Abstract
Heart failure with preserved ejection fraction (HFpEF) has recently emerged as an insidiously and increasingly prevalent heart failure phenotype. HFpEF often occurs in the context of hypertension and obesity and presents with diastolic dysfunction, ventricular hypertrophy, and myocardial fibrosis. Despite growing study of HFpEF, the causal links between early metabolic changes, bioenergetic perturbations, and cardiac structural remodeling remain unclear. This study sought to elucidate the contribution of the respective pathophysiological drivers of the HFpEF symptom suite using a recently developed two-hit mouse model. By studying the independent and concomitant consequences of hypertension and obesity-driven metabolic dysfunction on cardiac structure and function, we revealed the causative drivers of cardiac functional, structural, and metabolic remodeling in male HFpEF mice. We found that hypertensive male mice developed diastolic dysfunction and cardiac hypertrophy regardless of obesity status and that obese mice exhibited altered systemic glucose metabolism and increased cardiac mitochondrial fatty-acid metabolism independent of hypertension status. Taken together, our results suggest that the cardiac structural and metabolic HFpEF symptoms in this two-hit model occur as direct results of each of the two "hits." The results of this study help to clarify the pathogenic HFpEF cascade, providing causal insights that may aid in the development of more precisely targeted therapeutics.