International Journal of Cardiology 176 (2014) 1402–1404
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia Jennifer Kozlovski a,b, Jodie Ingles a,b, Vanessa Connell c, Lauren Hunt d, Julie McGaughran d, Christian Turner e, Andrew Davis c, Raymond Sy f, Christopher Semsarian a,b,f,⁎ a
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia Sydney Medical School, University of Sydney, Sydney, Australia Royal Children's Hospital, Melbourne, Victoria, Australia d Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia e The Heart Centre for Children, The Children's Hospital, Westmead, Sydney, NSW, Australia f Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia b c
a r t i c l e
i n f o
Article history: Received 30 July 2014 Accepted 2 August 2014 Available online 8 August 2014 Keywords: CPVT Genetics Arrhythmias Sudden death
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly lethal, inherited arrhythmogenic disorder first described in 1975 [1]. CPVT is characterised by polymorphic and/or bidirectional ventricular tachycardia in a structurally normal heart and is precipitated by the physiological release of catecholamines. CPVT has an estimated prevalence of 1 in 10,000 and is an important cause of sudden cardiac death (SCD) in the young [2,3]. The mean age at first symptom is 10 years [2,4–7] and SCD can be the first sign of disease [8,9]. Untreated, the mortality of CPVT reaches 30% by age 30 years [2,8,9]. Mutations in the ryanodine receptor 2 gene (RYR2) underlie the autosomal dominant form of CPVT and mutations in the cardiac calsequestrin gene (CASQ2) are responsible for an autosomal recessive form [2]. The diagnosis of CPVT is made following exercise-induced bidirectional ventricular tachycardia on exercise testing and/or genetic testing. The resting ECG is generally normal, often showing sinus bradycardia, while the echocardiogram classically shows a structurally normal heart [6,7,9,10]. Current class I recommendations for treatment include beta-blocker therapy and an implantable cardioverter defibrillator (ICD) therapy [11].
⁎ Corresponding author at: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, 2042 NSW, Australia. Tel.: +61 2 9565 6195. E-mail address: [email protected] (C. Semsarian).
http://dx.doi.org/10.1016/j.ijcard.2014.08.020 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Given that CPVT is a relatively rare and often under-diagnosed disease, the number of large cohort studies has been limited. The current study sought to describe for the first time a registry-based cohort of Australian families with CPVT. Patients enrolled in the Australian Genetic Heart Disease (AGHD) Registry [12] who met the diagnostic criteria for CPVT [3] and/or had a pathogenic RYR2 or CASQ2 mutation were included. Comprehensive patient and family history information was obtained directly from patients, the medical record and from the AGHD Registry. A retrospective review of all available cardiac investigations was performed, including 12-lead ECGs, transthoracic echocardiograms, 24-hour ECG monitors, exercise stress tests, cardiac MRIs, electrophysiological studies, drug provocation studies and ICD interrogation reports. Genetic testing results of the RYR2 and CASQ2 genes were obtained, where available. Those with a pathogenic RYR2 mutation were referred to as genotype-positive (G +) while those in whom no pathogenic mutation was identified were referred to as genotypenegative (G −). Patients with a history of SCD events, syncope or arrhythmias were referred to as phenotype positive (P +) and those with no significant history who were identified through predictive genetic testing were referred to as phenotype-negative (P −). A SCD event was defined as a cardiac arrest, an appropriate shock from an ICD, or ICD anti-tachycardia pacing. The characteristics of the CPVT families are summarised in Table 1. Twenty-three CPVT families were identified and there were on average two (ranges 1–11) living affected individuals per family. Twenty-two families (96%) reported a history of SCD events (including appropriate ICD therapies, resuscitated cardiac arrest and SCD) and 10 families (43%) reported a history of SCD. There was a mean of two (ranges 1–7) SCDs per family and median age of death was 19 years (b1–38). RYR2 testing had been performed in 20 families (87%) and the proband mutation detection rate was 60%. Seven novel pathogenic RYR2 mutations were identified and are summarised in Fig. 1. The characteristics of the 35 CPVT patients from the 23 families identified in this study are summarised in Table 2. The median age was 29 years (ranges 3–66) and 22 (63%) were female. The median age at first symptom was 11 years (ranges 4–50). The first presentation of disease included syncope (44%) and cardiac arrest (37%), and occurred during physical activity in 70%. SCD events had occurred in 21 patients
J. Kozlovski et al. / International Journal of Cardiology 176 (2014) 1402–1404 Table 1 Characteristics of CPVT families.
1403
Table 2 Characteristics of CPVT patients.
