Divergent Effects of Chronic Amiodarone Administration on Systolic and Diastolic Function in Patients With Heart Disease

Ahmed Ammar, MD, Maylene Wang, MD, and Bramah N. Singh, MD, PhD

The purpose of this study was to determine the effects of chronic amiodarone treatment on s stolic and dias- tolic function in patients with cardiac % isease undergo- ing treatment for resistant ventricular arrhythmias. pre- vious studies have shown that chronic amiodarone treatment either has no effect or increases left ventric- ular ejection fraction, but the effects on diastolic prop- erties of the ventricle have not been defined. Twelve male patients were given loading doses of amiodarone followed by a maintenance regimen. Serial measure- ments of heart rate, blood pressure, and indexes of systolic and diastolic function were measured by Do - pler echocardiographic techniques at baseline con s i- tions and at 2, 8, and 12 weeks of dru Changes in altered thyroid state were exclu i

therapy. ed by ser-

ial determinations of thyroid function. Amiodarone in- creased left ventricular e*$ction fraction (+16%, p 4.01 by 8 weeks), decreased presystolic ejection period/left ventricular ejection time (-120/o, p <O.?l !B" weeks), and increased velocity of circum erenttal fr r shorten- ing (+22%, p co.05 by 8 weeks). Amiodarone de- creased mitral inflow velocity peak E/peak A (-7%, p co.01 by 12 weeks), and increased deceleration and isovolumic relaxation times incrementally (+36% [p 4MOl I and +23% [ <o.OOll, respectively, at 12 weeks). Chronically a 8 ministered amiodarone can im- prove systolic function and exert a negative lusitropic action in patients with heart disease.

(Am J Cardiol 1995;75:465-469)

A miodarone, originally synthesized as a coronary vasodilator, has evolved as a major antiarrhythmic

agent for the prophylactic control of both supraventtic- ular and ventricular tachyarrhythmias.‘.2 Pharmacoki- netically and pharmacodynamically, the compound is complex.2 Its electrophysiologic properties during chro- nic drug administration are dominated by a progressive decrease in heart rate and prolongation of the action potential duration.’ The drug also has potent sodium and calcium channel-blocking properties associated with a noncompetitive antiadrenergic action.2 Amiodarone dif- fers from conventional ant&rhythmic agents in causing an extremely low incidence of proarrhythmic reaction. Moreover, rarely does it exacerbate or induce cardiac failure in most patients.4 Whereas the overall experience with chronic amiodarone treatment indicates that the drug does not reduce mean left ventricular ejection frac- tion (EF) or may even improve it.2 new or worsening congestive heart failure does develop in a few patients5v6 This occurrence was not related to specific baseline char- acteristics, such as levels of EF, end-diastolic volumes, or intercurrent myocardial infarction or cardiac arrhyth- mias. Heart failure seems to worsen without a decrease in systolic function or an increase in diastolic volume.

1:boi” !fii%AT Se& Unrvwity, ZcgaTk, Egypt, and Ire Ca:diaiogy Sec-

- a, West 10s Angeies Veterans Affairs Medcal Center, ard Department of Medicrne, Un versrty of Cal forma at LOS Angeles, Los Angeles, California. Dr. Ammo, was a visiting resoarch screntist under the ioint cuspices of USA-Eavct Peace Feliowsnia Pro gram, Washington, D.C. ‘This study wa~suaported /r pa” by the N\edica, Resmrch Service, Department of Veterars kfais, Wnsl- ington,, 3.C , the American Heart Assoctation. the Grea.er Los An

9 e

les Ahiliate, 1.0s Argcles. and t”,e Ar:hu, Dodd Fvllar houndatron or Cardiovascular Research, 10s Ange!es, Calkrnic Manuscript e ceived July 27, 1994. revrsed man\.scrrpt recerved and accepted October 3 1, 199h.

Address for reprints, Maylene Wong, MD, Cardiology Section fW 1 1 lE], Wes’ Los Angeles Vetcrans Affcrs ~~earcal Cente, Los Angeles, Californra 90073

The purpose of this study was to examine the time course of changes in systolic and diastolic function induced by treatment of arrhythmia with amiodarone. The specific hypothesis tested was that amiodarone’s action of lengthening the action potential duration by augmenting intracellular calcium load increases systolic while worsening diastolic function.

