CPVT Patients Research Articles

Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with potentially lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2). ObjectiveThe goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT. MethodsWe synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. ResultsCa2+ imaging revealed that 4 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic. ConclusionStructure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern. ObjectiveThis study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. MethodsClinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. ResultsThis is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). ConclusionThe discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.

A case involving tooth extraction of upper and lower third molars under general anesthesia in a patient with catecholaminergic polymorphic ventricular tachycardia

AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT), an inheritable arrhythmia, poses a grave risk of syncope or cardiac arrest.Case PresentationA 23‐year‐old female with CPVT history and implantable cardioverter‐defibrillator (ICD) implantation sought tooth extraction of her third molars. She underwent the procedure under general anesthesia to mitigate VT risk. Defibrillation function was temporarily halted during anesthesia induction, managed with total intravenous anesthesia. The postoperative course remained uneventful, obviating defibrillation intervention.ConclusionsThis case underscores the efficacy of general anesthesia in averting VT onset during oral surgery for CPVT patients, ensuring a safe and uneventful postoperative recovery.

Oral surgery under general anesthesia in a patient with catecholaminergic polymorphic ventricular tachycardia: A case report

AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a fatal arrhythmic disease. Herein, we report a case of third molar extraction performed under general anesthesia to avoid ventricular tachycardia.Case PresentationA 28‐year‐old woman presented with constant pain and bilateral mandibular gingival swelling. The patient had a history of CPVT diagnosis at 5 years of age, which had been managed with beta‐blockers and sodium channel blockers. Due to the contraindication of using epinephrine and the risk of CPVT induction due to pain, the extraction was conducted under general anesthesia.ConclusionOral surgery in CPVT patients requires appropriate anesthetic agent selection.

Efficacy and safety of the ICD in patients with catecholaminergic polymorphic ventricular tachycardia

Abstract Background Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a potentially fatal genetic arrhythmia syndrome and, despite optimal beta-blocker (BB) therapy, patients often experience life-threatening arrhythmic events (LAE). The role of implantable cardioverter defibrillators (ICD) on reducing mortality in patients with CPVT is debated. Purpose 1) To assess the survival benefit of ICD in the overall CPVT population; 2) to investigate the benefit-to-harm ratio in the population of CPVT patients carriers of ICD. Methods We followed-up consecutive patients with genetically-proven CPVT, treated with optimal BB mono-therapy. The probability of surviving at the occurrence of a first LAE (defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) during BB mono-therapy was compared between ICD carriers and non-ICD carriers. In the cohort of ICD carriers, we assessed the rate of a first major complication (i.e., a complication requiring surgical intervention) and we calculated the benefit-to-harm ratio of ICD (defined as rate of appropriate shocks on LAE over rate of major complications). Results We enrolled 228 CPVT patients with a pathogenic RYR2 (n=216) or CASQ2 (n=12) mutation, of whom 87 (38%) had an ICD implanted. Overall, during 1,558 person-years of follow-up, 31/228 (14%) patients experienced a first LAE on BB mono-therapy (annual LAE rate 2.0%, 95% CI: 1.4–2.8%). Of the 31 individuals who experienced an LAE, 21 patients had an ICD when the LAE occurred, and all survived after ICD intervention. Of the remaining 10 patients who were not carriers of an ICD, 6/10 (60%) survived after external defibrillation or spontaneous arrhythmia termination, while 4/10 (40%) died suddenly. The probability of surviving at the occurrence of a first LAE in BB mono-therapy was thirty-fold higher (Odds Ratio: 30.0, 95% CI: 1.4–629.0; p=0.029) in patients with an ICD, as compared to patients without an ICD. Overall, 15/87 (17%) patients with an ICD experienced a first major complication over 602 person-years of follow-up (2.5% per year, 95% CI: 1.4%-4.1%). Importantly, no patient died for a pro-arrhythmic effect or complications related to ICD. Comparing the rate of major complications to the rate of appropriate ICD shocks on LAE (LAE rate 4.7% per year, 95% CI: 3.1–7.0%), the benefit-to-harm ratio was 1.9, thus favouring the benefit of ICD therapy. Conclusions In our population, ICD therapy conferred a significant survival benefit in patients with CPVT at the occurrence of a first LAE. Overall, the benefit of ICD implant outweighed the harm, as shown by almost two times greater benefit-to-harm ratio. This study provides evidence supporting ICD implantation in patients with high-risk CPVT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente Funding Scheme of the Italian Ministry of Health

Clinical Characteristics, Genetic Basis and Healthcare Resource Utilisation and Costs in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia: A Retrospective Cohort Study.

