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.
Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts
