of morbidity or mortality in patients with RV myocardial infarction, pulmonary hypertension, and congenital heart disease (CHD). Right atrial dilatation and remodelling and postsurgical scars within the atria, as in postoperative CHD, represent important substrates for atrial flutter.4,21-24 Our study has demonstrated the propensity of HHD patients with RV systolic dysfunction to arrhythmias, but a prospective study with a larger sample size would be needed to corroborate the finding.

The strongest correlate to TAPSE was the septal mitral annular-plane systolic excursion (r = –0.541; p < 0.001). Other workers have found a strong correlation between TAPSE and RV ejection fraction,2 as well as indices of RV diastolic function.25 In the logistic regression model, age was among the predictors of TAPSE (OR = 1.035; p = 0.002), reconfirming the importance of age in predicting cardiovascular morbidity and mortality among persons with high blood pressure.15 Peripheral oedema is another clinical variable that was found to predict reduced TAPSE (OR = 2.921; p = 0.043), and its presence suggests the presence of RV failure. This finding is important, given that peripheral oedema is an easy-to-identify physical sign, and its presence increased the odds of reduced TAPSE almost three-fold.

The limitations of our study include the small sample size of

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patients with RV systolic dysfunction, as well as the limitation that is inherent to the study, which is the use of M-mode and 2D echocardiography to study the RV. Studies have shown the superiority of magnetic resonance imaging over other techniques for studying the right ventricle.26 However, echocardiography still has acceptable sensitivity, is widely available and affordable, and therefore has an important role in studying the right ventricle despite its limitation. In addition, TAPSE is easy to obtain, is reproducible, and is without significant inter-observer variability.2 To minimise this, all our echocardiograms were performed by a single individual.

Conclusion This study found that 29.6% of patients with HHD in Kano had RV systolic dysfunction in the form of reduced tricuspid annularplane systolic excursion. Such patients tended to be older, had evidence of worse LV systolic function and a higher prevalence of supraventricular arrhythmias. Several variables were found to correlate significantly with TAPSE, but the association was strongest with septal mitral annular-plane systolic excursion.

Predictors of reduced TAPSE included age, peripheral oedema and several echocardiographic variables. The presence of peripheral oedema increased the odds of reduced TAPSE about three-fold. We recommend that assessment of RV systolic function should be carried out routinely in all hypertensive patients requiring echocardiographic evaluation.

References 1. Bystrom B, Lindqvist P, Henein M. The right ventricle: knowing what is right. Int J Cardiovasc Imag 2008; 24: 701–702.

2. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 1984; 107(3): 526–531.

3. Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, et al. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000; 85: 837–842.

4. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance and management of right ventricular failure. Circulation 2008; 117: 1717–1731.

5. Myslinski W, Mosiecwicz J, Ryczak E, Barud W, Biłan A, Palusinski R, et al. Right ventricular function in systemic hypertension. J Hum Hypertens 1998; 12: 149–155.

6. Tumuklu MM, Erkorkmaz U, Ocal A. The impact of hypertension and hypertension-related left ventricle hypertrophy on right ventricle function. Echocardiograpy 2007; 24: 374–384.

7. Non-communicable Diseases (NCD) in Nigeria – rinal report of a national survey. Federal Ministry of Health – National Expert Committee on NCD, 1997.

8. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. J Postgrad Med 2002; 48: 206–208.

9. Lwanga SK, Lemeshow S. Sample size determination in health studies: a practical manual. Geneva, WHO 1991: 15.

10. Karaye KM, Sani MU. The impact of income on the echocardiographic pattern of heart diseases in Kano, Nigeria; Niger J Med 2008; 17(3): 350–355.

11. Sahn DJ, DeMaria A, Kisslo J, Weyman A. The committee on M-mode standardisation of the American Society of Echocardiography.

Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083.

12. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA.

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Recommendations for quantification of Doppler echocardiography: A report from the doppler quantification task force of the Nomenclature and Standards Committee of the American Society of Echocardiography.

J Am Soc Echocardiogr 2002; 15: 167–184.

13. Lindqvist P, Henein M, Kazzam E. Right ventricular outflow tract fractional shortening: an applicable measure of right ventricular systolic function. Eur J Echocardiogr 2003; 4: 29–35.

14. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, et al. Patterns of left ventricular hypertrophy and geometric remodelling in essential hypertension. J Am Coll Cardiol 1992; 19: 1550–1558.

15. World Health Organization, International Society of Hypertension writing group. 2003 World Health Organization (WHO) – International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11): 1983–1992.

16. Boon NA, Fox KAA, Bloom field P, Bradbury A. Cardiovascular disease. In: Haslett C, Chilvers ER, Boon NA, Colledge NR (eds).

Davidson’s Principles and Practice of Medicine, 19th edn. London: Churchill Livingstone, 2002: 357–481.

17. World Health Organization: Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO consultation.

Part I: diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, 1999.

18. Buxton AE, Calkins H, Callans DJ, DiMarco JP, Fisher JP, Greene HL, et al. ACC/AHA/HRS 2006 key data elements and definitions for electrophysiological studies and procedures: a report of the American College of Cardiology/American Heart Association task force on clinical data standards (ACC/AHA/HRS writing committee to develop data standards

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on electrophysiology). Circulation 2006; 114: 2523–2570.

19. Puwanant S, Priester TC, Mookadam F, Bruce CJ, Redfield MM, Chandrasekaran K. Right ventricular function in patients with preserved and reduced ejection fraction heart failure. Eur J Echocadiogr 2009; 10: 733–737.

20. Santamore WP, Gray L. Significant left ventricular contributions to right ventricular systolic function: mechanisms and clinical implications.

Chest 1995; 107: 1134–1145.

21. O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial infarction. Curr Probl Cardiol 2004; 29: 6–47.

22. Goldstein JA, Harada A, Yagi Y, Barzilai B, Cox JL. Hemodynamic importance of systolic ventricular interaction, augmented right atrial contractility and atrioventricular synchrony in acute right ventricular dysfunction. J Am Coll Cardiol 1990; 16: 181–189.

23. Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007; 153: 127–132.

24. Walsh EP, Cecchin F. Arrhythmias in adult patients with congenital heart disease. Circulation 2007; 115: 534–545.

25. Innelli P, Esposito R, Olibet M, Nistri S, Galderisi M. The impact of ageing on right ventricular longitudinal function in healthy subjects: a pulsed tissue Doppler study. Eur J Echocardiogr 2009; 10: 491–498.

26. Blecker GB, Steendijk P, Holman ER, Yu C-M, Breithardt OA, Kaandorp TAM, Schalij MJ, van der Wall EE, Nihoyannopoulos P, Bax JJ. Assessing right ventricular function: the role of echocardiography and complementary technologies. Heart 2006; 92(Suppl I): i19–i26: 10.1136/hrt.2005.082503.

News from the American Diabetes Association (ADA) Update from Orlando, USA, 25–29 June 2010 ACCORD retinopathy study shows intensive glycaemic control, and combination dyslipidaemia therapy with fenofibrate reduces retinopathy progression A study group of the ACCORD study has shown that targeting glycaemic control at the 6% HbA1c level and lipid therapy with fenofibrate instead of placebo significantly reduced the rate of progression of diabetic retinopathy.1 Intensive blood pressure control did not reduce progression.

The ACCORD study was an independent study sponsored by the National Heart, Lung and Blood Institute and companies did not participate in the study design or conduct, data accrual or analysis, or manuscript preparation, providing only the study drugs.

The more than 10 000 ACCORD patients with type 2 diabetes and HbA1c higher than 7.5% were randomly assigned to either the intensive glycaemic-control arm or standard control. Of these participants, 5 518 with dyslipidaemia were also randomly assigned in a two-by-two factorial design to receive simvastatin and fenofibrate or placebo. The remaining 4 733 participants were randomly assigned to either the intensive blood-pressure control (< 120 mmHg systolic blood pressure) or standard therapy (< 140 mmHg).

In this ACCORD eye study, participants with retinopathy at baseline were excluded; those included were comprehensively evaluated at baseline and at year four of the study. Progression of diabetic retinopathy was defined as at least three steps on the EDTRS severity scale, or development of retinopathy, requiring photocoagulation therapy or vitrectomy.

Results of the progression to retinopathy and moderate vision

Table 1. Progression to retinopathy and moderate vision loss Treatment Glycaemic therapy Intensive Standard Dyslipidaemia With fenofibrate With placebo Antihypertensive Intensive Standard

Progression of retinopathy n (%)

Moderate vision loss n (%)

104/1429 149/1427

(7.3) (10.4)

266/1629 273/1634

(16.3) (16.7)

52/806 80/787

(6.5) (10.2)

145/908 136/893

(16) (15.2)

67/647 54/616

(10.4) (8.8)

145/749 113/ 13

(19.4) (15.8)

loss are summarised in Table 1.

The early stoppage of the intensive glycaemic-control arm due to an increased rate of death from any cause after a mean of 3.5 years has influenced the retinopathy results in this arm, potentially underestimating the retinopathy benefits of good glycaemic control.

The beneficial effect of fenofibrate therapy on the progression of diabetic retinopathy at four years (6.3 vs 10.2% on placebo) provides further support to the findings of the FIELD study, which also showed visual benefits with fenofibrate.

J Aalbers, Special Assignments Editor 1. The ACCORD study group and ACCORD Eye study group. Effects of medical therapies on retinopathy p1.5rogression in type 2 diabetes. N Engl J Med 10.1056/NEJM oa1001288. Pub 29/6/2010.

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Value of trans-oesophageal echocardiography as a method of encouraging patients with chronic atrial fibrillation to use anticoagulation therapy A BAKALLI, L KAMBERI, G DRAGUSHA, N ZEQIRI, F GASHI, L PREKPALAJ

Summary Background: Despite the indisputable role of anticoagulation therapy for atrial fibrillation (AF) patients at risk for stroke, anticoagulants remain under-used in everyday clinical practice. We assumed that by performing trans-oesophageal echocardiography (TEE) on patients with AF who were not on anticoagulation treatment prior to the procedure, and by explaining to them the TEE images obtained, as well as the possible consequences of these findings, we could convince patients to start anticoagulation therapy. The main objective of the study was to assess the examined patients’ adherence to warfarin therapy over a two-year period.

Methods and results: We conducted a prospective TEE study from February 2006 to December 2008 on 70 patients with chronic AF who were not on anticoagulation treatment.

Mean patient age was 65.85 ± 10.02 years and 68.57% were women. Thrombus in the left atrial appendage was found in 25 (35.71%) patients. Fifty-four (77.14%) patients had thrombi or spontaneous echo contrast in at least one of their supraventricular cavities.

Following the procedure and with detailed explanation to the patients of their TEE findings, we managed to start anticoagulation therapy on 60 (85.71%) patients. At the end of the follow-up period of 23.76 ± 2.8 months, 53 (75.71%) patients remained on warfarin therapy. The rest of the surviving patients settled for thrombo-prophylaxis with aspirin.

Conclusion: TEE is a valuable method that, in addition to its diagnostic possibilities, could also serve as a convincing visual method of putting atrial fibrillation patients onto an anticoagulation regimen.

Keywords: atrial fibrillation, trans-oesophageal echocardiography, left atrial appendage thrombus Submitted 12/9/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 192–194

www.cvja.co.za

DOI: CVJ-21.002

The presence of non-valvular atrial fibrillation increases the risk of thrombo-embolism fivefold.1 Warfarin has been shown to be highly beneficial in the prevention of stroke or systemic thrombo-

Department of Cardiology, University Clinical Centre of Kosova, Prishtine, Kosova AURORA BAKALLI, MD, MS, abakalli@hotmail.com LULZIM KAMBERI, MD, MS GANI DRAGUSHA, MD, PhD NEXHMI ZEQIRI, MD, PhD FITIM GASHI, MD LAZER PREKPALAJ, MD

embolism in moderate- to high-risk patients with chronic atrial fibrillation. A recent meta-analysis of 29 trials, totalling 28 044 participants, which analysed the role of thrombo-prophylaxis in atrial fibrillation, showed that adjusted-dose warfarin significantly reduced the risk of thrombo-embolic events.2 Despite the unquestionable role of anticoagulation therapy in patients with non-valvular atrial fibrillation at moderate to high risk of stroke, it still remains under-used in clinical practice.3,4 Studies on clinical practice report that only a quarter to a half of eligible patients with atrial fibrillation undergo anticoagulation treatment.5,6 Under-usage of anticoagulation therapy can be attributed to two main aspects: physician and patient reluctance.

The aim of this study was to perform trans-oesophageal echocardiography (TEE) in patients with chronic non-valvular atrial fibrillation who did not take anticoagulation therapy prior to the procedure, in order to asses the prevalence of atrial thrombi and spontaneous echo contrast (SEC) in these patients. The main purpose was to evaluate their adherence to anticoagulation therapy after TEE, as well as to assess the morbidity and mortality associated with atrial fibrillation over a two-year follow-up period following the TEE procedure. Our hypothesis was that detection of thrombi or SEC by TEE would serve as a persuasive tool to convince the patient of the importance of anticoagulation therapy.

Methods We conducted a prospective TEE study from February 2006 to December 2008 on 70 patients with chronic non-valvular atrial fibrillation at moderate to high risk of stroke, who were not on anticoagulation therapy. TEE procedures were carried out from February to October 2006; thereafter these patients regularly visited an outpatient cardiology ward for a mean period of two years. The emphasis was on assessment of their adhesion to antithrombotic therapy.

Atrial fibrillation was diagnosed by at least two electrocardiograms (ECG), presenting with the absence of P waves before each QRS complex, and replaced instead by fibrillatory ‘f’ waves varying in size, shape and timing. Patients at moderate to high risk of stroke were those who, in addition to chronic non-valvular atrial fibrillation, also suffered from arterial hypertension, diabetes mellitus, vascular disease, heart failure, or previous stroke, transient ischaemic attack or systemic thrombo-embolic event.

Patient age was also taken into consideration when stratifying them into moderate or high stroke-risk category.

Comprehensive histories, physical examinations, laboratory tests, electrocardiograms, transthoracic echocardiography (TTE) and TEE were performed on all patients included in the study.

Patients who could not tolerate TEE were excluded. Written consent was obtained from all patients in the study.

Patients were asked specifically if they were aware of the

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importance of antithrombotic therapy for their medical condition, if their managing physician had suggested they start on anticoagulation therapy, and if this was so, if the patient had declined anticoagulant treatment.

All values were expressed as means ± SD or fractions. Statistical analyses were performed using statistical software (SSP, version 2.80, 2005).

Forty-eight (68.57%) patients were not aware of the importance of anticoagulation therapy for their condition. Thirty-six (51.43%) patients admitted that were advised by their physician to start on anticoagulation therapy. Patient refusal to take warfarin was mostly because of the fear of haemorrhage or the inconvenience of INR monitoring, due to frequency of monitoring or distance of the INR monitoring centre from the patient’s residence.

Mean left atrial diameter of the included patients was 51.74 ± 7.46 mm. SEC was present most frequently in the left atrium (in 64.29% of patients). Fifty-two (74.29%) patients had SEC in the left or right atrium, whereas 33 (47.14%) had SEC in both atria.

Thrombi were found most frequently in the left atrial appendage (25 cases) (Table 2), whereas 32 (45.71%) patients had thrombi in either the left or right atrial appendage. Additional transoesophageal data are presented in Table 2. Fifty-four (77.14%) patients had thrombi or SEC in at least one of their supraventricular cavities.

The mean follow-up period was 23.76 ± 2.8 months. During this period, one patient died as a consequence of ischaemic stroke. TEE was performed one month prior to the event and the deceased 66-year-old female was diagnosed with LAA thrombus, as well as the presence of SEC in both atria. One patient suffered an ischaemic stroke and two patients experienced transient ischaemic attacks over the follow-up period. Two patients were hospitalised due to signs and symptoms of heart failure.

Following the procedure and after thorough explanation of the TEE findings to the patients, we managed to start anticoagulation therapy on 60 (85.71%) patients. Thirty-five (50%), in addition to warfarin, took low-dose aspirin. The 10 (14.29%) patients who did not agree to start on anticoagulation with warfarin settled for thrombo-prophylaxis with aspirin.

At the end of the follow-up period, 53 (75.71%) patients remained on warfarin therapy. Five had stopped the anticoagulation regimen due to minor bleeding problems, while two patients had preferred to stop warfarin therapy due to an inability to have regular INR monitoring. However, these patients agreed to take low-dose aspirin.

Results

Discussion

Echocardiographic studies Conventional TTE and TEE were carried out in the presence of two skilled cardiologists using the Philips ie33 system. The TTE measurements were obtained from the parasternal long-axis view by two-dimensional targeted M-mode tracing according to the recommendations of the American Society of Echocardiography.

TEE was performed using a multiplane probe with a 7.0-MHz transducer.

All patients had fasted on the day of the TEE procedure. They were put under conscious sedation by intravenous Midazolam injection, which was given in a range from 1.5–5 mg. Topical anesthesia of the hypopharynx was achieved by lidocaine spray.

The left atrial appendage (LAA), as the major location of cardiac thrombi in patients with chronic non-valvular atrial fibrillation, was visualised from the two-chamber longitudinal view of the left atrium and left ventricle. Thrombus was defined as the presence of a distinct, well-contoured echogenic mass, identified in at least two different views. The presence of spontaneous echo contrast (SEC) was described as dynamic ‘smokelike’ echoes with swirling motion in the cavity. The impact of the white-noise artifact was excluded by adjusting the gain setting as required.

After the procedure, all acquired trans-oesophageal images were carefully explained to the patient and a companion. After elaborating on the possible consequences of the pathologies that were detected, patients were advised to start on anticoagulation treatment.

Statistical analysis

Seventy patients with chronic atrial fibrillation took part in this study. Mean patient age was 65.85 ± 10.02 years, and 68.57% were women. Other baseline patient characteristics are shown in Table 1. None of the patients was taking warfarin prior to the study; 61 (87.14%) patients were on aspirin before entering the study.

TABLE 1. BASELINE PATIENT CHARACTERISTICS Age (years) Female (%) Male (%) Hypertension (%) Coronary artery disease (%) Diabetes mellitus (%) Heart failure (%) History of stroke (%) Data are presented as mean ± SD or n (%).

n = 70 65.85 ± 10.02 48/70 (68.57) 22/70 (31.43) 54/70 (77.14) 29/70 (41.43) 25/70 (35.71) 20/70 (28.57) 9/70 (12.86)

Non-valvular atrial fibrillation increases the risk of stroke four- to fivefold in all age groups,1,7 with the main source of TABLE 2. TRANS-OESOPHAGEAL DATA OF THE PATIENT POPULATION LAD, TEE (mm) LAA maximal area (cm2) RAA maximal area (cm2) LA SEC (%) RA SEC (%) LA or RA SEC (%) LA and RA SEC (%) LAA thrombus (%) RAA thrombus (%) LAA or RAA thrombus (%) LAA and RAA thrombus (%) Data are presented as mean ± SD or n (%).

n = 70 51.74 ± 7.46 4.3 ± 1.93 0.99 ± 0.6 45/70 (64.29) 40/70 (57.14) 52/70 (74.29) 33/70 (47.14) 25/70 (35.71) 15/70 (21.43) 32/70 (45.71) 8/70 (11.43)

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thrombi being cardio-embolic, originating mostly from the left atrial appendage.8 Despite abundant information from ongoing clinical trials in favour of warfarin use in patients with chronic atrial fibrillation to prevent stroke, it remains a concern how to approach patients in order to implement the anticoagulation strategy in everyday clinical practice. The prescription rate of anticoagulation therapy for eligible atrial fibrillation patients is only 15 to 44%.9 Under-utilisation of anticoagulation therapy is due to either physician or patient reluctance. Factors contributing to physician under-prescription rates of warfarin therapy are mostly overestimation of the associated risks of warfarin therapy,10 or underestimation of the stroke risk.11 An important factor in patient reluctance, contributing to under-usage of anticoagulation therapy for chronic atrial fibrillation, was the lack awareness of thrombo-prophylaxis for this condition.12 Studies have shown that very few elderly patients with chronic atrial fibrillation realised the risk–benefit ratio of anticoagulation treatment.13 These data coincide with our findings, where 68.57% of patients with atrial fibrillation at moderate to high risk of stroke had no information concerning the importance of anticoagulation therapy. Even if the patient is well informed by the physician about the benefits of warfarin for their condition, they may still refuse to take the medication due to the difficulties of INR monitoring or adjustment to the dietary lifestyle.14 Pictograms have been shown to be a useful way of representing the risk–benefit ratio of warfarin for atrial fibrillation, thereby making the importance of anticoagulation treatment more understandable to patients.13 However, studies have demonstrated that providing additional information on warfarin use, such as the need for regular INR monitoring or abstinence from alcohol had a negative effect on the patient’s decision to opt for anticoagulation therapy.15 The large proportion of uneducated older people in Kosova, particularly women, presents a problem for physicians prescribing anticoagulation therapy for patients with chronic atrial fibrillation. This makes it challenging to explain to their patients the risk–benefit ratio of warfarin usage in numerical terms.

Therefore, we hypothesised that by creating visual images of their condition, patients would agree to start on anticoagulation treatment.

After the TEE procedure, the images were carefully explained to the patient and an accompanying person. The presence of thrombus was described as a potential cause of ischaemic stroke or other thrombo-embolic event, SEC was explained as a precursor of thrombus, and enlargement of the atria or atrial appendages was represented as a favourable condition for future thrombus formation.

This method proved to be effective in achieving a 75.71% rate of adherence to warfarin therapy and 100% to thromboprophylaxis with either warfarin or aspirin in our study population over a two-year follow-up period. We believe that our results demonstrate the importance of routine clinical use of TEE in patients

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with chronic non-valvular atrial fibrillation, as a tool to convince these patients of the need for anticoagulation treatment.

One limitation of this study was that a control group was not formed. Another was that a relatively small number of patients were included in the study.

Conclusion TEE is a valuable method not only to asses the presence of thrombi in the atrial appendage or SEC in patients with chronic atrial fibrillation, but is also a handy visual means of persuading patients to commence anticoagulation treatment.

References 1. Wolf PA, Abott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991; 22: 983–988.

2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrobotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146(12): 857–867.

3. Brass LM, Krumholz HM, Scinto JM, Radford M. Warfarin use among patients with atrial fibrillation. Stroke 1997; 28: 2382–2389.

4. Perez I, Melbourn A, Kalra L. Use of antithrombotic measures for stroke prevention in atrial fibrillation. Heart 1999; 82: 570–574.

5. Stafford RS, Singer DE. National patterns of warfarin use in atrial fibrillation. Arch Intern Med 1996; 156: 2537–2541.

6. Sudlow M, Thomson R, Thwaites B, Rodgers H, Kenny RA. Prevalence of atrial fibrillation and eligibility for anticoagulation in the community.

Lancet 1998; 352:1167–1171.

7. Hart RG, Benavente O, McBride R, Pearce LA. Antithrobotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501.

8. Mannining WJ, Silverman DI, Waksmonski CA, Oettgen P, Douglas PS. Prevalence of residual atrial thrombi among patients with acute thromboembolism and newly recognized atrial fibrillation. Arch Intern Med 1995; 155: 2193–2198.

9. Igbal MB, Taneja AK, Lip GYH, Flather M. Recent developments in atrial fibrillation. Br Med J 2005; 330: 238–243.

10. Lip GYH, Zarifis J, Watson RDS, Beevers DG. Physician variation in the management of patients with atrial fibrillation. Heart 1996; 75: 200–205.

11. Kutner M, Nixon G, Silverstone F. Physicians’ attitudes toward oral anticoagulants and anti-platelet agents for stroke prevention in elderly patients with atrial fibrillation. Arch Intern Med 1991; 151: 1950– 1953.

12. Lip GYH, Kamath S, Jafri M, Mohammed A, Bareford D. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation Project. Stroke 2002; 33: 238–242.

13. Fuller R, Dudley N, Blacktop J. Risk communication and older people – understanding of probability and risk information by medical inpatients aged 75 years and older. Age Aging 2001; 30: 473–476.

14. Howitt A, Armstrong D. Implementing evidence-based medicine in general practice: audit and qualitative study of antithrombotic treatment for atrial fibrillation. Br Med J 1999; 318: 1324–1327.

15. Fuller R, Dudley N, Blacktop J. Avoidance hierarchies and preferences for anticoagulation-semi qualitative analysis of older patients’ views about stroke prevention and the use of warfarin. Age Aging 2004; 33: 608–611.

IntroducIng rEVAtIo® A wEll EstAblIshEd PdE-5 InhIbItor rEgIstErEd for usE In PulmonAry ArtErIAl hyPErtEnsIon (PAh) REVATIO® helping your patients to do more...

