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European Journal of Heart Failure 2004 6(7):831-843; doi:10.1016/j.ejheart.2003.11.019
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© 2004 European Society of Cardiology

Heart failure—the importance of ethnicity

Michael D. Sosin, Gurbir S. Bhatia, Russell C. Davis and Gregory Y.H. Lip*

University Department of Medicine, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital Birmingham B18 7QH, England, UK

* Corresponding author. Tel.: +44-121-507-508; Fax: +44-121-554-4083 E-mail address: g.y.h.lip{at}bham.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
Heart failure is a major public health problem in the Western world. Aetiological factors involved in its development include hypertension, diabetes, and ischaemic heart disease—all of which differ in prevalence, and possibly mechanism, between patients of differing ethnicity. Unfortunately, epidemiological and therapeutic trials have involved almost exclusively white populations, and evidence from these trials cannot necessarily be assumed to be generalisable to populations that include high proportions of patients from other ethnic origins. This review will discuss the mechanistic and therapeutic differences that exist in heart failure between those of European origin, and patients from the major ethnic minority groups of the UK.

Key Words: Epidemiological • Therapeutic • Mechanistic

Received September 22, 2003; Revised October 31, 2003; Accepted November 6, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
Heart failure (HF) is a chronic disease associated with considerable morbidity and mortality. Patients typically suffer from exertional dyspnoea, peripheral oedema, and lethargy. Patients with HF have poor quality of life [1], and require frequent hospital admissions (and readmissions) [2]. Indeed, HF accounts for at least 5% of admissions to general medical and geriatric wards in British hospitals, and admission rates for HF in various European countries (Sweden, Netherlands, and Scotland) and in the United States have doubled in the past 10–15 years. It is, therefore unsurprising that HF directly accounts for 1.9% of the total healthcare expenditure in the United Kingdom, and a further 2% is taken up by ‘indirect’ costs, such as nursing home costs [3]. It should be noted that the prognosis of HF is also appalling, worse than that of prostate or breast cancer [4]. Furthermore, HF is increasing in prevalence in western society (unlike all other cardiovascular diseases) [5], and this trend is likely to continue as the population ages, and survival from myocardial infarction increases.

Aetiological factors involved in the development of HF include hypertension, diabetes, and ischaemic heart disease—all of which differ in prevalence, and possibly mechanism, between patients of differing ethnicity. Unfortunately, epidemiological and therapeutic trials have involved almost exclusively white populations, and thus, evidence from these trials cannot necessarily be assumed to be generalisable to populations that include high proportions of patients from other ethnic origins. This review will discuss the mechanistic and therapeutic differences that exist in HF between patients from different ethnic groups.

1.1. Search strategy
We performed a search using electronic databases (MEDLINE, EMBASE, DARE), using the search terms ‘heart failure’, ‘systolic dysfunction’, ‘diastolic dysfunction’ in combination with either ‘ethnicity’, ‘race’, ‘Caucasian’, ‘African Caribbean’, ‘Asian’, ‘mechanisms’; ‘epidemiology’; ‘pathophysiology’; ‘genetics’; ‘coronary artery disease’ or ‘ischaemic heart disease’; ‘genetics’; ‘smoking’; ‘alcohol’, etc—to cover the range of subheadings addressed in this review. In addition, the reference lists from papers were scrutinised and abstracts from national and international cardiovascular meetings were studied to identify further studies, published or unpublished.


   2. Heart failure: the size of the problem
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
Data from the Framingham study have shown that the lifetime risk of HF at age 40 is 21.0% (95% CI 18.7 to 23.2%) for men and 20.3% (95% CI 18.2 to 22.5%) for women [6]. Even in patients with no history of myocardial infarction, the lifetime risk was 11.4% (95% CI 9.6 to 13.2%) for men and 15.4% (95% CI 13.5 to 17.3%) for women. HF is, therefore an enormous health burden in western countries. Previous population-based studies have also shown that the most common cause of HF is coronary heart disease, followed by hypertension [7,8].

Nonetheless, such that is known about HF, such as the data quoted above, are essentially based on the study of almost exclusively White populations (Table 1). In some epidemiological studies, ethnicity has not even been reported. Additionally, many of the landmark therapeutic trials in HF which have established the benefits of treatments such as Angiotensin Converting Enzyme (ACE) inhibitors in HF included very few non-White patients (Table 2), in some cases simply reflecting the population of the countries in which these trials were carried out. Furthermore, it cannot be assumed that treatments validated in White populations will be equally efficacious in non-White populations.


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  		Table 1 Ethnicity of participants in epidemiological studies of LVSD and HF

 


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  		Table 2 Ethnicity of participants in HF treatment/prevention trials

 
Certainly, HF is also a significant health problem in non-White populations. Indeed, there is evidence that in certain ethnic groups, HF is even more prevalent, and may have a worse prognosis still than that seen in White populations. In adult African Americans, for example, the prevalence of HF has been estimated at 3%-higher than white counterparts [9]. This is not explained by coronary artery disease, as the prevalence of CAD is lower in black patients with HF [10]. This therefore throws some doubt on the applicability of the above epidemiological data to non-white populations. In addition, subanalysis of the Studies of Left Ventricular Dysfunction (SOLVD) showed that African American participants were at greater risk of death and hospitalisation than their white counterparts [10]. Furthermore, a recent observational study [11] of 29 732 patients hospitalised for HF in the US, in contrast, found lower 30 day and 1 year mortality among black patients, although readmission rates were much higher for the black subjects. Nonetheless, the study did exclude patients below the age of 65 years, which may have biased the results as black patients had a lower median age at onset of HF. Another recent study of a single-centre database of patients with heart failure due to left ventricular systolic dysfunction (which included 44% African Americans) found similar survival between Whites and African Americans; measures of morbidity such as hospitalisation rates were not presented, however, and again African American patients were found to be younger than their White counterparts [12].

In England and Wales, the largest non-White ethnic group are the South Asians (4.2%), followed by African Caribbeans (2.3%) (OPCS, data from 2001 to 2002), and there is marked regional variation. In a study of 348 acute HF admissions to a Birmingham City centre hospital serving a multi-ethnic population, 76% were White, 16% South Asian, and 8% were African Caribbean [13]. The non-White patients in this study were significantly younger than the White patients, suggesting an earlier onset of the syndrome of HF. If this is representative of the population with chronic HF in the local community, almost one quarter of the patients will have been treated according to an evidence base, which may not apply to them. A reanalysis of this study taking into account population data has suggested that the relative risk of HF in those aged 60–79 years was 3.1 (95% CI 1.9–4.9) for African Caribbeans, and 5.2 (95% CI 3.7–7.4) for South Asians [14].


   3. Differences in aetiology
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
3.1. Dilated cardiomyopathy
Whilst less common than ischaemic and hypertensive cardiomyopathy, dilated cardiomyopathy is a significant cause of HF. The condition may affect patients at any age, and may, therefore result in more morbidity and earlier mortality for a given patient than ischaemic cardiomyopathy. A recent US report found increased incidence of paediatric cardiomyopathy (including both hypertrophic and dilated cardiomyopathy) among African Americans (1.42 vs. 1.06 per 100 000, P<0.02) [15]. In addition, the Washington DC Dilated Cardiomyopathy Study found an increased risk of idiopathic dilated cardiomyopathy in adult African Americans (relative risk 2.6, 95% CI 1.6–4.3) [16].

The African Caribbean ethnic group were associated with increased mortality from dilated cardiomyopathy in the MRFIT (multiple risk factor intervention trial) cohort, although when the data was adjusted for economic factors, the association became non-significant (RR=1.58 and P=0.058 with adjustment for income) [17]. This study was limited by the use of death certificate data with inherent potential for inaccuracy.

In the UK, no large studies have addressed the relative prevalence of dilated cardiomyopathy between different ethnic groups.

