Chronic Effects Of Amiodarone Research Articles

Effects of Chronic Amiodarone on the Electrical Restitution in the Human Ventricle With Reference to Its Antiarrhythmic Efficacy

Dynamic instability of ventricular refractoriness represented by electrical restitution operates synergistically with tissue heterogeneity to increase the propensity for functional reentry leading to ventricular tachycardia/fibrillation (VT/VF). Little is known about the effect of chronic amiodarone on the electrical restitution in the human ventricle. Restitution kinetics of monophasic action potential duration (MAPD(90)) in the right ventricular outflow tract (RVOT) and apex (RVA), and of inverse of conduction time from RVOT to RVA (CT(-1)), were estimated by an S1-S2 protocol in 22 patients treated with amiodarone (180 ± 33 mg/day for 7 ± 9 months) and in 30 without treatment. In the untreated patients, the restitution kinetics of CT(-1) was steeper in the group with structural heart disease (SHD) (UNT(SHD+), n = 18) than without SHD (UNT(SHD-), n = 12), whereas MAPD(90) restitution parameters were comparable. In the amiodarone-treated patients (all with SHD), the shortest diastolic interval to produce a ventricular response (DI(min)) was increased, the maximum slope of MAPD(90) was flattened, and the magnitude of CT(-1) restitution was reduced as compared with UNT(SHD+). Sustained VT/VF was induced in 7 of 18 UNT(SHD+) (38.9%) and in 4 of 22 amiodarone-treated patients (18.2%, P = 0.07). Concomitant presence of increased CT(-1) restitution and dispersion of MAPD(90) restitution was required for the VT/VF induction. The suppression of VT/VF in the amiodarone-treated patients was associated with a smaller magnitude of CT(-1) restitution in the presence of limited dispersion of MAPD(90) restitution. Chronic amiodarone flattens restitution kinetics of MAPD(90) and CT(-1) in the human ventricle, which could be antiarrhythmic in patients with limited tissue heterogeneity.

Cellular electropharmacology of amiodarone.

The complex profile of amiodarone actions on the electrophysiological properties of cardiac cells reviewed in this article may be summarized as follows. As acute effects, amiodarone inhibits both inward and outward currents. The inhibition of inward Na+ and Ca2+ currents is enhanced in a use- and voltage-dependent manner, resulting in suppression of excitability and conductivity in both iNa- and iCa-dependent cardiac tissues. The inhibition is greater in the tissues stimulated at higher frequencies, and in those with less negative resting (or diastolic) membrane potentials. As outward currents, iK (iKr and iKs), iK,ACh and iK,Na are inhibited by acute amiodarone, iKl could also be inhibited at high concentrations of amiodarone. Acute effects of amiodarone on i(to) remain unclear. Previous reports on the acute effects of amiodarone on APD are conflicting, presumably because different ionic currents are responsible for the repolarization of action potential in different animal species, cardiac tissues and experimental conditions. APD would be shortened if the inhibitory action of amiodarone on the inward current is greater than on the outward current, and vice versa in the opposite case. The major and consistent chronic effect of amiodarone is a moderate APD prolongation with minimal frequency-dependence. This prolongation is most likely due to a decrease in the current density of iK and i(to). Chronic effects of amiodarone are modulated by tissue accumulation of amiodarone and DEA. Variable suppression of excitability and conductivity of the heart by chronic amiodarone might reflect direct acute effects of the parent drug and/or its active metabolite (DEA) retained at the sites of action. Chronic amiodarone was shown to cause a down-regulation of Kv1.5 mRNA in rat hearts, suggesting a drug-induced modulation of potassium channel gene expression. Electrophysiological changes in the heart induced by chronic amiodarone resemble those induced by hypothyroidism. Three mechanisms have been proposed to explain this hypothyroid-like action of amiodarone. Amiodarone and/or DEA may inhibit peripheral conversion from T4 to T3, cellular uptake of T4 and T3, and T3 binding to nuclear receptors (TR). The second and third mechanisms are considered to be more important than the first. Amiodarone or DEA could antagonize T3 action on the heart at a cellular or subcellular level. Two distinct characteristics in the cellular electropharmacology or amiodarone are different from those of other antiarrhythmic drugs. First, it acts on many different types of molecular targets including Na+, Ca2+, and K+ channels as well as adrenoceptors. Second, it may cause antiarrhythmic remodeling of cardiac cells, probably through a modulation of gene expression of ion channels and other functional proteins. We hypothesize that this remodeling is mediated most likely by cellular or subcellular T3 antagonism. Nevertheless, much remains to be studied as ot the acute and especially chronic effects of amiodarone on ionic currents, transporters, receptors and other molecules in cardia cells. The role of the cardiac hypothyroid state in the genesis of antiarrhythmic activity is still a matter of considerable controversy among investigators. Recently, two amiodarone analogues (SR 33589 and ATI-2001) showing a potent acute antiarrhythmic activity in animal models, have been developed [37,87,88,131]. These new compounds are not known to exhibit chronic antiarrhythmic potential or cardiac hypothyroidism activity. Unraveling these tissues will be required to understand the exact molecular and cellular mode of action of amiodarone and to find a new direction for the development of the ideal antiarrhythmic drugs of the future.