• Significantly improves exercise capacity (p<0.001) (1) • Significantly reduces mean pulmonary arterial pressure (p=0.04) (1) • Significantly improves physical functioning and general health (p<0.001) (2) ...without holding them back • Convenient oral dosing: 20 mg tds with or without meals • Adverse events are generally transient and mild to moderate (1,3) • Low discontinuation rate comparable to placebo • No monthly liver function testing required (3)

References: 1. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005;353(20):2148-2157. 2. Pepke-Zaba J, Gilbert C, Collings L, Brown MCJ. Sildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension. Chest 2008;133:183-189. 3. Croom KF, Curran MP. Sildenafil. A Review of its Use in Pulmonary Arterial Hypertension. Drugs 2008;68(3):338-397.

S4 REVATIO® Film-coated tablets (Reg. No. A40/7.1.5/0131). COMPOSITION: Each tablet contains 20 mg of sildenafil, as the citrate. PHARMACOLOGICAL CLASSIFICATION: A 7.1.5 Vasodilators – peripheral. INDICATIONS: Treatment of pulmonary arterial hypertension. REVATIO has been shown to improve exercise ability and to reduce mean pulmonary arterial pressure. CONTRA-INDICATIONS: Known hypersensitivity to any component of the tablet. Patients concurrently using nitric oxide donors or organic nitrates in any form. Concomitant use with ritonavir, erythromycin, saquinavir, ketoconazole and itraconazole. Severe hepatic or renal function. Pregnancy and Lactation. WARNINGS: No controlled clinical data in MI, stroke, or life-threatening arrhythmia within the last 6 months; resting hypotension (BP <90/50) or hypertension (BP >170/110); cardiac failure or CAD causing unstable angina and retinitis pigmentosa. Physicians should carefully consider whether patients with underlying CVD could be affected adversely by transient decreases in supine BP, especially in combination with sexual activity. Serious events, including MI, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, and hypertension have been reported. Most patients had pre-existing CV risk factors. Use with caution in patients with anatomical deformation of the penis, or conditions which may predispose to priapism. Patients taking alpha-blocker therapy may lead to symptomatic hypotension. Administer with caution to patients with bleeding disorders or active peptic ulceration. Decreased vision or loss of vision, has been reported. Exercise caution before driving, operating hazardous machinery or performing hazardous tasks. DOSAGE AND DIRECTIONS FOR USE: 20 mg three times a day approximately 6 to 8 hours apart with or without food. Dose adjustments may be required when co-administered with bosentan or other CYP3A4 inducers. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Most commonly reported side-effects included headache, flushing, dyspepsia, back pain, diarrhoea and limb pain. Other common side-effects include cellulitis, influenza, sinusitis, anaemia, fluid retention, insomnia, anxiety, migraine, tremor, paraesthesia, burning sensation, hypoaesthesia, visual acuity reduced, retinal haemorrhage, visual disturbance, photophobia, diploplia, chromatopsia, cyanopsia, abnormal sensation in eye, eye irritation, vertigo, bronchitis, epistaxis, rhinitis, cough, gastritis, gastroenteritis, gastro-oesophageal reflux disease, haemorrhoids, abdominal distension, alopecia, erythema, myalgia, gynaecomastia, pyrexia and weight increase. A sudden unilateral or bilateral decrease or loss of hearing (sensorinearal deafness) with or without associated vestibular symptoms has been reported. LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. Reg. No.: 1954/000781/07. P.O. Box 783720, Sandton 2146. Tel. No.: 0860 PFIZER (734937). PI Ref: 13/07/09. Please refer to the detailed package insert for full prescribing information. 01/01/REV/10/JA

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Concurrent resistance and aerobic training as protection against heart disease INA SHAW, BRANDON S SHAW, GREGORY A BROWN, JONES F CILLIERS

Summary This study was designed to compare the effects of aerobic and concurrent aerobic and resistance training on their ability to slow the rate of development and progression of coronary heart disease (CHD) in young adult males at low risk, as determined by the Framingham risk assessment (FRA) score.

Subjects were assigned to 16 weeks of three-times weekly aerobic training (AT) (n = 13), concurrent aerobic and resistance training (CART) (n = 13) or no exercise (NO) (n = 12).

Both AT and CART resulted in significant (p < 0.05) changes in total cholesterol (from 173.67 ± 29.93 to 161.75 ± 26.78 mg.dl-1 and from 190.00 ± 38.20 to 164.31 ± 28.73 mg.dl-1, respectively), smoking status (from 12.25 ± 5.08 to 10.33 ± 5.37 cigarettes per day and 12.00 ± 4.71 to 8.77 ± 5.10 cigarettes per day, respectively), high-density lipoprotein cholesterol (from 47.00 ± 11.85 to 57.50 ± 5.99 mg.dl-1 and 34.00 ± 8.53 to 46.77 ± 14.32 mg.dl-1, respectively), systolic blood pressure (from 126.17 ± 7.00 to 122.33 ± 3.17 mmHg and 131.54 ± 9.28 to 121.69 ± 7.87 mmHg, respectively) and therefore FRA score (from 3.58 ± 2.19 to 1.33 ± 2.27 and 5.77 ± 3.09 to 2.46 ± 2.90, respectively). Both modes of exercise were found to be equally effective in reducing CHD risk. These findings support the inclusion of resistance training into an aerobic training programme to lower CHD risk, which will afford subjects the unique benefits of each mode of exercise.

Keywords: cardiovascular disease, endurance training, exercise, risk assessment, weight training Submitted 6/10/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 196–199

www.cvja.co.za

Coronary heart disease (CHD) is the leading cause of death in western and developed countries, contributing to 60% of all deaths in the United States of America.1,2 The Centers for Disease Control and Prevention (CDC) and the American College of Sports Medicine (ACSM) recommend that to prevent CHD, every adult should achieve at least 30 minutes of moderateintensity physical activity on preferably all days of the week.3 While many studies have confirmed the benefit of exercise in

Department of Marketing and Sport Management, Vaal University of Technology, Vanderbijlpark, South Africa INA SHAW, PhD (Biokinetics)

Department of Sport, Rehabilitation and Dental Sciences, Tshwane University of Technology, Pretoria, South Africa BRANDON S SHAW, PhD (Biokinetics), shawbs@tut.ac.za JONES F CILLIERS (PhD Biokinetics)

Human Performance Laboratory, HPERLS Department, University of Nebraska, Kearney, USA

GREGORY A. BROWN, PhD (Health and Human Performance)

reducing the overall risk of CHD,4 according to the United States’ Department of Health, three out of five (60%) individuals in the United States do not achieve the required level of exercise, while a further 25% of the adult population do not exercise at all.5 The Framingham risk assessment (FRA) score is the most widely accepted tool in the United States for patient selection for primary intervention and prediction of coronary events over the next 10 years.6 The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines recommend FRA risk scoring in assessing absolute risk for CHD events.7 The search for the cause of CHD was started in the 1940s in the small community of Framingham in the United States.8 The Framingham Heart study was designed to generate information that would assist in the prevention and early detection of CHD. It is now the source of much of the knowledge on the risk of CHD and is synonymous with the ‘risk factor hypothesis’.

The use of the FRA tool is especially important as it is designed to estimate risk in adults who do not yet have CHD. The FRA tool also determines CHD risk from a group of variables (i.e. age, smoking status, systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol), rather than from a single variable.9 This FRA score can then be utilised to identify patients for primary or preventative treatments, including exercise.

Over several decades, volumes of information have been produced on aerobic training, its adaptations and its benefits in preventing CHD.10 Although the specific cardioprotective benefits of aerobic training are well known, resistance training is becoming increasingly popular among the general public and individuals who have substantial mobility limitations (especially the elderly), which preclude aerobic methods of exercise. This necessitated the determination of the effects of this mode of training on CHD risk. Research may reveal additional benefits from the inclusion of resistance training with or instead of more traditional modes of aerobic exercise. Well-known benefits of resistance training include increased muscle strength, increased lean tissue mass, maintenance of or increase in metabolically active tissue, and increased neuromuscular control and coordination.11 While it is commonly accepted that resistance training should be regarded as a complementary mode of exercise and not a substitute for aerobic training,11 unfortunately, it is not well understood what the effect of a concurrent aerobic and resistance training programme would be on CHD risk factors. Just as CHD is not a single condition, no single exercise-training programme is optimal for risk reduction in all individuals.12 Furthermore, while the necessary quantity and intensity of exercise for the primary prevention of CHD are becoming understood, most research to date focuses on the effect of a single mode of exercise on a single CHD risk variable in isolation.

The purpose of this study was to compare the effect of aerobic exercise alone, with that of aerobic combined with resistance

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training on the FRA scores of young males with few CHD risk factors. A finding that a combination of aerobic and resistance training could reduce several CHD risk factors simultaneously would be of critical importance, due to the synergistic benefits to be gained from each mode of exercise.

Methods Thirty-seven sedentary young adult males volunteered to participate in this study (mean age 25 years and six months).

Demographic data are presented in Table 1. Age was ascertained from date of birth. Since females may have a greater variability in CHD risk factors than males, only males were selected.13 The subjects were required to be free of any medical conditions that could have prevented them from optimising the benefits of their exercise training, they had to be inactive and weight stable at least six months before the study started and were not allowed to be on any weight-management programmes or pharmacological agents that could have affected the measured CHD risk factors.

All subjects underwent an identical battery of tests before and after the 16-week intervention period. All subjects were evaluated in the post-absorptive state following a 12- to 14-hour fast and at least 48 hours prior to or following any exercise. Prior to participation in the investigation, all volunteers gave written informed consent and underwent a screening history and physical examination. They were allowed to discontinue the study at any time.

This investigation was approved by the Institutional Review Board at the University of Johannesburg (formerly Rand Afrikaans University). Random assignment was made to one of the experimental exercise groups: aerobic training (AT) (n = 12) or concurrent aerobic and resistance training (CART) (n = 13), or to the non-exercising (NO) group (n = 12), using a schedule generated from a table of random numbers.

For descriptive purposes, anthropometric measurements were carried out according to the methods proposed by the International Society for the Advancement of Kinanthropometry (ISAK).14 Subjects were weighed to the nearest 0.1 kg on a calibrated medical scale (Mettler DT Digitol, Mettler-Toledo AG, Ch-8606 GreiFensee, Switzerland) wearing only running shorts.

Each subject’s height was measured to the nearest 0.1 cm via a standard wall-mounted stadiometer.

FRA score calculation The variables used in FRA calculation to estimate risk in adults who do not yet have CHD are age, smoking status, systolic blood pressure, total cholesterol value and high-density lipoprotein cholesterol value. Information on smoking habits in terms of the number of cigarettes smoked daily was obtained by a selfadministered seven-day questionnaire a week before the pre- and

TABLE 1. BASELINE SUBJECT DESCRIPTIVE DATA Group Variables NO (n = 12) AT (n = 12) Age (years) 25 ± 2.4 25 ± 5.6 Height (cm) 179.3 ± 11.9 176.8 ± 3.8 Body mass (kg) 80.3 ± 12.8 74.7 ± 8.2 Values are means ± standard deviation

CART (n = 13) 26 ± 3.1 178.7 ± 7.0 85.0 ± 12.8

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post-test.15 This was done in order to establish whether any modifications in the subject’s smoking habits took place during the course of the treatment period. At entry into the study, all subjects participated in a half-hour session on how to estimate the number of cigarettes smoked daily and how to complete the smoking form.

Each subject’s resting systolic (SBP) and diastolic blood pressure (DBP) was measured in the supine (recumbent) position after five minutes’ rest using a mercury sphygmomanometer (Alpk2 Sphygmomanometer, Japan). The mercury column was positioned at the same level as the subject’s heart during monitoring. The left arm of each subject was supported and utilised throughout the investigation. Subjects provided blood samples in the sitting position and samples were analysed for total cholesterol and high-density lipoprotein cholesterol concentrations following a nine- to 12-hour fast and prior to any exercise.16 Each parameter was assayed on a single day to eliminate inter-assay variability. For estimation of each subject’s FRA score, the present study utilised the point system of the Framingham Heart study.6

Training design All subjects participated in three 60-minute exercise sessions each week for 16 weeks. The aerobic training sessions started with the subjects warming up by cycling for five minutes at a heart rate of less than 100 beats per minute, followed by rowing, stepping, cycling and walking on a treadmill for a total of 45 minutes at 60% of their individual heart rate maximum. They cooled down with a five-minute cycle at a heart rate of less than 100 beats per minute. Age-predicted maximum heart rates were determined by subtracting their age from 220. Heart rate was measured continuously during the training sessions with a heart rate monitor (Polar Fitwatch, Polar Electro Oy, Finland).

The intensity of exercise was increased by 5% every four weeks.17,18 In an attempt to equalise for time across the two exercise groups, the subjects in the CART group had to perform 22 minutes of both aerobic training and resistance training.

The resistance training component of the programme required that the subjects perform two sets of 15 repetitions at 60% of one-repetition maximum (1-RM) for each of the eight prescribed exercises, which included shoulder press, latissimus dorsi pulldowns, seated chest press, low pulley row, crunches, unilateral leg press, unilateral knee extensions and unilateral prone hamstring curls. Subjects were under direct supervision during the training sessions, and all subjects were familiarised with the equipment before commencement of the experimental programmes.

The CART subjects had to perform a similar warm-up and cool-down protocol to that of the AT subjects. The weight training intensity was re-evaluated through 10-RM testing and the training programmes were adjusted by increasing the resistance accordingly to maintain 60% of the estimated 1-RM every four weeks.

The subjects in the NO group were instructed to remain inactive during the 16-week period.

Statistical analyses Quantitative data are expressed as means and standard deviations (SD). While Levene’s test was used to determine the equality or homogeneity of variance of the groups, the Brown and Forsythe F-test was utilised to determine equality of means. Following this, the present investigation also computed dependent t-tests

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to determine whether a significant difference existed between pre- and post-tests. Differences in anthropometric measures were compared using a one-way analysis of variance (ANOVA). When significant differences were found at the post-test, a Dunnett post hoc analysis was employed.

The control group’s data was utilised to calculate test–retest reliability by quantifying it using the intra-class correlation coefficient. Statistical significance was indicated by p ≤ 0.05.

Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS) version 14 (Chicago, IL).

Results Mean pre- and post-training values are reflected in Table 2. The NO, AT and CART groups were found to be statistically similar at the start of the study regarding total cholesterol levels (p = 0.084), smoking status (p = 0.763), high-density lipoprotein cholesterol levels (p = 0.201), systolic blood pressure (p = 0.339) and FRA scores (p = 0.548).

The data indicated that while there was no change in total cholesterol levels in the NO group from pre- to post-training (p = 0.678), both the AT and CART groups were found to have significantly (p < 0.05) decreased total cholesterol levels at posttraining (p = 0.004 and p = 0.007, respectively). Further post hoc analysis revealed that the aerobic and concurrent training had a comparable effect on total cholesterol levels (p = 0.324) and that both were more effective than no exercise (p = 0.004 and p = 0.008, respectively).

At the end of the 16-week period, there were no significant differences in the number of cigarettes smoked by the three groups. While the high-density lipoprotein cholesterol levels of the NO group did not change (p = 0.672), the AT and CART groups had increased high-density lipoprotein cholesterol levels (p = 0.001 and p = 0.001, respectively). Aerobic training was found to be as effective as concurrent training at increasing high-density lipoprotein cholesterol levels (p = 1.000) and both were more effective than no exercise (p = 0.030 and p = 0.005, respectively). Sixteen weeks of aerobic and concurrent training reduced systolic blood pressure (p = 0.049 and p = 0.002, respectively). However, the NO group was found to have significantly increased mean systolic blood pressure (p = 0.025).

Post hoc analysis revealed that aerobic and concurrent training proved equally effective for improving systolic blood pressure levels (p = 0.097). However, only concurrent training was more effective than no exercise (p = 0.000). FRA scores were not reduced in the NO group (p = 0.504), whereas both aerobic and

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concurrent training proved effective in reducing their FRA scores (p = 0.001 and p = 0.000). Aerobic and concurrent training were found to be equally effective (p = 0.484).

Discussion The FRA equation, which makes use of a group of variables rather than a single variable, is an accepted method of estimating absolute risk for CHD and is especially important in estimating the 10-year risk in adults who do not yet have CHD. Although most research to date focuses on a single mode of exercise and how it affects a single CHD risk variable, the present study provides new data on how two modes of exercise training influence the FRA scores of young adult males with few CHD risk factors.

We found that aerobic and concurrent aerobic and resistance training had a favourable effect on levels of total cholesterol and high-density lipoprotein cholesterol, systolic blood pressure and FRA score. This is noteworthy, since concurrent training decreased FRA score by the same amount as aerobic training alone, despite the fact that the subjects who engaged in the concurrent training did only half as much aerobic training as the aerobic-only training group.

With regard to the effect of aerobic training on the individual variables determining the FRA scores, several studies have found that this mode of exercise training had a favourable effect on levels of total cholesterol19-,22 and high-density lipoprotein cholesterol,4,17,20,23 and systolic blood pressure.20,24 Although the effect of aerobic training on the individual FRA variables is well documented,25 less is known about the effect of concurrent aerobic and resistance training.26 The present investigation obtained a seemingly novel result, with concurrent training resulting in a significant reduction in total cholesterol levels. While this study demonstrated increased high-density lipoprotein cholesterol values following concurrent training, Wallace et al.27 did not find significantly increased levels following their concurrent training programme. Although their study supports the findings of the present study, that concurrent training reduced systolic blood pressure, the study of Pierson et al.18 refutes these findings as they found unchanged systolic blood pressure values following concurrent training.

Conclusion These findings are noteworthy since the addition of resistance training to aerobic training can now be considered an alternative and effective treatment to reduce the risk and prevalence of CHD

TABLE 2. CHANGES IN FRAMINGHAM RISK ASSESSMENT SCORES FOLLOWING AEROBIC AND CONCURRENT AEROBIC AND RESISTANCE TRAINING IN HEALTHY PREVIOUSLY SEDENTARY YOUNG ADULT MALES Group NO (n = 12) AT (n = 12) CART (n = 13) Variables Pre-training Post-training Pre-training Post-training Pre-training Post-training 195.75 ± 10.49 194.83 ± 11.85 173.67 ± 29.93 161.75 ± 26.78* 190.00 ± 38.20 164.31 ± 28.73* TC (mg.dl-1) Smoking status (cigarettes per day) 12.42 ± 4.83 12.33 ± 4.77 12.25 ± 5.08 10.33 ± 5.37* 12.00 ± 4.71 8.77 ± 5.10* 49.33 ± 6.34 50.17 ± 8.97 47.00 ± 11.85 57.50 ± 5.99* 34.00 ± 8.53 46.77 ± 14.32* HDL-C (mg.dl-1) SBP (mmHg) 122.00 ± 5.72 124.67 ± 4.77* 126.17 ± 7.00 122.33 ± 3.17* 131.54 ± 9.28 121.69 ± 7.87* Total FRA score 5.00 ± 2.80 4.67 ± 2.46 3.58 ± 2.19 1.33 ± 2.27* 5.77 ± 3.09 2.46 ± 2.90* TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; SBP: systolic blood pressure; FRA: Framingham risk assessment *Significantly different when compared with pre-training values (p ≤ 0.05).

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in males. Participation in activities that require both aerobic and resistance components should be considered in future as a tool to lower absolute risk for CHD, since each mode of exercise has unique benefits.

The authors are grateful to the University of Johannesburg (formerly Rand Afrikaans University), Johannesburg, South Africa for the use of their laboratories at the Centre for Sport Science and Biokinetics, and the Vaal University of Technology, Vanderbijlpark, South Africa for its statistical consultation services.

References 1. American College of Sports Medicine (ACSM). ACSM’s Guidelines for Exercise Testing and Prescription. Baltimore: Lippincott Williams & Wilkins, 2006.

2. American Heart Association (AHA). Heart Disease and Stroke Statistics Update. Dallas: American Heart Association, 2003.

3. Pate RR, Pratt, M, Blair SN, Haskell WL, Macera CA, Bouchard C, et al.

Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. J Am Med Assoc 1995; 273(5): 402–407.

4. Young DR, Haskell WL, Jatulis DE, Fortmann SP. Associations between changes in physical activity and risk factors for coronary heart disease in a community-based sample of men and women: the Stanford Five-City Project. Am J Epidemiol 1993; 138(4): 205–216.

5. Heyward VH. Advanced Fitness Assessment and Exercise Prescription.

Champaign: IL: Human Kinetics, 1997.

6. Schisterman EF, Whitcomb BW. Coronary age as a risk factor in the modified Framingham risk score. BMC Med Imaging 2004; 4(1): 1.

7. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106(25): 3143– 3121.

8. Dawber TR, Meadows GF, Moore FE. Epidemiological approaches to heart disease: the Framingham Study. Am J Publ Hlth 1951; 41: 279–286.

9. Mora S, Redberg RF, Sharrett AR, Blumenthal RS. Enhanced risk assessment in asymptomatic individuals with exercise testing and Framingham risk scores. Circulation 2005; 112(11): 1566–1572.

10. Ballor DL, Poehlman ET. Resting metabolic rate and coronary heartdisease risk factors in aerobically and resistance-trained women. Am J Clin Nutr 1992; 56(6): 968–974.

11. Meka N, Katragadda S, Cherian B, Arora RR. Endurance exercise and resistance training in cardiovascular disease. Ther Adv Cardiovasc Dis 2008; 2(2): 115–121.

12. Chicco AJ. Exercise training in prevention and rehabilitation: which training mode is best? Minerva Cardioangiol 2008; 56(5): 557–570.

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13. Wilmore JH, Després JP, Stanforth PR, Mandel S, Rice T, Gagnon J, et al. Alterations in body weight and composition consequent to 20 wk of endurance training: the HERITAGE Family study. Am J Clin Nutr 1999; 70(3): 346–352.

14. Norton K, Olds T. Anthropometrica: A Textbook of Body Measurement for Sports and Health Courses. Marrickville, NSW: Southwood Press, 1996.

15. Fripp RR, Hodgson JL. Effect of resistive training on plasma lipid and lipoprotein levels in male adolescents. J Pediatr 1987; 111(6 pt 1): 926–931.

16. Thompson PD, Crouse SF, Goodpaster B, Kelley D, Moyna N, Pescatello L. The acute versus the chronic response to exercise. Med Sci Sports Exer 2001; 33: S438–S445.

17. Banz WJ, Maher MA, Thompson WG, Basset DR, Moore W, Ashraf M, et al. Effects of resistance versus aerobic training on coronary artery disease risk factors. Exp Biol Med (Maywood) 2003; 228(4): 434–440.

18. Pierson LM, Herbert WG, Norton J, Kiebzak GM, Griffith P, Fedor JM, et al. Effects of combined aerobic and resistance training versus aerobic training alone in cardiac rehabilitation. J Cardiopulm Rehabil 2001; 21(2): 101–110.

19. Dunn AL, Marcus BH, Kampert JB, Garcia, ME, Kohl HW (3rd), Blair SN. Reduction in cardiovascular disease risk factors: 6-month results from Project Active. Prev Med 1997; 26(6): 883–892.

20. Filipovsky J, Simon J, Rosolova H, Haman P, Petrikova V. Changes in blood pressure and lipid pattern during a physical training course in hypertensive subjects. Cardiology 1991; 78(1): 31–38.

21. Grandjean PW, Oden GL, Crouse SF, Brown JA, Green JS. Lipid and lipoprotein changes in women following 6 months of exercise training in a worksite fitness program. J Sports Med Phys Fitness 1996; 36(1): 54–59.

22. Ponjee GAE, Janssen EME, Hermans J, van Wersch JWJ. Regular physical activity and changes in risk factors for coronary heart disease: a nine months prospective study. Eur J Chem Clin Biochem 1996; 34(6): 477–483.

23. Lehman R, Kaplan V, Bingisser R, Bloch KE, Spinas GA. Impact of physical activity on cardiovascular risk factors in IDDM. Diabetes Care 1997; 20(10): 1603–1611.

24. Norris R, Carrol D, Cochrane R. The effects of aerobic and anaerobic training on fitness, blood pressure, and psychological stress and wellbeing. J Psychosom Res 1990; 34(4): 367–375.

25. Hakim AA, Curb JD, Petrovitch H, Rodriguez BL, Yano K, Ross GW, Abbot RD. Effects of walking on coronary heart disease in elderly men: the Honolulu Heart Program. Circulation 1991; 100(1): 9–13.

26. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Exercise type and intensity in relation to coronary heart disease in men. J Am Med Assoc 2002; 288(16): 1994–2000.

