与肌联蛋白相关的家族性扩张型心肌病：与疾病发病相关的因素

Titin-related familial dilated cardiomyopathy: factors associated with disease onset.

作者信息

Johnson Renee, Fletcher Robert A, Peters Stacey, Ohanian Monique, Soka Magdalena, Smolnikov Andrei, Abihider Katherine E, Ackerman Michael J, Ader Flavie, Akhtar Mohammed M, Amin Ahmad S, Ashley Euan A, Atherton John J, Austin Rachel, Baas Annette F, Bagnall Richard D, Ross Samantha Barratt, Blouin Jean-Louis, Brown Emily E, Bundgaard Henning, Cannie Douglas, Chmielewski Przemyslaw, Correnti Gemma, Crespo-Leiro Maria Generosa, Dal Ferro Matteo, Dellefave-Castillo Lisa M, Dominguez Fernando, Dooijes Dennis, Dybro Anne M, Ed Demri Youssef, El Hachmi Mohamed, Escobar-Lopez Luis, Foye Sarah Jajesnica, Franaszczyk Maria, Gigli Marta, Lopez Esther Gonzalez, Goudal Adeline, Graw Sharon, Guipponi Michel, Haan Eric, Haas Jan, Hammersley Daniel J, Hansen Frederikke G, Hayward Christopher S, Hey Thomas Morris, Heymans Stephane, Ho Carolyn Y, Houweling Arjan C, Ingles Jodie, Ingrey Angela, Jabbour Andrew, James Paul A, Jansweijer Joeri A, Jongbloed Jan D H, Keogh Anne M, Larrañaga-Moreira Jose M, Lekanne Deprez Ronald H, Macciocca Ivan, Macdonald Peter S, Mansencal Nicolas, Mansour Julia, Martinez-Veira Cristina, McDonough Barbara, McGaughran Julie, Medo Kristen, Merlo Marco, Michalak Ewa, Monserrat Lorenzo, Mountain Helen, Muller Steven A, Murphy Anne M, Murray Brittney, Oates Emily C, Ormondroyd Elizabeth, Pachter Nicholas, Paldino Alessia, Palmyre Aurélien, Pereira Naveen L, Picard Kermshlise C, Poplawski Nicola, Prasad Sanjay, Proukhnitzky Julie, Pruny Jean-Francois, Reant Patricia, Richard Pascale, Ronan Anne, Sedaghat-Hamedani Farbod, Semsarian Christopher, Storm Garrett, Stroeks Sophie, Syrris Petros, Taylor Matthew R G, Thomson Kate, Thompson Tina, van Tintelen J Peter, Vissing Christoffer Rasmus, Waddell-Smith Kathryn E, Wallis Mathew, Zentner Dominica, Arnott Clare, Marian Ali J, Oh Jaewon, Fokstuen Siv, James Cynthia A, Barriales-Villa Roberto, Meder Benjamin, Wahbi Karim, Giudicessi John R, Parikh Victoria N, Ware James S, Piriou Nicolas, Rooryck Caroline, Lakdawala Neal K, Mestroni Luisa, Sinagra Gianfranco, Elliott Perry M, Watkins Hugh, McNally Elizabeth M, Charron Philippe, van Spaendonck-Zwarts Karin Y, Garcia-Pavia Pablo, Peña-Peña Maria Luisa, Mogensen Jens, Christensen Alex Hoerby, Bilińska Zofia T, Rasmussen Torsten B, Seidman Jonathan G, Seidman Christine E, Te Riele Anneline S J M, Verdonschot Job A J, Pinto Yigal M, Christiaans Imke, Fatkin Diane

机构信息

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW 2052, Australia.

出版信息

Eur Heart J. 2025 Aug 11. doi: 10.1093/eurheartj/ehaf380.

DOI:10.1093/eurheartj/ehaf380

PMID:40796136

Abstract

BACKGROUND AND AIMS

Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

METHODS

An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM.

RESULTS

A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23).

CONCLUSIONS

Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

摘要

背景与目的

TTN基因的截短变异（TTNtv）是扩张型心肌病（DCM）最常见的遗传病因，但在普通人群中也作为偶然发现出现。本研究调查了与TTNtv临床表现相关的因素。

方法

在患有TTNtv相关DCM的家庭中进行了一项国际多中心回顾性观察研究。使用共享脆弱模型估计变异特征与DCM终生风险的关联，并使用逻辑回归估计个体水平临床风险因素概况（心脏状况、心血管合并症、生活方式）与DCM的比值比（OR）。

结果

共研究了1043个患有TTNtv相关DCM家庭中的3158名受试者。TTNtv阳性受试者发生DCM的可能性高21倍[OR，21.21；95%置信区间（CI），14.80 - 30.39]。男性发病较早，但不同类型和位置的TTNtv发病情况相似。临床风险因素的存在与DCM发病较早相关（OR，3.41；95%CI，2.06 - 5.64），有房颤病史使DCM发病几率增加两倍（OR，2.05；95%CI，1.27 - 3.32）。临床风险因素的患病率随年龄增加；然而，对于早发型（<30岁）疾病，DCM关联强度最大（OR，4.75；95%CI，2.35 - 9.60）。在明显发生DCM之前使用β - 肾上腺素能受体或肾素 - 血管紧张素系统阻断药物与DCM发病几率降低87%相关（OR，0.13；95%CI，0.08 - 0.23）。