Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization.
Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents (IKs) or rapidly activating K+ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs) prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.
Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Coro West 51031 Hoppin St., Providence, RI 02903, USA.
Katja E
KE
Odening
Omar
O
Hyder
Leonard
L
Chaves
Lorraine
L
Schofield
Michael
M
Brunner
Malcolm
M
Kirk
Manfred
M
Zehender
Xuwen
X
Peng
Gideon
G
Koren
D000200:Action Potentials; D000777:Anesthetics / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010597:Pharmacogenetics; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000633:toxicity*; D011817:Rabbits; D018570:Risk Assessment; D029597:Romano-Ward Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors
D000777:Anesthetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers