Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

BACKGROUND

The slow and rapid delayed rectifier K currents (I and I, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the 2 currents have been carefully documented, the respective physiological roles of I and I are less established. In this study, we sought to understand the individual roles of these currents and quantify how effectively each stabilizes the AP and protects cells against arrhythmias across multiple species.

METHODS

We compared 10 mathematical models describing ventricular myocytes from human, rabbit, dog, and guinea pig. We examined variability within heterogeneous cell populations, tested the susceptibility of cells to proarrhythmic behavior, and studied how I and I responded to changes in the AP.

RESULTS

We found that (1) models with higher baseline I exhibited less cell-to-cell variability in AP duration; (2) models with higher baseline I were less susceptible to early afterdepolarizations induced by depolarizing perturbations; (3) as AP duration is lengthened, I increases more profoundly than I, thereby providing negative feedback that resists excessive AP prolongation; and (4) the increase in I that occurs during β-adrenergic stimulation is critical for protecting cardiac myocytes from early afterdepolarizations under these conditions.

CONCLUSIONS

Slow delayed rectifier current is uniformly protective across a variety of cell types. These results suggest that I enhancement could potentially be an effective antiarrhythmic strategy.