Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

Background: The effects of alpha and ss adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of alpha and ss adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF. Methods: Genetic variants within the cis regions encoding the adrenergic receptors alpha 1A, alpha 2B, ss1, and ss2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases). Results: Lower alpha 1A or ss1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74-0.93, P = 0.001) and 0.95 (95% CI 0.93-0.97, P = 8 x 10(-6)). Conversely, lower alpha 2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05-1.12, P = 3 x 10(-7)). No evidence of an effect of lower ss2 activity on HF risk was found: OR 0.99 (95% CI 0.92-1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease. ConclusionsThis study provides genetic evidence that alpha 1A or ss1 receptor inhibition will likely decrease HF risk, while lower alpha 2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.