Cardiovascular Journal of Africa: Vol 32 No 6 (NOVEMBER/DECEMBER 2021)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 32, No 6, November/December 2021 AFRICA 329 level in permanent AF, compared to normal SR human atrial myocytes. 23 IK1 provides the repolarising current during the terminal repolarisation (phase 3 of the cardiac action potential). It is one of the most important currents in the perpetuation of re-entrant mechanisms, as was documented by both experiments 24,25 and computer simulations. 26,27 Therefore blockage of IK1 results in prolongation of the atrial potential duration and effective refractory period (ERP). Amiodarone blocks the channels that are upregulated by remodelling such as IK1 or by stimulation of the sympathetic nervous system. Therefore amiodarone’s pharmacological properties are thought to play a key role in treatment of long- standing persistent tachycardia. 28 Furthermore, the inhibitory effect of amiodarone on the inward Na + Ca 2+ currents determines a decrease in excitability and conductivity of cardiac tissues, especially when stimulated at higher frequencies. 29 Structural remodelling involves atrial enlargement and interstitial fibrosis. Left atrium dilation has been proven to be a precursor of AF as well as a prognostic factor for AF recurrence after cardioversion. A study showed that following the AF cardioversion, the left atrial fractional shortening was higher, while the left atrial stunning was lower in patients treated with amiodarone than in the subjects who received propafenone. 30 A key component of atrial remodelling is altered intracellular Ca 2+ signalling. 31,32 In normal hearts, Ca 2+ enters the cells with each action potential through L-type calcium channels (ICa,L), triggering Ca 2+ release. An elevated heart rate in AF leads to intracellular Ca 2+ overload that further engages several defence mechanisms. ICa,L reduction contributes to a decrease in Ca 2+ inward current, shortening the AF-related action potential duration (APD), which promotes re-entry. 33,34 Moreover it has been shown that patients at risk for AF have lower levels of ICa,L than patients with a low risk for AF, due to the downregulation mechanism. 35 Shinagawa et al . used an experimental model with the aim to compare the anti-arrhythmic effects of amiodarone with flecainide and dofetilide in atrial tachycardia-associated AF, as well as to analyse these AAD’s influence on the impact of atrial tachycardia on L-type calcium channel expression. 36 Mongrel dogs were subjected to atrial tachycardia at 400 beats per min for seven days while the AADs were started three days prior to the onset of tachypacing. They found that amiodarone had superior efficacy in the prevention of AF associated with atrial tachycardia remodelling, compared to flecainide or dofetilide. Furthermore, only amiodarone prevented both the changes in atrial ERP as well as the L-type Ca 2+ channel expression induced by tachycardia. Amiodarone also reversed already established remodelling after four days of atrial tachycardia. Therefore the amiodarone effect in preventing atrial remodelling may contribute significantly in the superior efficacy of this AAD. Electrophysiological properties of amiodarone: effect on atrial-His, His-ventricular, QT intervals It has been demonstrated that amiodarone’s electrophysiological effects are significantly different following intravenous and oral administration. 37-39 These differences are certainly relevant to understand intravenous amiodarone’s efficacy in the acute conversion of cardiac arrhythmias compared to the prophylactic effects of oral amiodarone in preventing arrythmia recurrences. When administered intravenously, amiodarone has a major effect on the atrioventricular (AV) node, which results in prolongation of the nodal conduction time, represented by the atrial-His (AH) interval. 40,41 Moreover, amiodarone significantly lengthens the functional refractory period (FRP) and ERP of the AV node. 40,42 This effect would lead to the termination of paroxysmal re-entrant supraventricular tachycardias and would account for reducing the ventricular response in AF and atrial flutter, which occasionally results in conversion. The same studies have shown that intravenous amiodarone administration has no significant effect on the atrial or ventricular ERP or on the QT interval. 40 By contrast, if amiodarone is administered orally, it may significantly lengthen the QT interval and prolong the APD in the atria, AV node and ventricles. 40,43 This explains the wide spectrum of amiodarone’s anti-arrhythmic effects as it increases the ERP in all myocardial tissues. Wellens et al. also found that following oral amiodarone, the ERP of the atrium and ventricle lengthens and the His-ventricular (HV) interval increases while intravenous amiodarone did not change these values. The AV node ERP and the AH interval were prolonged both after intravenous and oral amiodarone. 44 Efficacy of amiodarone versus other anti- arrhythmics for AF Class IC and class III AADs have been widely used for AF pharmacological conversion and their use could reduce AF recurrence rate by about 20 to 50% versus placebo. 45-47 The most important studies on the use of amiodarone versus other anti-arrhythmic drugs for the prevention of recurrent AF after conversion of AF are listed in Table 3. In the critical appraisal section, we focus on the most important studies among those listed in the tables. We highlight the studies with the largest number of patients, such as CTAF, SAFE-T, EAST-AF, DIONYSOS. Thereafter we also mention studies on fewer patients that confirm the above findings: AMIO-CAT confirmed the results from EAST-AF. Moreover, these studies on a large number of patients were the basis of the recommendations listed in the new guidelines for the management of patients with persistent AF. Critical appraisal The literature search resulted in 4 308 publications on amiodarone compared to other anti-arrhythmic drugs used in patients with AF undergoing pharmacological or electrical cardioversion. Amiodarone was tested against flecainide, propafenone, dronedarone, sotalol, carvedilol, diltiazem, disopyramide, quinidine and ranolazine. Thirty-one studies were selected, out of which 11 were randomised, controlled trials: four studies compared amiodarone with class I anti-arrhythmic drugs, 51,55,62,65 while six compared amiodarone with sotalol, 51-54,58,59 and one study compared amiodarone with dronedarone. 50 There were 452 patients in the studies comparing amiodarone versus class I AADs, 504 patients when comparing amiodarone and dronedarone, and 1 633 patients in the amiodarone-versus-sotalol studies. Altogether the results show that class I and III anti-arrhythmic drugs reduced AF recurrence after catheter ablation by 20 to