ライフサイエンスコーパス: CPVT

1 CPVT is a familial arrhythmogenic syndrome characterized

2 CPVT myocytes also evidenced characteristic arrhythmogen

3 CPVT results from stress-induced sarcoplasmic reticular

4 CPVT was the CID most likely to present with RSCA and HC

5 CPVT-associated RyR2 mutations cause fatal ventricular a

6 CPVT-associated RyR2 mutations result in "leaky" RyR2 ch

7 CPVT-linked mutations in hRyR2 did not alter resting car

8 dently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene

9 All 18 CPVT patients who fulfilled the inclusion criteria exhib

10 ted supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients.

11 ra-esophageal burst pacing protocol in the 3 CPVT mouse models (RyR2-R2474S+/-, 70%; RyR2-N2386I+/-,

12 A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and

13 In 6 CPVT patients (33%), VA were paradoxically suppressed as

14 rformed in silico mutagenesis to construct a CPVT model and then used a computational modelling and s

15 Dermal fibroblasts were obtained from a CPVT patient due to the M4109R heterozygous point RYR2 m

16 tiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, i

17 endence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naive indi

18 Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether P

19 erozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen t

20 and myocytes from wild-type (WT, n = 15) and CPVT mice lacking calsequestrin 2 (Casq2(-/-), n = 45),

21 [Na(+)]i was higher in both control and CPVT PCs than VMs, whereas the density of the Na(+)/Ca(2

22 ed arrhythmogenic syndromes, in general, and CPVT specifically.

23 ects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P).

24 pathetic denervation, patients with LQTS and CPVT have high levels of postoperative satisfaction.

25 lyzed left stellectomy specimens of LQTS and CPVT patients for signs of inflammatory activity.

26 LQTS and CPVT predominated in those <24 years of age, 30 (77%) of

27 een associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very e

28 TS and with overlapping features of LQTS and CPVT.

29 METHODS AND CPVT-associated genes RYR2 and CASQ2 variants were ident

30 h caused by arrhythmias long QT syndrome and CPVT.

31 red the prediction of protein damage between CPVT-associated variants identified in the ESP and those

32 reduced ventricular premature beats in both CPVT models (P<0.05).

33 culum fractional release was greater in both CPVT PCs and VMs than respective controls.

34 CALM-LQTS and CALM-CPVT are the prevalent phenotypes.

35 Compared with wild-type CaM, CPVT-CaMs caused greater RyR2 single-channel open probab

36 Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype o

37 his international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathog

38 mic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter col

39 (cardiac calsequestrin) knockout (Casq2-/-) CPVT mouse model.

40 To better understand how CASQ2 mutants cause CPVT, we expressed two CPVT-linked CASQ2 mutants, a trun

41 To define how CASQ2 mutations cause CPVT, we produced and studied mice carrying a human D307

42 The genetic variants that cause CPVT are usually highly penetrant.

43 scade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, inclu

44 stigated the effect of CaM mutations causing CPVT (N53I), long QT syndrome (D95V and D129G), or both

45 ous Ca(2+) waves in isoproterenol-challenged CPVT VMs pretreated with NS309.

46 fects compared with previously characterized CPVT mutations: decreased binding of the stabilizing sub

47 ariants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicio

48 malized myocyte Ca(2+) cycling and decreased CPVT in mutant mice, indicating RyR2 dysfunction was cri

49 sponsible for 60% of clinically well-defined CPVT cases.

50 h genotype-negative but clinically diagnosed CPVT.

51 apies may need to be different for different CPVT-linked variants.

52 clinical parameters accurately distinguished CPVT patients on beta-blocker monotherapy at low and hig

53 vation only in N-terminal and central domain CPVT variants.

54 K180R mice exhibit an autosomal dominant CPVT phenotype following exercise or catecholamine stres

55 VT phenotypic manifestations in our dominant CPVT mice model carriers of the heterozygous mutation R4

56 Here, we review each CPVT subtype and how CPVT mutations alter protein functi

57 functional characteristics with established CPVT-associated mutations in CALM1.

