Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K⁺ currents, including β-adrenergic (β-A)-sensitive I_Ks. Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the time course of molecular alterations underlying I_Ks downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to β-adrenergic receptor (β-AR) stimulation.

Methods and Results: Serial left-ventricular (LV) biopsies were collected from anesthetized dogs during sinus rhythm (SR; control) and at 3, 7 and 30 days of AVB. KCNQ1 mRNA and protein decreased within 3 days (protein expression 58±10% of control), remaining low thereafter. β1-AR mRNA and protein decreased more gradually to 53±8% at 7 days. In chronic-AVB LV myocytes, I_Ks-tail density was reduced: 1.4±0.3 pA/pF versus 2.6±0.4 pA/pF in controls. β-A enhancement of I_Ks was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. β-A early afterdepolarizations were induced in 4 of 13 chronic-AVB cells, but not in controls. In intact conscious dogs, isoproterenol shortened QT_c at SR (by −8±3% from 295 ms), left it unaltered at 3 days AVB (+1±3% from 325 ms) and prolonged QT_c at 30 days (+6±3% from 365 ms).

Conclusions: Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of β1-AR expression. Downregulation and blunted β-A activation of I_Ks contribute to the loss of β-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy.