Early pathological mechanisms in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF cases, yet evidence-based therapies remain lacking due to limited understanding of its underlying pathological mechanisms. Our study aimed to uncover early pathological mechanisms in HFpEF by exposing mice to dietary conditions resembling a Western diet-rich in fats, salt, and low in fiber-alongside excess mineralocorticoids to replicate significant aspects of human HFpEF. Echocardiography was performed at both 3-wk and 6-wk intervals postchallenge, revealing cardiac alterations as early as 3 wk. While ejection fraction remained preserved, mice exhibited signs of diastolic dysfunction, reduced stroke volume, and left atrial enlargement. In addition, changes in pulmonary flow velocities were noted by the 3-wk mark, suggesting elevated pulmonary pressure. Extracardiac comorbidities included organ congestion, increased adiposity, impaired glucose tolerance, and hypercholesterolemia. Molecular analyses unveiled evidence of low-grade inflammation, oxidative stress, and impaired NO-cGMP-PKG signaling, contributing to the observed decrease in titin phosphorylation, thereby impacting myocardial stiffness. In addition, impaired nitric oxide (NO) signaling might have influenced the alterations observed in coronary flow reserve. Moreover, dysregulation of calcium signaling in cardiomyocytes and reduced sarcoplasmic reticulum (SR) load were observed. Interestingly, elevated phosphorylation of cMyBP-C was linked to preserved ejection fraction despite reduced SR load. We also observed intestinal atrophy, possibly due to a high-fat diet, low dietary fiber intake, and diminished gut perfusion, potentially contributing to systemic low-grade inflammation. These findings reveal how excess mineralocorticoid salt-induced hypertension and dietary factors, like high-fat and low-fiber intake, contribute to cardiac dysfunction and metabolic disturbances, offering insights into early HFpEF pathology in this model. Our study demonstrates that feeding mice a Western diet rich in fat and salt and low in fiber alongside excess mineralocorticoids replicates aspects of human HFpEF. Cardiac alterations including diastolic dysfunction and decreased stroke volume with preserved ejection fraction were observed. Extracardiac effects included organ congestion, adiposity, glucose intolerance, and intestinal atrophy. Molecular analysis revealed inflammation, oxidative stress, impaired NO-cGMP-PKG signaling pathways, and altered calcium signaling in cardiomyocytes, shedding light on early pathological changes in HFpEF.