Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3
Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3
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DOI：
10.1093/cvr/cvq029
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发表时间：
2010-07-01
影响因子：
10.8
通讯作者：
Kirchhof, Paulus
中科院分区：
文献类型：
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作者：
Fabritz, Larissa;Damke, Dierk;Kirchhof, Paulus
在携带钠通道突变（LQT 3）的长QT综合征患者中的临床观察表明，副交感神经刺激引起的心动过缓可能诱发尖端扭转型室性心动过速（TdP）。β-肾上腺素受体阻滞剂在LQT 3 than in other forms of the disease.我们研究了体内和体外自主神经调节对心律失常的影响，并通过放射自显影术定量了杂合小鼠中的交感神经支配，杂合小鼠的Scn 5a基因编码心脏钠通道并增加了晚期钠电流（LQT 3小鼠）。胆碱能刺激卡巴胆碱引起bigemini和TdP在自由漫游LQT 3小鼠。没有心律失常引起的身体压力，精神压力，异丙肾上腺素，或阿托品。在离体心脏跳动中，卡巴胆碱本身不延长动作电位，但引起心动过缓和频率依赖性动作电位延长。毒蕈碱抑制剂AFDX 116可预防卡巴胆碱对心率和心律失常的影响。β-肾上腺素受体刺激抑制心律失常，缩短频率校正动作电位时程，增加频率，并使基因型之间的晚期钠电流差异最小化。在LQT 3心脏中β-肾上腺素受体密度降低。艾司洛尔、普萘洛尔或慢性普萘洛尔在体内的急性β肾上腺素受体阻滞并不能抑制心律失常。慢性氟卡尼预处理可预防心律失常（P均< 0.05），胆碱能刺激通过触发心动过缓引起LQT 3模型心律失常。β-肾上腺素受体密度降低，β-肾上腺素受体阻滞剂不能预防心律失常。钠通道阻滞和β-肾上腺素受体刺激通过缩短复极和最小化晚期钠电流差异来抑制心律失常。
Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (delta KPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05).Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.