ライフサイエンスコーパス: HCM

1 HCM elevates the systemic levels of free heme, which dam

2 HCM is caused by missense mutations in muscle proteins i

3 HCM is characterized by pronounced hypertrophy of cardio

4 HCM was a significant predictor for ESRD (unadjusted HR

5 HCM-LVSD affects ~8% of patients with HCM.

6 HCM/RCM mutations, therefore, highlight TNT1's essential

7 ated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24-0.44) for definite HCM-re

8 probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95% CI, 0.28-0.49) for definite, proba

9 for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.34-0.62) for definite or pro

10 29 cat hearts (12 normal and 17 HCM hearts) underwent micro-CT and pathologic examinatio

11 Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3(De

12 multicenter (n = 7) and multivendor (n = 3) HCM study obtained between November 2001 and November 20

13 Of 33 HCM genes, only 8 (24%) were categorized as definitive (

14 Of 4191 HCM variants in ClinVar, 31% were in genes with limited

15 A total of 50 HCM patients (47 +/- 15 years of age, 77% male) and 30 h

16 as then tested on a different dataset of 612 HCM and 12,788 control subjects.

17 possible HCM-related SCD (estimated 140 740 HCM person-years of observation).

18 providing additional support for KLHL24 as a HCM-associated gene.

19 TNNI3 but exhibit few clinically actionable HCM variants overall.

20 For those >40 years of age, HCM was the most common (33%) CID.

21 utations alone do not adequately explain all HCM clinical and pathobiological features.

22 s attended by the coroner, we identified all HCM-related SCDs in individuals 10 to 45 years of age be

23 Adding these genes to all HCM genetic panels should be considered.

24 tensity on plasma catecholamine levels among HCM patients has not been rigorously defined.

25 To test this hypothesis, we expressed an HCM myosin mutation, R249Q, in Drosophila indirect fligh

26 dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro.

27 Accurate diagnosis of an HCM mimic led to change in management (eg, enzyme replac

28 ic testing for at least 1 gene related to an HCM mimic.

29 including at least 1 gene associated with an HCM mimic (GLA, TTR, PRKAG2, LAMP2, PTPN11, RAF1, and DE

30 wing the association in univariate analysis, HCM itself remained a robust predictor of ESRD developme

31 8; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354.

32 standard ACMG and MYH7-ACMG guidelines, and HCM Genotype Predictor Score was used to provide a valid

33 d MBOAT2 can distinguish between healthy and HCM patients.

34 verse association between circRNA levels and HCM remained unchanged even after adjusting for confound

35 ctivated nonsense-mediated decay pathway and HCM disease development.

36 the CID most likely to present with RSCA and HCM the least.

37 ypertrophic cardiomyopathy (HCM), and apical HCM exhibit characteristic regional longitudinal strain

38 here is no known treatment for NS-associated HCM.

39 s that could contribute to the NS-associated HCM.

40 in age, sex, and clinical characteristics at HCM diagnosis over >4 decades.

41 Moreover, because HCM can take >=20 years to develop, the severity of the

42 ought to investigate the association between HCM and end-stage renal disease (ESRD).

43 The consistent associations between HCM and ESRD were shown in almost all subgroups other th

44 pertrophic and restrictive cardiomyopathies (HCM and RCM).

45 (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%

46 Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contract

47 ped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other

48 ndividuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature.

49 f patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is

50 Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease

51 End-stage (ES) hypertrophic cardiomyopathy (HCM) has been considered a particularly grim and unfavor

52 epidemiology of hypertrophic cardiomyopathy (HCM) has changed because of increased awareness and avai

53 c expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohort

54 PC3(Delta25) to hypertrophic cardiomyopathy (HCM) in a large patient cohort.

55 architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.

56 Hypertrophic cardiomyopathy (HCM) is a common genetic disorder characterized by left

57 Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily inv

58 Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes thickening of the

59 Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease w

60 Hypertrophic cardiomyopathy (HCM) is a worldwide genetic heart disease and a common c

61 Hypertrophic cardiomyopathy (HCM) is an inherited disease that causes thickening of t

62 Hypertrophic cardiomyopathy (HCM) is an uncommon but important cause of sudden cardia

63 ial ischemia in hypertrophic cardiomyopathy (HCM) is associated with poor outcomes.

