Abstract 5315: Arrhythmogenesis In Mutant KCNJ2 Associated Catecholaminergic Polymorphic Ventricular Tachycardia
Background: Mutations in KCNJ2 cause Andersen Syndrome, short QT syndrome. Recently it has been proposed that in few patients KCNJ2 mutations are present in patients with catecholaminerigc polymorphic VT (CPVT). In the world largest series of CPVT families (n=94) we identified 57 RyR2, 3 CASQ2 and 2 KCNJ2 mutations at positions S220I (SI) and T305I (TI). We studied cardiac myocytes expressing the 2 KCNJ2 mutants to test the hypothesis that they would produce alterations compatible with CPVT.
Methods: We engineered two Adenoviral (Adv) constructs containing mutant KCNJ2 clones with GFP as reporter gene under hPGK promoter. Guinea Pig cardiac myocytes isolated by enzymatic digestion through Langendorff perfusion were infected by Adv-vectors and after 48 hours whole cell patch clamp studies were performed.
Results: Compared with non-infected myocytes and GFP infected myocytes, SI and TI decreased Ik1 current by 50% to 60% (in −120mV, −20.1±1.6 pA/pF in control; −8.7±0.8 pA/pF in SI; −9.6±1.4 pA/pF in TI. p < 0.001), depolarized resting potential (−77.1±1.1mV in control; −71.7±0.8mV in SI; −71.6±1.7mV in TI. p < 0.01) and significantly prolonged APD90 (232±10.7ms in control; 331±20.9ms in SI; 351±31.7ms in TI. p < 0.05 ). Then we tested DAD and triggered activity (TA) occurrence in absence and presence of Isoproterenol in three groups. (see table⇓)
Conclusions: KCNJ2 mutations identified in CPVT patients when expressed in cardiac myocytes reduce Ik1 current, depolarize resting potential and prolong APD. DADs-dependent TA develops at rest in myocytes expressing the two mutants and TA worsens during adrenergic stimulation. These data provide the first evidence that KCNJ2 mutations identified in patients with CPVT facilitate development of DADs and that therefore triggered activity is the most plausible arrhythmogenic mechanisms also in this rare and less well define CPVT variant.