bims-hafaim 2026-05-31 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2026–05–31
nine papers selected by
Kyle McCommis, Saint Louis University

Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.
Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.
Metabolic inflexibility across heart failure phenotypes: mechanisms and type-specific therapeutic implications.
SGLT2 inhibitor dapagliflozin treats heart failure with preserved ejection fraction via the SIRT1/PGC-1α pathway.
Metabolic Remodeling Induced by Exercise: Emerging Mechanisms for Myocardial Protection in Cardiovascular Disease.
PPARα: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases.
Short-chain acyl-CoA dehydrogenase: a novel and promising therapeutic target for heart failure via modulation of mitochondrial fatty acid oxidation.
Glucose cotransporter-2 inhibitors on mortality and hospitalization in heart failure patients: a comprehensive meta-analysis.
Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.

Commun Biol. 2026 May 23.

Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.

Satadeepa Kal, Venkat R Chirasani, Nilima Biswas, Sumana Mahata, Suborno Jati, Kechun Tang, Teresa Pasqua, Ennio Avolio, Ramamurthy Chitteti, Shrabastee Chakraborty, Gautam Bandyopadhyay, Brian P Head, Geert van den Bogaart, Hemal H Patel, Debashis Sahoo, Sanjib Senapati, Sushil K Mahata.

Hypertension is a major risk factor for heart failure, characterized by impaired energy metabolism and mitochondrial dysfunction. The endogenous peptide catestatin (CST) has known cardiovascular protective effects, but its role in cardiac metabolism remains unclear. Here, we show that CST regulates cardiac metabolic pathways through integrated transcriptomic and network analyses, identifying cell-type-specific gene programs that are disrupted in its absence and restored with supplementation. Comparative analysis with human heart failure datasets reveals conserved alterations in glucose and fatty acid metabolism and mitochondrial function. Functional studies demonstrate that CST restores metabolic flexibility by shifting substrate utilization toward glucose oxidation. Mechanistically, CST enhances mitochondrial ATP production by interacting with ATP synthase and improving membrane potential and enzyme activity. These findings establish CST as a key regulator of cardiac energy metabolism and reveal an endocrine-mitochondrial signaling axis with therapeutic potential for hypertension-associated heart failure.

DOI: https://doi.org/10.1038/s42003-026-10310-z
Biomed Pharmacother. 2026 May 28. pii: S0753-3322(26)00595-0. [Epub ahead of print]200 119559

Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.

Yuting Zhou, Hao Tian, Zhongyuan Xia, Yonghong Xiong.

  Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.

Keywords:  Diabetic cardiomyopathy; Mitochondrial metabolic reprogramming; Mitochondrial quality control; Oxidative phosphorylation; Substrate utilization

DOI:  https://doi.org/10.1016/j.biopha.2026.119559
Apoptosis. 2026 May 29. pii: 162. [Epub ahead of print]31(6):

Metabolic inflexibility across heart failure phenotypes: mechanisms and type-specific therapeutic implications.

Li Chen, Xin-Rui Yang, Yan Jiang, Shi-Qi Cheng, Zhen-Xun Wan, Jin-Wen Wu, Ming-Tai Chen, Yuan-Yuan Li, Gang Luo, Meng-Nan Liu.

  Heart failure (HF) is a heterogeneous clinical syndrome characterized by phenotype-specific metabolic remodeling (e.g., ischemic vs. nonischemic, HF with HFrEF vs. HFpEF), with impaired metabolic flexibility serving as a central pathophysiological link. The physiological basis of normal cardiac metabolic flexibility is outlined, and the temporal trajectories and molecular mechanisms of metabolic remodeling across compensated, early decompensated, and end-stage HF are delineated. Key mechanisms, including dysregulated mitochondrial quality control, imbalanced substrate utilization, and transcriptional dysregulation are examined. Furthermore, multidimensional metabolic therapeutic strategies are summarized, and the translational potential of novel biomarkers (e.g., ketone bodies, acylcarnitines) is discussed. It is indicated the efficacy of metabolic therapies depends critically on HF phenotype, disease stage, and global metabolic network integrity. Future research is prioritized metabolomics-based precise phenotyping, dynamic monitoring of remodeling trajectories, and the development of systematic regulatory strategies featuring multi-target combinations and cardiac-specific delivery, so as to advance the clinical translation of metabolic therapies for HF.

