bims-hafaim 2025-06-08 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–06–08
seven papers selected by
Kyle McCommis, Saint Louis University

Characteristics of Cardiac Ketone Body Metabolism Throughout the Life Cycle.
Modulation of cardiac fatty acid or glucose oxidation to treat heart failure in preclinical models: a systematic review and meta-analysis.
Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway.
Why the Diabetic Heart Is Fatty.
Obesity and heart failure: exploring the cardiometabolic axis.
Visceral fat lipolysis by pancreatic lipases worsens heart failure.
GCN5L1 inhibits pyruvate dehydrogenase phosphorylation during cardiac ischemia-reperfusion injury.

Cardiovasc Ther. 2025 ;2025 5913327

Characteristics of Cardiac Ketone Body Metabolism Throughout the Life Cycle.

Lei Li, Xiaojian Song, Xiurui Ma, Yanwu Xu.

  Ketone bodies can serve as energy substrates for the heart and perform important molecular signal transduction functions. In recent years, the therapeutic potential of ketone bodies has become a research hotspot in the field of cardiovascular diseases. Many previous reviews have focused on ketone bodies from the perspective of cardiovascular diseases, especially heart failure. Nonetheless, the metabolism of cardiac ketone bodies under physiological conditions also warrants attention, as the consumption of a ketogenic diet or direct supplementation of ketone bodies from exogenous sources has become widely popular among healthy individuals for weight loss. Furthermore, recent clinical studies have shown that under physiological conditions, the level of ketone bodies is positively correlated with the incidence of cardiovascular diseases and mortality. On the basis of the differences in cardiac ketone body metabolism under healthy and disease conditions, in this review, we describe in detail the characteristics of cardiac ketone body metabolism and the significance of elevated circulating ketone body levels throughout the life cycle on physiological states.

Keywords:  heart; ketone body; metabolism; physiology

DOI:  https://doi.org/10.1155/cdr/5913327
Commun Med (Lond). 2025 Jun 04. 5(1): 213

Modulation of cardiac fatty acid or glucose oxidation to treat heart failure in preclinical models: a systematic review and meta-analysis.

Tom Fischer, Christina Schenkl, Estelle Heyne, Peter Schlattmann, Torsten Doenst, P Christian Schulze, T Dung Nguyen.

BACKGROUND: Current expert opinion on cardiac metabolism in heart failure (HF) suggests that inhibiting cardiac fatty acid oxidation (FAO) or stimulating cardiac glucose oxidation (GO) can improve heart function. However, systematic evidence is lacking, and contradictory data exist. Therefore, we conducted a comprehensive meta-analysis to assess the effects of modulating myocardial GO or FAO on heart function.
METHODS: We screened MEDLINE via Ovid, Scopus, and Web of Science until March 02, 2024 for interventional studies reporting significant changes in cardiac GO or FAO in established animal models of HF, such as ischemia-reperfusion, pressure overload, rapid pacing, and diabetic cardiomyopathy. We employed multivariate analysis (four-level random-effects model) to enclose all measures of heart function. Additionally, we used meta-regression to explore heterogeneity and contour-enhanced funnel plots to assess publication bias. The protocol is registered on PROSPERO (CRD42023456359).
RESULTS: Of a total of 10,628 studies screened, 103 studies are included. Multivariate meta-analysis reveals that enhancing cardiac GO considerably restores cardiac function (Hedges' g = 1.03; 95% CI: 0.79-1.26; p < 0.001). Interestingly, interventions associated with reduced myocardial FAO show neutral effects (Hedges' g = 0.24; 95% CI: -0.57-1.05; p = 0.557), while those augmenting myocardial FAO markedly improve function (Hedges' g = 1.17; 95% CI: 0.58-1.76; p < 0.001).
CONCLUSIONS: Our data underscore the role of cardiac metabolism in treating HF. Specifically, these results suggest that stimulating either myocardial FAO or GO may considerably improve cardiac function. Furthermore, these results question the current notion that inhibition of cardiac FAO is protective.

DOI: https://doi.org/10.1038/s43856-025-00924-5
Eur J Heart Fail. 2025 Jun 04.

Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway.

David M Kaye, Xiao Suo Wang, Yen Chin Koay, Mengbo Li, Bailey McIntosh, Yann Huey Ng, Michael Rahman, Yiyang Cao, Francine Z Marques, Cassandra Malecki, Shane Nanayakarra, Justin Mariani, Bing Wang, Sean Lal, Giovanni Guglielmi, John F O'Sullivan.

   AIMS: Although functional recovery of the failing heart with left ventricular assist device (LVAD) unloading can occur, the underpinning mechanism is unclear. We aimed to characterize the effect of myocardial biochemical effect of LVAD support in vivo and in vitro.
METHODS AND RESULTS: We performed targeted metabolomics and lipidomics on transcardiac (arterial and coronary sinus) blood samples collected from healthy volunteers (n = 13), patients with end-stage heart failure with reduced ejection fraction (HFrEF, n = 20), and LVAD-supported HFrEF patients (n = 18). Complementary biochemical studies in myocardial tissue samples from healthy donor, HFrEF and LVAD patients, and cardiomyoblasts were performed. Myocardial uptake of intermediates in purine, nucleotide, and tricarboxylic acid (TCA) cycle pathways was depressed in HFrEF patients, with recovery in LVAD patients. Glucose uptake was suppressed in HFrEF but restored in LVAD. Metabolite changes suggestive of impaired fatty acid oxidation were present in HFrEF but not in LVAD. We found that the metabolite citraconate was significantly released by HFrEF hearts compared to controls and this was corroborated, in separate patients, by increased levels of citraconate in HFrEF myocardium but not in LVAD. Whilst citraconate increased succinate deydrogenase (SDH) activity in cardiomyoblasts, its isomer itaconate suppressed SDH activity. SDH activity was maintained in HFrEF myocardium but was diminished in LVAD myocardium.
CONCLUSIONS: We report, for the first time, the in-vivo biochemical effects of LVAD unloading in the human heart. Our data identify citraconate as a potentially important regulator of the TCA cycle in the failing heart.