58 RyR2 may be a novel therapeutic approach for CPVT.

59 17 of 51 (33.3%) met diagnostic criteria for CPVT.

60 thmias, providing a possible explanation for CPVT.

61 Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Pane

62 riate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based rea

63 ether, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

64 RyR2 regulation as the disease mechanism for CPVT associated with CaM mutations and shows that CaM mu

65 y, our prediction of a novel polytherapy for CPVT was confirmed experimentally.

66 of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

67 ng, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogen

68 ls with a low pretest clinical suspicion for CPVT.

69 g is a promising mechanism-based therapy for CPVT.

70 hanistically and phenotypically differs from CPVT.

71 ceptor 2) oxidation measured in samples from CPVT hearts of the animals after the stress challenge.

72 ndria cristae in the ventricular tissue from CPVT mice, which led to a decrease in quaternary superco

73 Recombinant channels harboring CPVT-linked RyR2 mutations were functionally characteriz

74 he R4496C mutation in the RyR2) heterozygous CPVT mice.

75 Here, we review each CPVT subtype and how CPVT mutations alter protein function, RyR2 calcium rele

76 (R4743C), analogous to the established human CPVT mutant RyR2(R4497C), were unable to follow 3.7 Hz p

77 o reversed the arrhythmia phenotype in human CPVT induced pluripotent stem cell-derived cardiomyocyte

78 The prevalence of incidentally identified CPVT-associated variants is approximately 9% among WES t

79 In CPVT mice, the constitutive [Na(+)]i excess of PCs promo

80 in atrial myocytes is associated with AF in CPVT mice.

81 rred with greater frequency and amplitude in CPVT myocytes.

82 d was effective in suppressing arrhythmia in CPVT mice.

83 herapy strategy would suppress arrhythmia in CPVT mouse models.

84 U10 prevents life-threatening arrhythmias in CPVT mice, suggesting that the reduction of mutant RyR2

85 le for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively.

86 revention of exercise-induced arrhythmias in CPVT.

87 volved in Ca-dependent atrial arrhythmias in CPVT.

88 tentially accounting for arrhythmogenesis in CPVT linked to mutations in CASQ2.

89 o moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2

90 ttenuates mitochondria structural changes in CPVT, restoring more efficient electron transport chain

91 lemmal SK channel current (I(SK)) density in CPVT VMs.

92 siological role of sinus node dysfunction in CPVT, and whether the arrhythmogenic beats originate fro

93 (2+) handling attenuates RyR2 dysfunction in CPVT.

94 gest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions wit

95 is responsible for flecainide's efficacy in CPVT.

96 sufficient to explain flecainide efficacy in CPVT.

97 sufficient to explain flecainide efficacy in CPVT.

98 n of NS309 facilitated cristae flattening in CPVT ventricular tissue and restored supercomplexes and

99 that the clinical efficacy of flecainide in CPVT is because of the combined actions of direct blocka

100 The principal action of flecainide in CPVT is not via a direct interaction with RyR2.

101 sm of antiarrhythmic action of flecainide in CPVT.

102 tential by restoring repolarization force in CPVT VMs.

103 ous Ca(2+) release and were more frequent in CPVT PCs than CPVT VMs.

104 optical mapping of voltage and [Ca(2+)]i in CPVT hearts showed that spontaneous Ca(2+) release prece

105 dial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9-induced

106 ecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeu

107 In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using ade

108 cal inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets fr

109 eine-induced Ca(2+) transients, was lower in CPVT VMs and PCs than respective controls, and sarcoplas

110 oxygen species production by mitochondria in CPVT VMs.

111 whether this pathological trilogy occurs in CPVT knock-in (KI) mice bearing N-terminal (R176Q/+), ce

112 the R33Q mutation and its potential role in CPVT.

113 Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the abs

114 models, is a candidate therapeutic target in CPVT.

115 the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among

116 Ca(2+) spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-

117 Here, we introduced CPVT inducing mutations into the pharynx of Caenorhabdit

118 alcium waves and triggered beats in isolated CPVT myocytes.

