Cardiac Conduction in Myotonic Dystrophy
ROBERT C. GRIGGS, M.D.’ ROBERT J. DAVIS,
M.D.+
DAVID C. ANDERSON,
M.D.t
JAMES T. DOVE, M.D.5 Rochester, New York
From the Departments of Neurology and Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York. This study was supported by a grant from the Muscular Dystrophy Associations of America, Inc., and Grant RR00044 from the U.S. Public Health Service. These studies were presented in part at the meetings of the American Academy of Neurology and American College of Physicians, April 1973. Requests for reprints should be addressed to Dr. Robert C. Griigs, Department of Neurology, University of Rochester, School of Medicine and Dentistry, 260 Crlttenden Boulevard, Rochester, New York 14642. Manuscript accepted August 29, 1974. Recipent of an American College of Physicians Teaching and Research Scholarship. t Present address: 939 Riigeland Street, Cheyenne, Wyoming 6200 1. * Present address: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455. B Present address: 124 Pebblebeach Drive, Springfield, Illinois 62704, l
Cardiac conduction abnormalities are frequent in myotonic dystrophy and can result in complete heart block. In a study of 26 patients with myotonic dystrophy, first degree heart block was found to precede clinical presentatlon of the disease in 7 patients. His bundle electrocardiography in 11 patients demonstrated abnormalities throughout the entire conducting system, even in patients with only first degree heart block. In patfents with block of the right bundle branch or antertor fasckle of the left bundle branch, slowing in the remaining fascicles was always present. Therapy of myotonia with procatnamide stgntfkantly lengthened the P-R interval, and treatment with diphenythydantoin signtficantly shortened the P-R interval suggesting that dlphenylhydantoin may be preferable for therapy of myotonia in patients with myotonic dystrophy. Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia and degeneration of skeletal muscle. Many other organ systems may be involved including heart, lens, gonads, bone, brain and integument [ 11. In a majority of patients with myotonic dystrophy, electrocardiograms are abnormal, and cardiac arrhythmias and conduction disturbances are frequent [2-71. The abrupt appearance of heart block may account for the high incidence of sudden death [ 11. How frequently cardiac conduction abnormalities precede other disease manifestations is not known, and the site of conduction abnormalities has not been extensively studied electrophysiologically. We prospectively studied families with myotonic dystrophy to determine the frequency with which conduction abnormalities precede the clinical presentation of the disease. His bundle electrocardiography and atrial “tachypacing” (rapid atrial pacing) were performed in 11 patients to localize the site of conduction abnormalities and to try to predict in which patients life-threatening arrhythmias would develop. Since agents used to treat skeletal muscle myotonia
also have cardiac
trocardiogram
effects [8-lo], we monitored the elecduring quinine, procainamide and diphenylhydantoin
therapy. PATIENTS AND METHODS Twenty-six patients with myotonic dystrophy were studied. Thirteen adult patients (over age 17) with myotonic dystrophy in the Neuromuscular Disease Clinic at Strong Memorial Hospital were evaluated and their available adult family members at risk were subsequently screened. Thirteen additional patients with myotonic dystrophy were found during this screening. The diagnosis in all patients was based upon a positive family history, the presence of detectable weakness, clinical and electromyographic myotonia and cataracts. (In one patient clinical myotonia was equivocal, but
July 1975
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37
CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRIGGS
1
ONE SECOND
ET AL.
A
A H_ V
His bundle electrocardiogram (bottom trace) indicating the intervals assessed. The A wave reflects atrial depolarization, the H wave His bundle depolarization and V the ventricular depolarization all measured by the His bundle electrode.
FIgwe
1.
cataracts, frontal balding and electromyographic myotonia were present and two of his children have overt myotonic dystrophy.) Thirteen patients with myotonic dystrophy were admitted to the Clinical Research Center for His bundle electrocardiography and observation of the effects of quinine, procainamide and diphenylhydantoin therapy. His bundle recordings were successfully obtained on 11 patients. Patients were studied in the postabsorptive state without regular medication or premeditation. Bi- and tripolar, 6 French catheters (United States Catheter and Instrument Corp., Billerica, Mass., No. 5620, 5651, 5655) were used for His bundle recordings. These were passed percutaneously via the femoral vein under local xylocaine anesthesia. The recording catheter was positioned by fluoroscopic observation at the level of the tricuspid valve in order to record atrial, His bundle and ventricular electrograms. An additional bipolar pacing catheter (United States Catheter and Instrument Corp., Billerica, Mass., No. 5620, 5651, 5655) was passed from a median basilic vein cutdown to the level of the junction of the right atrium and superior vena cava for atrial tachypacing.
