bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–07–21
eight papers selected by
Kyle McCommis, Saint Louis University
  1. Cardiovascular outcomes of SGLT-2 Inhibitors Across BMI Spectrum in Heart Failure Patients: An Updated Systematic Review and Meta-Analysis.
  2. Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.
  3. Empagliflozin alters lipid metabolism in the myocardium and liver in a prediabetes model with severe dyslipidemia.
  4. S100A9 as a Key Myocardial Injury Factor Interacting with ATP5 Exacerbates Mitochondrial Dysfunction and Oxidative Stress in Sepsis-Induced Cardiomyopathy.
  5. Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction.
  6. A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling in C57Bl/6J and C57Bl/6N substrains.
  7. Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.
  8. Incretin-mediated control of cardiac energy metabolism.
  1. J Cardiovasc Pharmacol. 2024 Jul 08.
    Cardiovascular outcomes of SGLT-2 Inhibitors Across BMI Spectrum in Heart Failure Patients: An Updated Systematic Review and Meta-Analysis.
    Zhou Lingyan, Huang Zijia, Zeng Ya, Zhang Ying.
      Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have shown efficacy in improving cardiovascular outcomes in patients with chronic heart failure (HF). However, their impact on HF patients with varying BMI levels remains uncertain. To explore potential interactions between baseline BMI and the cardiovascular benefits of SGLT-2 inhibitors, we conducted a systematic review of studies from PubMed, Scopus, and the Cochrane Library database spanning from inception to March 2024. Eligible studies reported cardiovascular outcomes according to baseline BMI in HF patients treated with SGLT-2 inhibitors. Ultimately, our analysis included four studies encompassing 20,723 patients. We conducted separate random-effects meta-analyses for the composite outcome of first hospitalization for heart failure (HHF) or cardiovascular death (CVD), total HHF, CVD, and all-cause mortality. Compared with placebo, SGLT-2 inhibitors significantly reduced the risk of the composite outcome of first HHF or CVD (HR = 0.78, 95% CI: 0.72-0.83) and total HHF (HR = 0.73, 95% CI: 0.61-0.83), with consistent effects observed across different BMI categories (test for subgroup differences: P = 0.63 and P = 0.56, respectively). Furthermore, no statistical heterogeneity was found in the effects of SGLT-2 inhibitors on CVD (P = 0.84, I2 = 0%) as well as all-cause mortality (P = 0.52, I2 = 0%) across each baseline BMI subgroup in HF patients. No significant difference in safety was found between the placebo and SGLT-2 inhibitor arms. In conclusion, our findings suggest that the cardiovascular benefits of SGLT-2 inhibitors appear to be independent of baseline BMI in HF patients.
    DOI:  https://doi.org/10.1097/FJC.0000000000001610
  2. Circ Res. 2024 Jul 16.
    Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.
    Chen Gao, Zhaojun Xiong, Yunxia Liu, Meng Wang, Menglong Wang, Tian Liu, Jianfang Liu, Shuxun Ren, Nancy Cao, Hai Yan, Daniel J Drucker, Christoph Daniel Rau, Tomohiro Yokota, Jijun Huang, Yibin Wang.
       BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.
    METHOD: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.
    RESULTS: In contrast to the post-trans-aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-trans-aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.
    CONCLUSIONS: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.
    Keywords:  cardiology; heart failure; hypertension; risk factors; stroke volume
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324706
  3. Front Pharmacol. 2024 ;15 1393946
    Empagliflozin alters lipid metabolism in the myocardium and liver in a prediabetes model with severe dyslipidemia.
    Denisa Miklankova, Irena Markova, Martina Hüttl, Hana Malinska.
       Background and aims: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia.
    Materials and methods: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks.
    Results: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium.
    Conclusion: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.
    Keywords:  SGLT2 inhibitors; arachidonic acid; cardiovascular disease; empagliflozin; inflammation; ketone body; lipid metabolism
    DOI:  https://doi.org/10.3389/fphar.2024.1393946
  4. J Inflamm Res. 2024 ;17 4483-4503
    S100A9 as a Key Myocardial Injury Factor Interacting with ATP5 Exacerbates Mitochondrial Dysfunction and Oxidative Stress in Sepsis-Induced Cardiomyopathy.
    Hui Pei, Jie Qu, Jianming Chen, Guangju Zhao, ZhongQiu Lu.
       Purpose: Sepsis-induced cardiomyopathy (SICM) is a prevalent cardiac dysfunction caused by sepsis. Mitochondrial dysfunction is a crucial pathogenic factor associated with adverse cardiovascular adverse events; however, research on SICM remains insufficient.
    Methods: To investigate the factors contributing to the pathological progression of SICM, we performed a comprehensive analysis of transcriptomic data from the GEO database using bioinformatics and machine learning techniques. CRISPR-Cas9 S100A9 knockout mice and primary cardiomyocytes were exposed to lipopolysaccharide to simulate SICM. Transcriptome analysis and mass spectrometry of primary cardiomyocytes were used to determine the potential pathogenic mechanisms of S100A9. The mitochondrial ultrastructure and mitochondrial membrane potential (MMP) were detected using transmission electron microscopy and flow cytometry, respectively. Pink1/Parkin and Drp1 proteins were detected using Western blotting to evaluate mitochondrial autophagy and division. The mtDNA and mRNA levels of mitochondrial transcription factors and synthases were evaluated using real-time polymerase chain reaction.
