Region of slowed conduction acts as core for spiral wave reentry in cardiac cell monolayers

Lin, Joyce W.; Garber, Libet; Qi, Yue Rosa; Chang, Marvin G.; Cysyk, Joshua; Tung, Leslie

doi:10.1152/ajpheart.00631.2007

Cited by 23 publications

(22 citation statements)

References 27 publications

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“…However, there is ample evidence that this drug exerts proarrhythmic effects by slowing conduction, facilitating the formation of reentries under ischemic conditions. This observation has been supported by experimental and clinical studies undertaken by several authors (9,31,43,46,62) and also by the present work.…”

Section: Discussionsupporting

confidence: 89%

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Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Cardona

Trénor

Moltó³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Lidocaine is a class I antiarrhytmic drug that blocks Na(+) channels and exists in both neutral and charged forms at a physiological pH. In this work, a mathematical model of pH and the frequency-modulated effects of lidocaine has been developed and incorporated into the Luo-Rudy model of the ventricular action potential. We studied the effects of lidocaine on Na(+) current, maximum upstroke velocity, and conduction velocity and demonstrated that a decrease of these parameters was dependent on pH, frequency, and concentration. We also tested the action of lidocaine under pathological conditions. Specifically, we investigated its effects on conduction block under acute regional ischemia. Our results in one-dimensional fiber simulations showed a reduction of the window of block in the presence of lidocaine, thereby highlighting the role of reduced conduction velocity and safe conduction. This reduction may be related to the antifibrillatory effects of the drug by hampering wavefront fragmentation. In bidimensional acute ischemic tissue, lidocaine increased the vulnerable window for reentry and exerted proarrhythmic effects. In conclusion, the present simulation study used a newly formulated model of lidocaine, which considers pH and frequency modulation, and revealed the mechanisms by which lidocaine facilitates the onset of reentries. The results of this study also help to increase our understanding of the potential antifibrillatory effects of the drug.

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Section: Discussionsupporting

confidence: 89%

“…Thus, spatial dispersion of CV may also cause a spatial dispersion in refractoriness and could facilitate the formation of reentrant waves. Several studies (19,31,46,62) have extensively demonstrated this effect under ischemic conditions.…”

Section: Discussionmentioning

confidence: 95%

Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Cardona

Trénor

Moltó³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Several in vitro studies (23,38) of spiral wave dynamics of tissue-engineered cardiac monolayers provide additional experimental evidence that in critical regimes near the onset of block caused either by structural properties or rapid pacing, small variations in microstructure create variations in source load that can increase the likelihood of unidirectional conduction block, reentry, and possibly wave breakup. An imagebased three-dimensional modeling study of the structurally heterogeneous infarct border zone by Smaill et al (34) has also shown that the complex pathways created by strands of viable myocytes (as thin as 1 cell) interspersed with collagen can lead to unidirectional block, prolonged activation, action potentials with a slow rising foot, and, in a few cases, reentry during rapid pacing.…”

Section: Discussionmentioning

confidence: 99%

“…They found that regions with low, heterogeneous coupling, which they called the ectopic nexus, support spontaneous activity and that spatiotemporal variations in coupling at the boundary between wellcoupled and poorly coupled tissue can strongly influence the dynamics of propagating beats (1, 2, 32). Other studies (3,23) in patterned cardiac cell monolayers with a region of slow or zig-zag conduction have shown that intrinsic heterogeneities in microscale tissue structure at the boundary of the central zone can be unmasked by loading effects during rapid pacing, leading to unidirectional conduction block and spiral wave formation. These in vitro studies are consistent with recent microstructural modeling studies demonstrating that in critical regimes near the onset of conduction block, microscopic variations in source-load mismatch at the boundary between well-coupled and poorly coupled regions can facilitate the escape of focal wavefronts that may increase the likelihood of reentry (16).…”

mentioning

confidence: 99%

A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction

Hubbard

Henriquez

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Hubbard ML, Henriquez CS. A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction. Am J Physiol Heart Circ Physiol 306: H1341-H1352, 2014. First published March 7, 2014; doi:10.1152/ajpheart.00385.2013.-Regions of cardiac tissue that have a combination of focal activity and poor, heterogeneous gap junction coupling are often considered to be arrhythmogenic; however, the relationship between the properties of the cardiac microstructure and patterns of abnormal propagation is not well understood. The objective of this study was to investigate the effect of microstructure on the initiation of reentry from focal stimulation inside a poorly coupled region embedded in more wellcoupled tissue. Two-dimensional discrete computer models of ventricular monolayers (1 ϫ 1 cm) were randomly generated to represent heterogeneity in the cardiac microstructure. A small, central poorly coupled patch (0.40 ϫ 0.40 cm) was introduced to represent the site of focal activity. Simulated unipolar electrogram recordings were computed at various points in the tissue. As the gap conductance of the patch decreased, conduction slowed and became increasingly complex, marked by fractionated electrograms with reduced amplitude. Near the limit of conduction block, isolated breakthrough sites occurred at single cells along the patch boundary and were marked by long cell-to-cell delays and negative deflections on electrogram recordings. The strongest determinant of the site of wavefront breakthrough was the connectivity of the brick wall architecture, which enabled current flow through small regions of overlapping cells to drive propagation into the well-coupled zone. In conclusion, breakthroughs at the size scale of a single cell can occur at the boundary of source-load mismatch allowing focal activations from slow conducting regions to produce reentry. These breakthrough regions, identifiable by distinct asymmetric, reduced amplitude electrograms, are sensitive to tissue architecture and may be targets for ablation. focal activity; source-load mismatch; cardiac reentry; gap junction uncoupling; unipolar electrogram recording PATHOLOGICAL CHANGES, such as decreased expression of connexin43 and high levels of fibrosis, create regions of slow conduction that can facilitate arrhythmogenesis in the heart (13,26,33). In regions of slow conduction, gap junction uncoupling reduces electrical load, making it easier for focal (ectopic) beats to form while at the same time increasing the likelihood of tortuous, "zig-zag" conduction and unidirectional conduction block, two major mechanisms underlying reentry in diseased cardiac tissue (8,20,35,40). In particular, the boundary between poorly coupled diseased tissue and wellcoupled healthy tissue has been identified as a critical region of high source-load mismatch, and a number of experimental studies (11,32,34,41) have been used to understand how the interplay between focal activations and the underlying tissue structure of th...

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“…More than 850,000 people are hospitalized for arrhythmias each year and ventricular fibrillation (VF) is a leading cause of cardiac death[1]. Despite the intensive research in this area, the mechanism of VF is still poorly understood[2–5]. …”

Section: Introductionmentioning

confidence: 99%

Patterned cardiomyocytes on microelectrode arrays as a functional, high information content drug screening platform

et al. 2011

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Cardiac side effects are one of the major causes of drug candidate failures in preclinical drug development or in clinical trials and are responsible for the retraction of several already marketed therapeutics. Thus, the development of a relatively high-throughput, high-information content tool to screen drugs and toxins would be important in the field of cardiac research and drug development. In this study, recordings from commercial multielectrode arrays were combined with surface patterning of cardiac myocyte monolayers to enhance the information content of the method; specifically, to enable the measurement of conduction velocity, refractory period after action potentials and to create a functional reentry model. Two drugs, 1-Heptanol, a gap junction blocker, and Sparfloxacin, a fluoroquinone antibiotic, were tested in this system. 1-Heptanol administration resulted in a marked reduction in conduction velocity, whereas Sparfloxacin caused rapid, irregular and unsynchronized activity, indicating fibrillation. As shown in these experiments, patterning of cardiac myocyte monolayers solved several inherent problems of multielectrode recordings, increased the temporal resolution of conduction velocity measurements, and made the synchronization of external stimulation with action potential propagation possible for refractory period measurements. This method could be further developed as a cardiac side effect screening platform after combination with human cardiomyocytes.

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Region of slowed conduction acts as core for spiral wave reentry in cardiac cell monolayers

Cited by 23 publications

References 27 publications

Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction

Patterned cardiomyocytes on microelectrode arrays as a functional, high information content drug screening platform

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