The Natural History, Epidemiology, and Prognosis of HF
Heart failure is more common in African Americans and appears to be of worse severity. At the time of diagnosis, left ventricular function is more severely impaired and the clinical class is more advanced. The strongest risk factor for heart failure in African Americans appears to be hypertension, which is both more prevalent and more pathologic in African Americans. It is likely that heart failure represents an important end organ effect of hypertension. When affected by heart failure, African Americans experience a greater rate of hospitalization and may be exposed to a higher mortality risk as well. Genomic medicine has yielded a number of candidate single nucleotide polymorphisms that might contribute to the excess pathogenicity of heart failure in African Americans, but much more work needs to be done in larger cohorts. Effective therapy of heart failure must start with the recognition of the different manifestations of heart failure in African Americans. An increased awareness of the risk of hypertension followed by early and effective intervention may reduce the risk of heart failure in this population.

Cardiovascular morbidity and mortality is highest in African-American males while African-American females have a cardiovascular morbidity and mortality risk that is similar to that of white males. White females continue to enjoy the lowest morbidity/mortality risks due to cardiovascular disease. Given the lower rates of documented ischemic heart disease in the African-American population, this higher risk of cardiovascular disease and its consequences appears to be due to hypertensive heart disease and its sequelae, most notably left ventricular (LV) hypertrophy, LV dysfunction, and ultimately, heart failure. Heart failure affects 3% of the African-American population, which compares to only a 2% incidence in the general population. This would suggest a nearly 50% higher incidence of heart failure in African Americans but this also includes a nearly two-fold increase in risk for African-American women. Thus, heart failure in African Americans is a compelling public health problem ( Table 1 ).

The fundamental question in this discussion is "What is an African American?" The intent of this designation is to describe persons with African ancestral lines that have been admixed with European influences in North America and exposed to a Western lifestyle. This designation is less focused on physiological or biological variances and more likely representative of sociopolitical designations that reflect a complex interplay of social, political, environmental, and, to an uncertain extent, biological factors. For a race to be genetically distinct there must necessarily be within-race reproduction patterns that perpetuate genetic variances. These patterns are becoming less prevalent in contemporary society. The resulting heterogeneity of the African-American race would seem to greatly reduce the likelihood of any universally consistent pattern of inheritance yielding a genetic/biological profile that is highly variable within the African-American population. Thus, any traits ascribed to African Americans must be carefully reviewed and cannot be assumed to be universally applicable.

Any review of the medical literature focusing on ethnic/racial differences in cardiovascular disease is necessarily compromised by problems inherent in post hoc analyses of outcomes within subgroups for which the original clinical trials were not statistically powered to demonstrate. It is therefore implicit that certain presumptions and conclusions about racial differences in cardiovascular disease expression and/or response to medical therapy be interpreted cautiously, as more rigorously obtained data may yield different results.

Despite the lack of prospectively acquired data, quite a bit of information on the natural history of heart failure has been accumulated from major published trials. A review of the vasodilator heart failure trials (Vasodilator Heart Failure Trial [V-HeFT I] and Second Vasodilator Heart Failure Trial [V-HeFT II]), the angiotensin-converting enzyme inhibitor trials (Studies of Left Ventricular Dysfunction [SOLVD] Registry and SOLVD Prevention and Treatment Trials), and the β adrenergic receptor blocker trials (Beta Blocker Evaluation of Survival Trial [BEST], US Carvedilol Trials Program, Carvedilol Prospective Randomized Cumulative Survival Trial [COPERNICUS], and Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERITHF]) yields an aggregate of nearly 3000 well described African-American patients with heart failure. There is an intriguing consistency in the data.