27. Wallace MB, Mills BD, Browning CL. Effects of cross-training on markers of insulin resistance/hyperinsulinemia. Med Sci Sports Exer 1997; 29(9): 1170–1176.

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Prevalence of microalbuminuria in hypertensive patients and its associated cardiovascular risk in clinical cardiology: Moroccan results of the global i-SEARCH survey – a sub-analysis of a survey with 21 050 patients in 26 countries worldwide R HABBAL, AR SEKHRI, M VOLPE, i-SEARCH INVESTIGATORS

Summary Objectives: To determine the prevalence of microalbuminuria (MAU) in hypertensive outpatients visiting a cardiologist’s office or clinic and to describe the relationship between MAU and cardiovascular risk factors.

Methods: This was an international, observational, crosssectional study of 22 282 patients, with 457 subjects from Morocco in 40 cardiology centres. Inclusion criteria were: male and female outpatients aged ≥ 18 years with currently treated or newly diagnosed hypertension (≥ 140/90 mmHg at rest on the day of the study visit) and no reason for false positive microalbuminuria dipstick tests.

Outcome measures: Prevalence of microalbuminuria assessed using a dipstick test, co-morbid cardiovascular risk factors or disease and their relationship with the presence of MAU, and role of pharmacotherapy in modulating the prevalence of MAU. Results: The prevalence of microalbuminuria in hypertensive patients in Morocco (67.8%) was high compared to the worldwide prevalence (58.3%). Despite the fact that all physicians regarded MAU as important for risk assessment and therapeutic decisions, routine MAU measurement was performed in only 35% of the practices. In clinical cardiology, MAU is highly correlated with a wide variety of cardiovascular risk factors and cardiovascular disease.

While angiotensin receptor blockers (ARBs) appeared to be associated with the lowest risk of MAU, calcium channel blockers (CCBs) were more often used in this patient group.

Conclusions: Hypertensive, high-risk cardiovascular patients are common in clinical cardiology. Given the high prevalence detected, screening of MAU in addition to more aggressive multi-factorial treatment to reduce blood pressure as well as other cardiovascular risk factors is required.

Cardiology Department, Ibn Rochd University Hospital, Casablanca, Morocco R HABBAL, MD

Medical Affairs Department, sanofi-aventis, Casablanca, Morocco AR SEKHRI, MD, aminesekhri@gmail.com

University of Roma ‘La Sapienza’, 2nd Faculty of Medicine, S Andrea Hospital, Rome and IRCCS, Neuromed, Italy M VOLPE, MD i-SEARCH INVESTIGATORS

Keywords: microalbuminuria, prevalence, cardiology, hypertension, irbesartan, risk factors Submitted 17/10/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 200–205

www.cvja.co.za

The presence of albumin in the urine indicates a disturbance in the barrier function of the endothelial glomerular cells (podocytes).1,2 This parameter is measured in mg per 24 hours or µg/ ml urine. Excretion of albumin into the urine must be detected as early as possible, because once pathological thresholds are reached, progression to advanced renal disease may result. The range of 30–300 mg/24 hours, termed microalbuminuria (MAU), is accompanied by an increased incidence of clinical proteinuria, an increase in serum creatinine, and more frequent development of terminal renal insufficiency, in addition to increased cardiovascular risk.3 Albuminuria is frequently regarded as a disease of the kidneys. However, there is often a simultaneous secretion of albumin into the retinal bed (cotton wool spots).4 Moreover, pre-clinical studies have shown that, using labelled albumin, this disorder is also present in the whole vascular system including the myocardium5 and brain.6-8 From a cardiologist’s standpoint, therefore, albuminuria is of critical importance to determine the prognosis of patients with cardiovascular disease. Patients with myocardial infarction, for example, have a worse prognosis if albuminuria is present compared to no albuminuria.9-11 Furthermore, in patients with normal coronary arteries on angiography, the extent of endothelial dysfunction has been shown to correlate with the degree of albumin excretion.12 Overall it has been shown that MAU is more important than many established cardiovascular risk factors for the prediction of the further course and outcome.13 The International Survey Evaluating microAlbuminuria Routinely by Cardiologists in patients with Hypertension (i-SEARCH) was undertaken in 26 countries around the world in a total of 1 750 sites to provide epidemiological data on the prevalence of MAU and its associations with established cardiovascular risk markers and disease. This article reports the data for Morocco, worldwide results having been published recently.14

Methods This was an international, observational, cross-sectional study in which subjects were evaluated during a single visit (methods have been published previously14). It had a two-step epidemiological design. In the first step, prior to patient recruitment,

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participating physicians completed a site questionnaire that documented practice location (urban, suburban or rural) and type (community or hospital based) as well as duration of service, degree of awareness and experience in detection of MAU, and its clinical relevance. In the second step, at each site, consecutive patients fulfilling eligibility criteria were invited to participate in the study. The study was conducted in accordance with the ethical principles of the current Declaration of Helsinki and consistent with the international conference on harmonisation and good clinical practice.

Inclusion criteria were as follows: male and female outpatients aged 18 years or older, with currently treated or newly diagnosed arterial hypertension, defined as a seated systolic (SBP)/diastolic blood pressure (DBP) of ≥ 140/90 mmHg at rest on the day of the study visit. Patients with acute fever (> 38°C), renal disease (serum creatinine > 20 mg/l), concomitant urinary tract infection, treated with cimetidine, or having undertaken strenuous physical activity in the preceding 24 hours, as well as female subjects who were pregnant or menstruating were ineligible to participate due to the likelihood of false positive results.

Once enrolled, demographic data, cardiovascular history, risk factors and co-morbidities, symptoms and signs of cardiovascular disease and current chronic drug therapy were documented on the case report form. The following measurements were then carried out on each patient: heart rate, urinary albumin and creatinine concentration, and waist and hip circumference. To ensure consistency between study sites, all centres performed dipstick screening for MAU with sponsor-provided reagent strips (Microalbustix®), which have a sensitivity of 82.6%,15 and followed a standardised sample-collection and testing procedure.

Urine albumine levels were grouped into categories: 10, 30, 80 or 150 mg/l.

The primary objective of this study was to define the prevalence of MAU in hypertensive outpatients attending a cardiologist. Secondary objectives were to establish a correlation between the prevalence of MAU and known cardiovascular risk factors in the study population, and to increase physicians’ awareness of the importance of MAU screening to identify at-risk patients.

Statistical analyses Population characteristics were recorded as numbers, means and standard deviations, together with 95% confidence intervals (CI) for the means of quantitative variables, and numbers and percentages with 95% CI of the population for categorical data. Outcomes included prevalence of MAU with 95% CI, taking into account the cluster design effect using the Proc SURVEYMEANS in SAS for categorical variables. The association between high levels of MAU and cardiovascular risk factors was studied and odds ratios were calculated. For the calculations SAS version 8.2 was used.16

Results Over the six months’ recruitment period, 476 patients were screened at 40 cardiology practices in Morocco (22 282 worldwide). One patient did not sign the informed consent and 18 patients did not meet the pre-specified inclusion and exclusion criteria or had no documented albumin or creatinine values. The primary analysis was done on 457 patients.

Patients were on average 59.1 ± 11.1 years old, and 59.7% were female. The majority (81.4%) had uncontrolled hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) of duration 4.5 ± 4.5 years, and the mean blood pressure was 161.4 ± 27.7/91.1 ± 14.1 mmHg on the day of the study. Cardiovascular risk profiles of the Moroccan patients compared to the worldwide study TABLE 1. CARDIOVASCULAR RISK PROFILE (PRIMARY ANALYSIS POPULATION) Parameter (mean ± SD or %) Demographics Age (years) Male gender (%) BMI (kg/m2) Hypertension Duration (years) SBP (mmHg) DBP (mmHg) Proportion uncontrolled (140/90 mmHg) (%) Heart rate/sinus rhythm Heart rate (bpm) Sinus rhythm: yes (%) Cardiovascular risk factors Family history MI/CAD (%) Regular physical activity (%) Current/former smoker (%) Current diabetics (%) Diabetes type 1/type 2 (%) Duration of diabetes (years) Additional risk factors Total cholesterol (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Triglycerides (mmol/l) CRP (mg/dl) Serum creatinine (mmol/l) Creatinine clearance (ml/min) < 30 ml/min (%) 30–60 ml/min (%) 60–80 ml/min (%) 80–120 ml/min (%) > 120 ml/min (%) Co-morbidities Coronary artery disease (%) Congestive heart failure (%) Atrial fibrillation (%) History of ischaemic stroke History of TIA (%) Peripheral artery disease (%) Other cardiovascular disease LVH (indice de Sokolow en mm)

Morocco (n = 457)

Global survey (n = 21 050)

59.1 ± 11.1 40.3 28.6 ± 5.8

62.4 ± 11.7 52.3 28.9 ± 5.7

4.6 ± 4.5 161.4 ± 27.

91.1 ± 14.1 81.4

8.1 ± 7.7 149.2 ± 20.2 87.4 ± 11.8 76.8

74.7 ± 12.3 96.4

74 ± 12 94.8

14. 4 17.7 6.8/5.3 19.1 11.5/88.5 6.8 ± 5.5

27.8 35.0 14.2/20.5 27.5 4.9/95.1 7.9 ± 7.7

5.5 ± 1.2 1.3 ± 0.5 3.0 ± 1.4 1.6 ± 1.0 1.1 ± 0.9 91.9 ± 26.9 90.0 ± 35.5 0 21.3 23.7 36 19

5.3 ± 1.1 1.3 ± 0.5 3.2 ± 1.0 1.8 ± 1.0 0.9 ± 0.9 89.9 ± 23.8 87.9 ± 34.1 0.7 19.3 26.5 38.8 14.8

10.1 4.4 4.2 8.6 4.4 3.1

22.9 5.8 8.3 4.8 3.8 4.2

31.7 ± 9.4 24.8 ± 9.8 (n = 246) (n = 8 311) Ejection fraction ≤ 40% (%) 4.9 4.7 Carotid stenosis (%) 1.3 2.9 Aortic aneurysm (%) 0.4 1.4 SD: standard deviation, LVH: left ventricular hypertrophy, TIA: transient ischaemic attack, CRP: C-reactive protein, MI: myocardial infarction.

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30

27.60%

Morocco International

% of physicians

25 20

16.20%

15 10

14.63%

15.80% 12.20% 8.50%

7.32%

5 0

7.20%

2.44%

2.44%

11–20% 21–30% 31–40% Estimated prevalence of MAU

< 10%

> 40%

Fig. 1. Physician-estimated prevalence of MAU. known diagnosed

67.8%

% of patients

80

58.4%

60.3%

51.7%

60 40 20 0

60.3% 7.5%

6.71%

Morocco Global Estimated prevalence of MAU

Fig. 2. Prevalence of diagnosed and undiagnosed MAU.

population are summarised in Table 1.

According to Moroccan physicians, MAU is routinely measured in 35% (95% CI: 22–51%) of their practices versus 37% (95% CI: 35–40%) globally. When asked to estimate the frequency of MAU in hypertensive patients, 14.6% of physicians estimated it between 11 and 20% (27.6% globally). However, 61% of the physicians did not provide an estimation of prevalence of MAU (Fig. 1).

On the other hand, presence of MAU seemed to influence 97.4% of treatment decisions and particularly those relating to treatment of blood pressure (100%). Furthermore, 86.1% of physicians said that MAU also influenced decisions related to achieving glycaemic control. While the majority (95.12%) of physicians linked presence of MAU to a patient’s prognosis, all of them (100%) also felt that a diagnosis of MAU was relevant to improving the management of other cardiovascular risk factors.

These attitudes were largely comparable with their colleagues worldwide.

Within the primary analysis of the Moroccan population, few patients had impaired renal function and 7.5% had previously known albuminuria. However, urinalysis with a once-off dipstick test revealed that 67.8% of the study population had evidence of MAU (58.4%, globally), with prevalence rates slightly higher in men (69.0%) than women (67.0%) (Fig. 2).

Correlations between several cardiovascular risk factors and MAU were tested in the global study. The following factors appeared to be associated with presence of MAU: male gender, large waist circumference, SBP ≥ 120 mmHg, DBP ≥ 100 mmHg, creatinine clearance ≥ 50 ml/min, and the presence of diabetes, congestive heart failure, coronary artery disease (CAD), history

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TABLE 2. PREVALENCE OF MAU WHEN ASSOCIATED WITH THESE PARAMETERS Risk factors Gender: male female Waist circumference: high normal Blood pressure: (mmHg) SBP: ≥ 180 120–129 DBP: ≥ 110 80–84 Pulse pressure: (mmHg) > 80 51–60 Triglycerides: high (≥ 1.69 mmol/l) low (< 1.69 mmol/l) Diabetes: diabetes (+) diabetes (–) Regular physical activity: yes no

Number of patients

MAU prevalence (%)

184 273

69.02 (61.0–75.3) 67.03 (61.3–72.3)

290 160

72.41 (67.0–77.2) 59.38 (51.6–66.7)

138 38 49 113

72.46 (64.5–79.2) 65.79 (49.9–78.8) 71.43 (57.6–82.2) 69.03 (60.0–76.8)

100 108

66 (56.3–74.5) 63.89 (54.5–72.3)

73 101

73.97 (62.9–82.7) 61.39 (51.6–70.3)

87 368

68.97 (58.6–77.7) 67.39 (62.4–72.0)

81

62.96 (52.1–72.7)

376

68.88 (64.0–73.4)

of cerebral pathology, peripheral artery disease (PAD), dyspnoea or palpitations. On the other hand, MAU occurred less often in patients who had regular physical activity (< 4 h/week).

Table 2 summarises the prevalence of MAU when associated with these parameters in the Moroccan population in this study. The number of cardiovascular risk factors and cardiovascular diseases associated with the presence of MAU are shown in Figs 3 and 4.

Use of antihypertensive pharmacotherapy was more frequent in patients with the presence of MAU. Therefore CCBs (29 vs 21%), ACE inhibitors (32 vs 27%), thiazide diuretics (37 vs 31%) and beta-blockers (43 vs 42%) were more frequently prescribed in patients with MAU compared to patients without MAU. However patients with MAU received ARBs less often (23%) compared to patients without (25%).

Overall, the pharmacotherapy prescribed to patients with MAU was in the following order: beta-blocker > thiazide diuretics > ACE inhibitors > CCBs > ARBs (Fig. 5). The difference between prescriptions for CCBs and ARBs was significant.

Discussion The demographic characteristics of the present sample indicated that hypertensive high-risk patients are common in clinical cardiology. The population was mostly elderly with a substantial cardiovascular risk-factor profile and a considerable burden of co-morbidity. Therefore, microalbuminuria is not only a risk marker for diabetic nephropathy but also indicates a considerable increase in cardiovascular risk. The investigation of the interdependence of cardiovascular risk and microalbuminuria was of particular value in this patient population.

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100.0%

% of patients

100 80

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Morocco Global

83.3% 67.9%

67.5%

60

66.7%

55.7%

50.5%

70.2%

67.7% 64.3%

59.5%

69.7%

67.8%

58.4%

40 20 0

0

1

2

3 Number of risk factors

4

5

Total

Fig. 3. Number of cardiovascular risk factors associated with the presence of MAU. The risk factors concerned are: no regular physical activity, current smoking, known hyperlipidaemia, family history of myocardial infarction or documented coronary artery disease or diabetes.

The present sub-analysis of the Moroccan centres of the global i-SEARCH survey generated the following key results: (1) patients in Morocco were grossly comparable to the patient population of the global survey, except for a lower rate of diabetes and a higher rate of uncontrolled blood pressure; (2) the prevalence of MAU in hypertensive patients in clinical cardiology (67.83%) exceeded that found in the general population and in primary care, while physicians consider MAU as a cardiovascular risk marker; (3) MAU was associated with a number of cardiovascular risk factors and disease; (4) beta-blockers were more frequently prescribed in MAU-positive patients compared to ARBs or ACE inhibitors.

The prevalence of MAU found in this sample of hypertensive patients in a cardiological outpatient setting indicates that this cardiovascular risk factor is very common in clinical cardiology (67.83%). It was furthermore, substantially higher than found in studies on unselected persons in the general population,17,18 and patients in primary care.19,20 The HYDRA study in primary care, for example,19,21 has documented a prevalence of 21.2% of patients with hypertension and 37.8% of patients with both hypertension and diabetes. The global DEMAND study has documented a prevalence of MAU and hypertension of 39% in general practice.20 Explanations for the higher prevalence of MAU in i-SEARCH may be as follows: the study population was older than in most previous studies, and 27.5% of the enrolled hypertensive patients

80 60

Morocco Global

91.7% 74.0%

66.5% 56.7%

63.1%

71.0%

65.9% 50.0%

20 0

1 2 3 Number of CV disease

40

58.4%

40

0

50

67.8%

% of patients

% of patients

100

were diabetic, whereas in other studies,22-23 diabetic subjects were excluded. Patients with known albuminuria were also not excluded as was the case in the DEMAND study.20 This and the high-risk cardiovascular population attending a cardiologist in comparison to those seeking primary care may account for the observed differences and the higher prevalence reported in the present study.

Comparing the Moroccan results to the global ones, it is apparent that the prevalence of MAU is higher in Morocco (67.83 vs 58.4%). Despite this, the estimated true prevalence by physicians in their patient cohort, its assessment and the use of this marker for therapeutic decisions is low. This finding has also been documented for general practitioners (HYDRA).19 It reflects a discrepancy between physician awareness of the prognostic importance of MAU and actual screening for MAU in cardiology practice.

MAU was associated with a number of cardiovascular risk factors and disease in the present study. This observation is in line with previous data stemming from population-based studies17 and primary care.19,21 It indicates that MAU is common in patients referring to cardiology departments and is associated with a number of other cardiovascular risk factors. This association was previously described in clinical studies for males24 and older patients,25 those with diabetes,26 obesity,27 smoking,28 insulin resistance syndrome,29 left ventricular hypertrophy (LVH),30 left ventricular dysfunction31 and C-reactive protein32 (not significant in the present study).

Total

Fig. 4. Number of cardiovascular diseases associated with the presence of MAU: history of myocardial infarction or CABG, history of ischaemic stroke or carotid endarterectomy or carotid angioplasty, peripheral arterial disease.

42.7% 34.6%

30

26.5%

30.6% 23.4%

20 10 0

Betablockers

Thiazides

CCB Drug classes

ACE inhibitors

ARBs

Fig. 5. Use of pharmacotherapy overall and presence of MAU in specific classes.

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While not all parameters could be confirmed in the present study, the strong association of MAU with a variety of cardiovascular risk markers was evident. For instance, the prevalence of MAU in both diabetic and non-diabetic patients within the Moroccan population appeared to be comparable, whereas diabetes has been established as an important risk for MAU (OR: 1.24; 1.12–1.38) in the larger population of the global study.14 Interestingly, the prevalence of MAU was on the other hand particularly low in patients with more than four hours per week of regular exercise or those with high HDL cholesterol levels.

This finding is in line with previous reports that microalbuminuria is low in physically active patients and can even be reversed when patients are motivated to exercise.33

follow up would allow a closer investigation of the relationship between ARB use and the development or regression of microalbuminuria.

Therapeutic implications

The study was supported by sanofi-aventis. We acknowledge the support of all participating physicians.

A wide spectrum of treatment including statins, ACE inhibitors and ARBs has been shown to improve endothelial dysfunction, microalbuminuria and proteinuria. In the IDNT study,34 for example, the ARB irbesartan has been shown in patients with hypertension, diabetes and nephropathy to prevent the further deterioration of proteinuria in comparison to the CCB (amlodipine). In the IRMA-2 study in patients with hypertension, diabetes and microalbuminuria, it was even shown that early intervention resulted in a reversal and normalisation of albumin excretion.35 Evidence favouring ARBs over beta-blockers comes from a sub-analysis of the LIFE trial. Ibsen and colleagues compared atenolol and losartan with regard to the cardiovascular outcomes in patients with MAU and showed that a reduction in MAU was associated with a significantly reduced risk of non-fatal myocardial infarction, stroke and cardiovascular death.36 Therefore, it was of particular interest to test the differences between antihypertensive classes with regard to MAU in clinical practice. The interpretation of analyses was difficult because of unknown variables and the cross-sectional nature of the study, but it revealed that beta-blockers and CCBs were more widely prescribed than the ARBs in MAU-positive patients. It is possible to at least assert that the choice of antihypertensive drug was not in line with the study results discussed above.

Microalbuminuria is also a justified target for primary prevention, as seen in evidence of recent compelling results from the PREVENT-IT study.37 Healthy individuals with microalbuminuria, but without hypertension or hypercholesterolaemia, were treated either with placebo or RAS blockade. At four years’ follow up, microalbuminuria was effectively reduced, which was associated with a 44% reduction in cardiovascular events.

Strength and limitations The main strengths of our cross-sectional study included a large, referred cohort of hypertensive patients attending a cardiologist or internist, with validation of predefined primary and secondary endpoints. However, two limitations should be noted. First, microalbuminuria could only be assessed on a single occasion although guidelines recommend triple testing (two out of three tests need to be positive). Therefore the present data may not allow an exact quantification of how many patients would be positive or negative on a second occasion. However, other data suggest that this requirement will reduce the point prevalence by only one-fifth,38 up to a maximum of one-third.39 Second, a

Conclusions A high prevalence of microalbuminuria was detected in a random sample of hypertensive patients attending a cardiology outpatient setting, indicating that high cardiovascular risk is common in clinical practice. Early detection, in addition to a more aggressive multifactorial treatment based on inhibitors of the renin–angiotensin system (RAS blockade) to reduce blood pressure as well as other cardiovascular risk factors is warranted to facilitate not only secondary but also primary prevention.

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36. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45(2): 198–202.

37. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, et al; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110(18): 2809–2916.

38. Kalter-Leibovici O, Van Dyk DJ, Leibovici L, Loya N, Erman A, Kremer I, et al. Risk factors for development of diabetic nephropathy and retinopathy in Jewish IDDM patients. Diabetes 1991; 40(2): 204–210.

39. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.

Am J Kidney Dis 2003; 41(1): 1–12.

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Cardiovascular function and psychological distress in urbanised black South Africans: the SABPA study N MASHELE, JM VAN ROOYEN, L MALAN, JC POTGIETER

Summary Objective: The increased prevalence of cardiovascular disease risk factors in sub-Saharan Africa has increased the incidence of cardiovascular disease in this region but whether psychological distress contributes to this observed increased risk remains largely unclear.

The aim of this study was to investigate the association between cardiovascular function and psychological distress in urbanised black South African men (n = 101) and women (n = 99).

Methods: Resting cardiovascular variables were obtained by making use of the Finometer device and 24-hour ambulatory blood pressure (BP) measurements with the Cardiotens apparatus. Psychological questionnaires assessed the perception of health (General Health questionnaire) and depression status (DSM-IV criteria). The resting ECG (NORAV PC-1200) was used to determine left ventricular hypertrophy (LVH) by making use of the Cornell product. Confounders included age, obesity, alcohol intake, smoking and physical activity.

Results: The hypertensive groups were overweight, with lower vascular compliance and higher LVH (only men) compared to the normotensive groups. In hypertensive men, perception of health (somatic symptoms) was positively associated with blood pressure, while in hypertensive women it was associated with heart rate. Major depression was associated with LVH in hypertensive men and mean arterial pressure in hypertensive women. LVH and depression showed odds ratios of 1.02 (95% CI: 0.997–1.05) and 1.15 (95% CI: 1.01–1.32), respectively, in predicting hypertension in women.

Conclusions: Psychological distress was associated with higher blood pressure in hypertensive African men but also with the development of left ventricular hypertrophy in hypertensive African men and women.

Keywords: depression, perception of health, cardiovascular function, urbanised Africans, hypertension Submitted 20/10/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 206–211

www.cvja.co.za

School for Physiology, Nutrition and Consumer Sciences, North-West University, Potchefstroom Campus, Potchefstroom, South Africa N MASHELE, MSc, JM VAN ROOYEN, DSc, johannes.vanrooyen@nwu.ac.za L MALAN, PhD

School for Psychosocial Behavioural Sciences, North-West University, Potchefstroom Campus, Potchefstroom, South Africa JC POTGIETER, PhD

Cardiovascular disease (CVD) is one of the leading causes of death worldwide, with the greatest mortality occurring in lowand middle-income countries.1 In black Africans, CVD has been associated with an inherent salt sensitivity, low-renin hypertension and urbanisation.2-4 It remains largely unclear, though, whether the experience of psychological distress may contribute to the observed increase in CVD risk. With increasing environmental demands, such as experienced in urbanised areas, the inability to adapt or cope may manifest as behavioural (e.g. substance abuse, dietary changes, inactivity), psychological (e.g. depression and psychosomatic complaints) and medical (cardiovascular functioning and other physical illnesses) consequences.5,6-11 The effect of known confounders for CVD risk12 should therefore at least be acknowledged in this novel psycho-physiological approach.

