{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yang T"],"funding":["BLRD VA","American Heart Association-American Stroke Association","NHLBI NIH HHS","NIGMS NIH HHS"],"pagination":["224-34"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4101031"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["130(3)"],"pubmed_abstract":["<h4>Background</h4>New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.<h4>Methods and results</h4>Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).<h4>Conclusions</h4>Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability."],"journal":["Circulation"],"pubmed_title":["Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current."],"pmcid":["PMC4101031"],"funding_grant_id":["R01 HL049989","R01 HL104040","U01 HL104040","T32 GM007569","R01 HL071670","R01 HL088635","I01 BX000771","U01 HL088635","16FTF30130005","U01 HL049989","GM007569","U01 HL071670","U19 HL065962"],"pubmed_authors":["Knollmann BC","Roden DM","Stroud DM","Yang T","Chun YW","Mosley JD","Hong C"],"additional_accession":[]},"is_claimable":false,"name":"Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.","description":"<h4>Background</h4>New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.<h4>Methods and results</h4>Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).<h4>Conclusions</h4>Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Jul","modification":"2024-11-20T16:28:10.073Z","creation":"2019-03-27T01:32:11Z"},"accession":"S-EPMC4101031","cross_references":{"pubmed":["24895457"],"doi":["10.1161/circulationaha.113.007765","10.1161/CIRCULATIONAHA.113.007765"]}}