Bhaskaran Ashwin, Ben Yaou Rabah, Helms Adam S, Fayssoil Abdallah, Richard Pascale, Stojkovic Tanya, Anselme Frédéric, Labombarda Fabien, Chikhaoui Cathy, De Sandre-Giovannoli Annachiara, Jeru Isabelle, Leturcq France, Vigouroux Corinne, Dembele Mohamed, Elliott Perry, Savvatis Konstantinos, Zeppenfeld Katja, Bouguerra Hassina, Charron Philippe, Kumar Saurabh, Bonne Gisèle, Wahbi Karim, Lakdawala Neal K
Department of Cardiology, Westmead Hospital, Sydney, New South Wales, Australia.
Westmead Applied Research Centre, University of Sydney, Sydney, New South Wales, Australia.
JAMA Cardiol. 2025 Jul 2. doi: 10.1001/jamacardio.2025.2069.
Prior studies have suggested that patients with nonmissense (ie, truncating) variants causing LMNA cardiomyopathy have worse arrhythmic outcomes compared to those with missense variants. However, the effect of the spatial distribution of missense and truncating variants on clinical outcomes remains poorly understood.
To determine the association of the spatial distribution of missense and truncating LMNA variants with cardiac outcomes.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective, observational cohort study used data from an international registry (from January 2013 on) and data derived from tertiary cardiomyopathy centers (January 2000 and June 2017). Patients with likely pathogenic/pathogenic LMNA variants and no prior malignant ventricular arrhythmia (VA) were eligible for inclusion. Data analysis was completed from March 2022 to March 2025.
The primary outcome of time to VA was defined as sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, or other manifestations of hemodynamically unstable VA. The secondary composite outcome of advanced heart failure was defined as nonsudden cardiac death, implantation of a left ventricular assist device, or cardiac transplant. Outcomes were stratified by type of variant (missense or truncating), affected transcript position (head, rod, or tail), and location on the LMNA gene.
A total of 718 patients were included, among whom mean (SD) age was 41.1 (14.3) years, 381 patients (53.1%) were female, and mean (SD) baseline left ventricular ejection fraction was 55.8% (13.3%). Over a median follow-up of 4.2 years, 223 patients experienced the primary outcome of malignant VA and 109 experienced the secondary outcome of advanced heart failure. Patients with truncating variants had a higher risk of VA (hazard ratio [HR], 1.72; 95% CI, 1.19-2.48; P = .004) but no difference in advanced heart failure (HR, 0.94; 95% CI, 0.64-1.40; P = .77) compared with patients with missense variants. There were no significant differences in the primary and secondary outcomes when stratifying truncating variants by location on the LMNA gene or transcript position. In contrast, on multivariable analysis, missense variants affecting the tail domain of LMNA (HR, 0.35; 95% CI, 0.16-0.78; P = .02) and located in exons 7 through 12 (HR, 0.39; 95% CI, 0.17-0.89; P = .035) were associated with a significantly lower risk of the primary outcome of malignant VA.
In this retrospective cohort study, truncating LMNA variants were associated with worse arrhythmic outcomes independent of variant position, whereas missense variants affecting the tail domain and located in exons 7 through 12 had better arrhythmic and heart failure outcomes. Understanding the mechanisms underlying these differences may have future therapeutic implications.
先前的研究表明，与携带错义变异的患者相比，携带导致LMNA心肌病的非错义（即截短）变异的患者心律失常结局更差。然而，错义变异和截短变异的空间分布对临床结局的影响仍知之甚少。
确定错义变异和截短的LMNA变异的空间分布与心脏结局之间的关联。
设计、设置和参与者：这项多中心、回顾性、观察性队列研究使用了来自国际注册机构（从2013年1月起）的数据以及来自三级心肌病中心（2000年1月至2017年6月）的数据。携带可能致病/致病的LMNA变异且既往无恶性室性心律失常（VA）的患者符合纳入标准。数据分析于2022年3月至2025年3月完成。
VA发生时间的主要结局定义为心源性猝死、适当的植入式心律转复除颤器治疗或血流动力学不稳定VA的其他表现。晚期心力衰竭的次要复合结局定义为非心源性猝死、植入左心室辅助装置或心脏移植。结局按变异类型（错义或截短）、受影响的转录本位置（头部、杆部或尾部）以及在LMNA基因上的位置进行分层。
共纳入718例患者，其中平均（标准差）年龄为41.1（14.3）岁，381例患者（53.1%）为女性，平均（标准差）基线左心室射血分数为55.8%（13.3%）。在中位随访4.2年期间，223例患者发生了恶性VA的主要结局，109例患者发生了晚期心力衰竭的次要结局。与携带错义变异的患者相比，携带截短变异的患者发生VA的风险更高（风险比[HR]，1.72；95%置信区间，1.19 - 2.48；P = 0.004），但在晚期心力衰竭方面无差异（HR，0.94；95%置信区间，0.64 - 1.40；P = 0.77）。根据LMNA基因上的位置或转录本位置对错义变异进行分层时，主要和次要结局均无显著差异。相比之下，在多变量分析中，影响LMNA尾部结构域（HR，0.35；95%置信区间，0.16 - 0.78；P = 0.02）且位于外显子7至12（HR，0.39；95%置信区间，0.17 - 0.89；P = 0.035）的错义变异与恶性VA主要结局的风险显著降低相关。
在这项回顾性队列研究中，截短的LMNA变异与更差的心律失常结局相关，且与变异位置无关，而影响尾部结构域且位于外显子7至12的错义变异具有更好的心律失常和心力衰竭结局。了解这些差异背后的机制可能对未来的治疗具有启示意义。
