Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a Ryanodine Receptor Type 2 Missense Mutation

• Published in: Circulation Journal Vol. 84; no. 2; pp. 226 - 234
• Main Authors: Nozaki, Yoshihiro, Kato, Yoshiaki, Uike, Kiyoshi, Yamamura, Kenichiro, Kikuchi, Masahiro, Yasuda, Maki, Ohno, Seiko, Horie, Minoru, Murayama, Takashi, Kurebayashi, Nagomi, Horigome, Hitoshi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 24.01.2020
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Anti-Arrhythmia Agents - therapeutic use; Calcium Signaling; Catecholaminergic polymorphic ventricular tachycardia; Child; Child, Preschool; Death, Sudden, Cardiac - prevention & control; Defibrillators, Implantable; Electric Countershock - instrumentation; Exercise-induced syncope; Female; Flecainide - therapeutic use; Genetic Predisposition to Disease; HEK293 Cells; Heredity; Humans; Isolated Noncompaction of the Ventricular Myocardium - diagnostic imaging; Isolated Noncompaction of the Ventricular Myocardium - genetics; Isolated Noncompaction of the Ventricular Myocardium - metabolism; Isolated Noncompaction of the Ventricular Myocardium - therapy; Left ventricular non-compaction; Mutation, Missense; Pedigree; Phenotype; Retrospective Studies; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptor type 2; Sarcoplasmic Reticulum - metabolism; Sudden cardiac death; Tachycardia, Ventricular - diagnosis; Tachycardia, Ventricular - genetics; Tachycardia, Ventricular - metabolism; Tachycardia, Ventricular - therapy; Catecholaminergic polymorphic ventricular tachycardia; Left ventricular non-compaction; Sudden cardiac death; Exercise-induced syncope; Ryanodine receptor type 2
• ISSN: 1346-9843; 1347-4820; 1347-4820
• DOI: 10.1253/circj.CJ-19-0720

Background:Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the sameryanodine receptor type 2(RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC .Methods and Results:Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the sameRYR2-R169Q missense mutation and no other CPVT- or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca2+imaging and [3H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca2+release from the sarcoplasmic reticulum and increased fractional Ca2+release.Conclusions:The rare association of LVNC and CPVT phenotypes withRYR2mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.