Genotype-Specific Outcomes of Desmosomal Cardiomyopathies.

IF 35.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation Pub Date : 2025-05-23 DOI:10.1161/CIRCULATIONAHA.124.073475

Valerio Pergola, Alessandro Trancuccio, Deni Kukavica, Andrea Mazzanti, Carlo Napolitano, Gabriele Gaetano Scilabra, Kenneth Steele, Mirella Memmi, Patrick Gambelli, Andrea Sugamiele, Alessia Chiara Latini, Nicola Pisani, Giulio Mazzotta, Raffaella Bloise, Massimo Morini, Maira Marino, Silvia G Priori

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引用次数: 0

Abstract

Background: Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers.

Methods: This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency <10^-⁴) variants of uncertain significance were included. The arrhythmic end point was the occurrence of a life-threatening arrhythmic event, defined as sudden cardiac death, aborted cardiac arrest, or hemodynamically unstable ventricular tachycardia. The end-stage HF outcome was the composite of a fatal HF episode or cardiac transplantation.

Results: We included 533 DGV carriers (59% male; median [interquartile range] age, 39 [22-54] years) from 214 families: 503 of 533 had a single DGV (212 [40%] PKP2, 160 [30%] DSP, 97 [18%] DSG2, 34 [6%] DSC2) and 30 of 533 (6%) double DGVs. Overall, 83 of 533 (16%) experienced a life-threatening arrhythmic event (at age 40 [33-51] years), and 14 of 533 (3%) experienced end-stage HF (at age 57 [50-60] years). Multivariable analysis demonstrated that, compared with nonmissense PKP2 variants, nonmissense DSP variants (hazard ratio [HR], 2.3 [95% CI, 1.3-4.1]; P=0.008), missense variants in hotspot domains in DSP (HR, 2.7 [95% CI, 1.2-6.2]; P=0.010) and PKP2 (HR, 3.6 [95% CI, 2.0-6.5]; P<0.001), male sex (HR, 1.7 [95% CI, 1.1-2.8]; P=0.021), and double DGVs (HR, 3.4 [95% CI, 1.7-6.9]; P<0.001) were associated with a higher risk of a life-threatening arrhythmic event. Nonmissense DSP variants (HR, 5.0 [95% CI, 1.5-18.2]; P=0.009) and double DGVs (HR, 4.7 [95% CI, 1.0-19.3]; P=0.044) were also associated with increased risk of end-stage HF.

Conclusions: Among carriers of DGVs, genotype was associated with arrhythmic and HF outcomes, with type and location of the variant further modulating the natural history.

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桥粒体心肌病的基因型特异性结局。

背景：桥粒体基因变异（DGVs）与心律失常性心肌病的多种表型表现相关，但缺乏基因型特异性结果的数据。我们研究了DGV携带者基因型特异性心律失常和心力衰竭（HF）的结果。方法：本队列研究纳入了连续患者，进行桥粒体基因筛查。包括致病和罕见（等位基因频率-4）变异的不确定意义的携带者。心律失常的终点是发生危及生命的心律失常事件，定义为心源性猝死、流产的心脏骤停或血流动力学不稳定的室性心动过速。终末期HF结局是致命HF发作或心脏移植的综合结果。结果：我们纳入了533名DGV携带者(59%为男性；来自214个家庭的年龄中位数为39[22-54]岁，533个家庭中有503个家庭患有单一DGV (PKP2 212 [40%], DSP 160 [30%], DSG2 97 [18%], DSC2 34[6%])， 533个家庭中有30个（6%）患有双DGV。总体而言，533例患者中有83例（16%）经历了危及生命的心律失常事件（40岁[33-51]），533例患者中有14例（3%）经历了终末期心衰（57岁[50-60]）。多变量分析表明，与非错义PKP2变异相比，非错义DSP变异(风险比[HR]， 2.3 [95% CI, 1.3-4.1]；P=0.008)， DSP热点区域的错义变异(HR, 2.7 [95% CI, 1.2-6.2]；P=0.010)和PKP2 (HR, 3.6 [95% CI, 2.0-6.5]；PP=0.021)和双dgv (HR, 3.4 [95% CI, 1.7-6.9]；PDSP变异(HR, 5.0 [95% CI, 1.5-18.2]；P=0.009)和双dgv (HR, 4.7 [95% CI, 1.0-19.3]；P=0.044)也与终末期心衰风险增加相关。结论：在dgv携带者中，基因型与心律失常和心衰结局相关，变异的类型和位置进一步调节了自然史。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation 医学-外周血管病

CiteScore

45.70

自引率

2.10%

发文量

1473

审稿时长

2 months

期刊介绍： Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.