The SOLVD Registry was the first trial to demonstrate a significant difference in the putative etiology of LV dysfunction in African Americans with heart failure. Within the African-American patients, 32% appeared to have hypertension as the sole plausible cause of LV dysfunction as compared with only 4% of white patients in the SOLVD Registry. This finding has since been corroborated in all major published trials. A history of hypertension appears to be present in >50% of all African Americans in the major trials. Documented ischemic heart disease as a cause of heart failure occurs less frequently in the African American patient, an observation that was also initially put forward by analysis of the SOLVD Registry. When defined as a prior documented myocardial infarction or known epicardial coronary artery disease, ischemic heart disease appears to be present in approximately 35% of African-American patients with heart failure—a rate that is about half of that seen in white patients with heart failure. It is thus evident that a nonischemic etiology is responsible for heart failure in ≈65% of African Americans. The exact mix of hypertensive heart disease and idiopathic dilated cardiomyopathy (as well as the influence of alcoholic cardiomyopathy) is not discernible from published data. Therefore, the contribution of hypertensive heart disease as the sole explanation of LV dysfunction is likely to be between the 30% range reported in the SOLVD registry or the >50% incidence suspected in recently reported β-blocker trials (Figure 1).



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Heart failure in African Americans: incidence of coronary artery disease. Pooled data from major trials in heart failure reporting probable cause of left ventricular systolic dysfunction; US Carv=US Carvedilol Heart Failure Trials Program; BEST=β Blocker Evaluation of Survival Trial; AA=African American; non-AA=non-African American; other trial acronyms are expanded in the text





It is important to note that given a nearly 40% incidence of typical ischemic heart disease as a cause of heart failure in African-Americans, a practitioner would be remiss and in error to ignore a search for ischemic heart disease in African-American patients with heart failure.

A number of published trials have also consistently reported that the African-American patients within the trials are consistently younger, have more advanced LV dysfunction at the time of presentation, and have a more advanced clinical class. This advanced disease severity was particularly evident in the BEST trial and may have, in part, been the reason for less than robust outcomes within this patient group. These peculiar observations are perhaps due to the deleterious consequences of hypertension within an African-American patient. Hypertension is known to affect African Americans at a higher frequency, is associated with a higher incidence of stroke, especially hemorrhagic, and a strikingly higher incidence of end-stage renal disease, perhaps as much as 15- to 18-fold higher. The development of LV hypertrophy is three times more likely in the African-American patient, and the pattern of LV hypertropy is one known to be associated with adverse clinical events. Thus, it is quite plausible that in certain African Americans with hypertension there is a much more malignant vascular response that results in much more aggressive end-organ disease ( Table 2 ).

The plausible explanations for these observations are both frustrating and fascinating. No unifying proven hypothesis has yet been put forward to account for the malignant pathophysiology of hypertension in the African-American patient. However, there are newly emerging observations from genomic medicine that are ripe targets for future investigation and may perhaps identify a "hypertension–heart failure genotype" that will largely describe the variances in the natural history, epidemiology, prognosis, and response to medical therapy for heart failure seen in some African Americans.

Several candidate genomic markers have been described and include a G protein polymorphism seen in the 825T allele, which has been shown to be overexpressed in persons of African descent and is associated with hypertension and renal disease; a single nucleotide polymorphism of the transforming growth factor (TGF)-β gene that results in 40% higher levels of TGF β-1 and stimulation of mRNA for Endothelin-1; a 389Gly substituted β-1 receptor that may result in an impaired response to β-adrenergic stimulation and/or β-adrenergic receptor antagonism; and a recently described dual adrenergic receptor polymorphism affecting both the β-1 and α receptors, the results of which is a more robust release of norepinephrine from the presynaptic cleft (α receptor mediated), a more avid sensitivity for norepinephrine, and the induction of adenyl cyclase activity (β-1 receptor mediated).

