Cardiac arrhythmia

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Chapter 25 Cardiac arrhythmia

Objectives of treatment

In almost no other set of conditions is it so clearly obvious to remember the dual objectives, which are to reduce morbidity and mortality.

Arrhythmias are frequently asymptomatic but may be fatal even at first presentation. Indeed, an estimated 70 000 deaths per year are ascribed to ventricular arrhythmias just in the UK. Antiarrhythmic drugs themselves are also capable of generating arrhythmias (see below) and find use only in the presence of clear indications. In addition, antiarrhythmic agents are to a variable degree negatively inotropic (except for digoxin and possibly amiodarone). These observations provide important primary reasons for caution in the use of these drugs.

A background reason for a careful approach to antiarrhythmic treatment is the gulf between knowledge of their mechanism of action and their clinical uses. On the side of normal physiology, we can see the spontaneous generation and propagation of the cardiac impulse requiring a combination of specialised conducting tissue and inter-myocyte conduction. The heart also has backstops in case of problems with a sequential hierarchy of intrinsic pacemakers. By contrast, the available drugs are at an early stage of evolution, and useful antiarrhythmic actions are yet discovered by chance.

Doctors and drugs have historically generally interfered with cardiac electrophysiology at their peril. In emergencies, the most junior doctor in the team often needs to take action, and some rote recommendations are clearly necessary. The diagnosis and elective treatment of chronic or episodic arrhythmias require experience to achieve the best balance between risk and benefit and this realisation has led to the development of cardiac electrophysiology as a distinct therapeutically effective subspeciality of cardiology.

Antiarrhythmic drugs in general have had a hard time proving superior safety or efficacy over other therapeutic (non-drug) options.

Some physiology and pathophysiology

There are broadly two types of cardiac tissue.

The first type is ordinary myocardial (atrial and ventricular) muscle, responsible for the pumping action of the heart.

The second type is specialised conducting tissue that initiates the cardiac electrical impulse and determines the order in which the muscle cells contract. The important property of being able to form impulses spontaneously (automaticity) is a feature of certain parts of the conducting tissue e.g. the sinoatrial (SA) and atrioventricular (AV) nodes. The SA node has the highest frequency of spontaneous discharge, usually around 70 times per minute, and thus controls the contraction rate of the whole heart, making the cells more distal in the system fire more rapidly than they would do spontaneously, i.e. it is the pacemaker. If the SA node fails to function, the next fastest component takes over. This is often the AV node (approx. 45 discharges per min) or sites in the His–Purkinje system (discharge rate about 25 per min).

Altered rates of automatic discharge or an abnormality in the mechanism by which an impulse is generated from a centre in the nodes or conducting tissue, is one cause of cardiac arrhythmia, e.g. atrial fibrillation, atrial flutter or atrial tachycardia.

Ionic movements into and out of cardiac cells

Nearly all cells in the body exhibit a difference in electrical voltage between their interior and exterior, the membrane potential. Some cells, including the conducting and contracting cells of the heart, are excitable; an appropriate stimulus alters the properties of the cell membrane, ions flow across it and thereby elicit an action potential. This spreads to adjacent cells, i.e. it is conducted as an electrical impulse and, when it reaches a muscle cell, causes it to contract; this is excitation–contraction coupling.

In the resting state the interior of the cell (conducting and contracting types) is electrically negative with respect to the exterior, owing to the disposition of ions (mainly sodium, potassium and calcium) across its membrane, i.e. it is polarised. The ionic changes of the action potential first result in a rapid redistribution of ions such that the potential alters to positive within the cell (depolarisation); subsequent and slower flows of ions then restore the resting potential (repolarisation). These ionic movements separate into phases, which are briefly described here and in Figure 25.1, as they help to explain the actions of antiarrhythmic drugs.1

Classification of antiarrhythmic drugs

The classification still used partially relates to the phases of the cardiac cycle depicted in Figure 25.1.

Phase 0 is the rapid depolarisation of the cell membrane that is associated with a fast inflow of sodium ions through channels that are selectively permeable to these ions.

Phase 1 is a short initial period of rapid repolarisation brought about mainly by an outflow of potassium ions.

