Department of Legal Medicine, Faculty of Medicine, University of Toyama.
Department of Pediatrics, Faculty of Medicine, University of Toyama.
Circ J. 2022 Dec 23;87(1):111-119. doi: 10.1253/circj.CJ-22-0397. Epub 2022 Sep 7.
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.
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-of-function mutation with highly possible pathogenicity.
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.
特发性心动过缓被认为是由于心脏传导系统（CCS）在衰老过程中的病理性退行性变所致。似乎尚未对特发性心动过缓患者进行全面的遗传研究。
对 10 例有晚期心动过缓的尸检病例（6 名男性和 4 名女性；年龄：70-94 岁，81.5±6.9 岁；窦房结功能障碍[SND]和完全性房室传导阻滞[CAVB]各 5 例）进行了全外显子组测序的遗传研究。对 CCS 进行了形态计量学分析，并与性别、年龄和合并症相匹配的对照病例进行了比较。结果发现，SND 和 CAVB 分别存在严重的结细胞和远端房室传导系统丢失。然而，在 CAVB 病例中，房室结或近端希氏束的传导组织丢失并不明显。在 3 例 CAVB 和 2 例 SND 病例中发现了 13 个杂合潜在变异。这 13 个变异中，4 个是已知进行性心脏传导疾病相关基因中的错义变异：GATA4 和 RYR2。在其余 9 个变异中，有 5 个是功能丧失性突变，具有高度可能的致病性。
除了随着年龄的增长，心脏选择性脆弱区域的退行性变化外，CCS 的脆弱性可能与“罕见小效应变异”有关，这也可能是 CCS 退化导致“特发性”心动过缓的一个促成因素。
