22 Arrhythmias

• Arrhythmias are common and should be treated only if they cause symptoms or threaten haemodynamic failure.

• An understanding of the ionic basis of the cardiac action potential is important because drugs used in the treatment of cardiac arrhthymias act by altering the function of the trans-membrane ion channels.

• The heart is designed to work most efficiently in sinus rhythm. Any arrhythmia compromises cardiac function.

• Non-pharmacological treatments for arrhythmias are becoming more common.

• Atrial fibrillation is the most common arrhythmia and is associated with an increased risk of thromboemobolic stroke. All patients with atrial fibrillation should undergo assessment of their stroke risk.

• Antiarrhythmic drugs are grouped by the Vaughan–Williams classification based on their ability to block the movement of specific ions across the myocardial cell membrane.

• All antiarrhythmic drugs are also proarrhythmic in some circumstances.

• While drug treatment has been the mainstay of arrhythmia treatment, it is often of limited efficacy and may be associated with significant toxicity.

• ß-Blockers and amiodarone are the most commonly used antiarrhythmic drugs.

Normal cardiac electrophysiology

The normal cardiac rhythm, sinus rhythm, is characterised by contraction of first the atria and then the ventricles (systole) followed by relaxation (diastole) during which the heart refills with blood before the next cardiac cycle begins. This orderly sequence of contraction and relaxation is regulated by the heart’s electrical activity. Heart muscle cells (myocytes) are electrically active and capable of generating action potentials, which initiate contraction of the myocyte through a process known as excitation–contraction coupling. Adjacent myocytes form electrical connections through protein channels called gap junctions. An action potential in one myocyte causes current flow between itself and adjacent myocytes which in turn generate their own action potentials and in this way an ‘activation wavefront’ spreads though the myocardium, resulting in a wave of contraction.

Cardiac action potential

An understanding of the ionic basis of the cardiac action potential is important because drugs used in the treatment of cardiac arrhythmias act by altering the function of trans-membrane ion channels. Inherited abnormalities of ion channel function (‘channelopathies’) are an important cause of sudden cardiac death due to arrhythmia and are increasingly implicated in the pathogenesis of other arrhythmias including atrial fibrillation (AF).

The phospholipid membrane of cardiac myocytes is spanned by numerous proteins known as ion channels, whose permeability to specific ions varies during the cardiac cycle resulting in a resting (diastolic) membrane potential, diastolic depolarisation in cells with pacemaker activity, and action potentials.

The resting membrane potential of -60 to -90 mV occurs because the intracellular potassium (K⁺) concentration is much higher than the extracellular K⁺ concentration as a result of a transmembrane pump known as Na⁺–K⁺–ATPase, which pumps K⁺ ions into the cell in exchange for sodium (Na⁺) ions. K⁺ ions diffuse out of the cell through selective K⁺ channels (the inward rectifier current or I_K1) unaccompanied by anions, resulting in a net loss of charge and thus a negative resting, diastolic or phase 4, transmembrane potential (Fig. 22.1A).

Fig. 22.1 The cardiac action potential. (A) An action potential from ventricular myocardium. During diastole (phase 4), the resting transmembrane potential is constant at -90 mV. The upstroke (phase 0) of the action potential is due to the rapid influx of Na⁺ ions. The early phase of repolarisation (phase 1) is due to efflux of K⁺ ions, followed by a plateau phase (phase 2) at about 0 mV during which influx of Ca²⁺ ions is balanced by efflux of K⁺ ions. Towards the end of diastole, influx of Ca²⁺ ions diminishes and efflux of K⁺ ions increases, resulting in repolarisation (phase 3) back to the negative resting membrane potential. (B) An action potential from the sinus node. During diastole (phase 4), there is progressive depolarisation towards a threshold potential at which an action potential is triggered. The upstroke (phase 0) of the action potential is less steep than in ventricular myocardial cells because the sinus node cells lack ‘fast’ Na⁺ channels and so depolarisation is dependent upon influx of Ca²⁺ ions.

