Search

Objective: In many cardiac arrhythmias, both a triggering factor and a favorable myocardial substrate are required. Whereas the sympathetic nervous system may trigger tachyarrhythmias, its function as a long-term modulator of the myocardial substrate is less well understood. Therefore, we tested the hypothesis that regional sympathetic denervation at birth would produce an abnormal myocardial substrate. The comparator was the substrate associated with inherited, lethal tachyarrhythmias at 5 months of age in German shepherd dogs with incomplete sympathetic innervation. Methods: Mongrel dogs underwent right cardiac stellectomy (RSX) within the first day of life and were terminally studied with control littermates at 5 months of age. Results: On days 1–21 of life, RSX animals manifested significant QT prolongation on ECG and sudden, asystolic death. Beyond this age, QT intervals normalized and deaths did not occur. At 5 months, action potentials (AP) were recorded from Purkinje fibers (PF) and midmyocardial preparations in anteroseptal (AS) and posterobasal (PB) left ventricle. Early afterdepolarizations occurred only in left ventricular PF from RSX dogs. Isoproterenol prolonged AP duration in AS and shortened it in PB of RSX but not control dogs. The incidence of isoproterenol-initiated triggered activity and the amplitude of delayed afterdepolarizations were greater in RSX than control dogs. Conclusion: Five months after RSX heterogeneous alterations of LV electrophysiological properties were similar to those previously observed in animals having inherited deficits in sympathetic innervation and sudden death. This implicates the sympathetic nerves as long-term modulators of an arrhythmogenic substrate. That 5-month-old RSX dogs did not experience tachyarrhythmias or sudden death indicates that further anomalies — beyond those explicable by the substrate change — must exist to induce sudden death.

Objective: Ventricular pacing or arrhythmias can induce cardiac memory (CM). We hypothesized that clinically administered antiarrhythmic drugs alter the expression of CM, and that the repolarization changes characteristic of CM can modulate the effects of antiarrhythmic drugs. Methods: We studied conscious, chronically-instrumented dogs paced for two 1-h periods to study the effects of drugs on the evolution of memory (protocol 1) or for 21 days (protocol 2) to observe the effects of steady-state memory on drug actions. Dogs were treated in both settings with quinidine, lidocaine or E4031, in random order, and within therapeutic serum concentration ranges. Results: Pacing, alone, for 2 h significantly prolonged ERP only near the left ventricular pacing site, whereas pacing alone for 21 days prolonged ERP at all sites ( P

Objective: Clinical and experimental studies suggest that immature hearts are as or more sensitive than adult hearts to adverse effects of I Kr blocking drugs. We hypothesized that age-dependent changes in I Kr and I Ks contribute to the different repolarization reserves and proarrhythmic effects of I Kr blockers in the young and adult heart. Methods: Dogs aged 1–150 days and adults were used to study (1) proarrhythmic effects in situ of the I Kr blocker dofetilide; (2) dofetilide effects on action potential duration (APD) recorded with microelectrodes from left ventricular (LV) slabs; (3) I Kr and I Ks in single LV myocytes using whole-cell voltage clamp. Results: In situ, dofetilide-induced proarrhythmia occurred in 40% of adults, 86% of young (20–150 day) dogs and 0% of neonatal (1–19 day) dogs ( P

Objective: The incidence of atrial fibrillation increases with age. We hypothesized that aging-associated changes in the atrial action potential (AP) and conduction velocity provide a substrate for abnormal conduction and arrhythmogenesis. Methods: We used microelectrode techniques to record AP from the endocardium of the right atrial wall of dogs aged 1–5 (adult) and >8 years (old). Conduction velocity was measured between two microelectrodes 3–10 mm apart. Histological study was carried out to assess fibrosis. Results: Whereas resting potential, AP amplitude and V max did not differ with age, the plateau was more negative and AP duration was longer in old tissue. The L-type calcium current ( I Ca,L) agonist Bay K8644 (10−8–10−6 mol/l) elevated the plateau and shortened APD more in old than in adult, such that AP contour in old atria approached that of adult. In contrast, the I Ca,L blocker nisoldipine (10−8–10−5 mol/l) depressed the plateau in adult and had no effect in old. There was no difference between the two groups in conduction velocity of normal beats, whereas for early premature impulses, reduced conduction velocity and a wider time window manifesting slow conduction were detected in old in comparison to adult tissue. A twofold increase in the amount of fibrous tissue was detected in old atria. Conclusions: Our data show significant differences in contour of AP in adult and old atria. The responses to Bay K8644 and nisoldipine suggest a decreased I Ca,L in old atrial tissue. The alterations in AP contour and increased fibrosis may be responsible for slower conduction of early premature beats in old atria. The age-related changes in conduction of premature beats are consistent with those observed in patients with paroxysmal atrial fibrillation and may contribute to the greater propensity to atrial fibrillation in the aged.