bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒03‒20
seven papers selected by
Kyle McCommis
Saint Louis University

  1. J Clin Invest. 2022 Mar 15. pii: e157664. [Epub ahead of print]132(6):
      Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.
  2. Front Physiol. 2022 ;13 831829
      Cardiac function highly relies on sufficient energy supply. Perturbations in myocardial energy metabolism play a causative role in cardiac pathogenesis. Accumulating evidence has suggested that modifications of cardiac metabolism are also an essential part of the adaptive responses to various physiological conditions in the heart to meet specific energy needs. The review highlighted some new studies on basic myocardial energy substrate metabolism and updated recent findings regarding cardiac metabolic remodeling and their associated mechanisms under physiological conditions, including exercise and cardiac development. Studying basic metabolic profiles in the heart in these conditions can contribute to understanding the significance of metabolic regulation in the heart during physiological adaption and gaining further insights into the maladaptive metabolic changes associated with cardiac pathogenesis, thus opening up new avenues to exploring novel therapeutic strategies in cardiac diseases.
    Keywords:  cardiac disease; heart; metabolism; physiology; substrate utilization
  3. J Cardiovasc Transl Res. 2022 Mar 15.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.
    Keywords:  Cardiac remodeling; HFpEF; HFrEF; Heart failure; Mechanisms; SGLT2 inhibitors; SGLT2i
  4. Circulation. 2022 Mar 17.
      Background: Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux. Methods: Myocardial infarction in an acute setting of IR was examined via comparing loss vs. gain of function experiments in microRNA-210-deficient and wild type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer. Results: MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Consistently, inhibition of mitochondrial ROS with MitoQ reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that GPD2 played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of GPD2 negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction, and improved left ventricular fractional shortening and ejection fraction after the IR treatment. Conclusions: MicroRNA-210 targeting GPD2 controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.
  5. Cardiovasc Diabetol. 2022 Mar 18. 21(1): 45
      Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) demonstrate large cardiovascular benefit in both diabetic and non-diabetic, acute and chronic heart failure patients. These inhibitors have on-target (SGLT2 inhibition in the kidney) and off-target effects that likely both contribute to the reported cardiovascular benefit. Here we review the literature on direct effects of SGLT2is on various cardiac cells and derive at an unifying working hypothesis. SGLT2is acutely and directly (1) inhibit cardiac sodium transporters and alter ion homeostasis, (2) reduce inflammation and oxidative stress, (3) influence metabolism, and (4) improve cardiac function. We postulate that cardiac benefit modulated by SGLT2i's can be commonly attributed to their inhibition of sodium-loaders in the plasma membrane (NHE-1, Nav1.5, SGLT) affecting intracellular sodium-homeostasis (the sodium-interactome), thereby providing a unifying view on the various effects reported in separate studies. The SGLT2is effects are most apparent when cells or hearts are subjected to pathological conditions (reactive oxygen species, inflammation, acidosis, hypoxia, high saturated fatty acids, hypertension, hyperglycemia, and heart failure sympathetic stimulation) that are known to prime these plasmalemmal sodium-loaders. In conclusion, the cardiac sodium-interactome provides a unifying testable working hypothesis and a possible, at least partly, explanation to the clinical benefits of SGLT2is observed in the diseased patient.
    Keywords:  Cardiac function; Inflammation; Ion homeostasis; Metabolism; Oxidative stress; Sodium-glucose-cotransporter 2 inhibitors
  6. J Lipid Res. 2022 Mar 10. pii: S0022-2275(22)00027-X. [Epub ahead of print] 100194
      Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol (TAG) hydrolysis in LDs is catalyzed by adipose triglyceride lipase (ATGL), deficiency of which results in lethal cardiac steatosis. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol (DAG) lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-knockout (KO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous ATGL-KO (AKO) mice and AKO mice with cardiac-specific HSL overexpression (AKO+cHSL). We found that cardiac TAG content was 160-fold higher in AKO relative to wild type (Wt) mice, while that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPARα-regulated genes, and upregulation of genes involved in inflammation, fibrosis, and cardiac stress. In contrast, AKO+cHSL cardiac tissues exhibited expression levels similar to those observed in Wt mice. AKO cardiac tissues also exhibited macrophage infiltration, apoptosis, interstitial fibrosis, impaired systolic function, and marked increases in ceramide and DAG contents, while no such pathological alterations were observed in AKO+cHSL tissues. Furthermore, electron microscopy revealed considerable LDs, damaged mitochondria, and disrupted intercalated discs in AKO cardiomyocytes, none of which were noted in AKO+cHSL cardiomyocytes. Importantly, the lifespan of AKO+cHSL mice was comparable to that of Wt mice. We conclude cardiac HSL overexpression normalizes lipotoxic cardiomyopathy in AKO mice. These findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.
    Keywords:  apoptosis; beta-oxidation; ceramides; fatty acid; lipid droplets; lipotoxicity; macrophage; mitochondria; perilipins; triacylglycerol
  7. Eur J Heart Fail. 2022 Mar 13.
      AIM: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM vs placebo and evaluated the stability of this response over time.METHODS: Changes vs baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups . Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed.
    RESULTS: Overall, 760 (FCM: 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM vs 4.8 points with placebo (least-square mean difference [95% confidence interval (CI)]: 4.36 [2.14;6.59] points). A higher proportion of patients on FCM vs placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs 43.5%; odds ratio [95% CI]: 1.81 [1.30;2.51]), ≥10 (42.4% vs 29.3%; 1.73 [1.23;2.43]) or ≥15 (32.1% vs 22.6%; 1.46 [1.02;2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24.
    CONCLUSION: Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients. This article is protected by copyright. All rights reserved.
    Keywords:  Kansas City Cardiomyopathy Questionnaire; ferric carboxymaltose; health status; heart failure with reduced ejection fraction; iron deficiency; minimally clinically important difference; quality of life