Mechanistic Macro Models of Arrhythmias

Changes in the normal functioning of the above ion channels, in space and/or time as a result of arrhythmogenic stimuli, result in the initiation and maintenance of the two major macro mechanisms of arrhythmogenesis, namely ectopic foci and re-entry. Since regular rhythmic beating requires appropriate pacing, excitability, conduction, and refractoriness, disturbances of any of these four functions can give rise to arrhythmias via either, or both, of the two mechanisms.11

6.33.2.2.1 Ectopic foci

Ectopic foci (errors in pacing) occur when pacing occurs at sites that do not normally act as cardiac pacemakers. Most cardiac tissues do not exhibit pacing if entirely healthy, but previously stable tissue can be induced to pace as a result of damage and resulting stimuli that reduce the membrane potential, or its stability. It is not known whether such ectopic pacing involves revealing pacemaker currents that may be inherent in all tissue. The more obvious mechanism involved is early or late after-depolarizations due to membrane instability following intracellular calcium overload.

Re-entry (errors in conduction, and/or refractoriness) circuits (Figure 3)12 have their origin in regions of depressed excitability and conduction. Over certain ranges, such changes can result in a unidirectional block of conduction such that by conducting in one direction, but not in the other, re-entry circuits (rotors) are set up (Figure 3). Both macro and micro re-entry circuits are possible. In AV nodal tissue, macro re-entry is responsible for supraventricular tachycardia which can involve Ca2 + dependent conduction, or Na+ dependent aberrant conduction pathways. Reentry circuits (rotors) can fragment into multiple circuits, i.e., fibrillation. Torsades de pointes is an arrhythmia that is probably due to single re-entry rotor wandering around the ventricles.

Figure 3 Functional model of re-entrant arrhythmias. (a) Normal conduction pathways for an impulse arriving from the AV node and down the Purkinje (P) tissue into ventricular (V) tissue. The impulses from the two pathways meet, collide, and mutually extinguish each other in ventricular tissue at V'. Panel (b) Shows where one of the Purkinje branches is damaged (shaded area) such that both antegrade (normal) conduction and retrograde (reverse) conduction are blocked at X. This condition is known as bidirectional block, and does not generate arrhythmias. (c) Damaged area in one of the Purkinje branches that blocks conduction in the antegrade direction but, because of special conditions, allows very slow retrograde conduction through the damaged area (wavy line). This is known as unidirectional block. The retrograde conduction passes into the normal tissue beyond the block, and since the normal tissue is no longer refractory by the time the retrograde impulse arrives, it is excited and an extra beat created. The result of this type of block is the generation of a sustained re-entry cycle of activation (ventricular tachycardia) circulating through the unidirectionally blocked area. The necessary conditions for re-entry are a critical degree of block in the damaged tissue, as well as appropriate conduction and refractoriness in all other parts of the circuit. Reentry can be terminated by: (1) reducing excitability in the damaged area to convert unidirectional to bidirectional block; (2) changing conduction and/or refractoriness to abolish the re-entry circuit; the physical length of a re-entry circuit is the product of conduction velocity and refractory period. Therefore the limiting physical boundary for a re-entry circuit is the sum of (conduction velocity times refractory period in normal tissue) plus (conduction velocity times refractory period in the damaged tissue). Appropriate changes in the two properties in either tissue can make the occurrence of the re-entry circuit physically impossible.

How do the above models explain human arrhythmias? The answer to this question depends upon the type of arrhythmia (Table 1):

1. SA and AV nodal tachycardias are primarily due to excess neurotransmitter or hormone (norepinephrine or thyroxine), which increases pacing currents. Bradycardia is primarily due to ACh released from parasympathetic nerves. However, inherent defects in nodes or damage to nodes can cause alterations of rate. Fibrosis can damage such nodes.

2. Atrial arrhythmias are initiated by excess cardiac sympathetic nerve activity, scars, and fibrotic areas in the atria, or excessive stretch on atrial fibers. Such pathology can cause PACs from ectopic foci, or re-entry circuits in left, or right, or both atria (the two atria are not identical in this respect). A single maintained re-entry circuit will cause a tachycardia whereas multiple re-entries gives rise to atrial fibrillation. The site of origin of some atrial arrhythmias may be where large blood vessels enter the atria.

3. Conduction defects in the AV node will cause AV node block. Micro re-entry circuits can occur in the AV node and give rise to supraventricular nodal tachycardias.

4. The pathological mechanisms that give rise to atrial tachycardia and fibrillation also give rise to the same type of arrhythmias in ventricles. Thus, damage to Purkinje fibers will produce intraventricular conduction block, while in

Table 1 Possible mechanisms involved in the genesis of particular arrhythmias®

Arrhythmia

Cause

Mechanism

SA and AV nodal tachycardia

Bradycardia

Atrial arrhythmia

AV nodal block Ventricular arrhythmia

Excess norepinephrine from sympathetic nerve, or excess of other hormones, such as thyroxine Excess acetylcholine from parasympathetic nerve, damaged nodes due to nodal fibrosis Excess sympathetic nervous activity, scars, and fibrosis or stretch in atrial tissue

Damaged AV node/Purkinje tissues

Excess sympathetic nervous activity, scars, and fibrosis or stretch in ventricular tissue

Increase in pacing currents; micro re-entry circuits in the AV node can cause supraventricular nodal tachycardia Decrease in pacing currents or a 'sick' SA node

Ectopic foci and re-entry; single re-entry; leads to atrial tachycardia and multiple re-entries lead to atrial fibrillation; source is often near or in the veins entering atria Failure to conduct electrical signals from atria across to the ventricles Ectopic foci and re-entry; Single re-entry leads to ventricular tachycardia and multiple re-entries lead to ventricular fibrillation aSince ionic mechanisms are often of mixed origin, and cannot be readily identified, they are not considered in this table, only in the text.

Arrhythmias are categorized according to anatomical site.

the ventricles, single re-entry circuits result in ventricular tachycardia, and multiple circuits in ventricular fibrillation. Torsades de pointes is thought to arise as a result of after-depolarizations due to calcium overload, while induction of a re-entry circuit due to inappropriate heterogeneity of repolarization provides substrate for its maintenance.

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