bims-hafaim 2026-01-25 papers

Issue of 2026–01–25
five papers selected by
Kyle McCommis, Saint Louis University

Diabetes Metab J. 2026 Jan 19.

BDH1 Protects against Diabetic Cardiomyopathy by Improving Mitochondrial Function and Suppressing Cardiomyocyte Apoptosis Via Activation of the AKT/GSK3β Pathway.

Yan Wang, Yanan Cheng, Jianbo Wu, Yu Zhao, Di Wang, Longyan Yang, Dong Zhao.

Background: Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetes patients with no effective therapies currently available. A deeper understanding of the mechanisms underlying DCM is essential for identifying novel therapeutic targets.
Methods: DCM model was established in C57BL/6J mice by administering multiple low-dose intraperitoneal injections of streptozotocin (STZ) in combination with a high-fat diet (HFD). Proteomic profiling was conducted on cardiac tissues from control and DCM mice to identify differentially expressed proteins. The expression of β-hydroxybutyrate dehydrogenase 1 (BDH1, also known as 3-hydroxybutyrate dehydrogenase) in cardiac tissues and cardiomyocyte were determined by immunoblot and quantitative polymerase chain reaction. The function and mechanism of BDH1 in DCM were investigated using a cardiac-specific BDH1-overexpressing mouse model, combined with cardiomyocyte cell lines with either BDH1 overexpression or knockdown.
Results: BDH1 was markedly downregulated in cardiac tissues of DCM mice, as well as in cardiomyocytes treated with high glucose and palmitic acid (HGPA). Cardiac-specific overexpression of BDH1 markedly improved cardiac dysfunction and myocardial fibrosis in DCM mice. In vitro, BDH1 overexpression attenuated mitochondrial damage and inhibited apoptosis in cardiomyocytes induced by HGPA. Conversely, BDH1 knockdown exacerbated these pathological changes under HGPA conditions. Transcriptome analysis linked BDH1 expression to the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, and we confirmed that BDH1 overexpression reversed diabetes-induced inhibition of the AKT/glycogen synthase kinase 3β (GSK3β) pathway. The protective effects of BDH1 on mitochondrial function and cardiomyocytes apoptosis were abolished following treatment with AKT inhibitor (AKTi). Cardiac-specific overexpression of BDH1 markedly decreased β-hydroxybutyric acid (BHB, the predominant ketone body) levels in cardiac tissues of DCM mice. Elevated BHB levels suppressed AKT activation in cardiomyocytes, while BDH1 overexpression effectively restored AKT/GSK3β pathway activity and ameliorated BHB-induced mitochondrial dysfunction and cardiomyocytes apoptosis.
Conclusion: Our study demonstrates that BDH1 plays a protective role in DCM by regulating BHB level and activating the AKT/GSK3β pathway, thereby mitigating mitochondrial damage and cardiomyocyte apoptosis. BDH1 may be a promising therapeutic target for DCM.

Keywords: Diabetic cardiomyopathies; Glycogen synthase kinase 3 beta; Hydroxybutyrate dehydrogenase; Ketone bodies; Mitochondria

DOI: https://doi.org/10.4093/dmj.2025.0257

Cureus. 2025 Dec;17(12): e99752

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Lipid Modulation in Heart Failure: A Narrative Review.

Sina Neshat, Hazhir Moradi, Matin Bidares, Afshin Heidari, Alireza Falahati Marvast, Ronal Ortega, Kiyan Heshmat.

In heart failure (HF), atherogenic dyslipidemia and lipotoxicity contribute to adverse remodeling. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve HF outcomes, yet their lipid effects remain debated. This review aims to synthesize quantitative changes in lipid parameters and plausible mechanisms by which SGLT2i modulate lipoproteins in HF. Across trials and HF-focused cohorts, SGLT2i are associated with small increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and small decreases in triglycerides. Beyond concentrations, emerging data suggest qualitative remodeling - a shift toward less atherogenic LDL phenotypes (small-dense LDL (sd-LDL)↓) and increases in HDL2 - although evidence is limited and heterogeneous. Mechanistically, enhanced adipose lipolysis and hepatic β-oxidation/ketogenesis may raise ketone availability for the myocardium ("thrifty substrate"), while hepatic cholesterol pool-driven LDL receptor (LDLR) downregulation could explain modest LDL-C increases. These lipid shifts coexist with consistent reductions in HF events, independent of diabetes, implying benefits not captured by traditional lipid metrics alone. In HF, SGLT2i likely exert modest quantitative lipid changes but potentially meaningful qualitative lipoprotein remodeling alongside improved metabolic flexibility. Clinically, apolipoprotein B (ApoB)-targeted therapy (e.g., statins ± ezetimibe) remains essential when LDL-C/ApoB are above goal, with SGLT2i used for cardiorenal benefit. HF-specific trials powered for ApoB, sd-LDL, low-density lipoprotein particle number (LDL-P), HDL function, and lipidomics are lacking. In conclusion, SGLT2i produce small, mixed lipid changes in HF, but mechanistic and particle-level effects may align with improved outcomes; definitive HF-centric lipid studies are a priority.

