Model of unidirectional block formation leading to reentrant ventricular tachycardia in the infarct border zone of postinfarction canine hearts

AbstractBackgroundWhen the infarct border zone is stimulated prematurely, a unidirectional block line (UBL) can form and lead to double-loop (figure-of-eight) reentrant ventricular tachycardia (VT) with a central isthmus. The isthmus is composed of an entrance, center, and exit. It was hypothesized that for certain stimulus site locations and coupling intervals, the UBL would coincide with the isthmus entrance boundary, where infarct border zone thickness changes from thin-to-thick in the travel direction of the premature stimulus wavefront.MethodA quantitative model was developed to describe how thin-to-thick changes in the border zone result in critically convex wavefront curvature leading to conduction block, which is dependent upon coupling interval. The model was tested in 12 retrospectively analyzed postinfarction canine experiments. Electrical activation was mapped for premature stimulation and for the first reentrant VT cycle. The relationship of functional conduction block forming during premature stimulation to functional block during reentrant VT was quantified.ResultsFor an appropriately placed stimulus, in accord with model predictions: 1. The UBL and reentrant VT isthmus lateral boundaries overlapped (error: 4.8±5.7mm). 2. The UBL leading edge coincided with the distal isthmus where the center-entrance boundary would be expected to occur. 3. The mean coupling interval was 164.6±11.0ms during premature stimulation and 190.7±20.4ms during the first reentrant VT cycle, in accord with model calculations, which resulted in critically convex wavefront curvature and functional conduction block, respectively, at the location of the isthmus entrance boundary and at the lateral isthmus edges.DiscussionReentrant VT onset following premature stimulation can be explained by the presence of critically convex wavefront curvature and unidirectional block at the isthmus entrance boundary when the premature stimulation interval is sufficiently short. The double-loop reentrant circuit pattern is a consequence of wavefront bifurcation around this UBL followed by coalescence, and then impulse propagation through the isthmus. The wavefront is blocked from propagating laterally away from the isthmus by sharp increases in border zone thickness, which results in critically convex wavefront curvature at VT cycle lengths

Application of nonlinear methods to discriminate fractionated electrograms in paroxysmal versus persistent atrial fibrillation

Background and Objective: Complex fractionated atrial electrograms (CFAE) may contain information concerning the electrophysiological substrate of atrial fibrillation (AF); therefore they are of interest to guide catheter ablation treatment of AF. Electrogram signals are shaped by activation events, which are dynamical in nature. This makes it difficult to establish those signal properties that can provide insight into the ablation site location. Nonlinear measures may improve information. To test this hypothesis, we used nonlinear measures to analyze CFAE. Methods: CFAE from several atrial sites, recorded for a duration of 16 s, were acquired from 10 patients with persistent and 9 patients with paroxysmal AF. These signals were appraised using non-overlapping windows of 1-, 2- and 4-s durations. The resulting data sets were analyzed with Recurrence Plots (RP) and Recurrence Quantification Analysis (RQA). The data was also quantified via entropy measures. Results: RQA exhibited unique plots for persistent versus paroxysmal AF. Similar patterns were observed to be repeated throughout the RPs. Trends were consistent for signal segments of 1 and 2 s as well as 4 s in duration. This was suggestive that the underlying signal generation process is also repetitive, and that repetitiveness can be detected even in 1-s sequences. The results also showed that most entropy metrics exhibited higher measurement values (closer to equilibrium) for persistent AF data. It was also found that Determinism (DET), Trapping Time (TT), and Modified Multiscale Entropy (MMSE), extracted from signals that were acquired from locations at the posterior atrial free wall, are highly discriminative of persistent versus paroxysmal AF data. Conclusions: Short data sequences are sufficient to provide information to discern persistent versus paroxysmal AF data with a significant difference, and can be useful to detect repeating patterns of atrial activation

Determinants of the outcome of electrophysiologic study in patients with ventricular tachyarrhythmias