Characteristic
N
Characteristic
N
Number of families Number diagnosed with CPVT per family, mean (range) Sudden cardiac events Family history of SCD events, number (%) Family history of SCD, number (%) Number of SCD per family, mean (range) Age at death, median, years (range) Genetic testing RYR2 testing performed (%) RYR2 mutation detection rate (%) Novel RYR2 mutation (%) De novo mutations in proband, number (%) CASQ2 testing performed (%) CASQ2 mutation detection rate (%) Number confirmed negative by predictive testing, mean (range) Other Number first-degree relatives at-risk, mean (range)
23 2 (1–11)
Number of individuals Current age, median, years (range) Number of females (%) Symptoms Number of symptomatic patients (%) Number of patients who have had a sudden cardiac event (%) Age at first symptom, mean, years (range) Syncope as first symptom, number (%) Cardiac arrest as first symptom, number (%) Activity during first symptom — physical activity Activity during first symptom — emotional event Diagnosis Age at diagnosis, mean, years (SD) Genotype–phenotype Genotype positive with clinical disease, number (%) Genotype negative with clinical disease, number (%) Genotype unknown with clinical disease, number (%) Genotype positive with no clinical disease, number (%) Management Number prescribed a beta-blocker (%) Number with an ICD implanted (%) Primary prevention Secondary prevention Number with an ICD who have received ≥1 appropriate shock (%) Number with an ICD who have received ≥1 inappropriate shock (%) Number undergone a left cardiac sympathetic denervation (%)
35 29 (3–66) 22 (63)
22 (96) 10 (43) 2 (1–4) 19 (b1–38) 20 (87) 12 (60) 7 (35) 5 (20) 4 (17) 0 (0) 3 (0–12) 5 (0–19)
NB: SCD = sudden cardiac death.
(60%). Of the 27 patients with an ICD, 11 (41%) received at least one appropriate shock during a mean follow-up of 4.8 ± 3.2 years since implantation, while 4 (15%) patients received at least one inappropriate shock. Importantly, a mean delay of 9 years was observed from the first symptom of CPVT to diagnosis. The clinical and genetic features of Australian families with CPVT are consistent with CPVT cohorts described in North America and Europe. One notable difference was the delay to diagnosis, measured in patients presenting with symptoms from 1980 onwards. A mean delay of 9 years (median 5 years) from first symptom to diagnosis was observed in this study, compared with a mean delay of 3 years (ranges 2.0–4.8) in other CPVT cohorts described internationally [2,4–7,9]. This 9-year delay was present regardless of whether patients experienced their first symptom as a child or as an adult. Further, patients whose first sign of disease was a cardiac arrest also had a mean delay to diagnosis of 7 years. A delay to diagnosis is often reported in CPVT and is not surprising, given the characteristics of the disease. Patients often initially present with syncope — a common symptom with many aetiologies. Even when a cardiac cause is suspected, a normal ECG and echocardiogram often negates any further evaluation. A further barrier to the diagnosis of CPVT is the low awareness and recognition of the condition. CPVT is a relatively rare and newly described inherited arrhythmogenic disorder and so the collective experience of cardiologists in recognising the condition is likely to be low. Importantly, the delay to diagnosis in our cohort has improved dramatically over time, with the mean delay decreasing from 25 years in 1980–1989, to 11 years in 1990–1999, to less than 1 year from 2000 onwards. This improvement in delay to diagnosis most likely reflects better education and awareness of CPVT amongst cardiologists and allied health professionals.
R169P* R169Q R414C
A2387V Y2392C L2423F * R2474K *
27 (77) 21 (60) 16 (4–50) 12 (44) 10 (37) 19 (70) 3 (11) 26 (18) 12 (34) 12 (34) 5 (14) 6 (17) 32 (91) 27 (77) 10 (37) 17 (63) 11 (41) 4 (15) 7 (20)
NB: SD = standard deviation; ICD = implantable cardioverter defibrillator.
