Mechanisms Underlying Sinus Node Dysfunction in a Rat Model of Genetic Atrial Cardiomyopathy
Bibliographic record
Abstract
BACKGROUND: Sinoatrial node (SAN) dysfunction is commonly associated with atrial dysrhythmia (tachy-brady syndrome) and is a particularly important feature of inherited atrial cardiomyopathies leading to artificial pacemaker implantation. Essential MYL4 (myosin light chain-4) is an atrial-selective protein that associates with the myosin light chain and participates importantly in cardiacmuscle contraction. MYL4 gene variants encoding dysfunctional versions of MYL4 cause familial atrial cardiomyopathy with a high incidence of early SAN dysfunction (SND) and pacemaker requirement. In this study, we used a rat line, genetically modified to express an E11K gene mutation responsible for familial atrial cardiomyopathy, to address the mechanisms underlying SND. METHODS: Cardiac structure and function were assessed by echocardiography and in vivo telemetry recording. SAN function was studied in vivo with intracardiac electrophysiology and ex vivo with optical mapping. Mechanisms underlying SND were interrogated in vitro with the use of voltage and current clamp with tight-seal patch-clamp and Ca 2+ imaging of isolated SAN cardiomyocytes. Gene expression was assessed by quantitative polymerase chain reaction, and fibrosis was determined with Masson’s trichrome stain. RESULTS: Mutant Myl4-p.E11K +/+ rats exhibited worse SAN function compared with wild-type controls. In vivo, SND was demonstrated by ≈63% increase in sinus node recovery time compared with wild type. In vitro, SAN conduction velocity was reduced by ≈ 50% for Myl4-p.E11K +/+ compared with wild type. Isolated SAN cells showed ≈50% reduction in funny current and L-type Ca 2+ -current densities. Dysregulation of Ca 2 + homeostasis was observed in Myl4-p.E11K +/+ , with ≈30% slower time to peak and Ca 2+ decay. Masson’s trichrome staining showed ≈45% increase in SAN region collagen deposition in Myl4-p.E11K +/+. CONCLUSIONS: Myl4-p.E11K +/+ mutation causes progressive SND with aging, as a result of extensive abnormalities in the underlying determinants of SAN function, including ion-channel properties, Ca 2+ -homeostasis, and SAN structure. These observations provide new insights into the mechanisms of SAN abnormality in atrial cardiomyopathy.
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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 | 0.000 | 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) | 0.000 | 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".