Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value.

Objective: This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers.

Methods: The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2.

Results: Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes.

Conclusion: M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Conflict of interest statement

No other conflict of interest.

Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

A: Pedigree of family members. Shown in black are those members where EPS demonstrates a post-pacing prolonged QT. B: Pedigree of genetic testing. All 6 family members with a positive EPS were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T-RyR2). Four family members without RyR2 mutations did not

Fig. 1

A: Pedigree of family members. Shown in black are those members where EPS demonstrates a post-pacing prolonged QT. B: Pedigree of genetic testing. All 6 family members with a positive EPS were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T-RyR2). Four family members without RyR2 mutations did not

Fig. 2

Patient V-2 in pedigree; A: Initiation of AF leading to polymorphic VT and VF. VF occurred after a marked QT prolongation following a short-long sequence during AF. B: Magnification of the short-long sequence preceding the onset of VF.

Fig. 3

Rapid ventricular pacing from ICD lead in patient V-2 in pedigree. Notice the abnormal T wave only in the first sinus beat following the pause.

Fig. 4

EPS in four children of patient III-4 (proband's sister); A: Normal T wave on the first sinus beat following termination of rapid ventricular pacing in a non-M4109R-RyR2 carrier. B and C: Abnormal T wave on the first sinus beat following rapid ventricular pacing in two asymptomatic M4109R-RYR2 carriers (patients IV-2 and IV-4; respectively). D: Abnormal T wave on a late ventricular paced beat (S3) following short-long sequence of double right ventricular extrastimulation (S2S3) in another asymptomatic M4109R-RYR2 carrier (patient IV-6 in pedigree).

Fig. 5

Electropherograms demonstrating: A: Insertion of T to G at position 4126 predicting a substitution of Methionine for Arginine amino acid at position 4109 of RyR2 (M4109R); B: Heterozygous nucleotide insertion of T to C at position 3179 predicting a substitution of Isoleucine for Threonine amino acid at position 406 of RyR2 (I406T).

Fig. 6

Patient III-4; A: Marked QT prolongation on the first ventricular paced beat following rapid ventricular pacing during control. B and C: After intravenous flecainide, both the first post-pacing ventricular paced beat (B) and the first supraventricular escape beat (C) show a normal QT.