64 Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere prote

65 Hypertrophic cardiomyopathy (HCM) is considered a leading cause of sudden cardiac dea

66 Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases

67 Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease.

68 Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorde

69 or diagnosis of hypertrophic cardiomyopathy (HCM) mimics.

70 Hypertrophic cardiomyopathy (HCM) occurs as a spontaneous disease in cats, and is cha

71 r families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care.

72 5 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.

73 sed to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD),

74 oidosis, septal hypertrophic cardiomyopathy (HCM), and apical HCM exhibit characteristic regional lon

75 yopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM).

76 y of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progr

77 pathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively.

78 hat can prevent hypertrophic cardiomyopathy (HCM).

79 common cause of hypertrophic cardiomyopathy (HCM).

80 nd often lethal hypertrophic cardiomyopathy (HCM).

81 eading cause of hypertrophic cardiomyopathy (HCM).

82 lly abnormal in hypertrophic cardiomyopathy (HCM).

83 n patients with hypertrophic cardiomyopathy (HCM); however, its clinical application is hindered by a

84 mechanisms by which NS RAF1 mutations cause HCM and reveal downstream effectors that could serve as

85 A family history of childhood HCM was more common in those patients diagnosed with HCM

86 As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles i

87 Conclusively, HCM increased the risk of ESRD, regardless of known prog

88 S and perhaps other, more common, congenital HCM disorders.

89 In 105 consecutive HCM patients, we performed quantitative assessment of le

90 Eumelanin-enriched dark HCM regions mapped to phasors with shorter lifetimes and

91 croscopic and microscopic features (definite HCM-related SCD).

92 erson-years (95% CI, 0.24-0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI,

93 The ability of the CNN to detect HCM was then tested on a different dataset of 612 HCM an

94 ximately 50% of SP mutation carriers develop HCM over 15 years of follow-up.

95 21 mm), and 25 additional patients developed HCM during follow-up.

96 3.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on C

97 associated with a higher risk of developing HCM. Regular CMR should be considered in long-term scree

98 can live to advanced ages without developing HCM.

99 n comparing samples collected from different HCM treatment stages.

100 Of the 2,447 patients, 118 (4.8%) had ES-HCM (EF 39 +/- 9%; range 12% to 49%) at age 48 +/- 15 ye

101 Estimated HCM penetrance at 15 years of follow-up was 46% (95% con

102 Evolving HCM populations include progressively greater representa

103 ry of patients receiving care at experienced HCM centers.

104 EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind,

105 EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class,

106 le-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countri

107 Frequency of familial HCM declined over time (38.8% versus 34.3% versus 32.7%,

108 ted for ES (8.0%/year), but exceeded 10-fold HCM with preserved EF (0.2%/year; p < 0.001).

109 hus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a perso

110 reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource.

111 who did not fulfill diagnostic criteria for HCM at first evaluation.

112 going screening meet diagnostic criteria for HCM at first or subsequent evaluations, with the majorit

113 ents with HCM, 553 (8%) met the criteria for HCM-LVSD.

114 We investigated the disease mechanism for HCM myosin mutation R249Q by expressing it in the indire

115 rnal validation, but it may hold promise for HCM screening.

116 ort the first disease-specific treatment for HCM.

117 tion at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hyperte

118 n vasculature from 34 children who died from HCM or other causes and frequently found CD3+ CD8+ T cel

119 Isogenic iPSC lines were generated from HCM patients harboring MYBPC3 PTC mutations (p.R943x; p.

120 proteoforms in septal myectomy tissues from HCM patients exhibiting severe outflow track obstruction

121 odel-derived median probabilities for having HCM were 97% and 96%, respectively.

122 imal probability threshold of 11% for having HCM.

123 ilation (DCM), and NCCM with LV hypertrophy (HCM).