3.2. Valvular heart disease
Valvular heart disease is an important cause of heart failure. Childhood rheumatic fever is an important cause of valvular heart disease in later life. Treatment of the preceding streptococcal illness has greatly reduced the incidence of rheumatic fever in the western world, although in some areas resurgence has been reported in recent years [18]. Certainly the disease remains common in the developing world, and the proportion of heart failure due to valvular heart disease is likely, therefore to remain significant in first generation migrants. The relative prevalence of other causes of valvular heart disease (such as bicuspid aortic valve) in different ethnic groups is not known.

3.3. Diastolic heart failure
It has become apparent that many patients with clinical evidence of heart failure have preserved left ventricular systolic function, but abnormalities of ventricular relaxation (diastolic dysfunction). From available evidence it appears that diastolic heart failure is associated with significant mortality, although less than that of systolic heart failure.

Lack of consensus on the definitions of ‘diastolic dysfunction’ and ‘diastolic heart failure’ poses difficulties for the accurate assessment of its prevalence among the general population. To date no large study has assessed the prevalence of diastolic heart failure with reference to ethnicity. However, since hypertension is the predominant aetiological factor associated with diastolic dysfunction, and hypertension appears to account for a much larger proportion of cases of heart failure among the African American and African Caribbean groups in the UK (see below), than among Whites, it would seem likely that diastolic heart failure is particularly important among these groups.


   4. Pathophysiology
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
Clearly, as ischaemic heart disease and hypertension are the most common causes of HF, populations with more risk factors for coronary artery disease and more hypertension are more likely to develop HF. However, there appear to be more complex differences in the pathophysiology of HF between different ethnic groups.

4.1. Diabetes
Type II diabetes mellitus (DM) is a potent risk factor for coronary artery disease. Coronary atherosclerosis is enhanced in diabetics, and acute myocardial infarction (MI) causes 20% of deaths of diabetic subjects, and re-infarction and HF are more common in diabetic survivors of MI [19]. The Beta-blocker Evaluation of Survival Trial (BEST) found that diabetes was independently associated with increased mortality in patients with ischaemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, P=0.001) [20]. Additionally, experiments in animal models of diabetes suggest the existence of a separate diabetic cardiomyopathic process, distinct from coronary artery disease [21].

Certainly, DM is more common, and, therefore likely to contribute more to the burden of HF in South Asian and Black patients than Whites. South Asian and Black patients also appear to be particularly likely to develop diabetes in response to environmental factors such as westernisation of the diet, and obesity [22], whilst African–Americans have also been shown to have a prevalence of diabetes at least 12 times greater than that observed among native African blacks (12% and 1%, respectively) [22]. Similarly, Indian Asians living in urban areas of India have a prevalence of diabetes of approximately 8%, compared to 2% for those living in rural areas [22].

The prevalence of diabetes is increased four-fold in Indian Asians who have migrated to the UK compared to those living in India. Additionally, the prevalence of diabetes is increasing at a faster rate among African Americans than White Americans [22]. In a UK study of patients presenting with peripheral vascular disease, Makin et al. [23] found that African Caribbeans presented more frequently with symptomatic PVD than either Caucasians or South Asians, and further, that African Caribbean patients with PVD were more likely to have diabetes.

Type II Diabetes mellitus occurs when the balance between insulin production (β-cell function) and insulin sensitivity is upset, either by decreased insulin sensitivity (insulin resistance), or by decreased β-cell function. In UKPDS (the United Kingdom Prospective Diabetes Study), which included 82% whites, 10% South Asian, and 8% African Caribbeans, Insulin resistance was highest among the South Asian patients, and lowest among the African Caribbeans. Conversely, β-cell function was lowest in African Caribbeans, and highest among South Asian subjects [24]. Therefore, the predominant mechanism leading to diabetes appears to differ between ethnic groups. It is likely that the observed levels of β-cell function, and insulin sensitivity have developed in response to traditional diets; white subjects appear to have the best balance in the context of a modern western diet and lifestyle, although even among this group the prevalence of diabetes is rising. Clearly, prevention and treatment of diabetes are likely to have a significant role to play in the prevention of HF, and such measures are likely to particularly valuable amongst African Caribbean and South Asian patients.

4.2. Hypertension
Studies performed in the UK and USA show that the prevalence of hypertension is substantially higher in black than in white populations [25–28]. In addition, hypertensive US blacks have more frequent target end organ damage than whites, including left ventricular hypertrophy (LVH) [29,30]. Accordingly, there has been a great deal of research into pathophysiological differences in hypertension between Black and White patients. In contrast, there has been little research in hypertension in South Asian patients.

4.2.1. Salt sensitivity
African Caribbean subjects with and without hypertension are more salt-sensitive than white Americans [26]. Salt-sensitivity is loosely defined as an increase in blood pressure in response to relatively high sodium intake [31]. Salt-sensitive hypertensive patients also more frequently develop nephropathy, when compared to salt-resistant individuals.

4.2.2. Vascular reactivity
An exaggerated BP response to standardised laboratory physical and mental stressors (such as the cold pressor test, or video game challenge) in youths may predict essential hypertension in adult life [32]. There is evidence that normotensive Blacks may have a greater BP response to stress than age-matched whites. For example, Thomas et al. [33] studied healthy black and white American medical students, and found that blacks had significantly higher resting BP (though both groups were normotensive), and greater blood pressure responses both to the cold pressor test, and to exercise.

4.2.3. Nocturnal ‘dipping’ in blood pressure
In addition to increased vascular reactivity, both normotensive and hypertensive black subjects show a smaller nocturnal dip in blood pressure when compared with whites [34–36]. The 24 h ‘blood pressure load’ on the ventricles may, therefore be higher in black patients than whites, with the same clinic-measured blood pressure, leading to increased likelihood of developing LVH. It has also been reported that black patients with hypertension have a higher total peripheral resistance, and lower cardiac output than in whites [37]. Together with increased likelihood of LVH, this might suggest that the remodelling process in response to hypertension is different amongst ethnic groups.

4.3. The sympathetic nervous system
There is good evidence of differences in sympathetic activation between black and white patients, but virtually no studies have been done in South Asian patients. For example, Calhoun et al. [38] demonstrated greater muscle sympathetic nerve activation in response to the cold pressor test in normotensive blacks than whites. In addition, Blacks have been shown to have greater responses to cardiac β1- and β2-adrenergic stimuli and peripheral {alpha}1-adrenergic stimuli than whites [39–43], particularly in states of potassium depletion [44] (which occur commonly in HF due to diuretic therapy).

Nevertheless, studies of β-adrenoceptor density have shown conflicting results, with investigators reporting higher [43] equal [45], or lower receptor density [46] in black patients. For example, Lang et al. [47] demonstrated that the antihypertensive effect of clonidine (a central {alpha}2-adrenergic agonist) is blunted in normotensive blacks compared to normotensive whites despite a similar reduction in sympathetic activity, and interestingly, a separate study showed similar blunting in patients with mild-moderate HF [48]. Furthermore, there is a blunted vasodilatory response to intra-arterial infusion of isoproterenol (a β2 agonist) in normotensive blacks [49]. The combination of failure of peripheral vasodilatation, and increased cardiac response to adrenergic stimulation, could (at least in part) explain the increased vascular reactivity seen in blacks, although reduced responsiveness of BP to clonidine suggests that the contribution of the sympathetic nervous system to BP may be less in Blacks than in Whites.

Thus, differences in the sympathetic nervous system may be relevant to the future course of HF in hypertensive patients. Indeed, elevated levels of norepinephrine have been shown to be characteristic of decompensated HF [50,51], and ethnic differences in this important pathophysiological mechanism may be expected to have profound implications for HF treatment. In the short term, sympathetic overactivity restores blood pressure and cardiac output by stimulating myocardial contractility, and increasing peripheral resistance; however, as a result of increased myocardial oxygen demand, increased afterload and preload, these result in further clinical deterioration. Elevated norepinephrine level is also a poor prognostic factor in HF [52,53]. Nonetheless, there has been little research exploring sympathetic activation with respect to ethnicity in HF.

