New Insights into Sexual Dimorphism During Progression of Heart Failure and Rhythm Disorders

Mice overexpressing the human beta2-adrenergic receptors (TG4 mice) develop heart failure (HF) leading to higher mortality than WT mice. HF appears earlier in TG4 males and those animals have a more severe phenotype than TG4 females, with earlier appearance of sudden cardiac death, corroborating observations in human before menopause. We assessed the electrophysiological status of TG4 male and female mice through heart rate variability analysis (HRV), intracardiac electrophysiological exploration (IEE) and patch-clamp study in order to understand female protection. The role of gonadal hormones in HF progression was studied through gonadectomy procedure. HRV was decreased in TG4 comparing with WT, with a higher decrease in males (−48%) than in females (−35%). IEE revealed a lengthening of infrahisian conduction time (+29%) associated to a larger QRS duration (+27%) only in TG4 males. A high prevalence of spontaneous and electro-inducible premature ventricular contractions was observed only in old-TG4 males. No difference was observed in females with regards to arrhythmias. Gonadectomy improved cardiac phenotype in TG4 males whereas ovariectomy worsened it in females. TG4 left ventricular cardiomyocytes were hypertrophied only in males (169±7 vs. 204±11 pF, n = 20) but male and female TG4 presented an increase in action potential repolarisation with no gender-related difference as compared with WT (+200%). Longer action potentials reflected a significant decrease in outward voltage-gated K+ current densities in male and female TG4 cells. Assessment of histological alterations confirmed that high mortality in TG4 males is associated with severe cardiac fibrosis while in female no difference was found between WT and TG4 mice.In summary, the progression and severity of HF in TG4 mice are linked to sex-hormones. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.