Clinical and genetic modifiers of long-term survival in heart failure

Abstract

Objectives: This study sought to identify genetic modifiers of beta-blocker response and long-term survival in heart failure (HF).

Background: Differences in beta-blocker treatment effect between Caucasians and African Americans with HF have been reported.

Methods: This was a prospective cohort study of 2,460 patients (711 African American, 1,749 Caucasian) enrolled between 1999 and 2007; 2,039 patients (81.7%) were treated with a beta-blocker. Each was genotyped for beta1-adrenergic receptor (ADRB1) Arg389>Gly and G-protein receptor kinase 5 (GRK5) Gln41>Leu polymorphisms, which are more prevalent among African Americans than Caucasians. The primary end point was survival time from HF onset.

Results: There were 765 deaths during follow-up (median 46 months). beta-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking beta-blockers, ADRB1 Gly389 was associated with decreased survival in Caucasians (hazard ratio [HR]: 1.98, 95% confidence interval [CI]: 1.1 to 3.7, p = 0.03) whereas GRK5 Leu41 was associated with improved survival in African Americans (HR: 0.325, CI: 0.133 to 0.796, p = 0.01). African Americans with ADRB1 Gly389Gly GRK5 Gln41Gln derived a similar survival benefit from beta-blocker therapy (HR: 0.385, 95% CI: 0.182 to 0.813, p = 0.012) as Caucasians with the same genotype (HR: 0.529, 95% CI: 0.326 to 0.858, p = 0.0098).

Conclusions: These data show that differences caused by beta-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the beta-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.

Figure 1

Kaplan-Meier Curves of β-blocker treatment effect on heart failure survival A. Combined heart failure cohort, stratified by β-blocker usage (top inset, Caucasian Americans; bottom inset, African Americans). Solid line, β-blocker untreated; dashed line, β-blocker treated. B. Survival of β-blocker untreated heart failure subjects, stratified by race. C. Survival of β-blocker treated heart failure subjects, stratified by race. Solid line, Caucasian; dashed line, African American.

Figure 2

Kaplan-Meier Curves of ADRB1 Arg/Gly 389 effect on heart failure survival A. β-blocker untreated subjects stratified by ADRB1 389Gly carrier status (top inset, Caucasian Americans; bottom inset, African Americans). B. β-blocker treated subjects stratified by ADRB1 389Gly carrier status (top inset, Caucasian Americans; bottom inset, African Americans). Solid line, Arg/Arg 389; dashed line, Gly 389 carriers.

Figure 3

Kaplan-Meier Curves of GRK5 Gln/Leu 41 effect on heart failure survival. A. β-blocker untreated subjects stratified by GRK5 41Leu carrier status (top inset, Caucasian Americans; bottom inset, African Americans). B. β-blocker treated subjects stratified by GRK5 41Leu carrier status (top inset, Caucasian Americans; bottom inset, African Americans). Solid line, Gln/Gln 41; dashed line, Leu 41 carriers.

Figure 4

Kaplan-Meier Curves of β-blocker treatment effect on heart failure survival in subjects matched for ADRB1 Gly 389 and GRK5 Gln 41 homozygous genotype. A. Combined heart failure cohort, stratified by β-blocker usage (top inset, Caucasian Americans; bottom inset, African Americans). Solid line, β-blocker untreated; dashed line, β-blocker treated. B. Survival of β-blocker untreated heart failure subjects, stratified by race. C. Survival of β-blocker treated heart failure subjects, stratified by race. Solid line, Caucasian; dashed line, African American.