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Potential Diagnostic Role for a Combined Postmortem DNA and RNA Sequencing for Brugada Syndrome. 死后DNA和RNA测序对Brugada综合征的潜在诊断作用。
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-12-01 Epub Date: 2023-10-05 DOI: 10.1161/CIRCGEN.122.004251
Carlos Bueno-Beti, David C Johnson, Chris Miles, Joseph Westaby, Mary N Sheppard, Elijah R Behr, Angeliki Asimaki
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引用次数: 0
Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy. 肥厚性心肌病的基因型-表型分类。
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-12-01 Epub Date: 2023-11-28 DOI: 10.1161/CIRCGEN.123.004200
Lara Curran, Antonio de Marvao, Paolo Inglese, Kathryn A McGurk, Pierre-Raphaël Schiratti, Adam Clement, Sean L Zheng, Surui Li, Chee Jian Pua, Mit Shah, Mina Jafari, Pantazis Theotokis, Rachel J Buchan, Sean J Jurgens, Claire E Raphael, Arun John Baksi, Antonis Pantazis, Brian P Halliday, Dudley J Pennell, Wenjia Bai, Calvin W L Chin, Rafik Tadros, Connie R Bezzina, Hugh Watkins, Stuart A Cook, Sanjay K Prasad, James S Ware, Declan P O'Regan

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.

Methods: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.

Results: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88).

Conclusions: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

背景:肥厚性心肌病(HCM)是与异质性表型相关的心源性猝死的重要原因,但目前尚无系统的形态学分类或相关风险评估框架。在这里,我们定量调查了HCM中的基因型-表型关联,以获得疾病表达的数据驱动分类。方法:我们招募了436例HCM患者(中位年龄60岁;28.8%女性),有临床、遗传和影像学资料。来自新加坡的60例HCM患者的独立队列研究(中位年龄59岁;11%女性)和参考人群来自UK Biobank (n= 16691;平均年龄55岁;52.5%的女性)也被招募。我们利用机器学习分析了心脏磁共振成像左心室的三维结构,并建立了基于树的HCM表型分类。基因型和死亡风险分布被预测到树上。结果:与基因型阴性个体相比,HCM致病性或可能致病性变异携带者左心室体积较小,但基底间隔肥大较大,寿命缩短(平均随访时间9.9年)(风险比2.66 [95% CI, 1.42-4.96];页= 0.0001)。HCM的多基因风险也与不同的疾病表达模式和程度有关。该模型可推广到一个独立的队列(可信度,M1: 0.86-0.88)。结论:我们报告了一种数据驱动的HCM分类方法,用于识别具有相似形态学的患者群体,同时保留疾病严重程度、遗传风险和结果的连续性。这种方法将有助于理解疾病多样性的原因和后果。
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引用次数: 0
Compound Heterozygous Truncating Variants in the BAG5 Gene As a Cause of Early-Onset Dilated Cardiomyopathy. BAG5基因中的复合杂合子截短变体是早期发病的扩张型心肌病的原因。
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-12-01 Epub Date: 2023-10-24 DOI: 10.1161/CIRCGEN.123.004282
Shunsuke Inoue, Toshiyuki Ko, Seitaro Nomura, Takanobu Yamada, Bo Zhang, Zhehao Dai, Takahiro Jimba, Manami Katoh, Junichi Ishida, Eisuke Amiya, Masaru Hatano, Norifumi Takeda, Hiroyuki Morita, Minoru Ono, Issei Komuro
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引用次数: 0
Hypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants. RAF1富含半胱氨酸结构域变体继发的肥厚性心肌病。
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-12-01 Epub Date: 2023-10-31 DOI: 10.1161/CIRCGEN.123.004262
Dominic E Fullenkamp, Ryan M Jorgensen, Desiree F Leach, Arjun Sinha, Isabella M Salamone, Jamie R Johnston, Lisa M Dellefave-Castillo, Lubna Choudhury, Elizabeth M McNally, Lisa D Wilsbacher
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引用次数: 0
Combining Polygenic and Proteomic Risk Scores With Clinical Risk Factors to Improve Performance for Diagnosing Absence of Coronary Artery Disease in Patients With de novo Chest Pain. 将多基因和蛋白质组风险评分与临床风险因素相结合,提高诊断新发胸痛患者无冠状动脉疾病的能力。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-09-27 DOI: 10.1161/CIRCGEN.123.004053
Peter Loof Møller, Palle Duun Rohde, Jonathan Nørtoft Dahl, Laust Dupont Rasmussen, Samuel Emil Schmidt, Louise Nissen, Victoria McGilligan, Jacob F Bentzon, Daniel F Gudbjartsson, Kari Stefansson, Hilma Holm, Simon Winther, Morten Bøttcher, Mette Nyegaard

