bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2025–07–06
ten papers selected by
Kyle McCommis, Saint Louis University
  1. Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.
  2. Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure.
  3. Heterozygous MYH7 R403Q mutation impairs left atrial mitochondrial function in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy.
  4. Complexome profiling identifies changes in mitochondrial supercomplexes in murine heart failure.
  5. Loss of Elmsan1 in Cardiomyocytes Leads to Age-Dependent Cardiac Dysfunction and Reduced Lifespan.
  6. Multi-omics analysis of diabetic cardiomyopathy pathogenesis using a type 2 diabetic Zucker diabetic fatty rat model.
  7. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  8. Canagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces lung fibrosis in left heart dysfunction.
  9. The complementary effects of GLP-1 receptor agonists and SGLT2 inhibitors in transthyretin cardiac amyloidosis patients: A retrospective multicenter cohort study.
  10. Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice.
  1. J Mol Cell Cardiol Plus. 2025 Sep;13 100461
    Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.
    Nadina R Latchman, Tyler L Stevens, Kenneth C Bedi, Benjamin L Prosser, Kenneth B Margulies, John W Elrod.
       Background: Cardiomyocyte structural remodeling is reported as a causal contributor to heart failure (HF) development and progression. Growing evidence highlights the role of organelle apposition in cardiomyocyte function and homeostasis. Disruptions in organelle crosstalk, such as that between the sarcoplasmic reticulum (SR) and mitochondria, dysregulate numerous cellular processes that include calcium handling and cellular bioenergetics, two processes that are disrupted and implicated in cardiac pathophysiology. While the physical distance between organelles is thought to be essential for homeostatic cardiomyocyte function, whether the interactions and coupling of organelles are altered in human heart failure remains unclear.
    Methods: Here, we utilized transmission electron microscopy to characterize the role of organelle apposition in cardiomyocytes from patients with various etiologies of HF. Subsequently, we employed molecular approaches to examine expression changes of proposed organelle tethers.
    Results: We demonstrate that cardiomyocytes from dilated cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy hearts display smaller, rounded mitochondria as compared to nonfailing controls. Failing cardiomyocytes also exhibited disrupted SR-mitochondria juxtaposition and changes in the expression of various proposed molecular tethers. Further analysis revealed alterations in lipid droplet dynamics including decreased lipid droplet number and less lipid droplets in association with mitochondria in failing cardiomyocytes.
    Conclusion: We observed dysregulated organelle dynamics which was conserved across various etiologies of heart failure. Our results suggest that organelle structure and apposition is a possible contributor to human HF progression.
    Keywords:  Cardiomyocyte structure; Heart failure; Lipid droplet; Mitochondria; Organelle apposition; Sarcoplasmic reticulum; Tethering
    DOI:  https://doi.org/10.1016/j.jmccpl.2025.100461
  2. J Mol Cell Cardiol Plus. 2025 Sep;13 100459
    Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure.
    Mai Usui, Yu Tsurekawa, Tatsuya Ikehara, Atsuyuki Shimazaki, Archana Vijayakumar, Robert P Myers, G Mani Subramanian, Eisuke Murakami.
      Impaired myocardial energetics, including fatty acid oxidation (FAO), is a hallmark feature in the pathophysiology of various disorders. Deficiency of adipose triglyceride lipase (ATGL) results in impaired FAO which leads to severe heart failure due to massive triglyceride accumulation in cardiac muscle and coronary vasculature. Acetyl-CoA carboxylase 2 (ACC2) is a mitochondrial enzyme that regulates FAO; ACC2 inhibition increases transport of fatty acids into mitochondria for oxidation. In this study, the murine ATGL knockout (KO) model of severe heart failure was used to evaluate the effects ACC2 inhibition induced by whole body genetic KO (Atgl/Acc2 double KO mice) and pharmacological inhibition with TLC-3595, an oral, selective small molecule inhibitor of ACC2. Both genetic deletion of Acc2 and treatment with TLC-3595 in Atgl KO mice promoted mitochondrial FAO, reduced cardiac lipid accumulation and remodeling, and led to significant improvements in cardiac function, locomotor activity, and survival. Metabolite profiling of cardiac tissue of Atgl/Acc2 double KO mice and Atgl KO mice treated with TLC-3595 revealed ACC2-specific changes, including reduced malonyl-CoA and increased short-, medium-, and long-chain acylcarnitines, consistent with improved FAO. These findings support the therapeutic targeting of ACC2 for the treatment of heart failure associated with impaired FAO.
    Keywords:  ACC2; Cardiac metabolism; Cardiovascular therapeutics; Fatty acid oxidation; Triglycerides
    DOI:  https://doi.org/10.1016/j.jmccpl.2025.100459
  3. J Appl Physiol (1985). 2025 Jun 30.
    Heterozygous MYH7 R403Q mutation impairs left atrial mitochondrial function in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy.