METHODS The study was conducted in 12 male patients, aged

52 to 71 years, predominantly with coronary artery dis- ease. Amiodarone was prescribed for symptomatic ven- tricular tachycardia. Except for changing the dose of the drug from loading to maintenance, no other changes in medications were made during the study. All patients underwent a full clinical evaluation, thyroid function testing with estimations of serum triiodothyronine (T,), serum thyroxine (T,), and thyroid-stimulating hormone (TSH), routine and 24-hour ambulatory clectrocardiog- raphy, and Doppler echocardiographic examinations.

After baseline measurements, studies were repeated at 2, 8, and 12 weeks after starting amiodarone. Patients were examined for symptoms and signs of hypothy- roidism and heart failure. Amiodarone 800 mg twice dai- ly was administered for 1 week, then 400 mg twice dai- ly for 3 weeks. and 400 mg/day as a maintenance dose.

Thyroid function: Serum T, and TJ were measured by radioimmunoassay using commercial kits (Diagnostic Products Co, Los Angeles, California). Normal ranges are: T,, 1.3 to 2.7 nmol/L; and T,: 58 to 161 nmol/L. TSH was measured by immunoradtometric assay using a commercial kit (Hybritech, San Diego, California); normal values range from 0.4 to 5.3 mu/L.

Doppler echocardiimphy: Studies were performed with the Acuson 128 sonographic system (Acuson Cor- poration, Mountain View, California). 2.5 to 3.5 MHz transducer, and recorded on videocassette tape. Two-

TABLE I Baseline Characteristics

Patient Age no. (years) Diagnosis EDVI (ml/m21 LVEF

1 71 CAD 0.45 2 52 CAD E ,0.35 3 60 CAD 83 0.45 4 63 CAD 86 0.45 5 70 CAD 103 0.27 6 64 CAD 67 0.20 7 59 Cardiomyopathy 86 0.12 8 62 HC 42 0.32 9 70 Hypertension, CAD 53 0.34

10 64 Hypertension, CAD 0.39 11 61 Hypertension, CAD E 0.56 12 54 Hypertension, CAD 32 0.52

Mean 63 72 0.37 *SD*6 i22 *0.13

CAD = coronary artery disease; EDVI = enddiastolic volume index; HC = hypertrophic cordiomyopothy; LVEF = lefl ventricular ejection froclion.

dimensional echocardiograms were recorded of the left ventricle in the parastemal long- and short-axis, and api- cal 2- and 4-chamber views. Two-dimensionally direct- ed M-mode echocardiograms were recorded of the left ventricle in the short-axis view between the tips of the leaflets and papillary muscles. Pulse wave Doppler vel- ocities of diastolic mitral inflow were recorded, with the sample volume placed between the tips of the mitral leaflets adjusted to obtain maximal amplitude and min- imal spectra1 dispersion. Blood pressure was recorded at the beginning and end of the recording session using an

automatic sphygmomanometer (Paramed Technology Inc, Mountain View, California).

Wrasound analyses: The videotapes were digitized using an image processor (Tomtec Imaging Inc, Louisville, Colorado). Left ventricular end-systolic (ESV) and end-diastolic (EDV) volumes, expressed as indexes ESVI and EDVI, were calculated by Simpson’s biplane method. Left ventricular internal end-systolic (LVIDs) and end-diastolic (LVIDd) dimensions and posterior wall thickness (PWtb) were measured from leading edges. Velocity spectra were traced at the outer margins from the opening and closing artifacts. Individual readings were the mean of 5 consecutive cycles.

