Is Heart Failure in African Americans a Distinct Entity?

Robert L. Scott, MD, PhD

Disclosures

CHF. 2003;9(4) 

Abstract and Introduction

Heart failure remains a major health problem in the United States and is particularly problematic in the African American community where the disease exhibits excessive morbidity and mortality. Hypertension is a predominant etiology for heart failure among African Americans with an aggressive incidence of end-organ damage. Despite the advances in treatment of heart failure with neurohormonal attenuation, there appears to be inconsistency in the response of African Americans compared to Caucasians. This discordance with regard to response to treatment and etiology of heart failure between African Americans and Caucasians begets the question whether heart failure in African Americans is indeed a distinct clinical entity.

Mortality from heart failure is 2.5-times greater among African Americans compared to Caucasians <65 years of age.[1] African Americans develop heart failure at an earlier age and the hospitalization rates are substantially higher than those among Caucasians.[2,3] The reason for the worse morbidity and mortality in African American heart failure patients is unclear, thus begetting the question of whether heart failure in African Americans is truly a distinct clinical entity. In order to answer this question one must consider not only the etiology of heart failure but also the relative response to conventional heart failure therapy and participation in heart failure trials from which the evidence-based data are collated.

Although there are multiple etiologies for heart failure, the predominant factor in the United States is coronary artery disease. However, in African Americans the relative prevalence of hypertension as an attributable etiology of heart failure is substantially higher than among Caucasians ( Table 1 ). Also the severity of hypertension as well as associated end-organ damage such as end-stage renal disease, left ventricular hypertrophy, and coronary artery disease is comparatively worse in African Americans than in the general population.[3] Many investigators have demonstrated racial differences in the relative efficacy of various antihypertensive agents.[4,5] The renin angiotensin system would appear to play a lesser role in the maintenance of blood pressure in African Americans compared to Caucasians. This fact is partially attributed to lower plasma renin levels as well as more hypervolemia noted in African American hypertensive patients. Blood pressure lowering with angiotensin-converting enzyme (ACE) inhibitors may require higher doses in African Americans, but this should by no means preclude their use for both their renal-protective and endothelial enhancement effects. This is paramount given the results of the Heart Outcomes Prevention Evaluation (HOPE) trial[6] in which patients with known vascular disease demonstrated a reduction in cardiac events as well as the development of diabetes when treated with an ACE inhibitor.[6]

Many investigators have shown the use of β-adrenergic blocking agents (β blockers) to be less effective anti-hypertensive agents in African Americans than Caucasians.[3] This may be attributed to the fact that the adrenergic nervous system is not as critical in mediating blood pressure in African Americans as it is in other ethnic groups. Although β blockers are less effective antihypertensive agents in African Americans, there are clearly patient populations that benefit from β blocker therapy regardless of race. Patients who have suffered a myocardial infarction demonstrate improvements in both short-term and long-term mortality when treated with β blocker therapy irrespective of race.[7,8]

The angiotensin receptor blockers are a new class of agents that have demonstrated good clinical efficacy in blood pressure lowering in both African Americans and Caucasians.[9] Direct blockage of the angiotensin II receptor attenuates toxicity of angiotensin II generated by non-ACE pathways. The angiotensin receptor blockers have also demonstrated clinical benefits independent of blood pressure lowering such as enhancement of endothelial function and reductions in proteinuria.[10] In the recently presented Valsartan Heart Failure Trial (Val-HeFT),[11] there was a significant reduction in the combined end point of all-cause mortality and morbidity in heart failure patients treated with the combination of an angiotensin receptor blocker (valsartan) with an ACE inhibitor compared to ACE inhibitor-based therapy alone.[11]

While it is clear that proportionately more heart failure in African Americans is related to hypertension, this does not explain the worse clinical outcomes compared with similarly treated non-African American patients. In the Studies of Left Ventricular Dysfunction (SOLVD)-Treatment and SOLVD-Prevention trials,[12] African American heart failure patients treated with enalapril had significantly higher rates of total mortality, death from worsening heart failure, and the combined end point of stroke or pulmonary embolism. In fact, when one corrects for comorbidities as well as socioeconomic variables, the differences between African American and Caucasian patients treated with ACE inhibitors still persist. While this disparity suggests ACE inhibitor may be less effective in African Americans, it remains the standard of care and should be used in all heart failure patients when indicated.

