ライフサイエンスコーパス: CPVT

1 CPVT is a familial arrhythmogenic syndrome characterized

2 CPVT-associated RyR2 mutations cause fatal ventricular a

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

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

5 All 18 CPVT patients who fulfilled the inclusion criteria exhib

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

21 TS and with overlapping features of LQTS and CPVT.

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

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

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

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

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

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

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

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

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

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

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

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

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

35 h genotype-negative but clinically diagnosed CPVT.

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

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

38 RyR2 may be a novel therapeutic approach for CPVT.

39 thmias, providing a possible explanation for CPVT.

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

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

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

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

44 ls with a low pretest clinical suspicion for CPVT.

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

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

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

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

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

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

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

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

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

54 revention of exercise-induced arrhythmias in CPVT.

55 volved in Ca-dependent atrial arrhythmias in CPVT.

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

57 (2+) handling attenuates RyR2 dysfunction in CPVT.

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

59 sufficient to explain flecainide efficacy in CPVT.

60 sufficient to explain flecainide efficacy in CPVT.

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

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

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

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

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

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

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

68 the R33Q mutation and its potential role in CPVT.

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

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

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

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

73 alcium waves and triggered beats in isolated CPVT myocytes.

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

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

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

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

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

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

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

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

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

83 s are not necessarily the monogenic cause of CPVT.

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

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

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

87 /- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induc

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

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

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

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

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

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

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

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

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

97 rk activity, a typical cellular phenotype of CPVT.

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

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

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

101 ug mechanisms and efficacy in the setting of CPVT.

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

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

104 , 23.4+/-17 years) with either LQTS (n=8) or CPVT (n=4) and serious arrhythmias.

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

106 effects and proarrhythmic potential plaguing CPVT pharmacological management today.

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

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

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

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

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

112 tricular tachycardia in treatment-refractory CPVT patients.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

132 inergic polymorphic ventricular tachycardia (CPVT) is unclear.

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

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

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

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

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

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

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

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

141 inergic polymorphic ventricular tachycardia (CPVT).

142 inergic polymorphic ventricular tachycardia (CPVT).

143 induced polymorphic ventricular tachycardia (CPVT).

144 induced polymorphic ventricular tachycardia (CPVT).

145 inergic polymorphic ventricular tachycardia (CPVT).

146 inergic polymorphic ventricular tachycardia (CPVT).

147 inergic polymorphic ventricular tachycardia (CPVT)].

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

149 inergic polymorphic ventricular tachycardia [CPVT]).

150 inergic polymorphic ventricular tachycardia [CPVT]).

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

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

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

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

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

156 2+ leak in atrial myocytes isolated from the CPVT mouse models.

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

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

159 such events was significantly reduced in the CPVT cells.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

177 entral domain RyR2 mutations associated with CPVT and AF.

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

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

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

181 % of the variants previously associated with CPVT in the ESP population.

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

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

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

185 ectopy during stress testing consistent with CPVT.

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

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

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

189 ifibrillatory intervention for patients with CPVT.