From the mitral and aortic flow velocity spectra, the following were measured: (1) peak E- and A-wave velocities in cm/s, (2) peak E to peak A ratio, (3) decel- eration time (DT) (in milliseconds) from peak of E wave to baseline, (4) isovolumic relaxation time (IVRT) (in milliseconds), and (5) presystolic ejection period/left ventricular ejection time (PEP/LVET). The derived data were calculated as: EF (%) = (EDV-ESV)/EDV X 100, velocity of circumferential fiber shortening (Vcf, &-c/s) = (LVIDd-LVIDs)/(LVIDd X ejection time)7; merid- ional end-systolic stress (s/cm*) = (1.35 X systolic blood pressure X LVIDs)/4 X PWth (1 + PWth/LVlDs).s

The measurements were obtained by a single observ- er blinded to patient identity. Intraobserver errors were determined from 6 duplicate readings performed 8 weeks apart. The differences divided by the means were ex- pressed as percentages: LVIDs = 5.5%, LVIDd = 5.097,

2 0 L?

WEEKS

2 8 12

WEEKS

2 0 12

WEEKS

FIGURE 1. Effects of chronic amiodarone tmatment an thyroid hormane indexes and left ventricular systolic and diastolic function determined over 12 weeks. A summarizes the results of thyroid function tests and heart rate changes; 6, indexes of systolic func- tion; and C, indexes of diastolic function. Data paints represent the mean of intrasubiect differences between basefine and obser- vations made at 2, 8, and 12 weeks. Bars represent 1 SD. Measurements are in absolute units. Only variables with data achiev- ing statistical signrficance are depii. DT = deceleration time; E/A = ratio of peak early diastolic velocity ta peak atrial contraction velocitr; EF = e+tion fraction; HR = heart rate; WRT = isovdumic relaxation time; PEP/LVET = ratio of preejection period to left ventrrcdar ejection time; T = serum triiodothyronine; T, = serum thyroxine; TSH = serum thyrotropin; Vcf = velocity of circumferential fiber shortening; ‘p c 8.05; “p 4.01; *’ pc 0.001.

466 THt WERICAN JOURNAI. OF CARJOLOGY” VOL. 75 ,b’ARCH I, 1995

PWth = 5.2% ESV = 1.7% EDV = 1.9%, DT = OS%, and IVRT = 1.0%.

TABLE II Effects of Chronic Amiodarone Treatment on Thyroid and Cardiovascular Function

Statistics: The mean + SD for each variable was calculated for each time period and was subjected to repeatcd- measures analysis of variance to eval- uate patterns of change over time. Lin- ear, quadratic, and cubic trends were calculated and tested by F tests with significance set at p ~0.05. The mean within-subject differences and stan- dard deviations between baseline and each time period were determined and tested by paired t tests. For an overall (Y of 0.05, significance was adjusted to 0.017 for the 3 time-period compar- isons.

T; (nmol/tj+t 95 *21 TSH (mU/L)tr 2.5 * 1.1 Systolic BP (mm Hg) 131 * 28

Diastolic BP [mm Hg) 79* 10 Heart rote (beats/minl*r 68 It 9

Control 2 Weeks 8 Weeks 12 Weeks

T, Inmol/tl*t 1.8 zt 0.3 1.7 f 0.3 I ..5 + 0.2 1 .A + 0.2 146 * 15 2.7 * 1 .O 132 + 31 78 * 9

EDVI (ml/m .2 ) 72 t 22 ESVI [ml/m21 A6+ 18

125 * 22 139-c20 2.5 * 1.1 2.8 i 1.0 132 * 28 136 * 30 80 zt 8 78 * 8 65 + 7 56 + 8 73 k 20 70 e 22 AA+16 4oi 15 29 * 9 30 * 11

0.41 * 0.10 0.43 -c 0.10 0.34 * 0.06 0.32 * 0.06

62 * 28 63 +- 27 92 k 53 75 * 39 78 c 27 73 * 24

I. I

SVI (ml/m21 26t 12 Eiection fraction*r 0.37 * 0.13 PiP/LVET*t Vcf fcirc/sl* t

0.37 * 0.08 51 k28

mESS (g/cm2)* 79 + 44 Peak E (cm/s) 73 * 23 Peak A [cm/s)* 63 + 26 E/A* 1.49 * 1.09 DT (ms)*t 158*36 IVRT (ms)* 109 zt 29