Certain specialised myocytes form the cardiac conduction system and these cells have pacemaker activity, that is, they are capable of generating their own action potentials due to gradual depolarisation of the transmembrane potential during diastole (phase 4), referred to as the pacemaker potential (Fig. 22.1B). The pacemaker potential occurs as a result of (i) a gradual reduction in an outward K⁺ current called the delayed rectifier (I_K) current, (ii) increasing dominance of an inward current of Na⁺ and some Ca²⁺ ions known as I_f (f stands for ‘funny’) and (iii) an inward calcium current I_Ca through voltage-gated calcium channels. As a result of the pacemaker potential, the transmembrane potential gradually becomes less negative until a threshold potential is reached at which an action potential is triggered. The rate of depolarisation of the pacemaker potential, and hence the heart rate, is influenced by the autonomic nervous system. Sympathetic nervous system activation and circulating catecholamines increase the heart rate by binding to ß₁-adrenoreceptors leading to an increase in intracellular cyclic AMP, which results in changes to the permeability of the various ion channels responsible for the pacemaker current. Parasympathetic nervous system activation, mediated by muscarinic cholinergic receptors, has the opposite effect.

The rapid depolarisation of the cardiac action potential (Fig. 22.1A, phase 0) occurs because of a rapid increase in the permeability of the cell membrane to Na⁺ ions, which enter rapidly through ‘fast’ Na⁺ channels in a current known as I_Na. The I_Na current is brief as the ‘fast’ Na⁺ channels inactivate rapidly. The early phase of repolarisation (phase 1) is due to closure of the fast Na⁺ channels, an outward K⁺ current known as I_to (to – transient outward) and a further K⁺ current known as the ultra-rapid component of the delayed rectifier current or I_Kur. The plateau phase (phase 2) of the cardiac action potential occurs because the inward movement of Ca²⁺ ions (I_Ca) is balanced by the outward movement of K⁺ ions. Repolarisation (phase 3) occurs as I_Ca diminishes and two further components of the delayed rectifier (I_K) current known as the rapid (I_Kr) and slow (I_Ks) components predominate, with an important contribution from I_K1.

There is considerable variation in the expression of trans-membrane ion channels in different parts of the heart, with corresponding variation in the morphology of the action potential. The most marked example is that myocytes in the sinus and AV nodes contain few Na⁺ channels. The upstroke of the action potential in these cells is due, predominantly, to the influx of Ca²⁺ ions and, therefore, is considerably slower than the upstroke in other myocytes (Fig. 22.1B). The variation in ion channel expression throughout the heart is essential for normal cardiac function, helps to explain the pathophysiology of many inherited and acquired diseases complicated by cardiac arrhythmia and accounts for the relative selectivity of antiarrhythmic and other drugs for certain parts of the heart.

Refractoriness

The action potential of cardiac myocytes differs from that seen in nerve cells by the presence of a plateau phase during which the myocyte is electrically inexcitable and refractory, that is, incapable of generating another action potential. It is only towards the end of repolarisation (phase 3) that the myocyte regains excitability. The time interval between the onset of the action potential and the regaining of electrical excitability is known as the refractory period. Under most circumstance the refractory period of a cardiac myocyte corresponds closely to the duration of the cardiac action potential and, therefore, drugs that prolong action potential duration (APD) prolong the refractory period.

Normal cardiac conduction

During normal sinus rhythm (Fig. 22.2), an activation wavefront begins in the sinus node, a group of cells with pacemaker activity on the upper free wall of the right atrium. The rate of diastolic depolarisation and hence the rate of discharge of the sinus node is increased by sympathetic nerve stimulation, circulating catecholamines or sympathomimetic drugs mediated by ß₁-adrenoreceptors on the cell membranes of the sinus node myocytes. Parasympathetic (vagus) nerve stimulation exerts the opposite effect, mediated by muscarinic cholinergic receptors.

Fig. 22.2 The normal cardiac conduction system. During sinus rhythm, an activation wavefront spreads from the sinus (sinoatrial – SA) node across the atrial myocardium before entering the atrioventricular node. The activation wavefront then enters the bundle of His, which penetrates the annulus fibrosus and forms the only electrical connection between the atria and ventricles. The bundle of His divides into right and left bundle branches which ramify into a subendocardial network of Purkinje fibres that transmit the activation wavefront rapidly across the ventricles. Activation of the ventricles proceeds from endocardium to epicardium.

