bims-hafaim 2025-07-27 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–07–27
seven papers selected by
Kyle McCommis, Saint Louis University

Lowering Cardiac Branched-Chain Keto Acid Levels Enhances Cardiac Glucose Oxidation and Cardiac Efficiency via Enhancing Mitochondrial Insulin Signaling in Heart Failure.
Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.
Sodium-glucose Cotransporter-2 Canagliflozin's impact on cardiovascular disease in the setting of metabolic syndrome: A proteomic analysis.
Efficacy of sodium-glucose cotransporter 2 inhibitors for super-aged heart failure population.
Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Imbalance in Heart Failure Progression.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review.
Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.

Circ Heart Fail. 2025 Jul 25. e012012

Lowering Cardiac Branched-Chain Keto Acid Levels Enhances Cardiac Glucose Oxidation and Cardiac Efficiency via Enhancing Mitochondrial Insulin Signaling in Heart Failure.

Qutuba G Karwi, Liyan Zhang, Keshav Gopal, Cory S Wagg, Kim L Ho, Qiuyu Sun, Sai Panidarapu, Kaya Persad, Betüol Altuany, Shaden Damen, Ezra Ketema, Jody Levasseur, Thomas Pulinilkunnil, John R Ussher, Jason R B Dyck, Gary D Lopaschuk.

   BACKGROUND: Elevated levels of cardiac branched-chain amino acids (BCAAs) and their metabolites, namely branched-chain keto acids (BCKAs), contribute to the development of insulin resistance, contractile dysfunction, and adverse remodeling in the failing heart. However, there is still confusion about whether BCAA or BCKA mediate these detrimental effects in the failing heart.
METHODS: Cardiac-specific mitochondrial branched-chain aminotransferase, the enzyme that converts BCAA into BCKA, knockout (BCAT2-/-) mice underwent a sham or transverse aortic constriction surgery to induce heart failure. Changes in cardiac function and structure were monitored pre- and posttransverse aortic constriction using echocardiography, and metabolic flux through the tricarboxylic acid cycle was measured by perfusing isolated working hearts with radiolabeled energy substrates. Direct effects of BCAA and BCKA on cell hypertrophy were characterized using phenylephrine-induced cell hypertrophy in differentiated cells.
RESULTS: Lowering cardiac BCKA levels in BCAT2-/- failing hearts increases insulin-stimulated glucose oxidation rates via enhancing mitochondrial protein kinase B and pyruvate dehydrogenase complex activities. Increased glucose oxidation rates in BCAT2-/- failing hearts enhanced cardiac efficiency by decreasing myocardial oxygen consumption rates. However, cardiac BCAA accumulation was associated with excessive stimulation of the mammalian target of rapamycin signaling and aggravation of adverse cardiac remodeling in BCAT2-/- failing hearts. As a result, the impact of BCAA accumulation offsets the beneficial effects of lowering cardiac BCKA levels on cardiac insulin sensitivity and cardiac efficiency.
CONCLUSIONS: Lowering BCKA levels enhances cardiac glucose oxidation and cardiac efficiency by enhancing mitochondrial insulin signaling. BCAA accumulation worsens adverse cardiac remodeling by exacerbating cardiac mammalian target of rapamycin signaling.

Keywords:  animals; glucose; heart failure; insulin; keto acids

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.012012
Sci Signal. 2025 Jul 22. 18(896): eadp6006

Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.

Yan Sun, Abhishek Kumar Mishra, Vasanth Chanrasekhar, Michaela Door, Chase W Kessinger, Bing Xu, Peiyang Tang, Yunan Gao, Sarah Kamli-Salino, Katherine Nelson, Mirela Delibegovic, E Dale Abel, Jonanthan A Kirk, Maria I Kontaridis.

Cardiomyocytes (CMs) normally use fatty acid oxidation (FAO) as their primary energy source. In response to pathological stress, the substrate preference of CMs switches from FAO to glucose metabolism, leading to the development of heart failure. Obesity increases this pathological risk of cardiovascular disease. We focused on protein tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling, the abundance and activity of which are increased in brain, muscle, and adipose tissues in obese and/or diabetic animals and in obese human patients. We generated mice with CM-specific deficiency in PTP1B (PTP1Bfl/fl::ꭤMHCCre/+) to investigate the CM-specific role of PTP1B in response to cardiac dysfunction induced by high-fat diet (HFD) feeding. Although no physiological or functional cardiac differences were observed at baseline, PTP1Bfl/fl::ꭤMHCCre/+ mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis induced by HFD feeding. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased FAO and lipolysis but reduced glucose metabolism. Furthermore, phosphoproteomics analyses and mechanistic studies identified an axis involving the kinases PKM2 and AMPK downstream of PTP1B in the heart, which collectively acted to promote FAO and suppress lipogenesis. Together, these results suggest that CM-specific deletion of PTP1B prevents a substrate switch from FAO to glucose metabolism, protecting the heart against the development of HFD-induced cardiac hypertrophy and dysfunction.