71 i35 70 * 29 1.37 zt 1.02 1.28 -+ 0.96

RESULTS 187~28 206 + 28 120 f 22 134 zt 20

55 -c 7 76 * 22 46 rt 20 29 * 11

0.40 e 0.1 A 0.33 r 0.06

58 * 28 78+41 73 f 21 70 * 32

1.39 -c 1.03 215 * 27 134 zt 19

Demographic features and baseline left ventricular status of the patients are listed in Table I. The group con- sisted of men in their fifth to seventh decades, with predominant coronary artery disease, normal left ventricular end-diastolic volumes, and moderate-

Data presented os group meons * 1 SD at control, and at 2, 8, and 12 weeks during treatment, analyzed by repeated-measures analysis of variance for linear,’ tested by F test. Symbols also indicate significance at n = 0 05.

cubic,’ and quadratic’ trends, and

BP - blood pressure; DT = deceleration t’ une; E/A = rotlo of peak early diastolic velocity to peak atrial contraction velocity; ESVI - end-systolic volume index; IVRT = isovolumic relaxation time; mESS = meridional end-systolic stress; PEP/LVET = ratio of preejection period to left ventricular ejection time; SVI = stroke volume index; T, = serum triiodothyronine; T, = serum thyroxine; TSH = sewn thyrotropin; Vcf = velocity of circumferential fiber shortening; other abbreviations OS in Table I.

ly reduced EFs. The mean group data on thyroid func- tion, heart rate, blood pressure, and indexes of left ven- tricular function determined serially over 12 weeks are presented in Table II. Figure 1 summarizes the mean within-subject changes that reached statistical signifi- cance at baseline and at 2, 8, and 12 weeks.

Thyroid functian: At baseline, mean T,, T,, and TSH levels were normal. After 2 weeks of amiodarone trcat- ment, significant changes were seen in T, and T,. After 12 weeks, T, decreased to lower limits of normal and T, continued to increase, but within normal ranges. TSH levels remained within normal limits, but showed an upward trend, which reached significance at 8 weeks but not at 12 weeks.

Heart rate slowed significantly by a mean of -12 and -13 beats/min (-19%) at 8 and 12 weeks, respectively. Neither systolic nor diastolic blood pressure changed.

Systdic function: At baseline, mean left ventricular end-diastolic volume was normal and associated with a moderately depressed EF, with a commensurate decrease in stroke volume. With amiodarone therapy, end-dias- tolic volume did not change. EF increased linearly, then leveled, reaching a peak within-sub.ject change of +16% (p ~0.01) at 8 weeks. PEP/LVET decreased, reaching a plateau of -12% (p ~0.01) at 8 weeks. Vcf increased and tapered (+220/c; p ~0.05) at 8 weeks. Meridional stress showed a linear downward trend over time (p ~0.05). In 11 of 12 patients, EF and PEP/LVET showed improve- ment by the eighth or twelfth week. All 12 patients had an increase in Vcf by 12 weeks. In 10 of 12 patients, meridional stress decreased by 8 or 12 weeks.

Diastolic function: The diastolic velocities of patients 5,6 and 7 revealed a restrictive pattern with E to A ratios of 2.62 to 3.74; therefore, the baseline means for peak E, peak A, and E/A overlapped, with values reported in normal subjects aged 250 years.9 Baseline DT was short-

er than normal (p ~0.001); IVRT was prolonged com- pared with that in normal subjects (p ~0.05). With amio- darone, peak E did not change and peak A showed a sig- nificant linear increase, resulting in a significant linear decrease of E/A (p = O.OOl), manifested as a within-sub- ject change of -7% (p ~0.01) by 12 weeks. Both DT and IVRT lengthened signiEcantly over time as linear and quadratic trends that were significant as within-subject changes by 2 weeks (p <O.OOl and p ~0.05, respectivc- ly). The amiodarone effects on Doppler indexes were directionally the same for patients with velocity patterns of restriction and delayed relaxation.

Symptoms: Patients 5 to 8 had histories of congestive heart failure and minimal to moderate dyspnea before amiodarone administration. Dyspnea progressed to mod- erate and moderately severe between the eighth and twelfth weeks of treatment. All other patients denied having cardiac symptoms before treatment; however, patients 2 and 9 experienced minimal to moderate dys- pnea between the eighth and twelfth weeks. No patient had symptoms that required discontinuing amiodarone therapy.