4.4. Endothelial function
The vascular endothelium is effectively a large endocrine and paracrine organ consisting of a single cell layer covering the internal surface of blood vessels throughout the body. It detects haemodynamic changes and circulating signal factors, and responds by producing vasoactive substances [54]. The critical balance between these factors plays a major role in vascular homeostasis [55], such that endothelial dysfunction is associated with failure to correctly regulate blood pressure (BP) and haemostasis.

Defective endothelial function was first demonstrated in HF by Kubo and colleagues [56], who noted impaired forearm vasodilatation in response to intra-arterial methacholine in HF vs. control. Interestingly, one recent (small) study has shown that endothelial function (as assessed by flow-mediated dilatation) is impaired in healthy South Asian men as compared to healthy European whites [57]. Several groups have demonstrated that flow-mediated dilatation in response to endothelium-dependent vasodilators such as acetyl choline is impaired in African Americans [58,59]. In addition, the ARIC (Atherosclerosis Risk In Communities) study found that serum vWF (a marker of endothelial dysfunction) was positively and independently associated with cardiovascular risk in African Americans with diabetes [60]. There is some evidence, therefore, that endothelial function may differ between ethnic groups both in health and in cardiovascular disease, and this mechanism may at least partly explain the increased cardiovascular disease risk found in certain groups.

4.4.1. Endothelin-1 (ET-1)
ET-1 is a 21-residue peptide secreted by vascular endothelial cells, and is the most potent vasoconstricting substance yet discovered [61]. Nonetheless, there may be a misconception (probably based on many irrelevant animal studies) that ET-1 induces systemic vasoconstriction or may increase blood pressure; indeed, infusion of ET-1 in man results in renal vasoconstriction, but does not directly increase blood pressure [62], unlike what is seen for AT-II [63].

Nonetheless, levels of ET-1 have been reported to be elevated in hypertension, although not all studies have confirmed this [64–67]. In separate studies, normotensive male (but not female) blacks have higher basal levels of ET-1 [68], and release more ET-1 in response to physical and mental stress than whites [69], and furthermore, male and female black hypertensives have significantly higher ET-1 levels than white counterparts [70].

There is evidence that distribution and density of endothelin receptor subtypes (ETA – promotes vasoconstriction and ETB – promotes vasoconstriction or vasodilatation dependant upon location) differ between racial groups. For example, Ergul et al. [71,72] found that ETA and ETB were present on the vascular endothelium in both blacks and whites, but in whites, only ETA was detected on smooth muscle cells. In contrast, both receptor subtypes were detected on smooth muscle cells from black patients. Since the effect of endothelin depends upon the relative density of these two receptor subtypes, the action of this potent vasoconstrictor may differ between different ethnic groups. Little is known about endothelin physiology in South Asians.

It has recently been shown that ET-1 may, in addition to its vasoconstricting role, be involved in regulation of sodium and water by the kidney, and may be involved in the development of salt-sensitive hypertension – providing a link between the increased levels of ET-1 and the increased salt-sensitivity seen in blacks [73]. Although results with endothelin antagonists have thus far been disappointing in HF-for example, offering no further benefit over standard therapy, and possibly a risk of worsening of HF in the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in heart failure) study [74]. Thus, the (mainly experimental) studies suggest that the action of endothelins may be more significant in black patients and thus, further studies with reference to ethnicity may be helpful.

4.4.2. Nitric oxide production
NO is a potent vasodilator produced by vascular endothelial cells. NO is synthesised from L-arginine by the enzyme nitric-oxide synthase (NOS). Impaired production or release of NO by the endothelium in response to stimuli such as shear stress, may contribute both to increased peripheral vasoconstriction (which is characteristic of HF), and to thrombosis and thromboembolism, as lack of NO may promote monocyte and platelet adhesion to the endothelium. In the coronary arteries, this may cause further myocardial ischaemia and infarctions, which may cause further deterioration of cardiac function and are a frequent cause of death in patients with HF [75]. Furthermore, experimental studies suggest a role for the NOS pathway in development of salt-sensitive hypertension, whilst treatment with NOS inhibitors results in increased BP and reduced sodium excretion [76].

Both basal and receptor-stimulated NO activity are reduced in hypertensive patients [77], and in normotensive offspring of hypertensive parents [78]. In addition, Higashi et al. [79] recently showed that endothelial function is impaired in hypertensive patients who show a reduced or absent nocturnal dip in BP (‘non-dippers’) when compared to those who show a normal circadian BP pattern (‘dippers’). Furthermore, Houghton et al. [80] demonstrated that endothelial-dependent dilatation in the coronary artery is augmented in African American patients with normal coronary arteries following infusion of L-Arginine, whilst no such augmentation is seen in Whites. This evidence, therefore suggests that defective NO production may be more important in blacks then whites in the development of hypertension and subsequent HF.

In Dahl salt-sensitive rats, treatment with L-arginine normalises BP, and protects against renal injury [81]. Furthermore, Barton et al. studied NOS in salt-sensitive and salt-resistant rats [73] and found that in salt resistant rats, salt loading caused an increase in renal NOS activity and NO release. This effect was absent in Dahl salt-sensitive rats, and may thus represent a defective compensatory mechanism, which leads to the development of hypertension. Interestingly, endothelin-1 levels are increased in Dahl salt-sensitive rats, but not salt resistant rats, in response to salt loading. Furthermore, treatment with an endothelin receptor antagonist resulted in normalisation of NO release in salt-sensitive rats, which suggests that endothelin overexpression may be the primary defect, causing secondary suppression of NOS.

The possibility that endothelin itself inhibits NOS is supported by a study in hypercholesterolaemic pigs, which showed that treatment with an endothelin receptor antagonist resulted in increased NOS activity [82]. Indeed, NO has been shown to contribute to β-adrenergic mediated vasodilatation, and this mechanism may explain the blunted vasodilator response to β-adrenergic stimulus demonstrated in normotensive blacks, as mentioned above [49]. Defective NO production may, therefore have a role to play in the development of hypertension both due to reduced direct NO mediated (endothelium-dependent) vasodilatation, and reduced β-adrenergic (endothelium independent) mediated vasodilatation. However, Cardillo et al. [83] demonstrated defects in both NO-dependent and NO-independent vasodilatation in normotensive blacks, suggesting that changes in NO activity may be only one of several factors increasing hypertension in blacks.

4.5. The Renin-angiotensin-aldosterone system
The RAS, which in health acts to preserve circulatory homeostasis, is undoubtedly associated with the pathophysiology of HF. Falling cardiac output due to HF reduces renal blood flow, causing release of renin from the juxta-glomerular apparatus. Renin converts circulating angiotensinogen to angiotensin I, which is cleaved in turn by ACE to produce A-II. In addition to causing vasoconstriction, A-II leads to aldosterone release from the adrenal gland. This results in avid salt and water retention by the kidney, leading to oedema and weight gain – the classic features of HF [84].

Plasma renin activity (PRA) levels are demonstrably increased in HF, and the degree of increase has been shown to be of prognostic importance [85]. In addition, data from the first Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS-I) suggested that ACE inhibitors only improve mortality in HF patients with neurohormonal activation [86]. Nonetheless, Black patients with hypertension have lower plasma renin activity (PRA) when compared to whites [87,88] and it has been suggested that this difference may result in black hypertensive patients being less responsive to ACE inhibitors, and more responsive to calcium channel blockers and diuretics (see below). In the second Vasodilator-Heart Failure Trial (V-HeFT II), PRA levels were found to be lower among black patients, but only in those with a history of hypertension [89]. Furthermore, this study found that the response to ACE inhibitors was less marked among the black patients.

