Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7)

Abstract

Background: Andersen-Tawil syndrome, a skeletal muscle syndrome associated with periodic paralysis and long QT intervals on the ECG, has been linked to defects in KCNJ2, the gene encoding for the inward rectifier potassium channel (I(K1).)

Objectives: The purpose of this study was to examine the cellular mechanisms underlying the ECG and arrhythmic manifestations of Andersen-Tawil syndrome.

Methods: To investigate the effects of KCNJ2 loss-of-function mutations responsible for Andersen-Tawil syndrome, we used barium chloride (BaCl(2)) to inhibit I(K1) in arterially perfused wedge preparation. Transmembrane action potentials (APs) were simultaneously recorded from endocardial, midmyocardial, and epicardial cells, together with a transmural ECG.

Results: BaCl(2) (1 to 30 microM) produced a concentration-dependent prolongation of the QT interval, secondary to a homogeneous prolongation of AP duration of the three cell types. QT interval was prolonged without an increase in transmural dispersion of repolarization (TDR). Low extracellular potassium (2.0 mM), isoproterenol (20-50 nM), and an abrupt increase in temperature (36 degrees C-39 degrees C) in the presence of 10 microM BaCl(2) did not significantly increase TDR but increased ectopic extrasystolic activity. Early afterdepolarizations were not observed under any condition. Spontaneous torsades de pointes arrhythmias were never observed, nor could they be induced with programmed electrical stimulation under any of the conditions studied.

Conclusion: Our results provide an understanding of why QT prolongation associated with Andersen-Tawil syndrome is relatively benign in the clinic and provide further support for the hypothesis that the increase in TDR, rather than QT interval, is responsible for development of torsades de pointes.

Figure 1

Dose-dependent effect of barium chloride on trans-membrane and ECG activity in canine left ventricular wedge preparation. Superimposed action potentials (APs) recorded simultaneously from endocardial (Endo), midmyocardial (M), and epicardial (Epi) cells, together with transmural ECG (A). Composite data of dose-dependent effects of barium chloride 1 to 30 μM on QT interval, APD₅₀, and APD₉₀ in endocardial (Endo₅₀, Endo₉₀), midmyocardial (M₅₀, M₉₀), and epicardial (Epi₅₀, Epi₉₀) (B), on Tpeak-Tend, and on transmural dispersion of repolarization (TDR) (C). Basic cycle length = 2,000 ms. n = 7. ^*P <.05; ^**P <.01 vs control. BCL = basic cycle length.

Figure 2

Representative configuration of action potentials of three cell types and ECG characteristics. Endocardial (Endo), midmyocardial (M), and epicardial (Epi) APs were simultaneously recorded with transmural ECG under control conditions and in the presence of 10 μM BaCl₂.

Figure 3

Rate-dependent changes of action potential (AP) characteristics and QT interval under control condition and in the presence of 10 μM BaCl₂. Each trace shows superimposed APs recorded simultaneously from endocardial (Endo), midmyocardial (M), and epicardial (Epi) cells together with a transmural ECG at cycle lengths ranging from 500 to 4,000 ms. A: Control. B: Composite data of rate-dependent changes under control conditions. C, D: Recorded in the presence of 10 μM BaCl₂. n = 8. Endo = endocardial APD₉₀; Epi = epicardial APD₉₀; M = midmyocardial APD₉₀; QT = QT interval.

Figure 4

Warming-induced QT and action potential (AP) abbreviation in arterially perfused left ventricular wedge preparation pretreated with 10 μM BaCl₂. APs were recorded simultaneously from endocardial (Endo), midmyocardial (M), and epicardial (Epi) cells together with transmural ECG during a rise in perfusate temperature from 36°C to 39°C within 4 minutes (basic cycle length = 2,000 ms). Warming of the perfusate gradually and similarly abbreviates the APD of three cell types and the QT interval, resulting in reduction of Tpeak-Tend and transmural dispersion of repolarization (TDR). The tracings represent recordings of the response at 36°C, ∼37°C and 38°C, and 39°C. Note that endocardial AP failed to record at ∼38°C, so that the tracing is not shown.

Figure 5

A: Effect of isoproterenol. Endo = endocardial cell; Epi = epicardial cell; M = midmyocardial cell. B, C: Composite data of effect of isoproterenol (20 or 25 nM) in the LQT7 model. BaCl₂ 10 μM produced a similar prolongation of action potential duration (APD) of endocardial (Endo), midmyocardial (M), and epicardial (Epi) cells. Isoproterenol in the continuous presence of 10 μM BaCl₂ caused a sustained abbreviation of APD of three cell types without significant change in transmural dispersion. Basic cycle length = 2,000 ms. n = 8. Endo = endocardial APD₉₀; Epi = epicardial APD₉₀; M = midmyocardial APD₉₀; QT = QT interval. ^*P <.05 vs control; †P <.01 vs barium 10 μM; #No significant difference vs 10 μM BaCl₂.

Figure 6

Effect of extracellular potassium level in the presence of 10 μM BaCl₂. A: Superimposed action potentials simultaneously recorded from endocardial (Endo), midmyocardial (M), and epicardial (Epi) cells together with a transmural ECG at potassium concentrations of 2.0, 4.0, and 6.0 mM. B, C: Composite data of change in potassium level to low K (2.0 mM), normal K (4.0 mM), and high K (6.0 mM). Basic cycle length = 2,000 ms. n = 7. ^*P <.05 vs normal K; ^**P <.01 vs normal K.