bims-hafaim 2023-12-03 papers

Issue of 2023–12–03
six papers selected by
Kyle McCommis, Saint Louis University

Cell Death Differ. 2023 Nov 28.

Lipid overload-induced RTN3 activation leads to cardiac dysfunction by promoting lipid droplet biogenesis.

Dong Guo, Mingming Zhang, Bingchao Qi, Tingwei Peng, Mingchuan Liu, Zhelong Li, Feng Fu, Yanjie Guo, Congye Li, Ying Wang, Lang Hu, Yan Li.

Lipid droplet (LD) accumulation is a notable feature of obesity-induced cardiomyopathy, while underlying mechanism remains poorly understood. Here we show that mice fed with high-fat diet (HFD) exhibited significantly increase in cardiac LD and RTN3 expression, accompanied by cardiac function impairment. Multiple loss- and gain-of function experiments indicate that RTN3 is critical to HFD-induced cardiac LD accumulation. Mechanistically, RTN3 directly bonds with fatty acid binding protein 5 (FABP5) to facilitate the directed transport of fatty acids to endoplasmic reticulum, thereby promoting LD biogenesis in a diacylglycerol acyltransferase 2 dependent way. Moreover, lipid overload-induced RTN3 upregulation is due to increased expression of CCAAT/enhancer binding protein α (C/EBPα), which positively regulates RTN3 transcription by binding to its promoter region. Notably, above findings were verified in the myocardium of obese patients. Our findings suggest that manipulating LD biogenesis by modulating RTN3 may be a potential strategy for treating cardiac dysfunction in obese patients.

DOI: https://doi.org/10.1038/s41418-023-01241-x

bioRxiv. 2023 Nov 15. pii: 2023.11.10.564562. [Epub ahead of print]

Lipid metabolism drives allele-specific early-stage hypertrophic cardiomyopathy.

Arpana Vaniya, Anja Karlstaedt, Damla Ates Gulkok, Tilo Thottakara, Yamin Liu, Sili Fan, Hannah Eades, Ryuya Fukunaga, Hilary J Vernon, Oliver Fiehn, M Roselle Abraham.

Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes, that increase myocyte energy demand and lead to cardiac hypertrophy. But it is unknown whether a common metabolic trait underlies the cardiac phenotype at early disease stage. This study characterized two HCM mouse models (R92W-TnT, R403Q-MyHC) that demonstrate differences in mitochondrial function at early disease stage. Using a combination of cardiac phenotyping, transcriptomics, mass spectrometry-based metabolomics and computational modeling, we discovered allele-specific differences in cardiac structure/function and metabolic changes. TnT-mutant hearts had impaired energy substrate metabolism and increased phospholipid remodeling compared to MyHC-mutants. TnT-mutants showed increased incorporation of saturated fatty acid residues into ceramides, cardiolipin, and increased lipid peroxidation, that could underlie allele-specific differences in mitochondrial function and cardiomyopathy.

DOI: https://doi.org/10.1101/2023.11.10.564562

ESC Heart Fail. 2023 Nov 27.

Sodium-glucose cotransporter 2 inhibitors are associated with reduced risk of mortality and readmissions in heart failure.

Patric Karlström, Aldina Pivodic, Ulf Dahlström, Michael Fu.

AIMS: Compelling evidence from randomized trials has shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in heart failure (HF) across the spectrum of left ventricular ejection fractions. However, there are very few studies with real-world data.
METHODS AND RESULTS: A retrospective cohort analysis was performed based on patient-level data from the Swedish Heart Failure Registry (SwedeHF) linked with three other national registers. Patients included had an index registration between 3 September 2013 and 31 December 2020 in SwedeHF and were on treatment with guideline-recommended therapy without or with SGLT2i 3 months before or 6 months after their index registration. Endpoints were mortality or readmissions. Association between the use of SGLT2i and endpoints was studied using adjusted Cox models. In the overall cohort, 796/22 405 patients were included with/without SGLT2i. In patients with SGLT2i, 93.5% had diabetes mellitus. In the overall cohort, SGLT2i was statistically significantly associated with all-cause mortality {hazard ratio [HR]: 0.61 [95% confidence interval (CI) 0.48-0.79], P < 0.0001}, cardiovascular mortality [HR: 0.29 (95% CI 0.17-0.50), P < 0.0001], cardiovascular mortality or HF readmission [HR: 0.89 (95% CI 0.80-1.00), P = 0.046], and all-cause readmissions [HR: 0.90 (95% CI 0.81-0.99), P = 0.038]. Similar results were obtained for the diabetes cohort. However, no association with cause-specific readmissions was observed.
CONCLUSIONS: This nationwide real-world study indicates that patients with HF, in which majority coexisted with diabetes mellitus, who received SGLT2i were statistically significantly associated with lower risk for all-cause mortality, cardiovascular mortality, cardiovascular mortality or HF readmissions, and all-cause readmissions, in line with the randomized trials assessing SGLT2i.

