Amiodarone reduces QT dispersion in patients with hypertrophic cardiomyopathy

International Journal of Cardiology, 36 (1992) 345-349 0 1992 Elsevier Science Publishers B.V. All rights reserved

CARD10

345 0167.5273/92/$05.00

01510

Amiodarone reduces QT dispersion in patients with hypertrophic cardiomyopathy Athanase

Dritsas,

David Gilligan,

Petros

Nihoyannopoulos

and Celia M. Oakley

Department of Medicine, Clinical Cardiology, Hammersmith Hospital, Royal Postgraduate Medical School. London. UK (Received

20 March

1992: revision

accepted

16 April

Dritsas A, Gilligan D, Nihoyannopoulos P, Oakley CM. Atniodarone with hypertrophic cardiomyopathy. Int J Cardiol 1992;36:345-349.

1992)

reduces QT dispersion in patients

To compare QT interlead variability (dispersion) in patients who receive a class III antiarrhythmic with those not on antiarrhythmic therapy, we measured QT in all 12 leads of a standard ECG in 24 patients with hypertrophic cardiomyopathy, 12 (50%) of whom were on amiodarone monotherapy and 12 (50%) who were not on amiodarone or other cardioactive medication which could affect QT. Age, functional class, chamber dimension or the degree of left ventricular hypertrophy expressed by maximal wall thickness (21 _t 5 vs 20 + 4 mm; p = NSl was not different between the amiodarone and the non-amiodarone group. Maximal corrected QT (QTc) was greater in patients receiving (488 t 25 ms) compared to those not receiving amiodarone (451 f 23 ms) (p < 0.001). However, QTc dispersion defined as the difference of maximum minus minimum QTc was decreased in the amiodarone (48 + 10 ms) compared to the non-amiodarone group (78 + 17 ms) (p < 0.001). We conclude that in patients with hypertrophic cardiomyopathy, amiodarone prolongs QTc but reduces QTc dispersion. These results agree with expected changes in ventricular recovery time in patients who receive Class III antiarrhythmic agents and provide further support to the theory that QTc dispersion reflects regional differences in ventricular recovery time. Key words: Amiodarone;

QT; Hypertrophic

cardiomyopathy

Introduction Increased dispersion of ventricular recovery time has been associated with the occurrence of serious ventricular arrhythmias particularly in conditions where QT is prolonged, including the Correspondence to: Dr. A. Dritsas, Dept. of Medicine. Clinical Cardiology, Hammersmith Hospital, RPMS, Du Cane Rd., London W12 ONN, UK. Tel. 081-7432030. Fax 0817403169.

congenital long QT syndrome and post-myocardial infarction arrhythmias [l-3]. Dispersion of ventricular recovery time is usually measured by means of monophasic action potentials [41 or body surfac mapping [5,6]. However, recent studies [7.8] hav% suggested that QT interlead variability (dispersion), defined as the difference between the maximum and the minimum QT on the 12-lead ECG may be a simple non-invasive measure of regional variation in ventricular recovery time.

346

Hypertrophic cardiomyopathy is associated with high risk of ventricular arrhythmias and sudden death [9] and improved survival has been reported previously [lo] in patients with hypertrophic cardiomyopathy with ventricular tachycardia treated with amiodarone, a class III antiarrhythmic drug. Class III antiarrhythmic drugs possibly operate by decreasing dispersion via a homogeneous prolongation of recovery time. A reduction in QT dispersion was recently reported [ 111 in post-myocardial infarction patients who received sotalol compared to placebo. The present study reports on QT dispersion in patients with hypertrophic cardiomyopathy treated by amiodarone compared to those not on amiodarone or other class antiarrhythmic therapy which could have an effect on QT. Patients and Methods Patients Between 1989 and 1992, 72 consecutive patients with hypertrophic cardiomyopathy were investigated in our institution. Diagnosis of hypertrophic cardiomyopathy was established by twodimensional echocardiography in the absence of other cardiac or systemic disease which could produce left ventricular hypertrophy. Twelve (17%) of these patients comprised our group on amiodarone, selected to be on single long-term amiodarone and not receiving beta-adrenergic blockers or other class antiarrhythmic therapy. Amiodarone was prescribed due to frequent episodes of non-sustained ventricular tachycardia detected during Holter monitoring in 4 (33%1, strong family history of sudden death in 2 (17%), history of paroxysmal supraventricular tachycardia or atria1 fibrillation in 3 (25%) and prophylactically in 3 (25%) patients. All patients on amiodarone were on a maintenance dose of 200 mg daily. Our control group consisted of 12 (17%) patients with hypertrophic cardiomyopathy not on amiodarone at any stage. Ten (83%) patients from the control group were not on cardioactive treatment at the time of the study but there were 2 (17%) receiving a calcium antagonist (diltiazem and verapamil, respectively). In 3 (25%) control