Keywords:  HFrEF; LVAD; Lipidomics; Metabolomics; Myocardial metabolism; Remodelling

DOI:  https://doi.org/10.1002/ejhf.3704
Circ Res. 2025 Jun 06. 136(12): 1561-1563

Why the Diabetic Heart Is Fatty.

Yijun Yang, Zolt Arany.



Keywords:  Editorials; calcium signaling; diabetic cardiomyopathies; fatty acids; insulin resistance

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326677
Cardiovasc Res. 2025 Jun 03. pii: cvaf090. [Epub ahead of print]

Obesity and heart failure: exploring the cardiometabolic axis.

Jennifer J Rayner, Ines Abdesselam, Jiliu Pan, Andrew J M Lewis, Oliver J Rider.

  Obesity is one of the biggest risks to public health in both developed and developing countries, and yet incidence continues to skyrocket. Being the main risk factor for a large number of life-limiting conditions, obesity has the potential to cause enormous damage unless addressed urgently. Heart failure (HF) is the most common cardiovascular disease associated with obesity. The incidence of HF overall continues to rise and mortality rates remain high, despite the rapid and significant advances in pharmacotherapy which have recently transformed the landscape of HF treatment. Both obesity and heart failure are multisystem disorders which are closely interlinked. Obesity poses the body a number of challenges, ranging from haemodynamic, to neuroendocrine, to inflammatory, to intracellular physiology. This narrative review describes the pathophysiological 'vicious cycle' caused by the combination of obesity and HF. Management of obesity in established heart failure has for years been a controversial topic, and yet an increasing body of evidence suggests that there are numerous benefits to managing obesity and insulin resistance in heart failure. Here we review the existing evidence base, as well as exciting new developments, suggesting that we may finally be on the brink of a revolution in managing obesity in heart failure.

Keywords:  Heart failure; metabolic syndrome; obesity; weight loss

DOI:  https://doi.org/10.1093/cvr/cvaf090
Cell Rep Med. 2025 May 28. pii: S2666-3791(25)00220-4. [Epub ahead of print] 102147

Visceral fat lipolysis by pancreatic lipases worsens heart failure.

Nabil Smichi, Biswajit Khatua, Sergiy Kostenko, Cristiane de Oliveira, Bara El Kurdi, Kalpit Himmatbhai Devani, Shubham Trivedi, Megan Summers, Bryce McFayden, Sarah Navina, Krutika Patel, Sarah Jahangir, Marek Belohlavek, Vijay P Singh.

  Heart failure can be worse when associated with obesity, elevated serum pancreatic enzymes, elevated non-esterified fatty acids (NEFAs), or acute pancreatitis (AP). To understand this, here we study doxorubicin-induced heart failure, experimental AP, or pancreatic lipase-induced visceral fat necrosis in lean, genetically obese (ob/ob), or dual ob/ob pancreatic triglyceride lipase (PNLIP)-knockout mice. NEFA generation and resulting cardiac injury are measured. We note that ob/ob mice develop fat necrosis containing PNLIP and phospholipase A2. This generates excess NEFAs that worsen cardiac injury, cause hypotension, and reduce survival. All these are prevented by PNLIP deletion or pharmacologic inhibition. Live imaging shows that phospholipase A2 damages adipocyte membranes, resulting in PNLIP entry and leakage of adipocyte lipases. PNLIP hydrolyzes adipose triglyceride, generates NEFAs, and causes lipid droplet loss and adipocyte necrosis. Therefore, pancreatic injury can worsen antecedent heart failure by leaked PNLIP, causing excessive visceral adipose lipolysis. Inhibition of such lipolysis may improve heart failure outcomes.

Keywords:  adipose; cell death; fat; fatty acids; heart failure; lipase; lipid; mortality; necrosis; triglyceride

DOI:  https://doi.org/10.1016/j.xcrm.2025.102147
bioRxiv. 2025 May 19. pii: 2024.06.03.597148. [Epub ahead of print]

GCN5L1 inhibits pyruvate dehydrogenase phosphorylation during cardiac ischemia-reperfusion injury.

Paramesha Bugga, Michael W Stoner, Janet R Manning, Bellina As Mushala, Nisha Bhattarai, Maryam Sharifi-Sanjani, Iain Scott.

Myocardial infarction remains one of the leading causes of mortality. Reperfusion of the infarcted myocardium restores blood flow and reduces primary ischemic injury. However, despite its protective function, reperfusion is also associated with several deleterious outcomes that can result in ischemia-reperfusion (I/R) injury to cardiac tissue. While negative outcomes such as reactive oxygen species generation are strongly associated with I/R injury, cardiac energy metabolism is also greatly disrupted. Furthermore, previous studies have shown that the restoration of normal fuel oxidation in the myocardium regulates the extent of contractile recovery. A better understanding of the pathophysiological mechanisms underlying I/R injury may allow us to develop new treatments that limit the negative aspects of the process. In this study, we examined the role played by GCN5L1, a protein implicated in the regulation of energy metabolism, in I/R injury. We demonstrate that cardiac-specific loss of GCN5L1 promotes the inhibitory phosphorylation of pyruvate dehydrogenase in vitro and in vivo , a process likely to inhibit glucose oxidation, and that this corresponds to increased myocardial damage following ischemia-reperfusion (I/R) injury.

DOI: https://doi.org/10.1101/2024.06.03.597148