Ezeani Martin, Elom Sunday
Department of Chemical Pathology, Faculty of Health Science and Technology, College of Health Science, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria.
Department of Medical Biochemistry, Federal University Ndufu-Alike, Ikwo, Ebonyi State, Nigeria.
Open Heart. 2017 Dec 10;4(2):e000596. doi: 10.1136/openhrt-2017-000596. eCollection 2017.
The incidence of QT prolongation and torsades de pointes is on the rise due to the use of cardiovascular and non-cardiovascular drugs. Robust efforts have been made and are still ongoing to understand the underlying mechanisms that can enhance or prevent the development of drug-induced proarrhythmia. A caveat in the use of antiarrhythmic drugs is the ability to obtain safe action potential prolongation therapeutic effects, through IKr blockade. This remains as yet completely unachievable, as blockers of the potassium channel have not provided complete safe measures. Because of this, efforts at understanding the mechanisms of proarrhythmia have continued. PI3K/Akt signalling pathway appears to possess some potential advantage in this regard because cardiomyocytes intracellular dialysis with phosphatidylinositol (3,4,5)-trisphosphate (PIP3) normalises ion channel alterations and eliminates proarrhythmic features. However, there is a conundrum. Increased activities of PIP3 signalling can enhance cell proliferation and survival, and reduced activities of PIP3 signalling can lead to proarrhythmia. PI3K inhibitors used in cancer treatment have been found to cause proarrhythmia, and represent a potential avenue for the research and evaluation of potential effectiveness of a battery of antiarrhythmic and cancer drugs that are either currently in use or in development. Despite this knowledge, limited information is available on PI3K/Akt signalling and arrhythmogenesis. This highlights the need to search for new ways to improve testing of antiarrhythmic drugs and increase our understanding in PI3K/Akt signalling and arrhythmogenesis.
由于心血管药物和非心血管药物的使用，QT间期延长和尖端扭转型室速的发生率正在上升。人们已经并仍在做出巨大努力来了解可增强或预防药物性心律失常发生的潜在机制。使用抗心律失常药物时的一个注意事项是，能否通过抑制IKr获得安全的动作电位延长治疗效果。但这至今仍完全无法实现，因为钾通道阻滞剂尚未提供完全安全的措施。因此，对心律失常发生机制的研究仍在继续。PI3K/Akt信号通路在这方面似乎具有一些潜在优势，因为用磷脂酰肌醇(3,4,5)-三磷酸(PIP3)对心肌细胞进行细胞内透析可使离子通道改变正常化并消除心律失常特征。然而，存在一个难题。PIP3信号活性增加可增强细胞增殖和存活，而PIP3信号活性降低可导致心律失常。已发现用于癌症治疗的PI3K抑制剂会引起心律失常，这代表了一条研究和评估一系列现有或正在研发的抗心律失常药物和癌症药物潜在有效性的潜在途径。尽管有这些认识，但关于PI3K/Akt信号与心律失常发生的信息仍然有限。这凸显了寻找新方法来改进抗心律失常药物测试并增进我们对PI3K/Akt信号与心律失常发生理解的必要性。
