Abstract
BACKGROUND: Arrhythmia syndromes associated with KCNJ2 mutations have been described clinically; however, little is known of the underlying arrhythmia mechanism. We create the first patient inspired KCNJ2 transgenic mouse and study effects of this mutation on cardiac function, I(K1), and Ca(2+) handling, to determine the underlying cellular arrhythmic pathogenesis. METHODS: A cardiac-specific KCNJ2-R67Q mouse was generated and bred for heterozygosity (R67Q(+/-)). Echocardiography was performed at rest, under anesthesia. In vivo ECG recording and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type (WT) littermate controls and R67Q(+/-) mice. I(K1) measurements, action potential characterization, and intracellular Ca(2+) imaging from isolated ventricular myocytes at baseline and after adrenergic stimulation were performed in WT and R67Q(+/-) mice. RESULTS: R67Q(+/-) mice (n=17) showed normal cardiac function, structure, and baseline electrical activity compared with WT (n=10). Following epinephrine and caffeine, only the R67Q(+/-) mice had bidirectional ventricular tachycardia, ventricular tachycardia, frequent ventricular ectopy, and/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q(+/-) (n=8) and WT myocytes (n=9) demonstrated typical n-shaped I(K1)IV relationship; however, following isoproterenol, max outward I(K1) increased by ≈20% in WT but decreased by ≈24% in R67Q(+/-) (P<0.01). R67Q(+/-) myocytes (n=5) demonstrated prolonged action potential duration at 90% repolarization and after 10 nmol/L isoproterenol compared with WT (n=7; P<0.05). Ca(2+) transient amplitude, 50% decay rate, and sarcoplasmic reticulum Ca(2+) content were not different between WT (n=18) and R67Q(+/-) (n=16) myocytes. R67Q(+/-) myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development of early afterdepolarizations that occurred at phase 3 of action potential repolarization. CONCLUSIONS: KCNJ2 mutation R67Q(+/-) causes adrenergic-dependent loss of I(K1) during terminal repolarization and vulnerability to phase 3 early afterdepolarizations. This model clarifies a heretofore unknown arrhythmia mechanism and extends our understanding of treatment implications for patients with KCNJ2 mutation.