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Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy. 新型多路复用血浆生物标记物面板对肥厚型心肌病儿童具有诊断和预后潜力
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-06-01 Epub Date: 2024-06-07 DOI: 10.1161/CIRCGEN.123.004448
Gabriella Captur, Ivan Doykov, Sheng-Chia Chung, Ella Field, Annabelle Barnes, Enpei Zhang, Imogen Heenan, Gabrielle Norrish, James C Moon, Perry M Elliott, Wendy E Heywood, Kevin Mills, Juan Pablo Kaski

Background: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.

Methods: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.

Results: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044).

Conclusions: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.

背景:肥厚型心肌病(HCM)的临床定义是病理性左心室肥厚。我们之前开发了一个血浆蛋白质组学生物标记物面板,该面板与肥厚性心肌病成人患者的疾病严重程度和心脏性猝死风险的临床标记物相关。本研究的目的是调查成人生物标志物的效用,并对儿童期发病的 HCM 进行蛋白质组学研究:从 HCM 儿童的探索性血浆蛋白质组学筛选中确定了 59 个蛋白质生物标志物,并将其添加到我们现有的基于多重靶向液相色谱-串联/质谱分析法中。我们在从 148 名 HCM 患儿和 50 名健康对照者收集的血浆中对这些生物标记物与临床表型和结果的关联进行了前瞻性测试。利用机器学习技术开发了新型儿科血浆蛋白质组生物标志物面板:结果:先前确定的四个成人 HCM 标志物(果糖二磷酸醛缩酶 A、补体 C3a、talin-1 和 thrombospondin 1)和三个新标志物(糖原磷酸化酶 B、脂蛋白 a 和 profilin 1)在小儿 HCM 中升高。通过对训练队列(n=137)和验证队列(n=61)进行有监督的机器学习,该 7 个生物标记物面板可将 HCM 与健康对照组区分开来,训练数据集的曲线下面积为 1.0(灵敏度 100% [95% CI, 95-100];特异性 100% [95% CI, 96-100]),验证数据集的曲线下面积为 0.82(灵敏度 75% [95% CI, 59-86];特异性 88% [95% CI, 75-94])。在心脏性猝死高危儿童中发现的其他 4 种肽(载脂蛋白 L1、补体 5b、免疫球蛋白重常数ε和血清淀粉样蛋白 A4 肽)循环水平降低,可将其与低危和中危组完全区分开来,并预测死亡率和不良心律失常结果(危险比为 2.04 [95% CI, 1.0-4.2];P=0.044):结论:在儿童中,7 个生物标志物蛋白质组学面板能以较高的灵敏度和特异性将 HCM 与对照组区分开来,第二个 4 个生物标志物面板能识别不良心律失常结局(包括心脏性猝死)的高风险人群。
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引用次数: 0
Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias. 全基因组关联研究的元分析揭示了室上性心律失常的遗传机制。
IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-06-01 Epub Date: 2024-05-28 DOI: 10.1161/CIRCGEN.123.004320
Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz

Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).

Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.

Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.

Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

背景:大量数据支持室上性心动过速具有遗传基础,但对这些心律失常的遗传决定因素和分子机制却知之甚少。我们试图确定与房室结性返流性心动过速(AVNRT)和房室附属通路或房室往复性心动过速(AVAPs/AVRT)相关的遗传位点:我们对全基因组关联研究进行了多巢荟萃分析,以确定 AVNRT(4 项研究)和 AVAP/AVRT (7 项研究)的遗传位点。我们通过分析相关变异与心脏基因表达之间的关系、进行全转录组分析以及检查先前的全基因组关联研究,评估了支持候选基因潜在因果效应的证据:分析对象包括 2384 个 AVNRT 病例和 106 489 个参照者,以及 2811 个 AVAP/AVRT 病例和 1 483 093 个参照者。我们为 AVNRT 确定了 2 个重要基因位点,这意味着 NKX2-5 和 TTN 是疾病易感基因。全转录组关联分析支持 NKX2-5 的预测心脏表达减少与 AVNRT 之间存在关联。我们确定了 AVAP/AVRT 的 3 个重要基因位点,其中涉及 SCN5A、SCN10A 和 TTN/CCDC141。以前曾报道过几个基因位点的变异与心脏表型有关,包括心房颤动、中风、布鲁加达综合征和心电图间期:我们的研究结果突出表明,与离子通道功能(AVAP/AVRT)以及心脏发育和肌纤维(AVAP/AVRT 和 AVNRT)相关的基因区域是室上性心动过速易感性的重要潜在影响因素。
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引用次数: 0
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
{"title":"Transcription Factors Leave Their Mark on the Heart.","authors":"Yuchen Chang, Mathias Francois, Richard D Bagnall","doi":"10.1161/CIRCGEN.124.004598","DOIUrl":"10.1161/CIRCGEN.124.004598","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004598"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"title":"Resource of Gene Expression Data From a Multiethnic Population Cohort of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.","authors":"Wenjian Lv, Apoorva Babu, Michael P Morley, Kiran Musunuru, Marie A Guerraty","doi":"10.1161/CIRCGEN.123.004218","DOIUrl":"10.1161/CIRCGEN.123.004218","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004218"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
期刊
Circulation: Genomic and Precision Medicine
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