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Drug-Induced QT-Interval Prolongation and Proarrhythmic Risk

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Drug-Induced QT-Interval Prolongation and Proarrhythmic Risk Europace doi:10.1093/europace/eum169 Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 Eduard Shantsila, Timothy Watson, and Gregory YH Lip* University Department of Medicine, City Hospital, Birmingham B18 7QH, UK KEYWORDS Despite the large number of available antiarrhythmic agents, significant QT-interval prolongation and Proarrhythmia; risk of severe proarrhythmia, including torsade de pointes, limit pharmacological opportunities in the Antiarrhythmic drugs; management of atrial arrhythmias. The risk of proarrhythmia has been demonstrated in class I Atrial fibrillation and class III drugs, but significant variability has been observed between agents of the same class. Electrophysiological drug effects found to be important in the etiology of proarrhythmia include QT- interval prolongation through selective blockade of the delayed rectifying potassium current (IKr), early afterdepolarizations, transmural dispersion of repolarization, and a reverse rate dependence. Interestingly, less proarrhythmic potential is seen or anticipated with agents that are able to block multiple ion channels and those with atrial selectivity, despite moderate QT prolongation. This obser- vation has helped steer the development of newer drugs, with some promising preliminary results. Introduction Unfortunately, recurrence of AF is common, often requiring long-term drug therapy to improve maintenance From the early twentieth century, drug therapy has played an of sinus rhythm. For most current antiarrhythmic agents, important role in the management of atrial arrhythmias. Qui- the relapse rate is at least 50% during the first year,2–5 nidine was the first antiarrhythmic used to successfully although slightly better figures are seen with dofetilide6 restore and maintain sinus rhythm in atrial fibrillation (AF). and amiodarone.7,8 A number of studies have also demon- Subsequently, a large number of other drugs have become strated that flecainide and propafenone are effective available. Although the efficacy of many of these agents is drugs for preventing AF recurrence.9–11 The effectiveness of impressive, side effects are a frequent occurrence. Amongst flecainide is comparable to quinidine, but with fewer side the most worrying side effects are QT-interval prolongation effects.12 In contrast, propafenone is more effective for main- and risk of proarrhythmia, including torsade de pointes (TdP). tenance of sinus rhythm than quinidine and as effective as sotalol.13,14 Generally, however, class Ic drugs are preferred Pharmacological treatment for atrial to class Ia drugs in view of their better safety profile.12,13 fibrillation The success of electrical cardioversion for AF has been Pharmacological cardioversion of AF can be achieved using a quoted as between 75 and 93%, although this depends on left atrial size and co-existing structural heart disease, and number of drugs with different pharmacological properties, 15–17 including disopyramide, procainamide, quinidine (all class ultimately on the duration of AF. Where there is some Ia), flecainide, propafenone (both class Ic), dofetilide, ibuti- concern about a successful restoration of sinus rhythm (for lide, sotalol, and amiodarone (all class III). Currently, the example, previous cardioversion failure or early recurrence most commonly used drugs for chemical cardioversion are of AF), concomitant amiodarone or sotalol can be used flecainide, sotalol, and amiodarone. Little difference is pre-cardioversion to improve the success of electrical cardioversion.18 Such an approach is advocated by the observed between the route of administration for cardio- 2 version rates, although intravenous administration results in ACC/AHA/ESC guidelines on AF management. The frequency faster conversion. Indeed, in patients with recent onset AF, of recurrence of AF after electrical cardioversion is high, and successful cardioversion is reported in up to 80% of cases maintenance therapy with antiarrhythmic drugs such as amiodarone or sometimes b-blockers is somewhat useful to with oral therapy, rising only to 90% with intravenous 1 administration.1 prevent AF relapses. b-blockers are very effective at controlling ventricular rate and also may reduce the risk of AF recurrence following suc- * Corresponding author. Tel: þ44 121 554 3801; fax: þ44 121 554 4083. E-mail address: [email protected] cessful cardioversion (whether spontaneous, pharmacological, & The European Society of Cardiology 2007. All rights reserved. For permissions, please e-mail: [email protected] iv38 E. Shantsila et al. or electrical) and are currently used as first-line