Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Abstract

Background Cardiac device implantation can be complicated by inability to adequately place leads because of significant lead capture issues. This study sought to determine whether there are genetic bases that underlie poor lead capture. Methods and Results Retrospective review of all patients with structurally normal hearts who underwent new device implantation at Texas Children's Hospital between 2009 and 2014 was performed. Patients with inability to capture at 10 V or a final capture threshold ≥3 V at 0.4 ms during implant were analyzed. Among a total of 136 patients (median age, 13 years; range, 3 days to 46 years), 11 patients (8.1%) who underwent dual chamber device implantation had elevated thresholds in the atria (4), ventricle (3), or both chambers (4; atrial-lead threshold, 4.7±4.3 versus 0.7±0.3 V; ventricular-lead, 3.0±3.3 versus 0.7±0.3 V). All 11 patients presented with sinus node dysfunction and 10 had atrial arrhythmias. At implant, inability to find atrial capture was seen in 4 patients. Three demonstrated intermittent complete loss of ventricular capture after implantation: 1 has recurrent syncope, 2 eventually died. Genetic testing performed in 10 demonstrated 7 patients with 6 distinct SCN5A mutations, all predicted to be severe loss-of-function mutations by bioinformatic analyses. In the remaining patients, although putative pathogenic mutations were not found, multiple SCN5A polymorphisms were identified in 2 and a desmin mutation in 1. Conclusions This study suggests that significant capture issues at implant may be because of loss-of-function SCN5A mutations, providing new insights into SCN5A function. Recognition of this association may be critical for planning device implantation strategies and patient follow-up.

Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current

“…Yet despite this traditional dichotomy, there is marked overlap in the clinical presentation of patients [34]. The complexity of Nav1.5-associated diseases continues to increase as recent evidence suggestions that loss of function SCN5A mutations have been associated with sinus arrhythmia and poor pacemaker capture [35].…”

Mutations in NaV1.5 Reveal Calcium-Calmodulin Regulation of Sodium Channel

“…Although I Na does not contribute to the action potential of pacemaker cells, its presence in the periphery of the sinoatrial node can modulate impulse conduction and heart rate (Kodama et al, 1997). Hence, loss-of-function mutations in SCN5A can result in a nodal dysfunction (Benson et al, 2003; Lei et al, 2008; Gui et al, 2010; Ziyadeh-Isleem et al, 2014; Chiang et al, 2015; Milanesi et al, 2015).…”

Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

“…Шесть (43%) пробандов с известными мута-циями Q1118X [16][17][18] и G1743R [18][19][20][21], а так-же с новыми миссенс-мутацией F919S, нонсенс-мутацией E1574Х и мутациями сплайсинга IVS16DS-5A>G и IVS24AS+1G>A демонстриро-вали изолированный фенотип синдрома Бруга-да. У них отмечалось синкопальное течение за-болевания с личным (Q1118X, IVS24AS+1G>A, G1743R) и семейным (за исключением F919S, Q1118X и E1574Х) анамнезом ВСС, спонтанным Бругада-паттерном I типа на ЭКГ, в связи с чем необходимость в фармакологических пробах от-сутствовала.…”