Keywords:  Energy metabolism; Heart failure; Metabolic flexibility; Metabolic remodeling; Phenotype-specific therapy

DOI:  https://doi.org/10.1007/s10495-026-02376-1
Acta Biochim Biophys Sin (Shanghai). 2026 May 28. xx(xx): xx

SGLT2 inhibitor dapagliflozin treats heart failure with preserved ejection fraction via the SIRT1/PGC-1α pathway.

Shiwen Zhang, Yansong Cui, Jingwen Chen, Shuaishuai Zhou, Yujiao Zhang, Kuan Li, Yinglong Hou.

  Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF), yet the underlying mechanisms remain poorly defined. Given that mitochondrial dysfunction represents a central feature of HFpEF pathophysiology, we investigate whether modulation of mitochondrial homeostasis contributes to the cardioprotective effects of dapagliflozin. Using a Dahl salt-sensitive rat model of HFpEF, we find that dapagliflozin markedly improves diastolic function and attenuates cardiac hypertrophy, fibrosis, and apoptosis. These beneficial effects are accompanied by significant restoration of mitochondrial structure and function. Consistently, in an in vitro HFpE model, dapagliflozin enhances mitochondrial respiratory capacity in cardiomyocytes, indicating a direct mitochondrial regulatory effect. Mechanistically, integrative transcriptomic and experimental analyses identify the SIRT1/PGC-1α/Mitofusin-2 (Mfn-2) signaling axis as a critical pathway suppressed in HFpEF but reactivated following dapagliflozin treatment. Activation of this pathway promotes mitochondrial biogenesis and improves mitochondrial dynamics, thereby preserving cardiomyocyte homeostasis. Collectively, our findings reveal that dapagliflozin exerts cardioprotective effects in HFpEF by restoring mitochondrial homeostasis through the SIRT1/PGC-1α/Mfn-2 axis, providing mechanistic insight into SGLT2i-mediated benefits and highlighting mitochondrial regulation as a potential therapeutic strategy for HFpEF.

Keywords:  HFpEF; SGLT2 inhibitor; SIRT1/PGC-1α/Mfn-2 pathway; dapagliflozin; mitochondrial biosynthesis

DOI:  https://doi.org/10.3724/abbs.2026078
J Cardiovasc Transl Res. 2026 May 27. pii: 60. [Epub ahead of print]19(1):

Metabolic Remodeling Induced by Exercise: Emerging Mechanisms for Myocardial Protection in Cardiovascular Disease.

Tianwen Wei, Chang Zhou, Jieyun You, Yuxiao Sun, Qi Zhang.

  Cardiovascular diseases (CVDs), including coronary artery disease, heart failure, arrhythmias, hypertension, and cardiomyopathy, promote disease progression in part through profound disturbances in cardiomyocyte metabolism. These disorders are characterized by abnormal lipid and glucose metabolism and dysfunction of key metabolic regulatory systems, including fatty acid transport proteins and the AMPK/eNOS signaling axis. Exercise training regulates substrate selection and activates essential metabolic pathways, including PGC-1α and PPAR-α, thereby improving myocardial energy homeostasis and limiting cardiac injury. This review summarizes the mechanisms by which exercise modulates myocardial metabolism to delay or reverse disease progression across multiple forms of CVDs. Current evidence indicates that distinct cardiovascular pathologies exhibit unique metabolic abnormalities, suggesting that exercise interventions may exert disease-specific therapeutic effects by selectively targeting altered metabolic pathways.

Keywords:  Cardiovascular diseases; Exercise training; Metabolism

DOI:  https://doi.org/10.1007/s12265-026-10781-9
Cells. 2026 May 20. pii: 940. [Epub ahead of print]15(10):

PPARα: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases.

Maxime Roes, Claude Libert, Jolien Vandewalle.