4.6. Thrombosis
HF patients are at high risk of venous thromboembolism. In addition, there is evidence that thrombotic events may be involved both in the pathogenesis of HF (e.g. myocardial infarction), and in CHF mortality through both sudden and non-sudden death [90].

For example, elevated fibrin D-dimer levels (a marker of thrombogenesis and fibrin turnover) have been shown to predict MI in apparently healthy men [91]. Pieper et al. [92] studied fibrin D-Dimer levels in elderly subjects (age 72–101) in a community setting, and found that average levels were 40% higher in blacks than whites, even after controlling for known risk factors for thrombosis. This provides circumstantial evidence that thrombotic events may contribute to the higher mortality observed in black patients with HF, and deserves further investigation. To date, there is no clear evidence that antithrombotic therapy is beneficial in HF in sinus rhythm, although the available evidence does suggest benefit, at least in certain groups of patients [90]. It is possible that a patient's ethnicity may be an important factor in determining whether or not a particular patient would benefit from such therapy.

4.7. Atrial fibrillation
Atrial fibrillation is a common finding in HF, associated with increased risk of thromboembolic events, and decreased cardiac performance. The onset of atrial fibrillation in a patient with congestive HF is associated with worse prognosis. Despite hypertension being an important risk factor for atrial fibrillation, a recent electrocardiographic study of 2000 hospital attendees found that African Americans were less likely to have atrial fibrillation than American Whites (2.5% vs. 7.8%) [93]. Limited data from UK studies also suggest that Atrial fibrillation is less common in South Asian and Black patients in the community, but that a higher proportion of South Asian patients with atrial fibrillation require hospital admission compared to European Whites [94]. One UK study of patients admitted with acute heart failure found that African Caribbean and South Asian patients were less likely than their white counterparts to have atrial fibrillation at the time of admission [13]. Similarly, Vaccarino et al. found that African American patients presenting with acute heart failure were less likely than White Americans to have atrial fibrillation (14.6% vs. 28.0%, P=0.01) [95]. In addition, a UK study found that South Asian and Black patients attending a hospital anticoagulation clinic for atrial fibrillation were less aware of their diagnosis and of its potential complications [96]. Such reduced awareness might limit compliance with medication, which would be expected to increase the proportion of patients suffering an adverse event.


   5. Therapeutic options
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
5.1. Prevention-antihypertensive therapy
The effect of antihypertensive drugs differs between racial groups (Tables 3 and 4), with diuretics and calcium antagonists being the most efficacious agents in blacks [97,98]. For example, the Trial of Antihypertensive Interventions and Management (TAIM) study compared chorthalidone 25 mg daily with atenolol 50 mg daily, as well as investigating the effects of weight loss and sodium restriction on hypertension, and showed that black participants responded better to chlorthalidone plus weight loss; in contrast, the whites to responded best to atenolol plus weight loss [99].


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  		Table 3 Comparison of efficacy of antihypertensive agents between black and white patients

 
Angiotensin II receptor blockers such as losartan are widely used for the treatment of hypertension. They are well tolerated, and are often used in hypertension or HF where patients are intolerant of ACE inhibitors due to cough. The Losartan Intervention For Endpoint reduction (LIFE) trial [100], in which losartan was compared to atenolol in 9193 hypertensive patients with left ventricular hypertrophy, found a significant reduction in mortality with losartan, chiefly due to reduction in stroke. However, subanalysis by race has suggested that Black patients receiving losartan had significantly more cardiovascular deaths, MIs and strokes than those receiving atenolol [101]. It is important to note that only 6% of the participants in LIFE were black and further study is needed to confirm or refute the substudy findings.

5.2. Treatment with ACE inhibitors or hydralazine/nitrates
ACE inhibitors have been described as the cornerstone of modern HF management. However, their effectiveness may not be equal across all ethnic groups. Subanalysis of the SOLVD study data showed that the response to treatment with the ACE Inhibitor, Enalapril, was decreased in African-Americans [102]. In addition, a retrospective analysis of the V-HeFT II trial suggested that black patients with HF may derive less benefit from ACE inhibitors – importantly, they did not show a survival advantage of Enalapril over vasodilator therapy with combination Hydralazine/Isosorbide Dinitrate, unlike the white participants in this study [89]. This study also confirmed a lower BP response to ACE inhibition in black patients with HF. In addition, American Asian patients have been suggested to have a particularly high risk of cough with ACE inhibitors (50%), which may limit the tolerability of these drugs in this population [103].

5.3. Beta-blockers
As described above, beta-blockers used as monotherapy appear to work less well in black hypertensive patients [104]. In contrast, one small study found no difference in haemodynamic effects of metoprolol in Caucasian (including oriental) and non-Caucasian (mainly black) patients with HF on digoxin and ACE inhibitors – the authors postulated that this might be because the patients in their study were taking diuretics, unlike the patients in the hypertension trials [105]. The results of this study are limited by the unusual ethnic comparison and the significantly younger age of the non-Caucasian group. The mortality benefits of beta-blockers in HF have been compared between black and non-black patients in two trials, and the results are conflicting.

In the BEST (Beta Blockers Evaluation Survival Trial) study, the use of bucindolol was associated with a non-significant increase in the risk of serious clinical events in black patients, but reduced death or hospitalisation in non-black patients [106]. However, in the US Carvedilol Heart Failure Trials Program, the benefit of carvedilol in patients with symptomatic HF and EF<35% was apparent and of similar magnitude in both black and non-black patients [107]. The authors proposed that carvedilol might be effective in black patients unlike other beta-blockers because its additional {alpha}1-adrenergic receptor blocking activity. No HF beta-blocker trial has involved sufficient South Asian patients to provide comparative data.

5.4. Aldosterone blockade
The Randomised Aldactone Survival (RALES) study [108] demonstrated that aldosterone blockade with Spironolactone was associated with reduced mortality in patients with severe HF. The more recent EPHESUS study extended this, showing benefit of a more selective aldosterone blocker (eplerenone) in patients with less severe HF [109]. Thus, the use of aldosterone blockers is likely to increase in all patients with HF. One recent study of antihypertensive efficacy found that eplerenone was equally effective in black and white patients, but was superior to losartan amongst the black group [110]. Further study may demonstrate a similar efficacy in HF. To date, there the use of aldosterone blockade in South Asian patients has received little research attention.


   6. Future directions
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 
6.1. Omapatrilat
Omapatrilat is a drug that inhibits both ACE and neutral endopeptidase (NEP), a key enzyme responsible for the breakdown of natriuretic peptides and bradykinin. Inhibition of NEP, therefore leads to enhancement of the effects of these vasodilatory peptides, which may confer additional benefit when combined with ACE inhibition in HF. In treatment of hypertension, omapatrilat has been shown to cause a greater decrease BP than lisinopril alone [111].

Clinical studies in HF suggest that omapatrilat is at least as good as ACE inhibitor therapy at reducing death and hospitalisation in HF [112,113] but further studies are awaited. Thus far, data on omapatrilat for non-Whites is limited, but the high incidence of angio-oedema (particularly in African Carribean subjects) [114] may mean that further studies will be curtailed. The future of vasopeptidase inhibitors may depend upon the identification of high risk groups of patients with HF, which may derive net benefit from these agents. Studies which focus on ethnicity may help identify suitable groups.

6.2. Endothelial receptor blockers/superoxide dismutase
Particularly in black patients, as described above, the endothelin/NOS system may contribute more to hypertension and HF than the RAS, and, therefore, agents acting on this system may be expected to be particularly beneficial for these patients, perhaps having potential equivalent to that of ACE inhibitors in patients of European origin. Trials of agents such as bosentan with reference to ethnicity may produce favourable results, in contrast to the disappointing results seen in the general HF population.