Phase 2 is a period when there is a delay in repolarisation caused mainly by a slow movement of calcium ions from the exterior into the cell through channels that are selectively permeable to these ions (‘long-opening’ or L-type calcium channels).

Phase 3 is a second period of rapid repolarisation during which potassium ions move out of the cell.

Phase 4 begins with the fully repolarised state. For cells that discharge automatically, potassium ions then progressively move back into, and sodium and calcium ions move out of, the cell. The result is that the interior becomes gradually less negative until a certain (threshold) potential is reached, which allows rapid depolarisation (phase 0) to occur, and the cycle is repeated; the prevailing sympathetic tone also influences automaticity. Cells that do not discharge spontaneously rely on the arrival of an action potential from another cell to initiate depolarisation.

In phases 1 and 2 the cell is in an absolutely refractory state and is incapable of responding further to any stimulus, but during phase 3, the relative refractory period, the cell will depolarise again if a stimulus is sufficiently strong. The orderly transmission of an electrical impulse (the action potential) throughout the conducting system may be retarded in an area of disease, e.g. localised ischaemia or scar tissue due to previous myocardial infarction. An impulse travelling down a normal Purkinje fibre may spread to an adjacent fibre that has transiently failed to transmit, and pass up it in the reverse direction. Should such a retrograde impulse in turn re-excite the cells that provided the original impulse, re-entrant excitation becomes established and may cause an arrhythmia, e.g. ventricular tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, etc.

Most cardiac arrhythmias are due to either:

Classification of drugs

The Vaughan–Williams2 classification of antiarrhythmic drugs is still commonly used despite its many peculiarities, and on occasion provides a useful shorthand for referring to particular groups or actions of drugs.

Principal drugs by class

For further data see Table 25.1.

Class 1A (sodium channel blockade with lengthened refractoriness)

Quinidine

Quinidine is considered the prototype antiarrhythmic drug,3 although it is now used quite rarely and indeed is not available in some jurisdictions. It has a newly identified use that is unique in that it appears to be effective in reducing the risks of sudden cardiac death in those with Brugada syndrome.4 In addition to its class IA activity, quinidine slightly enhances contractility of the myocardium (positive inotropic effect) and reduces vagus nerve activity on the heart (antimuscarinic effect).

Class IC (sodium channel blockade with minimal effect on refractoriness)

Flecainide

Flecainide slows conduction in all cardiac cells including the accessory pathways responsible for the Wolff–Parkinson–White (WPW) syndrome.

One common indication – indeed where it is the drug of choice – is atrioventricular (AV) re-entrant tachycardia, such as AV nodal tachycardia or in the tachycardias associated with the WPW syndrome or similar conditions with anomalous pathways. This should be as a prelude to definitive treatment with radiofrequency ablation, which is the overall treatment approach of choice. Flecainide is also very useful in patients with paroxysmal atrial fibrillation, used in conjunction with an agent that blocks the AV node to protect against rapid conduction to the ventricle. Following the salutary findings of the CAST study,5 flecainide is now restricted to patients without evidence of coronary or structural heart disease. Indeed before it is used an echocardiogram is essential, and in patients at potential risk of coronary artery disease an exercise test or an alternative test of ischaemia is often conducted.

Class II (catecholamine blockade)

β-Adrenoceptor antagonists

(See also Ch. 24.)

β-Adrenoceptor blockers are effective in the prophylaxis of cardiac arrhythmia probably because they counteract the arrhythmogenic effect of catecholamines. The following actions appear to be relevant:

Class III (lengthening of refractoriness due to potassium channel blockade)

Amiodarone

Amiodarone is the most powerful antiarrhythmic drug available for the treatment and prevention of both atrial and ventricular arrhythmias. Even short-term use can result in serious toxicity, and its use should always follow a consideration or a trial of alternatives. Amiodarone prolongs the effective refractory period of myocardial cells, the AV node and of anomalous pathways. It also blocks β-adrenoceptors non-competitively.

Amiodarone is used in chronic ventricular arrhythmias and in atrial fibrillation, in which condition it both slows the ventricular response and may restore sinus rhythm (chemical cardioversion). It may also be used to maintain sinus rhythm after cardioversion for atrial fibrillation or flutter. Amiodarone has been used for the management of re-entrant supraventricular tachycardias associated with the WPW syndrome, but radiofrequency ablation is now the treatment of choice and amiodarone should not in general be used.