patients, episodes of asymptomatic non-sustained ventricular tachycardia were also identified during Holter monitoring in the past. None of the control patients had a history of supraventricular arrhythmia or atria1 fibrillation. A family history of sudden death was present in 2 (17%) patients from the control group. Both amiodarone patients and controls were in sinus rhythm without evidence of bundle branch block. Two-dimensional echocardiography A complete echocardiographic study was performed in each subject using a TOSHIBA SSH 160A ultrasound system with a 3.75 MHz transducer for cardiac imaging. All measurements were performed using recorded images on a 3/4 inch video tape recorder. Left ventricular diastolic and systolic dimensions were obtained from the short axis parasternal view. The extent of left ventricular hypertrophy was estimated from serial short axis views at three different levels (mitral, papillary, apex). At the mitral and papillary levels the left ventricle was divided into four equal sized regions that identified the anterior and posterior septum and the inferior and lateral walls. At the apical level the ventricle was divided into two regions identified as the anterior and inferior wall. Wall thickness was measured in each region by identification of the endocardial and epicardial borders. Maximal wall thickness was identified and the total number of hypertrophic segments (wall thickness > 13 mm) was also estimated out of 10 segmental thickness measurements. QT interval measurements Measurements were obtained from a standard resting ECG (25 mm/s speed). QT interval was measured in all 12 leads from the onset of QRS to the end of T wave, defined as a return to T-P baseline. The corrected QT (QTc) was calculated using Bazett’s formula (QTc = QT/ m). For each lead, wherever possible, three consecutive cycles were measured and an average QTc calculated. QTc dispersion was defined as the differ-

ence between the maximum and the minimum QTc occurring in any of the 12 leads. To eliminate the effect of number of measurable leads on QTc dispersion a corrected QTc dispersion was also calculated as QTc dispersion/square root of the number of leads possible to measure. All measurements were performed by a single observer blinded towards drug status in order to eliminate both interobserver variability and bias. Statistical analysis Statistical analysis was performed using the unpaired Student t-test with significance at p < 0.05. Data are expressed as means k standard deviation. Results Clinical and echocardiographic characteristics of patients with hypertrophic cardiomyopathy receiving or not receiving amiodarone are shown in Table 1. There was no difference between the two groups in age, functional class or chamber dimensions. Maximal wall thickness was identified in the anterior or posterior septal segment of the left ventricle in the majority of patients. The

TABLE

I

Clinical and echocardiographic trophic cardiomyopathy.

Age (yr) (range) Male/Female NYHA I NYHA II NYHA III LVDD (mm) LVSD (mm) LA (mm) MWT (mm) HS (no.)

indices of patients

with hyper-

Amiodarone (n = 12)

Non-amiodarone (n = 12)

p

49 f 17 (17-70)

39 + 14 (19-63) 7/5 7 (58%) 5 (42%)

NS

41+6 76+6 38&7 21+6 4+2

NS NS NS NS NS

6/6 7 (59%‘) 4 (33%‘) 1 (8%) 39+ x 7X&

Y

43*13 215 4 5+_ 2

TABLE

2

QT interval

RR Maximal

and variables

QT

Maximal QTc QTc dispersion Corrected QTc dispersion *

Amiodarone fn = 12)

Non-amiodarone (n = 12)

p

967+ 170 479+ 48 488+ 25 4X + 10

x51 f 107 417& 2Y 451+ 23 78k 17

0.06 < 0.001 < 0.001 < 0.001

14*

3

23_+

< 0.001

5

* Corrected QTc dispersion was defined as QTc dispersion divided by square root of number of measurable leads. All values are expressed in ms and shown as means&standard deviation.

extent of left ventricular hypertrophy expressed by either maximal wall thickness or the number of hypertrophied segments was similar between patients receiving or not receiving amiodarone. The pattern of left ventricular hypertrophy was asymmetric (septal/free wall ratio > 1.3) in 1I (92%) patients receiving amiodarone compared to 10 (83%) not receiving amiodarone. One patient from the amiodarone and 2 from the nonamiodarone group showed a concentric pattern of hypertrophy. ECG abnormalities of T wave were seen in all patients with hypertrophic cardiomyopathy. Maximal QTc was contained in one of the anteroseptal leads (Vl-V6) in 9 (75%) patients from the

. .

