Ventricular fibrillation is a lethal arrhythmia characterized by multiple wavelets usually starting from a single or figure-of-eight re-entrant circuit. Understanding the factors regulating vulnerability to the re-entry is essential for developing effective therapeutic strategies to prevent ventricular fibrillation. In this study, we investigated how pre-existing tissue heterogeneities and electrical restitution properties affect the initiation of re-entry by premature extrastimuli in two-dimensional cardiac tissue models. We studied two pacing protocols for inducing re-entry following the “sinus” rhythm (S1) beat: (1) a single premature (S2) extrastimulus in heterogeneous tissue; (2) two premature extrastimuli (S2 and S3) in homogeneous tissue. In the first case, the vulnerable window of re-entry is determined by the spatial dimension and extent of the heterogeneity, and is also affected by electrical restitution properties and the location of the premature stimulus. The vulnerable window first increases as the action potential duration (APD) difference between the inside and outside of the heterogeneous region increases, but then decreases as this difference increases further. Steeper APD restitution reduces the vulnerable window of re-entry. In the second case, electrical restitution plays an essential role. When APD restitution is flat, no re-entry can be induced. When APD restitution is steep, re-entry can be induced by an S3 over a range of S1S2 intervals, which is also affected by conduction velocity restitution. When APD restitution is even steeper, the vulnerable window is reduced due to collision of the spiral tips.
Sudden cardiac death due to ventricular fibrillation remains the leading cause of death in industrialized countries, while atrial fibrillation is the most common arrhythmia with significant morbidity and mortality. Anti-arrhythmic drugs have limited efficacy and may even increase mortality. One key question that is of both theoretical and clinical importance is how the arrhythmia is first initiated and what affects the probability of its occurrence. In the past two decades, mathematical modeling combined with theories of nonlinear dynamics has greatly improved our understanding of cardiac arrhythmias. In the present study, we used computer simulation to tackle this problem by studying how premature excitations induce re-entry in both heterogeneous and homogeneous tissue models and what critical parameters affect the likelihood of re-entry occurrence. The observations provide a theoretical bases for illuminating experimental findings and designing experimentally testable predictions for new biological experiments.
This work was supported by NIH/NHLBI Grant No. P01 HL078931, the Laubisch and Kawata endowments, and the NSF GK12 Fellowship (D.T.).
APD and CV restitution
Definition of re-entry
Vulnerability to re-entry by a single premature extrasystole in heterogeneous tissue
Effects of the size of the heterogeneity
Effects of symmetry
Effects of APD restitution slope
Effects of stimulation site
Vulnerability to re-entry by multiple premature extrasystoles in homogeneous tissue
Effects of CV restitution
Effects of APD restitution
Vulnerability of heterogeneous tissue to a single extrasystole
Vulnerability of homogeneous tissue to multiple extrasystoles
Clinical implications and limitations
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