L
ONE SECOND
Electrocardiogram leads I, II, Ill, aVR, aVL and aVF were monitored and recorded simultaneously with the His bundle electrogram (Figure 1). The bipolar catheter was attached to the A-C input of an electrocardiographic preamplifier (Princeton, Applied Research Corp., Princeton, N.J.-model PAR 113) and the frequency of the signal was filtered between 30 and 1,000 Hz. The tracings were recorded on a direct writing, fluid-jet oscillographic recorder with a broad frequency response of 0 to 500 Hz (Elema-Schiinander AB, Solna, -Sweden-Mingograph 81). Recording speeds tiere at 100 and 250 mm/set. The A-H interval recorded on the His bundle electrogram was measured from the onset of the A deflection to the onset of the H deflection and believed to represent A-V nodal conduction time (Figure 1). Measurements of P to H time and intracardiac recordings from the high atrial electrode were not performed. H-V time was measured from the onset of the H deflection to the earliest QRS activity on either the standard electrocardiogram leads or the His bundle electrogram. Intervals were measured over 5 to 10 consecutive cardiac cycles. After both electrodes were in position, base line recordings were made. Atrial tachypacing (Figure 2) was then carried out beginning at a rate 10 beats/ min faster than the base line heart rate. The rate was then increased in 10 beats/min increments to a rate of 150. Pacing was maintained at each level for 2 minutes, and the heart rate was allowed to return to base line before proceeding to the next level of pacing. Electrical hazard to patients was avoided by careful grounding of equipment and use of direct current instrumentation in all recording devices. The effects of the administration of diphenylhydantoin were also studied in four patients by serial observations during His bundle electrograms. After the base line observations, diphenylhydantoin was given slowly intravenously in 75 mg increments to a total dose of 8 mg/kg. After infusion of the entire dose, the pacing protocol was repeated. Pulse and blood pressure were closely monitored during diphenylhydantoin administration. There were no significant changes in vital signs or appearance of side effects, except for pain at the injection site. In later studies, diphenylhydantoin was given via catheter into the right atrium. Diphenylhydantoin level was not monitored during this part of
1
LEADlI
t STIMULUS ARTIFACT
38
July 1975
The American Journalof Medlclne Volume 59
i
F/gore 2. His bundle electrocardiogram in a 58 year okt man with first degree A-V block, left anterior hemiblock, right bundle branch block. During atrial tachypacing the Wenckebach phenomenon developed. At a higher rate of pacing 2: 1 A-V block developed.
CARDIAC
the study, but this dose therapeutic
The effects
be expected
to achieve
a
of oral quinine, procainamide
on the electrocardiogram of myotonia in 13 patients.
mide short-term
as 250 mg every as 1 g/day
was administered
intravenously
diphenylhydantoin
during the His bundle re-
given as 300 mg a day in the
first 7 patients and, when blood levels became
obtainable,
in
level
reached. change
amounts
Patients
in the degree
ially for action grams
were
were
and
taken
until
a
questioned
of myotonia percussion
deflection.
and later
read
status.
Electrocardiograms
search
Products,
Calif..
6901
ser-
Electrocardioattention
to the
from the precordial
Electrocardiograms
without
knowledge
were
monitored
W.
was
imperial
Hwy.,
lead were
of treatment (Avionic
Re-
Los Angeles,
Model 350) for 6 hours during a control period and
during long-term
procainamide
and diphenylhydantoin
ther-
apy. RESULTS Conduction
abnormalities
were
present
in 17 of the
I). These 17 patients all had first degree heart block (P-R interval greater than 0.20 second). In addition to their first degree heart block, two patients had left bundle branch block, five patients had left anterior hemiblock (i.e., a QRS axis of -30 or more unaccompanied by evidence of an inferior myocardial infarction) and five patients had right bundle branch block. Other 26 patients
with
TABLE ~_._.
His Bundle Electrocardiography
It
myotonic
dystrophy
t:T AL.
in
Abnormalities of Rhythm and Conduction Myotonic Dystrophy in 26 Patients
- .~~. _- __ __~_ No.
Conduction abnormalities First degree atrioventricular block Right bundle branch block Left bundle branch block Left anterior hemiblock Multiple ventricular premature beats Multiple atrial premature beats __ ~._ ~-~ ____. ____-
17 17
!j
? !< 6 2 ~.~~_ __ --.
any noticeable
and were examined
serially with particular
maximum
mounted
about
myotonia.