Dronedarone

While amiodarone is less pro-arrhythmic than other conventional antiarrhythmic drugs, e.g. flecainide (possibly because it is a ‘multi-channel blocker’), it has substantial non-cardiac toxic effects. Dronedarone is structurally similar to amiodarone but has no iodine component and reduced lipophilicity. Dronedarone thus has a shorter half-life and appears better tolerated, with low pro-arrhythmic risk.

Dronedarone has been shown to reduce the time to first recurrence of atrial fibrillation. In the EURIDIS and ADONIS clinical trials,6 patients taking dronedarone had a 25% reduction in the risk of AF recurrence over one year, compared with placebo. In the ATHENA study,7 dronedarone also reduced the combined risk of cardiovascular hospitalisation or all-cause death by 24% in patients with current or recent AF and an additional risk factor for death, compared with placebo. A post hoc analysis found that dronedarone, compared with placebo, was associated with a significant reduction in the risk of stroke in paroxysmal and persistent AF patients. Data from the DIONYSOS trial8 suggest that dronedarone may have an improved safety profile when compared to amiodarone, mainly driven by fewer thyroid and neurologic events and less premature discontinuation due to adverse events.

Class IV (calcium channel blockade)

Calcium is involved in the contraction of cardiac and vascular smooth muscle cells, and in the automaticity of cardiac pacemaker cells. Actions of calcium channel blockers on vascular smooth muscle cells appear with the main account of these drugs in Chapter 24. Although the three classes of calcium channel blocker have similar effects on vascular smooth muscle in the arterial tree, their cardiac actions differ. The phenylalkylamine, verapamil, depresses myocardial contraction more than the others, and both verapamil and diltiazem slow conduction in the AV node.

Verapamil

Verapamil (see also p. 397) prolongs conduction and refractoriness in the AV node and depresses the rate of discharge of the SA node. If adenosine is not available, verapamil is a very attractive and, with due care, safe alternative for terminating narrow complex paroxysmal supraventricular tachycardia. Verapamil should not be given intravenously to patients with broad complex tachyarrhythmias whatever the presumptive mechanism, for it may prove lethal.

Other antiarrhythmics

Digoxin and other cardiac glycosides9

Crude digitalis is a preparation of the dried leaf of the foxglove plants Digitalis purpurea or lanata. Digitalis contains a number of active glycosides (digoxin, lanatosides) whose actions are qualitatively similar, differing principally in rapidity of onset and duration of action; the pure individual glycosides are used. The following account refers to all the cardiac glycosides, but digoxin is the principal one.

Dose and therapeutic plasma concentration

(See Table 25.1.) Reduced dose of digoxin is necessary in: renal impairment (see above); the elderly (probably due to the decline in renal clearance with age); electrolyte disturbances (hypokalaemia accentuates the potential for adverse effects of digoxin, as does hypomagnesaemia); hypothyroid patients (who are intolerant of digoxin).

Cardiac effects of the autonomic nervous system

Some drugs used for arrhythmias exert their actions through the autonomic nervous system by mimicking or antagonising the effects of the sympathetic or parasympathetic nerves that supply the heart. The neurotransmitters in these two branches of the autonomic system, noradrenaline/norepinephrine and acetylcholine, are functionally antagonistic by having opposing actions on cyclic AMP production within the cardiomyocyte. Their receptors are coupled to the two trimeric GTP-binding proteins, Gs and Gi, which stimulate and inhibit adenylyl cyclase, respectively.

The vagus nerve

(cholinergic, parasympathetic), when stimulated, affects the heart in ways that are useful in the therapy of arrhythmias, by causing:

There is also reduced force of contraction of atrial and ventricular muscle cells.

Vagal stimulation can slow or terminate supraventricular arrhythmias, reflexly by physical manoeuvres (under ECG control, if possible).

Carotid sinus massage activates stretch receptors: external pressure is applied gently to one side at a time (but not to both sides at once). Some individuals are very sensitive to the procedure and develop severe bradycardia and hypotension.

