Abstract Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure among Veterans, yet there is currently a paucity of treatment strategies that have been proven to improve prognosis. A primary reason for the lack of effective therapies for this increasingly prevalent condition is the limited understanding of mechanisms underlying myocardial stiffening, a key pathophysiologic component of HFpEF that is directly linked to exertional dyspnea, the cardinal presenting symptom of the disorder. The overarching goal of this proposal is to address this problem by elucidating the role of repetitive stretch-induced remodeling of the cardiac extracellular matrix (ECM) as a mechanistic link between chronic coronary artery disease (CAD) and HFpEF, two conditions that are extremely common in the Veteran population. Based on our preliminary data from multiple clinically-relevant swine models of heart disease, we hypothesize that myocardial stiffening develops in the setting of chronic CAD as a result of repetitive stretch-induced fibrosis caused by intermittent elevations in left ventricular (LV) preload. If so, this may explain why such a large proportion of the HFpEF population exhibits angiographically-significant epicardial CAD (~60-70% in multiple cohorts) and might have important clinical implications related to the use of coronary revascularization in these patients, since the reversibility of repetitive stretch-induced myocardial fibrosis is unclear. To test this hypothesis, we will utilize a porcine model of chronic epicardial CAD to better understand how exposure to episodic preload elevation influences remodeling of ischemic and non-ischemic regions of the left ventricle in this setting. In Aim 1, implantable telemetry will be used for continuous hemodynamic monitoring to quantify the frequency of preload elevation in swine with either multi-vessel (MV-CAD) or single-vessel CAD (SV-CAD) and determine whether repetitive preload elevation is required for the development of interstitial fibrosis in remote, non-ischemic myocardium. In Aim 2, percutaneous angioplasty will be performed in swine with MV-CAD and swine with SV-CAD to determine if repetitive stretch-induced stiffening associated with MV- CAD dictates whether LV fibrosis is reversed by revascularization. Post-mortem analysis of isolated cardiac fibroblasts and decellularized cardiac ECM from these models will be completed in Aim 3 to assess the mechanistic role of ECM-dependent fibroblast activation in repetitive stretch-induced LV stiffening and determine whether increased ECM stiffness per se causes protracted fibroblast activation that promotes persistent fibrosis through a self-sustaining positive feedback loop. These aims will be addressed by a multi-disciplinary investigative team using an integrative research approach that combines serial investigation of regional and global myocardial mechanics with ex vivo mechanical and biological a...