Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

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, I-to,I-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 I-to (I-to,I-s), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DNxKv1.4(-/-)) mice that lack both I-to,I-f and I-to,I-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 (APD(75)) 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 I-to,I-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.