Around the beginning of the twentieth century, it was generally assumed that arrhythmias were caused by rapidly firing, ectopic foci (Rothberger and Winterberg 1909; Lewis et al. 1920), and this view was still held by Scherf and Cohen in 1953. The first studies that shed some light on the mechanisms of abnormal focal activity were those of Segers (1941) and Bozler (1943). (For a more complete account, see Cranefield and Aronson 1988.) Both authors recorded monophasic action potentials in isolated preparations of cardiac muscle exposed to elevated extracellular calcium concentrations and/or adrenaline. They observed single and series of afterpotentials, and in Bozler's words: "oscillatory afterpotentials provide a simple explanation for extrasystoles and paroxysmal tachycardia" (Bozler 1943).
Today, this arrhythmogenic mechanism is called triggered activity, that is impulse generation caused by afterdepolarizations (for an extensive review, see Wit and Rosen 1991). An afterdepolarization is a second depolarization which occurs either during repolarization of a propagated action potential (referred to as an early afterdepolarization), or after repolarization has been completed (a delayed afterdepolarization). Both types of afterdepolarizations may reach threshold and initiate action potentials, either singly or in a repetitive series. Early afterdepolarizations occur when heart rate is slow and action potential duration is long (as for instance in the congenital or acquired long Q-T syndrome), and the triggered rhythm is a "bradycardia-dependent tachycardia". Delayed afterdepolarizations occur in conditions when there is cellular calcium overload, such as during digitalis intoxication, exposure to catecholamines, reperfusion after a period of ischaemia or in heart failure. The amplitude of delayed afterdepolarizations, and hence the chance of initiating a salvo of repetitive responses, is increased at short cycle lengths ("tachycardia-dependent tachycardia").
For a long time, the fact that an arrhythmia can be initiated and terminated by an appropriately timed premature beat has been considered evidence that the arrhythmia is re-entrant in nature. The fact that this can also occur in triggered arrhythmia has caused some problems in identifying the mechanism of clinical arrhythmias. There are, however, some differences in the response of re-entrant and triggered arrhythmias to programmed electrical stimulation. Thus, for a re-entrant arrhythmia initiated by a premature stimulus there is an inverse relationship between the coupling interval of the premature impulse and the interval between this impulse and the first complex of the tachycardia, and this is not the case for triggered arrhythmias (Rosen and Reder 1981). On the basis of this criterion, tachycardias were re-entrant in nature in 417 out of 425 patients (most with ischaemic heart disease) in whom tachycardias could be initiated reproducibly by premature stimuli (Brugada and Wellens 1983). This gives some indication of the importance of re-entry and triggered activity for clinical arrhythmias.
Triggered activity depends on the presence of a propagated action potential, whilst automaticity occurs de novo. The basis for automaticity is a spontaneous, gradual fall in membrane potential during diastole, referred to as diastolic, or phase-four depolarization. Automaticity is a normal property of cardiac cells in the sinus node, in some parts of the atria and AV node, and in the His-Purkinje system. Normally, the sinus node is the dominant pacemaker of the heart over a wide range of frequencies, because diastolic depolarization in latent pacemakers is inhibited by so-called overdrive suppression. When a pacemaker cell is driven at a faster rate than its intrinsic spontaneous rate, the Na+/K+ pump is activated, which moves more Na+ ions out of the cell than K+ ions into the cell, thus generating a hyperpolarizing current which counteracts spontaneous diastolic depolarization. When overdrive is stopped, a period of quiescence follows until the rate of Na+/K+ pumping decreases, allowing latent pacemakers to depolarize spontaneously to threshold. If the quiescent period lasts too long, syncope may occur, causing the well-known Adams-Stokes attacks (Adams 1827; Stokes 1846). A shift in the site of impulse formation to a region other than the sinus node can occur following block of sinus impulses to atria or ventricles. Although sympathetic stimulation can enhance the rate of subsidiary pacemakers, the maximum rates in normal Purkinje fibres seldom will exceed 80 beats/min.
Atrial and ventricular myocardial cells normally do not show automaticity. When, however, diastolic potentials are reduced to less than about -60 mV, spontaneous diastolic depolarization occurs, resulting in repetitive activity. Such so-called abnormal automaticity is not overdrive suppressed and usually occurs at more rapid rates than normal automaticity. Therefore, even transient sinus pauses may permit the abnormal ectopic focus to manifest itself.
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