Cardiovascular
Research, Vol. 57 (3) (2003) pp. 599-614
© 2003 European Society of Cardiology. Published by Elsevier B.V. All rights
reserved.
PII: S0008-6363(02)00737-X
The Heart and Vascular Research Center,
MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive,
Hamman 322, Cleveland, OH 44109-1998, USA
Received 6 August 2002; accepted 21
October 2002
Time for primary review 22 days.
For nearly 100 years, beat to beat alternation of T wave amplitude,
termed T wave alternans (TWA), has been closely linked to electrical
instability in the heart. TWA is now established among the strongest markers of
susceptibility to sudden cardiac death. Since computer technology allows for
detection of very subtle yet clinically significant TWA during standard
exercise testing, TWA has been used increasingly as a noninvasive clinical tool
for identifying and treating patients at risk for sudden cardiac death. The
observation of TWA hastening ventricular tachyarrhythmias in an extraordinary
variety of clinical and experimental conditions suggest potential universality
of TWA in the pathophysiological mechanism of sudden death. High resolution
optical mapping studies have shown that TWA arises from alternans of
repolarization at the level of the ventricular myocyte. Cellular alternans is
likely due to the actions of one or more ionic currents and is closely related
to, if not directly dependent on, the kinetics of intracellular calcium
cycling. Impairment in calcium cycling at the cellular and sub-cellular levels
has been implicated in the mechanism of cellulcar alternans. Importantly,
spatially discordant alternans between cells is most likely a consequence of
heterogeneities of electrophysiological properties between cells which span the
ventricular wall, serving to amplify spatial heterogeneities of repolarization,
and forming a substrate for reentrant excitation. Through this mechanism, TWA
is linked directly and mechanistically to the pathogenesis of arrhythmias. Although
available data would suggest that TWA is certainly closely related to a
mechanism of arrhythmogenesis, and is a strong marker of clinical risk, the
precise sequence of events which triggers sudden cardiac death, and the
potential role of TWA in this process remains elusive.
Keywords:
Arrhythmia
(mechanisms); ECG; Sudden death; Ventricular arrhythmias
*Corresponding author. Tel.: +1-216-778-2005;
fax: +1-216-778-4924.
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