Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Introduction Higher progesterone concentrations are protective against drug‐induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug‐induced torsades de pointes (TdP). Methods and Results Female New Zealand white rabbits (2.5‐3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21‐day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs‐Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15‐minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo‐treated rabbits (3.8 [range, 2.8‐5.1] vs 0.7 [0.4‐1.7] ng/mL, P