Other methods include the Valsalva manoeuvre (deep inspiration followed by expiration against a closed glottis, which both stimulates stretch receptors in the lung and reduces venous return to the heart); the Müller procedure (deep expiration followed by inspiration against a closed glottis); production of nausea and retching by inviting patients to put their own fingers down their throat.

The effects of vagus nerve activity are blocked by atropine (antimuscarinic action), an action that is used to accelerate the heart during episodes of sinus bradycardia as may occur after myocardial infarction. The dose is 600 micrograms i.v. and repeated as necessary to a maximum of 3 mg.

Adverse effects are those of muscarinic blockade, namely dry mouth, blurred vision, urinary retention, confusion and hallucination.

Specific treatments11

Atrial fibrillation (AF)

Atrial fibrillation (AF) is the most commonly encountered arrhythmia. Its incidence increases with age and is estimated to affect approximately 6% of people over 65 years. AF increases the risk of stroke by four- to five-fold and death by around two-fold. The health-care costs associated with AF are substantial.

What management options are available?

Treatment can be divided into rhythm or rate control, utilising pharmacological and/or non-pharmacological therapies. Thromboembolic prevention is strongly advocated in all patients, the level of risk determining the degree to which this is pursued. Rhythm control should theoretically be superior to rate control, as the former maintains the physiological, sequential and coordinated pumping actions of the atria and ventricles. At the same time it should reduce the risk of thrombus formation in the atria. Clinical trials fail to support these arguments, although the use of differing anticoagulation regimens complicates interpretation of results. The potential side-effects of currently available anti-arrhythmic agents may negate any benefit conferred by maintenance of sinus rhythm (see below).

The therapeutic options for the management of atrial fibrillation are therefore complex and include asking questions that concern:

The information that should be considered is extensive and includes:

In many patients, AF is an incidental finding on the background of some existing cardiovascular disease, and with a large atrium. With a prolonged history of symptoms, rate-controlling medication such as a β-blocker, digoxin or calcium antagonist may suffice.

If the history appears shorter, and the atrium is of normal size, i.e. is unlikely to contain thrombus, or there has been recent onset of heart failure or shock, cardioversion should be considered. Electrical (DC) conversion is often favoured where treatment is either urgent or likely to be successful in holding the patient in sinus rhythm. Amiodarone can often provide pharmacological conversion over hours to days, and is also effective for patients who revert rapidly to AF after DC conversion. In cases in which the AF duration exceeds 48 h cardioversion should be delayed for at least a month to permit anticoagulation with warfarin, which should be continued for 4 weeks thereafter. If cardioversion is deemed urgent, then transoesophageal echocardiography should be used to show there is no thrombus visible in the left atrium.

In patients who have reverted to AF after previous conversions, amiodarone is the drug of choice prior to further attempts at cardioversion. Amiodarone may also be used to suppress episodes of paroxysmal atrial fibrillation, but dronedarone, sotalol or flecainide are preferred12 (Fig. 25.6). Radiofrequency ablation is now established as the treatment of choice in many patients with both paroxysmal and persistent atrial fibrillation and patients with symptomatic atrial fibrillation should ideally be referred to heart rhythm specialists for advice on further management.

Long QT syndromes

These are caused by malfunction of ion channels, leading to impaired ventricular repolarisation (expressed as prolongation of the QT interval) and a characteristic ventricular tachycardia, torsade de pointes (see Fig. 25.2).13 The symptoms range from episodes of syncope to cardiac arrest. Several drugs are responsible for the acquired form of the condition including antiarrhythmic drugs (see above), antimicrobials, histamine H1-receptor antagonists and serotonin receptor antagonists; predisposing factors are female sex, recent heart rate slowing, and hypokalaemia.14 Congenital forms of the long QT syndrome are due to mutations of the genes encoding ion channels, and exposure to drugs reveals some of these.

1 Dobrev D, Nattel S 2010 New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375:1212–1223.

2 Roden D M 2003 Antiarrhythmic drugs: past, present and future. Journal of Cardiovascular Electrophysiology 14:1389–1396.

