Cardiac Sensory and Sympathetic Nerve Dysregulation in Hypertrophic Cardiomyopathy

About This Grant

Project Summary Familial hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease with an estimated prevalence of 1:500 individuals in the general population. Sarcomere gene mutations result in the characteristic features of HCM include left ventricular (LV) hypertrophy, myocyte disarray, interstitial fibrosis, diastolic dysfunction, and high risk of cardiac arrhythmias and sudden death. Indeed, HCM is the number one cause of sudden cardiac death in young, otherwise healthy adults. Non-invasive treatments for HCM target symptoms and do not prevent or slow disease progression, underscoring the need for new therapies. Recently, a new small molecule negative ionotropic agent has shown promise in treating HCM, but long- term benefits remain to be reported. HCM research has focused primarily on genetics and molecular mechanisms impacting cardiomyocyte and LV structure and function. Hypercontractile sarcomeres accompanied by metabolic dysfunction and energy depletion are considered causal mechanisms. We propose that the aberrant mechanical and metabolic signals produced in HCM hearts are detected by cardiac sensory nerves, with the resulting abnormal reflexes contributing to acute cardiovascular instability, chronic and selective increases in sympathetic nerve activity to the heart, decreased parasympathetic activity, cardiac inflammation, fibrosis, and diastolic dysfunction. We hypothesize that cardiac spinal afferents (CSAs) in HCM exhibit increased chemosensitivity, reflecting increased [H+] produced by myocyte energy depletion/ischemia and increased neuronal expression of acid-sensing ion channel 3 (ASIC3). An alpha tropomyosin mouse model of HCM with cardiac-targeted mutation known to cause HCM in humans will be studied in male and female mice. Specific aims of the project are: 1) Test the hypothesis that HCM mice demonstrate a selective increase in cardiac sympathetic tone mediated by the cardiac spinal afferent reflex and dysfunction of the neuronal norepinephrine transporter, and 2) Test the hypothesis that increased activity of CSAs is mediated by ASIC3 and targeted cardiac ablation of CSAs will improve cardiac and autonomic function in HCM mice.The proposed studies using innovative, targeted, and complementary approaches will close gaps in knowledge regarding mechanisms causing sympathovagal imbalance in HCM prior to heart failure, the influence of cardiac innervation on the HCM heart, and the quest for disease-modifying therapies in HCM. Pursuant to the goals of the Academic Research Enhancement Award (R15), this project will also provide research opportunities in neural-cardiovascular physiology to undergraduate students studying human health at Michigan Technological University.