In the Vasodilator-Heart Failure Trial (V-HeFT I)[13] African American patients randomized to hydralazineisosorbide showed a reduction in mortality compared to patients maintained on digoxin and diuretic therapy. This was particularly intriguing given that no benefit was noted in similarly treated non-African American patients. In the V-Heft II trial[13] heart failure patients were treated with isosorbide-hydralazine versus enalapril without a true placebo group. There was a significant improvement in mortality in Caucasian patients treated with enalapril compared to isosorbidehydralazine which was not noted in similarly treated African American patients. One can postulate that the improvement in African American heart failure patients treated with vasodilator therapy (isosorbide-hydralazine) compared to neurohormonal attenuation (enalapril) is due to a favorable hemodynamic modification not seen in Caucasian patients.

In the recently completed Beta Blocker Evaluation Survival Trial (BEST),[14] New York Heart Association class III/IV patients were treated with the non-selective blocker bucindolol in addition to ACE inhibitor-based therapy vs. ACE inhibitor-based therapy alone. The African Americans treated with bucindolol demonstrated a trend toward higher mortality than those on ACE inhibitor therapy. Collectively, there was a reduction in hospitalizations for heart failure, but no reduction in total mortality. However, if one looks only at the non-black patients, there was a mortality reduction. The reason for the divergent outcomes between the black and non-African American patients is unclear. Bucindolol has been shown to exhibit intrinsic sympathomimetic activity in animal systems; however, this has not been the case in human myocardium.[15] There are inconsistent data as to whether heterogeneity in either the β2 or α2 receptors are modulators of hypertension in humans.[16,17] Since stimulation of the β2 receptor results in vasodilatation, polymorphism at the receptor may in fact confer variable sensitivity to adrenergic stimulation. It is conceivable that variable levels of adrenergic suppression mediated from the β receptor may explain the trend toward an adverse outcome in the African American patients treated with bucindolol. The poor clinical response noted in African American patients in the BEST trial is likely a manifestation of bucindolol in particular and not β blockers in general.

The recently presented Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study[23] showed comparable reductions in total mortality and the combined end point of mortality and hospitalizations for worsening heart failure between African American and Caucasian patients with severe heart failure treated with carvedilol. The United States Carvedilol trial[19,24] also noted comparable improvements in mortality and hospitalization for heart failure between African American and Caucasian heart failure patients treated with carvedilol. There was a trend toward similar improvements in mortality in African American patients treated with metoprolol-XL/CR in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) Trial.[25] Unfortunately, the small number of African Americans in MERIT-HF likely explains the lack of demonstrable benefit.

Without question, in essentially all of the systolic heart failure trials representation of African Americans is inexcusably poor ( Table 2 ). In fact, the same poor representation also exists for females in heart failure trials. This is problematic in that clinicians are forced to extrapolate the response of white males to the general population. The reasons for the marginal inclusion of African Americans are numerous and include the following: investigator bias, lack of patient education, patient mistrust toward medical institutions, and lack of patient access to medical systems. It is the duty of investigators to include all segments of the population in clinical trials, particularly African Americans and women.

On the horizon, the upcoming African American Heart Failure Trial (A-HeFT)[26] will randomize African American systolic heart failure patients to standard ACE inhibitor-based therapy vs. the addition of hydralazine-isosorbide. This is particularly intriguing when one considers the survival benefit noted in African American patients in V-HeFT I. Until there are systolic heart failure trials that adequately reflect all of society, the treatment of heart failure should not differ with regard to race or sex.

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