Disruption of the Cardiac-Coronary Axis as a Mechanism of HFpEF

Heart failure is the leading cause of mortality, and about 6.2 million adults in the United States have heart failure. Heart failure with preserved ejection fraction (HFpEF) has typical heart failure symptoms with mostly diastolic LV dysfunction but preserved ejection fraction. HFpEF is characterized by pronounced coronary microvascular dysfunction (CMD), the causal contribution of which is unclear. CMD is associated with coronary artery diseases (CAD), diabetic cardiomyopathy (DCM), ischemia with the non- obstructive coronary artery (INOCA), and HFpEF. Patients with CMD exhibit impaired acetylcholine-induced endothelial-dependent relaxation. Impaired endothelium- dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion and might lead to myocardial ischemia even without an obstructive coronary artery. We hypothesize that the myocardial deficiency perfusion caused by CMD will lead to myocardial ischemia, diastolic cardiac dysfunction, and fibrosis in HFpEF. So CMD plays a critical role in HFpEF. Moreover, our ex vivo study shows a deficiency of miR-21 that restores the NO- dependent coronary vasodilation. This application will address the underlying mechanism of how miR-21 regulates the coronary microvascular function, cardiac function and remodeling in HFpEF in a mouse model of HFpEF induced by a long-term high fat and high sugar diet. Such a preclinical modelof HFpEF has been validated in our preliminary data. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial-dependent dilation) by modulating miR-21can ameliorate HFpEF. We will test our hypothesis by an interdisciplinary approach encompassing a range of approaches and disciplines from molecular and cell analyses, vascular biology to physiology and pathophysiology, engendering the study of a novel mechanism of coronary microvascular dysfunction, such as tissue-specific knockouts and lineage tracing with 3D fluorescent imaging, measurement of vasodilation and myocardial blood flow in vivo by contrast echocardiography and cardiac function by echocardiography along with RNA-seq, sc RNA-seq, etc. Completing this project may lead to a new strategy to treat microvascular dysfunction and HFpEF and improve the cardiovascular prognosis of HFpEF.