100

550 .

6

NS

HS (no.) = number of hypertrophied segments: LA = left atrial diameter: LVDD = left ventricular diastolic diameter; LVSD = left ventricular systolic diameter; MWT = maximal wall thickness: NYHA = New York Heart Association functional class: NS = non-significant.

.

1 500-

E 0 6 1 .EI I I

. -

. .

1

. %

. . . . . .

. . . .

400 -

. .

E

. . . .

s ‘Z h :: e 0

.

5

-

450 -

. . . .

60.

.

. . .

60. .

. . . . . . .

40-

.

l.

P
Amcdarone

NOIT amcdarone

20

i

P
__ Amiodarone

NW amiodaron

Fig. 1. Maximal QTc and QTc dispersion in patients with hypertrophic cardiomyopathy on amiodarone compared to those not on amiodarone.

348

amiodarone group and 10 (83%) from the nonamiodarone group. It was technically possible to measure QT in all 12 leads in 12 (100%) patients from the amiodarone and 11 (92%) from the non-amiodarone group. In 1 patient from the non-amiodarone group it was possible to measure QT in 10 leads. Results on QT interval measurements and its variables for the amiodarone and the non-amiodarone group are shown in Table 2. Patients on amiodarone showed a prolonged QTc compared to those not on amiodarone. However, QTc dispersion was significantly less in the amiodarone group compared to the non-amiodarone group (Fig. 1). Discussion Our results showed that amiodarone treatment in patients with hypertrophic cardiomyopathy was associated with a prolongation in maximal QTc but a reduction in QTc dispersion compared to patients with hypertrophic cardiomyopathy not receiving amiodarone. The difference in QTc dispersion between the amiodarone and the non-amiodarone group is unlikely to be related to other structural/ anatomical differences as the two groups were similar in age, functional class, chamber dimensions, distribution or extent of ventricular hypertrophy. Our findings arc in agreement with expected changes in ventricular recovery time in patients receiving class Ill antiarrhythmic agents and provide further support to the theory that QT interlead variability reflects regional differences in ventricular repolarization. Prolongation of QT has been associated with both high risk of serious ventricular arrhythmia [12,13] and an antiarrhythmic drug effect [14]. This contradictory finding may be explained by the effects of class Ill agents on dispersion of ventricular repolarization. These agents probably operate by decreasing dispersion of recovery time despite QT prolongation. Support for this theory comes from an animal experiment 1151 showing that bretylium tosylate, a class Ill antiarrhythmic agent, can decrease ventricular fibrillation threshold by decreasing temporal dispersion of effective refractory periods. Recent studies [7,8] also sug-

gested that QT interlead variation on the surface ECG is not an artefact but represents regional differences in ventricular recovery time. In postmyocardial infarction patients randomized to either sotalol or placebo, sotalol QT prolonged QT but reduced QT dispersion compared to placebo [ll]. This finding is confirmed by the results of the present study, which to our knowledge is the first report on QT dispersion in hypertrophic cardiomyopathy, particularly in relation to the effects of class Ill antiarrhythmic drugs. Mean maximal QTc appears to be prolonged (> 440 ms) also in patients with hypertrophic cardiomyopathy not on amiodarone or other class antiarrhythmic drug which could have an effect on QT. This finding is confirmed by an earlier study [16] which suggested QT interval prolongation in hypertrophic cardiomyopathy compared to ventricular hypertrophy due to aortic stenosis. Recently, a report from a study [17] which examined diurnal changes of QT interval in a small number of patients with cardiomyopathies also demonstrated a prolonged QT at an RR interval of 1000 ms in patients with hypertrophic cardiomyopathy compared to normals. It is possible that QT prolongation in hypertrophic cardiomyopathy reflects an abnormal response to autonomic tone changes mediated by altered function of cardiac beta-adrenergic receptors [18-201. It is also possible that other factors, like fibrosis or myocardial disarray - a characteristic finding in hypertrophic cardiomyopathy [21] - rather than ventricular hypertrophy itself contribute to QT prolongation in hypertrophic cardiomyopathy. The relationship between length of QT interval or QT dispersion and the occurrence of ventricular tachycardia or sudden death in hypertrophic cardiomyopathy warrants further investigation. Study limitations Our patients were not randomized to amiodarone or placebo and further randomized trials involving large number of patients with hypertrophic cardiomyopathy are needed to reconfirm our results. Bazett’s formula was used in this study to correct QT for heart rate. This formula has limitations including slight overestimation at

