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Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A on morphology and electrophysiology

Department of Cardiology, University of Heidelberg, 69115 Heidelberg, Germany

Submitted 5 November 2003 ; accepted in final form 10 May 2004

Chronic atrioventricular (AV) block (CAVB) and biventricular hypertrophy in dogs increase susceptibility to drug-induced polymorphic ventricular tachycardia (PVT). In various rodent models, cyclosporin A (CsA) prevented hypertrophy. A similar effect in the CAVB model would allow us to determine whether hypertrophy represents an epiphenomenon, the cause of electrophysiological changes, and/or the anatomic substrate for PVTs. Upon AV node ablation, 6 dogs were studied acutely (AAVB), 25 dogs were kept for 6 (6W) and 12 wk (12W), receiving no treatment [CTL-CAVB-6W (n = 6) and CTL-CAVB-12W (n = 7)] or a daily oral dose of 10–20 mg/kg CsA directly (n = 6, CsA-CAVB-6W) or 6 wk after radio-frequency ablation (n = 6, CsA-CAVB-12W). For the final study, dogs were anesthetized, and 60 needles were inserted into both ventricles and connected to a multiplexer mapping system. Local effective refractory periods (ERPs) were determined at 56 ± 22 randomly selected sites (extrastimulus technique, basic cycle length = 800 ms). Arrhythmias within 30 min after application of almokalant (0.34 µmol/kg iv) were registered. The hearts were then excised to obtain the heart weight-body weight index (HBWI). Compared with AAVB, CTL-CAVB-6W and CTL-CAVB-12W showed increased HBWI and ERP associated with PVT inducibility in none of six AAVB dogs, four of six CTL-CAVB-6W dogs, and one of seven CTL-CAVB-12W dogs. Compared with 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 provides the essential substrate for the induction of PVTs in this model.

regression of hypertrophy; mapping; torsade de pointes

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