Signal-averaged electrocardiography in myotonic dystrophy

ELSEVIER

International Journal of Cardiology50 (1995)61-68

Signal-averaged electrocardiography in myotonic dystrophy * Pietro Vincenzo Fragola*“, Leonardo Cali, a, Giovanni Antoninib, Stefania Morinob, Mario Luzi”, Domenico De Nardoa, Dario Cannataa ‘Department of Intemal Medicine. School of Cardiovascular Diseases, University of Rome Tor Vergata, Via A. Torlonia 1.7, 00161 Rome, Italy bDepartment of Neurological Sciences. University of Rome La Sapienza, Rome, Italy

Received22 November1994;revisionaccepted7 March 1995 Abstract

We performed signal-averaged electrocardiography and 24-h ambulatory electrocardiographic monitoring in 53 patients with myotonic dystrophy to determine the incidence and clinical significance of ventricular late potentials. Patients were followed up for a mean period of 31 f 17 months (range II-68 months). At entry, none of the patients had bundle branch block on 12-leadelectrocardiogram and none had wall motion abnormalities on routine echocardiogram. Also, no patient had history of syncopeor clinical evidenceof ischemic heart diseaseor a documentedsustained ventricular tachycardia. A group of 47 healthy subjects matched for age and sex also underwent signal-averaged electrocardiography for comparison with the patient group. Late potentials were diagnosed in the presenceof at least two of the following measures:duration of the filtered QRS > 114 ms, root-mean-square voltage of the terminal 40 ms of the filtered QRS < 20 pV, and duration of the low-amplitude ( < 40 pV) signals of terminal filtered QRS > 38 ms. Late potentials were more frequent in patients than in controls: 18 of the 53 patients (34%) showed late potentials comparedwith four of the 47 controls (8.5%) (P < 0.01). In 45 patients (85%) no ventricular ectopy (40 cases)or infrequent premature ventricular complexes (live cases) were detected on Holter monitoring. Complex ventricular arrhythmias were traced in the remaining eight patients. These were six of the 18 patients with, and two of the 45 patients without late potentials (33% vs. 6%, respectively; P < 0.01). Only two of the eight patients with complex ventricular arrhythmias were documented to have repeated three-beat runs of ventricular tachycardia; both patients also had late potentials. During the period of observation there were no sudden deaths. Two patients required permanent pacemakersfor appearanceof serious conduction defectsand recurrent syncope. Therefore, ventricular late potentials are a frequent finding in patients with myotonic dystrophy. In our seriesthey were sensitive in predicting complex ventricular arrhythmias being present in 75% of casesand correctly identifying the patients with ventricular tachycardia. However, specificity and positive predictive value were unacceptable due to the high false-positive rate. Also, the absenceof cardiac catastrophic eventsduring follow-up calls in question the prognostic value of ventricular late potentials in myotonic dystrophy. Keywordr: Signal-averagedelectrocardiography; Myotonic dystrophy; Ventricular tachycardia; Sudden death 1. Introduction

* This paperwaspresentedin part at the VIII International Congressof NeuromuscularDisease,Kioto, Japan,1994. * Correspondingauthor.

Myotonic dystrophy, the commonest neuromuscular dystrophy in adults [l] is a progressive

0167-5273/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(95)02324-P

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multisystem disorder inherited with an autosomal dominant trait. Heart involvement is common and serious in myotonic dystrophy [2] and sudden cardiac death is one of the main causesof death, occurring with a remarkably high incidence (15-30% of patients) [3,4] compared to the general population [5]. Although the causes of sudden death in myotonic dystrophy are potentially numerous and have been only rarely determined in an individual patient [6], progressive deterioration of cardiac conduction disturbances terminating in heart block and asystole is believed to play a major role [7- 151.However, sudden death may occur despite pacemakerinsertion, implicating a mechanism for death other than heart block [3,16-181. Also, evidence exists that patients with this disease are prone to cardiac electrical instability since both clinical and inducible ventricular tachycardia have been demonstrated [3,12,16-221. Therefore, excluding the casesin which ventricular tachycardia representsan agonal event following severebradycardia [5], the arrhythmia is probably the primary mechanism in a subset of sudden deaths [2,16,18,20]. Therefore, identification of patients with myotonic dystrophy at increased risk for lifethreatening arrhythmias would be worthwhile. Ventricular late potentials detected by the signalhave averaged electrocardiogram been demonstrated to represent a powerful predictor of potentially lethal ventricular arrhythmias [23-261. Their presenceseemsto indicate areas of delayed and fragmented impulse conduction within the myocardium, a substrate for reentrant ventricular arrhythmias [24,27]. In the past, ventricular late potentials have been described in a patient with myotonic dystrophy who also had ventricular tachycardia on the electrocardiogram [28]. Recently, a study [29] revealed a high incidence of late potentials in patients with myotonic dystrophy, even in the absence of cardiac symptoms or clinically evident heart involvement, raising the possibility that ventricular arrhythmias could be an important determinant of death in this disease,more often than suspected. In that study [29], however, follow-up information was not reported. In the present investigation, we performed signal-averaged electrocardiogram and 24-h ambulatory electrocardiographic monitoring in a

