A Severe Inherited Arrhythmia Syndrome Highlights the Role of Fatty Acid Metabolism in the Regulation of Cardiac Electrical Activity

We have recently identified TECRL, which encodes the trans ‐2,3‐enoyl‐CoA reductase‐like protein, as a new life‐threatening inherited arrhythmia gene. More precisely, we have reported a homozygous rare variant in TECRL gene (p.Arg196Gln) in two unrelated patients diagnosed with long QT syndrome with recurrent exercise‐ and emotion‐induced arrhythmias. TECRL mutations are associated with electrophysiological and calcium‐handling abnormalities and a role for TECRL in fatty acid (FA) metabolism is suspected, however the exact mechanism underlying the electrical phenotype in TECRL patients remains unknown. The current study was undertaken to document the role of TECRL in lipid metabolism in order to better understand its implication in the regulation of cardiac electrical activity. Two approaches were used to characterize the impact of TECRL and its variant R196Q on FA metabolism. First, we studied cellular localization of TECRL and fatty acid profiling in two different cell lines, human induced‐pluripotent stem cells derived cardiomyocytes (hiPS‐CMs) and HEK293 cells overexpressing wild‐type (TECRL*R196) or mutant (TECRL*196Q) TECRL gene. Second, lipidomic analyses were conducted in plasma samples from two TECRL patients to better assess the impact of the disease‐associated TECRL*196Q variant on FA metabolism in vivo . Our immunofluorescence analysis in hiPS‐CMs confirms that TECRL is localised within the endoplasmic reticulum ‐ localization that was not modified by overexpression of the mutant variant. In addition, using an untargeted lipidomic approach we showed changes in phospholipid profiles when TECRL is overexpressed in HEK293 cells as compared to parental HEK293. Moreover, we detected a significant difference in FA profile when comparing the two alleles of TECRL*R196Q. Specifically, we show that levels of few phosphatidylcholines (PC) containing very‐long chain fatty acid (VLCFA >24 carbons) in position sn‐1 are increased by 1.8 to 2.9‐fold (p<0.005) in TECRL*196Q cells, suggesting a role for TECRL in VLCFA metabolism. Consistent with this, our lipidomic analysis conducted in plasma samples from two patients, revealed higher levels of long‐chain acylcarnitines (18–20 carbons) in TECRL patients as compared to controls individuals. Long‐chain acylcarnitines are known arrhythmogenic intermediary metabolites of FA and are responsible for arrhythmias in patients with VLCFA oxidation disorders. Interestingly, severe ventricular arrhythmias as well as a two‐fold increase in plasma levels of long‐chain acylcarnitines were observed in a patient that had underwent an epinephrine challenge. No changes in acylcarnitine profile were observed in this patient's asymptomatic father, who is heterozygous for this mutation, following the same epinephrine challenge. Altogether, these data highlight alterations in FA metabolism in cells overexpressing the two alleles of TECRL*R196Q and in plasma from TECRL patients. These modifications in PC composition and long chain acylcarnitines accumulation could contribute to electrophysiological anomalies leading to this severe inherited arrhythmia syndrome. More broadly, our data highlight that beyond genetic oxidation disorders, alterations in FA metabolism could play a pivotal role in production of arrhythmias. Support or Funding Information Montreal Heart Institute Foundation, Fondation du Grand Défi Pierre Lavoie