This study examined the clinical characteristics, genetic basis, healthcare utilisation and costs of catecholaminergic ventricular tachycardia (CPVT) patients from a Chinese city. This was a territory-wide retrospective cohort study of consecutive CPVT patients at public hospitals or clinics in Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and outpatient attendances were analysed over 19 years (2001-2019) followed by calculations of annualised costs (in USD). Sixteen patients with a median presentation age (interquartile range (IQR) of 11 (9-14) years old) were included. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and ventricular tachycardia/fibrillation (VT/VF). One patient had PVCs without VT/VF. Genetic tests were performed on 14 patients (87.5%). Eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2) gene. Seven variants have been described elsewhere (c.14848G A, c.12475C A, c.7420A G, c.11836G A, c.14159T C, c.10046C T and c.7202G A). c.14861C G is a novel RyR2 variant not been reported outside this cohort. Patients were treated with beta-blockers (n = 16), amiodarone (n = 3) and verapamil (n = 2). Sympathectomy (n = 8) and implantable-cardioverter defibrillator implantation (n = 3) were performed. Over a median follow-up of 13.3 years (IQR: 8.4-18.1) years, six patients exhibited incident VT/VF. At the patient level, the median (IQR) annualised costs for A&E, inpatient and outpatient attendances were 66 (40-95), 10521 (5240-66887) and 791 (546-1105), respectively. All patients presented before the age of 19. The yield of genetic testing was 57%. The most expensive attendance type was inpatient stays, followed by outpatients and A&E attendances.

769 Differential pharmacological modulation of arrhythmic phenotype in catecholaminergic polymorphic ventricular tachycardia: not all betablockers are the same

Abstract Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that predisposes patients to develop catecholamine-mediated ventricular arrhythmias (VA), manifesting as exercise- or emotion-induced syncope or cardiac arrest. Due to the catecholaminergic nature of CPVT, exercise stress test (EST) represents the most important diagnostic test. Although widely used in clinical practice to monitor response to therapy, how BBs modulate the occurrence of ventricular arrhythmias during EST in CPVT patients is unclear. To compare the relative efficacy of different classes of betablockers (BBs, β1-selective BBs vs. nadolol) on the arrhythmic manifestations during ESTs performed off-therapy and on-therapy in patients with CPVT. Methods and results We selected 72 patients (45 females) with pathogenic or likely pathogenic variants on RYR2 or CASQ2 from our cohort of 246 genotype-positive CPVT patients, who had at least one EST off-therapy and at least one EST during BB therapy. Overall, 507 ESTs (77 ESTs off-therapy, 29 ESTs during β1-selective BBs, and 401 during nadolol) were prospectively collected over 11.1 ± 6.8 years of follow-up and analysed, with a median of 5 ESTs per patient [interquartile range (IQR): 3–10 ESTs, range: 2–27 ESTs]. In the absence of therapy, VT was documented in 46/77 (60%) cases. BB therapy with nadolol significantly reduced VT at EST to 10% (41/398; P < 0.001). Conversely, β1-selective BBs did not significantly decrease VT incidence at EST (13/29, 45%, P = 0.289) as compared to baseline. Importantly, nadolol was superior in preventing VT both when compared to off-therapy [odds ratio (OR): 33.9, 95% confidence interval (CI): 15.6–73.5, P < 0.001] but also when compared to β1-selective BBs [OR: 18.0, 95% CI: 6.0–53.5, P < 0.001]. Although β1-selective BBs significantly increased the total exercise time free of arrhythmias (median 248 s, IQR: 212–315 s) as compared to baseline (median 83 s, IQR: 12–207 s; P < 0.001), arrhythmia-free exercise time during nadolol (median 381 s, IQR: 251–543 s) was significantly longer as compared to both off-therapy (P < 0.001) and β1-selective BBs (P = 0.020). Multivariate mixed effects logistic regression confirmed that at parity of time of occurrence of first arrhythmia and percentage of maximal heart rate reached, both of which were significantly associated to VT occurrence (P = 0.001 for both), the use of nadolol (OR: 0.23; 95% CI: 0.09–0.60; P = 0.011) was independently associated with decreased incidence of VT. Focusing on the 14 patients (overall 133 ESTs) who had at least one ESTs after the occurrence of VT in nadolol, we dissected the effect of dose increase on the probability of VT reoccurrence. Following the documentation of breakthrough VT, increasing the dose of nadolol by 0.5 mg/kg reduced by 2.5 times the probability of having a recurrence of VT (OR: −2.49, 95% CI: −3.96 to − 1.0; P < 0.001). Conclusions Once CPVT is diagnosed, nadolol at 1 mg/kg/day should be used as preferred therapy as it has been shown to suppress VT in most patients. In rare instances in which VA persist despite an adequate nadolol dose, dose increase to 1.5 mg/kg/day may represent an efficacious antiarrhythmic strategy.