prophylactic potential. However, IKr is often more susceptible to agents in paroxysmal AF. b-blockers have also been shown to drug effects that may manifest clinically as a prolonged reduce the frequency of post-operative AF, although sotalol QT interval and the emergence of other T- or U-wave (which also has class III effects) appears to be the most abnormalities on the surface electrocardiogram (ECG). effective in this setting. As AF commonly coexists with hyper- Moreover, pharmacological inhibition of the current IKr tension or congestive heart failure, b-blockers may also be appears to be responsible for the proarrhythmic effect of part of conventional therapy in such patients. antiarrhythmic, as well as non-antiarrhythmic, drugs. Rate-limiting, non-dihydropyridine calcium channel Wang et al.22 showed that an early ultra rapid component blockers (diltiazem, verapamil) are frequently used to of the delayed rectifier (IKur) contributes significantly to optimize rate control where b-blockers are contraindicated repolarization of the human atrial action potential. As IKur or ineffective. An intravenous b-blocker (for example, is present in atrial (but not in ventricular) myocytes in esmolol or metoprolol) or rate-limiting calcium antagonists man, it is a potential target for the development of drugs Downloaded from https://academic.oup.com/europace/article/9/suppl_4/iv37/497024 by guest on 25 September 2021 (diltiazem, verapamil) are indicated where urgent pharma- that prevent atrial re-entrant arrhythmias without a risk of cological rate control is required. Intravenous amiodarone ventricular proarrhythmia.23 is a useful alternative in situations where the administration of b-blockers or calcium antagonists is not feasible, such as Early afterdepolarization in the presence of heart failure. The prolongation of repolarization may promote action All current class Ia, Ic, and III antiarrhythmic drugs have potential instability with increased beat-to-beat variability significant side effects. This includes non-cardiovascular of duration. Subsequently, this may result in activation of effects (e.g. pulmonary fibrosis and thyroid dysfunction premature inward depolarization currents, known as an with amiodarone), and of particular importance, the risk early afterdepolarization (EAD).24 EADs are generally of life-threatening ventricular proarrhythmia including TdP considered to result from reactivation of the voltage- in up to 5% of patients.19,20 Most of these antiarrhythmic dependent Ca2þ current with secondary depolarization of drugs prevent or terminate AF by altering the function the cell.25 However, other mechanisms such as increased of potassium or sodium channels within the atrial cells. late sodium current and potassium blockade have also Blockade of potassium channels may prolong ventricular been proposed.26,27 Regardless of underlying mechanism, repolarization — and hence, the refractory period — result- when EADs have sufficient amplitude, they may trigger ing in QT-interval prolongation. Given the risk of severe pro- another action potential and promote triggered activity. As arrhythmia, the safety profile of many current antiarrhythmic a result EADs, especially when accompanied by the presence drugs is far from ideal. of a notably increased dispersion of repolarization (see below), may induce re-entry and may be responsible for Mechanisms of antiarrhythmic drug-induced initiation of a tachycardia. QT prolongation and proarrhythmia Dispersion of repolarization Blockade of ionic currents Repolarization of ventricular cardiomyocytes is further The QT interval represents the cellular ventricular action complicated by temporal and spatial inhomogeneity of the potential and is the net result of co-ordinated function of action potential. Significant regional heterogeneity of the various ionic currents. Naþ and Ca2þ inward currents are action potential profile and duration across the left ventricu- primarily responsible for the action potential upstroke and lar wall can be demonstrated, reflecting different functional depolarization, whereas outward Kþ currents in combination expression of ion channels of cells in different transmural with a reduction in depolarizing currents are predominantly regions of the left ventricular wall.28 For example, EADs are responsible for the myocyte repolarization. Furthermore, easily induced in a subset of myocardial cells from the the same outward Kþ currents lead to restoration of mid-ventricular myocardium, known as M cells, and in the 29 negative myocardial intracellular polarity at rest. His-Purkinje network. In response to IKr blockade, M cells Very high membrane resistance and low current flow demonstrate more pronounced action potential prolongation characterize the plateau phase of the
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