Keywords: Effectiveness; Heart failure; Real world; SGLT2is

DOI: https://doi.org/10.1002/ehf2.14582

J Cardiovasc Pharmacol. 2023 Nov 22.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy via Inhibition of Mitochondrial Fission.

Zhuo-Jing Yang, Chun-Ling Guo, Yu-Xin Gong, Long Li, Li-Li Wang, Hui-Min Liu, Ji-Min Cao, Zhao-Yang Lu.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for two weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum (IVS), left ventricle posterior wall diastole (LVPWd) and left ventricular posterior wall systole (LVPWs) were significantly increased, and ejection fraction (EF) was decreased compared with control mice. Masson and Wheat Germ Agglutinin (WGA) staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes (NRCMs), we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and NRCMs. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase Drp1 phosphorylation at S616 and decrease Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

DOI: https://doi.org/10.1097/FJC.0000000000001518

Cardiology. 2023 Nov 24.

Association between BMI and efficacy of SGLT2 inhibitors in patients with heart failure or at risk of heart failure: a meta-analysis based on randomized controlled trials.

Yisheng Zhou, Min Dai, Tongmin Huang, Bangsheng Chen, Zhiyi Xiang, Jiawen Tang, Meixia Zheng, Luyong Guo.

INTRODUCTION: This meta-analysis aimed to investigate the effect of SGLT2 inhibitors on the prognosis in patients with heart failure (HF) or at risk of heart failure across different body mass index (BMI).
METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library for all randomized controlled trials (RCTs) comparing SGLT2 inhibitors with placebo in patients with HF or at risk of HF and extracted relevant data up to April 2023 for meta-analysis.
RESULTS: A total of 29,500 patients were enrolled in the selected five studies. The results showed that patients treated with SGLT2 inhibitors had lower heart failure hospitalization (HHF) or cardiovascular (CV) mortality compared to those taking placebo (hazard ratio (HR)=0.73, p<0.001). Patients taking SGLT2 inhibitors also had a lower all-cause mortality rate than those taking placebo (HR=0.85, p=0.017). In BMI subgroup analysis, the HHF rate in the experimental group was lower than that in the control group at BMI ≤24.9 kg/m2, 25.0-29.9 kg/m2, and ≥30.0 kg/m2. There was no significant difference in CV mortality between the two groups at BMI ≤24.9 kg/m2 (HR=0.91, p=0.331) and 25.0-29.9 kg/m2 (HR=0.92, p=0.307). However, when the BMI was ≥30.0 kg/m2, CV mortality with SGLT2 inhibitors was lower than in the control group (HR=0.79, p=0.002). When patients had a BMI ≤24.9 kg/m2 (HR=0.85, p=0.033) and 25.0-29.9 kg/m2 (HR=0.83, p=0.046), the all-cause mortality was lower in the experimental group than in the control group. However, there was no significant difference between the two groups in patients with a BMI ≥30.0 kg/m2 (HR=0.87, p=0.094).
CONCLUSION: SGLT2 inhibitors improve prognosis in patients with HF or at risk of HF. This effect is affected by BMI.

DOI: https://doi.org/10.1159/000535297

bioRxiv. 2023 Nov 18. pii: 2023.11.17.567640. [Epub ahead of print]

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway.

Luís F Grilo, Kip D Zimmerman, Sobha Puppala, Jeannie Chan, Hillary F Huber, Ge Li, Avinash Y L Jadhav, Benlian Wang, Cun Li, Geoffrey D Clarke, Thomas C Register, Paulo J Oliveira, Peter W Nathanielsz, Michael Olivier, Susana P Pereira, Laura A Cox.

Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans. The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes. We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent ∼30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width. Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases.

DOI: https://doi.org/10.1101/2023.11.17.567640