bims-hafaim 2026-07-05 papers

Issue of 2026–07–05
three papers selected by
Kyle McCommis, Saint Louis University

Surgery. 2026 Jun 05. pii: S0039-6060(26)00294-1. [Epub ahead of print] 110369

Incretin-based therapies and altered myocardial metabolism in a swine model of ischemic heart disease in the setting of metabolic syndrome.

Clark Zheng, Kelsey Muir, Riya Reddy, Christopher Stone, Dwight D Harris, Frank W Sellke.

BACKGROUND: Coronary artery disease is the leading cause of morbidity and mortality worldwide. Incretin-based therapies, including dipeptidyl peptidase-4 inhibitors (eg, linagliptin) and glucagon-like peptide-1 receptor agonists (eg, semaglutide), have gathered interest for potential cardioprotective effects beyond glycemic control. This study examines how incretin mimetics alter myocardial metabolism in a large animal model of coronary artery disease with metabolic syndrome.
METHODS: Metabolic syndrome was induced in Yorkshire swine through administration of a high-fat diet over a 6-week period. Swine then underwent surgical placement of an ameroid constrictor on the left circumflex artery to model progressive coronary artery disease. Animals were randomized to receive daily treatment with high-fat diet semaglutide, high-fat diet linagliptin, or no drug (n = 8/cohort). After 5 weeks of treatment, cardiac tissue was harvested. The most ischemic myocardial regions were subjected to comprehensive proteomic and metabolomic profiling. Integrated multiomic data were analyzed, with statistical significance defined as log2(fold change) ≥0.7 or ≤-0.7 and P ≤.05. Immunoblotting and histology were performed to supplement and corroborate multiomics.
RESULTS: Semaglutide treatment was associated with upregulation of fatty acid biosynthesis, pentose phosphate pathway, and starch and sucrose metabolism, and downregulation of fatty acid beta-oxidation. Linagliptin treatment resulted in a similar but less pronounced metabolic profile, notable for downregulation of fatty acid oxidation. Multiomic pathway analysis also suggested increased flux into the citrate cycle in both high-fat diet semaglutide and high-fat diet linagliptin cohorts, further supporting increased glucose metabolism.
CONCLUSION: Glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 inhibitor linagliptin are associated with reduced fatty acid oxidation and increased glucose metabolism in a swine model of coronary artery disease with metabolic syndrome.

DOI: https://doi.org/10.1016/j.surg.2026.110369

J Cardiovasc Transl Res. 2026 Jun 30. pii: 80. [Epub ahead of print]19(1):

Metabolic Heterogeneity Across Heart Failure Subtypes Defined by Integrative Multi-Omics Analysis.

Yuzhou Xue, Lin Liu, Ming Xu, Ling Jin.

Heart failure (HF) is a heterogeneous syndrome with diverse etiologies, yet the metabolic determinants specific to its subtype remain unclear. We performed an integrative multi-omics analysis combining metabolomics, genetics, and single-cell transcriptomics to characterize metabolic signatures of distinct HF subtypes. By applying Mendelian randomization of 1,091 circulating metabolites, we identified distinct metabolic patterns: lipid metabolites, particularly sphingolipids, were associated with increased HF risk, while tricarboxylic acid (TCA) cycle intermediates exhibited potential protective effects. Subtype-specific differences included lipid remodeling in coronary heart disease (CHD)-related HF, TCA metabolism in hypertension (HTN)-related HF, and amino acid pathways in overweight-related HF. Integrative analyses highlighted candidate regulators such as UPP1, NEU3, CBS, SHMT1, PLD2, OGDHL, and SULT1A1/2. Single-cell data revealed cardiomyocyte-enriched expression of OGDHL, which was consistently downregulated in experimental HF models. These findings provide insight into metabolic heterogeneity in HF and identify OGDHL as a potential regulator of cardiac metabolic remodeling.

Keywords: Heart failure; Mendelian randomization; Metabolic heterogeneity; Metabolomics; OGDHL; Single-cell RNA-seq

DOI: https://doi.org/10.1007/s12265-026-10803-6

Cardiovasc Res. 2026 Jun 29. pii: cvag139. [Epub ahead of print]

Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.

Ying Li, Ziquan Sun, Haixia Duan, Mingyue Wu, Jing Yi, Gang Wang, Wenjuan Liu, Chenglin Zhang, Wanwen Cheng, Jicheng Li, Weixuan Chen, Kunfu Ouyang, Hui Tan, Yueheng Wu, Jie Liu.

AIMS: Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a heart failure-associated gene. However, the role of SYBU in regulating cardiac function remains unclear.
METHODS AND RESULTS: Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes (NRVMs). SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened heart failure under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy (SIM) and analysis of mitochondria-associated endoplasmic reticulum membrane (MAM) fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with RyR2 and SERCA2, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and PKA activation, inducing phosphorylation of Drp1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy.
CONCLUSION: Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signaling pathways could be a promising therapeutic strategy to restrain HF in pressure overload - induced cardiac hypertrophy.

Keywords: SR–mitochondria tethering; heart failure; mitochondrial dynamic; syntabulin

DOI: https://doi.org/10.1093/cvr/cvag139