目的:具有编码NaV1.5的SCN5A突变的患者通常表现出不同程度的电和结构改变,但是潜在的机制还没有完全阐明。我们在这里研究了Scn5a1798insD/小鼠模型中遗传背景和年龄对疾病严重程度的联合调节作用。
方法:体内心电图和超声心动图,离体电学和光学测绘,在来自FVB/N和129P2近交株的成年(2-7个月)和年龄(8-28个月)野生型(WT)和Scn5a1798insD/(MUT)小鼠中进行了组织学分析。心房-心室(AV)传导,心室传导,心室复极化由应变调节,基因型,和年龄。MUT小鼠存在衰老效应,两种菌株的老年MUT小鼠均显示QRS间隔延长和右心室(RV)传导减慢。129P2-MUT小鼠受到严重影响,成年和老年129P2-MUT小鼠表现出AV-和心室传导减慢,长时间的复极化,和自发性心律失常.此外,129P2菌株似乎对年龄依赖性电特别敏感,功能,和结构改变,包括RV传导减慢,左心室(LV)射血分数降低,RV扩张,和与FVB/N小鼠相比的心肌纤维化。总的来说,129P2-MUT小鼠表现出最严重的传导缺陷,RV扩张,和心肌纤维化,除了自发性心律失常和诱导性心律失常的频率最高。
结论:遗传背景和年龄均可调节Scn5a1798insD/+小鼠的疾病严重程度,因此可以解释,至少在某种程度上,在SCN5A突变患者中观察到的可变疾病表达。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,我们的发现强调了持续评估SCN5A突变患者心脏结构和功能的重要性。
OBJECTIVE: 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.
RESULTS: 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.
CONCLUSIONS: 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.