Journal of Cardiology 50 (1995) 61-68

relatively large group of patients with myotonic dystrophy who had not experienced cardiac symptoms and had no clinical evidence of important heart involvement by selection criteria. Also, patients were followed for a mean period of 31 i 17 months. The purpose of this study was to further establish the incidence of ventricular late potentials in this group of patients at low risk for cardiac events due to their myotonic dystrophy, and to assessthe usefulness of ventricular late potentials in predicting ventricular arrthythmias. We also sought to determine the prognostic implications, if any, of ventricular late potentials in these patients. 2. Materials and methods 2.1. Selection and characterization of patients The study group was drawn from 82 consecutive patients with myotonic dystrophy, attending our laboratories for a cardiological work-up, who were included in a long-term follow-up evaluation. To minimize the number of confounding variables in the interpretation of signal-averagedelectrocardiographic findings, only patients without conditions known or suspected to increase the prevalenceof ventricular late potentials were included in the study. Thus, patients were excluded if they had a history or clinical evidence of ischemic heart disease(three cases)or systemichypertension (two cases)(blood pressure > 145/90mmHg), history of syncope(nine cases)or documented sustained ventricular tachycardia (one case),clinical manifestation of cardiac failure (two cases),left ventricular regional wall motion abnormalities (seven cases) or left ventricular hypertrophy (wall thickness > 12mm) on echocardiogram (three cases),bundle branch block (12 cases) or nonspecific intraventricular conduction defects(three cases)on 1Zlead electrocardiogram. A total of 53 patients (37 men and 16 women, mean age 38 f 13 years; range 14-70 years) were suitable for study. On the basis of severity of skeletal muscle impairment [14], 23 patients (15 men and eight women; mean age 31 f 12 years) were classified as having mild disease, 18 (13 men and five women; mean age 39 f 11years) as having moderate disease,and 12

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(nine men and three women; mean age 49 f 10 years) as having severe disease. All included patients were in sinus rhythm and none complained of cardiac symptoms. None had ever been treated for myotonic dystrophy with the usual drugs, such as procainamide, diphenylhydantoin, mexiletine, or tocainide [30]. Of the 53 patients, 13 (25%) had abnormalities on 1Zlead electrocardiogram consisting of first-degree atrioventricular block (seven patients), left ventricular hypertrophy (R wave in lead Vs or V6 + S wave in lead Vi >35 mm) (two patients), and pathological Q waves (20.04 s in duration and > 3 mm in depth in at least two adjacent leads) (four patients) (Table 2). Of the 53 patients, four met echocardiographic criteria for mitral valve prolapse (Table 2), i.e. systolic posterior displacement >3 mm of one or both mitral leaflets beyond the plane of the mitral annulus in the parasternal long-axis view. 2.2. Control group

A group of 47 subjects without clinical, electrocardiographic or echocardiographic evidenceof cardiovascular diseases also underwent signalaveragedelectrocardiography for comparison with the patient group. The 47 normal control subjects were similar to the patients with regard to age and gender; they ranged in age from 15 to 68 years (mean age 39 i 14years) and 30 (64%) were male. 2.3. Signal-averaged electrocardiography

Signal-averaged electrocardiograms were performed the sameday as the ambulatory electrocardiographic recordings using a high-resolution electrocardiography system(Arrhythmia Research Technology, model 1200 EPX). Bipolar orthogonal X, Y, and Z leads were used to record approximately 250 beats with a noise level <0.3 rV. Each signal-averaged lead was filtered with the use of a bidirectional filter at 40 Hz. The filtered leads were combined into a vector magnitude, termed the filtered QRS complex. Based on previously defined normal values for signal-averaged electrocardiographic variables [31], ventricular late potentials were diagnosed in the presenceof at least two of the following mea-