Resting ECG measurements can identify abnormalities in children with catecholaminergic polymorphic ventricular tachycardia

Abstract Background Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited disease characterized by exercise- or emotionally-triggered life-threatening ventricular arrhythmias. The resting ECG is considered to be normal and diagnosis has depended on exercise testing that is difficult acutely post-arrest or in young children. Purpose To identify resting ECG abnormalities in children with CPVT through assessment of measurement matrix parameters compared to a cohort of normal children. Methods A discovery cohort of 65 CPVT patients from the Electrophysiology program were identified. After excluding those on antiarrhythmics or in an arrhythmia at the time of their baseline ECG, 31 cases were matched 3:1 by age and sex with 93 healthy controls. Each individual had baseline ECG parameters and 180 machine-derived ECG amplitudes and durations (measurement matrix) measured. Statistical differences between ECG measures were assessed using Student's T-Test adjusted with a False Detection Rate of 1%. Significant measures were processed in a machine-learning algorithm to derive a Tree Model to differentiate individuals with and without CPVT. Results No significant differences were detected between CPVT patients who had and did not have a cardiac arrest. Comparing the CPVT and control cohorts, significant repolarization differences were seen in the amplitudes of lateral (I, negative aVR, V5, V6) and anterior leads (V2, V3, V4) at the J-point, ST midpoint, ST endpoint, and T-wave. Specifically, individuals with CPVT had significantly lower mean amplitudes in all aforementioned leads except aVR where the mean amplitudes were higher. These data were then used to create a Tree Model of the discovery cohort displayed in Figure 1 with a resulting R2 of 0.74, sensitivity of 0.81, and specificity of 0.98. Conclusions Baseline differences in repolarization are detectable in the left and anterior chest leads using machine-derived measurements of baseline ECGs in patients with CPVT, which may guide clinical suspicion when evaluating the resting ECG. These results warrant further analysis including testing of the Tree Model with a validation cohort. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Scholar Award from the Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada to Trainee Dr. Taraneh TofighiCanadian Institute for Health Research Figure 1. CPVT Tree Model

Paediatric/young versus adult patients with congenital long QT syndrome or catecholaminergic polymorphic ventricular tachycardia

Abstract Introduction Congenital long QT syndrome (LQTS) and catecholaminergic ventricular tachycardia (CPVT) are less prevalent cardiac ion channelopathies than Brugada syndrome in Asia. The present study compared paediatric/young and adult patients with these conditions. Method This was a territory-wide retrospective cohort study of consecutive patients diagnosed with congenital LQTS and CPVT attending public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF). Results A total of 142 congenital LQTS (mean onset age= 27±23 years old) and 16 CPVT (mean presentation age=11±4 years old) patients were included. For congenital LQTS, arrhythmias other than VT/VF (HR=4.67, 95% confidence interval = [1.53–14.3], p=0.007), initial VT/VF (HR=3.25 [1.29–8.16], p=0.012) and Schwartz score (HR=1.90 [1.11–3.26], p=0.020) were predictive of the primary outcome for the overall cohort, whilst arrhythmias other than VT/VF (HR=5.41 [1.36–21.4], p=0.016) and Schwartz score (HR=4.67 [1.48–14.7], p=0.009) were predictive for the adult subgroup (>25 years old; n=58). All CPVT patients presented before the age of 25 but no significant predictors of VT/VF were identified. A random survival forest model identified initial VT/VF, Schwartz score, initial QTc interval, family history of LQTS, initially asymptomatic, and arrhythmias other than VT/VF as the most important variables for risk prediction in LQTS, and initial VT/VF/sudden cardiac death, palpitations, QTc, initially symptomatic and heart rate in CPVT. Conclusion Clinical and ECG presentation vary between the pediatric/young and adult congenital LQTS population. All CPVT patients presented before the age of 25. Machine learning models achieved more accurate VT/VF prediction. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier survival curve for LQTSKaplan-Meier survival curve for CPVT