DISCUSSION Our study has revealed that chronically administered

amiodarone in patients. with heart failure undergoing treatment for resistant arrhythmias induces divergent effects on systolic and diastolic function. The drug in- creased left ventricular EF and Vcf, and reduced PEP/ LVET and end-systolic stress, indicating an improvc- ment in systolic function. These Endings extend and con- Erm previous observations reported by a number of investigatorsiO.” who found that the drug either had no effect on ventricular function or tended to improve it. However, the most striking observation that has not been previously documented is the effect of the drug on dias-

ARRHY1l iMIAS AND CONDUCTION DISTIJRBANC’S/AE~\I~OARONE AND SYS-OLIC AND D ASTOJC FUNGI IOh 467

tolic function; amiodarone significantly prolonged IVRT (+23%), lengthened DT (+36%), and decreased the E to A ratio (-7%) at 12 weeks. These findings are consis- tent with a negative lusitropic action that could not be attributed to hypothyroidism.12

Bradycardia alone can change EF and PEP/LVET. However, in paced dogs, the increase in EF was not sig- nificant until the heart rate was slowed by 220% of con- trol.‘” In our patients, correcting systolic time intervals for heart rate did not account for the small but signifi- cant decrease in PEP/LVET at 2 weeks when the heart rate had slowed to only 3 beats/min; correcting such intervals would have predicted a change twofold greater than our results at 12 weeks.14 Vcf should decrease with bradycardia instead of increasing because of the inverse relation with LVET, which bradycardia prolongs. Thus, while the contribution from bradycardia cannot be entirely discounted, the trends toward improved systolic function were seen by 2 weeks when the heart rate had not begun to slow.

As for diastolic filling patterns, bradycardia decreas- es peak A wave, which would increase the ratio of E to A.ls The effect of lengthening atrioventricular conduc- tion on diastolic relaxation is not known, but chronic oral amiodarone minimally prolongs the PR interval 130 ms, the AH interval 125 ms, and the HV interval 510 ms, 16*17 all physiologically insignificant.

Amiodaronc has a complex pharmacologic profile,2,3 and the clTec‘ects of the drug on ventricular function need to be interpreted in light of its known actions on hemo- dynamic variables. I6 Amiodaronc has significant sodium and calcium channel blocking actions that may, along with its noncompetitive antiadrenergic effects, reduce ventricular function.2 Despite this, indexes of systolic function were improved after 8 weeks of continuous drug administration. Previous reports in humans have also suggested that the drug either has no effect or enhances ventricular function in patients with cardiac arrhythmias.2,‘0,” Rarely does it reduce ventricular EF during chronic drug administration. The mechanism for the seemingly low incidence of negative inotropic effect despite its potent sodium and calcium channel blocking actions and its antiadrenergic properties remains unan- swered. The question raised is whether the expected neg- ative inotropic effect of amiodarone is all but nullified, or even reversed as a consequence of prolonged cardiac repolarization induced by the drug.

Potential basis for the divergent effects of amiodarone an systolic and diastolic function: SIGNIFICANCE or: PKO- LONGID CARDIAC RIPOLARIZATION: Experimental and clinical studies have confirmed that amiodarone consis- tently lengthens the action potential duration as a func- tion of time.1.2,4 Other studies have suggested a relation between prolonged repolarization and increased myo- cardial contractility. 18*19 Singh and Vaughan WilliamszO found that sotalol, a p blocker that lengthens the action potential duration, exerted a positive inotropic effect in isolated cardiac niuscle. Kaumann and Olson21 also reported similar effects in isolated kitten papillary mus- cles. Subsequently, it has been found that the d-isomer of sotalol, being devoid of P-blocking activity, exerted a frankly positive inotropic action in cardiac muscle22 and

in animals with experimental heart failure.23 Other pure class I11 agents exert a positive inotropic effect.23 Thus, with our data, it seems reasonable to conclude tentatively that the same theory may hold true for amiodarone, in which the positive inotropic effect due to prolonged repolarization may reverse the depressant effect of the compound due to other associated properties, such as inhibition of’ sodium and calcium channels and p ad- renoreceptors.