To determine those factors predictive of the ability to both initiate and suppress ventricular tachyarrhythmias during electrophysiologic study, the results of programmed cardiac stimulation were evaluated in 261 patients: 66 presenting with nonsustained ventricular tachycardia, 91 with sustained ventricular tachycardia and 104 with ventricular fibrillation. Multivariate logistic regression analysis revealed that the presenting arrhythmia was a potent and independent predictor of the ability to provoke ventricular arrhythmias at electrophysiologic study; a history of myocardial infarction and male sex were also significant independent predictors. Of patients presenting with sustained ventricular tachycardia, 89% (81 of 91) had inducible ventricular arrhythmias compared with 61 (40 of 66) and 66% (69 of 104) of patients with nonsustained ventricular tachycardia and ventricular fibrillation, respectively.Complete suppression of inducible arrhythmias could be achieved in only 52% (34 of 66) of patients with sustained ventricular tachycardia, compared with 73 (24 of 33) and 75% (46 of 61) of patients presenting with nonsustained ventricular tachycardia and ventricular fibrillation, respectively. Multivariate analysis showed that the major independent determinants of the ability to suppress inducible arrhythmias were the number of drug trials performed before electrophysiologic study (inversely correlated) and the nature of the induced arrhythmia.The nature of the presenting clinical arrhythmia is, therefore, a highly significant and independent predictor of the ability to induce ventricular arrhythmias during electrophysiologic testing and an important determinant of the ability to suppress induced arrhythmias in patients with spontaneous ventricular tachyarrhythmias

Slow uniform electrical activation during sinus rhythm is an indicator of reentrant VT isthmus location and orientation in an experimental model of myocardial infarction.

BACKGROUND: To validate the predictability of reentrant circuit isthmus locations without ventricular tachycardia (VT) induction during high-definition mapping, we used computer methods to analyse sinus rhythm activation in experiments where isthmus location was subsequently verified by mapping reentrant VT circuits. METHOD: In 21 experiments using a canine postinfarction model, bipolar electrograms were obtained from 196-312 recordings with 4mm spacing in the epicardial border zone during sinus rhythm and during VT. From computerized electrical activation maps of the reentrant circuit, areas of conduction block were determined and the isthmus was localized. A linear regression was computed at three different locations about the reentry isthmus using sinus rhythm electrogram activation data. From the regression analysis, the uniformity, a measure of the constancy at which the wavefront propagates, and the activation gradient, a measure that may approximate wavefront speed, were computed. The purpose was to test the hypothesis that the isthmus locates in a region of slow uniform activation bounded by areas of electrical discontinuity. RESULTS: Based on the regression parameters, sinus rhythm activation along the isthmus near its exit proceeded uniformly (mean r2= 0.95±0.05) and with a low magnitude gradient (mean 0.37±0.10mm/ms). Perpendicular to the isthmus long-axis across its boundaries, the activation wavefront propagated much less uniformly (mean r2= 0.76±0.24) although of similar gradient (mean 0.38±0.23mm/ms). In the opposite direction from the exit, at the isthmus entrance, there was also less uniformity (mean r2= 0.80±0.22) but a larger magnitude gradient (mean 0.50±0.25mm/ms). A theoretical ablation line drawn perpendicular to the last sinus rhythm activation site along the isthmus long-axis was predicted to prevent VT reinduction. Anatomical conduction block occurred in 7/21 experiments, but comprised only small portions of the isthmus lateral boundaries; thus detection of sinus rhythm conduction block alone was insufficient to entirely define the VT isthmus. CONCLUSIONS: Uniform activation with a low magnitude gradient during sinus rhythm is present at the VT isthmus exit location but there is less uniformity across the isthmus lateral boundaries and at isthmus entrance locations. These factors may be useful to verify any proposed VT isthmus location, reducing the need for VT induction to ablate the isthmus. Measured computerized values similar to those determined herein could therefore be assistive to sharpen specificity when applying sinus rhythm mapping to localize EP catheter ablation sites

Depression and Risk of Sudden Cardiac Death and Coronary Heart Disease in Women Results From the Nurses' Health Study

ObjectivesWe assessed the association between depression and sudden cardiac death (SCD) and cardiac events among individuals without baseline coronary heart disease (CHD).BackgroundDepression is a risk factor for cardiac events and mortality among those with CHD, possibly from arrhythmia.MethodsWe studied depressive symptoms and a proxy variable for clinical depression consisting of severe symptoms and/or antidepressant medication use and their relationship to cardiac events in the Nurses' Health Study. Questionnaires in 1992, 1996, and 2000 assessed symptoms with the Mental Health Index (MHI-5), and antidepressant use was assessed in 1996 and 2000. Primary end points included SCD, fatal CHD, and nonfatal myocardial infarction.ResultsAmong 63,469 women without prior CHD/stroke in 1992, 7.9% had MHI-5 scores <53, previously found to predict clinical depression. Depressive symptoms were associated with CHD events, and the relationship was strongest for fatal CHD, where the association remained significant even after controlling for CHD risk factors (hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.11 to 2.00 for MHI-5 score <53). In models from 1996 onward, our proxy variable for clinical depression was most associated with SCD in multivariable models (HR: 2.33, 95% CI: 1.47 to 3.70), and this risk was primarily due to a specific relationship between antidepressant use and SCD (HR: 3.34, 95% CI: 2.03 to 5.50).ConclusionsIn this cohort of women without baseline CHD, depressive symptoms were associated with fatal CHD, and a measure of clinical depression including antidepressant use was specifically associated with SCD. Although antidepressant use might be a marker of worse depression, its specific association with SCD merits further study

