Figure 2.

The role of late I_Na in arrhythmia. An increase in late I_Na (gain of function) provides a depolarizing current during the plateau, prolonging the AP, and at the cellular level produces an early afterdepolarization (EAD) which at the tissue/organ level triggers Torsades des Pointes arrhythmia. It is important to point out that late I_Na might also contribute to re-entrant arrhythmia by prolonging refractoriness and producing unidirectional block. For completeness and contrast, “loss of function” generally refers to a loss of peak I_Na and can contribute to the substrate for reentry as shown, or to a loss of early I_Na that might lead to early repolarization and phase 2 reentry (not shown) thought to underlie Brugada syndrome arrhythmia. An increase in late I_Na is often called a “gain of function” especially when referring to mutations that increase late I_Na as in LQT3. Generally, the increase in late I_Na is out of proportion to the gain, if any, in peak I_Na.