Effects of long-term oral administration of amiodarone on the ventricular repolarization of rabbit hearts.

The chronic effects of amiodarone on ventricular repolarization were investigated in Langendorff-perfused rabbit hearts in comparison with the acute effects of other Class III antiarrhythmic drugs. Forty to fifty electrograms were recorded through modified bipolar electrodes from the anterior to the lateral epicardial surface of the ventricles under His-bundle pacing (1.0 Hz). In control hearts, epicardial activation proceeded from the apex to the base. The interval from the initial sharp negative deflection of the QRS complex to the apex of the T-wave (Q-aT), which reflects the action potential duration (APD) at the recording site, was longest in the apex and shortest in the base. Therefore, repolarization proceeded from the base to the apex. In hearts treated with oral amiodarone (100 mg/kg, 4 weeks), Q-aT was uniformly prolonged by 14-16% throughout the entire mapped area, whereas the activation sequence was unaffected, and a normal Q-aT gradient was well preserved from the apex to the base. The spatial inhomogeneity of left ventricular repolarization was not enhanced by drug treatment. Acute application of sotalol (30 mumol/L), E-4031 (0.1 mumol/L) or MS-551 (1.0 mumol/L) caused a much greater Q-aT prolongation in the apex than in the base, resulting in a marked enhancement of the spatial inhomogeneity of repolarization. These findings suggest that the propensity of chronic amiodarone to induce torsade de pointes less often than other Class III agents may result at least in part from its favorable effect on the spatial homogeneity of ventricular repolarization.

Acute and chronic effects of amiodarone on mammalian ventricular cells.

This article reviews experimental studies on the electrophysiological effects of amiodarone on mammalian hearts. Acute application of amiodarone (0.1-10 microM) to papillary muscles or single ventricular cells isolated from rabbits or guinea pigs caused a significant decrease in action potential duration (APD) as well as a marked use-dependent inhibition of the maximum upstroke velocity (Vmax) of action potential with fast recovery kinetics. Acute amiodarone also caused a concentration-dependent decrease in the calcium current (ICa) and the delayed-rectifier potassium current (IK). Action potentials recorded from papillary muscles or single ventricular cells isolated from the rabbits treated with oral amiodarone (100 mg/kg daily, 4 weeks) were characterized by a moderate frequency-independent prolongation of APD. There was no use-dependent Vmax inhibition. The ventricular cells treated with chronic amiodarone showed a significant decrease in the current density of ICa, IK and Ito. The amount of mRNA for Kv1.5, a Shaker-related potassium channel from the rats treated with chronic oral amiodarone was significantly lower than that from control rats. These results suggest that the major and consistent effects of chronic amiodarone is repolarization delay (Class III action) through a decrease in IK and Ito density, probably due to a modulation of gene expression of potassium channels. When amiodarone above a certain concentration is present in the extracellular space, fast kinetic Class I and Class IV actions would be added as acute effects.

P-274 - Acute and chronic effects of amiodarone on action potential and ionic currents in single rabbit ventricular myocytes.

P-274 - Acute and chronic effects of amiodarone on action potential and ionic currents in single rabbit ventricular myocytes.

Acute and chronic effects of amiodarone on delayed afterdepolarization and triggered automaticity in rabbit ventricular myocardium

The effects of amiodarone on delayed afterdepolarization (DAD) and triggered automaticity induced by low potassium (0.5 mEq/L) were evaluated on isolated rabbit right ventricular muscles, by means of standard microelectrode techniques. Triggered automaticity was induced in 6 of 10 muscles in the control group, in four of eight in the amiodarone-superfused group, and in three of four in the Tween 80-pretreated group. In contrast, triggered automaticity could be induced in only 2 of 10 amiodarone-pretreated muscles (n = 10) (20 mg/kg intraperitoneally, daily for 4 weeks; p < 0.05 compared to control and amiodarone-superfused groups). The amplitude of DAD was significantly lower in muscles isolated from rabbits pretreated with amiodarone compared to those from nontreated control rabbits (n = 17). The degree of reduction was significant during all three cycle lengths of stimulation tested (800, 600, and 400 msec), that is, 2.5 ± 1.8 vs 5.1 ± 1.8, 2.4 ± 2.1 vs 5.5 ± 2.3, and 3.3 ± 3.4 vs 9.3 ± 4.3, respectively (values are in millivolts of mean ± SD). Superfusion with amiodarone (3 μg/ml; n = 8) significantly ( p < 0.05) reduced the amplitude of DAD at 800 msec cycle length, but had no significant effect at cycle lengths of 600 and 400 msec. Tissue concentrations of amiodarone in the pretreated group were significantly ( p < 0.05) lower than those in the superfused group (10 ± 6.8 vs 21 ± 3.1 μg/gm). In contrast, however, tissue concentration of desethylamiodarone (a deethylated metabolite of amiodarone) was significantly higher in the pretreated compared to the superfused group (1.2 ± 0.5 vs 0.5 ± 0.2 μg/gm; p < 0.05). We conclude that chronic amiodarone treatment is significantly more effective than acute superfusion in reducing the amplitude of DAD and subsequent induction of triggered automaticity in rabbit ventricular myocardium.

Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction

In eight patients, the right ventricular effective refractory period, rate-dependent changes in intraventricular conduction (as reflected by QRS duration during ventricular paced cycle lengths of 600 to 250 ms) and results of programmed ventricular stimulation were determined in the control state, 5 minutes after the intravenous infusion of 10 mg/kg body weight of amiodarone and after 2 months of treatment with oral amiodarone. The right ventricular effective refractory period was 230 +/- 30 ms (mean +/- SD) in the control study, 248 +/- 27 ms after intravenous amiodarone (p less than 0.001) and 296 +/- 26 ms after oral amiodarone (p less than 0.001). In the control state, QRS duration was constant at all paced cycle lengths. Intravenous amiodarone resulted in a rate-dependent prolongation of QRS duration. This rate-dependent prolongation was markedly accentuated by oral amiodarone in six patients who had an elevated serum level of reverse triiodothyronine (T3) after 2 months of oral treatment, but it was not more pronounced than the effects of intravenous amiodarone in two patients with a normal reverse T3 serum level after oral therapy. Both intravenous and oral amiodarone either suppressed or modified the induction of ventricular tachycardia by programmed stimulation in some patients, but in a discordant fashion. The relative effects of intravenous and oral amiodarone on ventricular refractoriness and conduction and on ventricular tachycardia induction did not correlate with serum amiodarone levels. Chronic amiodarone therapy results in a marked prolongation in ventricular refractoriness compared with the relatively small but significant increase that occurs after intravenous amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic effects of amiodarone in patients with refractory ventricular tachycardia

We examined the chronic electrophysiologic, systemic, and pharmacologic effects of chronic oral amiodarone therapy in 24 patients with refractory ventricular tachycardia and organic heart disease. Chronic amiodarone therapy resulted in significant increases in R-R interval (from 798 ± 182 msec to 912 ± 100 msec; P < 0.01), P-R interval (from 205 ± 66 msec to 221 ± 87 msec; P < 0.02), QRS duration (from 103 ± 24 msec to 115 ± 28 msec; P < 0.001), and Q-Tc interval (from 413 ± 48 msec to 470 ± 46 msec; P < 0.001). Significant increases were also noted in P-A interval (from 36 ± 14 msec to 45 ± 13 msec; P < 0.05), A-H interval (from 119 ± 61 msec to 141 ± 87 msec; P < 0.02), and H-V interval (from 52 ± 12 msec to 64 ± 11 msec; P < 0.001). Electrophysiologic parameters showing changes included corrected sinus node recovery time (from 271 ± 140 msec to 425 ± 122 msec; P < 0.01), the effective refractory period of the atrium (from 263 ± 32 msec to 321 ± 47 msec; P < 0.01), the effective refractory period of the atrioventricular node (from 348 ± 109 msec to 478 ± 157 msec; P < 0.001), the effective refractory period of the ventricle (from 253 ± 21 msec to 291 ± 28 msec; P < 0.001), the atrial pacing cycle length producing A-V nodal Wenckebach (from 436 ± 109 msec to 531 ± 95 msec; P < 0.001), and the functional refractory period of the A-V node (from 422 ± 68 msec to 499 ± 95 msec; P < 0.001). Programmed electrical stimulation performed after 21–88 (mean 31) days of treatment was highly predictive of long-term results if suppression of arrhythmia induction was demonstrated (12 patients) or if the spontaneous arrhythmia was reinduced (5 patients). Induction of morphologically new ventricular tachyarrhythmias was frequent (42%) but had a low spontaneous recurrence rate (10%) during follow-up. Systemic parameters on chronic amiodarone therapy showed significant increases in total T 4 and reverse T 3, with no change in pulmonary function tests or left ventricular ejection fraction. Serum amiodarone levels at chronic electrophysiologic study ranged from 0.44–4.10 (mean 1.3) μg/ml. Long-term follow-up (2.5 to 20 months) demonstrated a marked improvement in clinical symptoms and mortality, but a significant recurrence rate of a well-tolerated slower arrhythmia persisted. Adverse effects on chronic amiodarone therapy were frequent (10 patients) and often disabling but required drug discontinuation in only 1 patient.