Sex Differences In Ventricular Function And Mortality In Sema3a Deficient Mice With Dilated Cardiomyopathy

Introduction: Clinical studies consistently report sex differences in heart failure (HF) outcomes. Disrupted cardiac sympathetic innervation patterns have not been investigated as a potential mechanism. Hypothesis: We aimed to explore whether cardiac sympathetic innervation patterns disrupted by deletion of the neurorepellent, Semaphorin3a (Sema3a), in murine dilated cardiomyopathy (DCM), has a deleterious effect in male compared to female mice. Methods: Utilizing the established Tg9 model of nonischemic HF (DCM+), we compared serial left ventricular ejection fraction (LVEF), ventricular arrhythmogenesis, mortality, and innervation patterns using immunohistochemistry in male vs. female DCM+Sema3a KO mice (with disrupted innervation) to male and female DCM+Sema3a WT animals. Results: Immunohistochemistry revealed greater disruption in sympathetic innervation amongst Sema3a deficient (DCM+Sema3a KO ) mice (n=11) compared to DCM+Sema3a WT (n=10) and WT mice (n=7) ( ****p<0.0001). There was no significant difference in arrhythmogenesis between DCM+Sema3a WT versus DCM+Sema3a KO mice. Mortality was significantly greater in DCM+Sema3a KO mice compared to DCM+Sema3a WT and WT mice (*p=0.04). This was attributable to pump failure, as LVEF was lower in DCM+Sema3a KO mice that died compared to DCM+Sema3a KO mice who did not (*p=0.03). When outcomes were compared for male versus female mice, we observed sex differences in mortality, with female DCM+Sema3a KO mice exhibiting higher mortality and greater LV dysfunction than males (*p=0.03). This difference was not seen in male vs female DCM+Sema3a WT mice, suggesting that the sex differences are related to Sema3a gene deletion, and thus, disrupted innervation patterns, not DCM alone. Conclusion: Our data suggests that there are sex-based differences in DCM outcomes that may involve Sema3a signaling. Further studies validating this finding and identifying underlying mechanisms are warranted.