6.3. Antithrombotic therapy
As yet there is no clear evidence for the use of antithrombotic therapy for HF patients in sinus rhythm, although prospective trials in progress may eventually provide this evidence [90]. It is possible that antithrombotic therapy may be beneficial only for selected high risk patients and further studies will be necessary to determine if racial differences exist in the benefits of antithrombotic therapy. As described above, black and South Asian patients receiving anticoagulants may be less aware of the reasons for treatment, and efforts must be made to provide adequate information, translated if necessary, when commencing such treatment.

6.4. Ongoing trials
The African-American Heart Failure Trial (A-HeFT), comparing combination hydralazine and isosorbide dinitrate with placebo, in African American patients with NYHA class III–IV symptoms, LVEF<35% on standard HF therapy, began recruitment in June 2001 [115]. This trial will hopefully provide clear evidence as to whether H–I combination is beneficial in HF among African-Americans. This trial is remarkable for the use of a combination mortality, morbidity and quality of life primary endpoint, and also for the inclusion of a genetic analysis, which may provide further data on genetic factors involved in the development of heart failure. There are no large ongoing therapeutic studies in HF involving significant numbers of South Asian patients.


   7. Access to care
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
8. Should ethnicity influence...
 9. Summary
 References
 
There is evidence from studies in the UK and USA that patients from ethnic minority groups may experience difficulties accessing care compared to their white counterparts. Such difficulties are likely to be multifactorial.

For example, Barakat et al. [116] studied Bangladeshi and White patients presenting with acute myocardial infarction, and found that the Bangladeshi patients were 89% less likely than whites to complain of central chest pain, and 87% less likely to use classic pain descriptions—irrespective of fluency in English. The study also found that ‘door to needle’ times for thrombolysis were almost doubled in the Bangladeshi group (42.5 vs. 26 min). Such a delay to thrombolysis is likely to result in a larger area of myocardial infarction, potentially increasing the likelihood of development of HF. Feder et al. [117] studied South Asian and White patients undergoing angiography, and found no differences in the proportion suitable for revascularisation, and no differences in the intended management of the treating physician. However, of those deemed suitable for revascularisation, South Asian patients were less likely to actually receive it. Data on patients refusing revascularisation were not collected, but it is possible that South Asian patients might be less willing to undergo revascularisation, which might lead on to increased rates of HF.

Access to care has not been studied in African Caribbean patients in the UK, but some data are available on African Americans. For example, Vaccarino et al. [95] found that among patients admitted with acute decompensated HF, African Americans had less favourable socio-economic and access to care indicators.

It is therefore possible that patients from these ethnic groups may experience delays in diagnosis and treatment, which could partially explain the increased risk of HF in these groups.


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  		Table 4 Summary of relative importance of aetiological factors by ethnic group based on available evidence

 

   8. Should ethnicity influence management decisions in heart failure?
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
9. Summary
 References
 
Many authors have discussed the validity of the concepts of race and ethnicity with respect to medical treatment decisions [118]. Some have even suggested that research comparing patients of differing ethnicity is ‘discriminatory’. While it may be concluded from the above evidence that treatment decisions may be more soundly based on full neurohormonal and genetic profiling than merely on ethnicity, such profiling is not widely available and expensive. If there are indeed differences in pathophysiology and response to treatment, as the evidence certainly suggests, while it would be unwise to base treatment decisions solely on ethnicity, to ignore ethnicity would be doing a disservice to patients with this debilitating disease.


   9. Summary
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
References
 
HF is a very significant health problem in the UK, and is likely to be even more important among patients of South Asian or African Caribbean origin. The population of the UK is changing, with increasing proportions of people from these groups. From the above evidence, it appears that the aetiology and optimum treatment of HF and other cardiovascular diseases may not be the same for patients of differing ethnicity. Many trials, which have established the benefits of drugs currently used to treat HF, did not include many non-white individuals, and, therefore a significant (and rising) proportion of the HF population are presently being treated according to an evidence base, which may not apply to them. Clearly, future trials of intervention in HF should be designed to accurately represent the population at risk. Additional studies are necessary to provide firm evidence as to the optimum treatment strategies for HF and other cardiovascular diseases in different ethnic groups. In particular, there are a paucity of data relating to those of South Asian origin. Many clinicians and guidelines take ethnicity into account when prescribing antihypertensive therapy, and this may also be necessary for HF in the future.


   Acknowledgements
 
MS and GB are funded by Birmingham Nuffield Hospitals Research Fellowships. We acknowledge the support of the Sandwell and West Birmingham Hospitals NHS Trust.


   References
Top
 Abstract
 1. Introduction
 2. Heart failure: the...
 3. Differences in aetiology
 4. Pathophysiology
 5. Therapeutic options
 6. Future directions
 7. Access to care
 8. Should ethnicity influence...
 9. Summary
 References
 