A long delay to diagnosis has the potential to lead to very significant and potentially tragic consequences. Undiagnosed CPVT patients are at a higher risk of SCD. Van der Werf et al. [13] recently performed an important meta-analysis of 11 studies that measured arrhythmic events (syncope, aborted cardiac arrest, SCD), near-fatal arrhythmic events (aborted cardiac arrest, SCD) and fatal arrhythmic events in 403 CPVT patients, with a mean follow-up period of 2 to 8 years. The majority of patients (88%) were on beta-blocker therapy during follow-up, yet the estimated 8-year arrhythmic, near-fatal and fatal event rates were 37.2%, 15.3% and 6.4%, respectively. One of these studies, by Hayashi et al. [2] followed 101 CPVT patients for a mean period of 7.9 years and found the absence of beta-blocker therapy to be an independent predictor of cardiac events (hazard ratio of 5.48 with 95% CI 1.8–16.7). Therefore greater education and awareness of CPVT is important to ensure these patients are diagnosed sooner, enabling the initiation of appropriate treatment and prevention strategies. The current study also sheds new light on some of the pathogenic mutations in the RYR2 gene that cause CPVT. There were 7 novel pathogenic RYR2 mutations reported for these patients (Fig. 1). Interestingly, in the total cohort, 5 out of 12 pathogenic RYR2 mutations identified were de novo mutations (absent in both parents). While the cohort of genotyped CPVT was relatively small, patients with RYR2 mutations
c.11880+13_11880+16delACTG * W4078G ** V4634E * c.14655+22T>C * ^ T4909I *
Fig. 1. Schematic representation of the RYR2 protein and the mutations identified in CPVT probands. All mutations identified were located in the N terminal, Central or C-terminal domain, where the majority of reported RYR2 mutations are clustered. * indicates a novel mutation. ** indicates a novel variant of unknown significance. ^ indicates the mutation was identified in two unrelated individuals in this study.
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J. Kozlovski et al. / International Journal of Cardiology 176 (2014) 1402–1404
were more likely to present with a cardiac arrest than patients without RYR2 mutations (67% vs 10%, p = 0.012) and had a poorer cardiac-event free survival (p = 0.015). Identification of RYR2 mutations in these families has its greatest utility in the predictive testing of the at-risk family members. In the 23 families identified, there were a mean of five first-degree family members at risk of developing disease, highlighting the importance of knowing the underlying genetic cause. Predictive genetic testing of asymptomatic relatives enables those found to be gene negative to be released from future clinical surveillance and reassured, or for those who test gene positive allows early diagnosis of disease, facilitating early therapeutic and prevention initiatives [14]. CPVT is a rare but potentially lethal inherited arrhythmogenic disorder that should be considered in young patients presenting with cardiac arrest or recurrent syncope. The index of suspicion should be increased in patients with a family history of SCD, especially at a young age, sinus bradycardia, normal QT interval on ECG, and a structurally normal heart on echocardiography. Exercise testing is essential in making the diagnosis of CPVT. Genetic testing is recommended for families affected by CPVT, as high mutation detection rates provide valuable information that guides management of family members. The current study represents the first report of the clinical and genetic features of Australian families with CPVT. Disclosures The authors report no relationships that could be construed as a conflict of interest. Acknowledgements JI is the recipient of a National Health and Medical Research Council (NHMRC) and National Heart Foundation of Australia Early Career Fellowship (#1036756). CS is the recipient of a NHMRC Practitioner Fellowship (#571084).
