Pathological and Comprehensive Genetic Investigation of Autopsy Cases of Idiopathic Bradyarrhythmia
Pathological and Comprehensive Genetic Investigation of Autopsy Cases of Idiopathic Bradyarrhythmia
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DOI：
10.1253/circj.cj-22-0397
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发表时间：
2023-01-01
影响因子：
3.3
通讯作者：
Nishida, Naoki
中科院分区：
文献类型：
--
作者：
Hata, Yukiko;Ichimata, Shojiro;Nishida, Naoki
背景：特发性缓慢性心律失常被认为是由于心脏传导系统（CCS）在衰老过程中的病理性变性。有似乎没有全面的遗传调查，在特发性缓慢性心律失常患者。方法和结果：10例尸检晚期缓慢性心律失常（6男4女;年龄：70-94岁，81.5 +/- 6.9岁; 5例窦房结功能障碍[SND]和完全性房室传导阻滞[CAVB]）进行了遗传调查，通过使用全外显子组测序。CCS的形态学分析与性别，年龄和共病匹配的对照病例进行。结果，SND和CAVB分别出现结细胞和远端房室传导系统的严重缺失。CAVB患者房室结和希氏束近端传导组织丢失不明显。在3例CAVB和2例SND病例中共发现13种杂合潜在变异。在这13个变异体中，4个在已知的进行性心脏传导疾病相关基因中是错义的：GATA 4和RYR 2。在其余的9个变异体中，5个是功能缺失突变，具有高度可能的致病性。结论：除了在年龄增长过程中心脏选择性脆弱区域的退行性变化外，CCS的脆弱性，这可能与“小作用的罕见变异体”有关，也可能是CCS退行性变的一个促成因素，导致“特发性”缓慢性心律失常。
Background: Idiopathic bradyarrhythmia is considered to be due to pathological degeneration of the cardiac conduction system (CCS) during aging. There appears to have been no comprehensive genetic investigations in patients with idiopathic bradyarrhythmia.Methods and Results: Ten autopsy cases with advanced bradyarrhythmia (6 men and 4 women; age: 70-94 years, 81.5 +/- 6.9 years; 5 cases each of sinus node dysfunction [SND] and complete atrioventricular block [CAVB]) were genetically investigated by using whole-exome sequencing. Morphometric analysis of the CCS was performed with sex-, age- and comorbidity-matched control cases. As a result, severe loss of nodal cells and distal atrioventricular conduction system were found in SND and CAVB, respectively. However, the conduction tissue loss was not significant in either the atrioventricular node or the proximal bundle of His in CAVB cases. A total of 13 heterozygous potential variants were found in 3 CAVB and 2 SND cases. Of these 13 variants, 4 were missense in the known progressive cardiac conduction disease-related genes: GATA4 and RYR2. In the remaining 9 variants, 5 were loss-offunction mutation with highly possible pathogenicity.Conclusions: In addition to degenerative changes of selectively vulnerable areas in the heart during advancing age, the vulnerability of the CCS, which may be associated with "rare variants of small effect,'' may also be a contributing factor to the degeneration of CCS, leading to ''idiopathic'' bradyarrhythmia.