  1. Hobbs F.D.R., Kenkre J.E., Roalfe A.K., Davis R.C., Hare R., Davies M.K. Impact of heart failure and left ventricular systolic dysfunction on quality of life. Eur Heart J (2002) 23:1867–1876.[Abstract/Free Full Text]
  2. Sutton G.C. Epidemiological aspects of heart failure. Am Heart J (1990) 120:1538–1540.[CrossRef][Web of Science][Medline]
  3. Stewart S., Jenkins A., Buchan S., McGuire A., Capewell S., McMurray J.J.V. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail (2002) 4:361–371.[Abstract/Free Full Text]
  4. Gillum R.F. Heart and stroke facts. Am Heart J (1993) 126:1042–1047.[CrossRef][Web of Science][Medline]
  5. Bonneaux L., Barendregt J.J., Meeter K., Bonsel G.J., Van der Maas P.J. Estimating clinical morbidity due to ischaemic heart disease and congestive heart failure: the future rise of heart failure. Am J Public Health (1994) 84:20–28.[Abstract/Free Full Text]
  6. Lloyd-Jones D.M., Larson M.G., Leip E.P., et al. Lifetime risk for developing congestive heart failure: the Framingham heart study. Circulation (2002) 106:3068–3072.[Abstract/Free Full Text]
  7. McKee P.A., Castelli W.P., McNamara W.B. The natural history of congestive heart failure: the Framingham study. N Engl J Med (1971) 285:1441–1446.[Web of Science][Medline]
  8. Cowie M.R., Wood D.A., Coats J.S., Thompson S.G., Poole-Wilson P.A., Suresh V., et al. Incidence and aetiology of heart failure: a population based study. Eur Heart J (1999) 20:421–428.[Abstract/Free Full Text]
  9. Data fact sheet: congestive heart failure in the United States: a new epidemic. Bethesda, Md.: National Heart, Lung, and Blood Institute, 1996.
  10. Dries D.L., Exner D.V., Gersh B.J., Cooper H.A., Carson P.E., Domanski M.J. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med (1999) 340:609–616. Erratum, N Engl J Med 1999;341:298.[Abstract/Free Full Text]
  11. Rathore S.S., Foody J.M., Wang Y., et al. Race, quality of care, and outcomes of elderly patients hospitalised with heart failure. J Am Med Assoc (2003) 289:2517–2524.[Abstract/Free Full Text]
  12. Dunlap S.H., Mallemala S., Sueta C.A., et al. Survival rates are similar between African American and white patients with heart failure. Am Heart J (2003) 146:265–272.[CrossRef][Web of Science][Medline]
  13. Lip G., Zarifis J., Beevers D.G. Acute admissions with heart failure to a district general hospital serving a multiracial population. Int J Clin Pract (1997) 51:223–227.[Web of Science][Medline]
  14. Chaturvedi N. Ethnic differences in cardiovascular disease. Heart (2003) 89:681–686.[Free Full Text]
  15. Lipshultz S.E., Sleeper L.A., Towbin J.A., Lowe A.M., Orav E.J., Cox G.F., et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med (2003) 348:1647–1655.[Abstract/Free Full Text]
  16. Coughlin S.S., Labenberg J.R., Tefft M.C. Black–white differences in idiopathic dilated cardiomyopathy: the Washington DC dilated Cardiomyopathy Study. Epidemiology (1993) 4:165–172.[Web of Science][Medline]
  17. Coughlin S.S., Neaton J.D., Sengupta A., Kuller L.H. Predictors of mortality from idiopathic dilated cardiomyopathy in 356 222 men screened for the Multiple Risk Factor Intervention Trial. Am J Epidemiol (1994) 139:166–172.[Abstract/Free Full Text]
  18. Veasy L.G., Tani L.Y., Hill H.R. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr (1994) 124:9–16.[CrossRef][Web of Science][Medline]
  19. Mahgoub M.A., Abd-Elfattah A.S. Diabetes mellitus and cardiac function. Mol Cell Biochem (March 1998) 180(1–2):59–64.[CrossRef][Web of Science][Medline]
  20. Beta Blockers Evaluation Survival Trial Investigators. The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol (2003) 42:914–922.[Abstract/Free Full Text]
  21. Duan J., Zhang H.Y., Adkins S.D., Ren B.H., Norby F.L., Zhang X., et al. Impaired cardiac function and IGF-I response in myocytes from calmodulin-diabetic mice: role of Akt and RhoA. Am J Physiol Endocrinol Metab (2003) 284:E366–E376.[Abstract/Free Full Text]
  22. Abate N., Chandalia M. The impact of ethnicity on type 2 diabetes. J Diabetes Complications (2003) 17:39–58.[CrossRef][Web of Science][Medline]
  23. Makin A.J., Silverman S.H., Lip G.Y. Ethnicity and peripheral vascular disease. Int J Clin Pract (2002) 56:645–648.[Web of Science][Medline]
  24. UK Prospective Diabetes Study Group. UK Prospective Diabetes Study, XII. Differences between Asian, Afro-Caribbean and White Caucasian type 2 diabetic patients at diagnosis of diabetes. Diabetic Medicine 1994;11:670–677.
  25. Hypertension Detection and Follow Up Program Cooperative Group. Race, education and prevalence of hypertension. Am J Epidemiol (1977) 106:351–361.[Abstract/Free Full Text]
  26. Cooper E.S., Kuller L.H., Saunders E., Martinez-Maldonado M., Caplan L.R., Yatsu F.M., et al. Cardiovascular diseases and stroke in African-Americans and other racial minorities in the United States: a statement of health professionals. Circulation (1991) 83:1462–1480.[Web of Science]
  27. Stamler J., Rhomberg P., Schonberger J.A., Shekelle R.B., Dyer A., Shekelle S., et al. Multivariate analysis of the relationship of seven variables to blood pressure. Journal of Chronic Disease (1975) 28:527–548.[CrossRef][Web of Science][Medline]
  28. Meade T.W., Brosovic M., Chakraborti R., Haines A.P., North W.R.S., Stirling Y. Ethnic group comparisons of variables associated with ischaemic heart disease. Br Heart J (1978) 40:789–795.[Free Full Text]
  29. Cooper R.S., Liao Y., Rotimi C. Is hypertension more severe among US blacks, or is severe hypertension more common? Ann Epidemiol (1996) 6:173–180.[CrossRef][Web of Science][Medline]
  30. Mayet J., Shahi M., Foale R.A., Poulter N.R., Sever P.S., McG Thom S.A. Racial differences in cardiac structure and function in essential hypertension. Brit Med J (1994) 308:1011–1014.[Abstract/Free Full Text]
  31. Sullivan J.M. Salt-sensitivity: definition, conception, methodology, and long-term issues. Hypertension (1991) 17(suppl. 1):I61–I68.[Web of Science][Medline]
  32. Light K.C., Sherwood A., Turner J.R. High cardiovascular reactivity to stress: a predictor of later hypertension development. In: Individual differences in cardiovascular response to stress—Turner J.R., Sherwood A., Light K.C., eds. (1992) New York, NY: Plenum Press. 281–293.
  33. Thomas J., Semenya K., Thomas C.B., Thomas D.J., Neser W.B., Pearson T.A., et al. Precursors of hypertension in black compared to white medical students. J Chronic Dis (1987) 40(7):721–727.[CrossRef][Web of Science][Medline]
  34. Murphy M.B., Nelson K.S., Oliner C.M., Elliot W.J. Higher nocturnal blood pressure in normal and hypertensive blacks compared with whites. Circulation (1988) 48:2268A.
  35. Harshfield G.A., Hwang C., Grim C. The circadian variation of blood pressure in blacks: influence of age, gender and activity. J Hum Hypertens (1990) 4:43–47.[Web of Science][Medline]
  36. Harshfield G.A., Alpert B.S., Willey E.S., Somes G.W., Murphy J.K., Dupaul L.M. Race and gender influence ambulatory blood pressure patterns of adolescents. Hypertension (1989) 14:598–603.[Abstract/Free Full Text]
  37. Hammond I.W., Alderman M.H., Devereux R.B., Luras E.M., Laragh J.H. Contrast in cardiac anatomy and function between black and white patients with hypertension. J Natl Med Assoc (1984) 76:247–255.[Medline]
  38. Calhoun D.A., Mutinga M.L., Collins A.S., Wyss J.M., Oparil S. Normotensive blacks have heightened sympathetic response to cold pressor test. Hypertension (1993) 22:801–805.[Abstract/Free Full Text]
  39. Rutledge D.R., Cardozo L., Steinberg J.D. Racial differences in drug response: isoproterenol effects on heart rate in healthy males. Pharm Res (1989) 6:182–185.[CrossRef][Web of Science][Medline]
  40. Dimsdale J.E., Graham R.M., Ziegler M.G., Zusman R.M., Berry C.C. Age, race, diagnosis, and sodium effects on the pressor response to infused norepinephrine. Hypertension (1987) 10:564–569.[Abstract/Free Full Text]
  41. Duey W.J., Bassett D.R. jr, Walker A.J., et al. Cardiovascular and plasma catecholamine response to static exercise in normotensive blacks and whites. Ethn Health (1997) 2:127–136.[Medline]
  42. Sherwood A., Hinderliter A.L. Responsiveness to alpha- and beta-adrenergic receptor agonists: effect of race in borderline hypertensive compared to normotensive men. Am J Hypertens (1993) 6:630–635.[Web of Science][Medline]