P-R interval which was measured giving
therapeutic
DYSTROPHY-GRIGGS
(18 to 61 years of age) -___.. Abnormalities
and diphenyl-
hour for a total of 1 g
for 1 week;
cordings were subsequently increasing
I
were studied during Quinine was adminis-
tered as 200 mg every 2 hours for a total of 1 g; procainaand long-term
TABLE
[ Ii]
range
hydantoin treatment
might
CONDUCTION IN MYOTONIC
(Table
cardiac abnormalities were much less frequent (Table I). Seven of the patients with first degree heart block were seen initially in the course of family screening and had not previously been recognized as having myotonic dystrophy. These patients all had clinically diagnosable myotonic dystrophy, but the diagnosis had never been made. His bundle electrocardiography performed in 11 patients demonstrated abnormalities in 8 patients (Table II). The His bundle studies of the two patients with normal P-R intervals were normal, but all but one of the patients with first degree heart block showed an abnormality of the His bundle electrogram. The H-V interval was prolonged in six and the A-H interval in five of the nine patients with first degree block. Since high atrial recording was not performed, the precise P-A interval was not determined but P-wave duration as measured from the electrocardiogram was from 100 to 115 msec in all patients. Atrial tachypacing produced higher degrees of block only in those patients who had ventricular con-
and Response to Atrial Tachypacing -_______ _ ~~___ His Bundle Recording Interval (msec)
A&F (yr) 25 35 40 21 1” A-V 40 1” A.!’ 58 1” A-V 30 1” A-V 1” A-V 29 40 1” A-V 58 1” A-V 39 lo A-V Normal Interval
Electrocardiogram ___Normal Normal Normal block block block block block + LAH block + LAH block + LAH + RBBB block + LAH + RBBB
A-H
tf-V
100 80 92 119 123 125 110 91 156 140 160 50-120
52 50 39 61 49 55 59 75 72 60 61 35-55
Responseto Atrial Tachypacing Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach
at at at at at at at
140 beats/min 140 beats/min 140 beats/min 140 beats/min 140 beats/mm 140 beats/min 140 beats/min
at at at at
130 beats/min, 130 beats/min, 120 beats/min, 120 beats/min,
2:l A-V 2:1A-V 2:l A-V 2:l A-V
block block block block
at at at at
150 beats/min 150 beats/min 130 beats/min 130 beats/min
...
__. NOTE: l” A-V block denotes first degree atrioventricular block(P-R interval > 0.20); LAH = left anterior hemiblock; RBBB = right bundle branch block. The A-H interval reflects conduction through the A-V node (proximal conduction); the H-V interval reflects conduction through the His and Purkinje pathways (distal conduction); Wenckebach response to atrial tachypacing was above the His bundle and hence A-V nodal in each case.
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CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRIGGS
TABLE
iii
Effect of Treatment Interval
ET AL.
of Myotonia on P-R-
Change ininterval During Age (yr)
Control
Quinine
25 35 40 21 40 58 30 29 40 58 39 61 42
0.170 0.160 0.165 0.190 0.200 0.215 0.200 0.190 0.185 0.250 0.215 0.220 0.190
0 0 +0.010 0 +0.005 +0,015 0 +0.015 +0.020 0 +0.010 0 -0.015
Increased
Decreased
Procainamide Chronic 0 +0.010 +0.020 +0.005 +0.045 +0.010 +0.030 +0.040 +0.020
Not given +0.010 +0.020 +0.020
6/13(significant 11/13(signifi-
at 0.10 level)
cant at 0.001
l/13
level) None
Diphenylhydantoin -0.030 -0.035 -0.015 -0.050 +0.005 -0.005 0 -0.010 -0.025 Not given -j-o.005 Not given Not given 2/10
7/10 (significantat 0.02level)
duction abnormalities in addition to first degree heart block (Table II). These patients had a Wenckebach phenomenon with failure of His bundle depolarization at rates less than 140 beats/min and 2: 1 A-V block at rates of 130 to 150 beatslmin (Figure 2). A comparison of the effects of quinine, procainamide and diphenylhydantoin therapy (Table Ill) showed that, although all three agents appeared to be equally effective in the treatment of myotonia, procainamide lengthened the P-R interval (5 to 45 msec) in 12 of 13 patients whereas diphenylhydantoin shortened the P-R interval in 8 of 10 patients ( 5 to 50 msec). These differences were significant at the 0.001 and 0.02 level, respectively. Quinine also lengthened the P-R interval in 6 of 13 patients, but the difference in length was less (5 to 10 msec) and the difference from base line values did not reach significance for the group as a whole (P = 0.10). In the last four patients studied, drug levels were determined and were in the therapeutic range for each agent except diphenylhydantoin which was low in one patient (quinine 4.0 to 4.9 mg/liter; procainamide 4.2 to 6.0 mg/liter; diphenylhydantoin 5.0 to 21 mg/ liter). No episode of a higher degree of block was detected by routine electrocardiography during shortterm administration of quinine, procainamide or diphenylhydantoin or by the 6 hour electrocardiographic monitoring during long-term procainamide or diphenylhydantoin therapy. Intravenous diphenylhydantoin (8 mg/kg) given to
40
July 1975