    Alexa Krause, Taylor J Kelty, Grace M Meers, Alan J Russell, Marc J Evanchik, Ben Barthel, Craig A Emter, R Scott Rector.
      Hypertrophic cardiomyopathy (HCM) can be caused by a MYH7 R403Q gene mutation, which drives pathological cardiac remodeling and may ultimately lead to heart failure. Here we sought to examine the effects of this mutation on cardiac mitochondrial function in a Yucatan mini-pig model of genetic HCM. Activity of key mitochondrial enzymes, citrate synthase and β-HAD, were significantly reduced in the left atria of HCM animals compared to the control group. However, left atrial mitochondrial respiration was significantly greater in HCM pigs vs controls in the following states: basal (42%, p=0.001), state 2 (47%, p=0.02) and uncoupled (p=0.003), potentiating a compensatory mechanism. Surprisingly, left ventricular mitochondrial respiration and mitochondrial enzymatic activity did not differ between the HCM model vs healthy control pigs. However, proteomic profiling revealed parallel mitochondrial dysfunction and impairment to energy metabolism processes in both chambers, such as inhibited fatty acid metabolism and mitogenesis in the left atria and increased mitochondrial dysfunction and concentration of fatty acids in the left ventricle. Collectively, the MYH7 R403Q mutation may contribute to HCM through chamber-specific mechanisms that promote mitochondrial dysfunction and impaired energy homeostasis. Further, these findings demonstrate the utility of this preclinical large animal model for identifying novel mechanisms underlying genetic heart failure with translational impact for individuals affected with HCM.
    Keywords:  MYH7 R403Q; SOMAscan; hypertrophic cardiomyopathy; mitochondrial dysfunction; swine
    DOI:  https://doi.org/10.1152/japplphysiol.00339.2025
  4. Am J Physiol Heart Circ Physiol. 2025 Jun 30.
    Complexome profiling identifies changes in mitochondrial supercomplexes in murine heart failure.
    Claire Fong-McMaster, Ella McIlroy, Michelle M Levesque, Stephanie Myers, Serena M Pulente, Gurrose Gahla, Ilka Lorenzen-Schmidt, Miroslava Cuperlovic-Culf, Arsalan S Haqqani, Erin E Mulvihill, Mary-Ellen Harper.
      Heart failure is characterized by metabolic derangements such as altered substrate metabolism and mitochondrial dysfunction. Mitochondrial supercomplexes, which are higher-order molecular structures comprised of multi-subunit complexes of the electron transport chain, are decreased in heart failure. To investigate the supercomplex proteome composition in heart failure, we used an in vivo myocardial infarction (MI) model in which mice exhibited reduced cardiac function, confirmed by two-dimensional echocardiography at 4 weeks post-infarction. To assess proteins within supercomplexes, we used an emerging technique known as complexome profiling. This technique involved separating out mitochondrial protein complexes using Blue-Native PAGE combined with mass spectrometry to identify proteins within supercomplex gel bands. We identified band-dependent decreases or increases in the relative abundance of subunits of the electron transport chain between MI and sham mice. Decreased abundance of proteins involved in α-ketoglutarate dehydrogenase metabolism including DLST was also identified in the supercomplex bands of MI mice compared to sham mice. In addition, decreased abundance of redox-related proteins such as SOD2 and changes in ribosome protein subunits were identified in the MI mitochondria. In conclusion, we identified changes in the mitochondrial supercomplex proteome in a murine model of heart failure, providing insight and novel mechanisms that may be contributing to the metabolic dysfunction in heart failure.
    Keywords:  Blue-Native PAGE; Respirasome; cardiomyopathy; mass spectrometry; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpheart.00278.2025
  5. Am J Physiol Heart Circ Physiol. 2025 Jun 30.
    Loss of Elmsan1 in Cardiomyocytes Leads to Age-Dependent Cardiac Dysfunction and Reduced Lifespan.
    Meimei Wang, Hui Li, Chaoshan Han, Yunxi Chen, Lihao He, Min Xie, Hind Lal, Vladimir G Fast, Douglas R Moellering, Jianyi Zhang, Rui Lu, Martin Young, Yang Zhou.