  43. Mills P.J., Dimsdale J.E., Ziegler M.G., Nelesen R.A. Racial differences in epinephrine and beta 2-adrenergic receptors. Hypertension (1995) 25:88–91.[Abstract/Free Full Text]
  44. Sudhir K., Forman A., Yi S.L., et al. Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans. Hypertension (1997) 29:1083–1090.[Abstract/Free Full Text]
  45. Stein M., O'Maley K., Kilfeater S. Ethnic differences in cyclic AMP accumulation: effect on alpha2, beta2, and prostanoid receptor responses. Clin Pharmacol Ther (1990) 47:360–365.[Web of Science][Medline]
  46. Isaacs K.D., Russouw J., du Plooy W.J. Differences in lymphocyte beta2-adrenoceptors clearly could explain reported differences in basal lymphocyte cAMP production in two ethnic groups. Med Sci Res (1993) 21:313–314.[Web of Science]
  47. Lang C.C., Stein M., He H.B., Belas F.J., Blair I.A., Wood M., et al. Blunted blood pressure response to central sympathoinhibition in normotensive blacks. Hypertension (1997) 30:157–162.[Abstract/Free Full Text]
  48. Lang C.C., Stein M., Nelson R., He H.B., Belas F.J., Blair I.A., et al. Sympathoinhibitory response to clonidine is blunted in patients with heart failure. Hypertension (1997) 30:392.[Abstract/Free Full Text]
  49. Lang C.C., Stein C.M., Brown R.M., Deegan R., Nelson R., He H.B., et al. Attenuation of isoproterenol-mediated vasodilatation in blacks. N Engl J Med (1995) 333:155–160.[Abstract/Free Full Text]
  50. Francis G.S., Goldsmith S.R., Levine T.B., Olivari M.T., Cohn J.N. The neurohormonal axis in congestive heart failure. Ann Intern Med (1984) 101:370–377.[Abstract/Free Full Text]
  51. Pouleur H., Benedict C.R., Rousseau M.R. Neurohormones in patients with ischemic left ventricular dysfunction. Crdiovasc Drugs Ther (1994) 8:313–317.[CrossRef]
  52. Rector T.S., Olivari M.T., Levine T.B., Francis G.S., Cohn J.N. Predicting survival for an individual with congestive heart failure using the plasma norepinephrine concentration. Am Heart J (1987) 114:148–152.[CrossRef][Web of Science][Medline]
  53. Cohn J.N., Johnson G.R., Shabetai R., Oeb H., Tristani F., Rector T.S., et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation (1993) 87(suppl. VI):VI.5, VI.16.
  54. Yanagisawa M., Kurihara H., Kimura S., et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (1988) 332:411–415.[CrossRef][Medline]
  55. Verma S., Anderson T.J. Fundamentals of Endothelial function for the clinical cardiologist. Circulation (2002) 105:546–549.[Free Full Text]
  56. Kubo S.H., Rector T.S., Bank A.J., Williams R.E., Heifetz S.M. Endothelium-dependent vasodilatation is attenuated in patients with heart failure. Circulation (1991) 84:1589–1596.[Abstract/Free Full Text]
  57. Chambers J.C., McGregor A., Jean-Marie J., Kooner J.S. Abnormalities of vascular endothelial function may contribute to increased coronary heart disease risk in UK Indian Asians. Heart (1999) 81:501–504.[Abstract/Free Full Text]
  58. Jones D.S., Andrawis N.S., Abernethy D.R. Impaired endothelial-dependent forearm vascular relaxation in black Americans. Clin Pharmacol Ther (1999) 65:408–412.[CrossRef][Web of Science][Medline]
  59. Khan D.F., Duffy S.J., Tomasian D., et al. Effects of black race on forearm resistance vessel function. Hypertension (2002) 40:195–201.[Abstract/Free Full Text]
  60. Adeniyi A., Folsom A.R., Brancati F.L., Desvorieux M., Pankow J.S., Taylor H. Incidence and risk factors for cardiovascular disease in African Americans with diabetes: the Atherosclerosis Risk in Communities (ARIC) study. J Natl Med Assoc (2002) 94:1025–1035.[Medline]
  61. Yanagisawa M., Kurihara H., Kimura S. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (1988) 332:411–415.[CrossRef][Medline]
  62. Jilma B., Szalay T., Dirnberger E., Eichler H.G., Stohlawetz P., Schwarzinger I., et al. Effects of endothelin-1 on circulating adhesion molecules in man. Eur J Clin Invest (1997) 27:850–856.[CrossRef][Web of Science][Medline]
  63. Krejcy K., Eichler H.G., Jilma B., Kapiotis S., Wolzt M., Zanaschka G., et al. Influence of angiotensin II on circulating adhesion molecules and blood leukocyte count in vivo. Can J Physiol Pharmacol (1996) 74:9–14.[CrossRef][Web of Science][Medline]
  64. Davenport A.P., Ashby M.J., Easton P., Ella S., Bedford J., Dickerson C., et al. A sensitive radioimmunoassay measuring endothelin-like immunoreactivity in human plasma: comparison of levels in patients with essential hypertension and normotensive control subjects. Clin Sci (Colch) (1990) 78:261–264.[Medline]
  65. Kohno M., Yasunari K., Murakawa K., Yokokawa K., Horio T., Fukui T., et al. Plasma immunoreactive endothelin in essential hypertension. Am J Med (1990) 88:614–618.[CrossRef][Web of Science][Medline]
  66. Shichiri M., Hirata Y., Ando K., Emori T., Ohta K., Kimoto S., et al. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension (1990) 15:493–496.[Abstract/Free Full Text]
  67. Schiffrin E.L., Thibault G. Plasma endothelin in human essential hypertension. Am J Hypertens (1991) 4:303–308.[Web of Science][Medline]
  68. Evans R.R., Phillips B.G., Singh G., Bauman J.L., Gulati A. Racial and gender differences in endothelin-1. Am J Cardiol (1996) 78:486–488.[CrossRef][Web of Science][Medline]
  69. Treiber FA, Jackson RW, Davis H, Pollock J, Kapuku G, Mensah GA et al. Racial differences in endothelin-1 at rest and in response to acute stress in adolescent males.
  70. Ergul S., Parish D.C., Puett D., Ergul A. Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension. Hypertension (1996) 28:652–655.[Abstract/Free Full Text]
  71. Ergul A., Shoemaker K., Puett D., Tackett R.L. Gender differences in the expression of endothelin receptors in human saphenous veins in vitro. J Pharmacol Exp Ther (1998) 285:511–517.[Abstract/Free Full Text]
  72. Ergul A., Tackett R.L., Puett D. Distribution of endothelin receptors in saphenous veins of African Americans: implications of racial differences. J Cardiovasc Pharmacol (1999) 34:327–332.[CrossRef][Web of Science][Medline]
  73. Barton M., Vos I., Shaw S., Boer P., D'Uscio L.V., Gröne H.-J., et al. Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis. J Am Soc Nephrol (2000) 11:835–846.[Abstract/Free Full Text]
  74. Kalra P.R., Moon J.C., Coats A.J. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol (2002) 85:195–197.[CrossRef][Web of Science][Medline]
  75. Uretsky B.F., Thygesen K., Armstrong P.W., Cleland J.G., Horowitz J.D., Massie B.M., et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation (2000) 102:611–616.[Abstract/Free Full Text]
  76. Mattson D.L., Lu S., Nakanishi K., Papanek P.E., Cowley A.W. Effect of chronic renal medullary nitric oxide inhibition on blood pressure. Am J Physiol (1994) 266:H1918–H1926.[Web of Science][Medline]
  77. Hirooka Y., Imaizumi T., Masaki H., et al. Captopril improves impaired endothelium dependent dilatation in hypertensive patients. Hypertension (1992) 20:175–180.[Abstract/Free Full Text]
  78. Taddei S., Virdis A., Mattei P., et al. Defective L-arginine-nitric oxide pathway in offspring of essential hypertension patients. Circulation (1996) 94:1298–1303.[Abstract/Free Full Text]
  79. Higashi Y., Nakagawa K., Kimura M., et al. Circadian variation of blood pressure and endothelial function in patients with essential hypertension: a comparison of dippers and non-dippers. J Am Coll Cardiol (2002) 40:2039–2043.[Abstract/Free Full Text]
  80. Houghton J.L., Philbin E.F., Strogatz D.S., et al. The presence of African American race predicts improvement in coronary endothelial function after supplementary L-Arginine. J Am Coll Cardiol (2002) 39:1314–1322.[Abstract/Free Full Text]
  81. Chen P.Y., Sanders P.W. L-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. Hypertension (1998) 31:918–924.[Abstract/Free Full Text]
  82. Taner C.B., Severson S.R., Best P.J., Lerman A., Miller V.M. Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia. J Appl Physiol (2001) 90:816–820.[Abstract/Free Full Text]
  83. Cardillo C., Kilcoyne C.M., Cannon R.O., Panza J.A. Attenuation of cyclic nucleotide-mediated smooth muscle relaxation in blacks as a cause of racial differences in vasodilator function. Circulation (1999) 99:90–95.[Abstract/Free Full Text]