The TGF-β-1 model is particularly attractive as TGF-β-1 is an inflammatory cytokine associated with increased extracellular matrix turnover and fibrosis. It is known to be associated with the development of end-stage renal disease, that is, glomerular hypertrophy, and LV hypertrophy. TGF-β-1 levels have been found to be strikingly elevated in African Americans with hypertension, and the subsequent stimulation of mRNA for Endothelin-1 leads to excess production of one of the most potent pressor substances in the cardiovascular system. Endothelin may be particularly problematic in the setting of salt-sensitive hypertension. Of note, in salt-sensitive hypertensive animals prone to the development of LV hypertrophy, endothelin appears to be associated with the conversion from LV hypertrophy to LV dysfunction and heart failure. Whether or not this hypothesis is operative in African Americans or others with salt-sensitive hypertensive heart disease has not been proven but perhaps merits future investigation. An impaired vasodilatory response to known vasodilators has been demonstrated in African Americans with hypertension. Measured forearm blood flow after regional stimulation with either nitroprusside or methacholine results in a reduced increase in forearm blood flow when compared with hypertensive white patients. The blunting of responsiveness to a direct NO donor (nitroprusside) or an indirect donor (methocholine) would suggest a defect in both endothelium dependent and independent vasodilatory mechanisms (Figure 2). Whether this is a reduction in synthesis of NO, that is, impaired activity of iNOS, or a reduction in the responsiveness to NO is not yet clear. It is interesting that the use of an NO donor in African Americans with heart failure has been demonstrated in the V-HeFT trials to be as effective as angiotensin-converting enzyme inhibitor therapy. This hypothesis is being tested in a prospective way in the ongoing African American Heart Failure Trial (A-HeFT). Within A-HeFT, the Genetic Risk Assessment of Heart Failure in African Americans (GRAHF) trial is being conducted as a dedicated genetic survey of a subset of the expected 1200 patients within the trial to determine whether or not candidate genes that may be responsible for accelerated LV dysfunction are over-expressed in African Americans.



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Heart failure in African Americans: incidence of hypertension. Pooled data from major trials in heart failure reporting probable cause of left ventricular systolic dysfunction; US Carv=US Carvedilol Heart Failure Trials Program; BEST=β Blocker Evolution of Survival Trial AA=African American; non-AA=non-African American; other trial acronyms are expanded in the text





There are other potential pathobiological markers of cardiovascular disease seen in African Americans, such as NO synthase, aldosterone synthase, and I/D polymorphisms of angiotensin II. However, no single marker has yet emerged as the responsible genetic marker of excessive LV dysfunction in the African-American population. It is likely that a genetic profile that is multifaceted will emerge as the best marker. The inherent heterogeneity of this racial group continues to frustrate genetic discoveries.

The prognosis of heart failure when it affects the African-American patient has been debatable. Originally, data from the SOLVD trial demonstrated that mortality due to heart failure was increased in African Americans, perhaps as much as 1.5 times higher in African-American men and nearly two-fold higher in African-American women. A more recent re-analysis of an admittedly lower-risk cohort of the SOLVD prevention and treatment trials, but one in which African-American and white patients were matched for LV dysfunction and trial participation, did not yield a significant difference in mortality. However, a substantial difference in hospitalizations was seen in those patients treated with enalapril (Figure 3). Perhaps the most valuable observation from the SOLVD database was the objective description of socioeconomic status in the trial participants. The investigators used an educational level of < 8th grade or > 12th grade as well as indices of financial stress as objective markers of socioeconomic status. The expected differences in educational level and financial distress were observed; however, after controlling for these variables, a persistent difference in mortality and morbidity was still seen suggesting a worse prognosis for the African-American patients. The SOLVD investigators were unable to explain differences in outcome due to socioeconomic factors—an explanation that would have been all too easy to embrace. These findings suggest that, indeed, certain physiological nuances may exist within the population of African Americans with heart failure, and thus, further study is required.



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Vasodilator reserve in hypertension. Comparison of forearm vasodilation in response to either nitroprusside (endothelium independent nitric oxide [NO] donor) or methacholine (endothelium dependent NO donor); in both models the resultant forearm vasodilatory response is impaired in African-American patients suggesting both impaired production of NO and reduced sensitivity to NO. Adapted from Clin Pharmacol Ther. 1997;62:436-443.[12]





It is important for practitioners to be aware that differences do exist in disease expression of heart failure in African Americans and variances in outcomes may likewise exist. Practitioners should be aware of the deleterious consequences of hypertension in this patient population while recognizing the need to be complete in any search for causes of LV dysfunction. Given the differing epidemiology of heart failure in African Americans, it would seem reasonable to consider an African-American patient with heart failure as a "higher risk" heart failure patient and to thus employ the best available treatment strategies for that patient. The emerging field of genomic medicine may help to further define the genotype of heart failure that is currently ascribed to African Americans, a population known to be diverse and truly heterogeneous.

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