cardiac abnormalities in myotonic dystrophy: electrophysiologic and histopathologic studies

Cardiac Abnormalities in Myotonic Dystrophy

Electrophysiologic and Histopathologic Studies

)ORGE MOTTA, M.D.

CHRISTIAN GUILLEMINALJLT, M.D. MARGARET BILLINGHAM, M.D.

WILLIAM BARRY, M.D.

JAY MASON. M.D.

Stunford, Culifomia

From the Division of Cardiology, Sleep Disorders Clinic and Research Center, and Department of Pathology, Stanford University School of Med- icine Stanford, California. This research was supported by National Institute of Neurological and Communicative Disorders and Stroke Grants NS 10727; Public Health Service Research Grant R.R.-70 from the General Clinical Research Centers, Division of Research Resources; and by INSERM to Dr. Guilleminault. Requests for re- prints should be addressed to Sleep Research Center (C. Guilleminault). TD 114, Stanford Llniversity School of Medicine, Stanford, Cali- fornia 94305. Manuscript accepted March 7, 1979.

Eight young adult male patients with myotonic dystrophy, mean age 26 years, underwent 24-hour Holter electrocardiographic monitoring and intracardiac electrophysiologic study. Right ventricular endomyocardial biopsies were performed at the end of the electrophysiologic study in five of them. The atria1 to His (A-H) interval was 155 msec in one case and 1130 msec in the remaining seven. The His to ventricle interval (H-V) was 155 msec in all patients. Twenty-four hour Holter electrocardiographic monitoring demonstrated more than 4 premature ventricular contractions per minute in two patients and marked cyclical sinus arrhythmia during sleep in two others. Electron microscopic analysis of the endomyocardial biopsy specimens disclosed no prominent sarcoplasmic reticulum abnormalities but prominent I bands compared to previously obtained controls. Myofibrillar degeneration was seen in all cases and was associated with abnormal mitochondria in two. Cardiac abnormalities can be detected very early in the evolution of myotonic dystrophy, even prior to the onset of cardiac symptoms. The reported abnormalities appear closely related to the pathologic process affecting other skeletal muscles.

Myotonic dystrophy is an hereditary multisystem disease featuring not only myotonia and muscle atrophy but also cataracts, gonadal atrophy, frontal baldness and mental impairment (11. The cardiac component of this disorder was recognized as early as 1911 by Griffith [z] who described a patient with myotonic dystrophy and an abnormal pulse. Subsequent investigators reported that cardiac involvement occurred frequently in patients with myotonic dystrophy, conduction and rhythm abnormalities being the most common cardiac manifestations. How- ever, severe cardiac disease has been thought to be relatively rare [3]. The present study describes electrophysiologic and histologic cardiac findings in eight young patients with myotonic dystrophy.

PATIENT POPULATION

Eight young adult male patients, mean age 26 years [range 18 to 33 years), with myotonic dystrophy were studied. Six patients had been referred because of excessive daytime sleepiness, two others because of palpitations. In each case the diagnosis was confirmed by clinical, neurologic evaluation, electromyo- grams and limb muscle biopsies. The severity of the muscular disease has been classified [4] into four grades: grade I. disease mild: grade II, disease moderately severe but patient still able to do light work: grade III, patient severely in- capacitated; and grade IV, patient bedridden. Six patients were classified as having grade I myotonic dystrophy, and the other two had grade II disease.

All patients underwent extensive clinical evaluation which included chest roentgenogram, 1%lead electrocardiogram, s-hour glucose tolerance test,

September 1979 The American Journal of Medicine Volume 67 467

CARDIAC ABNORMALITIES IN MYOTONIC DYSTROPHY-MOTTA ET AL.

immunoelectrophoresis and .&hour Holter electrocardiographic recording. All patients gave informed consent to un- dergo the reported study.

METHODS AND TECHNIQUES

Electrophysiologic Studies. Atria1 electrogram recordings and atria1 pacing were performed with a quadripolar electrode catheter inserted via the right internal jugular vein percutaneously. A His electrogram was recorded through a 5 French bipolar catheter inserted through the right femoral vein and advanced across the tricuspid valve. Surface electrocardiographic leads I, VF and VI were recorded si- multaneously with the atria1 and His bundle electrograms. Sinus node recovery times were measured after 1 minute’s pacing at multiple pacing rates between 100 and 150 beats/ min. Con’duction intervals and refractory periods were measured. Atrioventricular (A-V) conduction system refractory periods were determined by the atria1 extrastimulus technique as applied in our laboratory [5]. Myocardial Biopsy. Endomyocardial biopsy specimens were obtained by the use of a technique [6,7] modified from that of Sakakibara and Konno [8]. A bioptome catheter was intro- duced through the right internal jugular venous site used for the electrophysiologic study and advanced across the tricuspid valve to the apical portion of the right ventricular septum where serial biopsy specimens were obtained. Light Microscopy and Electronmicroscopy. Endomyocardial