  84. Weber K.T. Aldosterone in congestive heart failure. N Engl J Med (2001) 345:1689–1697.[Free Full Text]
  85. Schrier R.W., Abraham W.T. Hormones and haemodynamics in heart failure. N Engl J Med (1999) 341:577–585.[Free Full Text]
  86. Swedberg K., Eneroth P., Kjekshus J., et al. Effects of enalapril and neuroendocrine activation on prognosis in severe congestive heart failure (follow-up of the CONSENSUS trial). CONSENSUS Trial Study Group. Am J Cardiol (1990) 66:40D–44D.[CrossRef][Medline]
  87. Brunner H.R., Sealey J.E., Laragh J.H. Renin as a risk factor in essential hypertension: more evidence. Am J Med (1973) 55:295.[CrossRef][Web of Science][Medline]
  88. Rowlands D.B., DeGiovanni J., McLeay R.A.B., Watson R.D.S., Stallard T.J., Littler W.A. Cardiovascular response in black and white hypertensives. Hypertension (1982) 4:817–820.[Abstract/Free Full Text]
  89. Carson P., Ziesche S., Johnson G., Cohn J.N. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail (1999) 5:178–187.[CrossRef][Medline]
  90. Sosin M., Bhatia G., Lip G.Y.H. Should Chronic Heart Failure be treated with antithrombotic drugs? HeartDrug (2002) 2:295–302.
  91. Ridker P.M., Hennekens C.H., Cerksus A., Stampfer M.J. Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation (1994) 90:2236–2240.[Abstract/Free Full Text]
  92. Pieper C.F., Rao K.M., Currie M.S., Harris T.B., Cohen H.J. Age, functional status and racial differences in plasma D-dimer levels in community-dwelling elderly persons. J Ger Biol Sci Med Sci (2000) 55:M649–M657.
  93. Upshaw C.B. Jr. Reduced prevalence of atrial fibrillation in black patients compared with white patients attending an urban hospital: an electrocardiographic study. J Natl Med Assoc (2002) 94:204–208.[Medline]
  94. Gibbs C.R., Lip G.Y.H. Atrial fibrillation and ethnicity. Circulation (1999) 21:e153.
  95. Vaccarino V., Gahbauer E., Kasl S.V., Charpentier P.A., Acampora D., Krumholz H.M. Differences between African Americans and whites in the outcome of heart failure: evidence for a greater functional decline in African Americans. Am Heart J (2002) 143:1058–1067.[CrossRef][Web of Science][Medline]
  96. Lip G.Y., 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.[Abstract/Free Full Text]
  97. Materson B.J., Reda D.J., Cushman W.C., et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med (1993) 328:914–921. [Erratum, N Engl J Med 1994;330:1689.].[Abstract/Free Full Text]
  98. Saunders E., Weir M.R., Kong B.W., Hollifield J., Gray J., Vertes V., et al. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med (1990) 150:1707–1713.[Abstract/Free Full Text]
  99. Wassertheil-Smoller S., Oberman A., Blaufox M.D., Davis B., Langford H. The Trial of Antihypertensive Interventions and Management (TAIM) Study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Am J Hypertens (1992) 5:37–44.[Web of Science][Medline]
  100. The LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (2002) 359:995–1003.[CrossRef][Web of Science][Medline]
  101. The Life Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (2002) 359:1004–1010.[CrossRef][Web of Science][Medline]
  102. Exner D.V., Dries D.L., Domanski M.J., Cohn J.N. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med (2001) 344:1351–1357.[Abstract/Free Full Text]
  103. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS et al. ACC/AHA guidelines for the evaluation 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 (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). 2001. ACC Web site. Available at: (http:/www.acc.org/clinical/guidelines/failure/hf_index.htm).
  104. Cubeddu L.X., Aranda J., Singh B., et al. A comparison of verapamil and propranolol for the initial treatment of hypertension: racial differences in response. J Am Med Assoc (1986) 256:2214–2221.[Abstract/Free Full Text]
  105. Freudenberger R., Kalman J., Mannino M., Buchholz-Varley C., Ocampo O., Kukin M. Effect of race in the response to metoprolol in patients with congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol (1997) 80:1372–1374.[CrossRef][Web of Science][Medline]
  106. Beta Blockers Evaluation Survival Trial Investigators. A trial of the beta blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med (2001) 334:1659–1667.
  107. Yancy C.W., Fowler M.B., Colucci W.S., et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med (2001) 344:1358–1365.[Abstract/Free Full Text]
  108. Pitt B., Zannad F., Remm W.J., Cody R., Castaigne A., Perez A., et al. for the Randomised Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med (1999) 341:709–717.[Abstract/Free Full Text]
  109. Pitt B., Remme W., Zannad F., Neaton J., Martinez F., Roniker B., et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med (2003) 348:1309–1321.[Abstract/Free Full Text]
  110. Flack J.M., Oparil S., Pratt J.H., et al. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol (2 April 2003) 41(7):1148–1155.[CrossRef]
  111. Campese V.M., Lasseter K.C., Ferrarrio C.M., et al. Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive patients. Hypertension (2001) 38:1342–1348.[Abstract/Free Full Text]
  112. Rouleau J.L., Pfeffer M.A., Stewart D.J., et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet (2000) 356:615–620.[CrossRef][Web of Science][Medline]
  113. Packer M., Califf R.M., Konstam M.A., et al. Comparison of omnapatrilat and enalapril in patients with chronic heart failure: the Omnapatrilat versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE). Circulation (2002) 106:920–926.[Abstract/Free Full Text]
  114. Coats A.J. Omapatrilat–the story of Overture and Octave. Int J Cardiol (2002) 86:1–4.[CrossRef][Web of Science][Medline]
  115. Franciosa J.A., Taylor A.L., Cohn J.N., et al. African-American Heart Failure Trial (A-HeFT): rationale, design and methodology. J Card Fail (2002) 8:128–135.[CrossRef][Web of Science][Medline]
  116. Barakat K., Wells Z., Ramdhany S., Mills P.G., Timmis A.D. Bangladeshi patients present with non-classic features of acute myocardial infarction and are treated less aggressively in east London, UK. Heart (2003) 89:276–279.[Abstract/Free Full Text]
  117. Feder G., Crook A.M., Magee P., Banerjee S., Timmis A.D., Hemingway H. Ethinic differences in invasive management of coronary disease: prospective cohort study of patients undergoing angiography. Brit Med J (2002) 324:511–516.[Abstract/Free Full Text]
  118. Ghali J. Race, ethnicity, and heart failure. J Card Fail (2002) 8:387–389.[CrossRef][Web of Science][Medline]
  119. Davies M.K., Hobbs F.D., Davis R.C., Kenkre J.E., Roalfe A.K., Hare R., et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening Study: a population based study. Lancet (2001) 358:439–444.[CrossRef][Web of Science][Medline]
  120. Morgan S., Smith H., Simpson J., et al. Prevalence and clinical characteristics of left-ventricular systolic dysfunction amongst elderly patients in a general practice setting. Brit Med J (1999) 318:368–372.[Abstract/Free Full Text]
  121. McDonagh T.A., Morrison C.E., Lawrence A., Ford I., Tunstall-Pedoe H., McMurray J.J., et al. Symptomatic and asymptomatic left ventricular systolic dysfunction in an urban population. Lancet (1997) 350:829–833.[CrossRef][Web of Science][Medline]
  122. The SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med (1992) 327:685–691.[Abstract]
  123. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med (1991) 325:293–302.[Abstract]
  124. Pfeffer M.A., Braunwald E., Moyé L.A., et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival And Ventricular Enlargement Trial. N Engl J Med (1992) 327:669–677.[Abstract]
  125. The CONSENSUS Trial Study Group. Effects of Enalapril on mortality in severe congestive heart failure. N Engl J Med (1987) 316:1429–1435.[Abstract]
  126. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
  127. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]

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J D Newton, H M Blackledge, and I B Squire
Ethnicity and variation in prognosis for patients newly hospitalised for heart failure: a matched historical cohort study
Heart, December 1, 2005; 91(12): 1545 - 1550.
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