Diastolic dysfunction (DD) stems from a complex interplay of metabolic disorders and systemic inflammation that impairs the heart's relaxation and compliance, leading to compromised ventricular filling and reduced cardiac output. Key comorbidities include obesity, diabetes, and hypertension, which provoke endothelial dysfunction and an imbalance in myocardial oxygen utilization.
Coronary microvascular dysfunction (CMD) is emerging as a significant factor in the development of heart failure with preserved ejection fraction (HFpEF). CMD results from systemic and coronary endothelial inflammation driven by HFpEF-associated comorbidities. This inflammation impairs the availability of endothelial nitric oxide and the production of cyclic guanosine monophosphate, affecting cardiomyocytes. The ensuing cascade involves titin hypophosphorylation, leading to increased stiffness and hypertrophy in cardiomyocytes, activation of myofibroblasts, and interstitial fibrosis. These changes collectively contribute to the characteristic left ventricular diastolic stiffening seen in HFpEF.
Additionally, ischemic injury and viral infections can trigger sterile inflammation, contributing to cardiac remodeling and further impairing diastolic function. This cascade affects both the active relaxation and passive compliance phases of the heart's diastolic function, with early phases of HFpEF marked by reduced relaxation efficiency and advanced stages characterized by significantly reduced compliance. The resultant increase in ventricular stiffness necessitates higher filling pressures, leading to elevated atrial pressures and potential pulmonary edema, manifesting clinically as exercise intolerance. This progression underscores the pivotal role of chronic inflammation and myocardial changes in the pathophysiology of HFpEF.
