bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2021–08–29
ten papers selected by
Kyle McCommis, Saint Louis University
  1. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF.
  2. Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice.
  3. High Throughput Procedure for Comparative Analysis of In Vivo Cardiac Glucose or Amino Acids Use in Cardiovascular Pathologies and Pharmacological Treatments.
  4. Abnormalities in lysine degradation are involved in early cardiomyocyte hypertrophy development in pressure-overloaded rats.
  5. Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish.
  6. Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.
  7. Loss of Stearoyl-CoA Desaturase 1 leads to cardiac dysfunction and lipotoxicity.
  8. Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α.
  9. Perturbations in cardiac metabolism in a human model of acute myocardial ischaemia.
  10. Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.
  1. Eur Heart J. 2021 Aug 27. pii: ehab560. [Epub ahead of print]
    Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF.
    James P Curtain, Kieran F Docherty, Pardeep S Jhund, Mark C Petrie, Silvio E Inzucchi, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Piotr Ponikowski, Marc S Sabatine, Olof Bengtsson, Anna Maria Langkilde, Mikaela Sjöstrand, Scott D Solomon, John J V McMurray.
       AIMS: The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF).
    METHODS AND RESULTS: In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, 'other' ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group [hazard ratio 0.79 (95% confidence interval 0.63-0.99), P = 0.037], and the effect was consistent across each of the components of the composite outcome.
    CONCLUSIONS: Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.
    CLINICAL TRIAL REGISTRATION:  ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).
    Keywords:  Heart failure; Sodium-glucose cotransporter 2 inhibitor; Sudden death; Ventricular tachyarrhythmia
    DOI:  https://doi.org/10.1093/eurheartj/ehab560
  2. J Cardiovasc Transl Res. 2021 Aug 23.
    Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice.
    Xingxu Wang, Wei Wei, Jian Wu, Le Kang, Shuangquan Wu, Jiming Li, Yunli Shen, Jieyun You, Yong Ye, Qi Zhang, Yunzeng Zou.
      Aortic regurgitation (AR) is a volume overload disease causing eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis is involved in many cardiovascular diseases, but whether they also participate in AR-induced heart failure is still elusive. In this study, we found ER stress activation in myocardial samples from patients with AR. With a unique murine model of AR which induced eccentric cardiac hypertrophy and heart failure, we also found aggravation of cardiac ER stress and apoptosis, as evidenced by a reduction of Bcl-2/Bax ratio and an increase of caspase-3 cleavage. We then examined the signaling effectors involved in ER-initiated apoptosis and found volume overload specifically activated C/EBP homologous protein (CHOP), but not caspase-12 or Jun N-terminal kinase (JNK). Interestingly, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved cardiac function, and suppressed ER stress, apoptosis, and CHOP. Furthermore, genetic knockdown of CHOP inhibited cardiac Bcl-2/Bax ratio reduction and caspase-3 activation and rescued cardiac dysfunction. In summary, our findings suggest that ER stress-CHOP signaling is involved in the development of volume overload cardiac hypertrophy induced by AR through promoting cardiomyocytes apoptosis and provide a previously unrecognized target in heart failure induced by volume overload.
    Keywords:  Aortic regurgitation; Apoptosis; C/EBP homologous protein; Endoplasmic reticulum stress; Volume overload
    DOI:  https://doi.org/10.1007/s12265-021-10162-4
  3. Metabolites. 2021 Jul 30. pii: 497. [Epub ahead of print]11(8):
    High Throughput Procedure for Comparative Analysis of In Vivo Cardiac Glucose or Amino Acids Use in Cardiovascular Pathologies and Pharmacological Treatments.
    Marta Tomczyk, Mariola Olkowicz, Ewa M Slominska, Ryszard T Smolenski.