  Peroxisome proliferator-activated receptor alpha (PPARα) is a key transcriptional regulator of lipid metabolism, highly expressed in metabolically active organs such as the heart. In cardiomyocytes, where approximately 70% of energy is derived from fatty acid oxidation, PPARα plays a central role in maintaining metabolic homeostasis. Moreover, the transcription factor is implicated in postnatal maturation of the heart and immune modulation. Dysregulation of PPARα signaling has profound consequences for cardiac energy balance, particularly under stress conditions. Accordingly, its role has been extensively investigated in cardiovascular diseases, including ischemia/reperfusion, diabetic cardiomyopathy and sepsis-induced cardiomyopathy. Upon ischemia/reperfusion and sepsis, cardiac PPARα expression is typically downregulated, contributing to impaired fatty acid breakdown and reduced metabolic flexibility. In contrast, diabetic cardiomyopathy is characterized by sustained PPARα activation, promoting excessive fatty acid oxidation, lipid accumulation and lipotoxicity. These context-dependent effects highlight a complex role of PPARα in cardiac diseases. PPARα has emerged as a promising therapeutic target, as its modulation can alleviate cardiac injury in preclinical models. However, further research is required to validate its efficacy in human disease, improve cardiomyocyte-specific targeting strategies to minimize systemic side effects, and better define optimal timing of intervention, as inappropriate or prolonged modulation may lead to detrimental outcomes.

Keywords:  PPARα; diabetes; heart; ischemia/reperfusion; sepsis

DOI:  https://doi.org/10.3390/cells15100940
J Hypertens. 2026 May 08.

Short-chain acyl-CoA dehydrogenase: a novel and promising therapeutic target for heart failure via modulation of mitochondrial fatty acid oxidation.

Yingqin Liao, Jingyun Feng, Chunyu Chen, Yaxin Duan, Zhonghong Li, Yongshao Su, Jieyu Xing, Haiyun Chen, Guixiang Wang, Sigui Zhou.

   OBJECTIVE: Heart failure is a major global health problem with high morbidity and mortality. Dysregulated fatty acid oxidation (FAO) appears to be an important therapeutic target for directly improving cardiac function. Short-chain acyl-CoA dehydrogenase (SCAD) is a key enzyme in FAO. This study aimed to elucidate the role of SCAD in heart failure.
METHODS: Left anterior descending (LAD) coronary artery ligation in rats was used as an acute heart failure model, whereas aged spontaneously hypertensive rats (SHRs, 20 months old) served as a chronic heart failure model. We generated conventional SCAD knockout (KO) mice to evaluate the role of SCAD in heart failure. Additionally, adenovirus-mediated SCAD overexpression was employed. Heart sections from patients with heart failure were analyzed for SCAD expression.
RESULTS: SCAD expression was downregulated in chronic heart failure in aged SHRs. Subsequent experiments showed that aged SCAD-deficient mice (2 years old) developed spontaneous heart failure. Moreover, SCAD KO markedly exacerbated heart failure in transverse aortic constriction-operated mice. Conversely, adenovirus-mediated SCAD overexpression suppressed tert-butyl hydroperoxide-induced cardiomyocyte apoptosis in vitro and protected the heart against LAD ligation-induced heart failure after myocardial infarction in rats. Similarly, SCAD expression was decreased in the hearts of patients with heart failure.
CONCLUSION: SCAD has a negative regulatory effect on heart failure and may represent a novel therapeutic target.

Keywords:  ; AMP-activated protein kinase; AMPK; ATP; Ad-GFP; B-cell lymphoma 2; Bax; Bcl-2; Bcl-2–associated X protein; DHE; EF; FAO; FFAs; FS; KO; LAD; LVEDV; LVESV; LVIDd; LVIDs; MI; MOI; NRCM; PPARα; ROS; SCAD; SHRs; SV; TAC; TUNEL; WT; adenosine triphosphate; adenovirus-green fluorescent protein; cardiac output; cell apoptosis; dihydroethidium; ejection fraction; energy metabolism; fatty acid oxidation; fractional shortening; free fatty acids; heart failure; knockout; left anterior descending; left ventricular end-diastolic volume; left ventricular end-systolic volume; left ventricular internal end-diastolic dimension; left ventricular internal end-systolic dimension; multiplicity of infection; myocardial infarction; neonatal rat cardiomyocyte; oxidative stress; peroxisome proliferator-activated receptor α; reactive oxygen species; short-chain acyl-CoA dehydrogenase; spontaneously hypertensive rats; stroke volume; tBHP; terminal deoxynucleotidyl transferase dUTP nick end labeling; tert-butyl hydroperoxide; transverse aortic constriction; wild-type

DOI:  https://doi.org/10.1097/HJH.0000000000004345
Front Endocrinol (Lausanne). 2026 ;17 1758519

Glucose cotransporter-2 inhibitors on mortality and hospitalization in heart failure patients: a comprehensive meta-analysis.