An activation wavefront spreads across the atrial myocardium, leading to atrial contraction and generating the P wave on the surface electrocardiogram (ECG; Fig. 22.3). The last part of the atria to be activated is the atrioventricular (AV) node, the electrical and structural properties of which result in a slow conduction velocity, allowing atrial emptying to be completed before ventricular contraction begins and represented by the PR interval on the ECG. Conduction velocity in the AV node is increased by sympathetic nerve stimulation, circulating catecholamines or sympathomimetic drugs, mediated by ß₁-adrenoreceptors while parasympathetic (vagus) nerve stimulation exerts the opposite effect via muscarinic cholinergic receptors.

Fig. 22.3 The normal electrocardiogram (ECG). The P wave results from activation (depolarisation of the atria). The PR interval is isoelectric as the activation wavefront proceeds slowly through the atrioventricular node. The QRS complex reflects activation of the ventricles and is large compared to the P wave because of the much greater mass of the ventricular myocardium, and brief, reflecting extremely rapid conduction in the His–Purkinje system. The T wave represents ventricular repolarisation.

The atria and ventricles are electrically isolated from each other by the annulus fibrosus, the electrically non-conductive fibrous tissue forming the valve rings. In the normal heart, there is just one electrical connection between the atria and ventricles, the bundle of His, which conveys the activation wavefront from the AV node and penetrates the annulus fibrosus before dividing into the right and left bundle branches. The bundle branches ramify into a sub-endocardial network of Purkinje fibres, which convey the activation wavefront rapidly across the ventricles ensuring near-simultaneous contraction of the ventricular myocardium, and are represented by the narrow QRS complex of the ECG. Finally, the activation wavefront spreads from endocardium to epicardium. A wave of repolarisation then spreads across the ventricles resulting in the T wave. The QT interval on the ECG, therefore, represents the duration of ventricular depolarisation and repolarisation. There is an inverse relationship between the time to activation of different areas of the ventricular myocardium and APD such that the latest areas to be activated have the shortest APD. The purpose of this relationship is that repolarisation is rapid and uniform throughout the ventricular myocardium, which serves to maintain electrical stability.

Arrhythmia mechanisms

Cardiac arrhythmias occur because of abnormalities of impulse formation or propagation.

Abnormal impulse formation

Abnormal automaticity

Automaticity is another term for pacemaker activity, a characteristic possessed by all cells of the specialised cardiac conduction system during health and, potentially, by other cardiac myocytes during certain disease states. The rate of firing of a pacemaker cell is largely determined by the duration of the phase 4 diastolic interval (Fig. 22.4). This in turn is determined by (i) the maximum diastolic potential following repolarisation of the preceding action potential, (ii) the slope of diastolic depolarisation due to pacemaker currents and (iii) the threshold potential for generation of a new action potential. In the healthy state, there is a hierarchy of firing rates within the specialised conduction system with the highest rate in the sinus node followed by the AV node and then the His–Purkinje system. The sinus node is, therefore, the dominant pacemaker and determines the heart rate, while the pacemaker activity in the distal conduction system is ‘overdriven’ by the sinus node. Abnormal automaticity describes either accelerated pacemaker activity in cells of the distal cardiac conduction system such that they escape from overdrive suppression by the sinus node, or the development of pacemaker activity in cells that do not form part of the cardiac conduction system.

Fig. 22.4 Abnormal automaticity. A sinus node action potential is shown (in bold) with a characteristic slow upstroke. Following repolarisation, gradual diastolic depolarisation occurs as a result of pacemaker currents. When the threshold potential is reached a further action potential is generated. The rate of firing of the pacemaker cell is governed largely by the duration of the diastolic interval which is in turn determined by (A) the slope of diastolic depolarisation, (B) the threshold potential and (C) the maximum diastolic potential. Each of these (shown by dotted lines) may be altered by disease states leading to abnormal automaticity.

Triggered activity

Triggered activity describes impulse formation dependent upon afterdepolarisations. Early afterdepolarisations (EADs) occur during phase 2 or 3 of the cardiac action potential whereas delayed afterdepolarisations (DADs) occur during phase 4 (Fig. 22.5). In both cases, afterdepolarisation may reach the threshold potential required for generation of a new action potential.