      The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of methods to investigate changes in substrates' use in cardiac metabolism in vivo are complex and not suitable for high throughput testing necessary to understand and reverse these pathologies. Thus, this study aimed to develop a simple method that would allow for the analysis of cardiac metabolic substrate use. The developed methods involved the subcutaneous injection of stable 13C isotopomers of glucose, valine, or leucine with mass spectrometric analysis for the investigation of its entry into cardiac metabolic pathways that were deducted from 13C alanine and glutamate enrichments in heart extracts. The procedures were validated by confirming the known effects of treatments that modify glucose, free fatty acids, and amino acid metabolism. Furthermore, we studied changes in the energy metabolism of CD73 knock-out mice to demonstrate the potential of our methods in experimental research. The methods created allowed for fast estimation of cardiac glucose and amino acid use in mice and had the potential for high-throughput analysis of changes in pathology and after pharmacological treatments.
    Keywords:  catabolism; heart; mass spectrometry
    DOI:  https://doi.org/10.3390/metabo11080497
  4. BMC Cardiovasc Disord. 2021 Aug 21. 21(1): 403
    Abnormalities in lysine degradation are involved in early cardiomyocyte hypertrophy development in pressure-overloaded rats.
    Jialing Liu, Junhao Hu, Lanlan Tan, Qi Zhou, Xiaojing Wu.
       BACKGROUND: Cardiomyocyte metabolism changes before cardiac remodeling, but its role in early cardiac hypertrophy detection remains unclear. This study investigated early changes in plasma metabolomics in a pressure-overload cardiac hypertrophy model induced by transverse aortic constriction (TAC).
    METHODS: The TAC model was constructed by partly ligating the aortic arch. Twelve Sprague-Dawley rats were randomly divided into the TAC group (n = 6) and sham group (n = 6). Three weeks after surgery, cardiac echocardiography was performed to assess cardiac remodeling and function. Hematoxylin/eosin (HE), Masson, and wheat germ agglutinin (WGA) stains were used to observe pathological changes. Plasma metabolites were detected by UPLC-QTOFMS and Q-TOFMS. Specific metabolites were screened by orthogonal partial least squares discriminant analysis (OPLS-DA). Metabolic pathways were characterized by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the predictive value of the screened metabolites was analyzed by receiver operating characteristic (ROC) curve analysis.
    RESULTS: Three weeks after surgery, the TAC and sham groups had similar left heart function and interventricular septum and diastolic left ventricular posterior wall thicknesses. However, on pathological examination, the cross-sectional area of cardiomyocytes and myocardial fibrosis severity were significantly elevated in TAC rats. OPLS-DA showed different metabolic patterns between the TAC and sham groups. Based on the criteria VIP > 1 and P < 0.05, 13 metabolites were screened out. KEGG analysis identified disrupted lysine degradation through the related metabolites 5-aminopentanoic acid, N6-acetyl-L-lysine, and L-lysine, with areas under the ROC curve (AUCs) of 0.917, 0.889, and 0.806, respectively, for predicting compensated cardiomyocyte hypertrophy.
    CONCLUSION: Disruption of lysine degradation might be involved in early cardiac hypertrophy development, and related metabolites might be potential predictive and interventional targets for subclinical cardiomyocyte hypertrophy.
    Keywords:  Cardiac hypertrophy; Lysine degradation; Metabolomics; Nonenergetic metabolism; Pressure overload
    DOI:  https://doi.org/10.1186/s12872-021-02209-w
  5. Int J Mol Sci. 2021 Aug 06. pii: 8468. [Epub ahead of print]22(16):
    Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish.
    Deung-Dae Park, Bernd M Gahr, Julia Krause, Wolfgang Rottbauer, Tanja Zeller, Steffen Just.
      In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.
    Keywords:  cardiovascular disease; long-chain acylcarnitine; mitochondria; zebrafish
    DOI:  https://doi.org/10.3390/ijms22168468
  6. Int J Mol Sci. 2021 Aug 13. pii: 8711. [Epub ahead of print]22(16):
    Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.
    Juliana de Freitas Germano, Ankush Sharma, Miroslava Stastna, Chengqun Huang, Marianne Aniag, Angie Aceves, Jennifer E Van Eyk, Robert M Mentzer, Honit Piplani, Allen M Andres, Roberta A Gottlieb.
      Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.
    Keywords:  DMB; cellular respiration; early cardiac remodeling; glucagon-like peptide-1 receptor agonists; metabolism; mitochondrion; proteomics
    DOI:  https://doi.org/10.3390/ijms22168711
  7. J Exp Biol. 2021 Aug 23. pii: jeb.240432. [Epub ahead of print]
    Loss of Stearoyl-CoA Desaturase 1 leads to cardiac dysfunction and lipotoxicity.