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four patients during His bundle electrocardiography (Cases 1, 3, 8 and 11) produced only slight changes in the H-V interval (-10, i-3, -6, -t-3 msec, respectively). Blood levels were not monitored during intravenous administration of diphenylhydantoin. Larger doses were not given, and several patients were unable to tolerate the intravenous administration because of pain at the injection site. Subsequent experience demonstrated that the administration of diphenylhydantoin via a central venous catheter obviated the discomfort and permitted administration of the agent. COMMENTS This study confirms the high incidence of conduction abnormality in patients with myotonic dystrophy [2] and emphasizes the fact that first degree heart block (P-R interval > 0.20) is frequently present before other clinical features lead to diagnosis. (We have considered 0.20 as the upper limit of normal for the P-R interval. As others have pointed out [ 121, this limit may be high and an even greater proportion of patients niay have conduction abnormalities.) Seven of the 13 patients detected in the course of family screening had first degree heart block. The occurrence of cardiac abnormalities prior to other symptoms of the disorder has been noted in individual cases [5, lo], and in one series [ 131 several relatives had no signs of myotonic dystrophy. The youngest. such patient was a 2 year old with left axis deviation [5]. Also of note is the report of Wolintz et al. [ 141 of cardiac arrhythmias occurring 17 years prior to diagnosis at age 3 1. We did not detect any family member in this study who had first degree heart block and no other evidence of myotonic dystrophy, and thus the electrocardiographic abnormalities may be of limited value in family detection studies since slit lamp and electromyographic studies detect over 95 per cent of cases [ 151. Conduction abnormalities are not common in other forms of muscular dystrophy [ 161 or in other myotonic disorders [ 11, and thus conduction abnormalities are of supportive value in the diagnosis of myotonic dystrophy. Since many of the patients with first degree heart block had few symptoms referable to skeletal muscle, myotonic dystrophy should be considered in the differential diagnosis of patients with this abnormality on the electrocardiogram. His bundle electrocardiography revealed the H-V interval to be abnormal in seven of nine patients with first degree heart block. This prolongation of the interval from onset of the H spike to ventricular activation suggests that in these patients there is disease in all three fascicles of the ventricular conducting system. It is also possible, although less likely, that delay
CARDIAC
in the His bundle could contribute The
development
of
higher
to the prolongation.
degrees
of
block
ob-
served during atrial tachypacing may reflect abnormality in conduction above the His bundle since the A-H interval was prolonged in these patients. Although Wenckebach and 2:l A-V block can develop at rates below 140 beats/min, the occurrence of this response only in patients with severe intranodal disease supports involvement of the entire conducting system in many of these patients. In a recently published study of His bundle electrocardiography in a single family with myotonic dystrophy, conduction abnormalities were noted throughout the His-Purkinje system [ 171 Pathologic study of the S-A and A-V node and the His and Purkinje fibers has been performed in only two cases of myotonic dystrophy [6,18]. In a carefully studied patient [ 181, changes were observed in the A-V node and in both the right and left bundle branches, but they were not thought to be complete enough to disrupt conduction. However, atrial arrhythmias rather than conduction disturbances were prominent. In the only case with conduction abnormalities similar to ours, “Purkinje tissue was normal” [S]. This was in a 60 year old man who had right bundle branch block and left axis deviation but who may not have had heart block. The diffuse involvement which we are postulating, therefore, awaits pathologic confirmation. Since the conduction abnormalities occurred in our patients irrespective of age and have occurred in other young patients [5], it seems unlikely that the changes result from atherosclerosis. Moreover, since the abnormalities appear to be widespread, it seems unlikely that they reflect focal infarction secondary to vascular disease [ 191. Complete heart block has been noted in patients with myotonic dystrophy [ 14,18,20-231, and we have observed three patients with complete heart block of abrupt onset [24]. The high incidence of sudden death in myotonic dystrophy has been attributed to sudden arrhythmia [ 11. One aim of this investigation was to find parameters which might be of predictive value in determining which patients with myotonic dystrophy are particularly prone to the development of higher degrees of block. It has been suggested in conditions other than muscular dystrophy that the presence of bifascicular block (e.g.,right bundle branch block and left anterior hemiblock) may warrant consideration of pacemaker implantation [25]. There are no data, however, to indicate how likely such patients with myotonic dystrophy are to progress to complete heart block. Although atrial tachypacing did demonstrate abnormalities, the 6 hour electrocardiographic monitoring did not detect intermittent higher degrees of block. None of the patients
CONDUCTION IN MYOTONIC
that we have followed of their conduction
DYSTROPHY--GRIGGS
ET AL.