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sures:duration of the filtered QRS complex > 114 ms, root-mean-square voltage of the terminal 40 ms of the filtered QRS complex < 20 pV, duration of the low-amplitude (<40 pV) signals of the terminal filtered QRS complex >38 ms. 2.4. Ambulatory electrocardiographic monitoring

Twenty-four-hour ambulatory electrocardiographic monitorings were obtained using modified V1 and Vs bipolar leads and 24-h portable tape recorders (Oxford Instruments; model MR 14). Tapes were analyzed on Medilog 2 Oxford scanner. Initial scanning was performed at 60 times the normal speed. When definite or possible abnormalities were found, the scanner was switched to normal speed and the findings were printed on a electrocardiographic chart (speed 25 mm/s) for detailed analysis. Patients’ activity levels and symptoms were reported in diaries. All arrhythmias were reviewed by the operator and one of the investigators. Ventricular arrhythmias were classified in a manner similar to that of Lown et al. [32], according to the presenceof the following arrhythmia types: ventricular premature complexes, multiform ventricular premature complexes, ventricular couplets, ventricular tachycardia (13 consecutiveventricular premature complexes at a rate 1120 beats/min), R on T ventricular premature complexes.Also, ventricular arrhytmias were considered complex if frequent (at least 30/h), multiform, paired, R on T ventricular premature complexesor ventricular tachycardia were present. 2.5. Follow-up

After signal-averaged electrocardiograms and 24-h electrocardiographic recordings, patients were followed-up for a mean period of 31 f 17 months (range 1l-68 months). Follow-up data were obtained by regular medical visits, telephone contacts, or by review of medical records. 2.6. Statistical analysis

Data are expressed as mean values f 1 S.D. The unpaired t-test was used to compare differences between groups. Overall differences were

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considered significant for a P-value <0.05. The value of ventricular late potentials in predicting ventricular arrhythmias is presented as sensitivity, specificity and positive predictive accuracy, calculated by using standard formulas. 3. Results 3. I. Signal-averaged electrocardiography

Compared with the control group, patients with myotonic dystrophy showed significantly longer total filtered QRS duration and low-amplitude signals duration, and significantly lower rootmean-squarevoltage of the terminal 40 ms of the QRS complex (Table 1). Ventricular late potentials were more common in patients (18 of the 53, 34%) than in controls (four of the 47,8.5%). The criteria low-amplitude signals duration > 38 ms and rootmean square voltage < 20 PV resulted highly concordant, being present together in 17 of the 18 patients and in all of four controls with ventricular late potentials. Only one patient had late potentials becauseof the presenceof prolonged filtered QRS duration and reduced root-mean-square voltage. Also, five of the 18 patients with late potentials met all the three criteria. None of the four controls with late potentials had filtered QRS duration > 114ms. In comparing subgroups of patients with and without late potentials, there were no significant differences in 1Zlead echocardiography and echocardiographic findings, or se-

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verity of neuromuscular impairment (Table 2). Patients with late potentials were older than patients without late potentials. 3.1. Ambulatory electrocardiographic monitoring

The distribution of arrhythmias in patients according to maximal grade of ectopic beats is shown in Table 2. More patients in both groups with and without late potentials had single or paired atria1 premature complexes (44% and 31%, respectively). A patient who also had late potentials manifested one episode of nonsustained supraventricular tachycardia. In 45 patients (85%) no ventricular ectopy (40 cases) or infrequent (< 10/h) ventricular premature complexes (five cases)were detected. In the remaining eight patients (15%) complex ventricular arrhythmias were traced. The incidence of complex ventricula arrhythmias was significantly higher in patients with late potentials (six of 18; 33%) than in those without late potentials (two of 35; 6%) (P < 0.01) (Table 2). Therefore, the severity of ventricular ectopic activity appears to be associated with the presenceof late potentials. No patient had sustained ventricular tachycardia documented during ambulatory electrocardiographic monitoring. Nonsustainedventricular tachycardia was noted in two of the 18 patients who had late potentials. These were two women with severemyotonic dystrophy, aged49 and 50 years, respectively, who showed repeated (five and 34, respectively) three-beat runs

Table 1 Comparison between clinical and signal-averaged electrocardiographic data in the control subjects and in patients with myotonic dystrophy