Xiang Mao, Wenhua Liu, Bingqian Hu, Enguo Xu.

   Background: Heart failure (HF) remains a major global health challenge, with high rates of hospitalization and mortality despite advances in therapy. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed as antidiabetic agents, have demonstrated significant cardiovascular and renal benefits across a wide range of patients.
Objective: This study aims to evaluate the impact of SGLT2 inhibitors on all-cause mortality, heart failure hospitalization, and secondary outcomes, including NT-proBNP levels, left ventricular (LV) systolic function, and diuretic efficiency in patients with heart failure, irrespective of ejection fraction or diabetes status.
Methods: A systematic review and a meta-analysis were conducted according to PRISMA 2020 guidelines. Electronic databases (PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science) were searched for randomized controlled trials (RCTs) published between January 2017 and November 2025. A total of 15 eligible RCTs encompassing 28,484 participants were included. Data were extracted on clinical and functional outcomes, and pooled estimates were calculated using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated using Egger's and Begg's tests.
Results: SGLT2 inhibitor therapy was associated with a 14% reduction in all-cause mortality (HR = 0.86, 95% CI: 0.79-0.92; p < 0.001) and a 26% reduction in heart failure hospitalization (HR = 0.74, 95% CI: 0.68-0.81; p < 0.001). Heterogeneity was low for mortality (I² = 18%) and moderate for hospitalization (I² = 39%). SGLT2 inhibitors also significantly decreased the NT-proBNP levels (mean difference -168.4 pg/mL, 95% CI: -245.6 to -91.2; p < 0.001) and improved the LV systolic function (LVEF + 3.8%, 95% CI: +2.4 to +5.2; p < 0.001). Diuretic efficiency improved by an average of 480 mL/day (95% CI: +290 to +640; p = 0.002). The benefits were consistent across subgroups, including patients with HFrEF and HFpEF, with or without diabetes, and across individual SGLT2 inhibitors (empagliflozin, dapagliflozin, and sotagliflozin). No significant publication bias was detected.
Conclusions: SGLT2 inhibitors significantly reduce the mortality and heart failure hospitalizations while improving the biomarker and cardiac function parameters, independent of diabetes status or heart failure phenotype. The consistency and magnitude of benefit confirm a class effect and support SGLT2 inhibitors as foundational therapy for heart failure across all ejection fraction categories.

Keywords:  HFpEF; HFrEF; dapagliflozin; empagliflozin; heart failure; hospitalization; left ventricular function; meta-analysis

DOI:  https://doi.org/10.3389/fendo.2026.1758519
J Cardiovasc Transl Res. 2026 May 28. pii: 61. [Epub ahead of print]19(1):

Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.

Yu-Xin Kang, Yue Hu, Xi-Tong Sun, Xin-Biao Fan, Ao-Lin Li, Wen-Yu Shang, Yun-Feng Jia, Yi-Xuan Zhao, Miao-Miao Wei, Tian-Qi Wang, Zheng Zhang, Bo-Yu Zhu, Yong-Chun Liang, Jun-Ping Zhang.

  Mitochondrial dysfunction has long been recognized as a central driver of heart failure (HF) pathogenesis, and emerging evidence highlights that impaired mitochondrial communication, rather than merely energy metabolism dysfunction, plays a pivotal role in the initiation and progression of HF. These communication networks are critical for maintaining cardiac metabolic homeostasis, and their disruption in HF leads to dysregulated energy metabolism, oxidative stress, lipotoxicity, and impaired cardiomyocyte function. This review examines the functional interactions between mitochondria and these organelles in HF, with particular attention to phenotype-specific differences between HF with preserved ejection fraction and HF with reduced ejection fraction. Finally, we summarize current and emerging therapeutic strategies targeting mitochondrial communication, highlighting the potential for phenotype-tailored interventions that restore organelle interplay and metabolic balance in HF.

Keywords:  Energy metabolism; Heart failure; Lipotoxic substances; Mitochondrial communication; Mitochondrial dysfunction; Reactive oxygen species; Subcellular structures

DOI:  https://doi.org/10.1007/s12265-026-10776-6