Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Figure 1

Ca²⁺ overload in the SR during adrenergic stress leads to EADs and DADs causing arrhythmia in CPVT. During rest, depolarization of the CM membrane by inward current of sodium activates LTCCs leading to CICR and contraction. Adrenergic stimulus (Adr) leads to phosphorylation of RYR2 and SERCA2a via second messengers of the β-adrenergic pathway (cAMP, PKA) and causes Ca²⁺ overload in the SR. Mutations in RYR2 lead to altered threshold for SOICR and spontaneous Ca²⁺ leak from the SR. Sudden increase in intracellular Ca²⁺ activates NCX and causes membrane depolarization leading to EADs and DADs. Carvedilol (CAR) blocks the beta-adrenergic receptors (βAR) inhibiting the phosphorylation of Ca²⁺ handling proteins and decreasing the SR Ca²⁺ load. Flecainide (FLE) inhibits voltage-gated sodium channel (Na_v) and membrane depolarization leading to the inhibition of LTCC and RYR2 indirectly. CICR = Ca²⁺-induced Ca²⁺ release; SOICR = store overload-induced Ca²⁺ release; NCX = sodium Ca²⁺ exchanger; SERCA2a = sarcoplasmic reticulum Ca²⁺ ATPase; cAMP = cyclic AMP; PKA = protein kinase A. Both carvedilol and flecainide have a direct inhibiting effect on RYR2.