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Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients 血管性埃勒斯-丹洛斯综合征:荷兰全国 142 例患者的综合自然史研究
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-16 DOI: 10.1161/circgen.122.003978
Serwet Demirdas, Lisa M. van den Bersselaar, Rosan Lechner, Jessica Bos, Suzanne I.M. Alsters, Marieke J.H. Baars, Annette F. Baas, Özlem Baysal, Saskia N. van der Crabben, Eelco Dulfer, Noor A.A. Giesbertz, Apollonia T.J.M. Helderman-van den Enden, Yvonne Hilhorst-Hofstee, Marlies J.E. Kempers, Fenne L. Komdeur, Bart Loeys, Daniëlle Majoor-Krakauer, Charlotte W. Ockeloen, Eline Overwater, Peter J. van Tintelen, Marsha Voorendt, Vivian de Waard, Alessandra Maugeri, Hennie T. Brüggenwirth, Ingrid M.B.H. van de Laar, Arjan C. Houweling
BACKGROUND:Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease.METHODS:Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination.RESULTS:A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03).CONCLUSIONS:Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.
背景:血管性埃勒斯-丹洛斯综合征(vEDS)是一种罕见的结缔组织疾病,具有动脉、肠道和子宫破裂的高风险,由COL3A1的杂合致病变异引起。这项队列研究旨在进一步了解 vEDS 的自然史,并描述荷兰多中心队列中基因型与表型的相关性,以优化患者护理并提高对该疾病的认识。结果:共有 142 人(50% 为女性)参与了研究,其中包括 46 名指数患者(32%)。基因诊断时的总体中位年龄为 41.0 岁。半数以上的指数患者(54.3%)和亲属(53.1%)的体征高度提示vEDS。在这些人中,重大事件发生的频率并不高(P=0.90),但发生的年龄较小(P=0.01)。与女性相比,男性发生重大事件的频率更高,年龄更小(分别为 P<0.001 和 P=0.004)。主动脉瘤(P=0.003)和气胸(P=0.029)在男性中更为常见。结论:男性性别、COL3A1变体的类型和位置以及高度提示vEDS的体貌特征是导致重大事件发生和/或发病年龄提前的风险因素。这项针对荷兰vEDS患者的全国性多中心队列研究为改进vEDS患者的诊断、随访和治疗指南提供了宝贵的依据。
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引用次数: 0
Role of Genetic Testing for Cardiomyopathies in Pediatric Patients With Left Ventricular Dysfunction Secondary to Chemotherapy. 对化疗继发左心室功能障碍的儿科患者进行心肌病基因检测的作用
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-15 DOI: 10.1161/CIRCGEN.123.004353
Elena Bennati, Guglielmo Capponi, Silvia Favilli, Francesca Girolami, Alessia Gozzini, Gaia Spaziani, Silvia Passantino, Angela Tamburini, Annalisa Tondo, Iacopo Olivotto
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引用次数: 0
Crossing the Threshold of Therapeutic Hope for Patients With PKP2 Arrhythmogenic Cardiomyopathy. 跨越 PKP2 致心律失常性心肌病患者治疗希望的门槛。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-08 DOI: 10.1161/CIRCGEN.124.004572
Juan Mundisugih, Eddy Kizana
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引用次数: 0
Transcription Factors Leave Their Mark on the Heart. 转录因子在心脏上留下印记
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-03-18 DOI: 10.1161/CIRCGEN.124.004598
Yuchen Chang, Mathias Francois, Richard D Bagnall
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引用次数: 0
Resource of Gene Expression Data From a Multiethnic Population Cohort of Induced Pluripotent Stem Cell-Derived Cardiomyocytes. 多种族人群诱导多能细胞衍生心肌细胞的基因表达数据资源。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-19 DOI: 10.1161/CIRCGEN.123.004218
Wenjian Lv, Apoorva Babu, Michael P Morley, Kiran Musunuru, Marie A Guerraty
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引用次数: 0
DNA Methylation-Based Biomarkers of Protein Levels and Cardiovascular Disease Risk: Opportunities and Challenges for Precision Cardiology. 基于 DNA 甲基化的蛋白质水平和心血管疾病风险生物标志物:精准心脏病学的机遇与挑战。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-13 DOI: 10.1161/CIRCGEN.124.004571
Anne K Bozack, Ana Navas-Acien, Andres Cardenas
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引用次数: 0
Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction. TBX20 截断变体在扩张型心肌病和左心室不充盈中的作用
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-14 DOI: 10.1161/CIRCGEN.123.004404
Almudena Amor-Salamanca, Alfredo Santana Rodríguez, Hazhee Rasoul, José F Rodríguez-Palomares, Oana Moldovan, Thomas Morris Hey, María Gallego Delgado, David López Cuenca, Daniel de Castro Campos, María Teresa Basurte-Elorz, Rosa Macías-Ruiz, María Eugenia Fuentes Cañamero, Joseph Galvin, Raquel Bilbao Quesada, Luis de la Higuera Romero, Juan Pablo Trujillo-Quintero, Loida María García-Cruz, Ivonne Cárdenas-Reyes, Juan Jiménez-Jáimez, Soledad García-Hernández, María Valverde-Gómez, Iria Gómez-Díaz, Javier Limeres Freire, José M García-Pinilla, Juan R Gimeno-Blanes, Konstantinos Savattis, Pablo García-Pavía, Juan Pablo Ochoa

Background: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.

