Functional, structural, and dynamic basis of electrical heterogeneity in healthy and diseased cardiac muscle

Abstract

The electrophysiological properties of the ventricular myocardium are extremely heterogeneous. There are intrinsic electrical differences between the myocytes from different regions of the heart (most notably between the epicardium, midmyocardium, and endocardium), which are the result of different contributions of ionic currents to the transmembrane action potential. Sources of local anisotropy include directional differences in the distribution of gap junctions between adjacent myocytes and the presence of intercalated non-myocytes (e.g., fibroblasts), propagation boundaries, and wavefront collisions, which can lead to local variability of electrical load and, therefore, to nonuniform depolarisation and repolarisation. In addition, the complex anatomical arrangement of the myocardial fibres and nonuniform distribution of transmural mechanical stresses also contribute to electrical heterogeneity. Finally, dispersion of repolarisation is dynamically modified by the restitution properties of individual myocytes, stimulation rate, and the direction of conduction. All aspects of this electrical heterogeneity can be affected by different pathological conditions, such as myocardial ischaemia and cardiac hypertrophy. In particular, differential responses of various myocyte populations to these pathological stimuli and a marked increase in nonuniform anisotropy may be responsible for increased pro-arrhythmic potential in these conditions. In addition, the clinical effectiveness of anti-arrhythmic drugs may be related to their effects on electrical heterogeneity.

Introduction

Although our knowledge of the mechanisms responsible for cardiac arrhythmias has increased considerably in recent years, clinical attempts to control life-threatening ventricular arrhythmias with pharmacological agents have failed Echt et al. 1991, Waldo et al. 1996. Hence, there is a need to re-examine our understanding of the complexity of cardiac electrophysiology in relation to anti- or pro-arrhythmic drug actions.

Cardiac arrhythmias can be roughly divided into those resulting from abnormal impulse initiation and those resulting from abnormal impulse propagation. The former may be based on abnormal automaticity or triggered activity. The automaticity of normal pacemaker cells (the sinus node and the specialised fibres in the atria, the atrio-ventricular junction, the His-Purkinje system) occurs at physiological membrane potentials that are normal for these cell types and can be suppressed by stimulation at a rate faster than their spontaneous rate of firing (overdrive suppression). In contrast, cells whose resting membrane potential is reduced to levels less negative than their own normal level (e.g., due to ischaemia) can generate abnormal automaticity, characterised by a lack of overdrive suppression and a much faster rate than might be seen in these cells under normal conditions (Waldo & Wit, 1993). Another mechanism of abnormal impulse formation is triggered activity, which depends on the presence of early or delayed afterdepolarisations. Afterdepolarisations are oscillations of membrane potential that depend on the preceding transmembrane activity and occur during or after an action potential. Early afterdepolarisations occur during the action potential and are facilitated by cardiac hypertrophy, slow stimulation rates, hypokalaemia, hypomagnesaemia, hypoxia, acidosis, high concentrations of catecholamines, and a number of pharmacological agents (e.g., quinidine, disopyramide, sotalol) that prolong repolarisation Waldo & Wit 1993, Antzelevitch & Sicouri 1994. Delayed afterdepolarisations occur after full repolarisation, are related to intracellular calcium overload and calcium oscillations (e.g., caused by digitalis, catecholamines, myocardial infarction, cardiac hypertrophy), and increase as a stimulation rate increases Waldo & Wit 1993, Antzelevitch & Sicouri 1994. If early or delayed afterdepolarisations are sufficiently large to depolarise the cell membrane to its threshold potential, spontaneous action potentials can be induced (triggered activity).

The most likely mechanism of arrhythmias facilitated by increased electrical heterogeneity and abnormalities of impulse propagation is re-entry Han & Goel 1972, Kuo et al. 1985, Mitchell et al. 1986, Downar et al. 1988, Surawicz 1990. Namely, a properly timed stimulus can be blocked in one direction because of non-homogeneous refractoriness or impaired conduction, but it will continue to conduct in the other direction. A continuous circus movement of electrical activity will be established if the returning wavefront finds that the site of unidirectional block has recovered excitability, thus permitting conduction to proceed uninterrupted. It is known that for the self-sustained electrical activity to be established, certain critical conditions (determined by local refractory period, conduction velocity, and the length of the circular pathway) must be fulfilled. The likelihood of such an event is increased by local heterogeneity of excitability (nonuniform refractoriness). Another factor is heterogeneity and slowing of conduction, which, apart from facilitating induction of re-entry (by facilitating occurrence of a unidirectional block), is usually necessary to sustain re-entry (even in the presence of a fixed inexcitable area or unidirectional block). The reason is that even in the presence of a unidirectional block, the length of the potential re-entrant circuit is too short to allow enough time for the area of origin of the wavefront to regain excitability before it is re-entered by the travelling wavefront. It appears, therefore, that dispersion of excitability and conduction slowing are the main prerequisites for re-entry.

There are multiple sources of electrical heterogeneity in ventricular myocardium (both at a cellular and tissue level) that may have functional, structural, or dynamic bases. The aim of this review is to address a variety of mechanisms underlying electrical heterogeneity, which co-exist and interact with one another in physiological and pathophysiological conditions. As far as pathophysiological conditions are concerned, myocardial ischaemia and cardiac hypertrophy will be discussed, since they contribute significantly to electrical heterogeneity and arrhythmogenesis and remain major causes of sudden cardiac death (Myerburg et al., 1989). The complexity of heterogeneity is likely to become a major issue of anti-arrhythmic therapeutic interventions in the future and, therefore, the importance of electrical heterogeneity in arrhythmogenesis and the effectiveness of anti-arrhythmic drug therapy will also be discussed in this review.