Additionally, the loss of social and cultural support, which often accompanies urbanisation, may lead to psychosocial disruption and an associated increase in psychological distress.

This may contribute to the high incidence of hypertension in urban black Africans.11 In this study, self-report questionnaires on participants’ perception of their own health and depression13,14 were used to gain insight into the level of psychological distress experienced by them. A thorough description of these measures will be provided in the methods section.

Other studies have shown a relationship between depression and CVD, such as coronary heart disease (CHD) and coronary artery disease.15,16 Unfortunately, these studies focused on the role of depression in CVD post-cardiac event. Conflicting results were found with regard to depression and the development of hypertension in the African-American population. Shinn et al.17 found that their results did not support the character of depressive symptoms in the development of hypertension in normotensive adults.17 Other researchers found that the association between depression and the risk of hypertension compared favourably with better-established predictors of hypertension, such as obesity.18 To our knowledge, investigations exploring the association between psychological well being or functioning and CVD have not been done in the African context. Therefore, the aim of this study was to investigate whether there is a relationship between cardiovascular function and psychological distress in hypertensive and normotensive urbanised black Africans of the North West province of South Africa.

Methods The methods for this study were adapted and abbreviated from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study.19 The SABPA study was a multidisciplinary target-population study conducted in 2008. Included in the data collection were urbanised black Africans from governmental organisations in the North West province. During recruitment, two months prior to data collection, the protocol was

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explained to each participant and they were given an opportunity to ask questions. Thereafter informed consent was obtained.

Urbanised black African individuals (101 men and 99 women) between 25 and 60 years of age who complied with the inclusion criteria of having the same socio-economic status (SES) and work environment were included. The exclusion criteria were: pregnancy, lactation, high temperature (> 37°C), users of α- and β-blocking agents, users of psychotropic agents, blood donors or having been vaccinated in the past three months before taking part in the study.

The participants were stratified into two groups: hypertensive (HT) and normotensive (NT) men and women. This stratification was done according to the European Society of Hypertension (ESH) 2007 guidelines where average 24-hour ambulatory hypertensive status is defined as systolic and/or diastolic blood pressure (≥ 125–130/≥ 80 mmHg).20 The study was approved by the Ethics Committee of the North-West University, Potchefstroom Campus, in accordance with ethical guidelines of the World Medical Association’s Declaration of Helsinki.21

Experimental procedure The experimental procedure for each participant followed a twoday protocol. On the first day, the Cardiotens device (Meditech CE0120®) was applied and programmed to record the 24-hour BP of four participants, one each day of the working week. The physical activity meter was fitted around the waist and a physical activity (GPAIQ) questionnaire was completed at school.

Thereafter, the four participants left to resume their normal daily activities. The Cardiotens device recorded BP measurements in 30-minute intervals during the daytime and in 60-minute intervals during the night.

At approximately 16:40 the participants were transported to the Metabolic Unit research facility of the North-West University (research unit for human studies) where they stayed overnight.

The unit is well equipped with 10 furnished bedrooms, a kitchen, two bathrooms and a dining area. The procedures for the evening included a brief introduction to the apparatus to minimise the ‘white-coat effect’,22 and a tour of the facilities. Completion of the psychosocial battery of questionnaires followed, under supervision of registered psychologists and fieldworkers. The questionnaires were arranged in such a way as to reduce the effects of participant fatigue, with half the questionnaires being completed before dinner, and the remaining half thereafter. The participants had dinner at 18:00 and enjoyed their last beverages between 20:00 and 22:00 (tea/coffee and biscuits) before going to bed at 22:00.

The procedure for day two included the disconnection of the Cardiotens apparatus at 06:00. After obtaining the anthropometric measurements, the participants were taken to the blood pressure station where the cardiovascular measurements were obtained while the participants were in a semi-Fowlers position.

The same procedures were followed for the rest of the participants daily.

Demographic questionnaire Included in the demographic questionnaire were questions on smoking and alcohol consumption. These are self-report questions with a ‘yes’ or ‘no’ answer. Information on physical activity

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levels was obtained with the Global Physical Activity questionnaire.23 This measures the total physical activity participation in three domains: (1) activity at work, (2) travel to and from places and (3) recreational activities. The sum of these domains were then evaluated and summed in calories per week. Physical activity is classified as high (vigorous-intensity activity on at least three days, achieving a minimum of 1 500 METS-minutes/week, or seven or more days of any activity accruing at least 3 000 METS-minutes/week) or low (not meeting any of the above criteria).23

Psychological questionnaires The 28-item GHQ13 is used for the assessment of signs and symptoms of psychological dysfunction and is useful for understanding various sources of distress in occupational research.24 The GHQ is a measure of common mental health and focuses on symptom domains for depression, anxiety, somatic complaints and social withdrawal.23 The GHQ was validated for use within the Setswana-speaking population prior to the study.25 An example of items used in this questionnaire include: ‘Have you found everything getting on top of you?’, ‘Have you been getting scared or panicking for no reason?’ and ‘Have you been getting edgy and bad tempered?’.

Each of the above are then accompanied by four possible responses; ‘not at all’, ‘no more than usual’, ‘rather more than usual’ and ‘much more than usual’. In this study each item was evaluated using the binary scoring method.26 The two least symptomatic answers are given a score of nil (0) while the two most symptomatic answers are given a value of one (1). Total scores exceeding the threshold of four are classified as achieving ‘psychiatric caseness’. In general practice, individuals classified as achieving ‘psychiatric caseness’ would be likely to receive further attention.25 The reliability coefficients of the subscales for this questionnaire varied between 0.77 and 0.83.

The Patient Health questionnaire (PHQ) is a sensitive nineitem instrument for making criteria-based diagnosis of depressive disorders and it is also a reliable and valid measure of severity of depression.14 The scale is based on the actual nine criteria of diagnosis of the DSM-IV depressive disorders. The PHQ assesses diagnoses divided into threshold disorders (disorders that correspond to specific DSM-IV diagnoses, i.e. major depressive disorder) and sub-threshold disorders (disorders whose criteria include fewer symptoms than required for any specific DSM-IV diagnoses, i.e. other depressive disorders). The questionnaire scores each of the nine DSM-IV diagnostic criteria as being experienced ‘0’ (not at all) to ‘3’ (nearly every day).

For analysis, the PHQ-9 scores are divided into the following categories of increasing severity: 0–4, 5–9, 10–14, 15–19 and 20 or greater, which represent minimal, mild, moderate, moderately severe, and severe depression, respectively. Scores less than five signify the absence of depressive disorders, scores of 5–9 predominantly represent no depression or sub-threshold depression, scores of 10–14 represent a spectrum of individuals who may or may not display depression, and scores of 15 or higher usually are indicative of major depression.14 In this study, scores of ≤ 10 were considered as the absence of depression (MDD = 0) and values > 10 were considered as the presence of major depression (MDD = 1).14 The Cronbach alpha-reliability index for this sample was 0.81.

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Anthropometric measurements All measurements were standardised and taken in triplicate to the nearest 0.1 cm by registered biokineticists. Height was measured by making use of a stadiometer while the participant’s head was in the Frankfurt plane.27 Weight was measured to the nearest 0.1 kg using a Krups scale with the participants wearing minimal clothing. These measurements were used for the calculation of body mass index (body mass/height2).28 Physical activity was measured using an Actical® accelerometer (Montréal, Québec).29 Waist circumferences were measured with a metal tape at the midpoint between the lower costal border and the iliac crest, perpendicular to the long axis of the trunk.27

Cardiovascular measurements A Cardiotens apparatus (Meditech CE0120®) was used for the 24-hour ambulatory blood pressure measurement (SBP and DBP) and a 12-lead ECG (Norav PC-1200) was applied to obtain six resting cardiac cycles. Non-invasive rested continuous arterial blood pressure recordings were obtained for five minutes using the Finometer device (Finapres Medical Systems, Amsterdam, the Netherlands). The Fast Modelflo computer software programme analysed the results to provide: mean arterial pressure (MAP) and total peripheral resistance (TPR), arterial compliance (Cw) and heart rate (HR). Left ventricular hypertrophy (LVH) was calculated from the 12-lead ECG device using the following gender-specific formula: Cornell product: sum of all the leads, (RaVL + SV3 ≥ 2.8 mV in men and ≥ 2.0 mV in women)* QRS > 244 ms.30

Statistical analysis All data were analysed by means of the computer software package STATISTICA 8 (StatSoft, Inc., Tulsa, OK, USA, 2008). All data were normally distributed, hence parametric methods were used. A single 2 × 2 × 2 (hypertension × depression × gender) analysis of covariance (ANCOVA) was done to evaluate the main effects interactions for cardiovascular and psychological distress data. Subsequent 2 × 2 ANCOVA (24-h HT × depression) in men and women and (gender × depression) analyses followed.

The prevalence of smoking, alcohol consumption, hypertension, hypertension medication, physical activity (PAI) and depression were computed using the two-way Pearson Chi-square analysis.

One-way ANCOVA was used to compare the psychological and cardiovascular variables between the hypertensive and normotensive gender groups while independent of confounders (age, BMI, PAI, smoking and alcohol consumption).

Partial correlations followed to indicate associations between cardiovascular variables (WC, Cw, MAP, 24-h SBP and the Cornell product), depression (PHQ-9) and the common mental health domains of depression (GHQ_DS), anxiety (GHQ_AS), somatic symptoms (GHQ_SS) and social dysfunction (GHQ_ SD), as well as the GHQ_Total score (GHQ_T) separately in the hypertensive men and women. Partial correlations were done while adjusting for confounders (age, BMI, PAI and smoking and alcohol consumption).

Logistic regression analysis was done using hypertension as the dependent variable and GHQ_SS, PHQ_TT, Cornell product, blood pressure, MAP and vascular compliance as the predictor variables. The odds ratio was determined to measure effect size.

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The reliability of GHQ-28 and PHQ-9 were determined by the Cronbach alpha (α) reliability coefficient, which was between 0.77 and 0.83 for GHQ-28 and 0.81 for PHQ-9. Data were considered statistically significant at p ≤ 0.05.

Results The 2 × 2 × 2 (24-h HT × depression × gender) interactions were not significant for either of the cardiovascular variables, depression and perception of health data. For exploratory reasons, cardiovascular variables were evaluated in subsequent two-way ANCOVAs, (24-h HT × depression) in men and women, which showed significance for own perception of own health [GHQ-T (F: 1, 91) = 3.98, p = 0.05; GHQ-AS (F: 1, 91) = 4.02, p = 0.05] and GHQ-DS, [(F: 1, 91) = 4.17, p = 0.05]. The 2 × 2 (gender × depression) interaction showed a significant interaction for LVH [(F: 1, 163) = 7.30, p = 0.01].

Table 1 shows that more men were hypertensive (79%) than women (57%). The hypertensive men and women were older (p = 0.01), more obese (p < 0.01), and with larger waist circumference (WC) (p = 0.05) compared with their normotensive counterparts. The hypertensive groups also revealed a higher Cornell product value only in HT men (p = 0.06) coupled to a lower arterial compliance (p = 0.05), compared with the normotensive groups.

Table 2 reveals that in HT men, blood pressure (systolic, r = 0.24 and diastolic, r = 0.30) was associated with perceived health (GHQ_SS) and target end-organ damage (LVH). LVH (r = 0.32) was positively associated with depression whereas it was negatively associated (r = –0.26) with vascular compliance in HT men. In the HT women, HR correlated positively with the perception of somatic symptoms (r = 0.30). To determine the effect size of these associations in predicting hypertension, a logistic regression analysis was performed. Hypertension was used as the dependent variable and SBP, DBP, Cw, LVH, GHQ_SS and PHQ_TT were independent predictors. In only the women, depression and LVH showed an odds ratio of 1.15 (95% CI = 1.01–1.32) and 1.02 (95% CI = 0.998–1.05), respectively, as predictors of hypertension.

Discussion The main aim of this study was to investigate the interaction between cardiovascular function and psychological distress in urbanised black South Africans. The main findings of this study were that in HT men, blood pressure (SBP and DBP) was associated with the perception of more somatic symptoms and LVH, while LVH was also associated with depression (p = 0.001). In HT women, HR was associated with the perception of more somatic symptoms and MAP was associated with depression.

Additionally, this study showed that in HT African men, elevated BP and lower vascular compliance were both associated with the development of target end-organ damage.

Based on the DSM-IV depression criteria as measured with the PHQ-9, more women revealed a trend of experiencing depression compared to men, which is consistent with results found in African-Americans.31 When comparing the five levels of severity of depression, however, a new trend emerged.

While women were more prone to suffer from minimal (6%) to moderately severe (36%) depression, substantially more men

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TABLE 1. DESCRIPTIVE STATISTICS, MEAN (95% CI) OF THE HYPERTENSIVE AND NORMOTENSIVE MEN AND WOMEN INDEPENDENT OF CONFOUNDERS (AGE, BMI, SMOKING, ALCOHOL AND PHYSICAL ACTIVITY) Hypertensive men (n = 79) 44.39 (42.61; 42.17) 28.48 (27.24; 29.73) 100.6 (92.15; 109.07)

Normotensive men (n = 21) 39.10 (35.64; 42.55) 23.10 (20.65; 25.48) 82.13 (65.74; 98.53)

p-value 0.01

Hypertensive women (n = 57) 46.61 (44.58; 48.65) 34.63 (32.71; 36.54) 99.59 (95.90; 103.27)

Normotensive women (n = 42) 43.74 (41.37; 46.11) 30.38 (28.16; 32.61) 85.52 (81.23; 89.81)

p-value *Age (years) 0.07 < 0.01 < 0.01 *BMI (kg/m2) 0.05 Waist circumference (cm) < 0.01 *Smoking n (%) 26 (34.21) 5 (23.80) 0.42 3 (5.26) 0 (0) 0.13 *Alcohol n (%) 34 (43.04) 6 (28.57) 0.23 7 (12.28) 5 (11.90) 0.95 *PAI n (%) 56 (70.88) 15 (71.43) 0.80 41 (71.93) 34 (80.95) 0.27 HIV+ n (%) 12 (15.19) 2 (9.53) 0.20 4 (7.02) 1 (2.38) 0.30 Hypertension medication n (%) 14 (17.72) 1 (4.76) 0.14 15 (26.31) 6 (14.29) 0.15 TPR (mmHg/ml/s) 1.07 (0.04; 1.00) 1.05 (0.895; 1.21) 0.80 0.99 (0.90; 1.09) 0.92 (0.80; 1.03) 0.29 113.34 (110.12; 115.85) 101.53 (95.48; 107.58) < 0.01 105.68 (103.41; 107.95) 95.60 (92.88; 98.31) MAP (mmHg) < 0.01 1.84 (1.77; 1.92) 2.03 (1.87; 2.19) 1.74 (1.66; 1.81) 2.01 (1.92; 2.10) 0.05 < 0.01 CW (ml/mmHg) Heart rate (b/min) 68.20 (65.73; 70.68) 63.90 (58.67; 69.12) 0.16 70.39 (67.10; 73.69) 68.82 (64.87; 72.78) 0.56 89.65 (78.29; 101.02) 60.02 (32.44; 87.61) Cornell product (mV.ms) 0.06 60.53 (53.36; 67.71) 49.58 (40.98; 5820) 0.65 91.48 (88.68; 92.63) 76.92 (72.80; 81.04) 84.25 (82.47; 86.03) 72.38 (70.28; 74.48) 24-h DBP (mmHg) < 0.01 < 0.01 142 (138.84; 144.56) 122.61 (116.65; 128.58) < 0.01 137.10 (134.21; 139.91) 117.37 (114.01; 120.73) < 0.01 24-h SBP (mmHg) PHQ_TT 8.33 (7.07; 9.6) 8.31 (5.72; 10.90) 0.99 10.48 (8.92; 12.02) 10.12 (8.30; 11.95) 0.80 GHQ_T 7.21 (5.74; 8.68) 8.20 (5.13; 11.25) 0.58 9.23 (7.41; 11.04) 9.10 (6.93; 11.21) 0.91 GHQ_Somatic symptomsS 2.38 (1.91; 2.84) 2.35 (1.38; 3.32) 0.97 2.60 (1.95; 3.25) 2.74 (1.97; 3.51) 0.79 GHQ_Anxiety symptomsS 2.31 (1.77; 2.86) 2.60 (1.46; 3.72) 0.67 2.77 (2.10; 3.50) 3.10 (2.28; 3.90) 0.57 GHQ_Social dysfunctionD 1.70 (1.20; 2.20) 2.21 (1.18; 3.23) 0.39 2.44 (1.85; 3.01) 1.94 (1.25; 2.62) 0.29 GHQ_Depressive symptomsS 0.82 (0.48; 1.17) 1.03 (0.31; 1.76) 0.62 1.43 (0.84; 2.01) 1.30 (0.60; 1.97) 0.75 CI, 95% confidence intervals; n, number of participants; BMI, body mass index; PAI, physical activity index; TPR, total peripheral resistance; MAP, mean arterial pressure; CW, arterial compliance; 24-h SBP, 24-hour systolic blood pressure; 24-h DBP, 24-hour diastolic blood pressure; PHQ_TT, patient health questionnaire total score; GHQ_T, general health questionnaire total score; Statistical significance is considered when, p ≤ 0.05. Significant values are highlighted in bold. *not adjusted.

TABLE 2. PARTIAL CORRELATIONS IN HYPERTENSIVE AFRICAN MEN AND WOMEN: CARDIOVASCULAR VARIABLES WITH DEPRESSION (PHQ-9), PERCEPTION OF SOMATIC SYMPTOMS AND TARGET END-ORGAN DAMAGE (LVH) INDEPENDENT OF CONFOUNDERS (AGE, BMI, SMOKING, ALCOHOL AND PHYSICAL ACTIVITY) Hypertensive men Hypertensive women Target end-organ Perception of PHQ_major Target end-organ Perception of PHQ_major damage (LVH) somatic symptoms depression damage (LVH) health (GHQ_SS) depression r-value; p-value r-value; p-value r-value; p-value r-value; p-value r-value; p-value r-value; p-value Waist circumference (cm) –0.02; 0.86 0.13; 0.30 –0.18; 0.13 0.22; 0.06 0.04; 0.73 –0.16; 0.18 0.44; < 0.01 0.23; 0.05 MAP (mmHg) 0.18; 0.12 0.15; 0.21 0.20; 0.08 –0.14; 0.22 0.30; 0.01 Hear rate (b/min) 0.03; 0.81 0.15; 0.22 –0.05; 0.69 –0.13; 0.27 –0.03; 0.83 TPR (mmHg/ml/s) 0.13; 0.26 0.10; 0.41 0.10; 0.38 0.18; 0.11 –0.20; 0.08 0.05; 0.69 –0.26; 0.03 -0.15; 0.20 –0.12; 0.32 –0.10; 0.37 0.11; 0.35 –0.18; 0.13 CW (ml/mmHg) 0.24; 0.04 SBP (mmHg) 0.43; < 0.01 –0.00; 1.00 0.21; 0.06 –0.07; 0.55 0.05; 0.69 0.32; 0.01 0.30; 0.01 DBP (mmHg) –0.01; 0.97 0.12; 0.31 –0.11; 0.34 0.11; 0.35 0.35; < 0.01 Cornell product (mV.ms) – –0.07; 0.56 – 0.03; 0.83 –0.10; 0.40 LVH, left ventricular hypertrophy; BMI, body mass index; PAI, physical activity index; MAP, mean arterial pressure; HR, heart rate; TPR, total peripheral resistance; CW, arterial compliance; SBP, systolic blood pressure; DBP, diastolic blood pressure; Cornell product (> 2.44 mV.ms). PHQ_ major depression, scores of < 10 are considered as showing no depressive disorders; whilst a score >10 are considered to be major depressed. All cardiovascular variables were adjusted for age, BMI, PAI, smoking and alcohol consumption. Significant correlations are highlighted in bold.

(28%) seemed to suffer from severe depression in comparison to women (15%). These differences may be due to the discrepancies in the expression of depression by men and women. The expression of emotions, constrained by traditional notions of masculinity, may explain why the prevalence of depression was high in men even though they did not report symptoms of depression.32 African men had a higher prevalence of hypertension compared to the women, which was consistent with other studies done on this population group.4,8-11 If participants in this study were stratified into hypertensive and normotensive

groups, significant associations existed between the perception of somatic symptoms and 24-hour BP in the HT men. This finding suggests that individuals who suffer from high BP have a negative experience of their own physical health, and that they are aware of being physically not well. It has previously been found that increased BP manifests among Africans with a negative perception of their well being.11 This is also consistent with findings from other studies that showed that Africans may experience more chronic sympathetic system activation when exposed to social and environmental

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stressors.8,10 The same authors illustrated that in African men, an exaggerated peripheral resistance response could be seen.4,10,11 The perception of daily events as stressful might result in a negative experience of physical health, psychological distress and perceived poor health. These experiences may manifest as subjective stress, resulting in an exaggerated vascular response and subsequent increases in BP.33 Regarding the cardiovascular profile, our data revealed a practical significance for lower arterial compliance predicting HT (odds ratio 9.75), but it was also positively associated with the development of target end-organ damage.34,35 The cardiovascular profile in urban African men was additionally associated with depression. As 28% of them were severely depressed, a vicious circle seems apparent and CVD risk could be increased if psychological distress or depression persists.36 It has been shown that hypothalamic–pituitary–adrenocortical (HPA) axis hyperactivity has been associated with both hypertension and depression.

Whether HPA hyperactivity is a possible mechanism for the above associations in this population remains an unsubstantiated speculation that will require further investigation.37-39 A logistic regression analysis was also performed to show the effect size of depression, perception of health and cardiovascular variables as predictors for HT. Other studies have shown that in men, depression has been significantly associated with a variety of cardiovascular disorders, particularly the elevation of MAP.17,40,41 In this study, though, a weak association between depression and MAP was found only in hypertensive women.

Depressed women were 1.15 times more likely to develop hypertension than men, indicating that depression had a greater effect on HT in women than the other measured predictors. Therefore, individuals who were depressed had a greater chance of developing hypertension. As was found in African-Americans, depression was predictive of later incidence of hypertension.42 The possible reasons for this discrepancy in findings may lie in the difference in the populations under study. Different backgrounds, socio-economic status, living conditions and levels of stress and depression may be additional confounders for comparing studies in different settings. Moreover, the use of different psychological models in diagnosing depression may result in an incongruity in the sensitivity of the instruments.

Lastly, the urban African men revealed a 24-hour mean BP of 138/89 mmHg, which was higher than the ESH recommendations (> 125–130/> 80 mmHg), suggesting a possible need for new cut-off values (24-hour AMBP) for Africans. On the other hand, it could also indicate the seriousness of uncontrolled BP in urban black African men experiencing increased psychological distress, because only 16% of the HT men used antihypertensive medication and 79% conformed to the ESH criteria of hypertensive status. We therefore recommend that pre-hypertensive levels should be monitored and addressed with early non-pharmacological lifestyle modifications.

Possible limitations of the study include the small size of the study sample when subjects were divided in HT and NT groups.

Future research should incorporate the measure of psychological well being in addition to the measure of psychopathology, as it will provide a broader continuum for the classification of the mental health of those individuals falling within the threshold category. The lack of symptoms of depression in a certain part of the current sample should therefore not be interpreted as the presence of mental health.

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Conclusion This study showed that depression was significantly associated with certain measured cardiovascular variables and that depression was the most prominent contributor to HT. Major depression was associated with the development of pathological conditions such as the development of LVH, lower vascular compliance and elevated MAP, possibly through hyperactivity of the sympathetic nervous system. Perception of poorer health, in particular somatisation, could contribute to autonomic dysfunction in both men and women. The limited number of similar studies in an African population serves as motivation for more research in this area.

The authors acknowledge the contributions of the following SABPA team members: the anthropometric measurements done by biokineticists, supervised by Prof JH de Ridder, cardiovascular measurements supervised by cardiovascular physiologists, and the psychological data supervised by psychologists. This study was financially supported by the North-West University: AUTHER (African Unit for Transdisciplinary Health Research), and the National Research Foundation (NRF), Metabolic Syndrome Institute (France).

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13. Goldberg DP, Hiller VF. Manual of General Health Questionnaire.

England: NFER Publishing Windsor; 1978.

