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Title:
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Spatially Discordant Cellular Alternans as a Novel Mechanism for
Arrhythmogenesis in Heart Failure
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Keywords:
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Arrhythmias,Heart failure,Ventricular tachycardia,Ventricular action
potential,Electrophysiology
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Author Block:
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Lance D Wilson, Darwin Jeyaraj, Kenneth R Laurita, David S
Rosenbaum, Case Western Reserve Univ, Cleveland, OH
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Disclosure Block:
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L.D. Wilson, None; D. Jeyaraj, None; K.R.
Laurita, None; D.S. Rosenbaum, None.
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Unlabeled/unapproved:
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There are no unlabeled/unapproved uses of drugs or products
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T wave alternans, a powerful marker for sudden cardiac death, is
caused by beat-to-beat alternation of repolarization at the cellular level
and is closely linked to altered intracellular calcium cycling. Previously,
we showed that spatially discordant cellular alternans (DIS-ALT) amplifies
dispersion of repolarization and is a mechanism for reentrant
arrhythmogenesis. Since heart failure (HF) significantly alters calcium
cycling, we hypothesized that HF promotes arrhythmogenic DIS-ALT. High-resolution
optical mapping was used to simultaneously record action potentials from
the transmural surface of arterially perfused canine wedge preparations
(35° C) harvested from dogs with HF induced by chronic rapid pacing (n=5)
and unpaced controls (n=5). Action potential duration (APD) alternans was
induced by a ramp pacing protocol. The heart rate threshold for alternans
was significantly lower in HF dogs vs. controls (188±17 vs. 230±26 bpm,
p<0.02), demonstrating that HF myocytes are intrinsically more
susceptible to alternans. DIS-ALT was observed in 5/5 HF dogs and only 1/5
controls (p<0.05). In HF, DIS-ALT typically developed between regions of
epicardium and endocardium, leading to transmural conduction block. Ventricular
tachycardia (VT) was preceded by DIS-ALT in 4/5 HF dogs; however, VT was
not observed in any controls (p<0.05). Conclusions: HF
predisposes the myocardium to alternans, and importantly arrhythmogenic
DIS-ALT. Spatially discordant APD alternans represents a novel cellular
mechanism for VT in failing myocardium.
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