    Results: Bioinformatics analysis identified 12 common differentially expressed genes, including SERPINA3N, LCN2, MS4A6D, LRG1, OSMR, SOCS3, FCGR2b, S100A9, S100A8, CASP4, ABCA8A, and NFKBIZ. Significant S100A9 upregulation was closely associated with myocardial injury exacerbation and cardiac function deterioration. GSEA revealed that myocardial contractile function, oxidative stress, and mitochondrial function were significantly affected by S100A9. Knocking out S100A9 alleviates the inflammatory response and mitochondrial dysfunction. The interaction of S100A9 with ATP5 enhanced mitochondrial division and autophagy, inhibited MMP and ATP synthesis, and induced oxidative stress, which are related to the Nlrp3-Nfkb-Caspase1 and Drp1-Pink1-Parkin signaling pathways. The expression of mitochondrial transcription factors (TFAM and TFBM) and ATP synthetases (ATP6 and ATP8, as well as COX1, COX2, and COX3) was further suppressed by S100A9 in SICM. Targeted S100A9 inhibition by paquinimod partially reversed myocardial mitochondrial dysfunction and oxidative stress.
    Conclusion: The interaction of S100A9 with ATP5 exacerbates myocardial damage in sepsis by inducing mitochondrial dysfunction and oxidative stress.
    Keywords:  ATP5; S100A9; SICM; bioinformatics analysis; mitochondrial dysfunction
    DOI:  https://doi.org/10.2147/JIR.S457340
  5. Cardiovasc Diabetol. 2024 Jul 18. 23(1): 261
    Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction.
    Michael W Rudokas, Margaret McKay, Zeren Toksoy, Julia N Eisen, Markus Bögner, Lawrence H Young, Fadi G Akar.
      Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.
    Keywords:  Arrhythmia; Diabetes; Ischemia; Ischemia-reperfusion injury; Mitochondria; Mitochondrial dynamics; ROS (reactive oxygen species); ROS-induced ROS-release
    DOI:  https://doi.org/10.1186/s12933-024-02357-1
  6. Physiol Genomics. 2024 Jul 15.
    A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling in C57Bl/6J and C57Bl/6N substrains.
    Lorena Cascarano, Hrag Esfahani, Pierre Michel, Caroline Bouzin, Chantal Dessy, Jean-Luc Balligand, Lauriane Y M Michel.
      The prevalence of metabolic syndrome in cardiac diseases such as heart failure with preserved ejection fraction (HFpEF) prompts the scientific community to investigate its adverse effects on cardiac function and remodeling. However, the selection of a preclinical model of obesity-induced cardiac remodeling has proven more challenging with inconsistencies often found in very similar mouse models. Here, we investigated the implication of genetic background as well as diet composition to identify a suitable model of diet-induced cardiac alterations. C57Bl/6J and C57Bl/6N male mice were subjected to distinct obesogenic diets consisting of high-fat and moderate-sucrose content (HF-S) or High-Sucrose and moderate-lipid content (F-HS) versus matching control diets. 5-month dietary intervention with obesogenic diets induced weight gain, adipocyte hypertrophy and increased visceral and subcutaneous fat mass in both substrains. Obese mice showed similar impairment of glucose disposition and insulin tolerance, both strains developing insulin resistance within two months. However, echocardiographic follow-up and histological analysis confirmed that HF-S diet increases cardiac hypertrophy, interstitial fibrosis as well as left atrial area in the C57Bl/6J strain only. On the contrary C57Bl/6N exhibit cardiac eccentric remodeling under control diets, possibly owing to a genetic mutation in the myosin light-chain-kinase 3 (Mylk3) gene, specific to this substrain, which was not further enhanced under obesogenic diets. Altogether, the present results highlight the importance of carefully selecting the suitable mouse strain and diets to model diet-induced cardiac remodeling. In this regard, C57Bl/6J mice develop significant cardiac remodeling in response to HF-S, and seem a suitable model for cardiometabolic disease.
    Keywords:  adipocytes; heart failure; metabolic syndrome; myocardial remodelling; obesity
    DOI:  https://doi.org/10.1152/physiolgenomics.00044.2024
  7. Sci Rep. 2024 Jul 17. 14(1): 16493
    Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.
    Yusuke Kashiwagi, Tomohisa Nagoshi, Yoshiro Tanaka, Yuhei Oi, Haruka Kimura, Kazuo Ogawa, Makoto Kawai, Michihiro Yoshimura.
      Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.
    Keywords:  Angiotensin receptor-neprilysin inhibitor (ARNI); Heart failure; Ketone body
    DOI:  https://doi.org/10.1038/s41598-024-67524-6
  8. J Endocrinol. 2024 Jul 01. pii: JOE-24-0011. [Epub ahead of print]
    Incretin-mediated control of cardiac energy metabolism.
    Jordan Siu Fung Chan, Tanin Shafaati, John R Ussher.
      Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism, while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.
    DOI:  https://doi.org/10.1530/JOE-24-0011
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