Note on a possible proarrhythmic property of antiarrhythmic drugs aimed at improving gap-junction coupling.

Reduced conduction velocity (CV) in the myocardium is well known to increase the probability of arrhythmia and can be caused by structural changes, reduced excitability of individual myocytes, or decreased electrical coupling in the tissue. Recently, investigators have developed antiarrhythmic drugs that target the connections between individual myocytes with the goal of restoring tissue CV, specifically through increasing gap-junction coupling. In a simple but qualitatively relevant mathematical model, we show here that the introduction of a drug that improves intercellular conductance will indeed increase the CV. However, conditions that would require such a drug, such as fibrotic remodeling, may also increase the load of fibroblasts. Fibroblasts may couple to myocytes in much the same way as myocytes couple to each other, and therefore the use of such an agent may also improve coupling between myocytes and fibroblasts. We present numerical examples illustrating that when the load of coupled fibroblasts on myocytes is low or nonexistent, the drug works as expected, i.e., the drug increases CV. On the other hand, when the fibroblast load is high, changes in CV are nonmonotonic, i.e., the CV first increases and then decreases with an increase in dosage. The existence of coupled fibroblasts may therefore impair the effect of the drug, and under unfortunate conditions may be proarrhythmic.