bims-hafaim 2025-12-21 papers

Issue of 2025–12–21
six papers selected by
Kyle McCommis, Saint Louis University

J Am Heart Assoc. 2025 Dec 17. e042505

Sarco/Endoplasmic Reticulum Ca2+ ATPase Activation Shifts Cardiac Fuel Preference Without Impairing Cardiac Function in Obese Mice.

Deveena R Banerjee, Clinton M Hasenour, Mohsin Rahim, Tomasz K Bednarski, Amanda C Doran, David A Jacobson, Jamey D Young.

BACKGROUND: Activity of SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) affects cardiac metabolism and function and is under investigation in clinical trials. SERCA function also regulates glucose metabolism in multiple tissues, but it is unknown how these effects extend to the heart. Pressure overload-induced cardiac hypertrophy corresponds to increased cardiac glucose oxidation in obesity. We hypothesized that SERCA activation by the compound CDN1163 would increase ATP demand due to Ca2+ cycling, leading to increased fat oxidation to maintain cardiac energy homeostasis.
METHODS: In vivo [U-13C3]lactate tracer experiments were performed to assess fasting cardiac metabolic fluxes in Mc4r-/- mice fed a Western diet and treated with CDN1163. Fluxes were estimated by fitting a mathematical model of cardiac metabolism to 13C enrichment measurements of plasma and tissue metabolites taken at the end of the isotope infusion. Metabolic flux measurements were combined with echocardiography, gene expression, and enzymatic assays to assess the effects of SERCA activation on heart function and metabolism following 8 weeks of CDN1163 treatment.
RESULTS: CDN1163 increased cardiac ATPase activity, decreased cytosolic Ca2+ signaling, and decreased cardiac glucose uptake and glycolysis in obese mice. A greater fraction of mitochondrial acetyl-coenzyme A was obtained from nonglycolytic sources, such as fat, to sustain citric acid cycle flux, corresponding to an increase in mitochondrial activity. CDN1163 treatment upregulated gene expression of enzymes in β-oxidation and lipid handling. No changes in basal cardiac function or compensatory left ventricular remodeling were observed.
CONCLUSIONS: SERCA activation promotes flux from nonglucose substrates to fuel cardiac mitochondrial metabolism in obese mice.

Keywords: SERCA; cardiac metabolism; metabolic flux analysis; obesity

DOI: https://doi.org/10.1161/JAHA.125.042505

Circulation. 2025 Dec 18.

IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes.

BACKGROUND: We report IMPROVE-DiCE (Improve Diabetic Cardiac Energetics), a 2-part open-label, phase 2a trial evaluating the safety and effectiveness of ninerafaxstat, a novel therapeutic designed to enhance cardiac energetics. Between May and September 2021, part 1 enrolled patients with type 2 diabetes and obesity without heart failure with preserved ejection fraction (HFpEF). Between January 2023 and June 2024, part 2 enrolled patients with type 2 diabetes, obesity, and HFpEF.
METHODS: Forty-two participants received 200 mg ninerafaxstat twice daily (part 1, n=21, 43% women, 72±0.5 years of age, 4-8 weeks; part 2, n=21, 29% women, 71±6 years of age, 12 weeks). Myocardial energetics (phosphocreatine-to-ATP ratio [PCr/ATP], primary outcome) and function (rest and dobutamine stress) were assessed before and after treatment using magnetic resonance imaging, 31P- and 1H magnetic resonance spectroscopy. In part 1, hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to assess in vivo pyruvate dehydrogenase flux (n=9) and plasma metabolomics and proteomics were also performed.
RESULTS: In part 1, in patients with diabetes and obesity but without HFpEF, the heart was characterized by impaired pyruvate dehydrogenase flux, reduced PCr/ATP, triglyceride deposition, and diastolic impairment. Treatment with ninerafaxstat was associated with improved PCr/ATP (+0.39±0.49 [95% CI, 0.16-0.62]; Cohen's d, 0.79; P=0.002) and lower myocardial triglyceride (by 34%, P=0.03). In part 2, in patients with diabetes, obesity, and symptomatic HFpEF, the heart was characterized by reduced PCr/ATP, diastolic impairment, and failure of systolic augmentation to exercise. Consistently, treatment with ninerafaxstat was associated with improvement in PCr/ATP (+0.15±0.25 [95% CI, 0.03-0.26]; Cohen's d, 0.60; P=0.02), improved systolic augmentation to exercise (+1.4 L/min, P=0.04), improved exercise capacity (6-minute walk distance +16 m, P=0.02), and improved New York Heart Association class symptom burden.
CONCLUSIONS: These mechanistic phase 2a study results show that ninerafaxstat is safely tolerated and improves myocardial energetics in participants with obesity and diabetes without or with clinically manifest HFpEF.
REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04826159.

