The US population is characterized by significant racial/ethnic demographic transitions with an emerging number of special populations at risk for cardiovascular disease. Amongst the special populations with heart disease, it is heart failure in African-Americans that has become the prototypical model.
Heart Failure: An Enigmatic Disease in African-Americans
Chronic heart failure is no longer a fatal diagnosis. Rather, it is a treatable disease entity with significant improvements in morbidity and mortality expected from the best application of evidence-based treatment strategies. However, a critical review of clinical trials in heart failure questions whether or not African-Americans with heart failure are able to realize these significant improvements in outcomes. This concern is, in part, driven by the inconsistent representation of African-Americans in cardiovascular clinical trials, and is further complicated by the limitations of retrospective subgroup analyses of underrepresented subgroups. Despite these important provisos, lessons have been learned from the clinical trials that define heart failure in African-Americans.
African-Americans have a higher prevalence of heart failure compared with white Americans (3% versus 2%). When heart failure occurs in African-Americans, it has an enigmatic natural history. The disease occurs at an earlier age, and both the degree of left ventricular (LV) dysfunction and apparent disease severity are worse at the time of diagnosis. Hospitalization rates are higher in African-Americans, and concerns regarding decreased survival rates have not been resolved. The imputed etiology of LV dysfunction in African-Americans is more likely to be non-ischemic than in white Americans. As seen in Figure 1, there is a lower likelihood of documented ischemic heart disease as the putative cause of LV dysfunction and a greater likelihood of non-ischemic, principally hypertensive, disease as the sole potential explanation for LV dysfunction.
A number of plausible explanations for excess heart failure in African-Americans have been proposed, with no single proven causative theory. The psychosocial burdens of the African-American culture are easily recognizable and undoubtedly important, and no discussion about cardiovascular health and outcomes in African-Americans can be complete without acknowledging that healthcare disparities do exist. The deleterious influence of malignant hypertension and the burden of obesity and diabetic disease cannot be overlooked. Genomic medicine has much potential to uncover these important subgroup issues but is also quite incipient and remains problematic in interpretation.
What Clinical Trials Tell Us About Heart Failure in African-Americans
A number of major published trials have reported data as a function of race.A post hoc analysis of the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial results demonstrated that mortality from heart failure was higher in African-Americans, with a 1.8-fold increase for African-American men and a 2.4-fold increase for African-American women. A subsequent re-analysis that adjusted for the degree of LV dysfunction and for trial participation (i.e. SOLVD prevention or SOLVD treatment trial) yielded no differences in mortality, but showed a significantly higher risk (44%) for hospitalization in the African-American patients compared with white patients. A suggested explanation for these findings was an apparent lower responsiveness to angiotensin-converting enzyme (ACE) inhibitors consistent with a broad statement that ACE inhibitors are less effective in African-Americans.
Conflicting data points have emerged from the clinical trial experience with β-blockers. A recent RAND Corporation meta-analysis incorporated data reported by race from the major published β-blocker trials in heart failure. Whereas the aggregate benefit of β-blockers for white Americans was a 31% reduction in mortality, the apparent benefit of β-blockers in African-Americans was only a 3% reduction. These unfavorable data are heavily influenced by the negative outcomes from the Beta-blocker Evaluation of Survival Trial (BEST). However, the experience with carvedilol varies substantially from the observations seen with bucindolol. In both the US Carvedilol Heart Failure Trials program and the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), retrospective analyses by ethnicity showed statistically significant benefits with carvedilol. A summary of major clinical trials in heart failure that reported data as a function of race can be found in Table 1.
The clinical trial experience that has prompted the most intrigue in this arena is the original Vasodilator Heart Failure Trials (V-HeFT I and II).Within V-HeFT I, 180 patients were African-American. A post hoc retrospective analysis of V-HeFT I yielded the striking finding that the benefit of isosorbide dinitrate/hydralazine (ISDN/HYD) when added to diuretics and digoxin in African-American patients with heart failure resulted in a nearly incredulous 47% mortality advantage (see Figure 2). A similar retrospective analysis of V-HeFT II (ACE-inhibitor therapy versus ISDN/HYD) identified that the white patients responded better to an ACE inhibitor than to ISDN/HYD, while the African-American patients responded similarly to an ACE inhibitor or vasodilator regimen. These findings would suggest that, within the subgroup of African-Americans, a more robust response to ISDN/HYD was evident.
It is now apparent that the combination of ISDN and HYD represents more than a balanced vasodilating regimen. ISDN is a nitric oxide (NO) donor, and HYD has important antioxidant properties. NO plays an important role in the stabilization of vascular endothelium, and a deficient state of NO may lead to cardiovascular disease.
NO, originally named 'endothelium-derived relaxation factor', is fairly ubiquitous, with functions that include vasodilation, neurotransmission, and elimination of pathogens. It is produced by endothelial cells from a family of oxidoreductases that bear close homology to the cytochrome P450 system of enzymes.
Three 'synthases' have been identified: NO synthase 1 (NOS 1/neuronal NOS/nNOS), NOS 2 (inducible NOS/iNOS) and NOS 3 (endothelial NOS/eNOS). NOS 3 is activated by agonists acting on G-protein-coupled receptors (GPCRs) and by shear forces and changes in oxygen (O2) delivery. L-arginine and oxygen serve as substrates for NOS, while nicotinamide adenine dinucleotide phosphate (NADPH) serves as one of several co-factors. The by-product of NO synthesis is L-citrulline and NADP+. NO produces vasodilation by activating soluble guanylate cyclase (sGC) with subsequent production of cyclic guanosine monophosphate (cGMP) (see Figure 3).
NO influences organ function by its post-translational effects on effector molecules. This occurs most often at cysteine residues and is termed S-nitrosylation. S-nitrosylation of ion channels within the heart maintains normal calcium flux, which is important in systolic and diastolic function.
Superoxide (O2-) facilitates S-nitrosylation at physiological levels, but disrupts S-nitrosylation at pathological levels. It does so by targeting the same cysteine residues as NO and prevents S-nitrosylation from occurring. Pathological levels of O2- will also react with NO and lead to the production of peroxynitrite (ONOO-). This process of excess O2- production and disruption of S-nitrosylation is characteristic of oxidative stress. The balance between the effects of NO and O2- has been termed the 'nitroso-redox balance' (see Figure 4). If this balance is inclined towards low NO and excess O2-, cell injury may ensue.
African-Americans have demonstrable evidence of diminished NO bioavailability and enhanced production of ONOO-. It is plausible, but not yet proven, that the progression of cardiovascular disease, particularly heart failure, in African-Americans might be a result of not only an activated neurohormonal system, but also a deficient endogenous vasodilator/growth-inhibiting system. If this is a valid hypothesis, an adjunctive approach in the management of heart failure in African-Americans might be an increase in NO bioavailability along with a decrease in oxidant stress in a background consisting of traditional neurohormonal blockade. These issues may have direct bearing on the results of the African-American Heart Failure Trial (A-HeFT).
A-HeFT tested the hypothesis that the vasodilatory combination of ISDN and HYD given as adjunctive therapy to African-Americans with heart failure would be of benefit. One thousand fifty African-Americans with predominantly New York Heart Association (NYHA) class III heart failure were randomized in a double-blind placebo-controlled fashion to a fixed-dose combination of ISDN and HYD versus placebo in the setting of contemporary medical therapy for heart failure. The primary end-point was a composite of all-cause mortality, time to first hospitalization for heart failure and quality of life.
Inclusion criteria for this trial were LV dysfunction with a measured ejection fraction of 35% or less, or 45% or less with an LV internal dimension in diastole of 6.5cm or more, clinical stability on an evidence-based medical regimen, and heart failure disease severity of NYHA class III or IV. The usual exclusionary criteria applied, e.g. pregnancy, recent acute coronary syndromes, atypical causes of heart failure, and presence of other life-threatening illnesses.
Patients were treated with a fixed-dose combination tablet of ISDN 20mg/HYD 37.5mg given as one or two tablets three times daily. The target dose was ISDN 120mg and HYD 225mg daily. Follow-up was for up to 18 months with periodic assessment of LV size and function, B-type natriuretic peptide, and quality of life, along with assessment for the primary events. The study was terminated early due to a survival benefit of active therapy on the recommendation of an independent data safety and monitoring board.
The patient characteristics are noted in Table 2. Background therapy in this trial was consistent with contemporary evidence-based therapy for heart failure-renin-angiotensin system blockade was present in 87%. β-blockers were present in 77% of all patients.
The target dose of ISDN/HYD was achieved in 68% of the subjects. The mean dose of ISDN was 88mg once-daily and the mean dose of HYD was slightly less than 200mg once-daily. Adverse effects of therapy included headaches (47%) and dizziness (29.3%), but headaches of the severity to require discontinuation of study drug only occurred in 7% of cases. There was only one adjudicated case of lupus, but the incidence of joint pain was higher in those on study drug compared with placebo.
The results demonstrated a statistically significant reduction in the primary composite score consistent with a favorable effect of therapy. The individual components of the composite were also positive. All-cause mortality was reduced by 43%, time to first hospitalization was reduced by 39%, and the quality of life scores reflected an improvement in quality of life.
The implications of these findings are noteworthy. The mortality rate in the placebo-treated patients was approximately 10% - roughly consistent with what would have been expected for this disease severity on standard therapy for heart failure. To achieve a further 43% reduction in the risk of death accentuates the unique benefit of ISDN/HYD in combination with standard medical therapy in this patient cohort. When interpreted in the context of the 47% mortality advantage seen in V-HeFT I, the similarity of benefit irrespective of background therapy (i.e. 47% when background therapy is digoxin and diuretics versus 43% when background therapy is diuretics, ACE inhibitors, and β-blockers) would implicate a novel mechanism of action that is not otherwise modulated by standard therapies. It is tempting to consider enhanced NO availability as the imputed mechanism of action that is operative, but it is important to emphasize that A-HeFT is not a proof-of-concept trial for the efficacy of enhancing NO bioavailability. This, however, represents an important new direction in cardiovascular research, as does identifying the potential benefit of ISDN/HYD in a broader patient population.
Heart failure in African-Americans is likely to be a unique disease entity. Its natural history, epidemiology, and disease outcomes vary from heart failure in white patients. The influence of hypertension is inescapable and carries with it important public health concerns for more proactive disease prevention through effective treatment. The data regarding responsiveness to contemporary evidence-based medical therapy are inconsistent, but there are no data to support avoidance of evidence-based standard therapy, specifically ACE inhibitors and β-blockers.
On-going efforts to explain the excess cardiovascular disease burden in African-Americans have targeted mechanisms that lead to more malignant varieties of hypertension and genetic profiles that might predispose patients to more advanced LV dysfunction and/or lower responsiveness to medical therapy. The newest theory focuses on endothelial homeostasis with diminished NO bioavailability as the primary variable. The vasodilating regimen of ISDN and HYD has been identified as one that potentially increases NO bioavailability. A-HeFT tested the benefit of a fixed-dose combination of ISDN/HYD in a group of patients self-identified as African-American with class 3 heart failure already on appropriate medical therapy. The striking findings of an additional 43% improvement in mortality, 39% decrement in time to first hospitalization and improved quality of life represent landmark data that are likely to redefine the state of the art for heart failure in African-Americans.