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

AimsCatecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.Methods and resultsThree teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).ConclusionsSeven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Investigate clinical characteristics and genetic mutations of CPVT patients in Taiwan and risk stratification

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Technology Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia in children and young adults. RYR2 mutation accounts for 60% of CPVT patients. While many articles about CPVT are published in the Caucasian population, only a few studies are based on Asian ethnicity. A CPVT scorecard proposed using Caucasian patients is proven effective in reducing the burden of variants of uncertain significance (VUS) of RYR2 mutations is not yet tested in the Asian population. Purpose Identify mutations among Taiwanese CPVT patients and compare genetic and clinical results with other ethnicities. We also tested the efficacy of the CPVT scorecard in Taiwanese CPVT patients. Methods 40 clinically diagnosed CPVT patients and their family members were consecutively enrolled from multi-centers. We compared clinical characteristics and genetic results with other ethnicities, and applied the Caucasian CPVT scorecard to test whether it is applicable in Taiwanese CPVT patients. Results This is the first nationwide CPVT cohort in Taiwan. Among the 29 patients with CPVT-related gene mutation, 12 RYR2 variants was identified in our cohort with 5 of them unreported in previous studies. The RYR2 yield rate was 55%, similar to other ethnicities. Exercise-induced symptoms including syncope and cardiac arrest were more severe in Taiwanese CPVT cohort, compared to Japanese and Caucasian cohorts. The CPVT scorecard also successfully reduced the VUS rate for the Taiwanese cohort. Conclusions Our study demonstrated genetic difference in CPVT patients across ethnicities, suggesting the importance of genetic testing in Taiwan. The CPVT scorecard is applicable to Taiwanese CPVT patients and is a helpful tool in interpreting genetic test results in clinical practice. Clinical characteristics of the cohort Gender (male, %) 15 (52%) Mean age of onset (years) 18 ± 15 Exercise-related syncope or cardiac arrest (n, %) 23 (79%) Exercise-related cardiac arrest (n, %) 14 (48%) Family history of unexplained sudden cardiac death (n, %) 5 (17%) Heart rate (bpm) 73 ± 16 Exercise stress test or Holter positive (n, %) 14 (48%) Ventricular arrhythmia (n, %) 23 (79%) Beta-blockers only (n, %) 10 (35%) Intracardiac defibrillator implantation (n, %) 15 (52%) CPVT score 6 ± 3

Ca2+ handling in induced-pluripotent cardiomyocytes from female CPVT patient, and comparison to male

