Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity; however, it does not fully explain the observed toxicity variability between anesthetics. The authors hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity.


The authors investigated the effects of clinically relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell–derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n = 5 per group).


Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52 ± 11% and calcium-mediated repolarization duration to 122 ± 7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101 ± 6%, and 101 ± 26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80 ± 6% of control). Similarly, calcium pretreatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3 ± 2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8 ± 3.4 min and time to first arrhythmia by 12.0 ± 2.9 min). Calcium channel blocker nifedipine coadministration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity.


Our data illustrate differences in calcium dynamics between anesthetics and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.

Editor’s Perspective
What We Already Know about This Topic
  • Use of local anesthetics for perioperative pain control can be complicated by cardiotoxicity that may result in serious cardiac complications such as cardiac arrest.
  • There is variability in cardiac toxicity of local anesthetics, with increased cardiotoxicity encountered with longer-acting (e.g., bupivacaine) versus shorter-acting local anesthetics (e.g., ropivacaine). The mechanism for this differing propensity to cardiac toxicity is not well understood.
What This Article Tells Us That Is New
  • This study used human induced pluripotent stem cell–derived cardiomyocytes and found significantly altered cardiomyocyte calcium dynamics with bupivacaine but not ropivacaine. Calcium supplementation restored normal cardiomyocyte rhythm to bupivacaine-treated tissue. Calcium channel blockade selectively worsened bupivacaine cardiotoxicity.
  • This study used a rat model (female) of cardiac toxicity and found that pretreatment with calcium improved survival of bupivacaine- treated rats and reduced survival of ropivacaine-treated rats.