      Histone deacetylase (HDAC) complexes regulate pathological gene programs during heart disease progression. The recently identified mitotic deacetylase complex (MiDAC), which includes DNTTIP1, ELMSAN1, and HDAC1/2, remains the least characterized among these complexes. ELMSAN1 has been implicated in left ventricular remodeling, and its global deletion in mice leads to heart malformation. To investigate its role in mouse heart, we generated cardiomyocyte-specific Elmsan1 knockout (ELM cKO) using αMHC driven Cre recombinase. We analyzed both male and female animals across three experimental groups: αMHC-Cre (Cre control), ELM fl/fl (floxed control) and ELM cKO. In male ELM cKO mice, ejection fraction (EF) was significantly reduced by 12 weeks (45.64±3.12%), compared to αMHC-Cre (55.91±1.29%) and ELM fl/fl (59.16±3.70%) controls. By 24 weeks, EF declined further to 20.79%±4.52, representing a reduction of 46.4% (p<0.01) and 62.1% (p<0.0001) compared to αMHC-Cre and ELM fl/fl mice respectively. The heart failure phenotype in ELM cKO mice was supported by cardiomyocyte hypertrophy morphology, ventricular dilation, and shortened lifespan. Female ELM cKO mice exhibited similar defects with delayed onset. To investigate early molecular changes, we performed RNA sequencing on pre-symptomatic hearts from 8-week-old mice. A total of 1055 genes were differentially expressed in ELM ckO hearts, with 460 upregulated and 595 downregulated. Gene enrichment analysis revealed suppression of tricarboxylic acid cycle and key cardiac genes. These transcriptional changes were accompanied by decreased mitochondrial respiratory chain complex proteins, ultrastructural mitochondrial abnormalities, and impaired calcium handling. Our study demonstrates that Elmsan1 is pivotal for maintaining the heart function and hemostasis with advanced age.
    Keywords:  Elmsan1; HDAC1/2; MiDAC; cardiomyopathy; heart failure
    DOI:  https://doi.org/10.1152/ajpheart.00810.2024
  6. Sci Rep. 2025 Jul 02. 15(1): 22797
    Multi-omics analysis of diabetic cardiomyopathy pathogenesis using a type 2 diabetic Zucker diabetic fatty rat model.
    Kazuhiro Tanabe, Qianqian Zheng, Xuguang Zhang, Naoki Tanaka, Chihiro Hayashi, Asaka Yokota, Rina Otsuka, Tomoko Katahira, Motoyuki Kohjima, Makoto Nakamuta.
      Diabetic cardiomyopathy (DCM) is a leading cause of mortality in patients with diabetes, highlighting the need to better understand its mechanisms for effective treatment. The primary pathogenic mechanism of DCM is mitochondrial dysfunction associated with increased oxidative stress; however, the exact reasons why diabetes triggers this condition remain unclear. An 8-week-old male Zucker diabetic fatty rat model of type 2 diabetes was used for this analysis. Metabolomic and lipidomic analyses were conducted not only in the heart but also across several other organs to elucidate metabolic changes specifically occurring in the heart. Proteomic analysis and gene expression profiling using qPCR were performed on the heart to achieve a comprehensive understanding. The marked reduction of the radical scavenger carnosine and the increased gene expression of catalase and Sestrin2 in the heart suggested elevated oxidative stress. A decrease in Complex I proteins and an increase in Complex I gene expression indicate rapid mitochondrial turnover in diabetic cardiomyocytes. Additionally, the increased expression of adenylate kinase and xanthine oxidoreductase accelerated the adenosine monophosphate degradation pathway, leading to reactive oxygen species generation. These insights into mitochondrial dysfunction and metabolic disturbances could inform the development of innovative therapies and pharmacological approaches for managing diabetic heart failure.
    Keywords:  Diabetic cardiomyopathy; Metabolomics; Mitochondrial disfunction; Oxidative stress; Proteomics; ROS
    DOI:  https://doi.org/10.1038/s41598-025-04670-5
  7. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  8. Asian Cardiovasc Thorac Ann. 2025 Jul 03. 2184923251352222
    Canagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces lung fibrosis in left heart dysfunction.
    Meghamsh Kanuparthy, Dwight D Harris, Mark Broadwin, Christopher Stone, Jad Hamze, Keertana Yalamanchili, Sharif Sabe, Frank W Sellke.
      BackgroundLeft heart failure is the most common cause of pulmonary hypertension and increases morbidity and mortality. We investigate the use of canagliflozin, an antidiabetic Sodium-glucose Cotransporter-2 Inhibitor, which is first-line therapy in congestive heart failure, on pulmonary fibrosis in a porcine model of chronic myocardial ischemia.MethodologySixteen Yorkshire swine, eight in a normal diet control arm (NDC) and eight in the canagliflozin arm (CAN), underwent left thoracotomy and ameroid constrictor placement on the left circumflex artery. Seven weeks after placement, the swine underwent harvest procedure. During harvest, left ventricular contractility was quantified by direct left ventricular pressure-volume loops. Protein expression was quantified by immunoblotting and Masson's trichrome staining was utilized to assess perivascular collagen deposition.ResultsAnalysis of left ventricular ejection fraction demonstrated no significant difference between CAN and NDC. Western blot analysis demonstrated increases in TGFβ signaling pathways with decreased free TGFβ and TGFβ monomers in CAN pigs (p < 0.01). Downstream mediators of TGFβ were also increased in NDC with an increase in phospho-SMAD2/3 activity (p = 0.005). Masson's Trichrome analysis of lung tissue demonstrated a trend toward reduced perivascular collagen deposition in CAN swine lungs (p = 0.086).ConclusionsCanagliflozin ameliorates chronic fibrotic changes related to pulmonary hypertension in left ventricular failure. While there was a strong trend toward significance in histologic analysis, this may be limited by the duration of our model. Western blot analysis, however, demonstrates that CAN's modulation of TGFβ signaling pathways may play a role in the management of secondary pulmonary hypertension.
