Cardiometabolic impact of ketones in diastolic dysfunction progression in a HFpEF rat model

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge significantly associated with diastolic dysfunction, a condition often linked to metabolic syndrome and chronic kidney failure. Recent evidence suggests that ketone bodies may play a role in improving cardiac and metabolic parameters in HFpEF, but comparative effects of different ketone-raising strategies remain unclear. This study aimed to assess the impact of different therapeutic strategies including a ketogenic diet (KD), ketone salt (KS) supplementation and SGLT2 inhibitors on several parameters such as: cardiac hypertrophy, diastolic function, glucose metabolism, lipid profile, and renal function in a ZSF1 obese rat model of HFpEF. To this end, rats were assigned to either a control diet, KD, KS, or empagliflozin (SGLT2 inhibitor) treatment and evaluated using echocardiography, metabolic assays, and renal function parameters. All interventions reduced hyperglycaemia, while only KD and SGLT2 inhibitors improved lipid profiles and attenuated glomerular hyperfiltration. Notably, only KD and KS treatments reduced left ventricular mass, indicating a reversal of cardiac hypertrophy, though none of the treatments improved diastolic filling pressures. The findings suggest that ketone-based interventions may modulate pathological cardiac remodelling and metabolic derangements through different mecanisms than SGLT2 inhibitors. Thus, this study is able to further support the potential attenuation role of ketones in HFpEF related cardiac hypertrophy, metabolic dysfunction and renal impact. However, there still is a need of further investigate to explore the long-term effects, clinical relevance and safety of ketone therapies in HFpEF patients, particularly regarding their differential impact on cardiac and renal outcomes.