Age(years) Mate Total QRS duration (ms) LAS duration (ms) RMS-40 voltage (pV) Late potentials

Controls (N = 47)

Patients (N = 53)

P-value

39 l 14 64% 92.5 + 9.2 29.1 + 9.5 46.3 ct 31.9 4 (8.5%)

38 f 13 70% 103 l 9.3 35.3 f 10.8 26.7 zt 17.8 18 (34%)

NS NS <0.001 c 0.005 co.oo1 <0.005

Total QRS duration, duration of the filtered QRS complex; LAS duration, duration of the low-amplitude (< 4OpV) signals of the tenninaf tiltered QRS complex; RMS-40 voltage, root-mean-square voltage of the terminal 40 ms of the filtered QRS complex.

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Table 2 Clinical and laboratory data in patients with and without ventricular late potentials

Age (years) Male Grade of the disease Mild Moderate Severe Electrocardiagram Heart rate (beats/mm) QT corrected Normal findings First-degree atrioventricular block Left ventricular hypertrophy Abnormal Q waves Echocardiogram Mitral valve prolapse Holter monitoring Atrial premature complexes Supraventricular tachycardia Ventricular prematureccomplexes(< IO/h) Complex ventricular arrhythmias Ventricular premature complexes Frequent (> 30/h) Multiform Couplets With R on T Ventricular tachycardia

Patients with late potentials (N= 18)

Patients without late potentials (N = 35)

P-value

45.2 f II.3 56%

34.4 zt 12.9 77%


6 (33%) 1 (39%) 5 (28%)

II (49%) II (31%) 7 (20%)

NS NS NS

65 f IO 418 zt 22 I3 (72%) 3 (17%) 2 (11%)

66 f 14 412 + 27 21 (77%) 4 (I I%) 2 (6%) 2 (6%)

NS NS

I 8 (44%) I (6%) 6 (33%) 2 (11%) I (6%) I (6%) 2 (11%)

of ventricular tachycardia not associated with symptoms. On the other hand, none of the patients without late potentials had ventricular tachycardia on Holter monitoring. Therefore, the sensitivity of late potentials in identifying patients with ventricular tachycardia was lOO%, but specificity and positive predictive accuracy were poor (69% and 1l%, respectively) owing to the high number of false positives. When all patients with complex ventricular arrhythmias were considered, the predictive value of late potentials had a sensitivity of 75%, but a specificity of only 45%, and a positive predictive accuracy of only 33%. 3.2. Follow-up

The period of observation of patients with late

3 II (31%) 5 (14%) 2 (6%) I (3%) _1 (3%)

NS NS NS NS NS NS NS co.01 NS NS NS NS NS

potentials did not differ significantly from that of patients without late potentials (36 * 21 months, range 1l-68 months vs. 29 f 14 months, range 11-61 months, respectively; P = not significant). Mexiletine 200 mg two times a day was started in the two patients with ventricular tachycardia. In both patients the drug was discontinued a few days later by their personal general practitioners for gastrointestinal side-effects.Nobody else received drugs with antiarrhythmic properties. Two other patients who also had late potentials required permanent pacemaker insertion; both complained of syncopal episodes and showed advanced conduction defects (first-degree atrioventricular block plus left bundle branch block, and first- and second-degree atrioventricular block plus left anterior hemiblock and right bundle branch block, respectively). In both patients pacemakers were

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implanted elsewhereand electrophisiologic studies were not available. During observation there were no sudden deaths. One patient died from a car accident. With the exclusion of the subject who died, all patients were alive after a mean follow-up of 31 f 17 months and none complained of cardiac symptoms. Therefore, late potentials appear to be an unreliable predictor of sudden cardiac death in our patient group. 4. Discussion This study extends the application of signalaveraged electrocardiography to patients with myotonic dystrophy. In our experience we found an increased incidence of ventricular late potentials in these patients in comparison with normal subjects (34% vs. 8.5%, respectively; P < 0.005). These findings are in partial accordance with the only study available on this field [29] where an even higher incidence of late potentials is reported (67%, when two criteria for late potentials are present). We are unable to explain the difference in the frequency of late potentials since that study [29] is comparable to ours with regard to characteristics of study population, recording techniques and definition of late potentials. However, basedon these results, evidence emergesthat an abnormal signal-averagedelectrocardiogram is probably frequent in myotonic dystrophy, even in patients who have no cardiac symptoms or evidence of serious heart involvement due to the neuromuscular disease. An abnormal signal-averaged electrocardiogram has been correlated with areas of fragmented activation and slowed conduction within a diseasedmyocardium 124,271,potentially capable of supporting a reentry circuit. Histologic non-specific changesin the myocardium have been observed in most patients with myotonic dystrophy and mainly include fatty infiltration, excessivefibrosis, atrophy or disarray of both conduction system and myocardium [4,16,33]. These histopathological lesions, although not not serious to cause cardiac dysfunciton [34] or conduction disturbances, may explain well the presence of both ventricular late potentials and arrhythmias. A high frequency of abornal signal-averaged