14. Kroenke K, Spitzer RL, Williams. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med 2001; 16: 606–613.

15. Stansfeld SA, Fuhrer R, Shipley MJ, et al. Psychological distress a risk factor for coronary heart disease in the Whitehall II Study. Int J Epidemiol 2002; 31: 248–255.

16. Lett HS, Blumenthal JA, Babyak MA, et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.

Psychosom Med 2004; 66: 305–315.

17. Shinn EH, Poston WSC, Kimball KT, et al. Blood pressure and symptoms of depression and anxiety: a prospective study. Am J Hypertens 2001; 14: 660–664.

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18. Kabir AA, Whelton PK, Khan MM et al., Association of symptoms of depression and obesity with hypertension: the Bogalusa Heart study. Am J Hypertens 2005; 19(6): 639–645.

19. Schutte R, Schutte AE, Huisman HW, van Rooyen JM, Malan NT, Péter S, et al. Blood glutathione and sub-clinical atherosclerosis in African men: the SABPA study. Am J Hypertens 2009; 22: 1154–1159.

20. Giuseppe M, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension. Eur Heart J 2007; 28: 1462–1532.

21. World Medical Association. Declaration of Helsinki: Ethical principles for medical research involving human subjects. World Medical Association online 2005 Available at: http://www.wma.net/e/policy/ b3.htm. Accessed November 9, 2008.

22. Obrist PA. Cardiovascular Psychophysiology: A Perspective. London: Plenum Press, 1981.

23. World Health Organization 2003. The Global Physical Activity Questionnaire (GPAQ). Available at: http://www.who.int/entitty/chp/steps/ resources/GPAQ.htm Accessed: November 7, 2008.

24. Jackson G. The General Health questionnaire. Occup Med 2007; 57(1): 79.

25. Stapelberg R. Psychometric characteristics of the Cope and SACS in the Setswana-speaking South African group (MA). Potchefstroom University, Potchefstroom. 1999: 200.

26. Goldberg DP, Gater R, Sartorius TB, et al. The validity of two of the GHQ in the WHO study of mental illness in general health care. Psychol Med 1997; 27: 191–197.

27. Marfell-Jones M, Olds T, Stewart A, et al. International standards for anthropometric assessment. ISAK: International Society for the Advancement of Kinanthropometry, 2006: 58–87.

28. American College of Sports Medicine (ACSM). Guidelines for Exercise Testing and Prescription. 7th edn. Philadelphia: Lippincott Williams & Wilkins, 2006.

29. Heil DP. Predicting activity energy expenditure using the Actical® Activity Monitor. Res Q Exercise Sport 2006; 77(1): 64–80.

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30. Ang DSC, Lang CC. The prognostic value of the ECG in hypertension: where are you now? J Hum Hypertens 2008; 22: 460–467.

31. Riolo SA, Nguyen TA, Greden JF, et al. Prevalence of depression by race/ethnicity: findings from the National Health & Nutrition Examination study III. Am J Public Hlth 2005; 95(6): 998–1000.

32. Brownhill S, Wilhelm K, Barclay L, et al. ‘Big build’: hidden depression in men. Aust N Z J Psychiat 2005; 39(10): 921–931.

33. Appels A. Mental precursors of myocardial infarction. Br J Psychiat 1990; 156: 465–471.

34. Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic values of a new electrocardiographic method for the diagnosis of left ventricular hypertrophy in essential hypertension. J Am Coll Cardiol 1998; 31: 383–390.

35. Sundström J, Lind L, Arnlöv J, et al. Echocardiographic and echocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men. Circulation 2001; 103: 2346–2351.

36. Farmer A. Medical disorders in people with recurrent depression. Br J Psychol 2008; 192: 351–355.

37. Remme WJ. The sympathetic nervous system and ischemic heart disease. Eur Heart J 1998; 19(F): 62–71.

38. Reynolds RM, Walker BR, Syddall HE, et al. Altered control of cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life. Rev Neurosci 1999; 10: 117–139.

39. Gold SM, Dziobek I, Rogers K. Hypertension and hypothalamopituitary-adrenal axis hyperactivity affect frontal lobe integrity. J Clin Endocrinol Metab 2005; 90(6): 3262–3267.

40. Rieff M, Schwartz S, Northridge M. Relationship of depressive symptoms to hypertension in a household survey in Harlem. Psychosom Med 2001; 63: 711–721.

41. Dimsdale JE. Symptoms of anxiety and depression as a precursor to hypertension. J Am Med Assoc 1997; 277: 574–575.

42. Jonas BS, Frank P, Ingram DD. Are symptoms of anxiety and depression risk factors for hypertension? Arch Fam Med 1997; 6(1): 43–49.

Letter to the Editor Dear Sir In their article on long-term outcome associated with early repolarisation on electrocardiography, Tikkanen and colleagues (N Engl J Med 2009, 24 December)1 refer to the generally admitted definition,2,3 showing a figure with both slurring and notching patterns in subjects who died from arrhythmia. This is the longest-ever published follow-up study on the topic.

It would be useful to have data on the prognostic significance of each type of repolarisation. In our yet-to-be published registry,4 J-point elevation that was notched rather than a slurred variant appears to be strongly related to the history of transient loss of consciousness in black Africans. However, this finding needs to be studied prospectively.

In addition to the findings that inferior lead localisations and the magnitude of the J-point elevation ≥ 0.1 mV (mostly > 0.2 mV) are stronger predictors of death from cardiac causes or arrhythmia, we want to emphasise the importance of information on the degree of malignancy of each type of early repolarisation

on risk-stratification accuracy in subjects with this common pattern in the general population.

AIMÉ BONNY, aimebonny@yahoo.fr

Hôpital Pitié Salpêtrière, Paris, France

References 1. Tikkanen JT, Anttonen O, Junttila JM, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009; 361: 2529–2537.

2. Boineau JP. The early repolarization variant – an electrocardiographic enigma with both QRS and J-STT anomalies. J Electrocardiol 2007; 40(1): 3.e1–3.e10.

3. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358: 2016–2023.

4. Bonny A, Ditah I, Larrazet F, Frank R. Prevalence and significance of early repolarization pattern in Black Africans: Registry of two centers in Cameroon. Abstract, ESC 2009, Barcelona, Spain.

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Review Article The clinical quandary of left and right ventricular diastolic dysfunction and diastolic heart failure ERNST R SCHWARZ, RAJA DASHTI

Summary Diastolic heart failure is a common clinical entity that is indistinguishable from systolic heart failure without direct evaluation of left ventricular function. Diastolic heart failure is a clinical diagnosis in patients with signs and symptoms of heart failure but with preserved left ventricular function and normal ejection fraction, and is often seen in patients with a long-standing history of hypertension or infiltrative cardiac diseases. In contrast, diastolic dysfunction represents a mechanical malfunction of the relaxation of the left ventricular chamber that is primarily diagnosed by two-dimensional transthoracic echocardiography and usually does not present clinically as heart failure. The abnormal relaxation is usually separated in different degrees, based on the severity of reduction in passive compliance and active myocardial relaxation.

The question whether diastolic dysfunction ultimately will lead to diastolic heart failure is critically reviewed, based on data from the literature. Treatment recommendations for diastolic heart failure are primarily targeted at risk reduction and symptom relief. Currently, few data only are reported on diastolic dysfunction and its progression to systolic heart failure.

Keywords: diastolic heart failure, diastolic dysfunction, congestive heart failure, cardiomyopathy Submitted 25/9/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 212–220

www.cvja.co.za

Even though often interchangeably used in the clinical setting, there is a distinction between diastolic dysfunction and diastolic heart failure. A PubMed literature search revealed a total of 1 478 articles using the search terms diastolic heart failure and review. In contrast, only a few randomised controlled trials are available on diastolic heart failure alone. Controversy remains regarding the optimal therapy in patients with either diastolic dysfunction or diastolic heart failure.1 An important question is whether diastolic dysfunction does indeed lead to diastolic heart failure and how this progression occurs. Moreover, it is unclear whether diastolic dysfunction results in both diastolic and subsequently, systolic heart failure.

Cedars Sinai Heart Institute, Cedars-Sinai Medical Center and University of California Los Angeles (UCLA), Los Angeles, California

ERNST R SCHWARZ, MD, PhD, FACC, ernst.schwarz@cshs.org RAJA DASHTI, MD, FRCPC, FACC

In daily routine, heart failure is often separated into systolic and diastolic failure based on preservation of left ventricular ejection fraction.1 The terms ‘heart failure with preserved left ventricular function’ or ‘heart failure with normal ejection fraction’ are utilised to emphasise that the aetiology of the pathophysiology for this group of patients may go beyond diastolic dysfunction alone.2 Heart failure in general and diastolic heart failure in particular causes a significant financial burden and increasing consumption of healthcare resources, especially among the elderly population (i.e. for patients 65 years of age or older).3,4 This article will review the current knowledge of diastolic dysfunction and its progression to diastolic heart failure.

Diastolic dysfunction Diastolic dysfunction is a mechanical abnormality brought upon by a breakdown in the passive (compliance) and active (myocardial relaxation) intrinsic properties of the ventricle during diastole. Myocardial hypertrophy (e.g. left ventricular hypertrophy secondary to hypertension) and myocardial ischaemia have been shown to impair the energy-dependant process of myocardial relaxation. The increased afterload in patient with aortic stenosis or hypertension can also inhibit myocardial relaxation by reducing the ability of the left ventricle to contract to small end-systolic volume, and hence limit the ensuing elastic recoil’s ability to enhance myocardial relaxation. Also, diastolic dysfunction can be secondary to pathological states that adversely affect the passive compliance during diastole, such as increases in myocardial wall thickness observed in concentric hypertrophy as a result of longstanding hypertension, or in myocardial fibrosis in patients with infiltrative pathology.5

The role of echocardiography in the assessment of diastolic function Diastolic function can be evaluated non-invasively using twodimensional transthoracic echocardiography. The evaluation of left ventricular diastolic function should be an essential part of any echocardiography examination.6 The three phases of diastole consist of a period of isovolumic relaxation time (IVRT), followed by an early rapid diastolic filling period (E), a plateau, and finally a late filling due to the atrial contraction or atrial kick (A). These can be evaluated by using the pulse wave (PW) Doppler of the mitral valve and pulmonary veins. The left ventricular filling pattern obtained will therefore indirectly reflect the left ventricular filling pressures.

A complete left ventricular diastolic assessment should

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include assessment of the IVRT, peak E velocity, peak A velocity, E/A ratio, deceleration time (DT), and A duration, which are obtained from the transmitral inflow velocities (Fig. 1).

Pulmonary vein (PV) flow velocities are then measured, which A

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include four components: two systolic velocities (PVs1 and PVs2), diastolic velocity (PVd), and atrial flow reversal (PVa) (Fig. 2).7 Based on the echocardiographic parameters, diastolic dysfunction has been divided into three different grades of severity of ventricular compliance, relaxation rate and filling pressures.8 A

B B

C C

Fig. 1. Two-dimensional transthoracic echocardiography with four-chamber view (A); colour Doppler (B); and pulse-wave colour Doppler (C) showing normal mitral inflow velocity pattern.

Fig. 2. Pulse-wave colour Doppler showing normal pulmonary vein inflow velocity pattern.

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Stage one is the mildest form of diastolic dysfunction with delayed relaxation defined by an early filling to late or atrial filling (E/A) ratio less than 1, prolonged IVRT and prolonged DT. The systolic to diastolic pulmonary venous (S/D) ratio is greater than 1 (Fig. 3). Stage two is marked by a moderate level of dysfunction and defined by E/A of greater than 1 and/or greater than 2 with S/D less than 1, and is often called pseudonormalisation (with a normal diastolic filling pattern), caused by elevated left atrial pressures. This can be unmasked by reducing preload, for example by use of the Valsalva manoeuvre or application of sublingual nitroglycerine (Fig. 4). Stage three is marked by a restrictive filling pattern and signifies severe diastolic dysfunction, i.e. decreased compliance and marked increase in left atrial pressure. The E/A is greater than 2, IVRT and DT are short, and S/D is less than 1 (Fig. 5). The mitral A duration is shorter than the PVa duration (Fig. 6).

Mitral annular velocity by tissue Doppler imaging also has been used to assess diastolic function. This is referred to as E. The Em (mitral)/E¢ (annular) ratio has been found to correlate well with increased pulmonary capillary wedge pressure (PCWP). The E/E¢ ratio is normally less than 8. The E¢ is shown to be low, in restrictive stage less than 8. A ratio of greater than 15 indicates elevated PCWP (Fig. 7).9 Although rarely performed for evaluation of diastolic dysfunction alone, the most accurate invasive diagnostic technique is cardiac catheterisation with direct measurements of left ventricular end-diastolic pressure.10,11 Parameters of chamber stiffness are correlated with changes in pressure to changes in chamber volume.

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the years, a variety of co-morbid conditions have been associated with development of left ventricular diastolic dysfunction, such as myocardial scarring, transmural myocardial infarction, chronic constrictive pericarditis, chronic coronary artery disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, diabetic cardiomyopathy, hypertension, aortic stenosis as well as normal aging.12 The underlying connection in the possible aetiologies of left ventricular diastolic dysfunction is their ability to hinder one or both of the intrinsic diastolic properties of compliance or relaxation. Pathological states such as fibrosis and concentric hypertrophy can reduce compliance of the myocardium by increasing passive ventricular stiffness, thereby affecting the passive propA

Left ventricular diastolic dysfunction In its simplest form, left ventricular diastolic dysfunction is defined as impairment in the capacity of the left ventricle to accept blood without a compensatory increase in left atrial pressure.12 Patients with left ventricular diastolic dysfunction tend to have elevated left ventricular diastolic pressure in the presence of normal or even reduced left ventricular volume, as the pressure–volume curve in these patients is shifted upwards.13,14 Over

Fig. 3. Echocardiographic image of stage I diastolic dysfunction: impaired relaxation E < A, E/A ratio < 1.0, DT > 200 < IVRT > 90.

B

Fig. 4. A shows stage II diastolic dysfunction with pseudonormalised pattern where E/A reverses with valsalva manoeuvre (B).

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A

Fig. 5. Stage III diastolic dysfunction: restrictive stage of diastolic dysfunction: E/A ratio > 2.0, DT < 160, IVRT < 70.

B

Fig. 6. Doppler tissue imaging (DTI): E¢ < 7 indicates restrictive filling pattern. The E/E¢ > 15 suggests elevated PCWP.

erty of compliance in diastole. Ischaemia and disease processes leading to increased afterload affect diastole by impairment of the active rate of relaxation.

Left ventricular diastolic dysfunction and heart failure The prevalence as well as overall significance of diastolic heart failure has become distinctly apparent. Diastolic heart failure was originally reported in 1937 when Fishberg referred to it as ‘hypodiastolic failure’, a form of cardiac insufficiency secondary to inadequate filling of the left ventricle during diastole.15 A half a century later, Kessler became the first to discuss the clinical syndrome of diastolic heart failure.16 Over the years, a number of landmark publications have guided our current understanding in diagnosing diastolic heart failure.

Recognising the difficulty of non-invasive assessment of the LV diastolic function, in 2000, Vasan and Levy proposed a classification scheme for diagnosis of diastolic heart failure in the hope of reducing the difficulty of diagnosis of this rather prevalent pathology.17 According to the degree of diagnostic certainty,

Fig. 7. Difference between A duration (mitral) (A) and A duration of pulmonary vein (B) predicts elevated LVEDP or PCWP.

patients were partitioned into possible, probable, or definite diastolic heart failure. While keeping the need for evidence of heart failure for all categories, the diagnosis of probable or definite diastolic heart failure required evidence of normal left ventricular systolic function within three days of the initial heart failure event. Most importantly it was argued that ‘evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness’ is required for a definite diagnosis of diastolic heart failure.

More recently, Zile and colleagues have published several prospective studies, concluding that the diagnosis of diastolic heart failure does not require objective recording of left ventricular diastolic dysfunction but only documentation of preserved systolic function. In two separate studies utilising both Doppler echocardiography and cardiac catheterisation, the

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authors observed a statistically significant percentage of patients with clinical diagnosis of heart failure and normal ejection fraction (EF > 45%) to be suffering from abnormalities in active relaxation or passive compliance.18,19 The degree of involvement that left ventricular diastolic dysfunction plays in preserved ejection fraction heart failure is debatable and has been the major argument made by those that believe diastolic heart failure is the correct diagnosis for patients with heart failure and normal ejection fraction, given that these patients do not suffer from significant valvular, pericardial or pulmonary disease. Left ventricular diastolic dysfunction has also been found to be present in patients with heart failure and reduced ejection fraction, a form of heart failure that was originally believed to be mainly secondary to a systolic dysfunction pathophysiology.20

Clinical studies in patients with diastolic dysfunction In 1972 Gaasch and colleagues performed some of the first studies to evaluate the possible effects of left ventricular diastolic dysfunction. The authors described that left ventricular diastolic dysfunction has a negative impact on systolic function through its limitation of the Frank-Starling mechanism.21 Patients with conditions such as left ventricular hypertrophy have elevated left ventricular end-diastolic pressure and decreased compliance, which affects the lengthâ&#x20AC;&#x201C;tension relationship by decreasing muscle fibre stretch at any given peak systolic stress. This might explain why decreased exercise tolerance is one of the first clinical symptoms associated with echocardiographically diagnosed diastolic dysfunction.

Exercise tolerance in patients with left ventricular diastolic dysfunction who are asymptomatic at rest may be compromised secondary to the inability to enhance diastolic filling by the degree necessary to increase the cardiac output during exercise without causing an abnormal elevation in left atrial pressure.

Diastolic dysfunction has been found to be aggravated by exercise, especially with an increase in blood pressure. Recent studies have observed the development of left ventricular diastolic dysfunction in the presence of hypertension prior to the development of ventricular hypertrophy.22,23 Left ventricular diastolic dysfunction can therefore represent myocardial end-organ damage prior to progression to clinically relevant heart failure, although further trials are needed to support this hypothesis.

The magnitude of asymptomatic left ventricular diastolic dysfunction in the general population is still unclear. In an attempt to determine the prevalence of pre-clinical diastolic dysfunction, Redfield et al. performed a cross-sectional survey of 2 042 randomly selected residents over the age of 45 years in Olmsted County, Minnesota.24 The authors found the prevalence of asymptomatic echocardiographically diagnosed diastolic dysfunction to be 28%, with an increased prevalence seen in older patients, diabetics, and in patients with cardiovascular disease (hypertension, coronary artery disease, cardiomyopathies).

A prospective trial in 206 patients with the clinical diagnosis of heart failure (New York Heart Association Grade II or higher) reported that, based on echocardiographic parameters, 91% of 102 patients with an EF greater than 50% had some degree of diastolic dysfunction, and 92% of 71 patients with an EF of less than 40% suffered from left ventricular diastolic dysfunc-

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tion.25 Patients with reduced ejection fraction were more likely to have moderate to severe diastolic dysfunction in comparison to patients with preserved ejection fraction (27 vs 62%, respectively).

In patients with heart failure with preserved EF, left ventricular diastolic dysfunction was accompanied by left ventricular hypertrophy, while in patients with heart failure and reduced EF, left ventricular diastolic dysfunction was associated with left ventricular dilation and marked systolic dysfunction. The overall prognosis and mortality appears to be significantly influenced by the degree of left ventricular diastolic dysfunction in heart failure patients, regardless of ejection fraction.26

Clinical studies in patients with diastolic heart failure The American College of Cardiology and the American Heart Association (ACC/AHA) Task Force has previously stated that a definitive diagnosis can be made in heart failure patients with preserved EF if there is a decreased rate of ventricular relaxation with elevated LV filling pressure, clarifying the need for coexistence of normal contractility (LV systolic function) and LV volume.27 In further assessing such assumptions, Baicu et al. compared 75 patients with heart failure and normal ejection fraction with 75 patients without cardiovascular disease.

After analysing both echocardiographic parameters and data derived from cardiac catheterisation, it appeared that left ventricular systolic function, contractility and performance was intact in patients with presumed diastolic heart failure (with normal ejection fraction).28 In a review of data on left ventricular structure and function in heart failure patients with normal ejection fraction and hypertension, Zile and Lewinter have argued that left ventricular end-diastolic volume is within the normal range in patients with diastolic heart failure.29 The frequently quoted CHARM-preserved trial was one of two large trials, studying a total of 3 023 patients with heart failure with preserved EF of more than 40%, treated with the angiotensin receptor blocker candesartan.30 After a median follow up of 36.6 months, fewer candesartan-treated patients were hospitalised for heart failure compared with the placebo group (402 vs 566, p = 0.014), but there was no significant difference with regard to cardiovascular mortality. As an important finding on the side, a significant 40% reduction was seen in the development of new diabetes mellitus in the candesartan group compared with the placebo group (4 vs 7%, p = 0.005).

This has gained even more interest in view of recently published data on diabetes as an independent predictor of cardiovascular morbidity and mortality in heart failure patients, regardless of their EF,31 underlining the importance of controlling risks and co-morbidities in patients with diastolic heart failure.

The I-PRESERVE trial, published in 2008, studied 4 128 heart failure patients 60 years of age and older with an EF of at least 45% who were randomly assigned to receive 300 mg of the angiotensin receptor antagonist irbesartan or placebo. Primary event rates as assessed as a composite of death from any cause or hospitalisation for a cardiovascular cause in the irbesartan and placebo groups were 100.4 and 105.4 per 1 000 patient-years, respectively,32 which was not significantly different. In conclusion, neither candesartan (in the CHARM preserved trial) nor irbesartan (in I-PRESERVE) improved survival in these large trials in patients with pure diastolic heart failure.

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Right ventricular diastolic dysfunction Similar to left ventricular diastolic dysfunction, there have been multiple aetiologies associated with impairment in mechanical compliance as well as relaxation parameters that lead to right ventricular diastolic dysfunction. Over the years, right ventricular diastolic dysfunction has been observed in a variety of settings, including obesity, cystic fibrosis, chronic aortic stenosis, arterial hypertension and Chagas disease.33-36 Studies investigating the functional parameters of the right ventricle during diastole were slow to formulate due to the difficulty of correctly measuring right ventricular volume prior to the advent of Doppler echocardiography.37 The algorithm used for assessment and diagnosis of right ventricular diastolic dysfunction with Doppler echocardiography utilises pulsed-wave Doppler of the transtricuspid flow, hepatic venous flow and tissue Doppler imaging of the tricuspid annulus or tricuspid annular velocity.38 Normal hepatic venous flow is defined as a ratio of systolic to diastolic velocities greater than one with the atrial wave reversal less than half the maximum systolic wave velocity.39 Mild right ventricular diastolic dysfunction is defined by E/A < 1 in transtricuspid flow velocities, or 1 < E/A < 2 with S/D > 1 in hepatic vein flow and early component of the tricuspid annular tissue Doppler velocity (Et) less than atrial component of the tricuspid annular tissue Doppler velocity (At), or an atrial reversal wave more than half of the systolic wave of the hepatic vein flow.

Moderate or severe right ventricular diastolic dysfunction can be assumed to be present if a reduced or inverted systolic waveform, respectively, is present on the Doppler hepatic vein flow signal. Studies on pulmonary hypertension patients have led to the speculation that right ventricular diastolic dysfunction may be an independent factor contributing to right heart failure and death in patients with pulmonary hypertension.40 Gan et al. showed that in patients with pulmonary hypertension, the increase in right ventricular afterload resulted in ventricular hypertrophy and right ventricular diastolic dysfunction.41 The degree of diastolic dysfunction correlated with the severity of pulmonary hypertension, which improved with medical therapy that reduced afterload.

Right ventricular diastolic dysfunction in the setting of heart failure was first reported by Riggs in 1993.42 The author reported impaired right ventricular filling parameters in six children with dilated cardiomyopathy. Yu et al. published the first study that systematically assessed right ventricular diastolic dysfunction in 1996; comparing 114 patients with symptomatic heart failure (EF < 50%) with 31 patients with pulmonary hypertension (pulmonary systolic artery pressure > 40 mmHg) as well as 40 healthy subjects.43 The authors described a significant number of patients with systolic heart failure and/or pulmonary hypertension suffering from right ventricular diastolic dysfunction. Even after exclusion of patients with pulmonary hypertension, a statistically significant percentage of heart failure patients suffered right ventricular diastolic dysfunction.

In their analysis of 105 patients with systolic heart failure, Yu and Sanderson demonstrated right ventricular diastolic dysfunction to be present in 21% of patients as assessed by echocardiography.44 Although a low-powered study, the authors concluded that right ventricular diastolic dysfunction was an independent predictor for non-fatal hospital admissions for unstable angina or heart failure, even though it was not observed to be a prognostic

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factor for mortality, either alone or in combination with left ventricular diastolic dysfunction.