Cingolani et a124 recently reported that 2 pure class III agents which lengthen cardiac repolarization, DPI 201-106 by delaying sodium channel inactivation, alld E.4031 by blocking potassium channels, exert a signifi- cant negative lusitropic effect. They showed that in open- chest anesthetized dogs, the time constant of decline of isovolumic pressure increased after the injection of E4032 or DPI 201-106. These changes occurred in the absence of alterations in heart rate, mean arterial pres- sure, or left ventricular end-diastolic pressure. Both com- pounds increased the relaxation time and augmented the peak developed tension. These effects occurred in step with increases in the time course of repolarization. The authors suggested a causal link between the prolonga- tion of the action potential duration and the negative lusitropic effects of E4032 and DPI 201-106 due to increased intracellular calcium overload. A decrease in the rate of fall in the calcium ion concentration in cytosol should be followed by delayed myocardial relaxation.24 This issue has not been investigated with amiodarone or its derivatives.

Clinical impkations: Our data on amiodarone in pa- tients with heart disease, indicating that the drug may improve systolic function while having the potential to impair diastolic function, have important clinical impli- cations. Extensive clinical experience suggests that amiodarone rarely aggravates heart failure. Patients with heart failure and those with markedly reduced EFs remain relatively free of adverse effects, and the drug produces little or no effect on the central circulation (except for slowing heart rate),2 or on mean EF.2,25 In numerous trials of postinfarct patients, low-dose amio- darone did not exacerbate cardiac failure.4 A notewor- thy study using a low dose of 200 mg/day in patients with severe heart failure actually showed an increase in mean EF (from 0.19 to 0.29), and in exercise duration (from 483 to 907 seconds in 6 months), a significant improvement over placebo controls.” Our data indicat- ing that amiodarone delays relaxation are new and may provide the basis for the deterioration of heart failure in some patients, especially during initial high-dose load- ing regimens.26 Delayed relaxation may also account for the increases in ventricular filling pressure and reduced exercise tolerance in patients with hypertrophic car- diomyopathy taking amiodarone,27 and the decline in patients without obvious deterioration in systolic func- tion and increase in diastolic volumes.“*” However, such patients among those treated with amiodarone are rela- tively few.

Conchsion: Chronic administration of amiodarone in patients with cardiac disease and diminished left vcn- tricular EF improved systolic function but led to an im- pairment of diastolic function determined by Doppler

468 TI-IE AA/\tKICAN JOURNAL Of CAWIOLOGP VOL. 75 MARCH I, 1995

echocardiography. The drug increased left ventricular EF by 16% but increased DT by 23% and IVRT by 36%. Experimental data on the e!Tects of drugs that selective- ly lengthen rcpolarization in cardiac muscle indicate that the divergent effects of chronic amiodarone treatment may result from the drug’s well-known propensity to prolong the action potential duration. Our data suggest that most patients given amiodarone have increases in left ventricular EE The drug is therefore well tolerated even in those with heart failure, but congestion may worsen in some, with significant negative lusitropic effects of the compound.

1. Singh BN, Ahmed K. Cla\s III antiarrhythmx drugs. Curr 0pif1 Cur&/ 1994:

9:12 22. 2. Singh UN. Vcnkatebh S. Sademanee K. Josephson MA, Kannan R. The bistor- ical development. cellular electmphysiology and pharmacology of amiodarone. Pros Car-diow\c Dis 1989;3 I :249-280. 3. Singh HN. Vaughan William EM. The effect of amitxlarone. a new antiangina drug, on cardiac muscle. Hr J Phannurol 1970:39:657-667. 4. Sademanee K. Singh By. Stcvcnson WG, Weiss JN. Amiodarone and post-411 patlent\. Cirruloriofl lYY3;88:7*774. 5. Paola AV, Horowirz LU, Spielman SR. Brady P. Morganrotb I. Greenspan AM, Kay HR. Development of congestive hearc failure and alterations in left venlricu- lx function in patients with sustained ventricular rachyarrhythmias treated with amiodaronc. Am J Cordml lY87:60:27~280. 6. Trobaugb GB. Kudenchuk PJ. Greene Ill., Tutt RC, Kingston E. Gorham JP, Gross BW. Graham FL, Sean GK, Werner JA. Effect of amiodaronc on ventricu- lar function as measured by gated radionuclitlc angiography. Am J Cordial 1984: 54:1263-1X6. 7. Pwaskos JA, Grossman W. Saltr S. Dalcn JE. Dater 1.. A noninvasivc tech- nique for the determination of velocity of circumfcrcnlial tibcr rhonening m man. Circ Rrs 1971:29:61(~615. 8. Grossman W, Joncs D. McLaurin LP. Wall strc\s and patterns of hypatrophy. J Clirr Inw,~~ 1975;56:3&64. 9. Klein AL, Burstow DJ. Ta.jik AJ, 7xhanab PK. Bailey KR. Seward JB. Effects of age on left ventricular dimension\ and tilling dynamn in I17 normal persons. May C/L, Proc 1994;6!):2 12-224. 10. Sheldon RS, Mitchell LB, Duff I U. Wyse DG. Maynard DE. Right and left vcn- triculx function during chronic ammdarone therapy. Am J Co~lrol 1988:62: 73t%740.

