Lc. Baker et al., Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia, CIRCUL RES, 86(4), 2000, pp. 396-407
The heterogeneous distribution of ion channels in ventricular muscle gives
rise to spatial variations in action potential (AP) duration (APD) and cont
ributes to the repolarization sequence in healthy hearts. It has been propo
sed that enhanced dispersion of repolarization may underlie arrhythmias in
diseases with markedly different causes. We engineered dominant negative tr
ansgenic mice that have prolonged QT intervals and arrhythmias due to the l
oss of a slowly inactivating Kr current. Optical techniques are now applied
to map APs and investigate the mechanisms underlying these arrhythmias. He
arts from transgenic and control mice Evert isolated, perfused, stained wit
h di-4-ANEPPS, and paced at multiple sites to optically map APs, activation
, and repolarization sequences at baseline and during arrhythmias. Transgen
ic hearts exhibited a 2-fold prolongation of APD, less shortening (8% versu
s 40%) of APDs with decreasing cycle length, altered restitution kinetics,
and greater gradients of refractoriness from apex to base compared with con
trol hearts. A premature impulse applied at the apex of transgenic hearts p
roduced sustained reentrant ventricular tachycardia (n=14 of 15 hearts) tha
t did not occur with stimulation at the base (n=8) or at any location in co
ntrol hearts (n=12). In transgenic hearts, premature impulses initiated ree
ntry by encountering functional lines of conduction block caused by enhance
d dispersion of refractoriness. Reentrant VT had stable (>30 minutes) alter
nating long/short APDs associated with long/short cycle lengths and T wave
alternans. Thus, optical mapping of genetically engineered mice may help el
ucidate some electrophysiological mechanisms that underlie arrhythmias and
sudden death in human cardiac disorders.