HCN212-channel biological pacemakers manifesting ventricular tachyarrhythmias are responsive to treatment with If blockade
HCN212-channel biological pacemakers manifesting ventricular tachyarrhythmias are responsive to treatment with If blockade
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DOI：
10.1016/j.hrthm.2007.09.028
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发表时间：
2008-02-01
期刊：
影响因子：
5.5
通讯作者：
Rosen, MichaeL R.
中科院分区：
文献类型：
--
作者：
Plotnikov, Alexei N.;Bucchi, Annalisa;Rosen, MichaeL R.
背景生物起搏器的一个潜在问题是它们可能发生的故障，这可能会导致室性心动过速（VT）。目的本研究的目的是验证我们的假设，即如果VT使基于HCN通道的生物起搏器的植入复杂化，它们将被起搏器电流的抑制剂抑制，方法：我们构建了一个含有小鼠HCN 2的N-和C-末端以及小鼠HCN 1的跨膜区的嵌合通道（HCN 212），并将其植入HEK 293细胞中。48小时后，在全细胞膜片钳记录中，3 μ M伊伐布雷定（IVB）诱导的平均稳态阻滞显示HCN 1 = HCN 212> HCN 2电流。然后将HCN 212腺病毒构建体植入11只犬的犬左束支分支中。通过射频消融建立完全房室传导阻滞，并植入心室按需电子起搏器（VVI 45 bpm）。心电图，24小时Hotter监测，和起搏器日志记录检查进行了11 day.Results所有狗发生快速VT（> 120 bpm，最大速率= 285 +/- 37 bpm）在植入后0.9 +/- 0.3天，持续通过5 +/- 1天。在快速VT期间给予IVB，1 mg/kg，持续5分钟，24小时后，3只犬接受第二次给药。白色室性心动过速均在3.4 ± 0.6 min内终止，IVB对窦性心率无影响。结论：（1）IVB等抑制If的药物可控制If相关的心动过速，但IVB等抑制If的药物可控制If相关的心动过速，但IVB等抑制If的药物可控制If相关的心动过速。（2）体外实验表明，IVB对HCN 1和HCN 212亚型的稳态抑制作用大于对HCN 4亚型的稳态抑制作用;（3）与窦性心律相比，HCN 212注射部位引起的VT更容易受到抑制。这表明，在异位起搏功能的浓度下，IVB的选择性高于基于HCN 4的起搏功能。这可能会带来治疗益处。
BACKGROUND A potential concern about biological pacemakers is their possible malfunction, which might create ventricular tachycardias (VTs).OBJECTIVE The purpose of this study was to test our hypothesis that should VTs complicate implantation of HCN-channel-based biological pacemakers, they would be suppressed by inhibitors of the pacemaker current, If.METHODS We created a chimeric channel (HCN212) containing the N- and C-termini of mouse HCN2 and the transmembrane region of mouse HCN1 and implanted it in HEK293 cells. Forty-eight hours later, in whole-cell patch clamp recordings, mean steady state block induced by 3 mu M ivabradine (IVB) showed HCN1 = HCN212 > HCN2 currents. The HCN212 adenoviral construct was then implanted into the canine Left bundle branch in 11 dogs. Complete AV block was created via radiofrequency ablation, and a ventricular demand electronic pacemaker was implanted (VVI 45 bpm). Electrocardiogram, 24-hour Hotter monitoring, and pacemaker log record check were performed for 11 days.RESULTS All dogs developed rapid VT (> 120 bpm, maximum rate = 285 +/- 37 bpm) at 0.9 +/- 0.3 days after implantation that persisted through 5 +/- 1 days. IVB, 1 mg/kg over 5 minutes, was administered during rapid VT, and three dogs received a second dose 24 hours later. White VT terminated with IBV in all instances within 3.4 +/- 0.6 minutes, no effect of IVB on sinus rate was noted.CONCLUSION We conclude that (1) If-associated tachyarrhythmias-if they occur with HCN-based biological pacemakers-can be controlled with If-inhibiting drugs such as IVB; (2) in vitro, IVB appears to have a greater steady state inhibiting effect on HCN1 and HCN212 isoforms than on HCN4; and (3) VT originating from the HCN212 injection site is suppressed more readily than sinus rhythm. This suggests a selectivity of IVB at the concentration attained for ectopic over HCN4-based pacemaker function. This might confer a therapeutic benefit.