bims-hafaim Biomed News
on Heart Failure Metabolism
Issue of 2021‒05‒09
thirteen papers selected by
Kyle McCommis
Saint Louis University

  1. Oxid Med Cell Longev. 2021 ;2021 5512322
      Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.
  2. Eur J Clin Pharmacol. 2021 May 03.
      PURPOSE: Empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin have been shown in randomized controlled trials to improve cardiovascular, metabolic, and renal outcomes in heart failure patients. To date, there has not been any meta-analysis examining the differences in clinical outcomes across different SGLT2 inhibitors in heart failure patients.METHODS: Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched on 13 September 2020 for articles published from 1 January 2000 to 13 September 2020 examining the effect of SGLT2 inhibitors on cardiovascular, renal, and metabolic outcomes in heart failure patients. Frequentist network meta-analysis was performed on extracted data.
    RESULTS: Ten randomized controlled trials were included with a combined cohort of 15,373 patients. In heart failure patients, frequentist network meta-analysis demonstrated no demonstrable difference in treatment effect across the SGLT2 inhibitors for heart failure hospitalization, cardiovascular deaths, composite of cardiovascular deaths and heart failure hospitalizations, all-cause mortality, and a composite of cardiovascular deaths and non-fatal myocardial infarction and non-fatal stroke. There was no demonstrable difference in treatment effect for worsening renal function or the weighted mean difference for weight, hemoglobin A1c, and systolic blood pressure.
    CONCLUSIONS: There were no demonstrable treatment differences across SGLT2 inhibitors across cardiovascular, renal, and metabolic outcomes, although this needs to be interpreted considering the wide confidence intervals, limited number of included studies, and heterogeneity present. Future research of different SGLT2 inhibitors in head-to-head studies is warranted to determine if there is a drug class effect.
    Keywords:  Heart failure; Sodium/glucose cotransporter 2 (SGLT2) inhibitors
  3. Cell Death Differ. 2021 May 04.
      Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially cardiac hypertrophy and heart failure, are lacking. Here, we ask whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. An increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) mice and Snx3 transgenic (Snx3-cTg) mice were generated to evaluate the role of Snx3 in myocardial hypertrophy, fibrosis, and heart function by morphology, echocardiography, histological staining, and hypertrophic biomarkers. We report that Snx3-cKO in mice significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy at 12 weeks. Conversely, Snx3-cTg mice were more susceptible to ISO-induced cardiac hypertrophy at 12 weeks and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry, immunofluorescent staining, co-immunoprecipitation, localized surface plasmon resonance, and proximity ligation assay were performed to examine the direct interaction of SNX3-retromer with signal transducer and activator of transcription 3 (STAT3). We discovered that STAT3 was a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at EE. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. The pharmacological inhibition or knockdown of STAT3 reversed SNX3 overexpression-induced myocardial injury. STAT3 overexpression blunts the beneficial function of SNX3 knockdown on hypertrophic cardiomyocytes. We show that SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.
  4. Sci Rep. 2021 May 05. 11(1): 9544
      The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of β-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 ± 7% vs. 46 ± 8%, p < 0.0001 while administration 1.5 h before IR, at onset of reperfusion or ex-vivo did not. EMPA alleviated LV dysfunction irrespective of the reduction in IS. EMPA improved mitochondrial respiration and modulated myocardial interstitial metabolism while the concentration of β-hydroxybutyric acid was only transiently increased without any association with IS reduction. EMPA reduces infarct size and yields cardioprotection in non-diabetic rats with ischemic LV dysfunction by an indirect, delayed intrinsic mechanism that also improves systolic function beyond infarct size reduction. The mechanism involves enhanced mitochondrial respiratory capacity and modulated myocardial metabolism but not hyperketonemia.
  5. J Physiol. 2021 May 01.
      Metabolic diseases (MetD) embrace a series of pathologies characterize by abnormal body glucose usage. The known diseases included in this group are metabolic syndrome, prediabetes and diabetes mellitus type 1 and 2, all of them are chronic pathologies that present metabolic disturbances and are classified as multi-organ diseases. Cardiomyopathy has been extensively described in diabetic patients without overt macrovascular complications. The heart is severely damaged during the progression of the disease, in fact, diabetic cardiomyopathies are the main cause of death in MetD. Insulin resistance, hyperglycemia, and increased free fatty acid metabolism promote cardiac damage through mitochondria. These organelles supply most of the energy that the heart needs to beat and control essential cellular functions, including Ca2+ signaling modulation, reactive oxygen species production, and apoptotic cell death regulation. Several aspects of the common mitochondrial functions have been described to be altered in diabetic cardiomyopathies include impairments of energy metabolism, compromises of mitochondrial dynamics, deficiencies in the Ca2+ handling, increases in ROS production, and a higher probability of mitochondrial permeability transition pore opening. Therefore, the mitochondrial role in MetD mediated heart dysfunction has been studied extensively to identify potential therapeutic targets for improving cardiac performance. Herein we review the cardiac pathology in metabolic syndrome, prediabetes, and diabetes mellitus, focusing on the role of mitochondrial dysfunctions. This article is protected by copyright. All rights reserved.