Fig. 22.5 Triggered activity. (A) An early afterdepolarisation (EAD) occurring at the start of phase 3 of the cardiac action potential. (B) A delayed afterdepolarisation (DAD) occurring after repolarisation, during phase 4. Either EADs or DADs may reach the threshold potential for generation of a further action potential.

EADs are characteristic of the congenital and acquired long QT syndromes. The prolonged APD promotes reactivation of the inward calcium current I_Ca which may directly cause EADs during phase 2. Furthermore, action potential prolongation and ß-adrenoreceptor stimulation promote calcium overload in the sarcoplasmic reticulum. This in turn leads to the spontaneous release of calcium in bursts by the sarcoplasmic reticulum. The resultant increase in intracellular calcium concentration activates the transmembrane Na⁺/Ca²⁺ exchanger which moves one calcium ion out of the myocyte in exchange for three sodium ions and, therefore, results in an EAD during phase 3. In the long QT syndromes, an EAD may initiate a form of polymorphic ventricular tachycardia (VT) known as Torsade de Pointes. EADs are more prominent at slow heart rates.

DADs are seen during reperfusion following ischaemia, heart failure, digitalis toxicity and in catecholaminergic polymorphic VT. They occur because of spontaneous release of calcium in bursts by the sarcoplasmic reticulum, activating the Na⁺/Ca²⁺ exchanger as described for EADs and resulting in a DAD during phase 4. A DAD may result in a single extrastimulus (‘ectopic beat’) or in repetitive firing, that is, tachycardia. DADs are more prominent at rapid heart rates and during sympathetic nervous stimulation of ß-adrenoreceptors.

Abnormal impulse propagation

Re-entry

Many clinically important arrhythmias are due to re-entry, in which an activation wavefront rotates continuously around a circuit. Re-entry depends upon a trigger in the form of a premature beat, and a substrate, that is, the re-entry circuit itself. A precise set of electrophysiological conditions must be met in order for re-entry to occur (Fig. 22.6): (i) there must be a central non-conducting obstacle around which the re-entry circuit develops, (ii) a premature beat must encounter unidirectional conduction block in one limb (a) of the re-entry circuit, (iii) conduction must proceed slowly enough down the other limb (b) of the re-entry circuit that electrical excitability has returned in the original limb (a), allowing the activation wavefront to propagate in a retrograde direction along that limb, and (iv) the circulating activation wavefront must continue to encounter electrically excitable tissue. This is a function of the length of the re-entry circuit, the conduction velocity of the activation wavefront and the effective refractory period of the myocardium throughout the circuit. Class I antiarrhythmic drugs block sodium channels and, therefore, reduce the amplitude and rate of rise of the cardiac action potential and in so doing, reduce the conduction velocity of an activation wavefront. Class I antiarrhythmic drugs may exert their major antiarrhythmic effect by abolishing conduction altogether in areas of diseased myocardium forming part of a re-entry circuit in which conduction is already critically depressed. Class III antiarrhythmic drugs prolong cardiac APD and hence the refractory period. If previously activated cells in a re-entry circuit (the ‘tail’) remain refractory when the re-entrant wavefront (the ‘head’) returns to that area, conduction will fail and re-entry will be abolished. Drug-induced prolongation of the refractory period may, therefore, terminate and/or prevent re-entrant arrhythmias.

Fig. 22.6 Re-entry. During sinus rhythm, (A) an activation wavefront encounters a zone of fixed conduction block but can propagate anterogradely on either side of this zone, down limbs a and b of a potential re-entry circuit. A premature beat (B) encounters unidirectional conduction block in limb a but propagates anterogradely down limb b and re-enters limb a retrogradely. If limb a is now capable of retrograde conduction, the re-entry circuit is completed and re-entry continues (C) as long as the activation wavefront continually meets electrically excitable tissue.