References [1] Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J 1975;37:339–44. [2] Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119:2426–34. [3] Pflaumer A, Davis AM. Guidelines for the diagnosis and management of catecholaminergic polymorphic ventricular tachycardia. Heart Lung Circ 2012;21: 96–100. [4] Andrsova I, Valaskova I, Kubus P, et al. Clinical characteristics and mutational analysis of the RyR2 gene in seven Czech families with catecholaminergic polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 2012;35:798–803. [5] Celiker A, Erdogan I, Karagoz T, Ozer S. Clinical experiences of patients with catecholaminergic polymorphic ventricular tachycardia. Cardiol Young 2009; 19:45–52. [6] Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–9. [7] Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69–74. [8] Cerrone M, Colombi B, Bloise R, Memmi M, Moncalvo C. Clinical and molecular characterization of a large cohort of patients affected by catecholaminergic polymorphic ventricular tachycardia. Circulation 2004;110:III-552. [9] Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999;34:2035–42. [10] Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89:66–70. [11] Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006;8:746–837. [12] Ingles J, Semsarian C. The Australian Genetic Heart Disease Registry. Int J Cardiol 2013;168:e127–8. [13] van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175–83. [14] Ingles J, Semsarian C. Conveying a probabilistic genetic test result to families with an inherited heart disease. Heart Rhythm 2014;11:1073–8.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia Jennifer Kozlovski a,b, Jodie Ingles a,b, Vanessa Connell c, Lauren Hunt d, Julie McGaughran d, Christian Turner e, Andrew Davis c, Raymond Sy f, Christopher Semsarian a,b,f,⁎ a
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia Sydney Medical School, University of Sydney, Sydney, Australia Royal Children's Hospital, Melbourne, Victoria, Australia d Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia e The Heart Centre for Children, The Children's Hospital, Westmead, Sydney, NSW, Australia f Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia b c
a r t i c l e
i n f o
Article history: Received 30 July 2014 Accepted 2 August 2014 Available online 8 August 2014 Keywords: CPVT Genetics Arrhythmias Sudden death
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly lethal, inherited arrhythmogenic disorder first described in 1975 [1]. CPVT is characterised by polymorphic and/or bidirectional ventricular tachycardia in a structurally normal heart and is precipitated by the physiological release of catecholamines. CPVT has an estimated prevalence of 1 in 10,000 and is an important cause of sudden cardiac death (SCD) in the young [2,3]. The mean age at first symptom is 10 years [2,4–7] and SCD can be the first sign of disease [8,9]. Untreated, the mortality of CPVT reaches 30% by age 30 years [2,8,9]. Mutations in the ryanodine receptor 2 gene (RYR2) underlie the autosomal dominant form of CPVT and mutations in the cardiac calsequestrin gene (CASQ2) are responsible for an autosomal recessive form [2]. The diagnosis of CPVT is made following exercise-induced bidirectional ventricular tachycardia on exercise testing and/or genetic testing. The resting ECG is generally normal, often showing sinus bradycardia, while the echocardiogram classically shows a structurally normal heart [6,7,9,10]. Current class I recommendations for treatment include beta-blocker therapy and an implantable cardioverter defibrillator (ICD) therapy [11].
⁎ Corresponding author at: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, 2042 NSW, Australia. Tel.: +61 2 9565 6195. E-mail address: [email protected] (C. Semsarian).
http://dx.doi.org/10.1016/j.ijcard.2014.08.020 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Given that CPVT is a relatively rare and often under-diagnosed disease, the number of large cohort studies has been limited. The current study sought to describe for the first time a registry-based cohort of Australian families with CPVT. Patients enrolled in the Australian Genetic Heart Disease (AGHD) Registry [12] who met the diagnostic criteria for CPVT [3] and/or had a pathogenic RYR2 or CASQ2 mutation were included. Comprehensive patient and family history information was obtained directly from patients, the medical record and from the AGHD Registry. A retrospective review of all available cardiac investigations was performed, including 12-lead ECGs, transthoracic echocardiograms, 24-hour ECG monitors, exercise stress tests, cardiac MRIs, electrophysiological studies, drug provocation studies and ICD interrogation reports. Genetic testing results of the RYR2 and CASQ2 genes were obtained, where available. Those with a pathogenic RYR2 mutation were referred to as genotype-positive (G +) while those in whom no pathogenic mutation was identified were referred to as genotypenegative (G −). Patients with a history of SCD events, syncope or arrhythmias were referred to as phenotype positive (P +) and those with no significant history who were identified through predictive genetic testing were referred to as phenotype-negative (P −). A SCD event was defined as a cardiac arrest, an appropriate shock from an ICD, or ICD anti-tachycardia pacing. The characteristics of the CPVT families are summarised in Table 1. Twenty-three CPVT families were identified and there were on average two (ranges 1–11) living affected individuals per family. Twenty-two families (96%) reported a history of SCD events (including appropriate ICD therapies, resuscitated cardiac arrest and SCD) and 10 families (43%) reported a history of SCD. There was a mean of two (ranges 1–7) SCDs per family and median age of death was 19 years (b1–38). RYR2 testing had been performed in 20 families (87%) and the proband mutation detection rate was 60%. Seven novel pathogenic RYR2 mutations were identified and are summarised in Fig. 1. The characteristics of the 35 CPVT patients from the 23 families identified in this study are summarised in Table 2. The median age was 29 years (ranges 3–66) and 22 (63%) were female. The median age at first symptom was 11 years (ranges 4–50). The first presentation of disease included syncope (44%) and cardiac arrest (37%), and occurred during physical activity in 70%. SCD events had occurred in 21 patients
J. Kozlovski et al. / International Journal of Cardiology 176 (2014) 1402–1404 Table 1 Characteristics of CPVT families.
1403
Table 2 Characteristics of CPVT patients.
