Introduction: The prevalence of heart failure (HF) is higher in women than men from 80 years of age due to the greater occurrence of HF with preserved ejection fraction (HFpEF) in women. Compared to HF with reduced ejection fraction (HFrEF), patients with HFpEF are more likely older. Significant gender differences are suspected in HF development, regarding pathomechanism, adverse and reverse remodeling, clinical course, and management.

Methods: We studied 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls.

Results: TG male rats showed significantly higher mortality at 1 year than any other group. High blood pressure observed at 15 weeks in TG was reduced to normal, while heart rate increased at 1 year in both sexes. LV ejection fraction was specifically reduced in male, but not in female rats. Left ventricular (LV) diastolic dysfunction was evident in both TG sexes.  LV hypertrophy, increased LV ACE activity, and hypophosphorylated AMPK was specific to male rats. The gender difference was also observed in vascular function.  Acetylcholine sensitivity was decreased in females, while maximal vasodilation capacity to acetylcholine was reduced in males. Ca²⁺ sensitivity and active force production of isolated cardiomyocytes decreased in female but increased in male TG rats. Total phosphorylation of cMyBP-C was increased in both TG sexes, while Ser23/24 phosphorylation of cTnI was increased in TG males only. Cardiomyocyte passive stiffness was increased in TG animals, which was completely normalized by both PKG and CaMKII treatments in female, but not in male rats. The reduction of PKG expression and activity was more dramatic in TG females. CaMKII specific titin phosphorylations were generally decreased in both sexes in TG rats, except Ser4043 phosphorylation, which was increased in female TG rats.  

Conclusion: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male rats was attributed to reduced LV systolic function and increased LV stiffness. A sex-specific divergent regulation of PKG and CaMKII systems was identified as a molecular mechanism.