119 f AAV9-GFP-AIP to neonatal mice with a known CPVT mutation (RYR2(R176Q/+)) effectively suppressed ven

120 o an autosomal dominant form of Casq2-linked CPVT (CPVT2), but the underlying mechanism is not known.

121 idate arrhythmia mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses channel activ

122 Stellate ganglia of all 12 LQTS/CPVT patients revealed mild but distinct inflammatory in

123 gger or enhance electric instability in LQTS/CPVT patients who are already genetically predisposed to

124 significantly higher in the ganglia of LQTS/CPVT cases than in healthy controls (P=0.0018 and P=0.00

125 iction of AEs in patients with RYR2-mediated CPVT on beta-blocker monotherapy.

126 finity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either normal or modestly lower Ca affini

127 In permeabilized ventricular myocytes, CPVT-CaMs at a physiological intracellular concentration

128 alence of CaM mutations in genotype-negative CPVT patients is unknown.

129 r previously published missense and nonsense CPVT-associated variants reported in several comprehensi

130 We discovered a novel CPVT mutation in the CALM3 gene that shares functional c

131 s are not necessarily the monogenic cause of CPVT.

132 um (SR), are the second most common cause of CPVT.

133 have been identified as the genetic cause of CPVT: RYR2 (encoding ryanodine receptor calcium release

134 eration and unravel the underlying causes of CPVT, we investigated the effects of adenoviral-mediated

135 individuals (N=60 706) and a case cohort of CPVT cases (N=155).

136 In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry

137 /- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induc

138 Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator under

139 Diagnosis of CPVT often occurs after a major cardiac event, posing a

140 None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years)

141 Considering the spread distribution of CPVT mutations, we hypothesized that dysfunctional heter

142 In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeos

143 nditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagno

144 The recognition of these differing forms of CPVT and their different etiologies and mechanisms is an

145 t based on variant location and incidence of CPVT symptoms, and differences in treatment strategies w

146 tation and autosomal dominant inheritance of CPVT-CaM mutations and suggest that RyR2 interactions ar

147 r CPVT, are unlikely to represent markers of CPVT pathogenicity.

148 Even a 1:8 mixture of CPVT-CaM:wild-type-CaM activated Ca waves, demonstrating

149 ide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated C

150 suppressing arrhythmias in a murine model of CPVT.

151 The age of onset of CPVT differed significantly between RYR2 variants locate

152 coding variants and a median age of onset of CPVT of 11 years (interquartile range, 7-14 years).

153 entified a substantial overrepresentation of CPVT-associated variants in a large exome database, sugg

154 rk activity, a typical cellular phenotype of CPVT.

155 population, corresponding to a prevalence of CPVT of up to 1:150.

156 A small proportion of CPVT-CaM is sufficient to evoke arrhythmogenic Ca distur

157 r phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) we

158 s study compiled a comprehensive data set of CPVT-associated RYR2 variants and their clinical phenoty

159 echanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling

160 ug mechanisms and efficacy in the setting of CPVT.

161 Previous studies of CPVT patients mainly involved probands, so current insig

162 As in 2 CPVT mouse models and in a subset of CPVT patients.

163 This focus on CPVT allows us to take a "deep dive" and explore the ful

164 , 23.4+/-17 years) with either LQTS (n=8) or CPVT (n=4) and serious arrhythmias.

165 nagement of our patients with either LQTS or CPVT for a very long time and have been involved in ~500

166 -V2475F is phenotypically strong among other CPVT mutations and produces heterogeneous mechanisms of

167 effects and proarrhythmic potential plaguing CPVT pharmacological management today.

168 fic silencing by RNA interference to prevent CPVT phenotypic manifestations in our dominant CPVT mice

169 Flecainide completely prevented CPVT in two human subjects who had remained highly sympt

170 nhibits Na(+) and RyR2 channels and prevents CPVT.

171 These putative CPVT variants were identified in 41 out of 6131 subjects

172 and ventricular myocytes from RyR2(R4496C/+) CPVT mutant mice and littermate controls.