,biopsy tissue was fixed immediately in 10 per cent buffered formalin for light microscopy and in 2.5 per cent glutaral- dehyde and 2 per cent paraformaldehyde in O.lM sodium cacodylate buffer (pH 7.2) for electron microscopy. Tissue was processed in a conventional manner for light microscopic examination, and the slides were routinely stained with hematoxylin and eosin, and Masson’s trichrome. After fixation, tissue for ultrastructural examination was washed with several changes of cold buffer, postfixed with cold 2 per cent osmium tetroxide, stained en bloc with 2 per cent uranyl acetate and embedded in epoxy resin. Semithin sections of Epon@-embedded tissue were cut with an LKB III Ultratome and stained with toluidine blue for light microscopic examination for or- ientation and selection. Ultrathin sections were stained with lead citrate for 7 minutes. The tissue was then examined with a Hitachi H4 11-A electron microscope at 50 kv. In this study 10 blocks were examined for each patient.

RESULTS

Cardiovascular Findings (Table I). Only two (Cases 7 and 8) of the eight patients had some cardiovascular symptoms. Both of them were classified as having grade II myotonic dystrophy. They presented dyspnea on moderate exertion, near syncope and palpitations (episodic in Case 8). Cardiovascular examination revealed sinus bradycardia in Cases 2 and 4, and a third heart sound in Case 7 in which the patient presented with exertional dyspnea. This patient (Case 7) was the only one who had an abnormality on the chest roentgenogram-generalized cardiomegaly. The electrocardiogram was considered abnormal in five patients. Two patients (Cases 4 and 7) had complete bundle branch block, and two patients (Cases 1 and 8) had what we considered nonspecific intraventricular conduction

abnormalities (QRS >80 msec; QRS durations of 100 to 120 msec are generally considered at least a borderline abnormality). One patient (Case 7) also presented first degree A-V block. In this patient a permanent transvenous pacemaker was placed after the study because of the presence of marked H-V prolongation and episodic syncope. Six months after the pacemaker implantation, the patient died suddenly. (Results of the autopsy were not available. Since the patient died suddenly outside the hospital, the reason for his death can only be speculated.] Paroxysmal atria1 fibrillation was also documented on a routine electrocardiogram in Case 8. One patient (Case 2) had first degree A-V block (PR 2 220 msec]. Holter Electrocardiographic Recordings (Table II). Two patients (Cases 1 and 7) had several episodes of premature ventricular complex with a frequency of at least 4/min lasting 2 to 6 hours. This frequency of premature ventricular contractions is abnormal in light of ambulatory electrocardiographic monitoring studies carried out in normal subjects [9]. In one of these patients (Case i’), episodes of ventricular bigeminy and episodic atria1 tachycardia and fibrillation were documented in the recording. This patient, as already noted, died suddenly despite permanent pacing. Four other patients [Cases 2, 3, 4 and 6) demonstrated moderate sinus arrhythmia during sleep. Two of these (Cases 3 and 4) had marked cyclical sinus rate changes with RR intervals oscillating between approximately 700 and 1200 msec in one and between 800 and 1,250 msec in the other. Although sinus arrhythmia in itself is not an abnormality, the marked and recurrent rate changes noted in these last two cases is clearly an abnormality that, in our experience [lo], is seen only in patients with sleep apnea. A specific study to investigate respiratory func- tion during sleep in Cases 1 to 6 confirmed the presence of a sleep apnea syndrome, suspected from the Holter electrocardiographic monitoring, in these two patients (Cases 3 and 4) [ll]. Intracardiac Recordings (Table III). Conduction intervals, corrected sinus node recovery times and atrial, A-V nodal, ventricular and ventricular specialized conduction system refractory periods are summarized in Table III. Only one patient had an atria1 to His interval >140 msec. Seven patients had His to ventricle intervals >55 msec, and the remaining one (Case 6) had an interval of 55 msec (see Figures 1 and 2). One patient (Case 6) had prolonged atria1 and ventricular refractory periods. Atria1 effective refractory periods were determined at a paced cycle length of 750 msec. The interval of 325 msec in more than 2 standard deviations (SD] above the mean atria1 effective refractory period of 28 subjects under the age of 60 who underwent electrophysiologic studies in our laboratory and subsequently were found to have no evidence for myocardial or ischemic heart disease and no prolongation of intra- cardial conduction times. The interval 320 msec is within 2 SD of the mean effective refractory period of this studied group. The corrected sinus node recovery

468 September 1979 The American Journal of Medicine Volume 67

CARDIAC ABNORMALITIES IN MYOTONIC DYSTROPHY-h4OTTA ET AL.