Keywords: HFpEF; cardiac energy metabolism; diabetic cardiomyopathy; hyperpolarized MR; magnetic resonance imaging; obesity

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.074041

Diabetes Obes Metab. 2025 Dec 17.

Dapagliflozin and chiglitazar combination enhanced myocardial energy metabolism in high-fat diet-fed mice.

Jieying Liu, Jing Zhou, Shunhua Li, Ziyan Xie, Mengyu He, Jing Liu, Xuemei Ma, Miao Yu, Dongmei Wang, Xinhua Xiao.

AIMS: Oral antidiabetic drugs dapagliflozin and chiglitazar have shown potential effects in improving myocardial metabolism. This study aimed to investigate their combined impacts on cardiac energy metabolism in high-fat diet (HFD)-induced obesity mice.
METHODS: Male C57BL/6N mice were randomized into seven groups: (1) normal chow control, (2) high-fat diet (HFD) control, (3) dapagliflozin monotherapy, (4) low dose of chiglitazar monotherapy, (5) high dose of chiglitazar monotherapy and (6, 7) combination therapy groups with dapagliflozin and varying doses of chiglitazar. Myocardial tissues were subjected to targeted metabolomic analysis for free fatty acids (FFAs) species and key intermediates in central carbon metabolism pathways.
RESULTS: The combination therapy significantly improved overall metabolic phenotypes and reduced cardiac lipid droplet size in HFD mice. FFAs profile analysis showed an increased proportion of unsaturated FFAs and a decreased proportion of saturated FFAs. The central carbon metabolism analysis demonstrated alterations in energy metabolic pathways, including glycolysis, purine and pyrimidine metabolism, amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Combined analysis of FFAs and central carbon showed that the TCA cycle was accelerated and ATP production was increased compared with monotherapy. Decreased expression of acetyl-CoA carboxylase 1, increased expression of carnitine palmitoyltransferase 1, as well as elevated levels of citrate synthase and isocitrate dehydrogenase, were validated by Western blot.
CONCLUSIONS: The combination of dapagliflozin and chiglitazar improved cardiac fatty acid and central carbon metabolism, among which acceleration of metabolic flux through the TCA cycle, increased ATP production, and upregulation of key enzyme expression might represent the key beneficial mechanisms.

Keywords: chiglitazar; combination effect; dapagliflozin; energy metabolism; myocardial metabolism

DOI: https://doi.org/10.1111/dom.70327

Front Cardiovasc Med. 2025 ;12 1672513

Identification and validation of key biomarkers of the glycolysis-ketone body metabolism in heart failure based on multi-omics and machine learning.

Na Xiao, Jing Liu, Zhe Chen, Xiaoyong Geng.

Background: Metabolic remodeling, particularly involving glycolysis and ketone body metabolism, is a hallmark of heart failure (HF) pathophysiology. However, the regulatory network linking energy metabolism with immune dysregulation remains poorly understood.
Objectives: This study aimed to identify and validate key biomarkers within the glycolysis-ketone body metabolism axis that contribute to the progression of HF, and to explore their association with immune microenvironment alterations.
Methods: Transcriptomic data from HF patients were integrated with glycolysis and ketone metabolism gene sets. Differentially expressed genes (DEGs) were identified and analyzed through Weighted Gene Co-expression Network Analysis (WGCNA). Candidate genes were refined using machine learning algorithms (LASSO regression and Boruta), with functional enrichment assessed via Gene Set Enrichment Analysis (GSEA). Immune infiltration was profiled using ssGSEA, and regulatory networks were constructed by integrating miRNA and transcription factor predictions. Experimental validation was conducted in a murine myocardial infarction model using qPCR and cardiac ultrasound imaging.
Results: Five candidate genes related to glycolysis and ketone metabolism were identified, among which TIMP1 emerged as the key hub gene. TIMP1 expression was significantly elevated in HF and correlated with enriched pathways including inflammatory signaling and mitochondrial dysfunction. Immune profiling revealed that TIMP1 positively associated with the infiltration of activated CD8⁺ T cells and dendritic cells, potentially mediated by chemokines such as CCL2. Regulatory network analysis suggested that upstream transcription factors and miRNAs may contribute to TIMP1 overexpression. Animal model validation confirmed the upregulation of TIMP1 and other core genes, supporting its central role in HF progression.
Conclusion: This study identifies TIMP1 as a central regulator linking glycolysis-ketone metabolic imbalance with immune microenvironment dysregulation in heart failure. These findings offer new mechanistic insights and propose TIMP1 as a potential diagnostic biomarker and therapeutic target in HF.

