Loss of pitx2c causes early alterations in atrial calcium handling in zebrafish
Bibliographic record
Abstract
Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science, Innovation and Universities, Spain (PID2019-111456RB-100); Consejería de Educación, Cultura y Deportes, Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000223, co-funded by EU FEDER-ERDF) and grants for research groups from University of Castilla-La Mancha (2019-GRIN-27019, 2020-GRIN-29186 and 2022-GRIN-34301, co-funded by EU FEDER-ERDF) Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans. Genome-wide association studies revealed that AF is related to sequence variants in chromosomic regions in close proximity to the transcription factor PITX2, involved in cardiac development and asymmetry, and in morphogenesis of pacemaker regions such as the sinoatrial region and the atrioventricular canal, which receive significant input from the autonomic nervous system. AF patients showed reduced PITX2 mRNA levels. PITX2-/- atrial tissue showed lower expression of CACNA1C accompanied by lower L-type Ca2+ current density. A recent study revealed AF-like phenotypes, including fibrosis, structural and metabolic alterations, arrhythmia, and cardiac conduction defects in adult pitx2c -/- zebrafish. Nevertheless, Ca2+ handling alterations remain unexplored in this zebrafish model. Purpose In this study we investigated cardiac Ca2+ handling in pitx2c deficient zebrafish. Methods We used the transgenic zebrafish line Tg(myl7:Twitch-4) expressing a fluorescent Ca2+ indicator in the heart. We outcrossed pitx2c+/- fish with Tg(myl7:Twitch-4) pitx2c+/- and studied Ca2+ dynamics and cardiac function by videomicroscopy in the beating hearts of 5 days post fertilization (dpf) larvae. Larvae were treated with 100 µM carbachol to assess differential response to parasympathetic stimulation in pitx2c deficient larvae. Results We observed sinoatrial pauses in 40 % of pitx2c+/- larvae accompanied by an increase in heart rate variability. In addition, pitx2c+/- and pitx2c-/- larvae at 5 dpf showed differential response to carbachol, a cholinergic agonist, compared to their wild-type siblings. Moreover, carbachol significantly decreased heart rate in pitx2c+/- and pitx2c-/- 5dpf larvae compared to siblings. Furthermore, we also observed a reduction of the amplitude of Ca2+ transients due to a decrease in the systolic Ca2+ levels in the atrium of pitx2c+/- larvae. The rise time of the atrial Ca2+ transient was prolonged, with a decrease in the rise slope. These data suggest a lower Ca2+ entry in the atrium. Interestingly, pitx2c+/- and wild-type larvae showed similar ventricular Ca2+ handling and contractility. Conclusion These results suggest that loss of pitx2c induce early Ca2+ alterations in the atrium as well as sinoatrial dysfunction in zebrafish during embryogenesis. Furthermore, pitx2c deficiency in zebrafish larvae possibly alters autonomic innervation leading to differentiated cardiac response to carbachol.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".