Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
Europace. 2024 Jun 3;26(6). doi: 10.1093/europace/euae153.
Patients with mutations in SCN5A encoding NaV1.5 often display variable severity of electrical and structural alterations, but the underlying mechanisms are not fully elucidated. We here investigate the combined modulatory effect of genetic background and age on disease severity in the Scn5a1798insD/+ mouse model.
In vivo electrocardiogram and echocardiograms, ex vivo electrical and optical mapping, and histological analyses were performed in adult (2-7 months) and aged (8-28 months) wild-type (WT) and Scn5a1798insD/+ (mutant, MUT) mice from the FVB/N and 129P2 inbred strains. Atrio-ventricular (AV) conduction, ventricular conduction, and ventricular repolarization are modulated by strain, genotype, and age. An aging effect was present in MUT mice, with aged MUT mice of both strains showing prolonged QRS interval and right ventricular (RV) conduction slowing. 129P2-MUT mice were severely affected, with adult and aged 129P2-MUT mice displaying AV and ventricular conduction slowing, prolonged repolarization, and spontaneous arrhythmias. In addition, the 129P2 strain appeared particularly susceptible to age-dependent electrical, functional, and structural alterations including RV conduction slowing, reduced left ventricular (LV) ejection fraction, RV dilatation, and myocardial fibrosis as compared to FVB/N mice. Overall, aged 129P2-MUT mice displayed the most severe conduction defects, RV dilatation, and myocardial fibrosis, in addition to the highest frequency of spontaneous arrhythmia and inducible arrhythmias.
Genetic background and age both modulate disease severity in Scn5a1798insD/+ mice and hence may explain, at least in part, the variable disease expressivity observed in patients with SCN5A mutations. Age- and genetic background-dependent development of cardiac structural alterations furthermore impacts arrhythmia risk. Our findings therefore emphasize the importance of continued assessment of cardiac structure and function in patients carrying SCN5A mutations.
编码 NaV1.5 的 SCN5A 基因突变的患者常表现出电和结构改变的不同严重程度，但潜在机制尚未完全阐明。本研究旨在探讨遗传背景和年龄对 Scn5a1798insD/+ 小鼠模型疾病严重程度的综合调节作用。
在 FVB/N 和 129P2 近交系成年（2-7 个月）和老年（8-28 个月）野生型（WT）和 Scn5a1798insD/+（突变型，MUT）小鼠中进行了体内心电图和超声心动图、离体电和光学标测以及组织学分析。房室（AV）传导、心室传导和心室复极受品系、基因型和年龄的调节。MUT 小鼠存在老化效应，两种品系的老年 MUT 小鼠均表现出 QRS 间期延长和右心室（RV）传导减慢。129P2-MUT 小鼠受影响严重，成年和老年 129P2-MUT 小鼠表现出 AV 和心室传导减慢、复极延长和自发性心律失常。此外，与 FVB/N 小鼠相比，129P2 品系对年龄依赖性电、功能和结构改变特别敏感，包括 RV 传导减慢、左心室（LV）射血分数降低、RV 扩张和心肌纤维化。总体而言，与 FVB/N 小鼠相比，老年 129P2-MUT 小鼠表现出最严重的传导缺陷、RV 扩张和心肌纤维化，以及最高的自发性心律失常和可诱导性心律失常频率。
遗传背景和年龄均调节 Scn5a1798insD/+ 小鼠的疾病严重程度，因此至少部分解释了 SCN5A 基因突变患者中观察到的可变疾病表型。心脏结构改变的年龄和遗传背景依赖性发展进一步影响心律失常风险。因此，本研究结果强调了在携带 SCN5A 基因突变的患者中持续评估心脏结构和功能的重要性。
