bims-hafaim 2025-12-07 papers

Issue of 2025–12–07
three papers selected by
Kyle McCommis, Saint Louis University

Circ Res. 2025 Dec 04.

Increased CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress that Suppresses Gene Programs for Remodeling and Enables Rescue by Gene Transfer.

Andrew N Carley, Santosh K Maurya, Chandan K Maurya, Yang Wang, Amy Webb, Azariyas A Challa, Tatiana Gromova, Thomas M Vondriska, Zhentao Zhang, Hua Zhu, Ahlke Heydemann, Kenneth C Bedi, Christos P Kyriakopoulos, Craig H Selzman, Stavros G Drakos, Kenneth B Margulies, E Douglas Lewandowski.

BACKGROUND: CPT1 (carnitine palmitoyl transferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.
METHODS: CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9-mediated CPT1a overexpression (adeno-associated virus serotype 9.cTNT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.
RESULTS: CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. Adeno-associated virus-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (P<0.05). Delivery of adeno-associated virus serotype 9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.
CONCLUSIONS: The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.

Keywords: cardiac; glucose; heart failure; metabolism; myocytes; stroke volume

DOI: https://doi.org/10.1161/CIRCRESAHA.125.327403

Metabolism. 2025 Dec 03. pii: S0026-0495(25)00335-X. [Epub ahead of print] 156465

Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling.

Martin Riecan, Barbora Judita Kasperova, Michaela Vondrackova, Petra Janovska, Eliska Haasova, Katerina Adamcova, Peter Ivak, Daniel Hlavacek, Katerina Kroupova, Tomas Cajka, Jan Kopecky, Soňa Štemberková Hubáčková, Milos Mraz, Ivan Netuka, Vojtech Melenovsky, Martin Haluzik, Ondrej Kuda.

BACKGROUND: Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood.
AIMS: We aimed to characterize the metabolic remodeling of epicardial (EAT) and subcutaneous (SAT) adipose tissues in HF with reduced ejection fraction (HFrEF), focusing on lipid metabolism, fatty acid oxidation, and ketogenesis.
METHODS: Clinical and metabolomic profiling were performed on metabolically stable controls (n = 34), patients with mild HFrEF (n = 45), and severe HFrEF (n = 129). Metabolomics profiling identified over 800 metabolites in EAT and SAT. Clustering and pathway enrichment analyses defined depot-specific metabolic shifts across HF stages, while gene expression analyses provided mechanistic support.
RESULTS: Advancing HF was associated with declining cardiac function, systemic congestion, and a metabolic shift toward catabolism. Metabolomics revealed depot-specific adaptations: SAT transitioned smoothly to enhanced lipolysis, whereas EAT demonstrated impaired triacylglycerol replenishment and disrupted final turn of β-oxidation spiral. Both depots increased reliance on acylcarnitine degradation and lipolysis; however, EAT was uniquely characterized by late-stage impairment in mitochondrial and peroxisomal fatty acid oxidation, leading to elevation of 3-hydroxybutyrate and hydroxybutyrylcarnitine tissue levels. Ex vivo analyses of EAT explants showed significantly increased fraction of L-3-hydroxybutyrate enantiomer, produced by EAT, compared to D-3-hydroxybutyrate enantiomer originating from the liver.
CONCLUSIONS: HF progression drives major, depot-specific metabolic remodeling in adipose tissue. In advanced HF, EAT shows impaired fatty acid oxidation and enhanced local production of L-3-hydroxybutyrate in the vicinity of myocardium, highlighting the close metabolic cooperation in nutrient supply between EAT and the heart muscle through the coronary circulation.

Keywords: Acylcarnitines; Fatty acid oxidation; L-β-hydroxybutyrate; Lipidomics; Peroxisomes

DOI: https://doi.org/10.1016/j.metabol.2025.156465

J Cardiovasc Magn Reson. 2025 Nov 27. pii: S1097-6647(25)00155-3. [Epub ahead of print] 101993

Myocardial Energy Metabolism in Heart Failure: Systematic Review and Meta-analysis of ³¹P MRS PCr/ATP Ratio.

Jing Peng, Peng Sun, Jianxiu Lian, Baiyan Jiang, Yang Wu, Minyue Pei, Nan Li, Jiazheng Wang.

OBJECTIVE: Phosphorus-31 magnetic resonance spectroscopy (³¹P MRS) is the only non-invasive imaging modality that directly quantifies myocardial energy metabolism in vivo. While extensively studied, its readiness for clinical application in heart failure remains uncertain. This meta-analysis aimed to evaluate the association between myocardial phosphocreatine-to-ATP (PCr/ATP) ratio, measured by ³¹P MRS, and heart failure, as a step toward assessing its translational potential as a clinical biomarker.
METHODS: We systematically reviewed studies published from Jan 1, 1990, to Dec 31, 2024, using PubMed, Embase, and Web of Science. Eligible studies included cohort studies and randomised controlled trials reporting PCr/ATP ratios in heart failure patients and healthy controls. A random-effects model was used to estimate pooled odds ratios. Risk of bias was assessed using the ROBINS-E tool.
FINDINGS: Twenty-six observational studies met inclusion criteria; no randomised trials were identified. Meta-analysis showed a directionally consistent and substantial association between reduced PCr/ATP ratio and heart failure (odds ratio 7.62, 95% CI 4.90-11.85), with moderate between-study heterogeneity (I²=60% and the prediction interval is (1.35-42.92)). Studies at field strengths >1.5T showed reduced heterogeneity (I²=18.8%) with a comparable effect size (odds ratio 7.69, 95% CI 5.17-11.43). Pre-specified meta-regression did not identify significant moderators (age, female proportion, ejection fraction, NYHA class, field strength, or blood-pool correction; all p≥0.18).
INTERPRETATION: These findings support a clinically sizable but heterogeneous association between impaired myocardial energy metabolism-measured by reduced PCr/ATP ratio using ³¹P MRS-and heart failure. The consistency across subgroups, including HFpEF, suggests potential utility in early-stage or diagnostically challenging heart failure. The results support inclusion of PCr/ATP in prospective studies aimed at validating its clinical utility and advancing metabolic imaging toward routine cardiovascular care.

Keywords: (31)P MRS; cumulative evidence; energy metabolism; heart failure; myocardial function

DOI: https://doi.org/10.1016/j.jocmr.2025.101993