bims-hafaim 2025-06-29 papers

Issue of 2025–06–29
six papers selected by
Kyle McCommis, Saint Louis University

Nat Rev Cardiol. 2025 Jun 22.

Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.

Mathias Mericskay, Coert J Zuurbier, Lisa C Heather, Anja Karlstaedt, Javier Inserte, Luc Bertrand, Georgios Kararigas, Marisol Ruiz-Meana, Christoph Maack, Gabriele G Schiattarella.

The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.

DOI: https://doi.org/10.1038/s41569-025-01166-7

J Pharmacol Exp Ther. 2025 Jun 02. pii: S0022-3565(25)39832-0. [Epub ahead of print]392(7): 103619

The role of pyruvate metabolism in cardiovascular diseases.

Zijie Cheng, Haoqi Li, Dan Wu, Qingxun Hu.

Cardiovascular diseases remain the leading cause of mortality worldwide, with their incidence steadily rising in recent years. Pyruvate, the end product of glycolysis, serves as a critical metabolite in cellular energy metabolism by bridging cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. Its synthesis, transport, and metabolic conversion are tightly regulated by a range of enzymes and transporters, including pyruvate kinase, mitochondrial pyruvate carriers, pyruvate dehydrogenase complex, glucose transporters, and lactate dehydrogenase. Emerging evidence suggests that dysregulation of pyruvate metabolism plays a pivotal role in the pathogenesis of various cardiovascular conditions, including heart failure, ischemia-reperfusion injury, diabetic cardiomyopathy, and pulmonary hypertension. This review aimed to provide a comprehensive and integrative overview of the role of pyruvate metabolism in cardiovascular diseases by systematically analyzing recent findings from both experimental and clinical studies. Unlike previous reviews that focus on isolated enzymes or specific disease types, we adopted a systemic perspective to elucidate the entire pyruvate metabolic network and its crosstalk with mitochondrial function, redox homeostasis, and inflammatory signaling pathways. We also discuss the regulatory roles of key signaling cascades, such as PI3K-AKT, and the implications of genetic variations in enzymes involved in pyruvate metabolism. Finally, we highlight potential molecular targets within this pathway that could be leveraged for therapeutic intervention. By mapping these interconnections, our review underscores the therapeutic potential of targeting pyruvate metabolism as a novel strategy for treating cardiovascular disorders. SIGNIFICANCE STATEMENT: Pyruvate metabolism plays a crucial role in cardiovascular disease development and has attracted growing interest. While previous reviews have examined enzymes like PDC and PKM2, they often focus narrowly on specific pathways or disease types. This review offers a more integrated, system-level perspective, highlighting the roles of pyruvate metabolism in mitochondrial function, redox balance, and inflammation. It also identifies potential metabolic targets, aiming to support future therapeutic strategies in treating cardiovascular conditions.

Keywords: Cardiovascular disease; Metabolism; Pyruvate

DOI: https://doi.org/10.1016/j.jpet.2025.103619

Autophagy. 2025 Jun 24.

NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.

Mahmoud Abdellatif, Francisco Vasques-Nóvoa, João Pedro Ferreira, Junichi Sadoshima, Abhinav Diwan, Wolfgang A Linke, Guido Kroemer, Simon Sedej.

Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD+) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF. Targeted and untargeted cardiac acetylome profiling revealed no significant deacetylation of essential autophagy-related proteins, including ATG5, ATG7 and mammalian Atg8-family members (ATG8s), suggesting a SIRT (sirtuin)-independent mechanism of autophagy induction by nicotinamide. Instead, cardiac transcriptomic analysis revealed major shifts in insulin-IGF1 (insulin-like growth factor 1) signaling, a known autophagy inhibitory pathway. Nicotinamide supplementation reversed the HFpEF-associated increase in insulin-IGF1 signaling, whereas exogenous IGF1 counteracts nicotinamide-induced autophagy. Importantly, nicotinamide fails to exert cardioprotective effects in mice lacking the autophagy-related protein ATG5 in cardiomyocytes, implicating autophagy as essential for the therapeutic response. In patients with HFpEF, a metabolic shift diverting nicotinamide away from NAD+ biosynthesis toward catabolism strongly correlates with worsening heart failure and increased cardiovascular mortality, even after adjusting for traditional risk factors. In sum, we demonstrate that NAD+ replenishment improves cardiometabolic HFpEF by restoring cardiac autophagy through suppression of excessive IGF1 signaling.

Keywords: Acetylation; HFpEF; IGF1; insulin; nutrient signaling; sirtuins

DOI: https://doi.org/10.1080/15548627.2025.2522127

Cardiol Rev. 2025 Jun 27.

Targeting Superoxide to Prevent Diuretic Resistance and Reduce Heart Failure Mortality.

Wayne Kaesemeyer.

Diuretic resistance is a servomechanism involving superoxide that results in the need for escalating doses of diuretics in the treatment of heart failure. Without intervention, this typically is associated with increased heart failure mortality. Recent heart failure studies involving the use of SGLT2 inhibitors and GLP-1 agonists have shown reductions in the need for loop diuretics along with reductions in hospitalizations for heart failure and cardiovascular mortality. Multiple mechanisms have been suggested to explain the benefits of both these and related drugs, but this article is the first to propose superoxide-induced diuretic resistance as a therapeutic target for improving outcomes and reducing mortality in the treatment of heart failure.

Keywords: GLP-1 agonists; SGLT2 inhibitors; cardiorenal syndrome; diuretic resistance; glutathione; heart failure; superoxide

DOI: https://doi.org/10.1097/CRD.0000000000000969