Cytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome.
BACKGROUND
Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity. Previous ex vivo studies in drug-induced Andersen-Tawil syndrome (DI-ATS1) models have proposed that arrhythmia propensity in DI-ATS1 derives from cytosolic Ca(2+) ([Ca(2+)](i)) accumulation leading to increased triggered activity.


OBJECTIVE
The purpose of this study was to test the hypothesis that elevated [Ca(2+)](i) with concomitant APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.


METHODS
DI-ATS1 was induced in isolated guinea pig ventricles by perfusion of 2 mM KCl Tyrode solution containing 10 μM BaCl(2). APD and [Ca(2+)](i) from the anterior epicardium were quantified by ratiometric optical voltage (di-4-ANEPPS) or Ca(2+) (Indo-1) mapping during right ventricular pacing with or without the ATP-sensitive potassium channel opener pinacidil (15 μM).


RESULTS
APD gradients under all conditions were insufficient for arrhythmia induction by programmed stimulation. However, 38% of DI-ATS1 preparations experienced ventricular tachycardias (VTs), and all preparations experienced a high incidence of premature ventricular complexes (PVCs). Pinacidil decreased APD and APD dispersion and reduced VTs (to 6%), and PVC frequency (by 79.5%). However, PVC frequency remained significantly greater relative to control (0.5% ± 0.3% of DI-ATS1). Importantly, increased arrhythmia propensity during DI-ATS1 was associated with diastolic [Ca(2+)](i) accumulation and increased [Ca(2+)](i) transient amplitudes. Pinacidil partially attenuated the former but did not alter the latter.


CONCLUSIONS
The study data suggest that arrhythmias during DI-ATS1 may be a result of triggered activity secondary to prolonged APD and altered [Ca(2+)](i) cycling and less likely dependent on large epicardial APD gradients forming the substrate for reentry. Therefore, therapies aimed at reducing [Ca(2+)](i) rather than APD gradients may prove effective in treatment of ATS1.
Radwański
Przemysław B
PB
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112-5000, USA.
Veeraraghavan
Rengasayee
R
Poelzing
Steven
S
D000200:Action Potentials; D050030:Andersen Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D003600:Cytosol / Q000378:metabolism*; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D010496:Pericardium / Q000166:cytology / Q000378:metabolism*; D020110:Pinacidil / Q000494:pharmacology; D056969:Voltage-Sensitive Dye Imaging
D049990:Membrane Transport Modulators; D020110:Pinacidil; D002118:Calcium