A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia Junko Arakawa, Akira Hamabe, Takeshi Aiba, Tomoo Nagai, Mikoto Yoshida, Takumi Touya, Norio Ishigami, Hideki Hisadome, Shuichi Katsushika, et al. Heart and Vessels ISSN 0910-8327 Volume 30 Number 6 Heart Vessels (2015) 30:835-840 DOI 10.1007/s00380-014-0555-y
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Author's personal copy Heart Vessels (2015) 30:835–840 DOI 10.1007/s00380-014-0555-y
CASE REPORT
A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adultonset catecholaminergic polymorphic ventricular tachycardia Junko Arakawa • Akira Hamabe • Takeshi Aiba • Tomoo Nagai • Mikoto Yoshida Takumi Touya • Norio Ishigami • Hideki Hisadome • Shuichi Katsushika • Hirotsugu Tabata • Yoshihiro Miyamoto • Wataru Shimizu
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Received: 15 October 2013 / Accepted: 11 July 2014 / Published online: 5 August 2014 Ó Springer Japan 2014
Abstract Sudden cardiac death (SCD) in athletes \35 years of age are mostly due to congenital or acquired cardiac malformations or hypertrophic cardiomyopathy. However, ion channelopathies such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or long-QT syndromes, which are less frequently observed, are also potential pathogenesis of SCD in young athletes. CPVT is an inherited arrhythmia that is induced by physical or emotional stress and may lead to ventricular fibrillation syncope or SCD. Here, we report a case of athlete woman
J. Arakawa, A. Hamabe, T. Aiba and T. Nagai contributed equally to this work. J. Arakawa (&) A. Hamabe T. Nagai M. Yoshida T. Touya N. Ishigami S. Katsushika H. Tabata Department of Cardiology, Japan Self-Defense Forces Central Hospital, Ikejiri 1-2-24, Setagaya-ku, Tokyo 154-8532, Japan e-mail:
[email protected] J. Arakawa A. Hamabe T. Nagai M. Yoshida T. Touya N. Ishigami H. Hisadome S. Katsushika H. Tabata Department of Cardiology, KKR Mishuku Hospital, Tokyo, Japan T. Aiba W. Shimizu Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Y. Miyamoto Laboratory of Molecular Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan W. Shimizu Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
with adult-onset CPVT and aborted SCD who has a novel missense mutation (K4392R) in the cardiac RyR2 gene. Keywords Sudden cardiac death Catecholaminergic polymorphic ventricular tachycardia Cardiac ryanodine receptor
Introduction Sudden cardiac death (SCD) is relatively rare in children, adolescents, and young adults. However, once it happens, it is not only a tragedy for the patient’s family but also has a considerable impact on the community, especially when the patient is a young, healthy athlete. A variety of cardiovascular diseases can cause SCD in young athletes. The vast majority of these deaths in athletes \35 years of age are due to congenital or acquired cardiac malformations [1, 2] Ion channelopathies such as long-QT syndrome [3] and catecholaminergic polymorphic ventricular tachycardia (CPVT), which are among those conditions, are rare (3 %) [1]. CPVT is an inherited arrhythmia that is induced by physical or emotional stress and may lead to ventricular fibrillation, syncope, or SCD [4]. There have been a significant number of reports on the genetic background in CPVT cohorts, including mutations in the genes encoding cardiac calcium release channel of the sarcoplasmic reticulum (cardiac ryanodine receptor gene [RyR2]) and calsequestrin 2 protein (CASQ2 gene) as the major calcium ion reservoir within the sarcoplasmic reticulum [5–12]. Nyegaard M et al. [13] have also showed sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation and induced CPVT-like arrhythmia. Recently, Sy et al. [14] reported a bimodal distribution of onset of symptoms in CPVT at 10–20 and 32–48 years
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old, and the later-onset CPVT was more likely to occur in females and was less likely to have a RyR2 gene mutation. Here, we report a case of athlete woman who had been resuscitated from VF and aborted SCD caused by adultonset CPVT and identified a novel missense mutation (K4392R) in the RyR2 gene.
Case presentation A 30-year-old healthy athlete woman was hospitalized after resuscitation of an aborted SCD. She had attended a half-distance marathon competition and collapsed just after her finish. She immediately received cardiopulmonary resuscitation by bystanders and an automated external defibrillator (AED) successfully delivered shock therapy and recovered her consciousness. The stored electrocardiogram (ECG) of AED later revealed this event was caused by ventricular fibrillation (VF), which was terminated by an appropriate electrical shock (Fig. 1).