have thus far had progression
abnormalities
to higher degrees
of
block (12 to 24 months). A recently reported followup study of patients in whom right bundle branch block and left anterior hemiblock were detected as a chance electrocardiographic finding showed that only occasional patients progressed to complete heart block [25]. We are continuing to follow our patients with serial electrocardiographic evaluation. It remains to be determined whether His bundle electrocardiography or atrial tachypacing has any predictive value in patients with myotonic dystrophy. It is possible that use of induced extrasystoles as recently described [26] might give more information about the responsivity of the conducting system. Although quinine, procainamide and diphenylhydantoin are all known to effect cardiac conduction [8-lo], few investigators have considered these effects in treating myotonia. Procainamide has been demonstrated to prolong the A-H and H-V time on His bundle electrocardiography [8] of nondystrophic patients without conduction abnormalities whereas diphenylhydantoin has been known to shorten A-H time while not affecting the H-V interval [ 91. Munsat [ 271 in a double-blind study of the treatment with procainamide and diphenylhydantoin interval prolongation in three patients
of myotonia noted P-R during pro-
cainamide therapy but did not observe an effect with diphenylhydantoin. In our study, treatment of myotonia with procainamide was associated with a significant lengthening of the P-R interval, whereas during treatment with diphenylhydantoin the P-R interval was shortened. Quinine had an effect similar to procainamide, but the change was not statistically significant. Despite changes in cardiac conduction, there was no instance of an increase in the degree of heart block with any agent on routine or monitored electrocardiography. Blood levels obtained in four patients indicated that each agent was in the therapeutic range [ 281. Even the administration of diphenylhydantoin intravenously did not deleteriously effect the His bundle electrocardiogram in the four cases studied. Since the shortening of A-V conduction by diphenylhydantoin may be due to its autonomic actions [ 291, the difference between the agents may not reflect any true difference in effects on the cardiac conduction System. In three patients a slight shortening of the H-V interval was observed, but such shortening has not been seen in other studies with diphenylhydantoin [9]. It is possible that the diseased conduction system of these patients responded unexpectedly to the agent, but since the degree of shortening was small (3 to 10 msec) it may not be significant. In a comparison of the antimyotonic action of procainamide and diphenylhydantoin, Munsat [ 271 found
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41
CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRICXS ET AL.
the agents to be of equal therapeutic effectiveness. Although our own study was not performed to answer this question in a double-blind fashion, each patient was treated with procainamide, diphenylhydantoin and quinine, and all three appeared effective in therapy of myotonia. More recently, conflicting reports [30,31] as to the efficacy of diphenylhydantoin for myotonia have appeared. As noted by others [ 11, many patients with myotonic dystrophy have only moderate or slight myotonia and in these subjects therapy of myotonia is not necessary and will not be helpful. Of our 13 study patients treated for myotonia only 5 have been maintained on thera-
py, despite objective improvement
in myotonia in 11.
Nonetheless, most patients with myotonic dystrophy deserve a trial of therapy for myotonia, and if these agents are of equal effectiveness, diphenylhydantoin may be preferable to quinine or procainamide because it does not appear to have a deleterious effect on cardiac conduction. ACKNOWLEDGMENT We thank Drs. David Kramer and Pravin Shah for their assistance and advice on this study, and Mr. Dennis Edwards and Mr. Ted Sun for technical assistance.
REFERENCES 1.
6. 7. a.
9.
10.
11
12. 13.
14.
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16.
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Caughey JE. Myrianthopoulos NC: Dystrophia Myotonica and Related Disorders, SpringReM, Ill., Charles C Thomas, 1963, p 35. Spillane JD: The heart in myotonia atrophica. Br Heart J 13: 343,195l. Litchfield JA: A-V dissociation in dystrophia myotonica. Br Heart J 15: 357. 1953. Church SC: The heart in myotonia atrophica. Arch Intern Med 119: 176, 1967. Payne CA, Greenfield JC: Electrocardiographic abnormalities associated with myotonic dystrophy. Am Hear-l J 65: 436, 1963. Cannon PJ: The heart and lungs in myotonic muscular dystrophy. Am J Med 32: 765, 1962. Goodman RM: Genetic Disorders of Man, Boston, Little, Brown 8 Co., 1970, p 215. Rosen KM, Lisi KR. Berkowitz WD, Lau SH. Damato AN: The effects of procaine amide on atrioventricular and intraventricular conduction in man (abstract). Circulation 39 (supp 3): 173, 1969. Damato AN, Berkowitz WK. Patton RD. Lau SH: The effect of diphenylhydantoin on atrioventricular and intraventricular conduction in man. Am Heart J 79: 5 I, 1970. Rollo IM: Drugs used in the chemotherapy of malaria. The Pharmacologic Basis of Therapeutics (Goodman LS, Gilman A, eds), New York, Macmillan Co., 1970. Wallis W, Kutt H, McDowell F: Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology 18: 513, 1968. Herbert WH, Sobel BJ: “Normal” atrioventricular conduction. Am J Med 48: 145, 1970. Bundey S, Carter CO, Soothill JF: Early recognition of heterozygotes for the gene for dystrophia myotonica. J Neurol Neurosurg Psychiat 33: 279, 1970. Wolintz AH, Sonnenblick Eli. Engel WK: Stokes-Adams syndrome and atrial arrhythmias as the presenting symptoms of myotonic dystrophy, with response to electrocardioversion. Ann Intern Med 65: 1260. 1966. Polgar JG, Bradley WG. Upton ARM, Anderson J. Howat JML, Petit0 F, Roberts DF. Scopa J: The early detection of dystrophia myotonica. Brain 95: 761, 1972. Griggs RC: Hypertrophy and cardiomyopathy in the neuro-
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17.
