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-week and 6-week intervals post-challenge, revealing cardiac alterations as early as 3-weeks. While ejection fraction remained preserved, mice exhibited signs of diastolic dysfunction, reduced stroke volume, and left atrial enlargement. Additionally, changes in pulmonary flow velocities were noted by the 3-week 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. Additionally, impaired NO signaling might have influenced the alterations observed in coronary flow reserve. Moreover, dysregulation of calcium signaling in cardiomyocytes and reduced 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 low dietary fiber intake and diminished gut perfusion, potentially contributing to systemic low-grade inflammation. These findings reveal how excess mineralocorticoids-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.
