bims-hafaim 2025-04-13 papers

Issue of 2025–04–13
five papers selected by
Kyle McCommis, Saint Louis University

Am J Physiol Heart Circ Physiol. 2025 Apr 07.

Cardiac Energy Metabolism in Diabetes: Emerging Therapeutic Targets and Clinical Implications.

Archee Panwar, Sufyan Malik, Muhtasim Adib, Gary D Lopaschuk.

Patients with diabetes are at an increased risk for developing diabetic cardiomyopathy and other cardiovascular complications. Alterations in cardiac energy metabolism in diabetic patients, including an increase in mitochondrial fatty acid oxidation and a decrease in glucose oxidation are important contributing factors to this increase in cardiovascular disease. A switch from glucose oxidation to fatty acid oxidation not only decreases cardiac efficiency due to increased oxygen consumption, but it can also increase reactive oxygen species production, increase lipotoxicity, and redirect glucose into other metabolic pathways that, combined, can lead to heart dysfunction. Currently, there is a lack of therapeutics available to treat diabetes-induced heart failure that specifically target cardiac energy metabolism. However, it is becoming apparent that part of the benefit of existing agents such as GLP-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors may be related to their effects on cardiac energy metabolism. In addition, direct approaches aimed at inhibiting cardiac fatty acid oxidation or increasing glucose oxidation hold future promise as potential therapeutic approaches to treat diabetes-induced cardiovascular disease.

Keywords: diabetic cardiomyopathy; fatty acid ß-oxidation; glucose oxidation; mitochondria

DOI: https://doi.org/10.1152/ajpheart.00615.2024

Circ Res. 2025 Apr 11.

Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF.

Yen Chin Koay, Bailey McIntosh, Yann Huey Ng, Yang Cao, XiaoSuo Wang, Yanchuang Han, Saki Tomita, Angela Yu Bai, Benjamin Hunter, Ashish Misra, Christopher M Loughrey, Paul G Bannon, Sean Lal, Aldons J Lusis, David M Kaye, Mark Larance, John F O'Sullivan.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.
METHODS: We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.
RESULTS: We demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.
CONCLUSIONS: The canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.

Keywords: heart failure; ketone bodies; myocardium; oxygen consumption; stroke volume

DOI: https://doi.org/10.1161/CIRCRESAHA.124.325550

Circ Res. 2025 Apr 07.

Metabolic Coordination Structures Contribute to Diabetic Myocardial Dysfunction.

BACKGROUND: Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive.
METHODS: Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing.
RESULTS: Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Acbp was a significant lipid metabolism gene whose expression was upregulated. Consistently, ACBP expression levels were markedly elevated in the hearts of patients with diabetes and diabetic mice. Moreover, we constructed cardiomyocyte-specific Acbp knockout mice that exhibited attenuation of T2DM-induced cardiac remodeling and cardiac dysfunction, including attenuation of cardiac hypertrophy, fibrosis, ultrastructural damage, and enhanced cardiomyocyte contractility and cardiac function. Conversely, cardiac-specific Acbp overexpression via adeno-associated virus type 9, which encodes Acbp under the cTnT (cardiac troponin T) promoter, recapitulated cardiac dysfunction. Mechanistically, cardiac-specific Acbp knockout enhances glucose utilization in diabetic cardiomyocytes, suggesting a potential compensatory mechanism for insufficient ATP levels, highlighting its metabolic role. In addition, combined with mass spectrometry analysis revealed that ACBP binds MyBPC3 (myosin-binding protein C3) in T2DM individuals, which potentially prevents MyBPC3 from assisting the formation of cross-bridge structures between myosin and actin, thereby impairing myocardial contraction. Importantly, chromatin immunoprecipitation sequencing revealed that peroxisome proliferator-activated receptor γ regulates the transcriptional activity of Acbp.
CONCLUSIONS: Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM.

