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Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome

^a Masonic Medical Research Laboratory, Utica, New York, USA

View larger version (27K): [in a new window]   Figure 1 Effect of isoproterenol in the LQT1 model. Shown are superimposed action potentials recorded simultaneously from M and epicardial cells, together with a transmural ECG. BCL = 2,000 ms. Chromanol 293B (30 µmol/L) produced a homogeneous prolongation of APD of both cell types with no major change in the width of the T wave or in TDR. Isoproterenol (Iso, 100 nmol/L) in the continued presence of 293B dramatically prolonged the APD of the M cell (2 min) and maintained it prolonged as the effect approached a steady state (10 min), whereas the epicardial action potential was always abbreviated, resulting in a persistent increase in TDR and in a widening of the T wave, as commonly seen in LQT1 patients. APD = action potential duration; LQT1 = long QT syndrome 1; TDR = transmural dispersion of repolarization.

View larger version (28K): [in a new window]   Figure 2 Effect of isoproterenol in the LQT2 model. d-Sotalol (d-Sot, 100 µmol/L) produced a preferential prolongation of the M cell APD and an increase in TDR. Isoproterenol (Iso, 100 nmol/L) in the continued presence of d-Sot initially prolonged (2 min) and then abbreviated the APD of the M cell to the control level (10 min), whereas the APD of epicardial cell was always abbreviated, resulting in a transient increase in TDR. APD = action potential duration; LQT2 = long QT syndrome 2; TDR = transmural dispersion of repolarization.

View larger version (25K): [in a new window]   Figure 3 Effect of isoproterenol in the LQT3 model. ATX-II (20 nmol/L) produced a marked prolongation of APD of the M cell, more than that of the epicardial cell and a dramatic increase in TDR. Isoproterenol (Iso, 100 nmol/L) in the continued presence of ATX-II always abbreviated the APD of both cells, resulting in a persistent decrease in TDR. APD = action potential duration; LQT3 = long QT syndrome 3; TDR = transmural dispersion of repolarization.

View larger version (43K): [in a new window]   Figure 4 Composite data of the effect of isoproterenol in the LQT1, LQT2 and LQT3 models. In LQT1, isoproterenol (Iso) produced a persistent prolongation of the APD90 of the M cell and of the QT interval (at both 2 and 10 min), whereas the APD90 of the epicardial cell was always abbreviated, resulting in a persistent increase in TDR (A and B). In LQT2, isoproterenol initially prolonged (2 min) and then abbreviated the QT interval and the APD90 of the M cell to the control level (10 min), whereas the APD90 of epicardial cell was always abbreviated, resulting in a transient increase in TDR (C and D). In LQT3, isoproterenol produced a persistent abbreviation of the QT interval and the APD90 of both M and epicardial cells (at both 2 and 10 min), resulting in a persistent decrease in TDR (E and F). *p < 0.0005 vs. control; p < 0.0005; p < 0.005; p < 0.05, vs. 293B, d-Sotalol (d-Sot) or ATX-II. APD90 = action potential duration measured at 90% repolarization; LQT1, 2, 3 = long QT syndrome 1, 2, 3; TDR = transmural dispersion of repolarization.

View larger version (40K): [in a new window]   Figure 5 Composite data of the effect of propranolol (Prop, 1 µmol/L) to suppress the influence of isoproterenol (Iso, 100 nmol/L) on the QT interval (solid circle), the APD90 of M (open circle) and epicardial (Epi, open triangle) cells and TDR (solid circle) in the LQT1 (A and B), LQT2 (C and D) and LQT3 (E and F) models. In the LQT1 and the LQT2 models, propranolol completely prevented the influence of isoproterenol to persistently or transiently increase TDR. In the LQT3 model, propranolol completely suppressed the protective effect of isoproterenol to decrease TDR. The isoproterenol data reported here were recorded 10 min after addition of the catecholamine although similar results were obtained at 2 min in the presence of propranolol. *p < 0.0005 vs. control. APD90 = action potential duration measured at 90% repolarization; LQT1, 2, 3 = long QT syndrome 1, 2, 3; TDR = transmural dispersion of repolarization.

View larger version (42K): [in a new window]   Figure 6 Polymorphic ventricular tachycardia displaying features of Torsade de Pointes (TdP) in the LQT2 (A) and the LQT3 (B) models of arterially-perfused canine left ventricular wedge preparations. Each trace shows action potentials simultaneously recorded from M and epicardial (Epi) cells together with a transmural ECG. The preparation was paced from the endocardial surface at a BCL of 1,000 or 2,000 msec (S1). A: Spontaneous TdP induced in the LQT2 (d-Sotalol) model. The long episode of TdP (fourth group) was preceded by salvos of three consecutive beats (first group) and an isolated ventricular premature beat (third group), similar to the clinical experience. B: Stimulation-induced TdP in the LQT3 (ATX-II) model. ATX-II produced very significant dispersion of repolarization (first grouping). A single extrastimulus (S2) applied to the epicardial surface initiated TdP (second grouping). LQT1, 2 = long QT syndrome 1, 2.

View larger version (30K): [in a new window]   Figure 7 Incidence of spontaneous and programmed electrical stimulation (PES)-induced Torsade de Pointes (TdP) in the LQT1 (A), LQT2 (B) and LQT3 (C) models. Under control conditions (C), neither spontaneous nor PES-induced TdP were observed in any of the three models. In LQT1, TdP could be induced only after addition of isoproterenol (Iso) (at both 2 and 10 min). 0.5 or 1 µmol/L propranolol (Prop) completely suppressed the influence of isoproterenol to provoke both spontaneous and PES-induced TdP in this model. In the LQT2 and LQT3 models, TdP occurred in the presence of d-Sotalol (d-Sot) and ATX-II alone. In the LQT2 model, isoproterenol transiently increased the incidence of both spontaneous and PES-induced TdP (2 min) and then decreased it (10 min). Propranolol completely prevented these effects of isoproterenol. In contrast, isoproterenol always suppressed both spontaneous and PES-induced TdP (at both 2 and 10 min) in the LQT3 model. Propranolol reversed the protective effect of isoproterenol in LQT3, causing an increase in the incidence of TdP. LQT1, 2, 3 = long QT syndrome 1, 2, 3.