Women, but not men, have prolonged QT interval if depressed after an acute coronary syndrome

Aims Depression is a mortality risk marker for acute coronary syndrome (ACS) patients. We hypothesized that the QT interval, a predictor for risk of sudden cardiac death, was related to depressive symptoms in ACS. Methods and results We performed an analysis of admission electrocardiograms from hospitalized patients with unstable angina or non-ST elevation myocardial infarction from two prospective observational studies of depression in ACS. Depressive symptoms were assessed with the Beck Depression Inventory (BDI), and depression was defined as BDI score ≥10, compared with <5. Patients with QRS duration ≥120 ms and/or who were prescribed antidepressants were excluded. QT intervals were adjusted for heart rate by two methods. Our analyses included 243 men (40.0% with BDI ≥10) and 139 women (62.0% with BDI ≥ 10). Among women, average QT corrected by Fridericia's method (QTcF) was 435.4 ± 26.6 ms in the depressed group, vs. 408.6 ± 24.3 ms in the non-depressed group (P< 0.01). However, among men, average QTcF was not significantly different between the depressed and non-depressed groups (415.4 ± 23.6 vs. 412.0 ± 25.8 ms, P= 0.29). In multivariable analyses that included hypertension, diabetes, ACS type, left ventricular ejection fraction <0.40, and use of QT-prolonging medication, there was a statistically significant interaction between depressive symptoms and gender (P< 0.001). Conclusions In this ACS sample, prolongation of the QT interval was associated with depressive symptoms in women, but not in men. Further investigation of the mechanism of the relationship between depression and abnormal cardiac repolarization, particularly in women, is warranted to develop treatment strategies

Source-sink mismatch causing functional conduction block in re-entrant ventricular tachycardia

Ventricular tachycardia (VT) caused by a re-entrant circuit is a life-threatening arrhythmia that at present cannot always be treated adequately. A realistic model of re-entry would be helpful to accurately guide catheter ablation for interruption of the circuit. In this review, models of electrical activation wavefront propagation during onset and maintenance of re-entrant VT are discussed. In particular, the relationship between activation mapping and maps of transition in infarct border zone thickness, which results in source-sink mismatch, is considered in detail and supplemented with additional data. Based on source-sink mismatch, the re-entry isthmus can be modeled from its boundary properties. Isthmus boundary segments with large transitions in infarct border zone thickness have large source-sink mismatch, and functional block forms there during VT. These alternate with segments having lesser thickness change and therefore lesser source-sink mismatch, which act as gaps, or entrance and exit points, to the isthmus during VT. Besides post-infarction substrates, the source-sink model is likely applicable to other types of volumetric changes in the myocardial conducting medium, such as when there is presence of fibrosis or dissociation of muscle fibers

Localized reentry. Mechanism of induced sustained ventricular tachycardia in canine model of recent myocardial infarction.

This study was undertaken to investigate the mechanism underlying sustained monomorphic ventricular tachycardia (VT) in late experimental canine myocardial infarction. The hypothesis that sustained and "organized" continuous electrical activity (CEA) displaying a reproducible pattern with recurrent components recorded by bipolar endocardial, intramural, or epicardial electrodes in 10 animals during electrically induced sustained monomorphic VT represented reentrant excitation in an anatomically small area of the ventricle, was evaluated in the light of the following observations: Organized CEA always preceded the first monomorphic ventricular complex (QRS) of VT as well as the discrete local electrograms from closely surrounding sites during the initiation of VT. The site of organized CEA corresponded to the site of origin of sustained VT determined by iso-chronous contour map analysis of activation sequence. Ventricular pacing at rates more rapid than that of VT failed to terminate VT despite ventricular capture unless it transformed CEA into discrete local electrograms. VT could be terminated in three animals, with a single, critically timed premature stimulus delivered at a critically located focus close to the site of CEA, which would result in local capture and interrupted CEA. In six animals, surgical ablation of the site of organized CEA effectively prevented the reinitiation of sustained VT by programmed cardiac stimulation. These data showed that organized CEA and sustained VT were closely associated phenomena and suggested that organized CEA probably represented an important component of the tachycardia circuit