    Keywords:  Myocardial ischemia; cardiac; ischemic cardiomyopathy; lung—other; pulmonary arteries/veins (incl normal and diseased); pulmonary vascular resistance/hypertension; thoracic
    DOI:  https://doi.org/10.1177/02184923251352222
  9. Int J Cardiol. 2025 Jun 29. pii: S0167-5273(25)00610-2. [Epub ahead of print] 133567
    The complementary effects of GLP-1 receptor agonists and SGLT2 inhibitors in transthyretin cardiac amyloidosis patients: A retrospective multicenter cohort study.
    Ahmed K Mahmoud, Ibrahim Kamel, Kamal Awad, Juan Farina, Ramzi Ibrahim, Mahmoud Abdelnabi, Mohamed Allam, Hoang Nhat Pham, Julie Rosenthal, Eric Steidley, Steven J Lester, Benjamin Horn, Chadi Ayoub, Reza Arsanjani.
       BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive infiltrative cardiomyopathy that can lead to symptomatic heart failure (HF). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown favorable cardiovascular and metabolic effects, with significant benefits in ATTR-CA. With the widespread use of GLP-1 receptor agonists (GLP-1RAs), their potential in this population is of interest. This study sought to investigate the added effects of GLP-1RA to SGLT2i in ATTR-CA patients.
    METHODS: We identified patients with ATTR-CA and SGLT2i use from 2013 to 2024. Two cohorts were compared: patients on both GLP-1RA and SGLT2i and those on SGLT2i alone. Primary outcomes included all-cause mortality and major adverse cardiovascular events (MACE). Secondary outcomes were HF exacerbations, ischemic stroke, all-cause hospitalization, atrial fibrillation, and ventricular arrythmia.
    RESULTS: After propensity score matching, the GLP-1RA cohort had a significant reduction in all-cause mortality (1.8 % vs 5.5 %; HR 0.30, 95 %CI 0.16-0.55, p < 0.0001) and MACE (14.0 % vs 19.3 %; HR 0.64, 95 %CI 0.50-0.83, p = 0.0006) at 12-month follow-up. Additionally, GLP-1RA use was associated with lower risks of ischemic stroke, HF exacerbations, and all-cause hospitalization, with no significant difference in new-onset atrial fibrillation or ventricular arrhythmias.
    CONCLUSION: The combined use of GLP-1RA and SGLT2i in ATTR-CA appears to confer incremental prognostic value.
    Keywords:  Cardiovascular outcomes; GLP-1 receptor agonists; SGLT-2 inhibitors; Transthyretin cardiac amyloidosis
    DOI:  https://doi.org/10.1016/j.ijcard.2025.133567
  10. Nat Commun. 2025 Jul 01. 16(1): 5927
    Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice.
    Jibo Han, Liming Lin, Zimin Fang, Diyun Xu, Lintao Wang, Bozhi Ye, Xue Han, Xiaohong Long, Julian Min, Gaojun Wu, Guang Liang, Yi Wang.
      Cardiac hypertrophy leads to ventricular dysfunction and heart failure. Deubiquitinating enzymes are responsible for preserving the substrate protein stability and are essential to myocardial hypertrophy. In this study, we aimed to explore the role and regulatory mechanism of a cardiomyocyte-derived deubiquitinating enzyme, USP13, in cardiac hypertrophy. Here we show that USP13 was increased in hypertrophic myocardium and was mainly distributed in cardiomyocytes. Cardiomyocyte-specific Usp13 knockout aggravated TAC or Ang II-induced myocardial hypertrophy and dysfunction in male mice. Correspondingly, USP13 overexpression by AAV9 in hearts exerted a therapeutic impact on cardiac hypertrophy in male mice. Mechanistically, we identified STAT1 as a substrate of USP13 through interactome analysis. USP13 deubiquitinated STAT1, thereby reducing its degradation. Subsequently, USP13 promoted the STAT1-targeted Nppb gene transcription and enhanced mitochondrial function in cardiomyocytes. This study illustrated a beneficial effect of USP13 in hypertrophic cardiomyocytes and identified a cardiomyocyte-specific USP13-STAT1 axis in regulating cardiac hypertrophy.
    DOI:  https://doi.org/10.1038/s41467-025-61028-1
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