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence Nationale de la Recherche Introduction Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited disease manifested as syncope or sudden death in apparently healthy children or young adults, in the absence of structural cardiac disease. The ryanodine receptor (RyR2) R420Q mutation was identified in a Spanish 14-year-old boy who died suddenly due to emotional stress. We generated human induced-pluripotent (h-iPS) derived cardiomyocytes from two brothers (see Yin’s poster in this meeting). As most of sudden death occurs in males, we had the hypothesis that there might be some sex-dependent differences. Purpose and methods We aim to elucidate the key role of [Ca2+]i in the genesis of cardiac arrhythmia in female RyR2R420Q CPVT patients . We generated here hiPSC-CM from two sisters of the same family, one exhibiting the mutation RyR2R420Q and the other without the mutation used as control. The experiments were conducted at 30-35 days after differentiation into cardiomyocytes. Using confocal microscopy, we assessed intracellular [Ca2+]i handling both spontaneous and during electrical pacing. To record [Ca2+]i transients, h-iPS-CMs were electrically field stimulated by two Pt electrodes at 1Hz. Spontaneous Ca2+ sparks and Ca2+ waves were recorded in quiescent cells, after [Ca2+]i transients recordings. For SR Ca2+ load quantification, h-iPS-CMs were rapidly perfused with 10 mmol/L caffeine. To induce β-adrenergic activation, 100nM isoproterenol (ISO) was added in some experiments. All confocal Ca2+ images analyses were performed by home-made routines using IDL software. Results First, we verify by immunofluorescence the expression of alpha-actinin in the differentiated h-iPS-CMs. Then, by confocal microscopy we found that woman CPVT h-iPS-CMs presented longer cycle length than wt h-iPS-CMs, correlating with the bradycardia observed in CPVT patients. The amplitude of the Ca2+ transients were significantly higher for CPVT h-iPS-CMs compared to wt; however, after ISO perfusion Ca2+ transients did not show a significant increase in CPVT h-iPS-CMs compared to CPVT h-iPS-CMs before ISO. SR Ca2+ load presented no differences between groups but the time decay constant of the caffeine-evoked Ca2+ transients were significantly faster in CPVT h-iPS-CMs whereas it became slower after ISO perfusion. In addition, analysis of Ca2+ pro-arrhythmogenic events were significantly augmented in CPVT h-iPS-CMs compared to wt h-iPS-CMs. After ISO perfusion, pro-arrhythmogenic events in CPVT cells presented no significant difference compared to CPVT cell before ISO perfusion. Although proarrhythmogenic events were similarly higher in both male and female hiPSC-CM, the Ca2+ handling characteristics were slightly different. Conclusion The RyR2R420Q mutation in woman CPVT h-iPS-CMs provides a reliable model to study CPVT in human context.

Genealogy and clinical course of catecholaminergic polymorphic ventricular tachycardia caused by the ryanodine receptor type 2 P2328S mutation.

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD).AimsWe aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation.MethodsThe study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course.ResultsGenealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during β-blocker medication.ConclusionsPreviously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.

Epidemiology and clinical characteristics of atrial fibrillation in patients with inherited heart diseases.

The prevalence and clinical course of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is well described, though less so for other inherited cardiomyopathies (familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction); and inherited arrhythmia syndromes (long QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia [CPVT]). We examined the frequency, clinical characteristics and AF-related management and outcomes amongst this patient population. We retrospectively studied consecutive probands with inherited cardiomyopathy (n = 962) and inherited arrhythmia syndromes (n = 195) evaluated between 2002 and 2018. AF was observed in 5% to 31% of patients, with the highest frequency in HCM. Age of AF onset was 45.8 ± 21.9 years in the inherited arrhythmia syndromes compared with 53.3 ± 15.3 years in the inherited cardiomyopathies, with four CPVT patients developing AF at a median age of 20 years. Overall, 11% of patients with AF had a transient ischemic attack or stroke of which a total of 80% were anticoagulated; with 48% of events occurring at a CHA2 DS2 -VASc < 2. Amongst sarcomere-positive HCM, AF was independently associated with age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02-1.08; P = .0014), left atrial area (OR, 1.11; 95% CI, 1.05-1.17; P = .0005) and MYH7 variants (OR, 2.55; 95% CI, 1.16-5.61; P = .020). Up to one-third of inherited heart disease patients will develop AF. While common general population risk factors are key in patients with HCM, the genotype is independently associated with AF. Amongst inherited arrhythmia syndromes, AF is less common, though often occurs below the age of 50 years.

Generation of induced pluripotent stem cells (iPSCs) from an infant with catecholaminergic polymorphic ventricular tachycardia carrying the double heterozygous mutations A1855D in RyR2 and Q1362H in SCN10A

Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of a 4 month-old boy with catecholaminergic polymorphic ventricular tachycardia carrying the double heterozygous mutations RyR2-A1855D and SCN10A-Q1362H. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. The iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry RyR2-A1855D and SCN10A-Q1362H mutations and have a normal karyotype. They will be useful for studying the pathogenesis of CPVT patients with ≥2 variants.

Calcium release channel RyR2 regulates insulin release and glucose homeostasis.

The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone. MethodsThe study included 5 CPVT patients with a mutation in RYR2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone. ResultsBoth β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living. ConclusionFlecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities.