Right and left ventricular interaction in diastolic dysfunction The French physician Bernheim was one of the first to report the concept of ventricular interdependence in 1910, noting that right ventricular performance can be compromised through compression of the right ventricle by a dilated or hypertrophied left ventricle.45 In 1956, Dexter explained a possible mechanism for diastolic interdependence.46 The â&#x20AC;&#x2DC;reverse Bernheim effectâ&#x20AC;&#x2122; hypothesised an increase in right ventricular volume secondary to an atrial septal defect, which can cause the septum to be displaced toward the left ventricular cavity and inhibit left ventricular filling mechanisms. A decade later in 1967, Taylor et al. reported that the distension of one ventricle during diastole can affect the compliance of the neighbouring ventricle.47 The term diastolic ventricular interaction refers to the concept that compliance of one ventricle is influenced through a shared septum by the changes in volume, pressure, and/or compliance of the other ventricle.47 Although there are implications that diastolic ventricular interaction plays a role in exercise intolerance in patients with systolic heart failure, we currently do not have a great understanding of the possible role it may have in patients with diastolic heart failure. Ventricular interactions have been reported indirectly in patients with pathology of one ventricle and diastolic dysfunction of the neighbouring ventricle.

Right ventricular diastolic dysfunction has been observed in pathological conditions that result in elevated left ventricular pressure, such as systemic hypertension, aortic stenosis and hypertrophic cardiomyopathy.38,48,49 The reverse has also been reported in patients with elevated right ventricular volume or pressure with impaired left ventricular diastolic function.50 Furthermore, it has been suggested that right ventricular diastolic dysfunction observed in patients with heart failure but normal pulmonary artery pressures may be caused indirectly by coexistent left ventricular diastolic dysfunction secondary to ventricular interdependence.51 Although a realistic prospect, the possible role that diastolic ventricular interaction may play in the potential progression from diastolic dysfunction to clinical heart failure is currently not well established.

Progression of diastolic heart failure In 2001, Aurigemma et al. published the possible rate of progression from asymptomatic diastolic dysfunction to clinical heart failure.52 The study analysed 2 671 individuals without coronary heart disease, congestive heart failure or atrial fibrillation.

At baseline, 15% of the patients had diastolic dysfunction, determined by echocardiography, with 170 participants eventually developing heart failure after a five-year follow-up period (6.4%), concluding that echocardiographic findings can be suggestive of the development of heart failure.

Despite arguments regarding exercise limitations and left ventricular diastolic dysfunction representing a possible early marker of myocardial damage, the rate of progression from diastolic dysfunction to diastolic heart failure remains uncertain.

Currently there are no large clinical trials assessing the possible progression from asymptomatic right ventricular diastolic dysfunction to clinical right ventricular failure.

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Guidelines and therapy for diastolic heart failure The difficulties in the diagnosis of diastolic heart failure have been partly responsible for the limited number of larger randomised, controlled trials to guide treatment. In 1998, the European study group published one of the first widely analysed guidelines for diagnosis of diastolic heart failure, stating the need for evidence of heart failure with normal systolic function (LVEF ≥ 0.50) as well as evidence of abnormal filling, diastolic distensibility, LV relaxation or diastolic stiffness.53 The European Society of Cardiology recently published their latest guidelines for diagnosis of diastolic heart failure in 2007; providing specific guidelines on how to diagnose and exclude heart failure with normal ejection fraction.54 The guidelines have three major criteria for diagnosing heart failure with normal ejection fraction; (1) signs/symptoms of heart failure, (2) normal or mildly reduced systolic function (EF > 50% with a left ventricular end-diastolic volume index less than 97 ml/m2) and (3) evidence of left ventricular diastolic dysfunction.

The diagnostic strategy provided in this set of guidelines allows for non-invasive methods of assessing for left ventricular diastolic dysfunction through tissue Doppler parameters (early mitral valve flow velocity to early tissue Doppler lengthening velocity (E/E¢ > 15) and routine blood test biomarkers (brain natriuretic peptide > 200 pg/ml) to play a role in situations when invasive haemodynamic measurements (LV end-diastolic pressure > 16 mmHg or mean pulmonary capillary wedge pressure > 12 mmHg) are not available.

Current treatment of diastolic heart failure has been aimed at controlling blood pressure and tachycardia, using diuretics to control pulmonary congestion and peripheral oedema, and alleviation of myocardial ischaemia. The ACC/AHA also recommend using beta-adrenergic blocking agents, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium antagonists in those patients with controlled blood pressure, and digitalis in order to control heart failure symptoms. In the latest update of the ACC/AHA practice guidelines for the diagnosis and management of chronic heart failure in the adult, which comprises a document of 63 pages, the treatment of diastolic heart failure is summarised in less than one page.55 Chinnaiyan et al. described the combined use of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers and spironolactone as potential disease-modifying therapy.56 The authors believe that the effects of these drugs improve diastolic dysfunction and diastolic heart failure by regression of left ventricular hypertrophy and decreased collagen content. They recommend these drugs to be utilised in both the setting of decompensated diastolic heart failure as well as for the chronic outpatient management of diastolic heart failure. In the recently published Hong Kong diastolic heart failure study, 150 patients with heart failure and preserved ejection fraction were randomised to diuretics, ACE inhibitors or angiotensin II receptor blocker therapy.57 Only diuretic therapy reduced symptoms and improved quality of life during one-year follow up.

Currently, only a few large randomised clinical trials have assessed the possible benefit of pharmacotherapy at different stages of non-invasively diagnosed diastolic dysfunction, such as the CHARM Preserved trial and I-PRESERVE (see above).30,32 While hospitalisation rates have been reduced with candesartan therapy, survival rate mortality has not been improved in either

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of these trials.

Some small trials have been carried out in an attempt to evaluate possible benefits of pharmacotherapy for patients with left ventricular diastolic dysfunction and decreased exercise tolerance. Warner et al. studied 20 patients with mild diastolic dysfunction, diagnosed by Doppler echocardiography, with a marked hypertensive response to exercise.58 The authors reported that using the angiotensin II receptor blocker losartan, resting blood pressure was unchanged but the hypertensive response to exercise was reduced (from a mean systolic blood pressure (SBP) of 226 mmHg to a mean SBP of 193 mmHg).

Similar studies confirmed the benefits of angiotensin II receptor blockers on exercise tolerance by comparing its effects with calcium channel blockers (verapamil) or diuretics (hydrochlorothiazide). In two separate trials, Little et al. demonstrated that angiotensin II receptor blockers, calcium channel blockers and diuretics all have the ability to blunt an increase in SBP during exercise in patients with asymptomatic left ventricular diastolic dysfunction, but only angiotensin II receptor blocker therapy increased exercise duration and improved quality of life, as assessed by questionnaires.59,60

Conclusion Further research is needed to improve current knowledge of diastolic dysfunction and diastolic heart failure as well as its progression over time. The management of diastolic heart failure is currently aimed at symptomatic management and control of physiological factors known to affect ventricular relaxation, and control of risk factors and co-morbidities (such as hypertension and diabetes mellitus). A timeline for initiation of treatment for diastolic dysfunction has yet to be defined. It is anticipated but not proven whether early initiation of pharmacotherapy once diastolic dysfunction has been diagnosed even in the absence of symptoms will prevent or delay the onset of symptomatic heart failure.

References 1. Koprowski A, Gruchala M, Rynkiewicz A. Management of left ventricular diastolic heart failure: is it only blood pressure control? Curr Opin Cardiol 2009; 24: 161–166.

2. Zile MR, Baicu CF, Bonnema DD. Diastolic heart failure: definitions and terminology. Prog Cardiovasc Dis 2005; 47: 307–313.

3. Sanderson JE. Diastolic heart failure or heart failure with a normal ejection fraction. Minerva Cardioangiol 2006; 54: 715–724.

4. American Heart Association. 2007 Heart and Stroke Statistical Update.

Dallas, Texas: American Heart Association, 2007.

5. Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med 1992; 117: 502–510.

6. Tanaka N, Byori R. Non-invasive assessment of cardiac fucntion. J Am Soc Echocardiogr 2003; 51: 751–760.

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16. Kessler KM. Diastolic heart failure. Diagnosis and management. Hosp Pract 1989; 24:137–160.

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18. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, et al. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001; 104: 779–782.

19. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure – abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004; 350: 1953–1959.

20. Brucks S, Little WC, Chao T, Kitzman DW, Farrington DW, Gandhi S, et al. Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005; 95: 603–606.

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22. Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL, Purkayastha D, et al; Valsartan In Diastolic Dysfunction (VALIDD) Investigators. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet 2007; 369: 2079–2087.

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24. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.

J Am Med Assoc 2003; 289: 194–202.

25. Fukuta H, Little WC. Contribution of systolic and diastolic abnormalities to heart failure with a normal and a reduced ejection fraction. Prog Cardiovasc Dis 2007; 49: 229–240.

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27. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001; 38: 2101–2113.

28. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005; 111: 2306–2312.

29. Zile MR, Lewinter MM. Left ventricular end-diastolic volume is normal in patients with heart failure and a normal ejection fraction: a renewed consensus in diastolic heart failure. J Am Coll Cardiol 2007; 49: 982–985.

30. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al, CHARM investigators and committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003; 362: 777–781.

31. McDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL,

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32. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al, I-PRESERVE investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359: 2456–2467.

33. Mureddu GF, de Simone G, Greco R, Rosato GF, Contaldo F. Left ventricular filling pattern in uncomplicated obesity. Am J Cardiol 1996; 77: 509–514.

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35. Dourvas IN, Parharidis GE, Efthimiadis GK, Karvounis HI, Gemitzis KD, Styliadis IH, et al. Right ventricular diastolic function in patients with chronic aortic regurgitation. Am J Cardiol 2004; 93: 115–117.

36. Cicala S, Galderisi M, Caso P, Petrocelli A, D’Errico A, de Divitiis O, Calabro R. Right ventricular diastolic dysfunction in arterial systemic hypertension: analysis by pulsed tissue Doppler. Eur J Echocardiogr 2002; 3: 135–142.

37. Barros MV, Machado FS, Ribeiro AL, Da Costa Rocha MO. Detection of early right ventricular dysfunction in Chagas’ disease using Doppler tissue imaging. J Am Soc Echocardiogr 2002; 15: 1197–1201.

38. Chakko S, de Marchena E, Kessler KM, Materson BJ, Myerburg RJ. Right ventricular diastolic function in systemic hypertension. Am J Cardiol 1990; 65: 1117–1120.

39. Appleton CP, Hatle LK, Popp RL. Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987; 10: 1032–1039.

40. Denault AY, Couture P, Buithieu J, Haddad F, Carrier M, Babin D, et al.

Left and right ventricular diastolic dysfunction as predictors of difficult separation from cardiopulmonary bypass. Can J Anaesth 2006; 53: 1020–1029.

41. Gan CT, Holverda S, Marcus JT, Paulus WJ, Marques KM, Bronzwaer JG, et al. Right ventricular diastolic dysfunction and the acute effects of sildenafil in pulmonary hypertension patients. Chest 2007; 132: 11–17.

42. Riggs TW. Abnormal right ventricular filling in patients with dilated cardiomyopathy. Pediatr Cardiol 1993; 14: 1–4.

43. Yu CM, Sanderson JE, Chan S, Yeung L, Hung YT, Woo KS. Right ventricular diastolic dysfunction in heart failure. Circulation 1996; 93:1509–1514.

44. Yu HC, Sanderson JE. Different prognostic significance of right and left ventricular diastolic dysfunction in heart failure. Clin Cardiol 1999; 22: 504–512.

45. Bernheim PL. L’asystolie veneuse dans l’hypertrophie du coeur gauche par stenote concomitante du ventricule droit. Rev Med 1910; 39: 785.

46. Dexter L. Atrial septal defect. Br Heart J 1956; 18: 209–225.

47. Taylor RR, Covell JW, Sonnenblick EH, Ross J Jr. Dependence of ventricular distensibility on filling of the opposite ventricle. Am J Physiol 1967; 213: 711–718.

48. Frenneaux M, Williams L. Ventricular-arterial and ventricular-ventricular interactions and their relevance to diastolic filling. Progr Cardiovas Dis 2007; 49: 252–262.

49. Efthimiadis GK, Parharidis GE, Gemitzis KD, Nouskas IG, Karvounis HI, Styliadis IK, Louridas GE. Doppler echocardiographic evaluation of right ventricular diastolic function in isolated valvular aortic stenosis. J Heart Valve Dis 1999; 8: 261–269.

50. Efthimiadis GK, Parharidis GE, Karvounis HI, Gemitzis KD, Styliadis IH, Louridas GE. Doppler echocardiographic evaluation of right ventricular diastolic function in hypertrophic cardiomyopathy. Eur J Echocardiogr 2002; 3: 143–148.

51. Louie EK, Rich S, Levitsky S, Brundage BH. Doppler echocardiographic demonstration of the differential effects of right ventricular pressure and volume overload on left ventricular geometry and filling. J Am Coll Cardiol 1992; 19: 84–90.

52. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive

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heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001; 37: 1042–1048.

53. Working Group Report. How to diagnose diastolic heart failure.

European Study Group on Diastolic Heart Failure. Eur Heart J 1998; 19: 990–1003.

54. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539–2550.

55. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005; 112: e154–235.

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56. Chinnaiyan KM, Alexander D, Maddens M, McCullough P. Curriculum in cardiology: Intergrated diagnosis and management of diastolic hear failure. Am Heart J 2007; 153: 189–200.

57. Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart 2008; 94: 573–580.

58. Warner JG Jr, Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999; 33: 1567–1572.

59. Little WC, Wesley-Farrington DJ, Hoyle J, Brucks S, Robertson S, Kitzman DW, Cheng CP. Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004; 43: 288–293.

60. Little WC, Zile MR, Klein A, Appleton CP, Kitzman DW, WesleyFarrington DJ. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006; 98: 383–385.

Adcock enters deal with MSD; also with regard to the cardiovascular therapeutic arena Adcock Ingram entered into a five-year deal to co-promote and distribute MSD’s over-the-counter medicines and a selection of prescription medicines that are registered in South Africa. Although the financial effects of the transaction at this stage will not be material, it should go a long way in helping the country’s secondlargest pharmaceutical firm to grow, as it will enhance its diverse portfolio and broaden its pipeline of new products in the marketplace.

Jonathan Louw, the chief executive officer of Adcock, said working with MSD (the world’s second-largest pharmaceutical company) would also boost their credibility. ‘It (the collaboration) is strategically important for us. The partnership is in key areas where we already have strength, meaning we will enhance MSD’s ability to sell more products’, said Louw.

The products that will form part of the deal are for various therapeutic areas such as cardiovascular, women’s health and asthma. These are drugs such as Renitec for hypertension, Zocor for cholesterol, Singulair for asthma, Maxalt for migraines and over-the-counter products including Dmazin, Drixine and Tinaderm.

Adcock’s business comprises pharmaceutical and hospital products. It has a 10% market share in the local private pharmaceutical space. Stefan Oschmann,

the president for emerging markets at MSD, said the collaboration was significant for the New York-listed firm because it was part of their growth strategy in these markets. ‘Most pharmaceutical firms are shifting towards the so-called emerging markets because 90% of world pharmaceutical growth between 2010 and 2015 will be driven by emerging markets’, said Oschmann.

‘It is the first deal within that strategic plan. We need to be a global and local player. Governments are also important customers and governments in these markets want us to partner local companies to help grow their industries. They want us to do more research and provide better access to quality medicines and to create employment’, added Oschmann.

According to a statement on its website, MSD expects emerging markets to account for more than 25% of its global pharmaceutical and vaccine revenue in 2013, based on the implementation of the company’s strategy in emerging markets.

Last month, Adcock said it was planning to generate 30% of its revenue from outside of Africa within the next three years.

Lizelle Wentzel, the healthcare programme manager at Frost & Sullivan, said it would appear that MSD would gain the largest short-term benefit. ‘Adcock

Ingram is a well-recognised brand among the average consumer so there would seem to be a clear advantage to MSD in leveraging off that brand’, said Wentzel.

‘There may also be a longer-term component for MSD. They could be considering a future scenario in which products coming off patent could be manufactured as generics under licence with Adcock’, she added.

Wentzel said there were no obvious short-term benefits for Adcock, but said the company was probably thinking about the future and considering their need to build an international brand. ‘This sort of partnership should help that process’, she said.

In the year ended September, Adcock generated a turnover of R4.1 billion while net profit for the period was R789.8 million. MSD’s worldwide sales for the year ended December were $27.4 billion (R209 billion) while net income was $12.8 billion.

Last year, Acock’s competitor, Aspen Pharmcare, the largest drugmaker in Africa, bought rights to distribute GlaxoSmithKline products in South Africa for a minimum of 20 years via Pharmacare, its wholly-owned subsidiary.

Source: Cape Times, by Slindile Khanyile.

25 June 2010.

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Case Reports A halo in the heart during coronary angiography: calcified left ventricular aneurysm with thrombus formation H FOTBOLCU, K OZDEN, C SENGUL, D DUMAN, İ DİNDAR

Summary A 74-year-old man presented with chest pain and dyspnoea at the cardiology outpatient clinic. His past medical history included an anterior myocardial infarction in 2008. In the coronary angiogram, a ‘halo image’ was seen right after the injection of the contrast agent, and it corresponded with the location of the left ventricular aneurysm. A calcified left ventricular aneurysm with mural thrombus was confirmed with cardiac MRI and a CT scan.

Keywords: left ventricle aneurysm, calcification, cardiac MRI, CT Submitted 13/10/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 221–222

www.cvja.co.za

Case report A 74-year-old man presented with chest pain and dyspnoea at the cardiology outpatient clinic. His past medical history included an anterior myocardial infarction in 2008.

His ECG revealed normal sinus rhythm with poor R-wave progression in the precordial leads. A transthoracic echocardiogram demonstrated a left ventricular aneurysm with a mural thrombus and ejection fraction of 25%. The chest X-ray showed a peculiar oval calcified image related to a left ventricle aneurysm (Fig. 1). A nuclear stress test with thalium scintigraphy revealed apical mid-anterior, antero-lateral, antero-septum, infero-septum, inferior and infero-lateral scaring with minimal peri-infarct ishaemia. In the coronary angiography, a calcified aneurysm of the anterior wall similar to a huge ‘halo image’ was seen after the left main coronary artery injection, as well as a left anterior descending artery occlusion after the first diagonal branch (Fig. 2). No critical stenosis of the circumflex and right coronary artery was observed.

Left ventriculography was not performed because of the possibility of elevated left ventricular end-diastolic pressure, which might have caused the development of acute pulmonary oedema. A calcified left ventricular aneurysm with a mural thrombus was confirmed with cardiac MRI and a CT scan (Figs 3, 4). The patient was referred for coronary artery bypass surgery, however he refused to undergo this operation.

Discussion Left ventricular aneurysm (LVA) is a serious complication after acute myocardial infarction, and can lead to heart failure.

Despite recent progress in revascularisation techniques, a large transmural myocardial infarction often results in the formation of a dyskinetic or akinetic LVA. This is followed by an enlarged ventricular cavity and abnormal ventricular shape that permits maximal conversion of tension generated by the myocardium into cavity pressure, and then congestive heart failure, arrhythmia and thrombogenesis.1 Curvilinear calcification at the left ventricular apex strongly suggested the presence of an aneurysm. The distribution of this

Goztepe Medical Park Hospital, Division of Cardiology, Istanbul, Turkey HAKAN FOTBOLCU, MD, hakan_fotbolcu@yahoo.com KİVİLCİM OZDEN, MD CİHAN SENGUL, MD İSMET DİNDAR, MD

Haydarpaşa Numune Training and Research Hospital, Department of Cardiology, Istanbul, Turkey DURSUN DUMAN, MD

Fig. 1. Thoracic X-ray showing an enlarged heart, and an oval-shaped calcified structure (arrows) related to a calcified antero-apical left ventricular aneurysm.

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Fig. 2. Left anterior oblique coronary angiographic image with caudal angulation showing total occlusion of the left anterior descending artery and a halo in the heart after left coronary artery injection. (The black arrow shows the point of the left anterior descending artery occlusion and the white arrows show the edge of the calcified left ventricle aneurysm.)

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Fig. 4. Cardiac computed tomography confirming the left ventricle aneurysm (the arrows show the edge of the calcified left ventricle aneurysm).

calcification coincided with the typical location of left ventricular aneurysms, which are usually located at the apex and often involve the anterior and lateral walls. Trauma, cardioversion, infection and endocardial fibrosis are rare causes of coarse, amorphous myocardial calcifications, which are distinct from the fine, curvilinear calcifications of a left ventricular aneurysm.2 Similar previous case reports also demonstrated a calcified LVA using left ventriculography, chest X-ray, cardiac magnetic resonance imaging and computerised tomography.3-5 Interestingly, however, we showed a calcified LVA appearing like a huge halo image during coronary angiography.

References

Fig. 3. Cardiac magnetic resonance imaging confirming the left ventricle aneurysm with intramural thrombus formation (the arrows show the thrombus formation in left ventricle cavity).

1. Cabin HS, Roberts WC. True left ventricular aneurysm and healed myocardial infarction. Am J Cardiol 1980; 46: 754–763.

2. Kazamias TM, Caine TH, Rowe GG, Crumpton CW. Calcification of the interventricular septum. J Am Med Assoc 1970; 213: 1896–1898.

3. Charokopos N, Antonitsis P, Rouska E, Toumbouras M. Calcified aneurysm of the left ventricle mimicking hydatid disease of the lung. Eur J Cardiothorac Surg 2008; 33(5): 925.

4. Karaahmet T, Tigen K, Gurel E, Tanalp AC, Basaran Y. Dystrophic calcification of the aneurysmatic left ventricular apex. Congest Heart Fail 2009; 15(4): 196–198.

5. Nakajima O, Sano I, Akioka H. Images in cardiovascular medicine.

Marked calcified left ventricular aneurysm. Circulation 1997; 95(7): 1974.

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A coronary artery anomaly: type IV dual left anterior descending artery M CELIK, A IYISOY, T CELIK

Summary Coronary artery anomalies are seen in about 1.3% of patients undergoing coronary angiography. However, the dual type of left anterior descending (LAD) artery is a rare form of coronary artery anomaly. There are four types of dual LAD; type IV describes the anomaly of a rudimentary LAD artery terminating in the mid-portion of the anterior interventricular sulcus, and the presence of another LAD originating from the right coronary artery and continuing to the anterior interventricular sulcus.

Keywords: coronary artery anomaly, type IV dual left anterior descending artery Submitted 12/1/10, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 223â&#x20AC;&#x201C;224

www.cvja.co.za

DOI: CVJ-21.014

Congenital anomalies such as origin, course and distribution of coronary arteries occur in 0.64 to 1.3% of patients undergoing coronary angiography. Although 80% of these coronary anomalies are benign, 20% may cause symptoms.1 The left anterior descending (LAD) artery courses along the anterior interventricular sulcus (AIVS) towards the cardiac apex, and anomalies of this coronary artery are extremely rare.

The presence of a short and long LAD in the AIVS is described as a dual LAD. The short LAD travels and terminates in the AIVS and does not reach the cardiac apex, whereas the long LAD, which originates either from the left main coronary artery (LMCA) or the right coronary artery (RCA), enters the distal part of the AIVS and reaches the cardiac apex.2 There are four types of dual LAD. Type IV dual LAD differs from the first three types in the origination of the long LAD from the RCA. In this report, we present a case of type IV dual LAD.

Case report A 56-year-old woman with a two-year history of hyperlipidaemia was admitted to our hospital because of chest pain, especially during exercise. The physical examination and resting electrocardiogram (ECG) were normal and transthoracic echocardiography showed no wall-motion abnormality. Also, there was no abnormality in the standard biochemical tests. Her treadmill exercise test showed 1 to 2 mm down-sloping ST-segment depression in

Department of Cardiology, Gulhane Military Medical Academy, School of Medicine, Ankara, Turkey MURAT CELIK, MD ATILA IYISOY, MD TURGAY CELIK, MD, drcelik00@hotmail.com

leads V4 to V6. Subsequently, the patient underwent coronary angiography for the evaluation of coronary artery disease.

Coronary angiography revealed a coronary artery anomaly of type IV dual LAD with a short LAD, which originated from the LMCA and terminated in the mid-portion of the AIVS. The long LAD originated from the RCA, entered into the distal part of the AIVS and travelled towards the apex of the heart. There was no haemodynamically severe stenosis in her coronary arteries and a decision was made to treat medically. The patient was discharged in good condition without any complications.

