Sarcomere gene mutations cause hypertrophic cardiomyopathy (HCM), a common devastating disease. HCM is characterized by cardiac/myocyte hypertrophy, myocyte disarray, fibrosis, diastolic dysfunction, arrhythmias and risk of sudden cardiac death. While HCM may progress to heart failure, sudden death can occur before heart failure develops. While an enormous amount of knowledge of genetics and molecular mechanisms of cardiomyocyte dysfunction has been gained from animal models of HCM, very little is known regarding the roles of cardiac innervation and its interactions with the cardiac renin-angiotensin system (RAS) in HCM. We hypothesize that pathological remodeling of the heart, and cardiomyocyte energy depletion in HCM induces dysregulation of cardiac sensory nerve activity leading to cardiac sympathovagal imbalance, activation of cardiac RAS, and decreased baroreflex sensitivity, all of which promote arrhythmias and accelerate progression to congestive heart failure and death. We will utilize two established mouse models of HCM with cardiac-targeted human mutations and differing phenotypes to test our hypothesis.
Specific Aims of the project are to: (1) Determine roles of cardiac vagal and ?sympathetic? afferent nerves, and arterial baroreflex in mediating autonomic and cardiac dysfunction in HCM mice, and (2) Test the hypothesis that chronic infusion of the angiotensin peptide Ang-(1-7) to HCM mice will inhibit cardiac sympathetic tone and oppose deleterious actions of angiotensin II, resulting in less cardiac fibrosis and improved left ventricular (LV) function. Experimental approaches include telemetric monitoring of blood pressure, assessment of sympathetic and parasympathetic tone, and baroreflex sensitivity; assessment of cardiac function by echocardiograph, and LV pressure recordings; and chemical ablation of cardiac ?sympathetic? afferent neurons. Additionally, the angiotensin peptide Ang-(1-7) will be infused chronically to inhibit the cardiac RAS and sympathetic nerve activity for therapeutic benefit. The significance of this research relates to understanding the key roles played by cardiac sensory and sympathetic nerves, baroreflexes, and cardiac RAS in determining the severity of HCM and its progression to heart failure. In addition, a novel treatment [Ang-(1-7) infusion] for HCM will be tested with potential clinical implications.
Hypertrophic cardiomyopathy (HCM) is a common genetic disease that results in an enlarged, stiff heart that does not fill well with blood in between heart beats (diastolic dysfunction). Patients with HCM suffer from irregular heartbeats (arrhythmias) and heart failure, and are at high risk of sudden cardiac death. Studies in human subjects with HCM report impaired blood volume regulation, but little is known regarding mechanisms. Our research in mice has revealed abnormalities in sensory and sympathetic nerves in the heart that may contribute to HCM. The proposed research will explore underlying neural mechanisms and test the hypothesis that combined targeting of the brain and heart using a novel pharmacological (drug) treatment will improve heart function in HCM.