Contribution of ASICs to Cardiac Remodeling and Dysautonomia Associated with Heart Failure

Abstract

INTRODUCTIONThe American Heart Association projects that by 2030 more than 8 million American adults will have heart failure (HF). HF is a condition in which the heart muscle is unable to sufficiently pump blood to meet the needs of the body. A characteristic of HF, and a major driver of the disease process, is an imbalance in the autonomic nervous system. Our lab and others have shown that the Acid Sensing Ion Channel subunit 3 (ASIC3) is highly expressed in the sensory nerves innervating the heart. Recent studies showed that chemically ablating these nerves attenuates cardiac remodeling after myocardial infarction (MI).METHODSWild type (WT) and ASIC3‐/‐ mice underwent either left anterior descending coronary artery ligation or a sham surgery. Echocardiograms were done before surgery as well as two days and three weeks after surgery to evaluate the size and function of the heart. Radio telemeters were implanted one week after surgery to record hemodynamic changes to autonomic nervous system altering drugs. In a separate cohort a catheter was inserted into the left ventricle and isoproterenol was administered to evaluate left ventricular (LV) contractile reserve. Finally, histological staining was done on heart slices to quantify the level of fibrosis in each of the groups.RESULTSWe have demonstrated that knocking out ASIC3 prevents disadvantageous remodeling after MI in mice. Two days after MI surgery both WT and ASIC3‐/‐ mice have a decrease in their LV ejection fraction (LVEF), a measure for how well the left ventricle is able to pump blood to the rest of the body. However, three weeks after MI the ASIC3‐/‐ mice have a significant increase in their LVEF compared to their WT counterparts. However, preliminary autonomic studies found no differences between WT and ASIC3‐/‐. Also, there wasn’t a difference between WT Sham and WT MI, indicating that mice don’t undergo the same changes in autonomic tone that we see in other animals such as humans or rats. Although not statistically significant, isoproterenol infusion shows a trend towards a higher contractile reserve in ASIC3‐/‐ MI mice compared to WT MI mice.CONCLUSIONOur echo data shows that ASIC3 contributes to the remodeling that occurs after MI. Along with that, our data from the isoproterenol study indicates that knocking out ASIC3 in mice after MI may help to conserve cardiac contractile reserve. The preliminary work done for our autonomic studies indicate that the dysregulation of the autonomic nervous system in mice is different than what is expected from studies done in humans and rats.