Background: Patients with de novo chest pain, referred for evaluation of possible coronary artery disease (CAD), frequently have an absence of CAD resulting in millions of tests not having any clinical impact. The objective of this study was to investigate whether polygenic risk scores and targeted proteomics improve the prediction of absence of CAD in patients with suspected CAD, when added to the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) minimal risk score (PMRS).

Methods: Genotyping and targeted plasma proteomics (N=368 proteins) were performed in 1440 patients with symptoms suspected to be caused by CAD undergoing coronary computed tomography angiography. Based on individual genotypes, a polygenic risk score for CAD (PRSCAD) was calculated. The prediction was performed using combinations of PRSCAD, proteins, and PMRS as features in models using stability selection and machine learning.

Results: Prediction of absence of CAD yielded an area under the curve of PRSCAD-model, 0.64±0.03; proteomic-model, 0.58±0.03; and PMRS model, 0.76±0.02. No significant correlation was found between the genetic and proteomic risk scores (Pearson correlation coefficient, -0.04; P=0.13). Optimal predictive ability was achieved by the full model (PRSCAD+protein+PMRS) yielding an area under the curve of 0.80±0.02 for absence of CAD, significantly better than the PMRS model alone (P<0.001). For reclassification purpose, the full model enabled down-classification of 49% (324 of 661) of the 5% to 15% pretest probability patients and 18% (113 of 611) of >15% pretest probability patients.

Conclusions: For patients with chest pain and low-intermediate CAD risk, incorporating targeted proteomics and polygenic risk scores into the risk assessment substantially improved the ability to predict the absence of CAD. Genetics and proteomics seem to add complementary information to the clinical risk factors and improve risk stratification in this large patient group.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02264717.

