Mouse models of long QT syndrome

Abstract

Congenital long QT syndrome is a rare inherited condition characterized by prolongation of action potential duration (APD) in cardiac myocytes, prolongation of the QT interval on the surface electrocardiogram (ECG), and an increased risk of syncope and sudden death due to ventricular tachyarrhythmias. Mutations of cardiac ion channel genes that affect repolarization cause the majority of the congenital cases. Despite detailed characterizations of the mutated ion channels at the molecular level, a complete understanding of the mechanisms by which individual mutations may lead to arrhythmias and sudden death requires study of the intact heart and its modulation by the autonomic nervous system. Here, we will review studies of molecularly engineered mice with mutations in the genes (a) known to cause long QT syndrome in humans and (b) specific to cardiac repolarization in the mouse. Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models.

Figure 1. Electrocardiographic manifestations of the long QT syndrome

A, 12-lead ECG of a teenager with the Romano-Ward autosomal dominant long QT syndrome due to a mutation in HERG. B, ambulatory (Holter) monitor demonstrating Torsade de Pointes. Scale bar, 1 sec.

Figure 2. Cardiac ionic currents, action potentials and ECGs in humans versus mice

Major depolarizing and repolarizing currents are shown for the human and mouse heart. The size of the arrow for each current is roughly proportional to its magnitude, and arrows for outward currents point upward. Long QT loci (LQT1–LQT8) are listed near the current responsible for the phenotype. For each heart beat, action potentials of the first cells to depolarize are depicted as continuous lines and action potentials of the last cells to depolarize are depicted as dotted lines. APD₉₀ is the time until 90% repolarization of the action potential. The ECG of the mouse is the signal average of five consecutive beats, and the ECG of the human is a simulation. Note that the apparent QRS duration (‘QRS’) in the mouse corresponds to both depolarization and early repolarization.

Figure 3. Optical mapping of murine action potentials and programmed stimulation of ventricular tachycardia

A, optical action potentials from 4 regions of a control mouse. The heart is shown in the specially designed chamber used to abate motion artifacts; a schematic diagram of the photodiode array is superimposed over a digital image of the heart to identify the region from which action potentials were recorded. Action potentials recorded from 4 sites on the left ventricle are shown with arrows to denote the precise region of epicardium that fired these action potentials. Each trace is recorded from ∼300 × 300 μm² of tissue at 2 kHz sampling rate, with no spatial or temporal filtration. B, optical signals from 4 photodiodes demonstrating the induction of monomorphic ventricular tachycardia in a Kv1.1 dominant negative long QT mouse by a single extra stimulus applied at the apex (b). In each trace, two action potentials that were triggered at the basic cycle length S1–S1 = 200 ms are shown; the spike labelled ‘a’ is the last normal action potential which is followed by the premature pulse S2 that elicits spike b and elcits a re-entrant VT. Spike c is the first depolarization in VT. C, isochronal activation maps (1 ms apart) of the heart beat under sinus rhythm. D, isochronal activation map of the premature beat (b) which encounters a functional line of block and initiates the ventricular tachycardia.

Figure 4. ECG telemetry and programmed stimulation in mice

A, radiotelemetry electrocardiograms from an ambulatory control FVB strain mouse at baseline (left) and during a spontaneous episode of high degree heart block (right). B, spontaneous episode of non-sustained ventricular tachycardia in a Kv1.1 dominant negative transgenic mouse with APD and QT prolongation. C, inducible polymorphic non-sustained ventricular tachycardia in a control mouse using two right ventricular extra-stimuli (S2, S3) from a multipolar catheter placed through the internal jugular vein. Tracings provided by Dr Samir Saba, University of Pittsburgh.