    Bryon F Tuthill, Christopher J Quaglia, Eileen O'Hara, Laura Palanker Musselman.
      Diets high in carbohydrates are associated with type 2 diabetes and its comorbidities, including hyperglycemia, hyperlipidemia, obesity, hepatic steatosis and cardiovascular disease. We use a high-sugar diet to study the pathophysiology of diet-induced metabolic disease in Drosophila melanogaster. High-sugar diets produce hyperglycemia, obesity, insulin resistance, and cardiomyopathy in flies along with ectopic accumulation of toxic lipids, or lipotoxicity. Stearoyl-CoA desaturase 1 is an enzyme that contributes to long-chain fatty acid metabolism by introducing a double bond into the acyl chain. Knockdown of stearoyl-CoA desaturase 1 in the fat body reduced lipogenesis and exacerbated pathophysiology in flies reared on high-sugar diets. These flies exhibited dyslipidemia and growth deficiency in addition to defects in cardiac and gut function. We assessed the lipidome of these flies using tandem mass spectrometry to provide insight into the relationship between potentially lipotoxic species and type 2 diabetes-like pathophysiology. Oleic acid supplementation is able to rescue a variety of phenotypes produced by stearoyl-CoA desaturase 1 RNAi, including fly weight, triglyceride storage, gut development, and cardiac failure. Taken together, these data suggest a protective role for monounsaturated fatty acids in diet-induced metabolic disease phenotypes.
    Keywords:  Desat1; Drosophila; Lipotoxicity; SCD1; Stearoyl-CoA Desaturase 1
    DOI:  https://doi.org/10.1242/jeb.240432
  8. PPAR Res. 2021 ;2021 9947656
    Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α.
    Yufei Zhou, Ting Yin, Mengsha Shi, Mengli Chen, Xiaodong Wu, Kai Wang, Iokfai Cheang, Yanxiu Li, Hongcai Shang, Haifeng Zhang, Xinli Li.
       Materials and Methods: C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson's trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice.
    Results: Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1).
    Conclusions: Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.
    DOI:  https://doi.org/10.1155/2021/9947656
  9. Metabolomics. 2021 Aug 23. 17(9): 76
    Perturbations in cardiac metabolism in a human model of acute myocardial ischaemia.
    Sanoj Chacko, Mamas A Mamas, Magdi El-Omar, David Simon, Sohaib Haseeb, Farzin Fath-Ordoubadi, Bernard Clarke, Ludwig Neyses, Warwick B Dunn.
       INTRODUCTION: Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale.
    OBJECTIVES: This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach.
    METHODS: Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach.
    RESULTS: The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P < 0.05) when compared to baseline levels, respectively. Fatty acid beta-oxidation and anaerobic respiration, lysoglycerophospholipids, arachidonic acid, docosahexaenoic acid, tryptophan metabolism and sphingosine-1-phosphate were identified as mechanistically important.
    CONCLUSION: Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.
    Keywords:  Acute myocardial ischemia; Coronary sinus serum; Metabolism; Metabolomics; PCI
    DOI:  https://doi.org/10.1007/s11306-021-01827-x
  10. Eur Heart J. 2021 Aug 24. pii: ehab530. [Epub ahead of print]
    Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.
    Kazuma Oyama, Itamar Raz, Avivit Cahn, Julia Kuder, Sabina A Murphy, Deepak L Bhatt, Lawrence A Leiter, Darren K McGuire, John P H Wilding, Kyong-Soo Park, Assen Goudev, Rafael Diaz, Jindřich Špinar, Ingrid A M Gause-Nilsson, Ofri Mosenzon, Marc S Sabatine, Stephen D Wiviott.
       AIMS : We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM).
    METHODS AND RESULTS : DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients.
    CONCLUSIONS : In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM.
    CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.
    Keywords:  Cardiovascular death; Heart failure; Obesity; Sodium-glucose co transporter 2 inhibitors; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1093/eurheartj/ehab530
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