Fig. 1 An ambulatory electrocardiogram of the automated external defibrillator. A direct current shock (DC) successfully terminated ventricular fibrillation (VF)
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She had a history of syncope during a 3,000 m running 4 years before. A physical examination revealed a pulse rate of 64 beats per minute, blood pressure of 108/63 mmHg, and no heart murmur. We performed chest radiography, laboratory examination, echocardiography, coronary computed topographical angiography, and cardiac magnetic resonance imaging with intravenous contrast medium, which showed no structural heart disease without late gadolinium enhancement. A resting 12-lead ECG did not indicate any abnormalities, including long-QT or Brugada syndrome (Fig. 2). Holter ambulatory ECG monitoring revealed no atrial or ventricular arrhythmia. A signal-averaged ECG showed no late potential. Treadmill exercise testing was also normal without arrhythmia including PVCs (Bruce protocol stage 4, achieved 12 metabolic equivalents at a heart rate of 175 beats per minute). An electrophysiological study was performed with a catecholamine stress test, which was started with a bolus administration of 0.1 lg/kg of epinephrine followed by continuous intravenous infusion of 0.1 lg/(kg/min) of epinephrine [15]. After 1 min, bidirectional premature ventricular contractions appeared (#1, right bundle branch block configuration and inferior axis; #2, right bundle branch block configuration and superior axis; Fig. 3), which is a typical feature of CPVT. On the other hand, no QT interval prolongation was observed. Subsequently, programmed electrical stimulation was performed in the routine fashion. Atrial flutter and supraventricular tachycardia were induced, which were successfully treated with catheter ablation. No ventricular tachycardia or fibrillation
Fig. 2 A resting 12-lead electrocardiogram, showing normal sinus rhythm with the heart rate of 58 beats per minute, no ST-T abnormalities and QT interval prolongations
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We also assessed the sequencing data of 200 age-matched normal control individuals to distinguish this pathogenic mutations from polymorphisms.
Discussion
Fig. 3 A12-lead electrocardiogram during a catecholamine stress test, demonstrating bidirectional premature ventricular contractions (#1, right bundle branch block configuration and inferior axis; #2, right bundle branch block configuration and superior axis) were observed
was induced. According to the current guideline (class I) [16, 17], she was recommended and agreed with implantation of an implantable cardioverter-defibrillator (ICD). The patient was discharged from the hospital on propranolol at 30 mg daily. Genetic analysis for screening of the candidate genes of CPVT was performed at the laboratory of the National Cerebral and Cardiovascular Center (Suita, Osaka, Japan). In brief, Genomic DNA was isolated from whole blood using a DNA analyzer (QIAGEN GmbH, Hilden, Germany) [18]. Genetic screening for RyR2, CASQ2 was performed by direct sequencing method (ABI 3730 DNA Analyzer, life technology, USA) (Transgenomic, Omaha, NE, USA). The cDNA sequence numbering was based upon the GenBank reference sequence NG_008799 (NCBI) for the RyR2 and NG 008802.1 for the CASQ2. After written informed consent was obtained, blood specimens were collected from the patient and her mother. Genetic analysis detected a novel heterozygous missense mutation in the RyR2 gene (13175 A [ G, K4392R) in the proband and her mother who was asymptomatic (Fig. 4).
