I(Kr) contributes to the altered ventricular repolarization that determines long-term cardiac memory.

Objective: Cardiac memory (CM) is characterized by an altered T-wave morphology, which reflects altered repolarization gradients. We hypothesized that the delayed rectifier currents, I(Kr) and I(Ks), might contribute to these repolarization changes.

Methods: We studied conscious, chronically instrumented dogs paced from the postero-lateral left ventricular (LV) wall at rates 5-10% faster than sinus rate for 3 weeks.

The cAMP response element binding protein modulates expression of the transient outward current: implications for cardiac memory.

Objective: Long-term cardiac memory (LTCM), expressed as a specific pattern of T-wave change on ECG, is associated with 1) reduced transient outward potassium current (I(to)), 2) reduced mRNA for the pore-forming protein of I(to), Kv4.3, 3) reduced cAMP response element binding protein (CREB), and 4) diminished binding to its docking site on the DNA, the cAMP response element (CRE). We hypothesized a causal link between the decrease of the transcription factor CREB and down-regulation of I(to) and one of its channel subunits, KChIP2, in LTCM.

Developmental evolution of the delayed rectifier current IKs in canine heart appears dependent on the beta subunit minK.

Objectives: We tested the hypothesis that the developmental changes occurring in I(Kr) and I(Ks) can be explained by changes in the expression of ERG encoding I(Kr), and KCNQ1, the beta subunit minK, and the recently reported subunit FHL2 encoding I(Ks).

Background: The delayed rectifier current contributes importantly to the developmental evolution of the canine myocardial action potential. Specifically, in left ventricular epicardial myocytes, I(Ks) is absent and I(Kr) is the major repolarizing current until age 4 weeks.

Mechanisms of alpha-adrenergic potentiation of ventricular arrhythmias in dogs with inherited arrhythmic sudden death.

Objective: In German shepherd dogs having inherited arrhythmias and sudden death, pause-dependent arrhythmias are triggered by early afterdepolarizations (EADs) originating from left ventricular (LV) Purkinje fibers (PF). Heterogeneity of LV repolarization provides the arrhythmogenic substrate. To elucidate the mechanisms whereby alpha-adrenergic stimulation exacerbates these arrhythmias we tested the effects of phenylephrine on both arrhythmogenic trigger and substrate.

Heterogeneous ventricular repolarization provides a substrate for arrhythmias in a German shepherd model of spontaneous arrhythmic death.

Background: German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals.

Methods And Results: We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs.

Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia.

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.