TABLE I Cardiovascular Findings

MYotonic Case Age Dysirophy Cardiac Chest no. (vr) Class SYmptomS Exam Film Electrocardiogram

1 20 I None 2 33 I None

3 28 I None 4 28 I None

5 26 6 la 7 28

a 27

None None

Dyspnea on exertion; palpitations

Palpitations

NL Brady-

cardia NL

Brady- cardia NL NL

s3

NL

NL QRS 100 msec NL PR 220 msec

NL NL NL RBBB

NL NL

Cardio- megaly NL

NL NL LBBB: first degree A-V block

QRS 100 msec; paroxysmal atrial fibrillation

NOTE: RBBB = right bundle branch block; LBBB = left bundle branch block; NL = normal: A-V = atrioventricular; S3 = ventricular gallop.

TABLE II Holter Electrocardiographic Recordings

Case no. Findings

Uniform PVC > 4/min lasting 2 to 3 hours Mean heart rate while awake 55Imin; lowest during sleep 40/min; junctional rhythm and sinus arrhythmia during sleep Cyclical sinus arrhythmia during sleep; RR interval oscillating between 700 and 1,200 msec Mean heart rate awake 6O/min; cyclical sinus arrhythmia during sleep: RR interval oscillating between 800 and 1,250 msec Normal Sinus arrhythmia during sleep; RR interval oscillating between 800 and 1,200 msec PVC > 4/min at times ventricular bigeminy; atrial tachycardia and fibrillation Normal

-

TABLE 111 Electrophysiologic Data

Case No. RR QRS AH HV C SNRT AERP AVNERP AVNFRP RVERP VSCSRRP

1 860 100 125 65 330 320 1330 5380 280 440

2 1,130 a0 155 60 470 275 360 510 320

3 830 80 120 75 580 300 5320 5400 285 bib

4 1,020 140 125 65 1,300 260 330 440 340 495

5 a50 80 90 65 400 245 1260 5420 380 2440

6 820 80 130 55 310 325 330 430 370 415

7 820 180 140 90 170

a 775 100 130 70 . hi 2;; biS . iii

NOTE: All measurements in milliseconds. AH = atrial to His conduction interval; HV = His to ventricle conduction interval; SNRT = sinus node recovery time; AERP = atrial effective refractory period; AVNERP = A-V nodal effective refractory period; AVNFRP = A nodal functional refractory period; RVERP = right ventricular effective refractory period; VSCSRRP = ventricular specialized conduction system relative refractory period.

time was greater than 550 msec in two patients (Cases 3 and 4). Five patients had prolonged refractory periods of either the atrium, the A-V node, the ventricle or the ventricular specialized conduction system.

Light Electron Microscopy of the Myocardium (‘Table IV and Figures 3 through 5). Light microscopy revealed two patients with increased interstitial myocardial fibrosis. In one of these patients, prominent interstitial fatty infiltration was noted. Myocyte hypertrophy was noted in a third patient with otherwise normal histologic

findings on light microscopy. The remaining two patients had no significant abnormalities on light microscopic evaluation.

Electron microscopy revealed myofibrillar degeneration in all five patients subjected to biopsy and abnormal mitochondria (Figure 31 in two compared to biopsy findings in normal control subjects (Figure 4). All five patients had prominent I bands (Figure 5). Granular lysosomes were present in four. Mitochondriosis and sarcoplasmic reticulum abnormalities were not a prominent feature of the biopsy specimens.


CARDIAC ABNORMALITIES IN MYOTONIC DYSTROPHY-MOlTA ET AL.

Figure 1. Case 6. intracardiac electrogram recordings from patient. This patient had an H-V interval during spontaneous sinus rhythm of 55 msec. Regular sinus rhythm was present at the rate indicated in Table III. With an atrial extrastimulus producing an HIHP interval of 415 msec, the H-V interval increased by 15 msec and the His electrogram recording became fragmented (upper panel). With a more premature extrastimulus resulting in an HIHl interval of 425 msec, the H-V interval was further increased by a total of 35 msec to 90 and the H-H prime interval was proportionately increased.