Characteristic
N
Characteristic
N
Number of families Number diagnosed with CPVT per family, mean (range) Sudden cardiac events Family history of SCD events, number (%) Family history of SCD, number (%) Number of SCD per family, mean (range) Age at death, median, years (range) Genetic testing RYR2 testing performed (%) RYR2 mutation detection rate (%) Novel RYR2 mutation (%) De novo mutations in proband, number (%) CASQ2 testing performed (%) CASQ2 mutation detection rate (%) Number confirmed negative by predictive testing, mean (range) Other Number first-degree relatives at-risk, mean (range)
23 2 (1–11)
Number of individuals Current age, median, years (range) Number of females (%) Symptoms Number of symptomatic patients (%) Number of patients who have had a sudden cardiac event (%) Age at first symptom, mean, years (range) Syncope as first symptom, number (%) Cardiac arrest as first symptom, number (%) Activity during first symptom — physical activity Activity during first symptom — emotional event Diagnosis Age at diagnosis, mean, years (SD) Genotype–phenotype Genotype positive with clinical disease, number (%) Genotype negative with clinical disease, number (%) Genotype unknown with clinical disease, number (%) Genotype positive with no clinical disease, number (%) Management Number prescribed a beta-blocker (%) Number with an ICD implanted (%) Primary prevention Secondary prevention Number with an ICD who have received ≥1 appropriate shock (%) Number with an ICD who have received ≥1 inappropriate shock (%) Number undergone a left cardiac sympathetic denervation (%)
35 29 (3–66) 22 (63)
22 (96) 10 (43) 2 (1–4) 19 (b1–38) 20 (87) 12 (60) 7 (35) 5 (20) 4 (17) 0 (0) 3 (0–12) 5 (0–19)
NB: SCD = sudden cardiac death.
(60%). Of the 27 patients with an ICD, 11 (41%) received at least one appropriate shock during a mean follow-up of 4.8 ± 3.2 years since implantation, while 4 (15%) patients received at least one inappropriate shock. Importantly, a mean delay of 9 years was observed from the first symptom of CPVT to diagnosis. The clinical and genetic features of Australian families with CPVT are consistent with CPVT cohorts described in North America and Europe. One notable difference was the delay to diagnosis, measured in patients presenting with symptoms from 1980 onwards. A mean delay of 9 years (median 5 years) from first symptom to diagnosis was observed in this study, compared with a mean delay of 3 years (ranges 2.0–4.8) in other CPVT cohorts described internationally [2,4–7,9]. This 9-year delay was present regardless of whether patients experienced their first symptom as a child or as an adult. Further, patients whose first sign of disease was a cardiac arrest also had a mean delay to diagnosis of 7 years. A delay to diagnosis is often reported in CPVT and is not surprising, given the characteristics of the disease. Patients often initially present with syncope — a common symptom with many aetiologies. Even when a cardiac cause is suspected, a normal ECG and echocardiogram often negates any further evaluation. A further barrier to the diagnosis of CPVT is the low awareness and recognition of the condition. CPVT is a relatively rare and newly described inherited arrhythmogenic disorder and so the collective experience of cardiologists in recognising the condition is likely to be low. Importantly, the delay to diagnosis in our cohort has improved dramatically over time, with the mean delay decreasing from 25 years in 1980–1989, to 11 years in 1990–1999, to less than 1 year from 2000 onwards. This improvement in delay to diagnosis most likely reflects better education and awareness of CPVT amongst cardiologists and allied health professionals.
R169P* R169Q R414C
A2387V Y2392C L2423F * R2474K *
27 (77) 21 (60) 16 (4–50) 12 (44) 10 (37) 19 (70) 3 (11) 26 (18) 12 (34) 12 (34) 5 (14) 6 (17) 32 (91) 27 (77) 10 (37) 17 (63) 11 (41) 4 (15) 7 (20)
NB: SD = standard deviation; ICD = implantable cardioverter defibrillator.
