Figure 5.

Schematic illustration of the physiological and pathophysiological processes leading to arrhythmias upon increased I_Na,late. (a) In a healthy myocyte, excitation-contraction coupling controls contraction by periodically increasing and decreasing the intracellular Ca²⁺ concentration. (b) If I_Na,late is elevated, as in the case of many diseases, intracellular Na⁺ and a concomitant Ca²⁺ overload may lead to arrhythmias. High intracellular Na⁺ concentration can activate the reverse mode NCX to further load the cell with Ca²⁺. Ca²⁺ overload and the longer action potential duration predispose the cell to proarrhythmic events. Red arrows show Ca²⁺ related, while blue arrows show Na⁺ related processes. Dashed lines indicate the phosphorylation targets of the Ca²⁺ – CaM – CaMKII pathway. APD, action potential duration; CaM, calmodulin; CaMKII, Ca/calmodulin-dependent protein kinase II; DAD, delayed afterdepolarization; EAD, early afterdepolarization; I_Ca,L, L-type Ca²⁺ current; I_Na,early, the fast, early component of the Na⁺ current; I_Na,late, the persistent, late component of the Na⁺ current; NCX, Na⁺/Ca²⁺ exchange; NHX, Na⁺/H⁺ exchanger; NKP, Na⁺/K⁺ pump; PLN, phospholamban; PMCA, plasma membrane Ca²⁺-ATPase; RyR, ryanodine receptor; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase; SV, short term beat-to-beat variability of action potential duration