3 In 1912, K F Wenckebach, a Dutch physician (who described ‘Wenckebach block’) was visited by a merchant who wished to get rid of an attack of atrial fibrillation (he had recurrent attacks which, although they did not unduly inconvenience him, offended his notions of good order in life’s affairs). On receiving a guarded prognosis, the merchant inquired why there were heart specialists if they could not accomplish what he himself had already achieved. In the face of Wenckebach’s incredulity he promised to return the next day with a regular pulse, which he did, at the same time revealing that he had done it with quinine (an optical isomer of quinidine). Examination of quinine derivatives led to the introduction of quinidine in 1918 (Wenckebach K F 1923 Journal of the American Medical Association 81:472).

4 An inherited condition that is the major cause of sudden unexpected death syndrome (SUDS), commonly in young men.

5 Flecainide, encainide and moricizine underwent clinical trial to establish whether suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction. The study was terminated after preliminary analysis of 1727 patients revealed that the mortality rate in patients treated with flecainide or encainide was 7.7% compared with 3.0% in controls. The most likely explanation for the result was the induction of fatal ventricular arrhythmias, possibly in conjunction with ischaemia by flecainide and encainide, i.e. a proarrhythmic effect (Cardiac Arrhythmia Suppression Trial (CAST) Investigators 1989 Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. New England Journal of Medicine 321:406–412).

6 Singh B N, Connolly S J, Crijns H J et al; EURIDIS and ADONIS Investigators 2007 Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. New England Journal of Medicine 357:987–999.

7 Hohnloser S H, Crijns H J, van Eickels M et al; ATHENA Investigators 2009 Effect of dronedarone on cardiovascular events in atrial fibrillation. New England Journal of Medicine 360:668–678.

8 Le Heuzey J Y, De Ferrari G M, Radzik D et al  2010 A short-term, randomised, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. Journal of Cardiovascular Electrophysiology 21:597–605.

9 In 1775 Dr William Withering was making a routine journey from Birmingham (England), his home, to see patients at the Stafford Infirmary. While the carriage horses were being changed half-way, he was asked to see an old dropsical (oedematous) woman. He thought she would die and so some weeks later, when he heard of her recovery, was interested enough to enquire into the cause. Recovery was attributed to a herb tea containing some 20 ingredients, among which Withering, already the author of a botanical textbook, found it ‘not very difficult … to perceive that the active herb could be no other than the foxglove’. He began to investigate its properties, trying it on the poor of Birmingham, whom he used to see without fee each day. The results were inconclusive and his interest flagged until one day he heard that the principal of an Oxford College had been cured by foxglove after ‘some of the first physicians of the age had declared that they could do no more for him’. This put a new complexion on the matter and, pursuing his investigation, Withering found that foxglove extract caused diuresis in some oedematous patients. He defined the type of patient who might benefit from it and, equally importantly, he standardised his foxglove leaf preparations and was able to lay down accurate dosage schedules. His advice, with little amplification, served until relatively recently (Withering W 1785 An Account of the Foxglove. Robinson, London).

10 To the layperson, ‘shock’ treatment could be interpreted as frights (which stimulate the vagus, as described above), or as the electrical sort. Dr James Le Fanu quotes a Belfast doctor who reported a farmer with a solution that covered both possibilities. He had suffered from episodes of palpitations and dizziness for 30 years. When he first got them, he would jump from a barrel and thump his feet hard on the ground at landing. This became less effective with time. His next ‘cure’ was to remove his clothes, climb a ladder and jump from a considerable height into a cold water tank on the farm. Later, he discovered the best and simplest treatment was to grab hold of his high-voltage electrified cattle fence – although if he was wearing Wellington (rubber) boots he found he had to earth the shock, so besides grabbing the fence with one hand he simultaneously shoved a finger of the other hand into the ground.

11 See also UK Resuscitation Council guidelines (Figs 25.325.5).

12 The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) has issued guidance preferring these agents to amiodarone depending on the characteristics of the patient (see Fig. 25.6). A J Camm et al 2010 European Heart Journal 31:2369–2429.

13 French: torsade, twist; pointe, point. ‘Twisting of the points’, referring to the characteristic sequence of ‘up’ followed by ‘down’ QRS complexes. The appearance has been called a ‘cardiac ballet’.

14 Roden D M 2004 Drug-induced prolongation of the QT interval. New England Journal of Medicine 350:1013–1022.

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