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Canadian Journal of Cardiology

Could Branched-Chain Amino Acids Be a New Landmark in Metabolic Syndrome and Cardiac Arrhythmias?

Published:March 16, 2022DOI:https://doi.org/10.1016/j.cjca.2022.03.008
      To the Editor:
      We read with great interest the article published in the Canadian Journal of Cardiology, entitled “Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies by Remme.”
      • Remme C.A.
      Sudden cardiac death in diabetes and obesity: mechanisms and therapeutic strategies.
      We would like to provide some comments on the issue and article.
      Branched-chain amino acids (BCAAs) are essential amino acids; a deficiency in BCAAs leads to downregulation of signalling through the mammalian target of rapamycin (mTOR), which is a central regulator of cellular metabolism. It is assumed that persistent activation of the mTOR signalling pathway by increased BCAA concentrations plays a role in the pathogenesis of insulin resistance via interference with insulin signalling and increased degradation of insulin receptor substrates. Some studies have demonstrated that 1,25-Dihydroxyvitamin D (1,25-[OH]2D) augments BCAA catabolism, which leads to the downregulation of mTOR activation and improvement in insulin resistance.
      • Dimitrov V.
      • Barbier C.
      • Ismailova A.
      • et al.
      Vitamin D-regulated gene expression profiles: species-specificity and cell-specific effects on metabolism and immunity.
      Conversely, different studies that focused on melatonin reported that angiotensin-II-induced atrial BCAA accumulation aggravates tissue fibrosis and mitochondrial reactive oxygen species damage in mice, which is possibly linked to atrial fibrillation (AF). Melatonin prevented development of AF by increasing BCAA catabolism and attenuating atrial remodelling by activating the PKG-CREB-KLF15 axis.
      • Yu L.M.
      • Dong X.
      • Zhao J.K.
      • et al.
      Activation of PKG-CREB-KLF15 by melatonin attenuates angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism.
      Regarding the relationship between BCAAs and obesity and diabetes, BCAAs have been involved in platelet activity. The elevated levels of BCAAs and their catabolites in platelets may be responsible for the high platelet activity in type 2 diabetes mellitus.
      • Xu Y.
      • Jiang H.
      • Li L.
      • et al.
      Branched-chain amino acid catabolism promotes thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.
      Tropomodulin-3 propionylation by catabolites of BCAA increases platelet activity and consequently increases the risk of arterial thrombosis. In this study, BCAAs were also shown to significantly promote the aggregation and degranulation of human platelets.
      • Xu Y.
      • Jiang H.
      • Li L.
      • et al.
      Branched-chain amino acid catabolism promotes thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.
      This can be considered to be another mechanism in which BCAAs can trigger processes associated with myocardial ischemia with the changes in cardiac microstructure and increased proarrhythmic effects and sudden cardiac death.
      In considering the results of these studies, we believe that although the number of human studies remains insufficient, as many cellular reactions that are directly or indirectly related to BCAAs are clarified, their effects on clinical practice will be confirmed.

      Funding Sources

      No funding was provided for this article.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Remme C.A.
        Sudden cardiac death in diabetes and obesity: mechanisms and therapeutic strategies.
        Can J Cardiol. 2022; 38: 418-426
        • Dimitrov V.
        • Barbier C.
        • Ismailova A.
        • et al.
        Vitamin D-regulated gene expression profiles: species-specificity and cell-specific effects on metabolism and immunity.
        Endocrinology. 2021; 162: bqaa218
        • Yu L.M.
        • Dong X.
        • Zhao J.K.
        • et al.
        Activation of PKG-CREB-KLF15 by melatonin attenuates angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism.
        Free Radic Biol Med. 2022; 178: 202-214
        • Xu Y.
        • Jiang H.
        • Li L.
        • et al.
        Branched-chain amino acid catabolism promotes thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.
        Circulation. 2020; 142: 49-64

      Linked Article

      • Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies
        Canadian Journal of CardiologyVol. 38Issue 4
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          Ventricular arrhythmias and sudden cardiac death (SCD) occur most frequently in the setting of coronary artery disease, cardiomyopathy and heart failure but are also increasingly observed in persons suffering from diabetes mellitus and obesity. The incidence of these metabolic disorders is rising in Western countries, but adequate prevention and treatment of arrhythmias and SCD in affected patients is limited because of our incomplete knowledge of the underlying disease mechanisms. Here, an overview is presented of the prevalence of electrophysiological disturbances, ventricular arrhythmias, and SCD in the clinical setting of diabetes and obesity.
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      • Reply to Karadeniz et al.—Could Branched-Chain Amino Acids Be a New Landmark in Metabolic Syndrome and Cardiac Arrhythmias?
        Canadian Journal of CardiologyVol. 38Issue 8
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          I thank Dr Karadeniz et al. for their insightful comments. We recently reported that elevated branched chain amino acid (BCAA) levels have proarrhythmic effects by dysregulating cardiac repolarisation and cardiomyocyte calcium homeostasis in a mammalian target of rapamycin (mTOR) pathway–dependent manner.1 We furthermore showed that incubation of human induced pluripotent stem cell–derived cardiomyocytes with high levels of BCAAs induced action potential prolongation, intracellular calcium dysregulation, and arrhythmic events, indicating a direct effect on cardiomyocyte electrophysiology.
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