173 tricular tachycardia in treatment-refractory CPVT patients.

174 clinical data on patients with RYR2-related CPVT variants from articles published up to October 2020

175 Seven CPVT and four SQTS genes have valid evidence for disease

176 c SR Ca release events and exhibit a similar CPVT disease phenotype.

177 r understanding has grown tremendously since CPVT was first described as a clinical syndrome in 1995.

178 g the nematode pharynx for studying specific CPVT mutations and for drug screening.

179 This may inform which specific CPVT-linked RyR2 variants may benefit from therapeutic s

180 inergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular car

181 inergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (AR

182 inergic polymorphic ventricular tachycardia (CPVT) and atrial fibrillation (AF).

183 inergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of

184 inergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome.

185 inergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhyth

186 inergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhy

187 inergic polymorphic ventricular tachycardia (CPVT) are electric diseases characterized by catecholami

188 inergic polymorphic ventricular tachycardia (CPVT) are postulated to cause a distinctive form of Ca(2

189 inergic polymorphic ventricular tachycardia (CPVT) causes sudden cardiac death due to mutations in ca

190 inergic polymorphic ventricular tachycardia (CPVT) implies a crucial role for the N terminus.

191 inergic polymorphic ventricular tachycardia (CPVT) is a condition of abnormal heart rhythm (arrhythmi

192 inergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated w

193 induced polymorphic ventricular tachycardia (CPVT) is a familial disorder caused by cardiac ryanodine

194 inergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arr

195 inergic polymorphic ventricular tachycardia (CPVT) is a lethal, rare hereditary disease with an estim

196 inergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac arrhythmia syndrom

197 inergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrom

198 inergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndr

199 inergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia, with pathogenic va

200 inergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has

201 inergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated wit

202 inergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized

203 inergic polymorphic ventricular tachycardia (CPVT) is an inherited stress-induced arrhythmogenic dise

204 inergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine recept

205 inergic polymorphic ventricular tachycardia (CPVT) is unclear.

206 inergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS).

207 inergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death

208 inergic polymorphic ventricular tachycardia (CPVT) require spontaneous Ca(2+) release via cardiac rya

209 inergic polymorphic ventricular tachycardia (CPVT) was used for in vivo ECG recordings and for cell e

210 inergic polymorphic ventricular tachycardia (CPVT), a leading cause of sudden death in apparently hea

211 inergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhyth

212 inergic polymorphic ventricular tachycardia (CPVT), an inherited cardiac arrhythmia characterized by

213 inergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more suscepti

214 inergic polymorphic ventricular tachycardia (CPVT), certain cases of which are associated with mutati

215 inergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac even

216 inergic polymorphic ventricular tachycardia (CPVT), yet evidence supporting this mechanism at the cel

217 inergic polymorphic ventricular tachycardia (CPVT).

218 inergic polymorphic ventricular tachycardia (CPVT).

219 induced polymorphic ventricular tachycardia (CPVT).

220 induced polymorphic ventricular tachycardia (CPVT).

221 inergic polymorphic ventricular tachycardia (CPVT).

222 inergic polymorphic ventricular tachycardia (CPVT).

223 inergic polymorphic ventricular tachycardia (CPVT).

224 inergic polymorphic ventricular tachycardia (CPVT).

225 inergic polymorphic ventricular tachycardia (CPVT).

226 inergic polymorphic ventricular tachycardia (CPVT).

227 inergic polymorphic ventricular tachycardia (CPVT)].

228 inergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricula

229 inergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and inc

230 inergic polymorphic ventricular tachycardia [CPVT]).

231 inergic polymorphic ventricular tachycardia [CPVT]).

232 (catecholaminergic ventricular tachycardia; CPVT).

233 ease and were more frequent in CPVT PCs than CPVT VMs.

234 ed in this article, it has become clear that CPVT can occur as either a typical or atypical form.

