Ionic Mechanisms Underlying Abnormal QT Prolongation and the Associated Arrhythmias in Diabetic Rabbits: A Role of Rapid Delayed Rectifier K<sup>+</sup> Current
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Bibliographic record
Abstract
Abnormal QT prolongation with the associated arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. We performed whole-cell patch-clamp studies in a rabbit model of alloxan-induced insulin-dependent diabetes mellitus. We demonstrated that heart rate-corrected QT interval and action potential duration (APD) were prolonged by approximately 20% with frequent occurrence of ventricular tachyarrhythmias. Several K(+) currents were found decreased in diabetic rabbits including transient outward K(+)current (I(to)) that was reduced by approximately 60%, rapid delayed rectifier K(+) current (I(Kr)) reduced by approximately 70% and slow delayed rectifier K(+) current (I(Ks)) reduced by approximately 40%. The time-dependent kinetics of these currents remained unaltered. The peak amplitude of L-type Ca% current (I(CaL)) was reduced by approximately 22% and the inactivation kinetics was slowed; the integration of these two effects yielded approximately 15% reduction of I(CaL). The inward rectifier K(+) current (I(K1)) and fast sodium current (I(Na)) were unaffected. Simulation with LabHEART, a computer model of rabbit ventricular action potentials, revealed that inhibition of I(to) or I(Ks) alone fails to alter APD whereas inhibition of I(Kr) alone results in 30% APD prolongation and inhibition of I(CaL) alone causes 10% APD shortening. Integration of changes of all these currents leads to approximately 20% APD lengthening. Protein levels of the pore-forming subunits for these ion channels were decreased to varying extents, as revealed by immunoblotting analysis. Our study represents the first documentation of I(Kr) channelopathy as the major ionic mechanism for diabetic QT prolongation.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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 it