Sex-related differences in age-associated downregulation of human ventricular myocardial β1-adrenergic receptors

Abstract

Background: With increasing age, human ventricular myocardium exhibits selective downregulation of β1-adrenergic receptors (β1-ARs). We tested the hypothesis that sex differences exist in age-related changes in β1-ARs.

Methods: Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy. β1-AR and β2-AR densities, the frequency of β1-AR389 gene variants, and β-AR function were determined.

Results: Sex had a marked effect on the age-related decrease in β1-ARs. Female LVs had more pronounced downregulation (by 42% [p < 0.001] vs 22% [p = 0.21] in 31 male LVs) comparing the youngest (average age, 15.3 ± 5.5 years) to the oldest (average age, 50.8 ± 9.1 years) sub-groups. On regression analyses, female LVs exhibited a closer relationship between β1-AR density and age (r = -0.78, p <0.001 vs r = -0.46, p = 0.009 in males), with a second-degree polynomial yielding the best fit. There was no statistically significant relationship of β1-ARs to age in female or male idiopathic dilated cardiomyopathy LVs.

Conclusions: Sex affects age-related β-AR downregulation in normal human ventricles, with females exhibiting more profound decreases with increasing age. The curvilinear relationship between age and receptor density that plateaus around age 40 in women suggests an effect of sex hormones on β1-AR expression in the human heart.

Keywords: age; heart failure; left ventricle; sex differences; ventricular myocardium; β(1)-adrenergic receptors.