  6. Heart Fail Rev. 2021 May 05.
      Metabolic syndrome (MetS) refers to a group of cardiovascular risk elements comprising insulin resistance, obesity, dyslipidemia, increased glucose intolerance, and increased blood pressure. Individually, all the MetS components can lead to cardiac dysfunction, while their combination generates additional risks of morbidity and mortality. Growing evidence suggests that oxidative stress, a dominant event in cellular damage and impairment, plays an indispensable role in cardiac dysfunction in MetS. Oxidative stress can not only disrupt mitochondrial activity through inducing oxidative damage to mitochondrial DNA, RNA, lipids, and proteins but can also impair cardiomyocyte contractile function via mitochondria-related oxidative modifications of proteins central to excitation-contraction coupling. Furthermore, excessive reactive oxygen species (ROS) generation can lead to the activation of several mitochondria apoptotic signaling pathways, release of cytochrome c, and eventual induction of myocardial apoptosis. This review will focus on such processes of mitochondrial abnormalities in oxidative stress induced cardiac dysfunction in MetS.
    Keywords:  Cardiac dysfunction; Metabolic syndrome; Mitochondria; Oxidative stress; Reactive oxygen species
  7. J Cell Mol Med. 2021 May 04.
      MicroRNA-122 (miR-122) is one of several microRNAs elevated in heart failure patients. To investigate the potential role and mechanism of miR-122 in heart failure, we constructed a transgenic mouse overexpressing miR-122 in the heart. This mouse exhibited cardiac dysfunction (as assessed by transthoracic echocardiography), morphological abnormalities of the heart and cardiomyocyte apoptosis characteristic of heart failure. Mechanistically, we identified the Hand2 transcription factor as a direct target of miR-122 using a dual-luciferase reporter assay. In Tg-miR-122 mice and H9C2 cells with miR-122 mimics, we detected apoptosis and increased expression of dynamin-related protein-1 (Drp1). This effect was blocked with prior knockdown of Hand2 in vitro. Our work suggests that miR-122 causes cardiomyocyte apoptosis by inhibiting Hand2 and consequently increasing Drp1-mediated mitochondrial fission. Such a mechanism likely contributes to heart failure and so modulating this pathway could be therapeutically valuable against heart failure.
    Keywords:  Hand2; heart failure; miR-122; mitochondria-dependent apoptosis; mitochondrial fission protein Drp1
  8. Biomed Pharmacother. 2021 May 01. pii: S0753-3322(21)00415-7. [Epub ahead of print]139 111630
      BACKGROUND: Cardiac fibrosis occurs in ischemic and non-ischemic heart failure, hereditary cardiomyopathy, diabetes and aging. Energy metabolism, which serves a crucial function in the course and treatment of cardiovascular diseases, might have therapeutic benefits for myocardial fibrosis. Ginsenoside Rb3 (G-Rb3) is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases. Therefore, the study investigated the effect of chitosan (CS) @ sodium tripolyphosphate (TPP) nanoparticles conjugation with ginsenoside Rb3 (NpRb3) on myocardial fibrosis and studied its possible mechanisms. The results showed that NpRb3 directly participates in the remodeling of myocardial energy metabolism and the regulation of perixisome proliferation-activated receptor alpha (PPARα), thereby improving the degree of myocardial fibrosis. The study also verifies the protective effect of NpRb3 on energy metabolism and mitochondrial function by targeting the PPARα pathway. Therefore, the prepared nanodrug carrier may be a potential solution for the delivery of G-Rb3, which is a promising platform for oral treatment of myocardial fibrosis.
    Keywords:  Energy metabolism; Myocardial fibrosis; Nanoparticles conjugation with ginsenoside Rb3 (NpRb3); Oral bioavailability enhancement; Perixisome proliferation-activated receptor alpha (PPARα); Transforming growth factor beta 1 (TGF-β1)
  9. ESC Heart Fail. 2021 May 06.
      AIMS: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR).METHODS AND RESULTS: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS.
    CONCLUSIONS: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).
