The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia.
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SUBMITTER: Lieve KV
PROVIDER: S-EPMC4939313 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
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The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia.
Lieve Krystien Vv KV Wilde Arthur A AA van der Werf Christian C
Arrhythmia & electrophysiology review 20160501 1
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but severe genetic cardiac arrhythmia disorder, with symptoms including syncope and sudden cardiac death due to polymorphic VT or ventricular fibrillation typically triggered by exercise or emotions in the absence of structural heart disease. The cornerstone of medical therapy for CPVT is β-blockers. However, recently flecainide has been added to the therapeutic arsenal for CPVT. In this review we summarise current data on th ...[more]
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Project description:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca(2+) release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.
| S-EPMC2904954 | biostudies-literature
Project description:Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.
| S-EPMC5924967 | biostudies-literature
Project description:ImportanceCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively.ObjectiveTo determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT.Design, setting, and participantsThis investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing.InterventionsPatients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels.Main outcomes and measuresThe primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia).ResultsOf 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms.Conclusions and relevanceIn this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone.Trial registrationclinicaltrials.gov Identifier: NCT01117454.
| S-EPMC5548393 | biostudies-literature
Project description:BackgroundOwing to reports of recurrent cardiac events in some catecholaminergic polymorphic ventricular tachycardia (CPVT) patients using ?-blockers, safer alternatives are being investigated. Flecainide is an alternative adjunctive anti-arrhythmic agent known to provide incomplete protection to CPVT patients.MethodsTo investigate the efficacy and tolerability of flecainide, we searched 4 databases for retrospective cohort studies (RCs) and randomized controlled trials (RCTs) investigating the efficacy and safety of flecainide for CPVT patients. Data were extracted and analyzed (risk ratio [RR] or mean difference [MD]) using RevMan software. Seven RCs and 1 RCT (333 CPVT patients; 152 patients treated with flecainide) were identified.ResultsFlecainide monotherapy was superior to standard therapy in alleviating the risk of arrhythmic events (RR?=?0.46, confidence interval [CI]?=?[0.38, 0.56], P?<?.00001) and exercise-induced arrhythmia scores (MD?=?-0.39, CI?=?[-0.74, -0.05], P?=?.03). Combination therapy of flecainide and ?-blockers was superior to ?-blocker monotherapy in reducing the risk of arrhythmic and symptomatic events (RR?=?0.29, CI?=?[0.13, 0.69], P?=?.005; RR?=?0.36, CI?=?[0.20, 0.62], P?=?.0003, respectively), peak heart rate (MD?=?-16.81, CI?=?[-28.21, -5.41], P?=?.004), and exercise-induced arrhythmia scores (MD?=?-1.87, CI?=?[-2.71, 1.04], P?<?.0001). Flecainide did not increase the risk of all side effects (RR?=?0.76, CI?=?[0.42, 1.40], P?=?.38) compared to that with ?-blockers alone. No deaths were reported among patients treated with flecainide.ConclusionsFlecainide is an effective and safe anti-arrhythmic agent, and its use as a monotherapy might be a good alternative for CPVT patients with ?-blocker intolerance. Combination therapy was superior to ?-blocker monotherapy. More randomized clinical trials are required to explore the long-term efficacy and safety of flecainide in these patients.
| S-EPMC6716729 | biostudies-literature
Project description:RationaleAutosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia.ObjectiveTo determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+).Methods and resultsGuide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients.ConclusionsAAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.
| S-EPMC6206886 | biostudies-literature
Project description:BackgroundBiallelic variants of the CASQ2 are known to cause the autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease that predisposes young individuals to syncope and sudden cardiac death. To date, only about 24 CASQ2 variants have been reported in association with CPVT pathogenesis; furthermore, studies in Asians, especially in the Chinese population, are relatively rare. The aim of this study was to detect CASQ2 variants in Chinese patients with CPVT.MethodsWe used targeted next-generation sequencing (NGS) to identify CASQ2 variants in Chinese patients with CPVT. A screening process was performed to prioritize rare variants of potential functional significance. Sanger sequencing was conducted to conform the candidate variants and determine the parental origin.ResultsWe identified seven different CASQ2 variants, of which three (c.1074_1075delinsC, c.1175_1178delACAG, and c.838+1G>A) have not been previously reported. The variants exhibited autosomal recessive inheritance, and were detected in four unrelated Chinese families with CPVT. They included a nonsense variant c.97C>T (p.R33*) and a missense variant c.748C>T (p.R250C) in Family 1 with three CPVT patients; two heterozygous frameshift variants, c.1074_1075delinsC (p.G359Afs*12) and c.1175_1178delACAG (p.D392Vfs*84), in Family 2 with one CPVT patient; one pathogenic homozygous variant c.98G>A (p.R33Q) of CASQ2 in the CPVT patient of Family 3; and two heterozygous splicing variants, (c.532+1G>A) and (c.838+1G>A), in Family 4 with one CPVT patient.ConclusionTo our knowledge, this is the first systematic study of Chinese children with CASQ2 variants. Our work further expands the genetic spectrum of CASQ2-associated CPVT.
| S-EPMC6825949 | biostudies-literature
Project description:Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca2+ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2(R4496C)) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2(R4496C) and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca2+and isoproterenol; 66% of 12 RyR2/RyR2(R4496C) and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (P=0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2(R4496C) mice. Under current clamp, single Purkinje cells from RyR2/RyR2(R4496C) mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
| S-EPMC2515360 | biostudies-literature
Project description:BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmogenic disorder characterized by adrenergically induced ventricular tachycardia manifesting as stress-induced syncope and sudden cardiac death. While CPVT is not associated with dilated cardiomyopathy (DCM) in most cases, the combination of both disease entities poses a major diagnostic and therapeutic challenge.Case summaryWe present the case of a young woman with CPVT. The clinical course since childhood was characterized by repetitive episodes of exercise-induced ventricular arrhythmias and a brady-tachy syndrome due to rapid paroxysmal atrial fibrillation and sinus bradycardia. Medical treatment included propranolol and flecainide until echocardiography showed a dilated left ventricle with severely depressed ejection fraction when the patient was 32 years old. Cardiac magnetic resonance imaging revealed non-specific late gadolinium enhancement. Myocardial inflammation, however, was excluded by subsequent endomyocardial biopsy. Genetic analysis confirmed a mutation in the cardiac ryanodine receptor but no pathogenetic variant associated with DCM. Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next months, the patient developed progressive heart failure symptoms that were finally managed by heart transplantation.DiscussionManagement in patients with CPVT and DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic internal cardioverter-defibrillator implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.
| S-EPMC7793240 | biostudies-literature
Project description:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition of abnormal heart rhythm (arrhythmia), induced by physical activity or stress. Mutations in ryanodine receptor 2 (RyR2), a Ca2+ release channel located in the sarcoplasmic reticulum (SR), or calsequestrin 2 (CASQ2), a SR Ca2+ binding protein, are linked to CPVT. For specific drug development and to study distinct arrhythmias, simple models are required to implement and analyze such mutations. Here, we introduced CPVT inducing mutations into the pharynx of Caenorhabditis elegans, which we previously established as an optogenetically paced heart model. By electrophysiology and video-microscopy, we characterized mutations in csq-1 (CASQ2 homologue) and unc-68 (RyR2 homologue). csq-1 deletion impaired pharynx function and caused missed pumps during 3.7 Hz pacing. Deletion mutants of unc-68, and in particular the point mutant UNC-68(R4743C), analogous to the established human CPVT mutant RyR2(R4497C), were unable to follow 3.7 Hz pacing, with progressive defects during long stimulus trains. The pharynx either locked in pumping at half the pacing frequency or stopped pumping altogether, possibly due to UNC-68 leakiness and/or malfunctional SR Ca2+ homeostasis. Last, we could reverse this 'worm arrhythmia' by the benzothiazepine S107, establishing the nematode pharynx for studying specific CPVT mutations and for drug screening.
| S-EPMC5727474 | biostudies-literature
Project description:We report the first case of pregnancy in a pediatric patient with catecholiminergic polymorphic ventricular tachycardia (CPVT). Pregnant adolescents with CPVT are at high risk for NSVT and malignant VT during pregnancy, despite antiarrhythmic medication. They may receive multiple implantable cardioverter defibrillator (ICD) therapies. Such patients require close monitoring with special care during the first trimester.
| S-EPMC4831384 | biostudies-other