COMMENTS

Although the occurrence of cardiac disease in patients with myotonic dystrophy has been observed for many years, the pathogenesis of the cardiac involvement re- mains unknown. Age at the ‘time of appearance and progression of the symptomatic cardiac disease in myotonic dystrophy is unpredictable; no close correla- tion between the extent of cardiac disease and the severity of the skeletal muscle abnormality has been found

I31. The frequency of electrocardiographic abnormalities

accompanying myotonic dystrophy has been estimated between 85 and 90 per cent [IZ]. The most common electrocardiographic abnormalities observed in Church’s review of 236 cases were prolongation of the P-R interval beyond 200 msec and QRS widening beyond 80 msec. Atria1 arrhythmias were more frequent than ventricular arrhythmias. Interestingly, one patient presented with complete heart block [3]. This apparent low frequency of complete heart block in the face of a high prevalence of conduction abnormalities has also been noted by other investigators [13]. Similarly, con- trasted with the high frequency of electrocardiographic abnormalities, Church found only 16 per cent of patients

with symptoms referrable to the cardiovascular system [5]. Orndahl, wh o reviewed 195 cases, found only a i’ per cent prevalence of congestive heart failure [14]. All our patients had objective evidence of myocardial abnormalities, but only two had clearcut cardiac symptoms. These data suggest that, although cardiac involvement appears to be the rule in cases of myotonic dystrophy, symptomatic cardiac disease is less frequent. Never- theless, it is clear that a number of patients are severely affected from a cardiac standpoint, suffering from congestive heart failure, complete heart block and even sudden death.

Review of 33 reported electrophysiologic studies in patients with myotonic dystrophy, including our eight patients, reveals that the most common abnormality is prolongation of the H-V interval [15-201. In 24 of the 33 patients H-V intervals were reported to be greater than or equal to 140 msec. The reason for this apparent preference of involvement in the His Purkinje system is unclear. The clinical significance of these abnormalities of impulse formation and conduction can only be speculated upon because of a lack of sufficient long-term follow-up of patients with myotonic dystrophy and known electrophysiologic abnormalities. However, there is said to be a high incidence of sudden death in


CARDIAC ABNORMALITIES IN MYOTONIC DYSTROPHY--hlOTTA ET AL.

__-

iI lillllilllllllllllllilll~lllllllllll~ll~llllli II l~illl~illWl

Figure 2. iase 1. Intracardiac recordings from patient, the brother of the patient illustrated in Figure 1. The H-V interval is

65 msec. A premature atrial stimulus with cycle length 360 msec produced infra-Hisian block at an H-H interval of 440 msec.

TABLE IV Histopathologic Findings in Five Endomyocardial Biopsies

Case Light No. Microscopy

1 Myocyte hypertrophy 2 No significant abnormality 3 No significant abnormality 7 Interstitial fibrosis and fatty

infiltration; variation in myocyte and nuclear size

8 Interstitial fibrosis

Mitochondria

Electron Microscopy lntracytoplasmic

Vacuoles I Bands

- Myofibrillar Granular

Degeneration Lysosomes

Few abnormal Normal Normal Some abnormal

with few giant ones

Normal

- + + -

+ + + + + + +

- + + +

+ + + +

Figure 3. Electronmicrograph of patient with myotonic dystrophy. Note some myofibrillar loss (open arrows) and swollen mitochondria (dark arrows) compared with control (Figure 4). Magnification X 5,700, reduced by 29 per cent.

Figure 4. Electronmicrograph of normal control myocardium. Note compact mitochondria (arrows) and lack of I- bands. Magnification X 5,700, reduced by 29 per cent.


CARDIAC ABNORMALITIES IN MYOTONIC DYSTROPHY-MOTTA ET AL.

“. . . . . “I

dystrophy showing prominent l-bands (arrows). Magnification X 5,700, reduced by 29 per cent.

myotonic dystrophy [l], and other investigators have noted an incidence of complete heart block as summarized by Griggs et al. [18]. One patient in the present series also had complete heart block and was pacemaker-dependent. Thus, the available information suggests that electrophysiologic abnormalities in patients with myotonic dystrophy can contribute to morbidity and mortality of those patients, but the extent of and proper diagnostic and therapeutic approach to this problem is not known. It would seem, however, that patients with myotonic dystrophy and symptoms suggesting arrhythmias or conduction block should be carefully evaluated by ambulatory electrocardiographic monitoring and, when feasible, intracardiac electrophysiologic studies, to determine whether antiarrhyth- mic drug or pacemaker therapy might be indicated.