    Keywords:  31P-MRS; Diabetes; Empagliflozin; Heart failure; SGLT2 inhibitors; Trial design
  10. Curr Cardiol Rep. 2021 May 07. 23(6): 59
      PURPOSE OF REVIEW: Heart failure is responsible for a significant part of diabetes-associated cardiovascular mortality and morbidity. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are novel agents approved for the treatment of diabetes mellitus; in recent clinical trials, these agents have shown a significant reduction in cardiovascular death and hospitalization secondary to heart failure.RECENT FINDINGS: Clinical trials with specific heart failure outcomes have shown the benefit of SGLT-2 inhibitors in reducing the mortality and morbidity associated with heart failure. The guidelines for the management of diabetes mellitus recommend the preferential use of SGLT-2 inhibitors in patients with a history of cardiovascular disease. SGLT-2 inhibitors are potential game changers in the treatment of heart failure. Guidelines for prescription of these agents help assess risk-benefit analysis and personalize treatment for maximal benefit.
    Keywords:  Euglycemic diabetic ketoacidosis; Heart failure; Hospitalization for heart failure; Major adverse cardiovascular events; Sodium-glucose cotransporter-2 inhibitors
  11. J Cardiovasc Pharmacol. 2021 May 01. 77(5): 557-569
      ABSTRACT: Nuclear factor of activated T cells, cytoplasmic 4 (NFATc4), a nuclear transcription factor, has been implicated in cardiac hypertrophy through the enhancement of hypertrophic gene expression. However, the role of NFATc4 in mitochondrial modulation is mostly unknown. The current study aimed to investigate the role of NFATc4 in regulating mitochondrial function during phenylephrine (PE)-induced cardiac hypertrophy. Our results showed that overexpression of NFATc4 aggravated the PE-induced decrease in mitochondrial genesis, membrane potential, and mitochondrial gene expression as well as impaired mitochondrial respiration. However, knockdown of NFATc4 relieved PE-induced perturbations in mitochondria and cardiomyocyte hypertrophy. Mechanistically, by activating phosphoinositide-dependent kinase 1 and promoting a combination of AKT and phosphoinositide-dependent kinase 1, phosphorylation and sequential acetylation of PGC-1α were aggravated by NFATc4 and suppressed the activity of PGC-1α. In conclusion, NFATc4-regulated factors were shown to be associated with mitochondrial function and exacerbated PE-induced mitochondrial dysfunction. These findings revealed new roles of NFATc4 in cardiac hypertrophy.
  12. Front Pharmacol. 2021 ;12 677757
      Histone deacetylase (HDAC) expression and enzymatic activity are dysregulated in cardiovascular diseases. Among Class I HDACs, HDAC2 has been reported to play a key role in cardiac hypertrophy; however, the exact function of HDAC8 remains unknown. Here we investigated the role of HDAC8 in cardiac hypertrophy and fibrosis using the isoproterenol-induced cardiac hypertrophy model system.Isoproterenol-infused mice were injected with the HDAC8 selective inhibitor PCI34051 (30 mg kg-1 body weight). Enlarged hearts were assessed by HW/BW ratio, cross-sectional area, and echocardiography. RT-PCR, western blotting, histological analysis, and cell size measurements were performed. To elucidate the role of HDAC8 in cardiac hypertrophy, HDAC8 knockdown and HDAC8 overexpression were also used. Isoproterenol induced HDAC8 mRNA and protein expression in mice and H9c2 cells, while PCI34051 treatment decreased cardiac hypertrophy in isoproterenol-treated mice and H9c2 cells. PCI34051 treatment also reduced the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), transcription factors (Sp1, Gata4, and Gata6), and fibrosis markers (collagen type I, fibronectin, and Ctgf) in isoproterenol-treated mice. HDAC8 overexpression stimulated cardiac hypertrophy in cells, whereas HDAC8 knockdown reversed those effects. HDAC8 selective inhibitor and HDAC8 knockdown reduced the isoproterenol-induced activation of p38 MAPK, whereas HDAC8 overexpression promoted p38 MAPK phosphorylation. Furthermore, p38 MAPK inhibitor SB203580 significantly decreased the levels of p38 MAPK phosphorylation, as well as ANP and BNP protein expression, induced by HDAC8 overexpression.Here we show that inhibition of HDAC8 activity or expression suppresses cardiac hypertrophy and fibrosis. These findings suggest that HDAC8 could be a promising target to treat cardiac hypertrophy and fibrosis by regulating p38 MAPK.
    Keywords:  PCI34051; cardiac hypertrophy; fibrosis; histone deacetylase8; p38MAPK
  13. Cardiovasc Res. 2021 May 06. pii: cvab158. [Epub ahead of print]
      Macroautophagy/autophagy is a conserved catabolic recycling pathway in which cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions. Autophagy dysregulation has been observed and linked with the development and progression of several pathologies, including cardiovascular diseases, the leading cause of death in the developed world. In this review, we aim to provide a broad understanding of the different molecular factors that govern autophagy regulation and how these mechanisms are involved in the development of specific cardiovascular pathologies, including ischemic and reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiac remodeling, and heart failure.
    Keywords:  Autophagosome; cardiomyocyte; heart; lysosome; vascular