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

• Published in: Cardiovascular research Vol. 42; no. 1; pp. 65 - 79
• Main Authors: SOSUNOV, E. A, ANYUKHOVSKY, E. P, CHARPENTIER, F, LEGEAY, Y, LE MAREC, H, SHVILKIN, A, HARA, M, STEINBERG, S. F, DANILO, P. JR, ROSEN, M. R, MÖISE, N. S, MEROT, J, PROBST, V
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.1999
• Subjects: Action Potentials - drug effects; Adenylyl Cyclases - metabolism; Adrenergic alpha-Agonists - pharmacology; Adrenergic beta-Agonists - pharmacology; Animals; Autonomic Nervous System - physiopathology; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cells, Cultured; Death, Sudden, Cardiac - etiology; Dogs; Electrocardiography; Heart; Heart - physiopathology; Heart Rate - drug effects; Isoproterenol - pharmacology; Medical sciences; Models, Biological; Phenylephrine - pharmacology; Purkinje Fibers - drug effects; Receptors, Adrenergic, beta - metabolism; Ventricular Dysfunction - physiopathology; Heart; Fissipedia; Repolarization; Carnivora; Arrhythmia; Pathogenesis; Sudden death; Electrophysiology; Cardiovascular disease; Hereditary; Sympathetic nervous system; Left ventricle; Vertebrata; Mammalia; Heart disease; Animal; Dog
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/S0008-6363(98)00333-2

We tested the hypothesis that delayed afterdepolarization (DAD)-associated rhythms in German shepherd dogs with reduced anteroseptal left ventricular (LV) sympathetic innervation derive from abnormal beta-adrenergic receptor effector coupling. In anteroseptal LV midmyocardium of afflicted dogs, beta-receptor density was greater than that in normal dogs (P < .05), with affinity being equal in both groups. Basal and maximum isoproterenol (ISO) stimulated adenylyl cyclase activity of anteroseptal LV of afflicted dogs was greater than that in normal dogs (P < .05). Isolated anteroseptal M cell preparations of afflicted dogs studied with microelectrodes showed abnormal lengthening, rather than shortening of action potential duration in response to ISO, as well as a 61% incidence of 10(-7) mol/l ISO-induced triggered activity as compared to 12% in normals (P < .05). In contrast, there was no difference between afflicted and control dogs in triggered activity, beta-receptors or adenylyl cyclase activity in a normally innervated region of the ventricles. In this model there is an increase in beta-receptor density and beta-adrenergic stimulation of adenylyl cyclase and of triggered activity in anteroseptal myocardium but not in a normally innervated region of the heart. Hence, abnormal beta-adrenergic signal transduction appears associated with the neural abnormality identified in dogs with inherited VT.