Darkow Elisa, Nguyen Thong T, Stolina Marina, Kari Fabian A, Schmidt Constanze, Wiedmann Felix, Baczkó István, Kohl Peter, Rajamani Sridharan, Ravens Ursula, Peyronnet Rémi
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, Germany.
Medical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
Front Physiol. 2021 Apr 1;12:650964. doi: 10.3389/fphys.2021.650964. eCollection 2021.
In search of more efficacious and safe pharmacological treatments for atrial fibrillation (AF), atria-selective antiarrhythmic agents have been promoted that target ion channels principally expressed in the atria. This concept allows one to engage antiarrhythmic effects in atria, but spares the ventricles from potentially proarrhythmic side effects. It has been suggested that cardiac small conductance Ca-activated K (SK) channels may represent an atria-selective target in mammals including humans. However, there are conflicting data concerning the expression of SK channels in different stages of AF, and recent findings suggest that SK channels are upregulated in ventricular myocardium when patients develop heart failure. To address this issue, RNA-sequencing was performed to compare expression levels of three SK channels (, , and ) in human atrial and ventricular tissue samples from transplant donor hearts (no cardiac disease), and patients with cardiac disease in sinus rhythm or with AF. In addition, for control purposes expression levels of several genes known to be either chamber-selective or differentially expressed in AF and heart failure were determined. In atria, as compared to ventricle from transplant donor hearts, we confirmed higher expression of and , and lower expression of , whereas and were statistically not differentially expressed. Overall expression of was low compared to and . Comparing atrial tissue from patients with AF to sinus rhythm samples we saw downregulation of in AF, as previously reported. When comparing ventricular tissue from heart failure patients to non-diseased samples, we found significantly increased ventricular expression of in heart failure, as previously published. The other channels showed no significant difference in expression in either disease. Our results add weight to the view that SK channels are not likely to be an atria-selective target, especially in failing human hearts, and modulators of these channels may prove to have less utility in treating AF than hoped. Whether targeting SK1 holds potential remains to be elucidated.
为了寻找更有效、安全的心房颤动（AF）药物治疗方法，人们研发了主要作用于心房中主要表达的离子通道的心房选择性抗心律失常药物。这一理念使得药物能够在心房发挥抗心律失常作用，同时避免心室受到潜在的促心律失常副作用影响。有人提出，心脏小电导钙激活钾（SK）通道可能是包括人类在内的哺乳动物的心房选择性靶点。然而，关于SK通道在房颤不同阶段的表达存在相互矛盾的数据，并且最近的研究结果表明，当患者发生心力衰竭时，SK通道在心室心肌中上调。为了解决这个问题，我们进行了RNA测序，以比较来自移植供体心脏（无心脏病）、窦性心律或房颤心脏病患者的人类心房和心室组织样本中三种SK通道（SK1、SK2和SK3）的表达水平。此外，为了进行对照，我们还测定了一些已知在心房或心室中具有选择性表达，或在房颤和心力衰竭中差异表达的基因的表达水平。与移植供体心脏的心室相比，我们证实在心房中SK1和SK2的表达较高，而SK3的表达较低，而SK4和SK5在统计学上没有差异表达。与SK1和SK2相比，SK3的总体表达较低。将房颤患者的心房组织与窦性心律样本进行比较，我们发现如先前报道的那样，房颤中SK2表达下调。当将心力衰竭患者的心室组织与非患病样本进行比较时，我们发现如先前发表的那样，心力衰竭时心室中SK2的表达显著增加。其他通道在两种疾病中的表达均无显著差异。我们的结果进一步支持了这样一种观点，即SK通道不太可能是心房选择性靶点，尤其是在衰竭的人类心脏中，并且这些通道的调节剂在治疗房颤方面可能不如预期的那样有效。靶向SK1是否具有潜力仍有待阐明。
