Key result
Ketone bodies offer metabolic cardioprotection in heart failure but also signal disease severity.
This review examines the dual paradox of ketone bodies in heart failure, balancing their potential as adaptive energy substrates and therapeutic targets against their role as markers of disease severity and ketoacidosis risk.
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Ketone shift in HF remains of uncertain benefit; leaves open differential effects in HFrEF versus HFpEF and SGLT2i safety.
Heart failure (HF) is fundamentally a syndrome of disturbed energy metabolism. Although accumulating evidence indicates that the failing heart increases ketone utilization, whether this metabolic shift is adaptive or maladaptive remains debated, complicated by striking differences between HFrEF and HFpEF. Moreover, the cardiovascular benefits of SGLT2i are thought to be partially attributable to elevated circulating ketone levels, yet this same mechanism links to increased risk of ketoacidosis. This review dissects the dual role of ketone bodies in HF: as an alternative oxidative substrate under stress and a marker of disease severity, while mediating SGLT2i cardioprotection but posing safety risks. We focus on heterogeneity across HF subtypes and therapeutic strategies targeting ketone metabolism, including exogenous ketone supplementation, aiming to provide new perspectives for precision medicine.
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Hao et al. (2026) conducted a review in Heart failure (including HFrEF and HFpEF). Therapeutic strategies targeting ketone metabolism (including SGLT2 inhibitors and exogenous ketone supplementation) was evaluated. Ketone bodies play a dual role in heart failure as an alternative oxidative substrate and SGLT2i cardioprotective mediator while also serving as a severity marker linked to ketoacidosis risk.
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