Abstract
Heart failure with preserved ejection fraction (HFpEF), marked by cardiac diastolic dysfunction, contributes to half of all heart failure cases globally and poses a significant public health challenge. Effective therapies for HFpEF are rare, largely due to its complex and heterogeneous pathophysiology, which often involves multiple comorbidities. Berberine (BBR), an isoquinoline alkaloid, has demonstrated beneficial effects on multiple metabolic and cardiovascular disorders; however, its impact on cardiac diastolic dysfunction in HFpEF remains poorly understood. In this study, we utilized a rat model of HFpEF induced by a sustained high-fat/high-sucrose (HFHS) diet to explore the impact and mechanisms of BBR on diastolic dysfunction. The results revealed that BBR administration effectively alleviated cardiac diastolic dysfunction and alleviated extracardiac comorbidities, including increased weight, impaired glucose tolerance, hypercholesterolemia and hypertension, in rats fed an HFHS diet. Furthermore, BBR mitigated myocardial inflammation, oxidative stress, microvascular endothelial dysfunction, and notably restored the disturbed NO-cGMP-PKG pathway. Additionally, BBR reduced myocardial fibrosis and inhibited the abnormally activated TGF-β/Smads signaling. Moreover, BBR attenuated the systemic inflammation and corrected immune dysregulation in an HFHS diet-fed rats. Our study suggests that BBR exhibits multi-beneficial effects in the prevention and management of HFpEF, demonstrating its potential as a holistic therapeutic candidate for HFpEF.