In 1976, Coumel et al. [19] first described Adam–Stokes syndrome in children, caused by catecholaminergicinduced ventricular arrhythmia. Lately, Leenhardt et al. [4] reported its fatal clinical features in children in a 7-year observation. CPVT is currently recognized as one of the most malignant cardiac channelopathies that are expressed mostly in young patients with otherwise normal structural hearts with mortality rates of 30–50 % by 35 years of age [20]. However, Sy et al. [14] recently reported late-onset CPVT and described two different peaks of the symptom onset at 10–20 and 32–48 years old of age. They also suggested that the clinical manifestations of late-onset CPVT differ from those of young-onset CPVT. Patients with late-onset CPVT are more likely to be female, less likely to have RyR2 mutations, and at lower risk of SCD. Therefore, Sumitomo emphasized a new classification of CPVT according to onset year as follows: (1) juvenile type, before 20 years of age; and (2) adult type, after 20 years of age [21]. In this case, although her first symptom syncope occurred during long-term running at 26 years of age, the second symptom could be fatal without the use of an AED. In addition, a new mutation in the RyR2 gene was detected in both the patient and her mother. This case presentation has several clinical implications and limitations. The patient’s risk of SCD might not be so high in the daily life since her arrhythmic events occurred only after an extremely high physical stress. Indeed, the usual symptom-evoking treadmill exercise test failed to induce ventricular arrhythmias, but a catecholamine stress test could repeatedly induce typical polymorphic ventricular arrhythmias. Moreover, her mother, who had the same mutation in the RyR2 gene (13175 A [ G, K4392R), is healthy and asymptomatic without cardiac events such as ventricular fibrillation, syncope, or SCD. As such, it is possible that symptoms may occur only when an individual is under an extremely high physical or mental stress likely in a marathon competition. The oral administration of a b-blocker alone without an implantation of ICD might be another therapeutic choice if she could avoid such tough stress. Recently, Watanabe et al. [22] reported that the antiarrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca(2?) release and triggered beats in vitro. In addition, Van der Werf et al. [23] reported that flecainide is effective to reduce ventricular arrhythmias in patients with CPVT who have exercise-induced ventricular arrhythmias
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Fig. 4 A: Patient’s family tree. The proband and her mother have the same RyR2 mutation, but others had not been screened. B: DNA sequence analysis results of the patient. The arrow indicates a heterozygous mutation in the RyR2 gene (K4392R)
despite conventional therapy including oral b-blockers. However, in this case, the patient was resuscitated from VF, that should be necessary for implantation of an ICD. She accepted the implantation of an ICD. Therefore, flecainide with b-blockers might be more favorable therapeutic option, if she has a recurrence of symptoms of CPVT. A complete familial screening of her relatives was not performed. Thus, the genotype–phenotype correlation in this case is still controversial. Van der Werf C et al. [24] showed that arrhythmic events occurred in 12 cases of 51 the patient’s relatives (23.5 %) during a follow-up of 8 years and three events were fatal. According to prevention of SCD, the management of her relatives, including preventative treatment on the basis of the risk stratification, is needed [25–27]. To this end, it is important to provide social education of this inherited disease to enable us to easily access the patient’s relatives. RyR2 gene produces one of the largest ion channel proteins, comprising 4,967 amino acids; it localizes to the sarcoplasmic reticulum, and controls intracellular calcium release and cardiac contraction. There has been three discrete protein regions reported as ‘‘hot spots’’. For its potential physiologic role, these regions have been termed ‘‘domains’’ I, II, and III [8]. This novel RyR2 mutation K4392R locates domain III, which is the ‘‘channel region’’. The protein substitution of K4392R has following aspects: (1) both amino acids are positively charged, (2) the side chains are the same size. Such substitution may not be expected to produce a significant gain-of-function in the Ca2? release from sarcoplasmic reticulum. However, a single-nucleotide mutation from guanosine to adenosine, which resulted in the substitution of lysine for arginine, is reported to have functional abnormalities in Reifenstein’s syndrome [28]. Recently,
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Chen B et al. demonstrated that the Ca2? release variability (CRV) and synchronization of neighboring myocytes are one of the potential causes of clinical CPVT [29]. RyR2 mutations do not alter the channel function at rest, but display ‘‘a high degree’’ of CRV upon intense adrenergic stimulation. Due to above-mentioned reasons, we postulate that the RyR2 mutation, K4392R, could have produced CPVT events in this case. However, our speculation might have following weak points: (1) the mutation is inherited in an unaffected mother, (2) no functional studies had been performed. There could be the possibility of incomplete penetrance of this mutation. One study has reported a novel RyR2 gene variant (W4645R) may segregate the disease in the family with incomplete penetrance [30]. In addition, the most critical limitation is that this report is based on a single case observation.
Conclusions We experienced a healthy athlete woman resuscitated from SCD during a marathon competition who was diagnosed as an adult-onset CPVT and had a novel missense mutation K4392R in the cardiac RyR2 gene. We must take this into consideration for diagnosis and treatment of syncope or SCD in young adult athletes. Acknowledgments The authors thank Naotaka Ohta, Toshiko Shibata, Hiromi Fujiyama, Miyuki Hozan and Akihiro Fujiwara for excellent technical supports. This work was supported by grants from the Ministry of Health, Labor and Welfare of Japan (2010-145); a Grant-in-Aid for Scientific Research on Innovative Areas (22136011 A02, Aiba), a Grant-in-Aid for Scientific Research (C) (24591086 Aiba) from MEXT of Japan, and a Research Grant for Cardiovascular Diseases (H24-033 Shimizu, Aiba) from the Ministry of Health, Labor and Welfare, Japan.
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