11. Hamer AWF, .4rkles LB. Johns JA. Beneficial effects of low dose amiodaronc

in patient5 with confentivc cardiac failure: a placebo-controlled trial. J Am Co// Cardiol 1989;14:1768-1774.

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1982: 103:950-959. 17. Wellcnr HJ, Brugada P. Abdollah H, Dassen WR. A comparison of the elec- nophysiologic effects of intravenous and oral amndarone in the same patient. Cir- cdofwn 1984:69:12&l 24. 18. Kavaler I:. Membrane depolariation as a cause of tenwn development in mam- malian cardiac muscle. Am J Phyriol 1959:197:968-972. 19. Morad !vl, Trautwein W. ‘lhe effect of the duration of the action potential on contraction in rhe mammalian hcan muscle. Pflrc,qer;, Arc/r 1968;299:66-82. 20. Singh BN. Vaughan Williams EM. A third clacs of ;m!iarrhythmic action? Effects on atria1 and ventricular intracellular potenrials and other pharmacologic actions on cardiac ~nusclc 01’ YJ19Y9 and AH3474. HrJ Phormucol 1970:67S~X6. 21. Kaumann N. Olson CU. Temporal relationship between long-larring aftercon- tractions and action potentials in cat papdlq muscles. Science lY68:163:293- 2Y6. 22. Tande PM, Rcfsum Il. Class III anti-arhythmic action linked with positive isotropy: effects of the d- and I-iwmcr of sotalol on isolated rat atria al threshold and rupmthreshold stimulation. Phormawl 7rx1col 198X:63:272- -277. 23. Monensen E. Tande PM, Klow \‘E, Kefsum H. llemodynxnic effects of d- sotalol in acuw ischemic bean failure in dogs. Am Ilear/ J 1992; 123:97&977. 24. Cingolani HE. Wiedman RT. I.ynch JJ. Wenger HC. Scott AL, Siegl PKS. Stein RR. Ucgative lusitropic effect of DP 201. IO6 and EAO31. Possible role of prolonging action potential duration. J MO/ Ccl/ Cardro/ l(%l;22);22: 1025-10.34. 25. Singh BN. Arrhythmia control by prolonging rcpolarntion: the concept and its potential thcrapeuric impact. EIU Hrw~-r J 1993;( 1411):14-23. 26. Gonlieb SS. Riggio DW. Lauria S. Pe~en RW. Shorofsky SR. Cmes M. Fro- man I), Gold MR. High dose oral amicdarone loading cxcrts impanant hcmody- namic act~onc in patients with congertivc heart failure. J Am Co// Cardinl lY44:23: 5fa564. 27. Paulus WJ, Nellcna P, Heyndrickx GR. Andrie\ E. Effects of long-term treat- merit with amiodarone on exercise hemodynamic and left ventricular relaxation in paticnu wirh hypenrophic cardiomyopathy. Cir-rrrlofion lY86:74:544 554.

AK;~P HP$JAS AND CON!I!!CWJN DISTCKI~ANC~S/~\~IIODA~O~~ AND SYS’OLIC AND DlASTOLiC i 3NCWN 469