Chronically elevated branched chain amino acid levels are pro-arrhythmic
| العنوان: | Chronically elevated branched chain amino acid levels are pro-arrhythmic |
|---|---|
| المؤلفون: | Leander Beekman, Carol Ann Remme, Vincent Portero, Gerard A Marchal, Rafik Tadros, Arie O. Verkerk, A Blease, Paul Potter, I. Jane Cox, Svitlana Podliesna, Simona Casini, Gabi Kastenmüller, Christian Gieger, T Nicol, Tertius Hough, Moritz F. Sinner, Stefan Kääb, Annette Peters, Connie R. Bezzina, Martina Müller-Nurasyid, Michael W.T. Tanck, Sara Falcone, Jorien L. Treur, Antonius Baartscheer, Fay Probert |
| المساهمون: | Epidemiology and Data Science, APH - Methodology, Physiology, Cardiology, ACS - Heart failure & arrhythmias, Graduate School, Adult Psychiatry, ANS - Amsterdam Neuroscience, ACS - Amsterdam Cardiovascular Sciences, Medical Biology |
| المصدر: | Cardiovascular Research, 118(7), 1742-1757. Oxford University Press Cardiovasc. Res. 118:1742–1757 (2021) Cardiovascular research, 118(7), 1742-1757. Oxford University Press Portero, V, Nicol, T, Podliesna, S, Marchal, G A, Baartscheer, A, Casini, S, Tadros, R, Treur, J L, Tanck, M W T, Jane Cox, I J, Probert, F, Hough, T A, Falcone, S, Beekman, L, Müller-Nurasyid, M, Kastenmüller, G, Gieger, C, Peters, A, Kääb, S, Sinner, M F, Blease, A, Verkerk, A O, Bezzina, C R, Potter, P K & Remme, C A 2022, ' Chronically elevated branched chain amino acid levels are pro-arrhythmic ', Cardiovascular Research, vol. 118, no. 7, pp. 1742-1757 . https://doi.org/10.1093/cvr/cvab207Test |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, Physiology, Branched-chain amino acid, 030204 cardiovascular system & hematology, Sudden death, Sudden cardiac death, Afterdepolarization, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Physiology (medical), Internal medicine, Cardiac conduction, medicine, Animals, Humans, Myocytes, Cardiac, BCAA, Arrhythmia, Bcaa, Electrophysiology, Metabolism, Sudden Death, Heart Failure, Sirolimus, business.industry, Cardiac arrhythmia, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, Heart failure, Calcium, Metabolic syndrome, Cardiology and Cardiovascular Medicine, business, Amino Acids, Branched-Chain |
| الوصف: | Aim. Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and Results. We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs – leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions. Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. Translational perspectives. Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome. |
| وصف الملف: | application/pdf |
| تدمد: | 1755-3245 0008-6363 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::751f09554e89397bd6ba435a96e8ba26Test https://pubmed.ncbi.nlm.nih.gov/34142125Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....751f09554e89397bd6ba435a96e8ba26 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17553245 00086363 |
|---|