Clinical problems

Patients with a cardiac arrhythmia may present with a number of symptoms:

• The most common symptom is palpitation, an awareness of an abnormal heartbeat, although some patients with clearly documented arrhythmia have no palpitation. Arrhythmias start suddenly and, therefore, if the patient clearly describes palpitation of sudden onset (‘like flicking a switch’), this is a useful pointer to an arrhythmia rather than heightened awareness of sinus tachycardia, which has a less sudden onset.

• The heart is designed to work most efficiently in sinus rhythm. Any arrhythmia compromises cardiac function. Classical symptoms that arise due to reduced cardiac output include reduced exercise capacity, breathlessness and fatigue.

• Angina may accompany tachycardia, even in the absence of coronary artery disease. Tachycardia increases the metabolic rate of cardiac muscle and hence its demand for blood flow. Myocardial perfusion occurs predominantly during diastole and during tachycardia proportionately less time is spent in diastole and so myocardial demand for blood can exceed supply, resulting in angina.

• A sudden drop in cardiac output may accompany either bradycardia or tachycardia, causing episodes of dizziness (presyncope), loss of consciousness (syncope) or, in extreme cases, sudden death from cardiac arrest.

• Atrial tachyarrhythmias such as atrial flutter and atrial fibrillation may be complicated by the development of intracardiac thrombus, usually within the left atrial appendage. This thrombus may embolise to any part of the body but the most common clinical presentation is with a transient ischaemic attack or stroke.

Arrhythmias may aggravate heart failure in two ways: (i) the haemodynamic effect of the arrhythmia may precipitate heart failure or aggravate existing heart failure and (ii) prolonged tachycardia of any type may lead to tachycardia-induced cardiomyopathy.

Diagnosis

A detailed history should be obtained, covering all of the symptoms listed above. A characteristic of cardiac arrhythmias is their random onset. Symptoms occurring under specific circumstances are less likely to be due to arrhythmia, but there are exceptions including certain uncommon types of VT, some cases of supraventricular tachycardia (SVT) due to an accessory pathway and vasovagal syncope (faints). Other key features of the history include:

• A history of cardiac disease

• Other diagnosed medical conditions

• A full drug history, including over-the-counter medicines and recreational drugs including alcohol

• A family history of heart disease and of sudden unexpected death.

Physical examination is essential but often normal between episodes of arrhythmia. Mandatory investigation includes a 12-lead ECG and an echocardiogram to detect structural heart disease. Other investigations for structural and ischaemic heart disease may be indicated at this stage with the aim of detecting any underlying structural heart disease. If the history does not include sinister features such as syncope or a family history of sudden unexpected death at a young age, and the resting 12-lead ECG and echocardiogram are normal, then the patient can be reassured that they are extremely unlikely to have a serious heart rhythm disturbance. The extent of further investigation will be dictated by how troublesome the symptoms are.

The most certain way of reaching a firm diagnosis is a 12-lead ECG recorded during the patient’s symptoms demonstrating arrhythmia. As many arrhythmias occur intermittently, some form of ECG monitoring is often necessary. This may include a continuous ambulatory ECG (Holter) recording for up to 7 days at a time if the symptoms occur frequently or, for less frequent symptoms an event recorder, which may store ECG strips automatically if it detects an arrhythmia or if activated by the patient during their symptoms. An insertable loop recorder may be implanted subcutaneously and is an ECG event recorder with a battery life of about 3 years, making it a useful tool for the diagnosis of infrequent arrhythmias.

Management

Pathological tachycardia is conventionally defined as a resting heart rate over 100 beats/min and can be classified according to whether it arises in or involves the atria (supraventricular tachycardias) or the ventricle (ventricular tachyarrhythmias).

Supraventricular tachycardias

These are tachycardias arising from or involving the atria.

Two mechanisms account for most junctional re-entry tachycardias: both involve a macroreentry circuit (Fig. 22.8). AV nodal re-entry tachycardia (AVNRT) rotates around a circuit including the AV node itself and the so-called AV nodal fast and slow pathways, which feed into the AV node. Atrioventricular re-entry tachycardia (AVRT) comprises a re-entry circuit involving the atrial myocardium, the AV node, the ventricular myocardium and an accessory pathway, a congenital abnormality providing a second electrical connection between the atria and ventricles in addition to the His bundle, thus forming a potential re-entry circuit.