Sex differences in cardiac autonomic remodeling after myocardial infarction

ABSTRACT Cardiovascular diseases, including ventricular arrhythmias and heart failure, are an important cause of morbidity and mortality in the U.S. Ventricular arrhythmias (VT/VF), after myocardial infarction (MI) and in the setting of cardiomyopathy, remain an important cause of sudden cardiac death (SCD). While important sex differences in the incidence of SCD and VT/VF exist in the setting of ischemic and non-ischemic cardio- myopathy, the mechanisms behind these sex differences remain unknown. It is established that the autonomic nervous system plays an important role in the genesis of VT/VF and progression of heart failure. Chronic sympathetic activation and reduced parasympathetic function increase the risk of VT/VF and SCD. Pathological autonomic neural remodeling in response to MI alters myocardial responses to catecholamines, modifies myocardial innervation patterns that exacerbate electrical heterogeneities, and leads to alterations in sympathetic and parasympathetic efferent and afferent signaling, setting up the substrate for VT/VF and its dynamic modulation by the autonomic nervous system. Yet, it is unknown if there are sex differences in cardiac autonomic remodeling that underly the clinical differences observed in the presentation and outcomes of VT/VF after MI and in ischemic cardiomyopathy in men vs. women, and whether the sex hormone, estrogen, is a mediator of these differences. In order develop tailored and targeted therapies, it is critical to understand mechanisms that underly sex differences in sympathetic and parasympathetic dysfunction in the setting of cardiac disease. In this proposal, we aim to test the novel hypotheses that (1) sex differences exist in cardiac autonomic remodeling after MI and that these differences underly the occurrence of ventricular arrhythmias in males vs. females, and (2) estrogen plays a critical role in responses of the autonomic nervous system to myocardial injury, and hence pathogenesis of ventricular arrhythmias. In specific aim 1, we will test whether myocardial signaling in response to sympathetic and parasympathetic neurotransmitters and neuropeptides differ between male and female infarcted mice using optical mapping and novel FRET imaging techniques of intracellular cyclic AMP signaling. In aim 2, we will test whether sex differences exist in (i) cardiac innervation patterns (using tissue clearing), (ii) afferent and efferent responses to optogenetic stimulation of specific autonomic neural pathways, and (iii) autonomic ganglia neuronal changes and oxidative stress after MI. Aim 3 will evaluate the role of estrogen in improving MI induced myocardial and autonomic remodeling. Understanding sex differences in these fundamental autonomic and myocardial pathways has the potential to accelerate development of personalized, novel, sex-based disease-modifying therapies and tailor available therapies more appropriately by sex, reducing complications and side-effects.