During Holter electrocardiographic monitoring, marked cyclical sinus arrhythmia was noted during sleep in two of our patients. Similar arrhythmias have been documented in patients with sleep apnea [lo]. This cyclical arrhythmia is thought to be related to multiple apneic episodes that these patients have during sleep.

The histologic findings observed by light microscopy are similar to those noted by other investigators and represent nonspecific myopathic changes [21,22]. Fur- thermore, in two of our patients no significant abnormalities were noted on light microscopy. This might be due to limitation of sampling in the biopsy technique or, more probably, to limitations in classic histology.

In contrast to the light microscopy findings, all patients were found to have ultrastructural abnormalities of the myocardium. All biopsy specimens revealed myofibrillar degeneration when examined by electron microscopy. Prominent I bands were also noted in all specimens (Figure 5). This is an unusual finding in our experience of more than 1,300 endomyocardial biopsies, as fixation usually caused enough contraction to elimi- nate I bands. It might represent an early sign of myocyte degeneration. Two of the biopsy specimens showed slightly swollen mitochondria with separation of cristae (Figure 3).

There have been very few previous ultrastructural studies of the myocardium in patients with myotonic dystrophy. Bulloch et al. [23] described marked vacuo- lation of the sarcoplasmic reticulum and mitochon’drial abnormalities in one patient who underwent biopsy at the time of pacemaker implantation. Uemura et al. [16] found abnormal mitochondria as the most striking ultrastructural abnormality, whereas Tanaka et al. [24] described mitochondriosis and myofibrillar abnormalities. By contrast, in our study, sarcoplasmic reticulum abnormalities were not prominent, and only two patients had significant mitochondrial abnormalities.

The results of these limited studies suggest that there is not a pathognomonic myocardial ultrastructural abnormality in myotonic dystrophy and that the various changes described are nonspecific cardiomyopathic changes. Nevertheless, the significance of some of these findings, such as the prominent I bands, will have to be further examined by future biopsy studies.

An important aspect of this study is that our evaluation was carried out in young patients with myotonic dystrophy, most of them in the earliest stage of clinically apparent disease and some of them without clinical symptoms or signs of cardiovascular disease. All the asymptomatic patients were found to have anatomic and functional abnormalities of the myocardium when sensitive techniques were applied. This finding suggests that myocardial involvement is present at the very early stage of the disease and probably is part of the same genetically determined process involving other muscles. The idea that myocardial involvement is part of a common muscular dystrophic process has been sug- gested by other investigators [2l]. Following this con- cept, it can be hypothesized that the conduction system involvement in this disorder represents the expression of this genetically determined abnormality in a specialized tissue which has the same embryologic origin as cardiac muscle.

In conclusion, the findings of this study suggest that cardiac abnormalities occur early in the development of this disease and that they are probably an integral part of the pathologic process affecting other muscles.

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CARDIAC ABNORMALITIES IN I\4YUIUNIC DYSTROPHY lvlo1”I‘A t:?’ AI,.

4. Gillam PMS, Heaf PJD. Kaufman L. et al.: Respiration in dystrophia myotonica. Thorax 19: 112, 1964.

5. Mason JW, Winkle RA. Rider AK, et al.: The electrophysiologic effects of quinidine in the transplanted human heart. J Clin Invest 59: 481,1977.

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17. Schmitt J, Schmidt C, Clcrget, et al.: 1~s trouhlcs carcliaquos de la maladie de Stcincrt. Ann Mctl lntcrn 125: 195, 1974.

18. Griggs RC. Davis RJ. Anderson DC, Dove, JT: Cardiac conduction in myotonic dystrophy. Am 1 hled 50: 37, 1975.

19. Th’ery C, Ketelers JY, Gosselin B. et al.: Lc block auriculo- ventriculaire de la malndie dc conduction. Arch Ma1 Coeur 68: 1087.1975.

20. Meilhac B. Fleury G. Caspi G, et al.: Troulrlcs dc la conduction sine-auricularic et duriculo-\ic:ntricol~lirc clans la maladic tic Stcinert. Arch Mal Coour 60: 547, 1976.

21. Thomson AMP: Dystrophia cordis myotonica studied by serial histology of the pacemaker and conducting system. 1 Pathol Bacterial 96: 285, 1968.

22. Fisch C. Evans PV: The heart in dvstrouhica m\otonia Rcnort of an autopsieci case. N Engl J’Med 251: 527. 1954. ’

23. Bulloch RT. Davis II,. Hara M: Dvstrnohia mvotonica with heart block. A light and elect& mi&oscop& study. Arch Pathol 84: 130. 1967.

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cardiac abnormalities in myotonic dystrophy: electrophysiologic and histopathologic studies

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