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22. 23. 24. 25.
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muscular diseases. Circ Research 34, 35 (suppl II): 145, 1974. Josephson ME, Caracta AR, Gallagher JJ. Damato AN: Site of conduction disturbances in a family with myotonic dystrophy. Am J Cardio132: 114, 1973. Thomson AMP: Dystrophia cordis myotonica studied by serial histology of the pacemaker and conducting system. J Pathol 96: 285, 1968. Trevino AJ, Beller BM: Conduction disturbances of the left bundle branch system and their relationship to complete heart block. Am J Med 51: 374, 1971. Bulloch RT. Davis JL, Hara M: Dystrophia myotonica with heart block. A light and electron microscopic study. Arch Pathol 84: 130, 1967. Singson CR, Alexander S: Cardiovascular abnormalities in myotonic dystrophy. Lahey Clin Foundation Bull 20: 150. 1971. Rosenthal G, Chaffee WR: Cardiac arrhythmias in myotonic dystrophy. NY State J Med 67: 940. 1967. Spurny OM, Wolf JW: Prolonged atrial flutter in myotonic dystrophy. Am J Cardiol 10: 886, 1962. Griggs RC: Unpublished observations 1974. DePasquale NP, Bruno MS: Natural history of combined right bundle block and left anterior hemiblock (bilateral bundle branch block). Am J Med 54: 297, 1973. Damato AN, Lau SH, Helfant RH, Stein E, Berkowitz WD, Cohen SI: Study of atrioventricular conduction in man using electrode catheter recordings of His bundle activity. Circulation 39: 287, 1969. Munsat TL: Therapy of myotonia. A double-blind evaluation of diphenylhydantoin, procainamide, and placebo. Neurology 17: 359, 1967. Koch-Weser J: Drug therapy: Serum drug concentrations as therapeutic guides. N Engl J Med 287: 227, 1972. Bigger JT Jr, Strauss HC, Hoffman BF: Effects of diphenylhydantoin on atrioventricular conduction. Fed Proc 27: 406, 1967. Williamson PM: Effectiveness of phenytoin sodium in myotonia congenita. II International Congress on Muscle Diseases Excerpta Med Int Cong Series 237: 58, 1971. Thompson CE: Diphenylhydantoin for myotonia congenita. N Engl J Med 286: 803. 1972.
