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RELATED PAPERS |
1 University of Pittsburgh, Cardiovascular Institute and the
2 Department of Cell Biology and Physiology Pittsburgh, PA 15213, USA
3 Washington University School of Medicine, Department of Molecular Biology and Pharmacology, St Louis, MO, USA
Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, Ito,f, have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4–/–) that lack the slow component of Ito (Ito,s), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DNxKv1.4–/–) mice that lack both Ito,f and Ito,s, have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 ± 2.5 ms, P < 0.01, n = 6), Kv1.4–/– (28.4 ± 0.4 ms, P < 0.01, n = 5) and Kv4.2DNxKv1.4–/– (34.3 ± 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 ± 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 ± 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4–/– (14.2 ± 2.0 ms, n = 5, P < 0.05) and Kv4.2DNxKv1.4–/– (15.0 ± 3 ms, n = 5, P < 0.5) mice compared with controls (10 ± 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4–/– (n = 4/5) and Kv4.2DNxKv1.4–/– hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that Ito,f was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.
(Received 10 October 2006;
accepted after revision 13 November 2006;
first published online 16 November 2006)
Corresponding author G. Salama: University of Pittsburgh, School of Medicine, Dept of Cell Biology and Physiology, S312 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA. Email: gsalama{at}pitt.edu
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  C. Marionneau, S. Brunet, T. P. Flagg, T. K. Pilgram, S. Demolombe, and J. M. Nerbonne Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K+ Currents With Left Ventricular Hypertrophy Circ. Res., June 6, 2008; 102(11): 1406 - 1415. [Abstract] [Full Text] [PDF]
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 M. J. Killeen and I. N. Sabir Repolarization gradients and arrhythmogenicity in the murine heart J. Physiol., September 1, 2007; 583(2): 419 - 420. [Full Text] [PDF]
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R. Mantravadi, B. Gabris, T. Liu, B.-R. Choi, W. C. de Groat, G. A. Ng, and G. Salama Autonomic Nerve Stimulation Reverses Ventricular Repolarization Sequence in Rabbit Hearts Circ. Res., April 13, 2007; 100(7): e72 - e80. [Abstract] [Full Text] [PDF]
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