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Necessity to evaluate PI3K/Akt signalling pathway in proarrhythmia
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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729307/ https://www.ncbi.nlm.nih.gov/pubmed/29259786 http://dx.doi.org/10.1136/openhrt-2017-000596 |
Sumario: | 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. |
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