Polyunsaturated fatty acids as anti-arrhythmic agents.

项目摘要 心脏动作电位主要由钠通道和钙通道产生，它们使心肌细胞的钙离子通道减少。 膜电位，并通过钾通道，恢复膜电位和终止 动作电位主要的心脏钾电流之一是缓慢激活钾电流IKs， 有助于动作电位终止。在IKs中发现了超过300种不同的遗传突变 导致患者心律失常的通道。IKs通道调节心脏收缩的长度 而降低IKs通道活性的突变导致心脏收缩延长， 导致长QT综合征反过来，长QT综合征是室颤和突发性心律失常的危险因素。 心源性死亡我们已经确定了一个家族的化合物，激活IKs通道，并具有抗炎作用。 当应用于心肌细胞时。我们将在这里测试这些化合物是否恢复行动的长度 在长QT综合征患者的人心肌细胞中的潜力。我们还将测试这些的效果 化合物在离体动物心脏中和在具有长QT综合征突变的转基因动物中的体内作用， 以便开发恢复QT间期的药物，并在未来的临床试验中进行测试。我们还将 使用双电极电压钳在异源表达的IKs通道上测试这些化合物的变体， 以确定这些化合物对IKs通道作用的重要结构。我们亦会 IKs通道的突变以确定这些化合物的结合位点。最后，我们将测试 这些化合物可以逆转不同类型的长QT综合征引起的IKs通道的不同缺陷 突变这将在异源系统和人心肌细胞中进行测试。预期 这些实验的结果将提供概念验证，即这类化合物可以缩短 心脏动作电位和防止心律失常，并将提供初步的动物模型数据，开始 这些化合物的临床试验。我们预计，这种新的抗疟疾药物的开发将导致 更好地治疗心律失常和预防LQTS患者的心源性猝死。

Project Summary The cardiac action potential is primarily generated by sodium and calcium channels, which depolarize the membrane potential, and by potassium channels that repolarize the membrane potential and terminate the action potential. One of the major cardiac potassium currents is the slowly activating potassium current IKs that contribute to the action potential termination. Over 300 different inherited mutations have been found in IKs channels that cause cardiac arrhythmias in patients. IKs channels regulate the length of the cardiac contraction and mutations that decreases the activity of IKs channels result in a prolongation of the cardiac contraction, leading to Long QT Syndrome. In turn, Long QT syndrome is a risk factor for ventricular fibrillation and sudden cardiac death. We have identified a family of compounds that activate IKs channels and are antiarrhythmic when applied to cardiomyocytes. We will here test whether these compounds restores the length of the action potential in human cardiomyocytes from Long QT Syndrome patients. We will also test the effect of these compounds on in ex vivo animal hearts and in vivo in transgenic animals with Long QT Syndrome mutations, in order to develop drug that restores the QT interval and that can be tested in future clinical trial. We will also test variants of these compounds on heterologously expressed IKs channels using two-electrode voltage clamp, to determine the important structure of these compounds for their effects on IKs channels. We will also make mutations of IKs channels to determine the binding site of these compounds. Finally, we will test the efficacy of these compounds to reverse different defects in IKs channels caused by different types of Long QT syndrome mutations. This will be tested both in heterologous systems and in human cardiomyocytes. The anticipated results of these experiments will provide proof-of-concept that this family of compounds can shorten the cardiac action potential and prevent cardiac arrhythmia, and will provide preliminary animal model data to start clinical trials of these compounds. We anticipate that this development of new anti-arrhythmic drugs will lead to better treatments of cardiac arrhythmias and the prevention of sudden cardiac deaths in LQTS patients.