124 In HCM, this ring was disrupted by reduced FA, consistent w

125 In HCM, women are older at diagnosis, partly modified by ge

126 nfidence interval: 1.2 to 5.3; p = 0.015) in HCM and remained significant even after correcting for L

127 ICDs should be considered when EF is <50% in HCM.

128 aling may be a novel therapeutic approach in HCM.

129 al fibrosis and reduced exercise capacity in HCM.

130 d be the first in vivo marker of disarray in HCM and a potential independent risk factor.

131 ime, muscular mitral-aortic discontinuity in HCM.

132 l abnormalities or contracile dysfunction in HCM iPSC-CMs as compared to isogenic controls.

133 rdiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro.

134 nterstitial fibrosis, as assessed by ECV, in HCM patients, even in segments free of LGE.

135 new insight into worsening renal function in HCM, and active surveillance for renal function should b

136 nsiveness and improved diastolic function in HCM.

137 al manifestations of altered hemodynamics in HCM.(C) RSNA, 2020.

138 LVM determined by micro-CT was higher in HCM than normal hearts.

139 uration based on their frequent inclusion in HCM testing and prior association reports.

140 detect and quantitate inducible ischemia in HCM patients.

141 FA was consistently lower in HCM than normal hearts.

142 nd fibrosis and determine myocardial mass in HCM.

143 ical outcomes based on specific mutations in HCM patients is limited.

144 ysregulation of protein kinase A pathways in HCM.

145 ffect on long-term myocardial performance in HCM, which should be investigated further.

146 Diastolic FA was reduced in HCM compared with control subjects (0.49 +/- 0.05 vs. 0.

147 ors hypothesized that FA would be reduced in HCM due to disarray and fibrosis that may represent the

148 e the diagnostic yield of genetic testing in HCM.

149 prior angiotensin receptor blocker trials in HCM.

150 and co-occurrence of pathogenic variants in HCM genes.

151 of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensur

152 ternative splicing, and genetic variation in HCM.

153 ignificant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (

154 significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%,

155 nosis for end-stage heart failure in a large HCM cohort with contemporary management strategies.

156 e of therapeutic benefit in sarcomere-linked HCM.

157 infection can cause human cerebral malaria (HCM) with high mortality rates.

158 Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium

159 agement strategy and clinical course of many HCM patients, making the likelihood of sudden death prev

160 MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructi

161 uctive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

162 The MAVERICK-HCM trial was a multicenter, double-blind, placebo-contr

163 concomitant pathways that, together, mediate HCM in RAF1 mutant iPSC-derived cardiomyocytes.

164 latively normal functional capacity and mild HCM features.

165 microbial culture in a human colonic model (HCM).

166 n; instead, it suggests that for some myosin HCM mutations, hypertrophy is a compensation for decreas

167 the commonly proposed hypothesis that myosin HCM mutations increase muscle contractility, or causes a

168 study was to determine the incidence of new HCM diagnosis in SP mutation carriers.

169 ow insight is facilitating the design of new HCM therapeutics, including those that regulate metaboli

170 The incidence of new HCM-LVSD was ~7.5% over 15 years.

171 with a verified HCM diagnosis and 51,153 non-HCM age- and sex-matched control subjects.

172 design, 178 participants with nonobstructive HCM (age, 23.3+/-10.1 years; 61% men) were randomized in

173 ity Cardiomyopathy Questionnaire and a novel HCM-specific instrument.

174 r mitral-aortic discontinuity in obstructive HCM.

175 se-control study of men with non-obstructive HCM and age-matched controls.

176 In patients with mild non-obstructive HCM, plasma catecholamine levels remain stably low at ex

177 m, P<0.001), while prevalence of obstructive HCM was greater in recent cohorts (peak gradient >30 mm

178 tinuity in 5 young patients with obstructive HCM.

179 ess FA as a noninvasive in vivo biomarker of HCM myoarchitecture and its association with ventricular

180 Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and pres

181 to evaluate myocardial strain in carriers of HCM sarcomere mutation.

182 of genes previously reported as causative of HCM and commonly included in diagnostic tests have limit

183 Although the genetic cause of HCM has been linked to mutations in genes encoding sarco

184 chain gene (beta-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin func

185 importance of molecular characterization of HCM phenotype and presents an opportunity to identify br

186 to unravel the pathobiological complexity of HCM.

