It's been known that men with low testosterone levels are more likely to have caridac problems. However, it has not been clear if there is a causal relationship. Does low testosterone cause cardiac problems or is it only a marker for other health problems associated with cardiac problems, such as obesity? This mouse study establishes a mechanism by which low testosterone can cause diastolic dysfunction:
"The impact of long-term gonadectomy (GDX) on cardiac contractile function was explored in the setting of aging. Male mice had a bilateral GDX or sham-operation (4 weeks) and were investigated at 16-18 months. Ventricular myocytes were field stimulated (2 Hz; 37°C). Peak Ca2+ transients (fura-2) and contractions were similar in GDX and sham, although Ca2+ transients (50% decay time=45.2 ± 2.3 vs. 55.6 ± 3.1 ms; p<0.05) and contractions (tau=39.1 ± 3.2 vs. 69.5 ± 9.3 ms; p<0.05) were prolonged in GDX. Action potential duration was increased in GDX myocytes but this did not account for prolonged responses, as Ca2+ transient decay was slow even when GDX cells were voltage-clamped with simulated "sham" action potentials. Western blots of proteins involved in Ca2+ sequestration and efflux showed that Na+-Ca2+ exchanger and sarco-endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) protein levels were unaffected, while phospholamban was dramatically higher in aging GDX ventricles (0.24 ± 0.02 vs. 0.86 ± 0.13; p<0.05). Myofilament Ca2+ sensitivity at physiological Ca2+ was similar, but phosphorylation of essential myosin light chain (ELC/MLC-1) was reduced by ≈50% in aging GDX hearts. M-mode echocardiography showed no change in systolic function (e.g. ejection fraction). Critically, pulse wave Doppler echocardiography showed that GDX slowed isovolumic relaxation time (12.9 ± 0.9 vs. 16.9 ± 1.0 ms; p<0.05), indicative of diastolic dysfunction. Thus, dysregulation of intracellular Ca2+ and myofilament dysfunction contribute to deficits in contraction in aging hearts exposed to testosterone deficiency. This suggests that low testosterone helps promote diastolic dysfunction in the aging heart."
"The impact of long-term gonadectomy (GDX) on cardiac contractile function was explored in the setting of aging. Male mice had a bilateral GDX or sham-operation (4 weeks) and were investigated at 16-18 months. Ventricular myocytes were field stimulated (2 Hz; 37°C). Peak Ca2+ transients (fura-2) and contractions were similar in GDX and sham, although Ca2+ transients (50% decay time=45.2 ± 2.3 vs. 55.6 ± 3.1 ms; p<0.05) and contractions (tau=39.1 ± 3.2 vs. 69.5 ± 9.3 ms; p<0.05) were prolonged in GDX. Action potential duration was increased in GDX myocytes but this did not account for prolonged responses, as Ca2+ transient decay was slow even when GDX cells were voltage-clamped with simulated "sham" action potentials. Western blots of proteins involved in Ca2+ sequestration and efflux showed that Na+-Ca2+ exchanger and sarco-endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) protein levels were unaffected, while phospholamban was dramatically higher in aging GDX ventricles (0.24 ± 0.02 vs. 0.86 ± 0.13; p<0.05). Myofilament Ca2+ sensitivity at physiological Ca2+ was similar, but phosphorylation of essential myosin light chain (ELC/MLC-1) was reduced by ≈50% in aging GDX hearts. M-mode echocardiography showed no change in systolic function (e.g. ejection fraction). Critically, pulse wave Doppler echocardiography showed that GDX slowed isovolumic relaxation time (12.9 ± 0.9 vs. 16.9 ± 1.0 ms; p<0.05), indicative of diastolic dysfunction. Thus, dysregulation of intracellular Ca2+ and myofilament dysfunction contribute to deficits in contraction in aging hearts exposed to testosterone deficiency. This suggests that low testosterone helps promote diastolic dysfunction in the aging heart."