Keywords: canagliflozin; dapagliflozin; empagliflozin; heart failure; lipid profiles; sglt-2 inhibitors

DOI: https://doi.org/10.7759/cureus.99752

Front Cardiovasc Med. 2025 ;12 1687255

Improving metabolic support during normothermic ex-situ heart perfusion.

Mitchell J Wagner, Sanaz Hatami, Parham Hassanzadeh, Gopinath Sutendra, Jennifer Conway, Darren H Freed.

Ex-situ heart perfusion (ESHP) is an innovative technology that has the power to greatly improve donor heart utilization and may eventually provide a platform for improvement of suboptimal hearts. However, its impact is limited by functional decline whilst on the platform, which is characterized by the development of oxidative stress and inflammation. Pathologic metabolism during normothermic ESHP may be an underlying factor in the development of such characteristics, however it is understudied within the context of machine perfusion. In the following review article, we discuss the limitations of the current metabolic substrate provision approach during ESHP (analogous to post-prandial glucose and insulin) from a mechanistic standpoint. We discuss alternative approaches and substrates that may be more conducive to physiologic preservation and recovery on the platform. We advocate for a support strategy mimicking fasting insulin and glucose, and alternative substrates such as free fatty acids and ketone bodies, which may be more adapted to the non-physiologic state encountered during ESHP. Throughout, we outline research gaps yet to be explored that would enable substrate provision approaches during machine perfusion of the donor heart to be further optimized.

Keywords: cardiac metabolism; ex-situ heart perfusion; heart transplantation (HTx); machine perfusion; organ preservation

DOI: https://doi.org/10.3389/fcvm.2025.1687255

Int J Physiol Pathophysiol Pharmacol. 2025 ;17(5): 158-168

The dual role of SGLT2 inhibitors: glycemic control and cardioprotection in anthracycline-treated cancer patients.

Azad Mojahedi.

Anthracyclines are vital chemotherapy drugs for treating various cancers, including solid tumors and blood cancers; however, they cause dose-dependent cardiotoxicity, manifesting as cardiomyopathy, arrhythmias, and heart failure (HF). Cardiotoxicity, driven by oxidative stress, mitochondrial dysfunction, and other mechanisms, limits its use and affects long-term patient outcomes. Meanwhile, sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed for type 2 diabetes, offer cardiovascular benefits beyond glucose control, such as reduced HF hospitalization and mortality. These benefits stem from improved myocardial energetics, reduced fibrosis, and improved regulation of cardiac ion homeostasis. Experimental studies, including animal models, have shown that SGLT2 inhibitors, such as empagliflozin, preserve cardiac function and reduce inflammation in anthracycline-induced cardiotoxicity. Clinical data, although limited to small retrospective studies, suggest lower mortality and fewer cardiovascular events in anthracycline-treated cancer patients using SGLT2 inhibitors. However, variability in the study design highlights the need for a systematic evaluation. This systematic review aimed to critically assess the cardiovascular outcomes associated with SGLT2 inhibitor use in cancer patients treated with anthracyclines, evaluating their dual role in glycemic control and cardioprotection, and to identify evidence gaps to inform therapeutic strategies for optimizing long-term cardiovascular health in this vulnerable population.

Keywords: Heart failure; anthracyclines; cardiotoxicity; sodium-glucose co-transporter-2 inhibitors

DOI: https://doi.org/10.62347/GAXZ3059

Eur J Pharmacol. 2026 Jan 16. pii: S0014-2999(26)00043-9. [Epub ahead of print] 178561

Vericiguat Inhibits the Progress of Cardiac Hypertrophy and Prevents Hypertrophy-Induced Heart Failure by Multiple Mechanisms.

Ying-Qi Liu, Yi Zhang, Yu Song, Qin Yang, Guo-Wei He.

Heart failure (HF) is often a result of cardiac hypertrophy, and it is still the main public health challenge. Although vericiguat has been proved to be effective in treating heart failure through soluble guanylate cyclase (sGC), its potential preventive effects on myocardial hypertrophy and the exact related mechanisms are still unclear. We aimed to investigate the mechanism of the effectiveness of vericiguat in treating HF, focusing on its multi-targets of therapeutic effect. Echocardiographic assessments performed after treatment of vericiguat revealed significant improvements in cardiac function compared to untreated controls (TAC+SS). Biochemically, vericiguat effectively reversed the decrease of cGMP levels observed in hypertrophic mice hearts. Histological analysis showed that hypertrophy and fibrosis were reduced, myofibril arrangement, mitochondrial function and autophagy were improved, and the swelling of the sarcoplasmic reticulum was reduced. This study for the first time demonstrates that in addition to the direct effect of cGMP signaling, vericiguat may target and regulate HDAC1 expression and may repair sarcoplasmic reticulum swelling and enhance autophagy in hypertrophic hearts. We conclude that the preventive effect of vericiguat on the HF through multiple mechanisms and the results emphasize the potential clinical usefulness of vericiguat in the prevention of the progress of HF.

Keywords: cGMP; cardiac hypertrophy; heart failure; vericiguat

DOI: https://doi.org/10.1016/j.ejphar.2026.178561