Methods: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.

Results: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.

Conclusions: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

背景:在扩张型心肌病(DCM)患者中,只有不到 40% 发现了致病/可能致病的基因变异。TBX20 与先天性心脏缺陷有关;尽管有人提出它与左心室不充盈(LVNC)和 DCM 有关,但它仍被认为是一个与这些表型有关的证据有限的基因。本研究试图调查 TBX20 截短变异体(TBX20tv)与 DCM/LVNC 之间的关联:方法:通过新一代测序对 7463 例诊断为 DCM 或 LVNC 的非亲缘关系探查者、22 773 例内部对比组(肥厚型心肌病、通道病或主动脉疾病)探查者和 124 098 例外部对照(gnomAD 数据库中的个体)进行了 TBX20 测序。计算了TBX20tv在DCM/LVNC中的富集程度,确定了选定家系中的共分离情况,并分析了携带者的临床特征和预后:与内部组(1/22 773;0.004%)和外部对比组(4/124 098;0.003%)相比,TBX20tv在DCM/LVNC中富集(24/7463;0.32%),几率比为73.23(95% CI,9.90-541.45);PPTBX20tv与21个家系的DCM/LVNC表型共分离,LOD综合评分为4.53(强关联)。在 57 名 TBX20tv 患者(49.1% 为男性;平均年龄为 35.9±20.8 岁)中,41 人(71.9%)表现为 DCM/LVNC,其中 14 人(34.1%)还伴有先天性心脏缺陷。中位随访 6.9 年(95% CI,25-75:3.6-14.5)后,9.7% 的 DCM/LVNC 患者出现终末期心力衰竭,4.8% 的患者出现恶性室性心律失常:结论:TBX20tv 与 DCM/LVNC 相关;约三分之一的病例存在先天性心脏缺陷。与 TBX20tv 相关的 DCM/LVNC 具有非侵袭性表型的特点,重大心血管事件的发生率较低。TBX20 应被视为 DCM 和 LVNC 的确定基因,并被常规纳入这些表型的基因检测中。
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引用次数: 0
CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults. CYB5R3 T117S 基因突变与黑人成年人的主要不良心脑血管事件有关。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-14 DOI: 10.1161/CIRCGEN.123.004271
Rahul Chaudhary, Adam C Straub, Felix E Y Aggor, Ifeoluwa Onasanya, Jordan Richardson, Patrick J Strollo, Steven E Reis, Oladipupo Olafiranye
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引用次数: 0
Multiplexed Functional Assessments of MYH7 Variants in Human Cardiomyocytes. 人类心肌细胞中 MYH7 变异的多重功能评估
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-02-16 DOI: 10.1161/CIRCGEN.123.004377
Clayton E Friedman, Shawn Fayer, Sriram Pendyala, Wei-Ming Chien, Alexander Loiben, Linda Tran, Leslie S Chao, Ashley McKinstry, Dania Ahmed, Stephen D Farris, April Stempien-Otero, Erica C Jonlin, Charles E Murry, Lea M Starita, Douglas M Fowler, Kai-Chun Yang

Background: Pathogenic autosomal-dominant missense variants in MYH7 (myosin heavy chain 7), which encodes the sarcomeric protein (β-MHC [beta myosin heavy chain]) expressed in cardiac and skeletal myocytes, are a leading cause of hypertrophic cardiomyopathy and are clinically actionable. However, ≈75% of MYH7 missense variants are of unknown significance. While human-induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes to enable the interrogation of MYH7 variant effect in a disease-relevant context, deep mutational scanning has not been executed using diploid hiPSC derivates due to low hiPSC gene-editing efficiency. Moreover, multiplexable phenotypes enabling deep mutational scanning of MYH7 variant hiPSC-derived cardiomyocytes are unknown.

Methods: To overcome these obstacles, we used CRISPRa On-Target Editing Retrieval enrichment to generate an hiPSC library containing 113 MYH7 codon variants suitable for deep mutational scanning. We first established that β-MHC protein loss occurs in a hypertrophic cardiomyopathy human heart with a pathogenic MYH7 variant. We then differentiated the MYH7 missense variant hiPSC library to cardiomyocytes for multiplexed assessment of β-MHC variant abundance by massively parallel sequencing and hiPSC-derived cardiomyocyte survival.