187 ough ES remains an important complication of HCM, contemporary treatment strategies, including ICDs a

188 Confirmation of HCM was based on typical macroscopic and microscopic fea

189 l intelligence approach for the detection of HCM based on 12-lead electrocardiography (ECG).

190 ECG-based detection of HCM by an artificial intelligence algorithm can be achie

191 ts) and the risk for incident development of HCM-LVSD (thin filament variants).

192 plinary clinic, with a clinical diagnosis of HCM and genetic testing of at least 46 cardiomyopathy-as

193 ing between 1994 and 2017 after diagnosis of HCM in a first-degree relative.

194 netic testing is helpful in the diagnosis of HCM mimics in patients with no or few extracardiac manif

195 A quantitative histogram of HCM melanins was generated by identifying the image pixe

196 Although the natural history of HCM-LVSD was variable, 75% of patients experienced adver

197 Thus, long-term systemic impact of HCM is still unclear.

198 is study sought to estimate the incidence of HCM-related SCD and its association with exercise in a l

199 The incidence of HCM-related SCD and its relationship to exercise have no

200 The incidence of HCM-related SCD in the general population 10 to 45 years

201 proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably

202 The number of HCM patients required to treat with ICDs to save 1 patie

203 3 does not contribute to the pathogenesis of HCM in vitro.

204 rgy conservation and that pathophysiology of HCM results from destabilization of these conformations.

205 Nearly 40 percent of HCM-causing mutations are found in human beta-cardiac my

206 tratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91;

207 lic/low Ca(2+) conditions in the presence of HCM/RCM lesions.

208 The prognosis of HCM-LVSD has reportedly been poor, but because of its re

209 After recognition of HCM-LVSD, the median time to composite outcome was 8.4 y

210 (Delta25) alone are not at increased risk of HCM, and this variant should not be tested in isolation;

211 Our data suggest that the risk of HCM, previously attributed to MYBPC3(Delta25), can be ex

212 usly have been declared at increased risk of HCM.

213 his highlights the need for greater study of HCM genetics in non-White populations.

214 viding a future perspective for treatment of HCM.

215 ear differences between early and late onset HCM mutations.

216 of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin.

217 ed 73 relatives with NCCM and 34 with DCM or HCM without NCCM.

218 defects similar to that described for other HCM-linked genes providing additional support for KLHL24

219 age 39.5 +/- 18.1 years), identified at our HCM centre were studied prospectively.

220 exome sequencing, was detected in ~1% of our HCM cohort.

221 nsible for a substantial decrease in overall HCM-related mortality (to 0.5%/y) and independent of pat

222 cTSD was predictive of preclinical and overt HCM disease status (P < .01).

223 rol participants, preclinical HCM, and overt HCM was 14% +/- 4, 17% +/- 4, and 22% +/- 7, respectivel

224 l participants), and participants with overt HCM (P < .001 vs control participants), respectively.

225 dynamic demands of hibernation or pathogenic HCM variants.

226 ) and pheomelanin-enriched lighter pigmented HCM regions mapped to phasors with longer lifetimes and

227 and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study.

228 6 cases of definite, probable, and possible HCM-related SCDs, respectively, were identified, corresp

229 28-0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years of o

230 ment regulation and that one of the possible HCM-causing mechanisms by the R21H mutation is through a

231 cTSD for control participants, preclinical HCM, and overt HCM was 14% +/- 4, 17% +/- 4, and 22% +/-

232 participants, participants with preclinical HCM (P = .496 vs control participants), and participants

233 Multivariable analysis to predict HCM status was performed by using multinomial logistic r

234 chondrial metabolic activity, and preventing HCM.

