Chronic Testosterone Deficiency Promotes Maladaptive Remodeling in The Hearts of Aging Male Mice

Abstract

Testosterone levels decrease with age in men, while the risk for cardiovascular diseases (CVDs) increases. Low testosterone levels are associated with CVDs. Testosterone primarily exerts its effects via androgen receptors (AR), which are also present in the heart. The impact of testosterone on the aging heart is not well understood. We hypothesized that chronically low testosterone levels in aging will have deleterious effects on heart structure and function. However, first we wanted to understand whether physiological testosterone levels in male mice can impact the heart. We found that both young and aged mice with higher testosterone levels had thicker left ventricular (LV) walls and higher LV mass. Testosterone levels in young mice did not influence systolic function, and young mice with higher testosterone levels had prolonged relaxation. By contrast, aged mice with higher testosterone levels had increased ejection fraction and shorter relaxation times. Next, we investigated the effects of chronic testosterone deficiency on heart structure and function across the life course of the mice by subjecting the mice to an early life gonadectomy (GDX). Our results indicated that by 18 months of age, GDX mice had smaller left ventricles and developed signs of diastolic dysfunction. Aged GDX mice also showed QT prolongation and more arrhythmias. Studies in isolated ventricular myocytes revealed increased triggered activity and prolonged action potentials caused by an increase in late inward sodium current (INa-L) in GDX mice. Blocking NaV1.8 channels normalized electrical activity. Since some older men take anti-androgenic drugs for conditions like prostate cancer, we also wanted to understand the effects of flutamide (AR antagonist) on aged hearts. Our results showed that flutamide treatment reduced LV size and mass. Flutamide also prolonged relaxation as well as slowed repolarization. Hearts from flutamide-treated mice also had lower rates of pressure development and decay and increased mRNA expression of certain calcium reuptake genes. Therefore, testosterone levels can influence cardiac structure and function and chronically low levels of testosterone or blocking androgen receptors can cause maladaptive structural remodeling, promote diastolic dysfunction, and slow ventricular repolarization in aging, increasing the risk of developing arrhythmias and heart failure with preserved ejection fraction.