A long delay to diagnosis has the potential to lead to very significant and potentially tragic consequences. Undiagnosed CPVT patients are at a higher risk of SCD. Van der Werf et al. [13] recently performed an important meta-analysis of 11 studies that measured arrhythmic events (syncope, aborted cardiac arrest, SCD), near-fatal arrhythmic events (aborted cardiac arrest, SCD) and fatal arrhythmic events in 403 CPVT patients, with a mean follow-up period of 2 to 8 years. The majority of patients (88%) were on beta-blocker therapy during follow-up, yet the estimated 8-year arrhythmic, near-fatal and fatal event rates were 37.2%, 15.3% and 6.4%, respectively. One of these studies, by Hayashi et al. [2] followed 101 CPVT patients for a mean period of 7.9 years and found the absence of beta-blocker therapy to be an independent predictor of cardiac events (hazard ratio of 5.48 with 95% CI 1.8–16.7). Therefore greater education and awareness of CPVT is important to ensure these patients are diagnosed sooner, enabling the initiation of appropriate treatment and prevention strategies. The current study also sheds new light on some of the pathogenic mutations in the RYR2 gene that cause CPVT. There were 7 novel pathogenic RYR2 mutations reported for these patients (Fig. 1). Interestingly, in the total cohort, 5 out of 12 pathogenic RYR2 mutations identified were de novo mutations (absent in both parents). While the cohort of genotyped CPVT was relatively small, patients with RYR2 mutations
c.11880+13_11880+16delACTG * W4078G ** V4634E * c.14655+22T>C * ^ T4909I *
Fig. 1. Schematic representation of the RYR2 protein and the mutations identified in CPVT probands. All mutations identified were located in the N terminal, Central or C-terminal domain, where the majority of reported RYR2 mutations are clustered. * indicates a novel mutation. ** indicates a novel variant of unknown significance. ^ indicates the mutation was identified in two unrelated individuals in this study.
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were more likely to present with a cardiac arrest than patients without RYR2 mutations (67% vs 10%, p = 0.012) and had a poorer cardiac-event free survival (p = 0.015). Identification of RYR2 mutations in these families has its greatest utility in the predictive testing of the at-risk family members. In the 23 families identified, there were a mean of five first-degree family members at risk of developing disease, highlighting the importance of knowing the underlying genetic cause. Predictive genetic testing of asymptomatic relatives enables those found to be gene negative to be released from future clinical surveillance and reassured, or for those who test gene positive allows early diagnosis of disease, facilitating early therapeutic and prevention initiatives [14]. CPVT is a rare but potentially lethal inherited arrhythmogenic disorder that should be considered in young patients presenting with cardiac arrest or recurrent syncope. The index of suspicion should be increased in patients with a family history of SCD, especially at a young age, sinus bradycardia, normal QT interval on ECG, and a structurally normal heart on echocardiography. Exercise testing is essential in making the diagnosis of CPVT. Genetic testing is recommended for families affected by CPVT, as high mutation detection rates provide valuable information that guides management of family members. The current study represents the first report of the clinical and genetic features of Australian families with CPVT. Disclosures The authors report no relationships that could be construed as a conflict of interest. Acknowledgements JI is the recipient of a National Health and Medical Research Council (NHMRC) and National Heart Foundation of Australia Early Career Fellowship (#1036756). CS is the recipient of a NHMRC Practitioner Fellowship (#571084).
References [1] Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J 1975;37:339–44. [2] Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119:2426–34. [3] Pflaumer A, Davis AM. Guidelines for the diagnosis and management of catecholaminergic polymorphic ventricular tachycardia. Heart Lung Circ 2012;21: 96–100. [4] Andrsova I, Valaskova I, Kubus P, et al. Clinical characteristics and mutational analysis of the RyR2 gene in seven Czech families with catecholaminergic polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 2012;35:798–803. [5] Celiker A, Erdogan I, Karagoz T, Ozer S. Clinical experiences of patients with catecholaminergic polymorphic ventricular tachycardia. Cardiol Young 2009; 19:45–52. [6] Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–9. [7] Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69–74. [8] Cerrone M, Colombi B, Bloise R, Memmi M, Moncalvo C. Clinical and molecular characterization of a large cohort of patients affected by catecholaminergic polymorphic ventricular tachycardia. Circulation 2004;110:III-552. [9] Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999;34:2035–42. [10] Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89:66–70. [11] Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006;8:746–837. [12] Ingles J, Semsarian C. The Australian Genetic Heart Disease Registry. Int J Cardiol 2013;168:e127–8. [13] van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175–83. [14] Ingles J, Semsarian C. Conveying a probabilistic genetic test result to families with an inherited heart disease. Heart Rhythm 2014;11:1073–8.