Keywords: glycolysis; heart failure; immune infiltration; ketone body metabolism; machine learning

DOI: https://doi.org/10.3389/fcvm.2025.1672513

Eur Heart J Imaging Methods Pract. 2025 Oct;3(4): qyaf146

Cardiac energetics in severe mitral regurgitation: relationship with eccentric hypertrophy, stroke volume, and effects of valve repair.

Mark A Peterzan, William T Clarke, Hannah A Lake, David Dearlove, John A Henry, Andrew J M Lewis, Moritz J Hundertmark, Jennifer J Rayner, Andrew P Apps, William D Watson, Rana A Sayeed, Craig A Lygate, Stefan Neubauer, Christopher T Rodgers, Oliver J Rider.

Aims: Understanding changes in ATP metabolism may lead to improved risk stratification in severe primary mitral regurgitation (MR). Here, we seek to compare the energetic phenotype of volume-overload pathological hypertrophy with athletic hypertrophy and with the normal heart under catecholamine stress.
Methods and results: Nineteen severe-MR patients underwent cardiac magnetic resonance and 31P-spectroscopy for energetics, including phosphocreatine to adenosine triphosphate ratio (PCr/ATP), the pseudo-first-order forward rate constant of the creatine kinase reaction (k f) and CK flux (k f × [PCr]). When compared with 20 healthy controls, severe MR was associated with lower PCr/ATP (1.58 ± 0.32 vs. 2.08 ± 0.28, P < 0.001). This is related to the severity of regurgitation (r -0.59, P < 0.001) but not to LVEF (r -0.20, P = 0.23) or LV systolic strain (P = 0.18). When compared to 17 athletes with similarly increased end-diastolic volume (athletes 107 ± 10 mL/m2 vs. 114 ± 22, P = 0.29), severe MR had greater total cardiac output (by 42%, P < 0.001), and lower PCr/ATP (by 28%, P < 0.001) and CK flux (by 41%, P = 0.04). When compared to normal hearts during dobutamine stress at matched cardiac output levels, median k f (by 45%, P = 0.08) and CK flux (by 53%, P = 0.02) were lower in severe MR. PCr/ATP increased (by 17%, P = 0.04) following mitral valve repair (MVR) in a subset of patients (n = 14, median 7 months). Seven patients during MVR and six patients without volume loading donated LV biopsy, revealing that creatine was not lower in severe MR.
Conclusion: Even with normal LVEF, severe MR is associated with reduced PCr/ATP, CK k f, and CK flux. PCr/ATP reduction resolved with MVR. Thus, targeting CK capacity and/or flux may be a therapeutic strategy to prevent/treat systolic failure in MR.

Keywords: PCr/ATP; mitral regurgitation; mitral valve repair; myocardial energetics; phosphorous spectroscopy

DOI: https://doi.org/10.1093/ehjimp/qyaf146

Cardiol Rev. 2025 Dec 15.

Therapeutic Value of SGLT2 Inhibitors in the Management of Congestive Heart Failure.

Omar Seyam, William H Frishman, Wilbert S Aronow.

Initially developed as antihyperglycemic agents, sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated therapeutic efficacy at every level of the cardiovascular disease spectrum. Multiple cardiovascular outcome trials have shown that SGLT2 inhibitors significantly reduce hospitalizations for heart failure as well as major adverse events. SGLT2 inhibitors have demonstrated remarkable advantages in lowering the risk of heart failure, even in individuals without diabetes, including those with heart failure. The exact mechanisms by which SGLT2 inhibitors provide cardiovascular protection are still unknown despite their widespread usage, indicating the need for more research. SGLT2 inhibitors have transformed the treatment of cardiovascular disease, providing substantial therapeutic promise for a wide range of patients. They are anticipated to become more and more important in the prevention and management of cardiovascular disease.

Keywords: diabetes mellitus; heart failure; sodium-glucose transporter 2 inhibitors

DOI: https://doi.org/10.1097/CRD.0000000000001154