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.
Mechanisms of phase‐3 early afterdepolarizations and triggered activities in ventricular myocyte models
