American Heart Journal
Volume 146, Issue 2 , Pages 203-206, August 2003

Does race matter in heart failure?

  • Clyde W. Yancy, MD

      Affiliations

    • University of Texas Southwestern Medical Center/St Paul University Hospital, Dallas Tex, USA
    • Corresponding Author InformationReprint requests: C. Yancy, MD, UT Southwestern Medical Center, 5323 Harry Hines Blvd, CS7-102, Dallas TX 75390-9047, USA.

Article Outline

 

In this issue of the Journal, Dunlap et al have evaluated a clinically relevant, large single-center heart failure database to further address the natural history of heart failure in African American patients.1 Their analysis suggests that survival rates of African American patients with heart failure are similar to that of Caucasian patients and that perhaps prior observations suggesting a less good survival were overstated.

To be fair, the data used by Dunlap et al are single-center data with uncontrolled treatment algorithms. Hospitalizations, an important marker of disease morbidity, were not included in the analysis. The data are incompletely adjusted because renal function, even when it is only moderately affected, is now known to be an independent marker of outcomes in heart failure, and African American patients, especially those with an antecedent history of hypertension, are at unique risk for renal insufficiency. Also, the use of β-blocker therapy is limited to <5% of the population studied (likely reflecting the time when these data were collected). Finally, the decisions about referral to transplantation are often arbitrary and may not be applied in an equitable manner for African American patients. However, these are important data that reflect on a much larger issue: Does race matter in heart failure?

As noted in the paper by Dunlap, a number of clinical observations on heart failure in African American patients have been made. For African American patients, what appears to be most consistent and reliable are these issues: when affected with heart failure, African American persons are younger, as noted in Dunlap’s study; more advanced left ventricular dysfunction is present in African American patients; the clinical severity is more advanced in African American patients; and the frequency of hospitalization is higher in African American patients.2

The Studies of Left Ventricular Dysfunction (SOLVD) database originally suggested definite mortality disadvantages in the African American group. Even after adjusting for objective markers of socioeconomic factors, especially financial distress and educational level, these differences persisted.3 However, these data were from a post-hoc analysis that did not adjust for ventricular function or for clinical trail (prevention or treatment) participation. The subsequent re-analysis, which controlled for these variables, was only able to identify a weak non-significant trend toward excess mortality. However, a statistically significant difference in hospitalization was persistent.4 Investigators at the University of Texas Southwestern has recently published a re-analysis of the SOLVD Prevention Trial and demonstrated that the benefit of the angiotensin-converting enzyme (ACE) inhibitor enalapril was similar for both groups, but that the rate of heart failure development was higher in the African American cohort.5

Review of other clinical trials has yielded terribly inconsistent findings on outcome and the response to neurohormonal antagonists (Table I). Whereas the Veterans Administration Heart Failure Trial (V-HeFT) I and II6 and the Beta-blocker Evaluation of Survival Trial (BEST)7 yielded data attesting to clinically important differences in outcomes between black and non-black groups, the Carvedilol experience, both the US Carvedilol Heart Failure Trials Program8 and Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial9 demonstrated an absence of difference and perhaps striking efficacy. Identifying outcomes according to race in all the major heart failure trials has been hindered because none of the trials were prospectively designed or powered in an a priori manner to identify differences in this important subgroup. Thus, the practitioner seeing the African American patient is left with an incomplete database, lingering questions about the responsiveness to drug therapy, and, in the most worrisome way, a major concern that the African American patient is at higher risk.

Table I. Clinical trial characteristics
StudyPercent of AADesignInterventionResults
V-HeFT I [6]29%Double-blind RCT; primary end point: mortalityPlacebo vs hydralazine/isosorbide nitrateAnnual mortality rate decreased from 17.9% to 9.7%; P = .04
Background: diuretics and digoxin
V-HeFT II [6]27%Double blind RCT; primary end point: mortalityHydralazine/isosorbide dinitrate vs enalaprilAnnual mortality rate: 12.9% to 12.8%; P = NS
Background: diuretics and digoxin
SOLVD-treatment [3]12%Double blind RCT; primary end point: mortalityPlacebo vs Enalapril in NYHA Class II/III HFNo mortality difference blacks vs non-blacks in a matched population, RE: LVEF and clinical trial participation; RR 0.92 vs. 0.95; higher hospitalization rate for blacks; RR 0.95 vs 0.54; P = 0.005
SOLVD-prevention [5] Double blind RCT; primary end point: mortalityPlacebo vs, Enalapril in NYHA class I/II HFNo difference in the prevention of heart failure using enalapril; statistically significant difference in the incidence of heart failure; RR 1.81; P < 0.001
BEST [7]23%Double blind RCT; primary end point: all cause mortalityPlacebo vs Bucindolol in NYHA Class III and IV; randomization stratified for women and blacksNonsignificant 17% increase in risk of death on bucindolol; P = .27
Background: diuretics, ACE-inhibitors; digoxin at investigator’s discretion
MERIT-HF [2]<5%Double blind RCT; primary end point mortalityPlacebo vs Metoprolol Succinate in NYHA class II/IV; mostly II/IIIInsufficient numbers to ascertain efficacy
U.S. Carvedilol Trials Program [8]20%4 concurrent trials; double blind RCT design; mortality was not a predetermined end pointPlacebo vs Carvedilol in NYHA class II-IV; mostly II/III with protocol participation determined by 6 minute walk time; background: diuretics, ACE-inhibitors and digoxin at investigator’s discretionSimilar efficacy between black and non-black groups; reduction in death for any cause or hospitalization for any cause 48%; reduction in worsening of heart failure 54%
COPERNICUS [9]5%Double blind RCT design; primary end point: all cause mortalityPlacebo vs Carvedilol in NHYA class III/IV; LVEF <0.25 (mean 0.19)Similar efficacy between black and non-black groups despite small number of blacks

To date, all the published data on African American subjects with heart failure have failed to prove in an incontrovertible way that any of the currently accepted guidelines for best practice are harmful or inappropriate for the African American patient. Trepidation about the use of ACE-inhibitors, β-blockers, bypass graft surgery, or cardiac transplantation is unfounded and would be medically inappropriate. The data from Dunlap et al would support the foregoing statement.

The first critical issue is how is race defined? As a self-designation, it becomes much more of a sociopolitical moniker and less a physiologic descriptor. Additionally, the very necessary features of race, intermarriage, and reproduction are decidedly variable in North America, and the perpetuation of the African American race will be noted by more, rather than less, heterogeneity. Yet persons of similar social circumstances and with similar ancestors are more likely to have certain genetic tendencies. This is supported by a number of observations from clinical experience and from the emerging field of genomic medicine. Hypertension is particularly problematic in African American persons. The incidence of end-stage renal disease is between 10- and 20-fold higher; the incidence of hemorrhagic stroke and fatal stroke is higher, the likelihood of left ventricular hypertrophy is 3-fold higher, and even when blood pressure is controlled, the degree of subsequent renal impairment remains higher.10 These findings would suggest that hypertension, which is known to be over-represented in African American patients with heart failure, is a particularly malignant process.

There are early signals that fibrosis may be genetically predestined in a cohort of African American persons. Levels of transforming growth factor Beta-1, a cytokine known to be involved in fibrosis, are highest in African American persons with hypertension.11 A described polymorphism is noted in African American persons that leads to excessive production of transforming growth factor-B-1. Endothelin levels have also been noted to be higher, and atrial natriuretic peptide levels may be lower. Most recently, single nucleotide polymorphisms in Aldosterone synthase and eNOS have been described and could likewise be responsible for an excessive proliferative or fibrotic process.12 Separate observations have been made suggesting a subsensitivity of the renin-angiotensin-aldosterone system and the sympathetic nervous system. Despite having a similar level of left ventricular dysfunction, African American patients with heart failure have lower norepinephrine levels.6 Recently, it became evident that even though African American persons are more likely to have a subsensitive beta-1 receptor polymorphism (ie, the Gly-389 substitution13), those with heart failure are most likely to have the beta-1 receptor polymorphism of increased affinity for norepinephrine in concert with an alpha receptor polymorphism that increases the presence of norpepinephrine in the synaptic cleft.14 This “duality of risk” predisposes them to worse left ventricular dysfunction and a less good clinical course. Table II lists already described polymorphisms , candidate polymorphisms, or both that put the African American patient at risk for cardiovascular disease.

Table II. Candidate polymorphisms that put African American patients at risk for cardiovascular disease
Genetic polymorphismClinical implications
β 1 adrenergic receptor; Gly-389Sub-sensitive β-1-receptor; decreased affinity for agonist and less cAMP generation; [Ref 13]
β 1 adrenergic receptor; ARG-389/alpha 2C Del322-325 receptorPresence of both polymorphisms is associated with increased risk for heart failure in blacks; RR 10.11 when both are present [Ref 14]
eNOSSub-sensitive Nitric Oxide system [Ref 12]
Aldosterone Synthase? Excessive fibrosis [Ref 12]
TGF-β 140% higher TGF Beta 1 levels;? Higher endothelin levels;? More fibrosis [Ref 11]
G Protein 825-T AlleleMarker of low rennin HTN, LVH & stroke [Ref 16]

Without question, all the data from the emerging field of genomic medicine must be evaluated, at best as hypothesis-generating and not definitive. All the published databases are limited by referral bias to the investigating centers, and there is a paucity of data from healthy individuals that happen to be African American, so that the baseline population distribution of these variables is unknown. However, the potential exists within the field of genomic medicine to more precisely define the real risk of cardiovascular disease in African American persons. More importantly, the discovery of definitive genetic platforms that predispose persons to disease will provide probes for the entire population at risk. It is quite likely that the phenotype of “heart failure” in African American patients represents a clustering of genotypes that predispose a more aggressive cardiovascular disease profile.