ROBERT C. GRIGGS, M.D.’ ROBERT J. DAVIS,
M.D.+
DAVID C. ANDERSON,
M.D.t
JAMES T. DOVE, M.D.5 Rochester, New York
From the Departments of Neurology and Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York. This study was supported by a grant from the Muscular Dystrophy Associations of America, Inc., and Grant RR00044 from the U.S. Public Health Service. These studies were presented in part at the meetings of the American Academy of Neurology and American College of Physicians, April 1973. Requests for reprints should be addressed to Dr. Robert C. Griigs, Department of Neurology, University of Rochester, School of Medicine and Dentistry, 260 Crlttenden Boulevard, Rochester, New York 14642. Manuscript accepted August 29, 1974. Recipent of an American College of Physicians Teaching and Research Scholarship. t Present address: 939 Riigeland Street, Cheyenne, Wyoming 6200 1. * Present address: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455. B Present address: 124 Pebblebeach Drive, Springfield, Illinois 62704, l
Cardiac conduction abnormalities are frequent in myotonic dystrophy and can result in complete heart block. In a study of 26 patients with myotonic dystrophy, first degree heart block was found to precede clinical presentatlon of the disease in 7 patients. His bundle electrocardiography in 11 patients demonstrated abnormalities throughout the entire conducting system, even in patients with only first degree heart block. In patfents with block of the right bundle branch or antertor fasckle of the left bundle branch, slowing in the remaining fascicles was always present. Therapy of myotonia with procatnamide stgntfkantly lengthened the P-R interval, and treatment with diphenythydantoin signtficantly shortened the P-R interval suggesting that dlphenylhydantoin may be preferable for therapy of myotonia in patients with myotonic dystrophy. Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia and degeneration of skeletal muscle. Many other organ systems may be involved including heart, lens, gonads, bone, brain and integument [ 11. In a majority of patients with myotonic dystrophy, electrocardiograms are abnormal, and cardiac arrhythmias and conduction disturbances are frequent [2-71. The abrupt appearance of heart block may account for the high incidence of sudden death [ 11. How frequently cardiac conduction abnormalities precede other disease manifestations is not known, and the site of conduction abnormalities has not been extensively studied electrophysiologically. We prospectively studied families with myotonic dystrophy to determine the frequency with which conduction abnormalities precede the clinical presentation of the disease. His bundle electrocardiography and atrial “tachypacing” (rapid atrial pacing) were performed in 11 patients to localize the site of conduction abnormalities and to try to predict in which patients life-threatening arrhythmias would develop. Since agents used to treat skeletal muscle myotonia
also have cardiac
trocardiogram
effects [8-lo], we monitored the elecduring quinine, procainamide and diphenylhydantoin
therapy. PATIENTS AND METHODS Twenty-six patients with myotonic dystrophy were studied. Thirteen adult patients (over age 17) with myotonic dystrophy in the Neuromuscular Disease Clinic at Strong Memorial Hospital were evaluated and their available adult family members at risk were subsequently screened. Thirteen additional patients with myotonic dystrophy were found during this screening. The diagnosis in all patients was based upon a positive family history, the presence of detectable weakness, clinical and electromyographic myotonia and cataracts. (In one patient clinical myotonia was equivocal, but
July 1975
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37
CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRIGGS
1
ONE SECOND
ET AL.
A
A H_ V
His bundle electrocardiogram (bottom trace) indicating the intervals assessed. The A wave reflects atrial depolarization, the H wave His bundle depolarization and V the ventricular depolarization all measured by the His bundle electrode.
FIgwe
1.
cataracts, frontal balding and electromyographic myotonia were present and two of his children have overt myotonic dystrophy.) Thirteen patients with myotonic dystrophy were admitted to the Clinical Research Center for His bundle electrocardiography and observation of the effects of quinine, procainamide and diphenylhydantoin therapy. His bundle recordings were successfully obtained on 11 patients. Patients were studied in the postabsorptive state without regular medication or premeditation. Bi- and tripolar, 6 French catheters (United States Catheter and Instrument Corp., Billerica, Mass., No. 5620, 5651, 5655) were used for His bundle recordings. These were passed percutaneously via the femoral vein under local xylocaine anesthesia. The recording catheter was positioned by fluoroscopic observation at the level of the tricuspid valve in order to record atrial, His bundle and ventricular electrograms. An additional bipolar pacing catheter (United States Catheter and Instrument Corp., Billerica, Mass., No. 5620, 5651, 5655) was passed from a median basilic vein cutdown to the level of the junction of the right atrium and superior vena cava for atrial tachypacing.
L
ONE SECOND
Electrocardiogram leads I, II, Ill, aVR, aVL and aVF were monitored and recorded simultaneously with the His bundle electrogram (Figure 1). The bipolar catheter was attached to the A-C input of an electrocardiographic preamplifier (Princeton, Applied Research Corp., Princeton, N.J.-model PAR 113) and the frequency of the signal was filtered between 30 and 1,000 Hz. The tracings were recorded on a direct writing, fluid-jet oscillographic recorder with a broad frequency response of 0 to 500 Hz (Elema-Schiinander AB, Solna, -Sweden-Mingograph 81). Recording speeds tiere at 100 and 250 mm/set. The A-H interval recorded on the His bundle electrogram was measured from the onset of the A deflection to the onset of the H deflection and believed to represent A-V nodal conduction time (Figure 1). Measurements of P to H time and intracardiac recordings from the high atrial electrode were not performed. H-V time was measured from the onset of the H deflection to the earliest QRS activity on either the standard electrocardiogram leads or the His bundle electrogram. Intervals were measured over 5 to 10 consecutive cardiac cycles. After both electrodes were in position, base line recordings were made. Atrial tachypacing (Figure 2) was then carried out beginning at a rate 10 beats/ min faster than the base line heart rate. The rate was then increased in 10 beats/min increments to a rate of 150. Pacing was maintained at each level for 2 minutes, and the heart rate was allowed to return to base line before proceeding to the next level of pacing. Electrical hazard to patients was avoided by careful grounding of equipment and use of direct current instrumentation in all recording devices. The effects of the administration of diphenylhydantoin were also studied in four patients by serial observations during His bundle electrograms. After the base line observations, diphenylhydantoin was given slowly intravenously in 75 mg increments to a total dose of 8 mg/kg. After infusion of the entire dose, the pacing protocol was repeated. Pulse and blood pressure were closely monitored during diphenylhydantoin administration. There were no significant changes in vital signs or appearance of side effects, except for pain at the injection site. In later studies, diphenylhydantoin was given via catheter into the right atrium. Diphenylhydantoin level was not monitored during this part of
1
LEADlI
t STIMULUS ARTIFACT
38
July 1975
The American Journalof Medlclne Volume 59
i
F/gore 2. His bundle electrocardiogram in a 58 year okt man with first degree A-V block, left anterior hemiblock, right bundle branch block. During atrial tachypacing the Wenckebach phenomenon developed. At a higher rate of pacing 2: 1 A-V block developed.
