Local Anesthetics Induce Cardiac Toxicity Through Distinct Effects on Calcium Dynamics: Implications For Clinical Prevention
Bibliographic record
Abstract
INTRODUCTION The clinically safe dose of local anesthetics is limited by their induction of potentially lethal cardiac arrhythmias, which occurs in ~50,000 people in the US per year. While this drug toxicity is often attributed to non‐specific block of cardiac sodium channels, studies on isolated channels fail to show any clinically relevant difference between more harmful (i.e. bupivacaine, BUP) and less harmful (i.e. ropivacaine, ROP) anesthetics. We sought to determine the mechanisms of toxicity and arrhythmogenesis for BUP and ROP, revealing prevention and treatment strategies to improve clinical safety. METHODS We cultured beating 2D‐tissues of human iPSC‐derived cardiomyocytes and treated them with clinically relevant concentrations of BUP or ROP. We then analyzed changes to ion and contractile dynamics using the xCELLigence RTCA Cardio and the cytosolic calcium dye FLIPR5. As an inotrope, calcium was tested for its ability to recover contractile dysfunction. Our in vitro findings were validated in a rat model of BUP toxicity. Anesthetized animals were infused with either saline or CaCl 2 (10 mg/kg over 5 min) in the tail vein, followed by either 2 mg/kg/min BUP or ROP, until asystole. Cardiac activity was monitored via ECG and invasive arterial blood pressure recordings, and analysed using non‐linear regression incorporating the effects of drug treatment, sampling time, and animal variability. RESULTS In human iPSC cardiomyocytes, both anesthetics affected contractility, beat rate, rhythm, excitation‐contraction coupling, and sodium channel activity as expected, with BUP causing a greater adverse effect. BUP, but not ROP, additionally delayed calcium wave duration by 20% and reduced overall calcium flux by 66%. Interestingly, CaCl 2 co‐treatment with BUP abolished aberrancy in all toxicity metrics, where CaCl 2 co‐treatment with ROP exacerbated toxicity. Further investigation into intracellular calcium dynamics revealed BUP‐specific defects in diastolic and systolic calcium flux, which were mitigated by CaCl 2 co‐treatment. Our in vivo model validated these findings, with ROP showing less toxicity than BUP in all observed metrics. CaCl 2 pre‐treatment mitigated the BUP‐mediated decline in beat rate and diastolic arterial pressure, but had no effect, or exacerbated outcomes, in ROP‐treated rats. Furthermore, CaCl 2 pre‐treatment reduced arrhythmia onset and QRS widening cased by BUP, but exacerbated these arrhythmia metrics and reduced survival with ROP. CONCLUSIONS We found that BUP, but not ROP, caused a baseline dysfunction in calcium dynamics in human iPSC‐derived cardiomyocytes. Calcium pre‐treatment prevented BUP, but exacerbated ROP cardiotoxicity in both in vitro and in vivo models. Together, our results implicate distinct calcium signaling and dynamics in eliciting the higher clinical cardiotoxicity of the BUP local anesthetic, and show how calcium can be used to protect against the arrhythmogenic effects of BUP overdose. Support or Funding Information Canadian Institutes of Health Research This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".