Evaluation of Genes Encoding for the Transient Outward Current (Ito) Identifies the KCND2 Gene as a Cause of J-Wave Syndrome Associated With Sudden Cardiac Death

Abstract

782J -wave syndromes refer to a spectrum of ECG observations characterized by early ST-segment takeoff from the terminal QRS or J-point.1,2 The associated QRS segment may demonstrate terminal slurring, representing a J wave concealed within the QRS complex, or present a more distinctly visible notch representing a J wave. Brugada syndrome is the most well-characterized J-wave syndrome, both in terms of clinical and genetic features. Alternative patterns of J-wave syndromes have long been recognized, commonly involving the inferolateral ECG leads and until recent years were considered a benign ECG pattern. 3-8 Clinical Perspective on p 789In 2008, Haïssaguerre and colleagues 9 challenged the concept that inferolateral patterns of J-wave syndromes are a benign entity, reporting a higher prevalence of inferolateral J waves in previously well individuals experiencing a sudden cardiac arrest. Further data corroborated the observation that inferolateral J-wave ECG patterns are prevalent in 20% to 30% of survivors of unexplained cardiac arrest, which is considerably higher than that found in healthy controls. 10,11The electrophysiological mechanism underlying the manifestation of J waves on the ECG has been elegantly demonstrated using ventricular wedge preparations and has been shown to be the result of transmural dispersion of the early repolarizing current, the transient outward current (I to ), which Background-J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I to )-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I to in patients with J waves on ECG. Methods and Results-Comprehensive mutational analysis was performed on I to -encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I to density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in I to resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural I to gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome. Conclusions-These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I to -encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes. (Circ Cardiovasc Genet. 2014;7:782-789.)

Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome

“…The J wave syndromes and IVF have also been associated with gain of function mutations in the transient outward potassium current (I to ). 17, 32–39 …”

“…4, 12 Higher intrinsic levels of I to were shown to account for the greater sensitivity of the inferior LV wall to development of VT/VF in the setting or ERS. 4 The outward shift in the balance of currents was attributable to mutations in genes causing a gain of function in IK-ATP ( KCNJ8 and ABCC9 ) or I to ( KCNE5 mutation and rare polymorphism in DPP10 ) 13–17 or loss of function in I Ca ( CACNA1C, CACNB2 and CACNA2D1 ) 18, 19 or I Na ( SCN5A and SCN10A ). 20, 21 The goal of a pharmacologic approach to therapy should therefore be to produce an inward shift in the balance of current flowing during the early phases of the LV epicardial AP.…”

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

“…Gain-of-function mutations in KCND3 have been implicated in BrS [40] with an enhanced I to current gradient within the right ventricle where KCND3 expression is the highest. Gain-of-function mutations in KCND2 have been associated with J-wave syndromes, including BrS [41]. KCNE3 , encoding MiRP2, decreases the I to current by interacting with the channel Kv4.3 and results in increased I to magnitude and density in the human heart, which could underlie the pathogenesis of BrS-pattern ECG [42].…”

Transmural gradients in ion channel and auxiliary subunit expression

“…Recently, detection of a KCND2 (Kv4.2) gene mutation in a patient with J-wave syndrome led to the suggestion that the Kv4.2 subunit might also contribute to the generation of I to,f in human heart (Perrin et al, 2014). The significance of this finding remains to be clarified since multiple investigators have shown that this gene is not expressed at significant levels in the human heart (Bertaso et al, 2002; Dixon et al, 1996; Gaborit et al, 2007; Isbrandt et al, 2000; Rosati et al, 2008; Zhu et al, 1999).…”