Genomic variation and neurohormonal intervention in heart failure

Abstract

Neurohormonal activation is an important driver of heart-failure progression, and all pharmacologic interventions that improve heart-failure survival inhibit this systemic response to myocardial injury. Adrenergic stimulation of beta(1) receptors in the kidney results in the release of plasma renin, the conversion of peptide precursors to angiotensin II (a2), and ultimately the production of aldosterone. beta(1)-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists all act by inhibiting the activity of critical protein of this core pathway: the beta(1) receptor, ACE, the a2 receptor, and aldosterone synthase. Investigation of the pharmacogenetic interactions of the ACE D/I polymorphism and heart-failure therapy demonstrates the power of genomics to target therapeutics. This review explores how genetic variation in genes involved in neurohormonal activation influences heart-failure outcomes and the impact of pharmacotherapy.

Figure 1. RAAS pathway and site of action of drug therapies and functional polymorphisms

Major pharmacologic therapies which improve survival in heart failure in white boxes: beta blockers, ACE inhibitors, ARBs (angiotensin receptor blockers) and Aldo (aldosterone) receptor antagonists all act on RAAS. In grey boxes are major genetic polymorphisms which influence outcomes and the impact of therapy including β₁Arg389, G protein β 3 subunit (GNB3 T haplotype linked to low plasma renin), ACE D/I (deletion/Insertion) and aldosterone synthase (CYP11B2) promoter

Figure 2

Transplant-free survival By ACE D/I genotype, GRACE study, University of Pittsburgh (reference 11). A. Overall cohort, ACE D allele associated with poorer event free survival, n=479, p=0.026 B: Subset with no beta blocker therapy, n=277, p=0.004 C. Subset treated with beta blocker therapy, n=202, p=0.97

Figure 3

Relative Risk of event (death or transplantation) by beta blocker use, GRACE study: Overall cohort and by ACE D/I genotype, DD,DI and II (adapted from table 4, reference 11)

Figure 4

Transplant-free survival By ACE D/I genotype, GRACE study, University of Pittsburgh (reference 14). A. Event-free survival by ACE genotype, β1-selective beta blocker only (n=85), p=0.51. B. Event-free survival by ACE genotype, β1,2- non-selective beta blocker (n=117), p=0.80

Figure 5

Transplant-free survival By ACE D/I genotype, GRACE study, University of Pittsburgh (reference 11). A. Subset on low dose ACE inhibitors and no beta-blockers, ACE D allele associated with poorer event free survival, n=130, p=0.005 B. Subset with high dose ACE inhibitor therapy and no beta blockers, n=117, p=0.47

Figure 6

Relative Risk of event (death or transplantation) by ACE inhibitor dose use, GRACE study: Overall cohort and by ACE D/I genotype, DD,DI and II (adapted from table 4, reference 11)

Figure 7

LVEF at 6 months in AHeFT: Comparison by treatment group, placebo or ISDN-HYD (fixed combination of isosorbide dinitrate and hydralazine) of the impact of Aldosterone promoter genotype. The -344C allele associated with lower LVEF at six months for subjects on placebo (p=0.05) but not on ISDN-HYD (p=0.79) (reference 26)

Figure 8

AHeFT: Impact of Aldosterone promoter genotype on LVEF at 6 months Overall and in subjects treated with aldosterone receptor antagonist (sprironolactone) The -344C allele associated with a trend toward lower LVEF at six months overall (p=0.098) which was more pronounced for subjects on spironolactone (p=0.03). (reference 26)

Figure 9

Transplant-free survival by endothelial nitric oxide synthase (NOS3) codon 298 polymorphism, GRACE study, University of Pittsburgh: Overall cohort (n=469): Asp²⁹⁸ variant (solid line, n=266), Glu²⁹⁸ homozygotes (dashed line, n=203). Event-free survival significantly poorer in subjects with the Asp²⁹⁸ variant, p=0.03 (reference 33)