Multiple Mechanisms in the Long-QT Syndrome by Dan M. Roden, Ralph Lazzara, Michael Rosen, Peter J. Schwartz, Jeffry Towbin, and G. Michael Vincent Circulation Volume 94(8):1996-2012 October 15, 1996 Copyright © American Heart Association, Inc. All rights reserved.

Examples of lead II rhythm strips in patients with LQTS Examples of lead II rhythm strips in patients with LQTS. A, Initiation of torsades de pointes. Examples of lead II rhythm strips in patients with LQTS. A, Initiation of torsades de pointes. Top strip shows example of adrenergic dependence: the preceding sinus rate is rapid, and there is no pause before the onset of the arrhythmia. Bottom example, pause dependence: the onset of torsades de pointes is preceded by a short-long-short cycle due to a ventricular extrasystole and a postextrasystolic pause. B, Distinctive T-wave patterns reported in three types of LQTS.18 The T wave was broadest in patients with KVLQT1 mutations (top), T-wave amplitude was lowest in patients with HERG (IKr) mutations (middle), and onset of the T wave was most delayed in patients with SCN5A (sodium channel) mutations (bottom). C, TU-wave lability. Top strip demonstrates QT alternans, with a QT interval that on alternate beats is as long as the RR interval. Bottom strip, pause-dependent lability of a prominent U wave. Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

Relationship between the AP and individual ion currents. Relationship between the AP and individual ion currents. Currents making up the APs are listed on the left, and time courses for each are shown schematically below the AP. Ion channel genes encoding the currents are listed on the right. Revised and reproduced by permission.159 Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

Possible ionic mechanisms underlying AP prolongation, EADs, and triggered activity. Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

A potential mechanism underlying QT alternans at rapid rates. A potential mechanism underlying QT alternans at rapid rates. Top, ECG, ventricular APs, and a repolarizing current that deactivates slowly (light arrow). When rate is increased (bottom), residual repolarizing current is present at the beginning of a subsequent AP (heavy arrow). As a result, the succeeding AP is shortened, and an alternans pattern emerges. Slow deactivation is one characteristic of IKs. Mutations in other currents that normally deactivate rapidly could also produce this effect; other studies5355 suggest a role for oscillations in intracellular calcium concentration. More complex patterns of QT alternans (eg, in T-wave vectors [Fig 1C]) might arise if this mechanism were operative in a heterogeneous fashion across the ventricular wall. Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

Genes in LQTS chromosomal location. Genes in LQTS chromosomal location. Ideograms of chromosomes 11, 7, 3, and 4 showing the locations of the LQT1-4 genes. Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

A, Schematic of the HERG protein product. A, Schematic of the HERG protein product. The protein has the six membrane-spanning segments characteristic of other potassium channels. The locations of the described mutations in HERG that cause LQTS are shown; their functional consequences are listed in Table 3 and described in the text. Reproduced by permission.160 B, Currents recorded in response to 4-second test pulses to −60, −40, −20, 0, and +10 mV in oocytes injected with 1.5 ng cRNA encoding wild-type (WT) HERG (top), A561V (middle), or 1.5 ng of both RNAs (bottom). A small endogenous current but no HERG current was recorded in oocytes injected with A561V cRNA alone, indicating that this mutant causes a loss of function. Currents recorded when both RNAs were injected were smaller than those for the wild-type channel alone, indicating a dominant negative effect. C, Current-voltage relations for the three types of expression experiments illustrated in B. Not only was the amplitude of HERG tail currents in coinjected oocytes much smaller than expected for oocytes injected with 3.0 ng wild-type cRNA (dominant negative effect), but current recorded in coinjected oocytes also activated at more negative potentials than did wild type, suggesting altered function of the mutant/wild-type heterotetramer. B and C adapted by permission.101 Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.

A, Structure of human heart sodium channel gene (SCN5A) and location of reported mutations that cause LQTS (see also Table 3). A, Structure of human heart sodium channel gene (SCN5A) and location of reported mutations that cause LQTS (see also Table 3). The structure contains four roughly homologous domains (DI-DIV), each resembling a potassium channel subunit such as that shown in Fig 6A. It is thought that the four domains (for sodium channels) or four subunits (for potassium channels) assemble as shown at lower left to form a functional pore-forming protein. Adapted by permission.160 B, Comparison of current recorded when wild-type SCN5A (left) or ΔKPQ mutant (right) is expressed in Xenopus oocytes. In each panel, current recorded after exposure to the sodium channel–specific toxin tetrodotoxin (TTX) is also shown (dotted lines). Wild-type current activates and inactivates rapidly, and by ≈100 ms after the onset of the voltage clamp pulse, no residual current is present. In contrast, the ΔKPQ mutant displays a persistent inward current (arrows); this current would result in prolongation of the AP and thus QT prolongation. Reproduced by permission.36 Dan M. Roden et al. Circulation. 1996;94:1996-2012 Copyright © American Heart Association, Inc. All rights reserved.