New Therapies Based on New Insights in Inherited Arrhythmia Syndromes

Inherited arrhythmia syndromes are caused by mutations in genes generally encoding ion channel (subunits). This knowledge has led to a recent increase in the therapeutic armentarium for these disease entities, frequently aimed to directly target the molecular defect. Indeed, the genetic basis has become the basis for therapy choices in a number of disease entities. In the long QT syndrome the genetic substrate determines the risk, age window and triggers of cardiac events. Therapeutic decisions as to life style measurements to be taken (among others avoiding specific triggers) and the age of start treatment are genotype-dependent. Also the pharmacological therapy bears gene-specific elements. In catecholaminergic Ventricular tachycardia (CPVT) mutations in the Ryanodine receptor gene (RyR2) are responsible for a leaky RyR protein. Studies in isolated bilayers containing RyR2 receptors indicated that flecainide blocks the RyR protein effectively. Subsequent studies in a CASQ2 knockout mouse model, mimicking human CPVT, shows a strong antiarrhythmic effect of flecainide. Finally, also in CPVT patients, with either a pathogenic RyR2 or CASQ2 mutation and not suffciemtly protected by b-blockers, flecainide demonstrated a potent antiarrhythmic effect. This development clearly underscores the importance of unravelling the genetic basis of these arrhythmia syndromes. It is hoped and believed that patients with far more prevalent arrhythmias will also benefit from this exciting development.

Diagnosis-specific characteristics of ventricular tachycardia in children with structurally normal hearts

Improved mechanistic insights and clinical tools provide increasing diagnostic refinement for ventricular tachycardia in young patients with structurally normal hearts, yielding potentially important prognostic and management implications. The purpose of this study was to survey the clinical characteristics and outcomes of otherwise healthy children with ventricular tachycardia (VT) who were classified according to contemporary diagnostic criteria. A single-center retrospective review of patients younger than 18 years of age with VT diagnosed between January 1980 and December 2005 was undertaken. Patients with significant systemic illness or with underlying structural or functional heart disease were excluded. A total of 77 patients met inclusion criteria and were grouped as follows: accelerated idioventricular rhythm (AIVR; n = 19), right ventricular tachycardia (RVT; n = 30), left ventricular tachycardia (LVT; n = 23), and catecholamine sensitive polymorphic VT (CPVT; n = 5). AIVR patients were youngest at diagnosis and had the most benign natural history, while the opposite was true of CPVT patients. Ablation was attempted in 2/30 RVT (50% success) and 10/23 LVT (80% success) patients. Severe cardiac events occurred in 3/23 LVT (no deaths) and 2/5 CPVT (one death) patients. The natural history and appropriate management of VT in young patients with structurally normal hearts are highly dependent on the specific diagnosis. LVT and CPVT are associated with significantly greater morbidity and mortality than AIVR and RVT.

Clinical Spectrum and Prognostic Factors of Pediatric Ventricular Tachycardia

There have been no studies on the clinical characteristics and prognostic factors of pediatric ventricular tachycardia (VT). Eighty-one patients with pediatric VT were studied retrospectively at a single center. The median follow-up period was 6.0 years (0.7-23.5 years). Patients were categorized into 6 groups: idiopathic VT (IVT, n=37), catecholaminergic polymorphic VT (CPVT, n=10), congenital heart disease-associated VT (n=15), myocarditis-associated VT (n=8), cardiomyopathy-associated VT (CMP-VT, n=5) and miscellaneous. The age distribution of VT had 2 peaks (infant and teenager). VT with left bundle branch block configuration was more frequently nonsustained than VT with right bundle branch block configuration (61% vs 8%). Although 22% were asymptomatic, 38% experienced syncope or seizure and 16% had cardiac arrest. The overall mortality rate was 7.4%. The expected life span without cardiac arrest was <4 years in the CMP-VT group and the 10-year survival rate in CPVT patients was approximately 55%. Onset at infancy, monomorphic type and transcatheter/surgical ablation were related to the successful resolution of VT. Logistic regression analysis revealed that CPVT, CMP-VT, polymorphic VT and sustained VT were significantly correlated with death or cardiac arrest. The clinical features and prognosis of pediatric VT differed with the VT type, clinical categories and onset age. Accurate diagnosis and proper treatment according to the clinical categories may improve the outcome.