Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry

Abstract

Previously, using an animal model of T-wave alternans in structurally normal myocardium, we demonstrated that repolarization can alternate with opposite phase between neighboring myocytes (ie, discordant alternans), causing spatial dispersions of repolarization that form the substrate for functional block and reentrant ventricular fibrillation (VF). However, the mechanisms responsible for cellular discordant alternans and its electrocardiographic manifestation (ie, T-wave alternans) in patients with structural heart disease are unknown. We hypothesize that electrotonic uncoupling between neighboring regions of cells by a structural barrier (SB) is a mechanism for discordant alternans. Using voltage-sensitive dyes, ventricular action potentials were recorded from 26 Langendorff-perfused guinea pig hearts in the absence (ie, control) and presence of an insulating SB produced by an epicardial laser lesion. Quantitative analysis of magnitude and phase of cellular alternans revealed that in controls, action potential duration alternated in phase at all ventricular sites above a critical heart rate (269+/-17 bpm), ie, concordant alternans. Also, above a faster critical heart rate threshold (335+/-24 bpm), action potential duration alternated with opposite phase between sites, ie, discordant alternans. In contrast, only discordant but not concordant alternans was observed in 80% of hearts with the SB, and discordant alternans always occurred at a significantly slower heart rate (by 68+/-28 bpm) compared with controls. Therefore, the SB had a major effect on the alternans-heart rate relation, which served to facilitate the development of discordant alternans. Whether a SB was present or not, discordant alternans produced considerable increases (by approximately 170%) in the maximum spatial gradient of repolarization, which in turn formed the substrate for unidirectional block and reentry. However, by providing a structural anchor for stable reentry, discordant alternans in the presence of a SB led most often to sustained monomorphic ventricular tachycardia rather than to VF, whereas in the absence of a SB discordant alternans caused VF. SBs facilitate development of discordant alternans between cells with different ionic properties by electrotonically uncoupling neighboring regions of myocardium. This may explain why arrhythmia-prone patients with structural heart disease exhibit T-wave alternans at lower heart rates. These data also suggest a singular mechanism by which T-wave alternans forms a substrate for initiation of both VF and sustained monomorphic ventricular tachycardia.

Control of Electrical Alternans in Canine Cardiac Purkinje Fibers

“…Without control, this magnitude is largest in the state of discordant alternans shown in the top panel of Fig. 1(c), which is directly analogous to the state that has been shown to promote the initiation of high-frequency reentrant spiral waves in ventricular tissue [2][3][4][5]. In contrast, this magnitude is reduced in the standing wave mode induced by feedback control shown in the bottom panel of Fig.…”

“…Because heart cells are refractory to further stimulation during an action potential, alternans of APD results in an alternans of refractoriness, the magnitude of which may vary across different regions of the heart. Several studies have shown that the resulting spatial dispersion of refractoriness facilitates the development of local conduction block [2][3][4][5], which may in turn cause the normally planar wave of electrical excitation in cardiac tissue to break and form spiral waves [6]. If the spiral waves also encounter regions of disparate refractoriness, they may disintegrate into multiple wavelets, which may account for the onset of the lethal heart rhythm disorder ventricular fibrillation [7][8][9].…”

Approche multi-échelle appliqué à la modélisation de l’activité électrique du coeur

“…Dans un modèle expérimental de défaillance cardiaque induite par la stimulation rapide et prolongée des ventricules, l'augmentation de la pression auriculaire entraîne un taux important de mort cellulaire et le remplacement des myocytes nécrosés par du collagène, ce qui correspond à la fibrose [14]. Ce remodelage engendre l'isolation électrique des myocytes voisins et forme des barrières à la propagation propices au processus de réen-trée [15]. L'interaction onde-obstacle peut augmenter la courbure de l'onde électrique, ce qui ralentit sa propagation et module la durée du potentiel d'action [16,17].…”

Noninvasive Diagnosis of Cardiac Sarcoidosis Using Microvolt T-Wave Alternans

“…8) Cell-to-cell uncoupling, caused by the insulating structural barriers seen in some types of heart diseases, augment the transmural gradients of action potential duration through inhibition of electrotonic influence from neighboring cells. 9) We speculated that granulomatous changes of the ventricles associated with lymphocyte infiltration or fibrosis, or both, would cause cell-to-cell uncoupling and increase the transmural gradient of action potential duration, which would result in the augmentation of MVTWA in patients with cardiac sarcoidosis. We therefore hypothesized that noninvasive examination of MVTWA allows prediction of cardiac involvement in patients with sarcoidosis.…”