Keywords: cardiomyopathies; heart diseases; lipid metabolism; myocytes, cardiac; myosins

DOI: https://doi.org/10.1161/CIRCRESAHA.124.326044

J Cardiovasc Pharmacol. 2025 Apr 08.

Flavin adenine dinucleotide ameliorates pressure overload-induced heart failure by activating the short-chain acyl-CoA dehydrogenase.

Chunyu Chen, Xue Qin, Yuhong Cao, Liyuan Qing, Zhichao Ma, Qingping Xu, Huan Peng, Guifang Jin, Zhicheng Yang, Jieyu Xing, Sigui Zhou.

Flavin adenine dinucleotide (FAD), a cofactor that catalyzes the reaction of flavin protein, participates in fatty acid β-oxidation, which has been shown to inhibit pathological cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. However, the therapeutic advantage of FAD for heart failure treatment has not been investigated. This study aimed to explore the effects and underlying mechanisms of FAD in a transverse aortic constriction (TAC)-induced heart failure mouse model and in vitro tert-Butyl hydroperoxide (tBHP)-induced cardiomyocyte apoptosis model experiments. FAD considerably inhibited tBHP-induced cardiomyocyte apoptosis. In addition, FAD significantly increased the activity and expression of the short-chain acyl-CoA dehydrogenase (SCAD) enzyme and ATP content while reducing the content of free fatty acids and reactive oxygen species both in vitro and in vivo. Meanwhile, FAD increased the mitochondrial membrane potential, suppressed mitochondrial membrane swelling, and decreased myocardial fibrosis and TUNEL-positive apoptosis cells in the TAC-induced heart failure mice. In conclusion, our results indicate that FAD plays a positive role in preventing and treating heart failure, which can be attributed in part to the activation of SCAD.

Keywords: apoptosis; energy metabolism; flavin adenine dinucleotide; heart failure; short-chain acyl-CoA dehydrogenase

DOI: https://doi.org/10.1097/FJC.0000000000001698

Cardiovasc Diabetol. 2025 Apr 04. 24(1): 155

Metabolic rewiring and inter-organ crosstalk in diabetic HFpEF.

Lingyun Luo, Yuyue Zuo, Lei Dai.

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge. Initially, for an extended period, HFpEF was simply considered as a subset of heart failure, manifesting as haemodynamic disorders such as hypertension, myocardial hypertrophy, and diastolic dysfunction. However, the rising prevalence of obesity and diabetes has reshaped the HFpEF phenotype, with nearly 45% of cases coexisting with diabetes. Currently, it is recognized as a multi-system disorder that involves the heart, liver, kidneys, skeletal muscle, adipose tissue, along with immune and inflammatory signaling pathways. In this review, we summarize the landscape of metabolic rewiring and the crosstalk between the heart and other organs/systems (e.g., adipose, gut, liver and hematopoiesis system) in diabetic HFpEF for the first instance. A diverse array of metabolites and cytokines play pivotal roles in this intricate crosstalk process, with metabolic rewiring, chronic inflammatory responses, immune dysregulation, endothelial dysfunction, and myocardial fibrosis identified as the central mechanisms at the heart of this complex interplay. The liver-heart axis links nonalcoholic steatohepatitis and HFpEF through shared lipid accumulation, inflammation, and fibrosis pathways, while the gut-heart axis involves dysbiosis-driven metabolites (e.g., trimethylamine N-oxide, indole-3-propionic acid and short-chain fatty acids) impacting cardiac function and inflammation. Adipose-heart crosstalk highlights epicardial adipose tissue as a source of local inflammation and mechanical stress, whereas the hematopoietic system contributes via immune cell activation and cytokine release. We contend that, based on the viewpoints expounded in this review, breaking this inter-organ/system vicious cycle is the linchpin of treating diabetic HFpEF.

Keywords: Diabetes; HFpEF; Inflammation; Inter-organ crosstalk; Metabolism

DOI: https://doi.org/10.1186/s12933-025-02707-7