Discussion Coronary artery anomalies have become more relevant since the widespread application of coronary angiography. Interventional cardiologist should therefore be more familiar with these anomalies in order to make a more accurate diagnosis. Dual LAD is one of these coronary artery anomalies.

The presence of two coronary arteries in the AIVS is described as dual LAD. Spindola-Franco and colleagues3 reported that the incidence of dual LAD was about 1% in normal hearts and most of the patients were asymptomatic. Nevertheless, this anomaly can be found relatively often in patients with congenital heart disease such as tetralogy of Fallot and complete transposition of the great arteries.4 The anomalous origin of the left circumflex artery from the right coronary artery, associated with type IV dual LAD has also been reported.5 Spindola-Franco and co-workers3 reported an angiographic description of dual LAD and classified it into four subtypes according to the origin and course of the long LAD. Type I: the long LAD courses in the AIVS, descends on the left ventricular side of the short LAD, and then re-enters at the distal part of the AIVS. Type II: the long LAD courses in the AIVS, descends on the right ventricular side of the short LAD, and then re-enters at the distal part of the AIVS. Type III: the long LAD courses intramyocardially proximally in the ventricular septum, and appears on the epicardial surface in the distal part of the AIVS. Type IV: the long LAD unusually originates from the right coronary artery and then enters the AIVS. In our patient, the long LAD originated from the RCA and entered the distal part of the AIVS. Therefore the diagnosis of type IV dual LAD, according to the classification of SpindolaFranco and colleagues,3 was made.

Type IV dual LAD is a rare congenital anomaly of the coronary arteries and it may cause misdiagnosis, and mistreatment when diagnosed. When a short or a hypoplastic LAD is present in the proximal part of the AIVS, type IV dual LAD should be kept in mind. The exact description of coronary artery anatomy is essential in patients undergoing percutaneous coronary intervention or coronary artery bypass graft (CABG) operations.6 The short LAD can be misdiagnosed as a total occlusion of the LAD; however, the diagnosis of dual LAD (type IV) can be

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Fig. 1. The short LAD originating from the LMCA terminated in the middle part of the AIVS. LMCA: left main coronary artery, LAD: left anterior descending artery, LCX: left circumflex coronary artery, AIVS: anterior interventricular sulcus.

Fig. 2. The long LAD originating from the RCA traversed the right ventricular infindubulum and entered the distal part of the AIVS. LAD: left anterior descending artery, RCA: right coronary artery, AIVS: anterior interventricular sulcus.

made by the absence of retrograde flow and the detection of a second coronary artery originating from the RCA towards the AIVS. Also, the long LAD originating from the RCA can be misdiagnosed as a conus branch. But it should be kept in mind that it differs from a conus branch by the presence of septal and diagonal branches. Furthermore, there is a risk of incorrect placement of the graft in a CABG operation, so the recognition of a dual LAD may also increase the success rate of surgery.4

References

Conclusion The LAD is the most important coronary artery and being aware of the nature, anatomy and congenital anomalies of the LAD may help physicians make the correct diagnosis and treatment in patients undergoing percutaneous coronary intervention or CABG operations.

1. Yamanaka O, Hobbs RE. Coronary artery anomalies in 126,595 patients undergoing coronary arteriography. Cathet Cardiovasc Diagn 1990; 21(1): 28–40.

2. Yoshikai M, Kamohara K, Fumoto H, Kawasaki H. Dual left anterior descending coronary artery: report of a case. Surg Today 2004; 34(5): 453–455.

3. Spindola-Franco H, Grose R, Solomon N. Dual left anterior descending coronary artery: angiographic description of important variants and surgical implications. Am Heart J 1983; 105(3): 445–455.

4. Sajja LR, Farooqi A, Shaik MS, Yarlagadda RB, Baruah DK, Pothineni RB. Dual left anterior descending coronary artery: surgical revascularization in 4 patients. Tex Heart Inst J 2000; 27(3): 292–296.

5. Tutar E, Gulec S, Pamir G, Alpman A, Omurlu K, Oral D. A case of type IV dual left anterior descending artery associated with anomalous origin of the left circumflex artery in the presence of coronary atherosclerosis.

J Invasive Cardiol 1999; 11(10): 631–634.

6. Oral D, Berkalp B, Pamir G, Omurlu K, Erol C. Significance of dual left anterior descending coronary artery in interventional cardiology. A case report. Angiology 1996; 47(8): 825–829.

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Serotonin and catecholaminergic polymorphic ventricular tachycardia: a possible therapeutic role for SSRIs? S CHEN, Q DUAN, K TANG, D ZHAO, Y XU

Summary

Cardiovasc J Afr 2010; 21: 225–228

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare malignant arrhythmia, usually diagnosed in the adolescent years. The diagnosis can typically be made by one or more of the following: a positive family history, exercise electrocardiography, ambulatory ECG monitoring and/ or an intra-cardiac, electrophysiological examination. This is a case report of a patient with CPVT that was refractory to treatment with beta-blockade and an implanted automatic cardioverter defibrillator. However, after a selective serotonin re-uptake inhibitor (SSRI) was added to the therapeutic regimen, no further episodes of ventricular tachycardia occurred during the following two years.

DOI: CVJ-21.005

Keywords: catecholamine, polymorphic, ventricular tachycardia, gene mutation, selective serotonin reuptake inhibitor Submitted 7/11/09, accepted 10/3/10

Department of Cardiology, 10th People’s Hospital of Tongji University, Shanghai, China

SHUNJUAN CHEN, MD KAI TANG, MD DONGDONG ZHAO, MD YAWEI XU, MD, ddcsj2008@163.com

Department of Scientific Research, Tongji Hospital of Tongji University, Shanghai, China QIANGLIN DUAN, MD

Fig. 1. 12-lead ECG of patient’s ventricular tachycardia.

www.cvja.co.za

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the malignant ventricular arrhythmias, which was first reported by Leenhardt in 1995. CPVT is a familial disease with genetic mutations detectable in approximately 50% of patients.

These include the RyR2 (ryanodine receptor) and CASQ2 (calsequestrin) mutations.1 CPVT often presents during childhood and the adolescent years, with the main clinical manifestation of sudden syncope during exercise or episodes of emotional distress. During such episodes there are often no known triggers present, such as electrolyte disturbances. It is important to exclude one of the primary ion channel diseases, such as longQT syndrome (LQTS) and Brugada syndrome.

Case report A 23-year-old woman presented to our clinic with the clinical problem of repeated syncope events over the past 15 years. These attacks were more frequent during episodes of emotional distress.

During 2004, 24-hour ambulatory ECG monitoring was done by the referring hospital. It revealed frequent episodes of multifocal ventricular premature contractions. Because of this, metoprolol (12.5 mg twice daily) was prescribed. The patient was also sent for a psychological evaluation, and anxiety disorder with panic attacks was diagnosed and, subsequently, paroxetine (20 mg daily) was also prescribed.

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Thereafter the patient was asymptomatic with no further syncope attacks for a period of a year. Because of the asymptomatic period, the patient stopped the metoprolol and paroxetine without medical consultation in 2005.

Two weeks before admission to our hospital, the episodes of syncope reappeared more intensely than before.

Electrocardiography on admission demonstrated non-torsade de pointes ventricular tachycardia (Fig. 1). The regular ECG after admission showed ventricular ectopic beats (Fig. 2A) and supraventricular ectopic beats (Fig. 2B). Subsequent ambulatory ECG monitoring (22 hours and 53 min) after hospitalisation

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demonstrated a ventricular rate varying from 101 to 40 beats per minute and frequent polymorphic premature ventricular contractions with 416 episodes per hour.

A comprehensive biochemical evaluation, which included a coagulation profile, liver and kidney functions, electrolytes, glucose, auto-antibodies, thyroid hormone levels and thyroid antibodies, and antibodies to Coxsackie virus, were all within normal limits. Resting echocardiography showed normal cardiac structure and function, mild mitral regurgitation, the left atrial dimension was 38 mm (25–40 mm), interventricular septum (IVS) was 11 mm (6–11 mm), left ventricular dimensions (LVIDd

A

B

Fig. 2. Regular ECG after admission. A: ventricular beats, B: supraventricular ectopic beats.

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Fig. 3. Premature ventricular contractions and short episodes of PVT occurred after intravenous infusion of isoproterenol.

and LVIDs) were 45 mm (37–56 mm) and 30 mm (23–35 mm), and left ventricular ejection fraction (LVEF) was 64% (> 50%).

After admission, the patient was treated with potassium and magnesium supplementation and beta-blocker therapy. During an intra-cardiac electrophysiological examination, repeated right atrial and ventricular stimulation did not evoke any atrial arrhythmia, ventricular tachycardia or ventricular fibrillation.

Whenever the ventricular rate increased to more than 100 beats/min, frequent premature ventricular contractions and short episodes of polymorphic ventricular tachycardia were observed (Fig. 3). All of these episodes terminated spontaneously after a few minutes. The diagnosis of CPVT was made.

It was decided to perform ICD implantation without radiofrequency ablation. Postoperatively, the patient continued taking a beta-blocker orally. Six months after ICD implantation, pacemaker programming revealed two appropriate ICD discharges (Fig. 4). As the patient had previously been diagnosed with anxiety disorder and panic attacks, Seroxat (SSRI) 20 mg daily was added, and during a two-year follow-up period, no further ICD discharges occurred.

Discussion CPVT is an arrhythmic disorder with a high fatality rate. The incidence of adverse events, including syncope, ventricular tachycardia and ventricular fibrillation at 40 years of age is about 80%,2 and between 20 and 30 years, the incidence of sudden cardiac death is 30 to 50%.3 Currently, there are two known genetic mutations in CPVT, namely, RyR2 and CASQ2.4 These two ion channels mediate the transportation of calcium ions from the sarcoplasmic reticulum into the cytoplasm. Mutations in these two genes lead to intracellular calcium overload as the

basis for the subsequent arrhythmias.

Sympathetic stimulation may lead to delayed after-depolarisations (DAD) and triggered activity, which will also induce arrhythmias. Cerrone et al.5 demonstrated that anesthetised mice with RyR2 mutations had a higher incidence of CPVT than in the isolated heart, suggesting that sympathetic stimulation may have an impact on CPVT. Beta-blockers are the first-line agents for the treatment of CPVT. They are used to prevent episodes of ventricular tachycardia. However, the efficacy of beta-blockers in CPVT is inferior when compared to LQT1 syndrome (KCNQ1 gene mutation), but is comparable to the LQT2 syndrome. Even if anti-adrenergic drugs are used, there is still a sudden death rate of 10% in CPVT, and 50% of patients taking beta-blockers may need ICD implantation.

For patients who experience episodes of ventricular tachycardia during an exercise stress test despite taking beta-blockers, as well as patients who still experience syncope attacks after taking the maximum load of beta-blockers, ICD implantation is recommended. There are also reports on the treatment of CPVT by cardiac sympathectomy.6 For patients experiencing recurrent ICD discharges after ICD implantation, or patients with poor compliance in taking beta-blockers, cardiac sympathectomy may be considered.

The physiological basis for the beneficial effect of cardiac sympathectomomy is as follows: as cardiac sympathectomy can reduce local norepinephrine release by the cardiac sympathetic nerves in the myocardium, malignant ventricular arrhythmias caused by the adrenergic stimulant action may be reduced.

ICD implantation does not reduce the occurrence of catecholaminergic polymorphic ventricular tachycardia events.

Appropriate and inappropriate ICD discharges are often caused by exercise, leading to a decline in the quality of life. Moreover,

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Fig. 4. ICD discharges.

inappropriate discharge will easily lead to the release of endogenous catecholamines, causing a potentially fatal sympathetic electrical storm. For such patients, cardiac sympathectomy can be beneficial.6 Of course, the effectiveness of cardiac sympathectomy still needs to be verified, and this treatment may be considered in patients who experience recurrent ICD discharges despite a loading dose of beta-blocker therapy.

Some studies have shown that SSRIs can reduce the morbidity and mortality of patients with depression after acute coronary syndrome.2 Autonomic regulation of cardiac function is usually expressed by non-invasive measurements of heart rate variability (HRV), which is a powerful independent predictor of mortality within the first year after myocardial infarction (MI).

It was reported that HRV was significantly lower in coronary disease patients with depression compared with non-depressed patients.7,8 A study showed that SSRIs facilitated the recovery of HRV after MI.9 With depression, chronic depletion of neurotransmitters such as serotonin in the central synaptic clefts could lead to interruption of inhibitory inputs to central sympathetic centres, thereby increasing sympathetic neural discharge. There is increased sympathetic activity in patients with depression. It has been shown that stimulation of central 5-HT receptors can also lead to sympatho-excitation.9 In this case, it was found that the patient no longer had ICD discharges after an SSRI was added, possibly indicating that SSRIs may reduce sympathetic activity and have a beneficial therapeutic effect in CPVT. This may provide us with a novel tool to deal with CPVT and improve the quality of patients’ lives.8 It was reported that SSRIs had no impact on the release of adrenaline in the hearts of patients with anxiety disorder and panic attacks, but cardiac and whole-body norepinephrine spillover was significantly reduced in those subjects who initially had elevated sympathetic activity.10 It was also demonstrated that in such patients with anxiety disorder and near-normal cardiac norepinephrine levels, QT variability was not correlated with cardiac norepinephrine spillover, and SSRI treatment was ineffective.

The findings of Hildreth et al., however, suggested that abnormal serotonergic control of vagal input to the heart might

contribute to increased cardiovascular risk.11 The mechanism of anxiety or depression as the trigger(s) for arrhythmias or shock remains unclear.

We suggest that the possible beneficial therapeutic role of serotonin re-uptake inhibitors in the treatment of patients with polymorphic ventricular tachycardia merits further study.

References 1. Leite LR, Henz BD, Macedo PG, et al. Catecholaminergic polymorphic ventricular tachycardia: a current overview. Future Cardiol 2009; 5: 191–199.

2. Swenson JR, O’Connor CM, Barton D, et al. Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol 2003; 92: 1271–1276.

3. Sumitomo N, Sakurada H, Taniguchi K, et al. Association of atrial arrhythmia and sinus node dysfunction in patients with catecholaminergic polymorphic ventricular tachycardia. Circ J 2007; 71: 1606–1609 4. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2007; 18: 791–797.

5. Cerrone M, Noujaim SF, Tolkacheva EG, et al. Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res 2007; 101: 1039–1048.

6. Makanjee B, Gollob MH, Klein GJ, et al. Ten-year follow-up of cardiac sympathectomy in a young woman with catecholaminergic polymorphic ventricular tachycardia and an implantable cardioverter defibrillator. J Cardiovasc Electrophysiol 2009; 20: 1167–1169.

7. Carney RM, Saunders RD, Freedland KE, et al. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 76: 562–564.

8. Kuijpers PM, Honig A, Wellens HJ. Effect of treatment of panic disorder in patients with frequent ICD discharges: a pilot study. Gen Hosp Psychiatry 2002; 24: 181–184.

9. McFarlane A, Kamath MV, Fallen EL, et al. Effect of sertraline on the recovery rate of cardiac autonomic function in depressed patients after acute myocardial infarction. Am Heart J 2001; 142: 617–623.

10. Baumert M, Lambert GW, Dawood T, et al. QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder. Am J Physiol Heart Circ Physiol 2008; 295: H962–H968.

11. Hildreth CM, Padley JR, Pilowsky PM, et al. Impaired serotonergic regulation of heart rate may underlie reduced baroreflex sensitivity in an animal model of depression. Am J Physiol Heart Circ Physiol 2008; 294: H474–H480.

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Coeur en sabot F AZIZ, M ABED

Summary In tetralogy of Fallot (TOF), the most common form of cyanotic congenital heart disease, only a few patients reach adulthood without surgical correction. We present a case of a woman with TOF who was diagnosed at the age of 39 when she presented with features of congestive heart failure. The main factor contributing to her longevity included the slow development of her pulmonary artery stenosis together with left ventricular hypertrophy. Less than 3% of all patients with uncorrected TOF survive beyond their 40s but late operative repair is still a valuable option. This case provides an insight into the late outcome of an older patient with uncorrected TOF. Keywords: uncorrected TOF, congestive heart failure, longevity Submitted 1/12/09, accepted 10/3/10 Cardiovasc J Afr 2010; 21: 229–231

www.cvja.co.za

DOI: CVJ-21.010

More than 40 years have passed since the first successful repair of tetralogy of Fallot (TOF), and currently, excellent results for the repair of most TOF variants have been achieved. Although most patients undergo radical repair during infancy and childhood, patients remaining undiagnosed and untreated until adulthood can still be treated. These patients have either a previous palliative or natural collateral circulation to the lung or a mild form of right ventricular outflow tract (RVOT) obstruction. A few case reports of patients with TOF surviving until their eighth decade of life have been reported.1 The survival data of patients with TOF who have died without surgical treatment reveal that 66% lived to the first year of life, 56% to two years, 49% to three years, and 25% to 10 years of age. Thereafter, the hazard function (or the instantaneous risk of death at any given age) remains essentially constant at 6.4% per year, so that only 3% of persons born with TOF are alive at 40 years of age. The natural history of the disease is influenced by the severity of the anatomical defect, primarily the severity of the pulmonary stenosis.2

min. Her jugular vein distention was raised about 15 cm above the sternal angle with a prominent A wave. She had central and peripheral cyanosis (Fig. 1). The pericardial examination was significant for the visible apex beat pulsations in the fifth intercostal space in the mid-axillary line and there were also visible pulsations along the parasternal border and second intercostal space. The apex beat was palpable in the fifth intercostal space with ill-sustained heave. The second heart sound was palpable in the second intercostal space.

Auscaltation of the heart revealed S1, S2 and S4 along with a systolic murmur of grade 4/6 with maximum intensity in the left second intercostal space. Lung auscultation revealed bilateral crackles up to one-third of the chest bilaterally. The abdominal examination was significant for tender hepatomegaly, which was four fingers below the costal margins, and the total hepatic span was measured to be 19 cm. She had bilateral pedal oedema extending up to the lower abdomen and involving the external genitalia (Figs 2, 3). She also had grade II clubbing bilaterally.

The chest X-ray showed a large boot-shaped heart (Figs 4–6).

The patient was admitted to the critical care unit with a diagnosis of congestive heart failure and she was started on empirical therapy. The next day an echocardiogram was done, which showed marked left ventricular hypertrophy, a dilated left and right atrium and severe tricuspird regurgitation associated with severe pulmonary artery stenosis, ventricular septal defect (VSD) and moderate to severe right ventricular hypertrophy. On the basis of these findings, a diagnosis of tetrology of Fallot was made and the patient was referred for corrective surgery.

Discussion The unusual longevity in some cases of tetralogy of Fallot is probably related to comparatively favorable anatomical abnormalities. Higgins,3 after reviewing the literature, concluded that longevity is determined predominantly by the early development

Case report A 39-year-old female patient was admitted to our hospital with dyspnoea as the main symptom. She had had a murmur since childhood but it was never investigated, and she was not able to play as a child due to dyspnoea. Her dyspnoea had increased in the previous two weeks, as had her generalised body oedema.

On physical examination, she was found to have blood pressure of 90/60 mmHg with a regular heart rate of 66 beats per

Department of Internal Medicine, MSSM, Jersey City Campus, New Jersey, USA FAHAD AZIZ, MD, Fahadaziz.md@gmail.com MARY ABED, MD

Fig. 1. Central cyanosis.

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Fig. 4. Chest X-ray postero-anterior view.

Fig. 2. Anterior abdominal wall oedema.

Fig. 3. Oedema extending up to the upper thigh.

Fig. 5. Chest X-ray lateral view.

of collateral circulation to the lungs and the progressive narrowing with age of the initially mild infundibular stenosis.

In adults with TOF there are several differences noted from the classic description of this lesion in children. These include a very large VSD with greater frequency of combined infundibular and valvular pulmonary stenosis. Usually adults with TOF present with congestive heart failure in 33% of cyanotic and 38% of acyanotic patients; characteristic chest pain occurring in early

adult life; a symptomatic quiescent period during the second decade of life; normal or increased pulmonary vasculature in 42% of cyanotic patients and absence of this hypervascularity in 70% of acyanotic patients; and ECG evidence of right bundle branch block in 58% and tall peaked P waves in 66% of cyanotic patients, and predominantly right ventricular hypertrophy in 46% of acyanotic patients.3 Special considerations for anaesthetic and post-operative

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failure leads to the development of bilateral pleural effusions that may appear multiple times and may take weeks to months to resolve completely.

Although complete repair of TOF in the neonate is associated with excellent intermediate-term survival,4 the overall survival of surgically treated adult patients with TOF is also acceptable.

The major benefit of complete repair in adults is their functional improvement. On the other hand, late complications closely related to chronic hypoxia, such as arrhythmia and ventricular dysfunction, might require more careful follow up after the surgical correction.5 There are a limited number of cases of patients who have lived with untreated TOF until adulthood. This case serves as a reminder of TOF as a differential diagnosis in cynotic patients with congestive heart failure, and its unique manifestations and management.

Fig. 6. Non-enhanced CT scan of the chest.

References

management in adults with TOF are: fibrosed and stiff right ventricle, a tendency to develop congestive heart failure and bilateral pleural effusions, and the presence of major aortopulmonary collateral arteries (MAPCAs). The progressive narrowing of the initially mild pulmonary artery stenosis in our patient undoubtedly contributed to her longevity and then deterioration of her symptoms later in her life.

Post-operatively, these patients are at risk of developing pulmonary oedema, because of increased pulmonary vascularity and large MAPCAs and may require prolonged ventilation with positive end-expiratory pressure (PEEP). Congestive cardiac

1. Yang X, Freeman LJ, Ross C. Unoperated tetralogy of Fallot: case report of a natural survivor who died in his 73rd year; is it ever too late to operate? Postgrad Med J 2005; 81: 133–134.

2. Bertanou EG, Blackstone EH, Hazerlrig JB, et al. Life expectancy without surgery in tetralogy of Fallot. Am J Cardiol 1978; 42: 458–466.

3. Higgins CB, Mulder RG. Tetralogy of Fallot in the adult. Am J Cardiol 1972; 29: 837–846.

4. Hirsch JC, Mosca RS, Bove EL. Complete repair of tetralogy of Fallot in the neonate: results in the modern era. Ann Surg 2000; 232(4): 508–514.

5. Atik FA, Atik E, da Cunha CR, Caneo LF, Assad RS, Jatene MB, et al. Long-term results of correction of tetralogy of Fallot in adulthood.

Cardiothorac Surg 2004; 25(2): 250–255.

Watch these dates 28 August – 1 September 2010

European Society of Cardiology congress (ESC)

Stockholm, Sweden

www.escardio.org

11 September 2010

Cape Kidney Association’s annual fundraiser

Peninsula Room, Kenilworth Race Course, Cape Town, SA

Contact Molly Fabe on 021 448-0817

14–17 October 2010

Vascular Society of Southern Africa congress (VASSA)

KwaMaritane, North West Province, SA

www.vascularsociety.co.za

13–17 November 2010

American Heart Association congress

Chicago, Illinois, USA

www.americanheart.org

27–31 May 2011

10th PASCAR congress

Kampala, Uganda

Charles_mondo@yahoo.com.au

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Drug Trends in Cardiology ARBs and possible cancer risk The recent meta-analysis published in the Lancet Oncology, with comment from Dr Steve Nissen,1,2 has raised questions around a possible cancer risk and the use of ARBs. The Cardiovascular Journal of Africa will be publishing a fuller report on this matter in a forthcoming issue of the Journal.

In the interim, Boehringer-Ingelheim has issued the following pertinent comments.

J Aalbers, Special Assignments Editor

Comment from Boehringer Ingelheim Boehringer Ingelheim affirms safety of telmisartan with an analysis of 50 000 patients and strongly disagrees with the publication of Sipahi et al.1 in Lancet Oncology June 2010 Telmisartan, an angiotensin receptor blocker, is one of the best-researched drugs worldwide. It has been studied in clinical trials in more than 50 000 patients. Its positive safety profile has been confirmed also in a market exposure of 34.5 million patient years.

Convincing safety data for patients with a high cardiovascular risk were collected in the three long-term outcome trials ONTARGET, PRoFESS and TRANSCEND, which followed some of the patients for up to five years. Following rigorous assessment of the data from these studies it was concluded that there was no association with an increased risk of cancer in the telmisartan arms.

Sipahi et al.1 published a meta-analysis in the June issue of Lancet Oncology, claiming that angiotensin receptor blockers (ARBs) used to lower hypertension are associated with a modestly increased risk of new cancer diagnosis. The finding is mainly based on the combination arm of telmisartan and ramipril, an angiotensin converting enzyme (ACE) inhibitor, and not on the trial arms of each compound separately.

