Chronically elevated branched chain amino acid levels are pro-arrhythmic

Abstract

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.

Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy

“…These have reported significant age-related changes such as alterations in beta-oxidation mechanisms, with significantly lower levels of acylcarnitines, dysregulation of the TCA cycle, and a higher abundance of proteins involved in the process of glycolysis/gluconeogenesis such as glucose-6-phosphate and fructose-6-phosphate [ 67 , 68 ]. Nevertheless, our results report additional differences between the two groups not reported previously to be influenced by age, highlighting the increased concentrations of aspartate and the lower concentrations of BCAAs, as reports in the literature have suggested higher levels of BCAAs with increasing age, leading to activation of mTOR signaling and resulting in some of the structural and functional alterations observed in the aging myocardium [ 67 , 69 , 70 , 71 , 72 ]. On the other hand, the altered substrates in the TCA cycle in the present study have not been reported in other metabolomic profiling analyses related to aging.…”

Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

“…This prognostic association has also been observed in adolescents (McCormack et al, 2013 ). More recently, elevated BCAAs have been associated with negative cardiovascular outcomes (Du et al, 2018 ; Le Couteur et al, 2020 ; Portero et al, 2021 ; Sun et al, 2017 ).…”

Reply to Karadeniz et al.—Could Branched-Chain Amino Acids Be a New Landmark in Metabolic Syndrome and Cardiac Arrhythmias?

“…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) pathwayedependent manner. 1 We furthermore showed that incubation of human induced pluripotent stem cellederived cardiomyocytes with high levels of BCAAs induced action potential prolongation, intracellular calcium dysregulation, and arrhythmic events, indicating a direct effect on cardiomyocyte electrophysiology. 1 However, this does not preclude the possibility that BCAAs also exert proarrhythmic effects through other mechanisms.…”

“…1 We furthermore showed that incubation of human induced pluripotent stem cellederived cardiomyocytes with high levels of BCAAs induced action potential prolongation, intracellular calcium dysregulation, and arrhythmic events, indicating a direct effect on cardiomyocyte electrophysiology. 1 However, this does not preclude the possibility that BCAAs also exert proarrhythmic effects through other mechanisms. As mentioned by Karadeniz et al, a potential modulatory effect of BCAAs on platelet activity may be of relevance, but this requires further investigation.…”