349

low heart rates, but is probably the best available formula [22]. QTc was also used instead of QT for analysis of QTc dispersion to avoid errors induced by interlead variation in cycle length. Two patients from the non-amiodarone group were on calcium antagonists; however, these agents do not have a significant effect on QT. Conclusion In this study amiodarone treatment in patients with hypertrophic cardiomyopathy reduced QTc dispersion despite maximal QTc prolongation compared to patients not receiving amiodarone. Our results further support the theory that QT dispersion on the surface electrocardiogram reflects regional differences in ventricular recovery time. Further studies are needed to establish first the value of QT interlead variability as an arrhythmogenic marker and second its wider use to assess the effects of antiarrhythmic medication in hypertrophic cardiomyopathy. References Kuo CS, Munakata K, Reddy CP, Surawitz B. Characteristics and possible mechanisms of ventricular arrhythmia dependant on the dispersion of action potential durations. Circulation 1983;67:1356-1357, Ambroggi L, De Bertoni T. Locati E, Stramba-Badiale M, Schwartz PJ. Mapping of body surface potentials in patients with the idiopathic long QT syndrome. Circulation 19X6:74:1334-1345, Schwartz PJ. Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978;57:1074-1077. Franz MR, Bargheer K, Rafflenbeul W, Haverish A, Lichtlen PR. Monophasic action potential mapping in human subjects with normal electrocardiograms: direct evidence for the genesis of the T wave. Circulation 1987;75:379-386. Sylven JC, Horacek BM, Spencer A, Klassen GA, Montague TJ. QT interval variability on the body surface. J Electrocardiol 1984;17:179-188. 6 Mirvis DM. Spatial variation of QT intervals in normal persons and patients with acute myocardial infarction. J Am Coll Cardiol 1985;5:625-631. 7 Cowan CJ. Yussof K, Moore M et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988;61:83-87.

8 Day CP. McComb JM. Campbell RWF. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990:63:342-344. 9 McKenna WJ, Camm AJ. Sudden death in hypertrophic cardiomyopathy: assessment of patients at high risk. Circulation 1989;80:1489-1492. 10 McKenna WJ. Oakley CM. Krikler DM. Goodwin JF. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985;53:412-416. II Day CP. McComb JM, Matthews J. Campbell RWF. Reduction in QT dispersion by sotalol following myocardial infarction. Eur Heart J 1991;12:423-427. 12 Roden DM. Woolsey RL. Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: indications for patient care. Am Heart J 1986: 111:3088-1093. I3 Jervell A, Lange-Nielsen. Congenital deafmutism, functional heart disease. with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59-68. 14 Vaughan Williams EM. Delayed ventricular repolarization as an antiarrhythmic principle. Eur Heart J 1985;h(suppl D):145-149. T. 15 Innoue H. Toda 1. Nozaki A. Matsuo H, Sugimoto Effects of bretylium tosylate on inhomogeneity of refractoriness and ventricular fibrillation threshold in canine hearts with quinidine-induced long QT interval. Cardiovast Res 19X5;19:655-660. 16 Engler RL. Smith P. LeWinter M, Gosink B. Johnson A. The electrocardiogram in asymmetric septal hypertrophy. Chest 1979;75:167-173. A, Inoue H, Sugimoto T. Diurnal 17 Yanagisawa-Miwa changes in QT intervals in dilated cardiomyopathy and hypertrophic cardiomyopathy. Am J Cardiol 199 I; 67: 142X- 1430. cardiovascular 18 Koga Y, Itaya M, Toshima H. Increased response to epinephrine in hypertrophic cardiomyopathy. Jpn Heart J 1985:26:727-740. 19 Golf S, Myhre E, Abdelnoor M, Anderson D, Hanson V. Hypertrophic cardiomyopathy characterized by betaadrenoceptor density. relative amount of beta-adrenoceptor subtypes and adenylate cyclase activity. Cardiovasc Res 1985;19:693-699. 20 lida K, Sugishita Y, Matsuda M et al. Difference in the response to isoproterenol between asymmetric septal hypertrophy and symmetric hypertrophy in patients with hypertrophic cardiomyopathy. Clin Cardiol 3986;9:7-12. 21 Maron BJ. Roberts WC. Quantitative analysis of cardiac muscle disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation 1979;59:689-706. 22 Ahnve S. Correction of the QT interval for heart rate. Review of different formulas and the use of Bazett’s formula in myocardial infarction. Am Heart J 1985; 109:568-574.