Patient health and safety is the primary concern of Boehringer Ingelheim. The

company continually monitors safety data for all medical products. Boehringer Ingelheim’s comprehensive internal safety data analysis of primary data contradicts the conclusions about an increased risk of potential malignancies mentioned

by Sipahi et al.1 All studies with telmisartan included patients with cardiovascular risk factors due to age and co-morbidities.

Specifically, in ONTARGET, with more than 25 000 patients, no statistically significant difference with respect to malignancies was observed in patients treated with telmisartan vs ramipril. In TRANSCEND, a 6 000 patient trial, the difference did not reach significance either. In the PRoFESS trial, another large-scale trial with more than 20 000 patients, the telmisartan arm showed fewer cases of malignancies than the placebo arm. Considering the analysis of all three trials, an effect of telmisartan on malignancies was not observed.

In ONTARGET, the one treatment arm with a combination of telmisartan and ramipril was associated with a modestly increased risk of malignancies. Consistent with our commitment to transparency, data from ONTARGET, TRANSCEND and PRoFESS have all been published and been widely shared with regulatory authorities since 2008. It should be noted that product labelling for telmisartan does not recommend the combination of telmisartan and ACE inhibitors such as ramipril.

‘Our research efforts have centred on the need to protect patients, especially older patients, from cardiovascular risks such as myocardial infarction or stroke.

Telmisartan fulfills this need. It is the only ARB that has cardiovascular protection in its label and has become a valuable treatment option in the management of hypertension and cardiovascular risk.

Doctors and patients appreciate its excellent safety profile.

In pre-clinical trials, clinical trials and day-to-day patient exposure with telmisartan, we have not seen any significant finding related to malignancies.

Patients should consult with their physicians before making any decision regarding their antihypertensive therapy’, said Prof Dr Klaus Dugi, Corporate Senior Vice President, Medicine at Boehringer Ingelheim.

Peer-reviewed meta-analyses of aggregate published data like Sipahi et al.1 have their appropriate place in scientific research. However, these analyses have well-recognised limitations, such as combining study summaries rather than analysing individual patient data.

Telmisartan is one of the most studied antihypertensives in clinical trials, which have all been made publically available. It is widely used as medication to lower blood pressure and protect patients against severe cardiovascular events such as myocardial infarction and stroke.

Please be advised: In some countries Micardis has not yet been registered for the cardiovascular protection indication.

Please refer to the package insert approved by the local regulatory authority.

S3 Micardis® 40 and 80 mg. Each tablet contains telmisartan 40 and 80 mg, respectively.

S3 Pritor® 40 and 80 mg. Each tablet contains telmisartan 40 and 80 mg, respectively.

For further information please contact: Dr Kevin Ho, medical director: Tel: + 27 11 348-2517; e-mail: kevin.ho@ boehringer-ingelheim.com Sue Thomas, medical information manager: Tel: + 27 11 348-2514; e-mail: sue.thomas@ boehringer-ingelheim.com 1. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang J. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Published online June 14, 2010 DOI:10.1016/514702045(10)70106-6.

2. Nissen SE. Comment: Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Published online June 14 2010; DOI:10.1016/51470-2045(10)70142X.

It's the shell that makes R

safer.

Safety-Coated R

81mg The ORIGINAL low dose aspirin for optimum cardio-protection pH

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.

122274

BETTER BP CONTROL AND ACTIVE CARDIOVASCULAR RISK REDUCTION WITH ADALAT® XL 2 ADALAT® XL • significantly lowers blood pressure while reducing cardiovascular risk3 • can be safely used for the long-term treatment of patients with coronary disease and angina pectoris4 • is effective and safe in a broad spectrum of patients3 ADALAT® XL 20 • provides a low nifedipine dose for initial therapy or combination therapy and allows for greater flexibility in dosing1

Long-term commitment to Life References: 1. ADALAT® XL package insert. 2. Constance C. Which CCB is the better choice? Clinicians Corner 2003;Volume 1. 3. Heagerty AM. Nifedipine gastrointestinal therapeutic system – Hypertension management to improve cardiovascular outcomes. Int J Clin Pract 2005;59:1112-1119. 4. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomized, controlled trial. Lancet August 31, 2004.

S3 ADALAT® XL 20 Tablets. Each tablet contains 20 mg nifedipine. Reg. No.: A39/7.1/0634. S3 ADALAT® XL 30 Tablets. Each tablet contains 30 mg nifedipine. Reg. No.: Y/7.1/314. S3 ADALAT® XL 60 Tablets. Each tablet contains 60 mg nifedipine. Reg. No.: Y/7.1/315. For full prescribing information refer to the package insert approved by the medicines regulatory authority. ZA.GM.ADAL.11-2009.0012

Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, t/a Bayer Schering Pharma. 27 Wrench Road, Isando, 1609. Tel: (011) 921-5911.

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High-risk patients benefit most from nifedipine GITS–telmisartan combination Two very effective antihypertensive medications with well-established and significant cardiovascular outcome studies have been combined and used for the first time in early combination therapy in the TALENT study. Results from this multicentre, prospective, randomised, doubleblind trial were announced at the 2010 European Society of Hypertension (ESH) congress held in June in Oslo, Norway, and highlighted the rapid, safe and effective blood pressure-lowering action of this combination.1 The TALENT (Study evaluating Efficacy of Nifedipine GITS – Telmisartan combination in Blood Pressure Control and Beyond: Comparison of Two studies) enrolled 405 patients with office systolic blood pressure at a baseline of ≥ 135 mmHg and with a high cardiovascular risk because of diabetes, the metabolic syndrome, and echocardiographic/ECG evidence of left ventricular hypertrophy or microalbuminuria. Patients could be admitted to the trial if other antihypertensive medication (ACE inhibitors, other ARBs, or CCBs) could be safely withdrawn.

Patients were randomised to initial 0 weeks

8 weeks

administration of telmisartan (80 mg/day) plus nifedipine GITS (20 mg/d), telmisartan alone, or nifedipine GITS alone in a 2:1:1 ratio. Treatment was continued for 24 weeks, shifting the monotherapy groups to combination therapy after eight weeks (Fig. 1).

Office and ambulatory blood pressure was measured after two, eight, 16 and 24 weeks and after eight, 16, and 24 weeks, respectively. Up-titration occurred when needed but not to blood pressure levels below 120 mmHg.

Results Initiating treatment with the combination therapy resulted in earlier blood pressure control. This was maintained throughout the study period both with regard to office and ambulatory blood pressure control, which was reduced by 14.2/3 mmHg and 10/4.7 mmHg, respectively.

Both combination and monotherapy substantially lowered systolic and diastolic blood pressure. The 24-hour data showed that the effect was consistent throughout the 24-hour period. Of importance is that longer-term control was similar, irrespective of the initial monotherapy 16 weeks Double-blind treatment

Double-blind treatment Nifedipine GITS 20mg + telmisartan 80mg

Nifedipine GITS 20mg

24 weeks

Nifedipine GITS 20mg + telmisartan 80mg

Telmisartan 80mg

Optional 8-week extension of combination therapy with up-titration of nifedipine GITS as required

Mancia G. The TALENT Study, European Cardiology. 2008; 4: 1.

Fig. 1. TALENT study design.

treatment strategy followed or whether the combination was initiated first.

In terms of the evidence-based reduction of cardiovascular outcomes, telmisartan in the ONTARGET2 studies and nifedipine GITS in the ACTION,3 INSIGHT,4 and ENCORE5 trials have best-in-class results. This evidence, together with the South African and international guidelines’ emphasis on the use of early effective antihypertensive agents in high-risk patients, raises the importance of the TALENT results in everyday clinical practice.

J Aalbers, Special Assignments Editor 1. Mancia G, Parati G, Bilo G, Ruilope L on behalf of the TALENT investigators. Early blood pressure control by the nifedipine GITS/telmisartan combination. Abstract.

ESH, Oslo, 2010.

2. The ONTARGET investigators. Telimsartan, ramipril, or both in patients at high risk of vascular events. N Engl J Med 2008; 358: 1547–1559.

3. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364: 849–857.

4. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–372.

5. ENCORE I study group. Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function). Circulation 2003; 107: 422–428.

Litha Healthcare Group Ltd has acquired balance of shares in Pharmafrica With the concluding of the final signatories, Litha Healthcare Group Ltd has acquired the balance of shares in Pharmafrica that were not owned by the group. Four years ago the company purchased a 26% stake in Pharmafrica as

part of that company’s equity drive.

Pharmafrica markets branded ethical specialities and over-the-counter pharmaceutical products including brands such as Ecotrin and DS-24.

Litha Healthcare Group Ltd is a JSE-

listed company with diversified operations in biotechnology, pharmaceutical and medical devices. The acquisition of Pharmafrica forms part of the group’s strategy to grow its pharmaceutical division.

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Increased heart rate in high-risk hypertensives related to increased heart failure and sudden death High-risk hypertensives with a heart rate above 80 beats per minute (bpm) have an increased risk of cardiovascular events, particularly heart failure and sudden death, according to a new analysis of the Valsartan Anti-hypertensive Longterm Use Evaluation (VALUE) trial, presented at the 2010 American Society of Hypertension congress (ASH).1 Both baseline and in-trial tachycardia, measured every year by ECG, were strong, independent predictors of cardiovascular events.

The VALUE trial, first reported almost six years ago, showed that valsartan and

amlodipine-based therapy were essentially equal in reducing the primary endpoints of cardiac morbidity or mortality in patients with hypertension and at least one high-risk factor.2 The study was conducted over five years.

The researchers also identified that most of the risk occurred in those trial participants with heart rates of 79 bpm or more. There was a striking increase in the primary endpoint in the highest quintile of heart rate (≥ 79 bpm) compared with the pooled lower four quintiles.

Annual incidence of new primary endpoint events in the highest quintile

(compared with the lower four) was 30% higher in the first year of the study, 55% higher in the third year, 52% more in the fourth, and 46% higher in the fifth year of the study. A similar trend was seen throughout the trial for the heart failure and sudden death components of the endpoint.

The negative effect of the in-trial tachycardia was not modified by the blood pressure control achieved in the study. The relative increase in the primary endpoint of the tachycardic group was 68% in the blood pressure-controlled and 63% in the blood pressure-uncontrolled groups (p < 0.0001).

The results of the SHIfT trial will answer unequivocally whether reducing the heart rate in patients with systolic heart failure with the specific heart ratelowering agent ivabradine, will improve prognosis. The trial randomised to either ivabradine or placebo, heart failure patients in NYHA classes II to IV, with ejection fraction less than 35% and a heart rate greater than 70 bpm, who were already being treated with beta-blockers, ACE inhibitors and diuretics. The primary endpoint of the study is cardiovascular death and hospitalisation for heart failure.

The SHIfT study is the largest ever study undertaken in heart failure, with 6 500 patients. The results of the SHIfT study will be announced at the hotline session on 29 August 2010 at the European Society of Cardiology’s annual congress in Stockholm.

This trial is pivotal to the clinician’s perception of the value of heart rate lowering with ivabradine to reduce cardiovascular morbidity and mortality in these high-risk cardiovascular patients.

J Aalbers, Special Assignments Editor 1. Julius S, Palatini P, Kjeldsen S, et al.

Tachycardia predicts CV events in the VALUE trial. American Society of Hypertension 2010 scientific meeting. May 1–4, 2010, New York, NY. Abstract LB-OR-01.

2. VALUE study highlights the need for aggressive blood pressure lowering in high-risk patients. Cardiovasc J Afr 2004; 15(4): 191–192.

3. New ASCOT analysis: Beta-blockers not beneficial in hypertensives with tachycardia hypertension. September 15, 2009, published ahead of print.

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Cardiovascular and diabetes research in Africa to benefit from Servier sponsorship South African experts in the field of cardiovascular and diabetes medicine have recently been awarded significant support

by Servier Laboratories, South Africa, to provide missing vital data on these conditions in African communities.

Servier has contributed to three initiatives, one being the establishment of a cardiovascular research chair in the Department of Medicine, Faculty of Health Sciences, University of Cape Town. The first incumbent of this clinical and research chair is Prof Karen Sliwa.

‘I hope during this tenure to focus on both laboratory-based and clinical cardiology research and provide novel insights into the mechanisms of cardiovascular conditions such as, for example, peripartum cardiomyopathy’, said Prof Karen Sliwa, newly appointed professor of cardiovascular research and director of the Hatter Cardiovascular Research Unit and also in a joint appointment at the Institute for Infectious Diseases and Molecular Medicine, University of Cape Town.

‘Servier’s support of this joint position is by means of an unconditional grant and this is a very welcome development, as longterm grants of this nature occur infrequently in African countries and in South Africa’, Prof Sliwa acknowledged.

Prof Sliwa is a specialist physician and cardiologist, holding a PhD from the University of the Witwatersrand. In addition, she is a specialist in tropical diseases, having completed a diploma in tropical medicine (DTM&H) and her doctoral thesis on Leishmanaisis at the Hadassah University in Jerusalem, Israel.

Drawn to the Hatter Institute because of its excellent laboratory facilities and research and educational activities established by Prof Lionel Opie over many years, Prof Sliwa has also initiated a new clinic with both the Department of Cardiology, under Prof Patrick Commerford’s leadership, and the Department of Obstetrics and Gynaecology, to provide a service for women with a cardiac condition who become pregnant and develop heart disease during/following pregnancy.

Diabetes research benefits from Servier support As part of this ongoing commitment to medical research in South Africa, Servier has funded a second prevalence and first trend survey of diabetes among urban Africans

in South Africa. The last time a study of this kind was undertaken was in the 1990s.

A further Servier-sponsored study will be undertaken in KwaZulu-Natal to determine the genetic basis of diabetes among the Zulu community and to provide essential information on the genetic vulnerabilities and trends in diabetes among this South African community.

Steve Speller, CEO of Servier South Africa stressed the importance of this initiative. ‘From Servier’s perspective, the support of research into diabetes and cardiovascular disease, be it epidemiological, clinical or laboratory based, remains an important priority for the company. The increased incidence of diabetes in developing countries such as South Africa has reached almost epidemic proportions and research is therefore not only important to better understand how to treat diabetes, but also to understand the magnitude of the problem so that resources can be allocated appropriately.’

Diabetes prevalence study in urban Africans This prevalence study was initiated as a collaborative undertaking by UCT’s Department of Medicine and the MRC Research Unit for Chronic Diseases of Lifestyle. The study is being lead by Prof Naomi Levitt (UCT), with Dr Krisela Steyn and co-workers from both institutions.

Data collection for this study has already been completed from among the representative sample of 25- to 74-year-old urban Africans, randomly selected from the townships of Langa, Guguletu, Crossroads, Nyanga and Khayelitsha. More than a thousand participants were examined for the presence of diabetes and other cardiovascular risk factors.

Commenting on the relevance of this study, Prof Levitt pointed out that there are no available data that track the trends in diabetes prevalence in urban South Africans. ‘With increasing obesity and rapid urbanisation, with its accompanying lifestyle changes and increases in psychosocial stress, diabetes is highly likely to be on the increase in our African communities. This Servier-sponsored study will be indicative of prevalence changes among urban black South Africans in other major urban settings across the country and will provide vital data for policymakers in Government’, Prof Levitt stressed.

Genetic determinants of type 2 diabetes in black South Africans A large study of the genetic basis of type 2 diabetes among black South Africans has been initiated at the University of KwaZuluNatal with financial support from Servier Laboratories, South Africa.

This is an important study as there is currently very little data available on the genetic polymorphisms that predispose or protect black Africans from developing type 2 diabetes. Equally, there is not a great deal known about genetic polymorphisms in type 1 diabetes in black South Africans, although Dr Fraser Pirie and co-workers have identified a polymorphism in the TLR 3 gene which may be associated with type 1 diabetes in South Africans of Zulu descent in KwaZulu-Natal.1 Smaller studies of black South Africans with type 2 diabetes have been undertaken by Dr Pirie and colleagues to identify whether genetic variants identified in European subjects could be detected in Indian and African subjects ‘These studies are small and statistically underpowered, but have indicated that these variants present in Caucasians are not well represented in our African population’, Dr Pirie pointed out.

The current study will be a full genome study of 1 500 type 2 diabetic patients and 1 500 controls from the African population of Zulu descent in KwaZulu-Natal.

Collaboration with Oxford University will allow this large-scale genetic study to be done using automated genetic profiling.

‘With 3 000 samples being evaluated, we should be able to determine which polymorphisms occur commonly in our population and relate these variants/loci to the occurrence of type 2 diabetes, hypertension and obesity’, Dr Pirie said.

There are similar studies being undertaken in Uganda with support from universities in the UK and this will provide additional insights on African communities. ‘We are hoping to complete the study in the next two to three years and provide unique data of significant value to our South African and African communities’, Dr Pirie concluded.

This study will provide vital data, which is currently lacking, as to the genetic basis of diabetes pertinent to African populations.

1. Pirie FJ, Pegoraro R, Motala AA, Rauff S, Rom L, Govender T, Esterhuizen TM. Tolllike receptor 3 gene polymorphisms in South African blacks with type 1 diabetes. Tissue Antigens 2005; 66(2): 125–130.

AFRICA

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Amlodipine + atorvastatin single pill is the most effective choice for primary prevention Preventing cardiovascular events in at-risk patients is greatly enhanced if a single pill is prescribed for the commonly occurring risks of hypertension and dyslipidaemia.

In this new study using data from a commercially managed healthcare organisation in the United States, only one in five patients adhered to and took their preventative tablets as medication for dyslipidaemia and hypertension if they were taken as two individual tablets. If the medication was given as a single tablet, in this case atorvastatin plus amlodipine, adherence improved to one in two patients.

This 150% increase in compliance is very significant and applies to everyday clinical practice, compared to lower compliance differences between single pills and two or more pills, which was

found in specially designed compliance studies.

The overall benefit in terms of the reduction in cardiovascular events is substantiated in this study, which showed similar low rates (1.88 per 100 personyears) for patients who were adherent to their medication (whether one pill or two), compared to 2.47 events per 100 person-years in non-adherent patients.

In essence, if the single pill increases compliance two-fold and compliance reduces events by 30% compared to noncompliance, the role of the single pill in primary prevention is the most effective choice for commercially managed healthcare funds.

The evaluation of the US commercially managed healthcare system included patients with hypertension and dyslipi-

TABLE 1. ADHERENCE MEASURES FOR SPAA AND CCB + STATIN (TWO PILLS) IN PRIMARY-PREVENTION PATIENTS CCB + statin (n = 17 910)

SPAA (n = 1 537) Six months Number (%) of patients with PDC ≥ 80% Mean PDC (SD) Median PDC 12 months Number (%) of patients with PDC ≥ 80% Mean PDC (SD) Median PDC 18 months Number (%) of patients with PDC ≥ 80% Mean PDC (SD) Median PDC

868 0.73 0.83

56.5% (0.26)

712 0.66 0.75

46.3% (0.30)

650 0.62 0.72

42.3% (0.31)

3 825 0.49 0.50

21.4% (0.31)

3 529 0.46 0.46

19.7% (0.31)

3 342 0.43 0.42

18.7% (0.32)

p-value < 0.001 < 0.001 < 0.001

daemia but without diabetes, and evaluated the cardiovascular events in adherent patients in categories of either two pills or the single-pill calcium channel blocker (SPAA) and a statin.

The primary outcome measure was the rate of cardiovascular events occurring in the six- to 18-month period following the index date, set as the date when the patient was started on either the SPAA or the two-drug, two-pill regimen. Patients who had a cardiovascular event in the preceding six months were excluded from the analysis.

Adherence levels were much higher for the single-pill approach (Table 1).

Importantly, the reduction in cardiovascular events in adherent patients was the same regardless of whether patients were on a single- or two-pill treatment regimen.

J Aalbers, Special Assignments Editor 1. Chapman RH, Yeaw J, Roberts CS. Association between adherence to calciumchannel blocker and statin medications and likelihood of cardiovascular events among US managed care enrolees. BMMC Cardiovasc Disorders 2010, 10:29 doi:10.1186/14712261-10-29.

< 0.001 < 0.001 < 0.001

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TABLE 2. CARDIOVASCULAR EVENTS FROM SIX MONTHS FOLLOWING INITIATION OF SPAA OR CCB + STATIN IN PRIMARY-PREVENTION PATIENTS

R

NonOverall Adherent adherent SPAA CCB + statin (n = 19 447) (n = 4 693) (n = 14 754) (n = 1 537) (n = 17 910) 12-month event rate Total events (n) Total person-years Incidence rate per 100 person-years Overall event rate Total events (n) Total person-years Incidence rate per 100 person-years

452 19 447 2.32 818 38 074 2.15

88 4 693 1.88 164 9 139 1.79

364 14 754 2.47 654 28 935 2.26

19 1 537 1.24 38 2 734 1.39

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 4, July/August 2010

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Book Review The Sinatra Solution. Metabolic Cardiology Stephen T Sinatra, MD, FACC Basic Health Publications Inc, 2005 ISBN 1-59120-158-6

With less self-aggrandisement, this book might have carried an alternative title You and your Mitochondria, with a subtitle such as Take Care of your Mitochondria, and your Body Will Take Care of the Rest!

The term ‘mitochondrion’ comes from the Greek [mitos = thread, and chondrion = granule]. Every nucleated cell in our bodies contains mitochondria, sometimes – as in cardiomyocytes – thousands per cell, and these organelles produce the energy in the form of ATP for all our vital functions.

The author nicely expresses his gratitude to all of his patients who allowed him the freedom to treat them by means that were, and probably still are in the eyes of many clinicians, somewhat experimental, unconventional and unorthodox. His reported success in terms of much improved health in many of those of his patients who were crippled by their poor cardiovascular status and who were not responding to conventional pharmacotherapy, provides much of the raison d’être for the text.

Persons who have had recent senior-school biology will readily understand most of the chapters. However the more technical ones such as Chapter 3, which carries the caption ‘ATP: The Miracle of Life’, and some sections of the subsequent chapters which deal in detail with what he has enticingly called the ‘awesome foursome’ i.e. d-ribose, l-carnitine, coenzyme-Q10 and magnesium, may not be too digestible for those whose human biochemistry is somewhat rusty! For such persons the book is a good tutorial.

Nevertheless, the gist of the author’s message will emerge very clearly – and I would compress it along these lines: •• Without mitochondria we would not be who we are.

•• Without healthy mitochondria we are not what we should be.

•• Mitochondria need d-ribose, l-carnitine, co-enzyme Q10, along with adequate magnesium, as very fundamental essentials for their proper function/survival.

•• Many seriously dysfunctional cardiovascular conditions, along with

a host of other metabolic and ‘low-energy’ syndromes, as well as statin-induced myalgias, are improved and corrected by ensuring a good intake of these fundamental mitochondrial nutrients.

•• Recommendations for appropriate supplementation with these biochemicals are provided, and case histories of seriously ill patients illuminate the benefits of careful use of these supplemental biochemicals.

•• Conventional cardiovascular medications are by no means eschewed, but while they address the signs/symptoms of the disorders, the basic energy defect must be corrected. The reminder that cardiac diastole is far more energy demanding than systole, helps explain ‘diastolic failure’.

There is no doubt that the current medical literature supports amply all the major contentions of the author. Big-Pharma doesn’t ‘sell’ these concepts to practitioners, and it is a sad reflection on our profession that it takes popularisation-type efforts and publications such as this one to spread such vital messages.

Unfortunately, there is no mention of the vast population of persons with mitochondrial cytopathy, particularly those who are HIV positive, including those receiving ARVs. Indeed it must be realised that much of the ‘íllness’, morbidity and mortality of HIV-positive persons is related to the loss and severely sub-optimal function of their mitochondria.

In closing, I would without temerity, propose that in 2010 there is overwhelming justification to expand the ‘awesome foursome’ to found the ‘livesome fivesome’, by adding the essentiality of adequate vitamin D to his regimen, and I doubt that the well-informed Dr Sinatra would gainsay this. This remains a readable book for stimulating interest in, and for providing the rationale for, looking after our vital mitochondria, so that they may look after us.

John Straughan

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CardioVascular Journal of Africa (official journal for PASCAR)

• Advance publications • Encouraging patients with chronic atrial fibrillation to use anticoagulation therapy • Concurrent resistance and aerobic training • Microalbuminuria in hypertensive patients

• Right ventricular systolic function using tricuspid annular-plane systolic excursion Cardiovascular Journal of Africa . Vol 21, No 4, July/August 2010

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• Metabolic syndrome indicators in urban black South African men

• Diastolic heart failure • A halo in the heart during coronary angiography