Cellular basis for atrial fibrillation in an experimental model of short QT1: implications for a pharmacological approach to therapy.
BACKGROUND
Short QT (SQT) syndrome (SQT) 1 is an inherited sudden death syndrome often associated with atrial fibrillation (AF). We examined the cellular basis for AF in a newly developed experimental atrial model of SQT1.


METHODS
Action potentials (APs) were recorded from the pectinate muscle (PM) and crista terminalis (CT) regions of coronary-perfused canine right atrial preparations, together with a pseudoelectrocardiogram. The I(Kr) agonist PD-118057 (20 microM) was used to mimic the gain of function in I(Kr) known to underlie SQT1.


RESULTS
The I(Kr) agonist significantly abbreviated the AP duration (APD) of CT and PM and of the effective refractory period (ERP) measured in PM (n = 28). Spatial dispersion of repolarization (SDR), defined as inter-regional differences of APD, increased from 27 +/- 17 ms to 51 +/- 32 ms (P = .002; n = 28). AF could be induced by a single premature stimulus after but not before exposure to PD-118057 in 26/28 (93%) preparations. Quinidine (10 microM), which prolonged APD and ERP, but not lidocaine (20 microM) or E-4031 (5 microM), which prolonged only ERP or APD, respectively, was effective in preventing the PD-118057-mediated AF. In the presence of PD-118057, isoproterenol (100 nM) further abbreviated both APD and ERP and facilitated induction of sustained AF in five of six preparations.


CONCLUSIONS
The I(Kr) agonist recapitulates the electrophysiologic and arrhythmic manifestations of SQT1. Abbreviation of APD and ERP and amplification of SDR predispose to the development of AF by creating the substrate for reentry. Quinidine, but not E-4031 or lidocaine, was effective in preventing AF in this setting.
Nof
Eyal
E
Masonic Medical Research Laboratory, Utica, NY, USA.
Burashnikov
Alexander
A
Antzelevitch
Charles
C
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*; D002722:Chlorobenzenes; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D007545:Isoproterenol / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
C517140:2-(4-(2-(3,4-dichlorophenyl)ethyl)phenylamino)benzoic acid; D000889:Anti-Arrhythmia Agents; D002722:Chlorobenzenes; D062367:ortho-Aminobenzoates; D008012:Lidocaine; D011802:Quinidine; D007545:Isoproterenol