背景:被转诊评估可能的冠状动脉疾病(CAD)的新发胸痛患者经常没有CAD,导致数百万次检测没有任何临床影响。本研究的目的是研究多基因风险评分和靶向蛋白质组学是否能改善疑似CAD患者无CAD的预测,将其添加到PROMISE(用于评估胸痛的前瞻性多中心成像研究)最低风险评分(PMRS)中。方法:对1440名接受冠状动脉计算机断层扫描血管造影术的疑似CAD症状患者进行基因分型和靶向血浆蛋白质组学(N=368种蛋白质)。根据个体基因型,计算CAD的多基因风险评分(PRSCAD)。在使用稳定性选择和机器学习的模型中,使用PRSCAD、蛋白质和PMRS的组合作为特征进行预测。结果:预测无CAD时,PRSCAD模型的曲线下面积为0.64±0.03;蛋白质组学模型,0.58±0.03;PMRS模型为0.76±0.02。遗传和蛋白质组学风险评分之间没有发现显著的相关性(Pearson相关系数,-0.04;P=0.013)。全模型(PRSCAD+蛋白质+PMRS)在没有CAD的情况下产生0.80±0.02的曲线下面积,实现了最佳的预测能力,明显优于单独的PMRS模型(P15%的预测概率患者。结论:对于胸痛和中低度CAD风险的患者,将靶向蛋白质组学和多基因风险评分纳入风险评估大大提高了预测无CAD的能力。遗传学和蛋白质组学似乎为临床风险因素增加了补充信息,并改善了这一大样本的风险分层ient组。注册:URL:https://www.Clinicaltrials:政府;唯一标识符:NCT02264717。
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引用次数: 0
Novel Insights Into DMD-Associated Dilated Cardiomyopathy. DMD相关扩张型心肌病的新见解。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-09-27 DOI: 10.1161/CIRCGEN.123.004384
Teresa Wang, Jessica Chowns, Sharlene M Day
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引用次数: 0
Cardiac Sarcoidosis Mimickers: Genetic Testing in Undifferentiated Inflammatory Cardiomyopathies. 心脏结节病模拟:未分化炎症性心肌病的基因检测。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-07-04 DOI: 10.1161/CIRCGEN.123.004099
Matteo Castrichini, Kolade M Agboola, Hridyanshu Vyas, Omar F Abou Ezzeddine, Konstantinos C Siontis, John R Giudicessi, Andrew N Rosenbaum, Naveen L Pereira
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引用次数: 0
Contemporary Polygenic Scores of Low-Density Lipoprotein Cholesterol and Coronary Artery Disease Predict Coronary Atherosclerosis in Adolescents and Young Adults. 当代低密度脂蛋白胆固醇和冠状动脉疾病的多基因评分预测青少年和年轻人的冠状动脉粥样硬化。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-07-06 DOI: 10.1161/CIRCGEN.122.004047
Rodrigo Guarischi-Sousa, Elias Salfati, Pik Fang Kho, Kruthika R Iyer, Austin T Hilliard, David M Herrington, Philip S Tsao, Shoa L Clarke, Themistocles L Assimes
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引用次数: 0
Implementation of Rapid Genome Sequencing for Critically Ill Infants With Complex Congenital Heart Disease. 复杂先天性心脏病危重婴儿快速基因组测序的实施。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-07-07 DOI: 10.1161/CIRCGEN.122.004050
Thomas Hays, Rebecca Hernan, Michele Disco, Emily L Griffin, Nimrod Goldshtrom, Diana Vargas, Ganga Krishnamurthy, Miles Bomback, Atteeq U Rehman, Amanda T Wilson, Saurav Guha, Shruti Phadke, Volkan Okur, Dino Robinson, Vanessa Felice, Avinash Abhyankar, Vaidehi Jobanputra, Wendy K Chung

Background: Rapid genome sequencing (rGS) has been shown to improve care of critically ill infants. Congenital heart disease (CHD) is a leading cause of infant mortality and is often caused by genetic disorders, yet the utility of rGS has not been prospectively studied in this population.

Methods: We conducted a prospective evaluation of rGS to improve the care of infants with complex CHD in our cardiac neonatal intensive care unit.

Results: In a cohort of 48 infants with complex CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in 8 (62%) cases with diagnostic results. These included 2 cases in whom genetic diagnoses helped avert intensive, futile interventions before cardiac neonatal intensive care unit discharge, and 3 cases in whom eye disease was diagnosed and treated in early childhood.

Conclusions: Our study provides the first prospective evaluation of rGS for infants with complex CHD to our knowledge. We found that rGS diagnosed genetic disorders in 27% of cases and led to changes in management in 62% of cases with diagnostic results. Our model of care depended on coordination between neonatologists, cardiologists, surgeons, geneticists, and genetic counselors. These findings highlight the important role of rGS in CHD and demonstrate the need for expanded study of how to implement this resource to a broader population of infants with CHD.

背景:快速基因组测序(rGS)已被证明可以改善危重婴儿的护理。先天性心脏病(CHD)是婴儿死亡的主要原因,通常由遗传疾病引起,但rGS的效用尚未在该人群中进行前瞻性研究。方法:我们对rGS在我们的心脏新生儿重症监护室改善复杂CHD婴儿护理方面进行了前瞻性评估。结果:在一个由48名患有复杂CHD的婴儿组成的队列中,rGS在13名(27%)个体中诊断出14种遗传性疾病,并在8名(62%)有诊断结果的病例中导致临床管理的改变。其中包括2例基因诊断有助于避免心脏新生儿重症监护室出院前的强化、无效干预,以及3例在儿童早期诊断和治疗眼病的病例。结论:据我们所知,我们的研究首次提供了rGS对患有复杂CHD的婴儿的前瞻性评估。我们发现rGS在27%的病例中诊断出遗传性疾病,并在62%的诊断结果中导致管理的改变。我们的护理模式依赖于新生儿学家、心脏病学家、外科医生、遗传学家和遗传顾问之间的协调。这些发现突出了rGS在CHD中的重要作用,并表明需要扩大研究如何将这一资源应用于更广泛的CHD婴儿群体。
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引用次数: 1
Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants. RBM20变体携带者发生室性心律失常和心力衰竭的风险。
IF 7.4 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-10-01 Epub Date: 2023-08-18 DOI: 10.1161/CIRCGEN.123.004059
Douglas E Cannie, Alexandros Protonotarios, Athanasios Bakalakos, Petros Syrris, Massimiliano Lorenzini, Bianca De Stavola, Louise Bjerregaard, Anne M Dybro, Thomas M Hey, Frederikke G Hansen, Marina Navarro Peñalver, Maria G Crespo-Leiro, Jose M Larrañaga-Moreira, Fernando de Frutos, Renee Johnson, Thomas A Slater, Lorenzo Monserrat, Anshuman Sengupta, Luisa Mestroni, Matthew R G Taylor, Gianfranco Sinagra, Zofia Bilinska, Itziar Solla-Ruiz, Xabier Arana Achaga, Roberto Barriales-Villa, Pablo Garcia-Pavia, Juan R Gimeno, Matteo Dal Ferro, Marco Merlo, Karim Wahbi, Diane Fatkin, Jens Mogensen, Torsten B Rasmussen, Perry M Elliott

Background: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes.

Methods: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction.

Results: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point.

Conclusions: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

背景:据报道,2%至6%的扩张型心肌病家族性病例存在RBM20变异,可能与致命的室性心律失常和快速心力衰竭进展有关。我们试图确定RBM20变异携带者的不良事件风险以及性别对结果的影响。方法:从12个心肌病单位中连续招募携带RBM20变体的先证者及其亲属。主要终点是恶性室性心律失常(MVA)和终末期心力衰竭(ESHF)的复合。MVA和ESHF终点也分别进行了分析,并对男性和女性进行了比较。检测MVA同期的左心室射血分数(LVEF)。将患有左心室收缩功能障碍的RBM20变异携带者(RBM20LVSD)与患有特发性左心室收缩功能紊乱的变异难以捉摸患者进行比较。结果:143名RBM20变异携带者(71名男性;中位年龄35.5岁)的纵向随访数据可用;143人中有7人在基线时发生MVA事件。136例无基线MVA的患者中有30例(22.0%)达到主要终点,136例中有16例(11.8%)出现新的MVA,男性和女性之间没有显著差异(log秩分别为P=0.07和P=0.98)。143名患者中有20名(14.0%)出现ESHF(17名男性和3名女性;log秩为P35%。5岁时,67名RBM20LVSD患者中有15名(22.4%)达到主要终点,而197名特发性左心室收缩功能障碍患者中有7名(3.6%)达到主要终点(对数秩PRBM20变体携带使主要终点的风险增加了6.0倍。结论:与特发性左心室收缩功能障碍相比,RBM20变体与MVA和ESHF的高风险相关。男性和女性RBM20变体携带者的MVA风险相似,但男性与ESHF密切相关。
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引用次数: 0
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Circulation: Genomic and Precision Medicine
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