A Severe Inherited Arrhythmia Syndrome Highlights the Role of Fatty Acid Metabolism in the Regulation of Cardiac Electrical Activity
Bibliographic record
Abstract
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
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".