Journal oj Cardiology 50 (1995) 61-68

electrocardiogram in this setting would not be surprising and an association betweenventricular late potentials and ventricular arrhythmias could also be supposed. In the present study Holter monitoring revealed complex ventricular arrhythmias in 8 of the 53 patients (15%)with a significantly higher incidence in patients with late potentials (6 of 18: 33%) compared to those without late potentials (2 of 35: 6%) (P < 0.01). Ventricular tachycardia was detected in 2 patients with severediseasewho also showed late potentials. Therefore, although ventricular tachycardia was uncommon in our series, it was associated with late potentials. Also, late potentials were present in the majority of patients with complex ventricular arrhythmias that may supply the trigger for reentrant tachycardia. On the other hand, more patients with late potentials did not have ventricular arrhythmias. Therefore, the presenceof ventricular ectopy on ambulatory electrocardiogram could not be predicted on the basis of the presence of ventricular late potentials. It must be noted, however, that sustained ventricular tachycardia, the most characteristics arrhythmia for late potentials, was not observed in our patients. Since late potentials are a marker for this type of arrhythmia and their prediction of nonsustained ventricular tachycardia or other ventricular ectopy is much lower [35], our results are not unexpected.Also, in the present study there were no sudden cardiac deaths over a mean period of 31 * 17 months. Therefore, late potentials appeared particularly poor at predicting sudden death in our patient group. The selection criteria used for our study participation initially eliminated some patients who potentially were at high risk for cardiac arrhythmic events; it is well known that late potentials provide significant prognostic information when assessedin high risk subsets of patients. From our data, the clinical relevance of ventricular late potentials in patients with myotonic dystrophy who have no other arrhythmic risk factors remains uncertain. Our study does not support the hypothesis that late potentials should be considered an ominous sign in patient with myotonic distrophy. Also, it is doubtful whether they represent in all cases the electrophysiologic basis of ventricular arrhythmias or

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merely reflect a feature of the patient’s clinical protile, that of a diseasedmyocardium with delayed impulse conduction, without participating in arrhythmogenesis. More extensive studies and longer period of follow-up are necessary before the usefulnessof signal-averagedelectrocardiogram in myotonic dystrophy is fully appreciated. In the last years most studies into cardiac involvement in myotonic dystrophy focused attention on the progression of cardiac conduction disturbances in an attempt to provide firm data for a proper therapeutic approach [2,13-U]. With further advances in the noninvasive detection of patients at risk for arrhythmic events prognosis of myotonic dystrophy can only be expected to improve. 4.1. Study limitations The present study has some limitations. First, although 24-h ambulatory electrocardiographic monitoring is an established method for detecting arrhythmias, a longer period of recording might have identified more patients with ventricular tachycardia or other complex arrhythmias. Second, in our asymptomatic patients we did not perform electrophysiologic study to analyze susceptibility to ventricular tachycardia. Certainly, this procedure might have been effective for evaluating the role of late potentials in arrhythmogenesis. However, it is our opinion that ventricular vulnerability should not be systematically investigatedin asypmtomatic patients with myotonic dystrophy [2,22] for humanitarian reasons. References [I] Harper PS. Myotonic dystrophy. In: Major problems in neurology. 2nd ed. London: W.B. Saunders, 1989; 21: 114-116. [2] Fragola PV, Luzi M, Calb L et al. Cardiac involvement in myotonic dystrophy. Am J Cardiol 1994; 74: 1070-1072. [3] Cannom DS, Wyman MG, Goldreyer BN. Clinical and induced ventricular tachycardia in a patient with myotonic dystrophy. J Am Colt Cardiol 1984; 4: 625-628. [4] Nguyen HH, Wolfe JT 3d, Holmes DR Jr., Edwars WD.

Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases.J Am COBCardiol 1988; 11: 662-671.

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