■尽管长QT综合征的临床管理取得了重大进展,一些患者没有得到β受体阻滞剂治疗的充分保护.美西律是一种众所周知的钠通道阻滞剂,在钠通道介导的长QT综合征3型患者中具有已证实的疗效。我们的目的是使用源自患者特异性人诱导多能干细胞的心肌细胞评估美西律在2型长QT综合征(LQT2)中的疗效。转基因LQT2兔模型,和LQT2患者。
■心率校正场电位持续时间,QTc的代理人,在来自2例LQT2患者的人诱导多能干细胞中测量(KCNH2-p。A561V,KCNH2-p.R366X)使用多孔多电极阵列系统在美西律之前和之后。在从转基因LQT2兔(KCNH2-p)分离的心肌细胞中评估了90%复极化时的动作电位持续时间(APD90)。G628S)在基线和美西律应用后。对96例LQT2患者给予美西律治疗。在QTc缩短≥40ms的情况下,患者被定义为应答者。通过泊松回归模型评估了美西律的抗心律失常疗效。
■急性接受美西律治疗后,与二甲基亚砜对照相比,来自两名LQT2患者的人诱导多能干细胞显示心率校正场电位持续时间显著缩短.在从LQT2兔分离的心肌细胞中,急性美西律显著缩短APD90(ΔAPD缩短113ms),表明在不同的LQT2模型系统中,美西律介导的缩短作用很强。长期(n=60)或在急性口服药物测试后(n=36)对96例LQT2患者给予了美西律:65%的患者仅长期服用美西律,75%的患者进行了急性口服测试是应答者。试验过程中基础QTc与ΔQTc之间存在显着相关性(r=-0.8;P<0.001)。口服药物测试正确预测了93%的患者的长期疗效。Mexiletine将年平均事件发生率从0.10(95%CI,0.07-0.14)降低至0.04(95%CI,0.02-0.08),发病率比为0.40(95%CI,0.16-0.84),反映了事件发生率降低了60%(P=0.01)。
■美西律显著缩短LQT2人诱导多能干细胞的心脏复极化,在LQT2兔子模型中,在大多数LQT2患者中。此外,美西律显示抗心律失常疗效。因此,美西律应被视为LQT2高危患者常规治疗的有效治疗选择。
UNASSIGNED: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of
mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.
UNASSIGNED: Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD90) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application.
Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of
mexiletine was evaluated by a Poisson regression model.
UNASSIGNED: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD90 by 113 ms, indicating a strong
mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (r= -0.8; P<0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate (P=0.01).
UNASSIGNED: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore,
mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.