Much needed efforts are underway to further address these issues of race in cardiovascular medicine. The Jackson Heart Study is an National Institutes of Health-funded “Framingham-like” study of the natural history of cardiovascular disease in African American patients. The Dallas Heart Disease Project, funded by the Reynolds Foundation, is a remarkable effort to define the distribution of risk factors, both clinical and genetic, in a large urban population that includes both African American persons without known cardiovascular disease and a similar concurrent population of patients who are not African American. The United Investigators to Evaluate Heart Failure (UNITE-HF) database takes the single center experience of the current study further and includes the potential for additional genetic analyses in a population of individuals, African American and non-African American, that have been very well described.

The African American Heart Failure Trial (A-HeFT)15 is well underway and is testing the hypothesis that African American persons have a subsensitive nitric oxide system and that the augmentation of nitric oxide homeostasis with a nitric oxide donor/anti-oxidant, Bidil (isosorbide dinitratrate/hydralazine) will improve clinical outcomes when added to a regimen of ACE inhibitors and β-blockers—the latter being present in >75% of enrolled subjects. More than 400 patients have been enrolled, and the study is expected to complete enrollment in 2004, with results to follow after the last patient has experienced an 18-month follow-up. Included in A-HeFT is a genetic analysis, Genetic Risk Assessment in Heart Failure (GRAPH), that will evaluate a number of candidate genetic markers. The A-HeFT trial is a remarkable study for several reasons. It is the first heart failure trial performed only with African American subjects, and thus it has faced a number of unique challenges in recruitment and retention. Also, it is using a composite end point that includes mortality, morbidity, and quality of life as the primary end point—this is a first for a major clinical trial in heart failure.

The totality of the accumulated data and pending data from ongoing studies will hopefully answer the question whether race matters in heart failure. The likely answer will be “yes”; a group of patients do exist that appear to be at particular risk for less good outcomes. Currently this group shares the same racial designation, a grouping that is overtly crude and completely arbitrary. What will hopefully emerge, however, are the exact clinical and genetic descriptors of race that will supercede something as nebulous as skin color and address the more compelling and appropriate physiological traits that put all persons at risk for heart failure.

This exercise of defining cardiovascular disease according to race is important not because of a need for inclusiveness, but because of appropriate concerns that a group exists that is at peculiar risk. If these discussions stop at the current level of understanding, the risk exists to dispense care along poorly defined racial lines and thus would be a disservice. Rather, we need to complete this database, discover what makes heart failure so pervasive in our society, and be certain that effective medical therapy is instituted for all persons with heart failure.

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References 

  1. Dunlap SH, Mallemala S, Sueta CA, et al. Survival rates are similar between African American and white patients with heart failure. Am Heart J 2003;146:265–72
  2. Yancy CW. Heart failure in African Americans (a cardiovascular enigma). J Card Fail. 2000;6:183–186
  3. Dries DL, Exner DV, Gersh BJ, et al.  Racial differences in the outcome of left ventricular dysfunction. N Engl J Med. 1999;341:298
  4. Exner DV, Dries DL, Domanski MJ, et al.  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
  5. Dries DL, Strong MH, Cooper RS, et al.  Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol. 2002;40:311–317
  6. Carson P, Ziesche S, Johnson G, et al.  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
  7. The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659–1667
  8. Yancy CW, Fowler MB, Colucci WS, et al.  Race and the response to adrenergic blockade with carvedilol in patients with heart failure. N Engl J Med. 2001;344:1358–1365
  9. Carson P, Fowler MB, Mohacsi P, et al.  Effect of carvedilol in black patients with severe heart failure (results of the COPERNICUS Study). [abstract] Circulation. 2001;104:II-754
  10. Saunders E. Hypertension in minorities: blacks. Am J Hypertens 1995;8:115–9S
  11. August P. TGF Beta-1 overexpressed in African American hypertensives. Proc Natl Acad Sci U S A. 2000;97:3479–3484
  12. McNamara DM, Dennis M, Hollubkov R, et al.  Genetic risk assessment of cardiac events, GRACE. Circulation. 2001;103:1644
  13. Mason DA, Moore JD, Green SA, et al.  A gain of function polymorphism in a G-protein coupling domain of the human beta-1 adrenergic receptor. J Biol Chem. 1999;274:12670–12674
  14. Small KM, Wagoner LE, Levin AM, et al.  Synergistic polymorphisms of beta 1 and alpha 2C adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002;347:1135–1142
  15. Franciosa JA, Taylor AL, Cohn JN, et al.  African American Heart Failure Trial (A-HeFT) (rationale, design, and methodology). J Card Fail. 2002;8:128–135

PII: S0002-8703(03)00241-2

doi:10.1016/S0002-8703(03)00241-2

American Heart Journal
Volume 146, Issue 2 , Pages 203-206, August 2003

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