Mechanisms Of Arrhythmia
Arrhythmias are abnormalities of the heart rate or rhythm caused by disorders of impulse generation or conduction.
All parts of the cardiac conduction system demonstrate a spontaneous phase 4 depolarization (automaticity), and are therefore potential or latent pacemakers. Because sinoatrial node (SAN) pacemaking is of the highest frequency (70–80 beats/min), it causes overdrive suppression of pacemaking by the atrioventricular node (AVN) (50–60 beats/min) or Purkinje fibres (30–40 beats/min). However, ischaemia, hypokalaemia, fibre stretch or local catecholamine release may increase automaticity in latent pacemakers, which can then ‘escape’ from SAN dominance to cause arrhythmias.
Triggered automaticity is caused by afterdepolarizations. These are oscillations in the membrane potential that occur during or after repolarization. Oscillations large enough to reach threshold initiate premature action potentials and thus heart beats (Figure 48a). This may occur repeatedly, initiating a sustained arrhythmia either directly or by triggering re-entry (see below). After depolarization magnitude is influenced by changes in heart rate, catecholamines and parasympathetic withdrawal.
Early afterdepolarizations (EADs) occur during the terminal plateau or repolarization phases of the action potential. They develop more readily in Purkinje fibres than in ventricular or atrial myocytes. EADs can be induced by agents that prolong action potential duration and increase the inward current. For example, drugs such as sotalol which block K+ currents can cause EADs and triggered activity by delaying repolarization, especially when the heart rate is slow. The abnormal rhythms induced by such drugs resemble torsade de pointes, a type of congenital arrhythmia.
Delayed afterdepolarizations (DADs) occur after repolarization is complete, and are caused by excessive increases in cellular [Ca2+]. DADs can be caused by catecholamines, which increase Ca2+ influx through the L-type Ca2+ channel, and by digitalis glycosides, which increase [Ca2+]i (see Chapter 47). They can also occur in heart failure, in which myocyte Ca2+ regulation is impaired. The oscillation of membrane potential following the increase in [Ca2+]i is caused by a transient inward current involving Na+ occurrence and magnitude of DADs and the likelihood that they will cause arrhythmias is increased by conditions that enhance this current. These include increased Ca2+ release from the sarcoplasmic reticulum and longer action potentials, which cause larger increases in [Ca2+]i. Therefore, drugs prolonging action potential duration may trigger DADs, whereas drugs shortening the action potential have the opposite effect. The magnitude of the transient inward current is also influenced by the resting membrane potential, and is maximal when this is approximately −60 mV.
Re-entry occurs when an impulse that is delayed in one region of the myocardium re-excites adjacent areas of the myocardium more than once. The initiating impulse is often premature, for example having resulted from triggered automaticity. One type of re-entry, termed anatomical, requires the presence of three conditions:
· There must exist an anatomical circuit around which the impulse can circulate (a process termed circus movement). This circuit can utilize parallel conduction pathways such as two Purkinje fibre branches, or the AVN and an accessory atrioventricular conduc- tion pathway.
· Impulse conduction at some point in the circuit should be slow enough to allow the region in front of the impulse to recover from refractoriness. This region is termed the excitable gap.
· The circuit must also include a zone of unidirectional block where conduction is blocked in one direction while remaining possible in the other.
Wolff–Parkinson–White (WPW) syndrome is an uncommon supraventricular arrhythmia (population incidence 0.1–0.2%) which provides a prototypical example of anatomical re-entry (see Chapter 49). People with WPW have a congenital accessory (extra) conduction pathway (formerly termed the bundle of Kent) between an atrium and ventricle, which is often situated on the left free wall of the heart. Thus, as shown in Figure 48b, normal atrial depo- larization (black arrows) is conducted to the ventricles through both the AVN and the accessory pathway (blue arrows). The accessory pathway has properties differing from that of the AVN. First, it conducts more rapidly than the AVN, so the part of the ventricle to which the pathway connects depolarizes before the rest (pre-excitation), resulting in a widened QRS complex. Secondly, the accessory pathway has a longer refractory period than the AVN. Thus, if a premature impulse arises in an atrium (red arrows), it may be conducted normally to the ventricles via the AVN (1 in Figure 48), but may not be conducted forwards through the accessory pathway, which is still refractory from the previous impulse (2). However, when the impulse through the AVN is dis- tributed to the ventricles (3), it will encounter the distal end of the accessory pathway (4) which has now had time to recover its excit- ability, and will be conducted backwards through this pathway into the atrium (5). It can then traverse the AVN again and continue to cycle though the anatomical circuit encompassing the AVN, His–Purkinje system, ventricles, accessory pathway and atrium (1–3–4–5). The ventricles are excited with each circuit, which causes a tachycardia because the impulse cycles more quickly than the SAN spontaneously depolarizes.
It is noteworthy that the ‘border zone’ between healthy myocardium and the scar resulting from the healing of a myocardial infarct (see Chapter 44) typically contains a mixture of living muscle cells and connective tissue. In some cases, a narrow band (‘isthmus’) of still-viable muscle cells spans an area of non-conducting scar, thereby connecting two regions of healthy myocardium (Figure 48c). Conduction of the impulse by the isthmus may be slowed or even demonstrate effective unidirectional block because this tissue takes so long to recover its excitability between action potentials. This arrangement provides conditions analogous to those that WPW (think of the isthmus as playing the part of the accessory pathway and the healthy myocardium to the side of the non-conducting scar as mimicking the AVN), and is thought to cause many ventricular arrhythmias arising in patients following myocardial infarct healing.
Functional re-entry does not require an anatomically defined circuit, and tends to arise when conduction is impaired or repolarization is delayed in a region of myocardium, usually as result of ongoing ischaemia or damage from a previous myocardial infarction. Under these conditions, the firing of frequent or premature impulses can cause the front of one wave of depolarization to collide with the tail of the preceeding wave where it has been slowed (Figure 48d). The second wave is unable to proceed into the region of the myocardium that is still refractory, but at the edges of this region it curls into itself, forming twin ‘whirlpools’ of depolarization, termed rotors. Rotors can similarly form under some conditions if an impulse collides with a structural obstacle such as a scar. Once formed, rotors may persist and continue to emit spiral waves of depolarization with a frequency determined by the rotation period of the spiral; these excite the heart and cause tachycardia. The formation of such spiral waves, and the further fragmentation of the waves of depolarization they generate, is thought to underlie the genesis of the chaotic electrical activity that results in the total loss of atrial or ventricular coordinated contrac- tion termed fibrillation (see Chapters 49 and 50).
The sympathetic nervous system and arrhythmias
Sympathetic stimulation of the heart results in results in a variety of β-receptor mediated effects enabling positive chronotropy and inotropy (see Chapters 12 and 13). These include the acceleration of impulse generation and conduction by the SA and AV nodes, respectively. In cardiac muscle cells Ca2+ influx and release are facilitated leading to an increased rise in [Ca2+]i during the action potential, and the activities of multiple ion channels are modulated in such a way as to enhance conduction and decrease refractoriness. These effects are crucial for the normal tuning of cardiac function, but excessive sympathetic stimulation of the heart during myocardial infarction, or in the context of cardiac scarring, ischemia, chronic heart failure or cardiomyopathy, can be arrhythmogenic. The reasons for this are not well understood, but may relate to observations that the myocardium is innervated more densely in some areas than in others and that ion channel expres- sion also varies between different parts of the ventricles. Thus, sympathetic activation may exaggerate intrinsic regional inhomogeneities in conduction velocity and refractoriness. These effects are likely to promote triggered automaticity and functional reentry and therefore tachycardia and fibrillation.