235 lic activity may be beneficial in preventing HCM in "at risk" patients with identified Gly203Ser gene

236 (95% CI, 0.34-0.62) for definite or probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95%

237 pathways by which NS RAF1 mutations promote HCM remain elusive, and so far, there is no known treatm

238 of imaging over genetic testing in promoting HCM diagnoses and urges efforts to understand genotype-n

239 We show the validity of previously reported HCM genes using an established method for evaluating gen

240 R population has characteristics of low-risk HCM.

241 stasis, we used 2 mouse models of sarcomeric HCM (cardiac troponin T R92L and R92W) with differential

242 Using a patient's strength of sarcomeric HCM phenotype for variant adjudication can increase sign

243 t functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H2

244 We sequenced HCM disease genes in Singaporean patients (n=224) and Si

245 Six of the seven HCM mutations were clearly distinct from a set of previo

246 dy suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct g

247 with ischemic heart disease, after ICD shock HCM patients rarely experience transformation to heart f

248 Singaporean HCM patients had significantly fewer confidently interpr

249 ding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018;

250 se AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Sin

251 ric proteins; hence, it is critical to study HCM at the level of proteoforms to gain insights into th

252 These results provide evidence that HCM mutations can modulate myosin activity by disrupting

253 a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-

254 showed a linear distribution indicating that HCM melanins are a ratio of two fluorophores, eumelanin

255 ts, mean age was 54.8 +/- 15.9 years for the HCM group and 57.5 +/- 15.5 years for the control group.

256 In the HCM, the incidence rate for ESRD gradually increased wit

257 Methods The HCM genetic database at our center was used for identifi

258 n the majority of patients, diagnosis of the HCM mimic based on clinical findings alone would have be

259 notype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can further reduce the burd

260 One pathway commonly linked to HCM progression is calcium homeostasis dysregulation, th

261 Patients at Tufts HCM Institute, from 2004 to 2017, were identified with E

262 gain insights into the mechanisms underlying HCM.

263 bly consistent, regardless of the underlying HCM-causing mutations.

264 for identification of patients who underwent HCM-directed genetic testing including at least 1 gene a

265 e-site variants in 56 of 557 (10%) unrelated HCM probands.

266 Results There were 1731 unrelated HCM patients who underwent genetic testing for at least

267 genic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%,

268 lead ECG from 2,448 patients with a verified HCM diagnosis and 51,153 non-HCM age- and sex-matched co

269 Data from 11 high-volume HCM specialty centers making up the international SHaRe

270 cause of RSCA for those >40 years of age was HCM.

271 ndings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional

272 nduced cortical brain injury associated with HCM pathogenesis as well as for testing agents that redu

273 siology and improve symptoms associated with HCM.

274 more common in those patients diagnosed with HCM (n=32 [56%] versus n=257 [23%]; P<0.001).

275 Materials and Methods Participants with HCM and their family members participated in a prospecti

276 A total of 13 patients with HCM (51 years +/- 16 [standard deviation]; 10 men) and 1

277 sults This study included 1073 patients with HCM (733 men; mean age, 49 years +/- 17 [standard deviat

278 ring follow-up in 10,300 adult patients with HCM (age 62.1 years, male 67.3%) and 51,500 age-, sex-ma

279 We included 64 patients with HCM and 53 healthy controls to the study and quantitativ

280 myopathy must be considered in patients with HCM and progressive conduction system disease.

281 As a result, the majority of patients with HCM deliberately reduce their habitual physical activity

282 Overall, 7286 patients with HCM diagnosed at an age >=18 years between 1961 and 2019

283 Systolic EVV in patients with HCM was 7 mL +/- 5, which was significantly associated w

284 In patients with HCM with and without sarcomeric mutations, the model-der

285 From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD.

286 icance that were identified in patients with HCM, predicted functional consequences and associations

287 Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35%

288 escribe the natural history of patients with HCM-LVSD.

289 utility of genetic testing for patients with HCM.

290 ted LGE scar quantification in patients with HCM.

291 art failure and arrhythmias in patients with HCM.

292 d adverse clinical outcomes in patients with HCM.

293 As) as potential biomarkers in patients with HCM.

294 sity exercise prescription for patients with HCM.

295 d MBOAT2 were downregulated in patients with HCM.

296 e adverse clinical outcomes in patients with HCM.

297 HCM-LVSD affects ~8% of patients with HCM.

298 at myectomy in 106 consecutive patients with HCM.

299 apacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949).

300 g-term outcomes in mutation carriers without HCM.