DOI: https://doi.org/10.1126/scisignal.adp6006
Eur J Pharmacol. 2025 Jul 17. pii: S0014-2999(25)00729-0. [Epub ahead of print]1003 177975

Sodium-glucose Cotransporter-2 Canagliflozin's impact on cardiovascular disease in the setting of metabolic syndrome: A proteomic analysis.

Jad Hamze, Dwight D Harris, Christopher Stone, Kelsey C Muir, Mark Broadwin, Meghamsh Kanuparthy, Ruhul Abid, Frank W Sellke.

   RATIONALE: Ischemic heart disease (IHD) is the leading cause of global mortality and is often complicated by metabolic syndrome (MetS), making its management challenging. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, such as canagliflozin (CAN), have demonstrated cardioprotective effects, but the precise molecular mechanisms underlying these benefits in the setting of IHD and MetS remain unclear.
OBJECTIVES: This study aimed to investigate the myocardial phenotypic changes induced by CAN treatment using a highly sensitive proteomic approach in a large animal model of IHD and MetS.
FINDINGS: In a swine model of MetS and chronic myocardial ischemia, CAN treatment led to significant metabolic shifts, including the downregulation of glycolysis and gluconeogenesis and the upregulation of oxidative phosphorylation and electron transport chain activity. Proteomic analysis revealed increased expression of vesicular and mitochondrial transport proteins in chronically ischemic myocardium and elevated thioredoxin levels in non-ischemic myocardium, indicating improved mitochondrial function, reduced oxidative stress, and enhanced cytoskeletal remodeling.
CONCLUSIONS: CAN treatment induces extensive myocardial adaptations that contribute to its cardioprotective effects, particularly by optimizing myocardial metabolism, mitigating oxidative stress, and promoting ventricular remodeling. These findings provide valuable insights into the therapeutic potential of CAN in IHD and MetS and highlight the utility of proteomics in advancing heart failure treatment strategies.

Keywords:  Canagliflozin (SGLT-2 inhibitor); Cardioprotection; Ischemic heart disease; Metabolic syndrome; Mitochondrial function; Proteomics

DOI:  https://doi.org/10.1016/j.ejphar.2025.177975
Int J Cardiol. 2025 Jul 19. pii: S0167-5273(25)00690-4. [Epub ahead of print]439 133647

Efficacy of sodium-glucose cotransporter 2 inhibitors for super-aged heart failure population.

Jun-Ichi Noiri, Hidekazu Tanaka, Susumu Odajima, Wataru Fujimoto, Hiroshi Okamoto, Chihiro Fujii, Hiroshi Tsunamoto, Yu Nishihara, Shun Nagai, Koya Uemura, Terunobu Fukuda, Eriko Hisamatsu, Hiromasa Otake.

   BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are indicated for patients with all phenotypes of heart failure (HF). Despite the current unprecedented super-aged society in real-world settings, the efficacy of SGLT2 inhibitors in super-aged HF patients, especially those of ≥80 years, remains unknown.
METHOS: This study was conducted across three hospitals in Japan, including 238 HF patients ≥80 years (mean 84.2 ± 3.3 years), who were treated with SGLT2 inhibitors (dapagliflozin or empagliflozin). SGLT2 inhibitors were used for HF, with preserved ejection fraction in 131 patients (55.0 %), mildly-reduced ejection fraction in 54 patients (22.7 %), and reduced ejection fraction in 53 patients (22.3 %). Among 238 patients, 191 (80.3 %) continued SGLT2 inhibitors, while 47 (19.7 %) discontinued SGLT2 inhibitors (for any reason) during follow-up. The primary outcome was a composite of cardiovascular death or worsening HF, with a median follow-up duration of 2.73 (2.08-3.52) years.
RESULTS: Cumulative incidence curves modified by the Simon-Makuch method with a time-varying Cox regression analysis showed that HF patients with continued SGLT2 inhibitor treatment had significantly favorable outcomes, which remained consistent after adjustment for baseline characteristics by propensity score matching, and discontinuation of SGLT2 inhibitors was the strongest contributing factor to the outcome by a multivariable analysis. Moreover, the multivariable analysis identified a higher clinical frailty scale score as an independent factor associated with discontinuation of SGLT2 inhibitors.
CONCLUSIONS: This study provides real-world evidence supporting the use of SGLT2 inhibitors in super-aged patients with HF, emphasizing the importance of appropriately assessing the continuation of SGLT2 inhibitors.

Keywords:  Heart failure; Sodium-glucose cotransporter 2 inhibitor; Super-aged society

DOI:  https://doi.org/10.1016/j.ijcard.2025.133647
J Cardiovasc Transl Res. 2025 Jul 25.

Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Imbalance in Heart Failure Progression.

Tao He, Jianmei Sha, Yuxin Hu, Caihong Shao, Yi Zhou, Lu Chen, Jianhua Yao, Junli Gao.

  The heart grows in response to both pathological and physiological stimuli. Pathological hypertrophy often leads to cardiomyocyte loss and heart failure (HF), whereas physiological hypertrophy paradoxically protects the heart. Comparing these two types of hypertrophy can elucidate the differences and connections in their molecular mechanisms, which is pivotal for unraveling the pathogenesis of HF. This study compares pathological (TAC-induced) and physiological (exercise-induced) cardiac hypertrophy using single-cell and bulk transcriptomics. Mitochondrial fusion/fission imbalance emerged as a key dysregulated pathway in both models. An early increase in the fusion/fission ratio (2 weeks post-TAC) resembled exercise-induced remodeling, while a progressive decline at 5-8 weeks marked transition to pathological hypertrophy. By 11 weeks, suppressed fusion and increased fission led to heart failure. Downregulation of fusion genes (Mfn1, Mfn2, Opa1) and upregulation of fission genes (Fis1, Dnm1l) highlight mitochondrial dynamics as critical drivers of disease progression.

Keywords:  Heart failure; Mitochondrial fission; Mitochondrial fusion; Pathological hypertrophy; Physiological hypertrophy; Single-cell transcriptomics

DOI:  https://doi.org/10.1007/s12265-025-10662-7
Cureus. 2025 Jun;17(6): e86368

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review.

Amir Saeed, Bilal Younas, Ali Rohan, Usman Haider, Asad Mukhtar, Marriam Nazir, Maryam.

  Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by impaired ventricular filling and increased heart failure hospitalizations. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated cardiovascular and renal benefits in various heart failure populations, but their effects on HFpEF remain an area of growing interest. This study aims to evaluate the impact of SGLT2 inhibitors on key clinical outcomes in patients with HFpEF, including cardiovascular death, hospitalization for heart failure, exercise capacity, symptoms (as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ)), kidney disease progression, and other renal outcomes. A systematic review of randomized controlled trials (RCTs) assessing the effects of SGLT2 inhibitors (empagliflozin, dapagliflozin, sotagliflozin, canagliflozin, and ertugliflozin) in HFpEF patients was conducted. This systematic review was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) principles. The literature was searched using open-access, full-text English papers from January 2015 to April 2025 across PubMed, Embase, and the Cochrane Library. A total of 108 articles were retrieved through the initial search. After screening and checking for eligibility according to the pre-specified inclusion criteria, the methodological quality was assessed in 17 included studies using the Mixed Methods Appraisal Tool (MMAT) score. The MMAT Score 4 indicates a medium risk of bias (ROB), and the MMAT Score 5 indicates a low ROB. Ten studies had low ROB and were classified as "high quality." Seven had uncertain ROB, lowering the evidence by one point to "moderate quality," while one study had a high ROB. SGLT2 inhibitors were associated with significant reductions in cardiovascular death and heart failure-related hospitalizations. Improvements in KCCQ total symptom scores were observed, indicating enhanced patient-reported outcomes. The renal benefits of SGLT2 inhibitors were evident, with a reduction in kidney disease progression and a marked decrease in cardiovascular-related renal outcomes.

Keywords:  cardiovascular death; exercise capacity; hfpef; hospitalization; kansas city cardiomyopathy questionnaire; renal outcomes; sglt2 inhibitors

DOI:  https://doi.org/10.7759/cureus.86368
Eur Heart J. 2025 Jul 24. pii: ehaf491. [Epub ahead of print]

Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.

Christoph Maack, Jan Dudek, Edoardo Bertero, Emmanouil Tampakakis, Hilary J Vernon.

  Mitochondrial cardiomyopathies are a heterogeneous group of disorders caused by dysfunction of mitochondrial energy production due to genetic mutations affecting mitochondrial or nuclear DNA. Mitochondrial cardiomyopathies can include a wide range of cardiac manifestations and are frequently associated with other multisystemic symptoms, including skeletal myopathy, neurological deficits, and metabolic disturbances. Advances in genetic testing have improved diagnostic accuracy, but early identification remains challenging due to the variable clinical presentation and clinical overlap with other cardiomyopathies. Therapeutic strategies are still evolving, with current management focusing on symptom control and mitigation of mitochondrial dysfunction. This review aims to provide a comprehensive overview of the pathophysiology, clinical features, diagnostic approaches, and treatment options for mitochondrial cardiomyopathies, highlighting the ongoing need for research into effective therapies and improved patient outcomes.

Keywords:  Bioenergetics; Heart failure; Mitochondrial cardiomyopathy; mtDNA

DOI:  https://doi.org/10.1093/eurheartj/ehaf491