Chronic AV-block (CAVB) and biventricular hypertrophy in dogs increases susceptibility to drug-induced polymorphic ventricular tachycardia (PVT). In various rodent models, Cyclosporine A (CsA) prevented hypertrophy. A similiar effect in the CAVB-model would allow to determine whether hypertrophy represents an epiphenomenon, the cause of electrophysiologic changes and/or the anatomic substrate for PVTs. Upon AV node ablation, 6 dogs were studied acutely (A-AVB), 25 dogs were kept for 6 (6W) and 12 weeks (12W), receiving either no treatment (n=6, CTL-CAVB-6W; n=7, CTL-CAVB-12W) or a daily oral dose of 10-20 mg/kg CsA, either directly (n=6, CsA-CAVB-6W) or 6 weeks after RF-ablation (n=6, CsA-CAVB-12W). For the final study dogs were anesthetized, 60 needles were inserted into both ventricles and connected to a multiplexer mapping system. Local refractory periods (ERPs) were determined at 56 ± 22 randomly selected sites (extrastimulus technique, basic cycle length 800 ms). Arrhythmias occurring within 30 minutes after application of Almokalant (0.34 µmol/kg i.v.) were registered. The hearts were then excised to obtain the heart-to-body-weight-index (HBWI). Compared to AAVB, CTL-CAVB-6W and CTL-CAVB-12W showed increased HBWI and ERP associated with PVT inducibility in 0/6 AAVB dogs, 4/6* CTL-CAVB-6W dogs and 1/7 CTL-CAVB-12W dogs. Compared to CTL-CAVB-6W and CTL-CAVB-12W, CsA-CAVB-6W and CsA-CAVB-12W partially prevented hypertrophy or led to a regression of hypertrophy without reducing ERP prolongation. Despite ERP prolongation, PVTs were no longer inducible with CsA treatment. Thus, prolongation of refractoriness seems to provide the trigger, but hypertrophy the essential substrate for the induction of polymorphic ventricular tachycardias in this model.