Effects of refractory gradients and ablation on fibrillatory activity

Background The mechanisms involved in onset, maintenance, and termination of atrial fibrillation are not well understood. A biophysical model could be useful to determine how the events unfold. Method A two-dimensional cellular automaton consisting of 576 × 576 grid nodes was implemented to demonstrate the types of electrical activity that may occur in compromised atrial substrate. Electrical activation between nodes was made anisotropic (2:1), and the refractory period (RP) was adjusted from 74 to 192 ms in the spatial domain. Presence of collagen fibers were simulated as short lines of conduction block at many random grid sites, while ablation lesions were delineated as longer lines of block. An S1-S2 pulse from one grid corner was utilized to initiate simulated electrical activity. Simulations were done in which 1. no ablation lines, 2. random ablation lines, and 3. parallel ablation lines were added to the grid to determine how this affected the formation and annihilation of rotational activity after S1-S2 stimulation. Results As the premature (S2) wavefront traversed the grid, rotational activity formed near boundaries where wavefronts propagated from shorter to longer refractory regions, causing unidirectional block, and were anchored by fiber clusters. Multiple wavelets appeared when wavefronts originating from different driving rotational features collided, and/or by their encounter with RP discontinuities. With the addition of randomly orientated simulated ablation lesions, followed by reinduction of fibrillatory activity, mean activation interval (AI) prolonged from a baseline level of 144.2 ms–160.3 ms (p < 0.001 in most comparisons). During fibrillatory activity, when parallel ablation lines were added to short RP regions, AI prolonged to 150.4 ms (p < 0.001), and when added to long RP regions, AI prolonged to 185.3 ms (p < 0.001). In all cases, AI prolongation after simulated ablation resulted from reduced number and/or from the isolation of local drivers, so that distant drivers in short RP regions activated long RP regions N:1, while distant drivers in long RP regions activated short RP regions at a relatively slow rate. Conclusions An automaton model was found useful to generate and test hypotheses concerning fibrillatory activity, which can then be validated in the clinical electrophysiology laboratory

Use of an automaton model to suggest methods for cessation of intractable fibrillatory activity

BACKGROUND: Atrial fibrillation (AF) is the most common heart arrhythmia, and permanent AF is an intractable medical problem. If cessation of permanent AF were possible, via extensive substrate ablation or multisite stimulation, it could significantly improve the public health. METHOD: A cellular automaton composed of 576 × 576 computerized grid nodes, described in detail previously, was used to test hypotheses concerning the cessation of fibrillatory electrical activity. A refractory period gradient across the grid, and addition of randomly located nonconducting fibers, were utilized as conditions leading to fibrillatory activity. A premature S1-S2 stimulus was applied to one grid corner, resulting in unidirectional conduction block at some locations, followed by rotational activity and random propagation of activation wavelets throughout the grid, none of which terminated spontaneously. Simulated ablation lesions of dimension 20 × 20 grid nodes, imparted at core locations of rotational activity, and multisite electrode stimulation (MES) applied at nodes where recovery of excitability had occurred, were used in attempts to terminate fibrillatory activity. Six impositions of random fiber location were utilized in separate trials. RESULTS: Simulated ablation lesions eliminated the targeted swirling vortices; however, additional vortices then often appeared at other locations. After ablating approximately one third of the grid area, localized vortices were eliminated, but individual wavelets continued to propagate about longer viable pathways forming at ablation lesions. Thus extensive ablation was unsuccessful in terminating arrhythmia. However, MES applied uniformly throughout the grid, with a coupling interval slightly longer than the maximum refractory period, terminated fibrillatory activity in some trials. More efficaciously, application of MES with a coupling interval half the maximum refractory period of the grid succeeded in capture of activation at all nodes, and when followed by a doubling of the MES coupling interval, resulted in cessation of all fibrillatory activity. CONCLUSIONS: It is possible to terminate simulated fibrillatory activity in a computerized grid that would otherwise be intractable, using multisite stimulation with a coupling interval related to the maximum refractory period of the substrate. If each MES stimulating electrode could be individually controlled, it would be possible to apply a stimulation pattern mimicking the normal heart activation sequence