Download Role of Structural Barriers in the Mechanism of Alternans

Role of Structural Barriers in the Mechanism of AlternansInduced Reentry
Joseph M. Pastore, M.S., Manish H. Shah, B.S., David S. Rosenbaum, M.D.
The Heart and Vascular Center, MetroHealth Campus of Case Western Reserve University, Cleveland,
Ohio
Short Title: Alternans-Induced Reentry
Presented in part at the 20th annual scientific sessions of the North American Society of Pacing and
Electrophysiology, Toronto, 1999
Address correspondence to:
David S. Rosenbaum, M.D.
Director, Heart and Vascular Center
Professor of Medicine, Biomedical Engineering, Physiology and
Biophysics
MetroHealth Campus, Case Western Reserve University
2500 MetroHealth Drive, Hamman 330
Cleveland, Ohio 44109-1998
TEL: (216) 778-2005
FAX: (216) 778-4924
e-mail: [email protected]
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ABSTRACT
Background: Previously, using an animal model of T wave alternans in structurally normal myocardium,
we demonstrated that action potential duration (APD) can alternate with opposite phase between
neighboring cells (i.e. discordant alternans) causing spatial dispersions of repolarization which form the
substrate for functional block, reentry, and ventricular fibrillation (VF). We hypothesize that electrotonic
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uncoupling between neighboring regions of cells by structural barriers is a mechanism for discordant
alternans.
Methods and Results: Optical action potentials were recorded simultaneously from 128 ventricular
sites in 24 Langendorff perfused guinea pig hearts. In 5 experiments, the ventricle was paced over a
broad range of steady-state heart rates in the absence (i.e. control) and presence of a structural barrier
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produced by a 10x2 mm epicardial laser-lesion. In controls, APD alternated in phase at all ventricular
sites above a critical heart rate, i.e. concordant alternans. Also, above a faster critical heart rate
threshold, APD alternated with opposite phase between sites, i.e. discordant alternans. In contrast, only
discordant alternans, not concordant alternans, was observed in 80% of hearts with the structural
barrier, and discordant alternans always occurred at a significantly (p<.05) slower heart rate (by 6
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bpm) compared to control.
Conclusions: These data also suggest a singular mechanism by which T-wave alternans forms a substrate
for initiation of both VF and VT.
Key Words: reentry, alternans, torsade de points, action potentials, arrhythmia, ion channels, mapping
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T-wave alternans is a beat-to-beat fluctuation in the amplitude of the electrocardiographic T
wave that repeats once every other beat, and has been closely associated with ventricular arrhythmias
and sudden cardiac death1-4. Visually-apparent T-wave alternans is known to hasten cardiac electrical
instability in a surprisingly wide variety of experimental5-10 and clinical4, 11-13 conditions. More
recently, using sensitive signal processing techniques, we found that the detection of microvolt-level,
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visually-inapparent T-wave alternans is also a strong predictor of vulnerability to ventricular arrhythmias
in patients14. Interestingly, T-wave alternans has been closely associated with polymorphic VT15, VF16,
Torsade de Pointes4, 17, and sustained monomorphic VT18 both in the absence of structural heart
disease, and in patients with advanced cardiomyopathy. Therefore, a greater understanding of the
mechanisms underlying T-wave alternans may provide important new insights into the pathophysiology
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of sudden cardiac death in a variety of clinical circumstances.
METHODS
Experimental Preparation
Hearts from 24 male retired breeder guinea pigs were rapidly excised and perfused as
Langendorff preparations with oxygenated (95% O2, 5% CO2) Tyrode’s solution containing (mmol/L)
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experiments, the endocardial surface was eliminated using a cryoablation procedure described
previously25. This procedure produces a th
electrophysiological properties25 and served to restrict propagation to the surface from which action
potentials were recorded. Hearts were stained with 100 ml of the voltage-sensitive dye di-4-ANEPPS (20
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Optical Mapping System
Previously, we have developed an optical action potential mapping system that is capable of
resolving membrane potential changes as small as 0.5 mV simultaneously from 128 sites across the
anterior epicardial surface of the intact guinea pig ventricle (see 25-27 for details). In order to map
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ventricular action potentials from sites around the entire periphery of the structural barrier, an optical
magnification of 1.2X was used which corresponded to a total mapping area of 15 mm x 15 mm, 1.25
mm inter-pixel spatial resolution, and 1 ms temporal resolution.
Measurement of Electrical Alternans
A previously validated experimental model of pacing-induced steady-state T-wave alternans16
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was used because, as is the case in patients, electrical alternans in this model persists over time (i.e.
alternans are not transient), does not require ischemic damage, and principally involves the T-wave
rather than the QRS complex14. Alternans of cellular repolarization time (RT) was determined by
measuring differences in local RT (relative to the stimulus artifact) on consecutive beats. RT and
activation times (AT) were determined from each action potential using previously described
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algorithms25, 27, 29, and all analyses were visually verified by one investigator (JMP).
RESULTS
Effect of Structural Barrier on Baseline Electrophysiology
To verify that the application of the structural barrier did not substantially alter the baseline
electrophysiology of the myocardium, conduction velocity and APD were compared at a baseline heart
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rate of 150 bpm during control and in the presence of the structural barrier. Mean conduction velocity
transverse to fibers measured during control (24
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est)
DISCUSSION
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For more than three quarters of a century, T-wave alternans has been closely associated with
susceptibility to ventricular arrhythmias in remarkably broad patient populations both with14 and
without4 structural heart disease. Furthermore, T-wave alternans is now available as a clinical tool to
screen for patients at risk for sudden cardiac death. Recently, we demonstrated that T-wave alternans
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is linked to the mechanism of reentry by discordant alternans which develop between cells possessing
different electrophysiological properties16.
Importantly, discordant alternans greatly amplifies
dispersion of repolarization which produce conditions necessary for functional block and reentry. We
hypothesized that electrical uncoupling by a structural barrier increases the propensity for discordant
alternans which may explain a mechanism for T-wave alternans and arrhythmias in patients with
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structural heart disease.
ACKNOWLEDGMENTS
This study was supported by National Institutes of Health grant RO1-HL54807
TABLES
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REFERENCES
1.
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Lewis T: Notes upon alternation of the heart.
Quart.J.Med. 1910;4:141-144 This is the
continuation of the reference
FIGURE LEGENDS
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Figure 1. Experimental setup. Langendorff-perfused guinea pig heart was stained with voltage sensitive
dye and action potentials were mapped form a 1.5 cm x 1.5 cm mapping area (square grid). The left
ventricle was stimulated (square pulse symbol) over a broad range of CLs in absence (i.e. control) and
presence of a structural barrier. ECGs were recorded from electrodes immersed in the saline effluent.
RA: Right Atrium; LA: Left Atrium; RV: Right Ventricle; LV: Left Ventricle; LAD: Left Anterior Descending
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Coronary Artery.
Figure 2.
Effect of structural barrier on repolarization alternans. Top graph illustrates relationship
between local repolarization alternans and heart rate in absence (i.e. control, open circles) and presence
(filled circles) of structural barrier. Notice in both cases repolarization alternans occurs above a
threshold heart rate that is lower with structural barrier (240 bpm) compared to control (300 bpm).
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Repolarization alternans is also demonstrated by superposition of average even and odd action
potentials at right. Bottom graph plots relationship between T-wave alternans and heart rate. Notice
that presence of structural barrier shifts curve to the left.