235 We conclude that CPVT-causing CASQ2 missense mutations function as null a

236 We conclude that CPVT-linked RyR2 variants at baseline may not exhibit th

237 We discovered that CPVT patients with mutant leaky RyR2 present with glucos

238 Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky

239 her frequency of damaging variants among the CPVT-associated variants not identified in the ESP datab

240 models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron micr

241 2+ leak in atrial myocytes isolated from the CPVT mouse models.

242 R2 mutation and reprogrammed to generate the CPVT-hiPSCs.

243 d transients, and triggered activity) in the CPVT cardiomyocytes that worsened with adrenergic stimul

244 such events was significantly reduced in the CPVT cells.

245 to development of triggered activity in the CPVT-hiPSCs-CMs.

246 f delayed afterdepolarizations in 69% of the CPVT-hiPSCs-CMs compared with 11% in healthy control car

247 sm and pathophysiological link between these CPVT-related missense mutations of hCSQ2 and the resulti

248 Our data show clearly that all three CPVT-related mutations lead to significant reduction in

249 he resulting arrhythmias, we generated three CPVT-causing mutants of hCSQ2 (R33Q, L167H, and D307H) a

250 We report expression of three CPVT-linked human RyR2 (hRyR2) mutations (S2246L, N4104K

251 We examined AF susceptibility in these three CPVT mouse models harboring RyR2 mutations to explore th

252 Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the

253 , a SR Ca(2+) binding protein, are linked to CPVT.

254 Application of NS309 to CPVT VMs increased I(SK).

255 w CASQ2 mutants cause CPVT, we expressed two CPVT-linked CASQ2 mutants, a truncated protein (at G112+

256 Furthermore, two CPVT-inducing CASQ2 mutations, which cause mechanistical

257 es the pathophysiologic mechanism underlying CPVT due to RyR2 or CASQ2 mutations and suggests a thera

258 olic Ca(2+) is a common mechanism underlying CPVT.

259 surrounding the tissue mechanisms underlying CPVT, such as the pathophysiological role of sinus node

260 Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice),

261 ID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%)

262 CaMs) exhibited reduced Ca affinity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either norma

263 We tested whether CPVT-linked RyR2 variants in the N-terminal (R176Q/+), c

264 died recombinant CaM mutants associated with CPVT (N54I and N98S) or LQTS (D96V, D130G, and F142L).

265 mon defect of RyR2 mutations associated with CPVT and AF, which could potentially be suppressed by ca

266 entral domain RyR2 mutations associated with CPVT and AF.

267 missense variants previously associated with CPVT and compared the prediction of protein damage betwe

268 shows that CaM mutations not associated with CPVT can also affect RyR2.

269 identified variants in genes associated with CPVT from WES clinical testing represent disease-associa

270 % of the variants previously associated with CPVT in the ESP population.

271 Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (V

272 h RyR2 and pacing-induced AF associated with CPVT mutations.

273 , TRND, and KCNJ2) have been associated with CPVT pathogenesis.

274 ant did not have EST results consistent with CPVT.

275 ectopy during stress testing consistent with CPVT.

276 ic triggers in animal models and humans with CPVT and suggest a broader role for the Purkinje fiber n

277 In mice with CPVT, sodium channel block alone did not prevent ventric

278 221 publications analyzed, 964 patients with CPVT (351 male, 463 female) were identified with 263 RYR

279 SN levels were elevated in patients with CPVT and following ventricular arrhythmia-induced cardia

280 We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (

281 potent stem cells derived from patients with CPVT with different disease-causing mutations to determi

282 cytes derived from 2 different patients with CPVT with different pathogenic mutations demonstrated in

283 A data set of patients with CPVT would improve the diagnosis and treatment of patien

284 s randomized clinical trial of patients with CPVT, flecainide plus beta-blocker significantly reduced

285 atments that are available for patients with CPVT, their efficacy, and how therapy could be improved

286 ifibrillatory intervention for patients with CPVT.

287 the diagnosis and treatment of patients with CPVT.

288 nt therapies to prevent AEs in patients with CPVT.