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Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil

Takeshi Aiba, MD, PhD^*, Wataru Shimizu, MD, PhD^,*, Masashi Inagaki, MD^*, Takashi Noda, MD, PhD^*, Shunichiro Miyoshi, MD, PhD, Wei-Guang Ding, MD, PhD, Dimitar P. Zankov, MD^,||, Futoshi Toyoda, PhD, Hiroshi Matsuura, MD, PhD, Minoru Horie, MD, PhD^|| and Kenji Sunagawa, MD, PhD^*

^* Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Suita, Osaka, Japan
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan
^|| Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

View larger version (26K): [in a new window]   Figure 1 Transmembrane action potentials simultaneously recorded from the epicardial (Epi), midmyocardial (M), and endocardial (Endo) regions and a transmural electrocardiogram (ECG) at basic cycle length of 2,000 ms under each study condition. (A) Control. (B) E-4031 (1µmol/l). (C) Chromanol 293B (10µmol/l). (D) 293B + E-4031 (acquired long QT syndrome [LQTS] condition). (E) Epinephrine infusion (Epine: 0.5µmol/l) under acquired LQTS condition. (F) Addition of verapamil (Verap) 2.5 µmol/l under acquired LQTS condition. (G) Further addition of Epine in the continued presence of Verap under acquired LQTS condition. Numbers at bottom of each ECG denote transmural dispersion of repolarization (ms).

View larger version (14K): [in a new window]   Figure 2 Spontaneous early afterdepolarization and subsequent Torsade de Pointes under the acquired long QT syndrome condition (293B 10 µmol/l + E-4031 1 µmol/l). Basic cycle length = 3,000 ms. Recordings and abbreviations as in Figure 1.

View larger version (26K): [in a new window]   Figure 3 Dose-dependent effect of Verap (0.1 to 5 µmol/l) on transmembrane and ECG activity under acquired LQTS condition (293B 10 µmol/l + E-4031 1 µmol/l). (A) Superimposed action potentials recorded simultaneously from the epicardial and M regions together with a transmural ECG. (B) Composite data of the effect of Verap on QT interval (solid squares), action potential duration measured at 90% repolarization (APD90) of Epi (open triangles) and M (open circles) regions and transmural dispersion of repolarization (TDR) (solid diamonds). Basic cycle length = 2,000 ms. *p < 0.05 vs. 293B + E-4031; p < 0.01 vs. 293B + E-4031; ¶p < 0.05 vs. M region by analysis of variance with Bonferroni's test. Abbreviations as in Figure 1.

View larger version (18K): [in a new window]   Figure 4 Sensitivity of IKs in the epicardial (Epi), midmyocardial (M), and endocardial (Endo) cells to inhibition by chromanol 293B. (A) Representative superimposed current traces elicited by 3-s depolarizing voltage-clamp steps applied from a holding potential of –50 mV to +50 mV in an epicardial cell, before (control) and during exposure to 293B at a concentration of 0.1, 1, 5, 10, and 30 µmol/l. The IKr inhibitor E-4031 (3 µmol/l) was present throughout. Tail currents were demonstrated on an expanded scale. (B) The percent block of IKs in the Epi (open circles), M (open squares), and Endo (open triangles) cells. The degree of IKs inhibition was measured as the fraction of the tail current reduced by each concentration of 293B with reference to the control amplitude of the tail current. Smooth curves through the data points represent a least-squares fit of a Hill equation: percent block = 100/(1 + (IC50/[293B])nH), yielding the concentration required for the half-maximal block (IC50) and the Hill coefficient (nH). pA = pico (x 10–12) Ampere.

View larger version (21K): [in a new window]   Figure 5 Detection of IKr and IKs in the epicardial (Epi), midmyocardial (M), and endocardial (Endo) cells. Depolarizing test pulses (to +30 mV for 300 ms) were repetitively applied (every 2 s) from a holding potential of –50 mV to activate IK, and membrane currents were recorded from the Epi, M, and Endo cells, before (trace 1), and 2 min after exposure to 3 µmol/l E-4031 (trace 2), and 2 min after further addition of 30 µmol/l 293B in conjunction with 3 µmol/l E-4031 (trace 3). pA = pico (x 10–12) Ampere.

View larger version (15K): [in a new window]   Figure 6 Effect of both IKr and IKs suppression on the simulated action potentials from the epicardial (Epi), midmyocardial (M), and endocardial (Endo) cells. (A) Superimposed action potentials simulated under baseline condition (dotted lines) and after both IKr and IKs suppression (70% and 80%, respectively) (solid lines). (B) Effect of maximum conductance of Ito (Gto) on the simulated epicardial action potential (Vm), ICa,L magnitude, and the net charge entry calculated by integration of the ICa,L under the condition of both IKr and IKs suppression. Basic cycle length = 2,000 ms. EAD = early afterdepolarization.