Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
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ABSTRACT:
SUBMITTER: Watanabe H
PROVIDER: S-EPMC2904954 | biostudies-literature | 2009 Apr
REPOSITORIES: biostudies-literature
Publications
Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
Watanabe Hiroshi H Chopra Nagesh N Laver Derek D Hwang Hyun Seok HS Davies Sean S SS Roach Daniel E DE Duff Henry J HJ Roden Dan M DM Wilde Arthur A M AA Knollmann Björn C BC
Nature medicine 20090329 4
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 ...[more]
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Project description: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 the efficacy and role of flecainide in the treatment of CPVT.
| S-EPMC4939313 | biostudies-literature
Project description:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA).To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation.Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2(-/-) mice (6/7) and significantly reduced the VA score (atropine: 0.6±0.2 versus vehicle: 1.7±0.3; P<0.05). Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum-predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In 6 CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise.Accelerated supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced ventricular tachycardia in treatment-refractory CPVT patients.
| S-EPMC3601570 | 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:RATIONALE:Autosomal-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. OBJECTIVE:To 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 RESULTS:Guide 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. CONCLUSIONS:AAV 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:RATIONALE:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca2+ leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias. OBJECTIVE:To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca2+ leak. METHODS AND RESULTS:Confocal microscopy was used to assess the effects of tetracaine and 9 derivatives (EL1-EL9) on spontaneous Ca2+ sparks in ventricular myocytes isolated from RyR2-R176Q/+ mice with CPVT. Whereas each derivative suppressed the Ca2+ spark frequency, derivative EL9 was most effective at the screening dose of 500nmol/L. At this high dose, the Ca2+ transient amplitude was not affected in myocytes from WT or R176Q/+ mice. The IC50 of EL9 was determined to be 13nmol/L, which is about 400× time lower than known RyR2 stabilizer K201. EL9 prevented the induction of ventricular tachycardia observed in placebo-treated R176Q/+ mice, without affecting heart rate or cardiac contractility. CONCLUSIONS:Tetracaine derivatives represent a novel class of RyR2 stabilizing drugs that could be used for the treatment of the potentially fatal disorder catecholaminergic polymorphic ventricular tachycardia.
| S-EPMC5164850 | biostudies-literature
Project description:Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca²? ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca²? load and Ca²? leak. Conversely, PLN-KO accelerates Ca²? sequestration and aborts arrhythmogenic spontaneous Ca²? waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca²?-triggered arrhythmias.We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT.We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-associated RyR2-R4496C mutant mice. Ca²? imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/- ventricular myocytes during sarcoplasmic reticulum Ca²? overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca²? sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca²? overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca²? ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li? failed to convert mini-waves to cell-wide SCWs in PLN-/-/RyR2-R4496C+/- ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs.Our results demonstrate that despite severe sarcoplasmic reticulum Ca²? leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca²? sequestration represents an effective approach for suppressing Ca²?-triggered arrhythmias.
| S-EPMC3864692 | biostudies-literature
Project description:BACKGROUND:Biallelic 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. METHODS:We 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. RESULTS:We 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. CONCLUSION:To 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: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