Ishikawa Taisuke, Ohno Seiko, Murakami Takashi, Yoshida Kentaro, Mishima Hiroyuki, Fukuoka Tetsuya, Kimoto Hiroki, Sakamoto Risa, Ohkusa Takafumi, Aiba Takeshi, Nogami Akihiko, Sumitomo Naokata, Shimizu Wataru, Yoshiura Koh-Ichiro, Horigome Hitoshi, Horie Minoru, Makita Naomasa
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Heart Rhythm. 2017 May;14(5):717-724. doi: 10.1016/j.hrthm.2017.01.020. Epub 2017 Jan 17.
Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown.
The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations.
We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases.
We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001).
SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.
家族性病态窦房结综合征（SSS）通常归因于编码心脏钠通道SCN5A和起搏通道HCN4的基因突变。我们之前发现，携带SCN5A突变的SSS表现出早期发病且男性居多。尽管最近有关于HCN4突变导致的SSS患者发生房颤（AF）和左心室心肌致密化不全（LVNC）并发症的报道，但其总体临床谱仍不清楚。
本研究旨在调查携带HCN4突变的SSS患者的临床和人口统计学特征。
我们对38个无亲缘关系的SSS家族进行了基因筛查，并通过膜片钳技术对突变的SCN5A和HCN4通道进行了功能分析。我们还通过对48例携带HCN4（n = 16）和SCN5A（n = 32）突变的SSS先证者（包括先前报道的病例）以及538例散发性SSS病例进行荟萃分析，评估了家族性SSS的临床特征。
在我们的家族性SSS队列中，我们鉴定出两个HCN4和三个SCN5A功能丧失性突变。对HCN4突变携带者的荟萃分析显示，其诊断时的年龄（39.1±21.7岁）显著低于散发性SSS患者（74.3±0.4岁；P<.001），但显著高于SCN5A突变携带者（20.0±17.6岁；P =.003）。此外，与SCN5A突变携带者（17.8±16.5岁；P<.001）相比，HCN4突变携带者更常伴有AF（43.8%）和LVNC（50%），且起搏器植入时的年龄更大（43.5±22.1岁）。
携带HCN4突变的SSS可能形成一个独特的SSS亚组，其特征为青春期后临床表现较早，且常伴有AF和LVNC。