Results: Both the multiplexed assessment of β-MHC abundance and hiPSC-derived cardiomyocyte survival accurately segregated all known pathogenic variants from synonymous variants. Functional data were generated for 4 variants of unknown significance and 58 additional MYH7 missense variants not yet detected in patients.

Conclusions: This study leveraged hiPSC differentiation into disease-relevant cardiomyocytes to enable multiplexed assessments of MYH7 missense variants for the first time. Phenotyping strategies used here enable the application of deep mutational scanning to clinically actionable genes, which should reduce the burden of variants of unknown significance on patients and clinicians.

背景:MYH7(肌球蛋白重链 7)编码在心肌细胞和骨骼肌细胞中表达的肉瘤蛋白(β-MHC [β肌球蛋白重链]),其致病性常染色体显性错义变异是肥厚型心肌病的主要病因之一,而且在临床上是可行的。然而,≈75% 的 MYH7 错义变异意义不明。虽然人类诱导多能干细胞(hiPSC)可以分化成心肌细胞,从而在疾病相关的背景下对MYH7变异效应进行检测,但由于hiPSC基因编辑效率较低,还没有使用二倍体hiPSC衍生物进行深度突变扫描。此外,能够对 MYH7 变异 hiPSC 衍生心肌细胞进行深度突变扫描的可复用表型也是未知的:为了克服这些障碍,我们使用 CRISPRa 靶向编辑检索富集技术生成了一个 hiPSC 文库,其中包含适合深度突变扫描的 113 个 MYH7 密码子变体。我们首先确定,在肥厚型心肌病人心脏中,β-MHC 蛋白缺失会导致致病性 MYH7 变异。然后,我们将 MYH7 错义变体 hiPSC 文库分化为心肌细胞,通过大规模平行测序和 hiPSC 衍生的心肌细胞存活率,对 β-MHC 变异丰度进行多重评估:结果:β-MHC 变异丰度的多重评估和 hiPSC 衍生的心肌细胞存活率都准确地将所有已知的致病变异与同义变异分离开来。针对在心肌病患者中检测到的 4 个意义不明的变体以及在患者中尚未检测到的另外 58 个 MYH7 错义变体,生成了功能数据:本研究利用 hiPSC 分化成疾病相关的心肌细胞,首次实现了对 MYH7 错义变异的多重评估。本研究采用的表型分析策略能够对临床上可操作的基因进行深度突变扫描,从而减轻意义不明的变异给患者和临床医生带来的负担。
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引用次数: 0
Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study. 代谢风险评分对心力衰竭死亡率的增量价值:一项基于人群的研究
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-04-01 Epub Date: 2024-03-22 DOI: 10.1161/CIRCGEN.123.004312
Jungnam Joo, Joseph J Shearer, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Maureen Sampson, Suzette J Bielinski, Nicholas B Larson, Hoyoung Park, Katherine M Conners, Sarah Turecamo, Véronique L Roger

Background: Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.

Methods: Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.

Results: The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.

Conclusions: This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.

背景:心力衰竭是一种异质性综合征,死亡率居高不下。核磁共振波谱技术实现了高通量代谢组学,适用于精准表型分析。我们旨在利用靶向代谢组学得出代谢风险评分(MRS),从而改善心衰患者的死亡率风险分层:方法:利用核磁共振测量心衰社区队列血浆中的 21 种代谢物(脂蛋白亚种、支链氨基酸、丙氨酸、GlycA、酮体、葡萄糖和柠檬酸盐)。MRS 是通过 LASSO 惩罚性 Cox 回归和时间验证得出的。评估了 MRS 与死亡率之间的关系,以及与 Meta-Analysis Global Group in Chronic Heart Failure 临床风险评分和 NT-proBNP(N-末端前 B 型钠尿肽)水平相比,风险分层是否有所改善:研究共纳入 1382 名患者(中位年龄 78 岁,52% 为男性,43% 射血分数降低),5 年生存率为 48%(95% CI,46%-51%)。MRS 包括 9 种代谢物的测量。在验证数据集中,MRS 每增加 1 SD,死亡率就会增加很多(危险比为 2.2 [95% CI, 1.9-2.5]),在调整了慢性心力衰竭 Meta-Analysis Global Group 评分和 NT-proBNP 后,死亡率仍然增加(危险比为 1.6 [95% CI, 1.3-1.9])。这些关联在射血分数上没有差异。综合分辨和净再分类指数以及Uno's C统计表明,与Meta-Analysis Global Group in Chronic Heart Failure和NT-proBNP相比,MRS的加入提高了分辨能力:结论:在心力衰竭社区队列中开发的这一 MRS 与巨大的超额死亡风险相关,并在既定风险评分和临床标记物之外改善了风险分层。
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引用次数: 0
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Circulation: Genomic and Precision Medicine
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