Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death

Objective: We tested the hypothesis that delayed afterdepolarization (DAD)- associated rhythms in German shepherd dogs with reduced anteroseptal left v entricular (LV) sympathetic innervation derive from abnormal beta-adrenergi c receptor effector coupling. Methods and Results: In anteroseptal LV midmy ocardium of afflicted dogs, beta-receptor density was greater than that in normal dogs (P<.05), with affinity being equal in both groups. Basal and ma ximum isoproterenol (ISO) stimulated adenylyl cyclase activity of anterosep tal LV of afflicted dogs was greater than that in normal dogs (P<,05). Isol ated anteroseptal M cell preparations of afflicted dogs studied with microe lectrodes showed abnormal lengthening, rather than shortening of action pot ential duration in response to ISO, as well as a 61% incidence of 10(-7) mo l/l ISO-induced triggered activity as compared to 12% in normals (P<.05). I n contrast, there was no difference between afflicted and control dogs in t riggered activity, beta-receptors or adenylyl cyclase activity in a normall y innervated region of the ventricles. Conclusion: In this model there is a n increase in beta-receptor density and beta-adrenergic stimulation of aden ylyl cyclase and of triggered activity in anteroseptal myocardium but not i n a normally innervated region of the heart. Hence, abnormal beta-adrenergi c signal transduction appears associated with the neural abnormality identi fied in dogs with inherited VT. (C) 1999 Elsevier Science B.V. All rights r eserved.