CARDIAC
the study, but this dose therapeutic
The effects
be expected
to achieve
a
of oral quinine, procainamide
on the electrocardiogram of myotonia in 13 patients.
mide short-term
as 250 mg every as 1 g/day
was administered
intravenously
diphenylhydantoin
during the His bundle re-
given as 300 mg a day in the
first 7 patients and, when blood levels became
obtainable,
in
level
reached. change
amounts
Patients
in the degree
ially for action grams
were
were
and
taken
until
a
questioned
of myotonia percussion
deflection.
and later
read
status.
Electrocardiograms
search
Products,
Calif..
6901
ser-
Electrocardioattention
to the
from the precordial
Electrocardiograms
without
knowledge
were
monitored
W.
was
imperial
Hwy.,
lead were
of treatment (Avionic
Re-
Los Angeles,
Model 350) for 6 hours during a control period and
during long-term
procainamide
and diphenylhydantoin
ther-
apy. RESULTS Conduction
abnormalities
were
present
in 17 of the
I). These 17 patients all had first degree heart block (P-R interval greater than 0.20 second). In addition to their first degree heart block, two patients had left bundle branch block, five patients had left anterior hemiblock (i.e., a QRS axis of -30 or more unaccompanied by evidence of an inferior myocardial infarction) and five patients had right bundle branch block. Other 26 patients
with
TABLE ~_._.
His Bundle Electrocardiography
It
myotonic
dystrophy
t:T AL.
in
Abnormalities of Rhythm and Conduction Myotonic Dystrophy in 26 Patients
- .~~. _- __ __~_ No.
Conduction abnormalities First degree atrioventricular block Right bundle branch block Left bundle branch block Left anterior hemiblock Multiple ventricular premature beats Multiple atrial premature beats __ ~._ ~-~ ____. ____-
17 17
!j
? !< 6 2 ~.~~_ __ --.
any noticeable
and were examined
serially with particular
maximum
mounted
about
myotonia.
P-R interval which was measured giving
therapeutic
DYSTROPHY-GRIGGS
(18 to 61 years of age) -___.. Abnormalities
and diphenyl-
hour for a total of 1 g
for 1 week;
cordings were subsequently increasing
I
were studied during Quinine was adminis-
tered as 200 mg every 2 hours for a total of 1 g; procainaand long-term
TABLE
[ Ii]
range
hydantoin treatment
might
CONDUCTION IN MYOTONIC
(Table
cardiac abnormalities were much less frequent (Table I). Seven of the patients with first degree heart block were seen initially in the course of family screening and had not previously been recognized as having myotonic dystrophy. These patients all had clinically diagnosable myotonic dystrophy, but the diagnosis had never been made. His bundle electrocardiography performed in 11 patients demonstrated abnormalities in 8 patients (Table II). The His bundle studies of the two patients with normal P-R intervals were normal, but all but one of the patients with first degree heart block showed an abnormality of the His bundle electrogram. The H-V interval was prolonged in six and the A-H interval in five of the nine patients with first degree block. Since high atrial recording was not performed, the precise P-A interval was not determined but P-wave duration as measured from the electrocardiogram was from 100 to 115 msec in all patients. Atrial tachypacing produced higher degrees of block only in those patients who had ventricular con-
and Response to Atrial Tachypacing -_______ _ ~~___ His Bundle Recording Interval (msec)
A&F (yr) 25 35 40 21 1” A-V 40 1” A.!’ 58 1” A-V 30 1” A-V 1” A-V 29 40 1” A-V 58 1” A-V 39 lo A-V Normal Interval
Electrocardiogram ___Normal Normal Normal block block block block block + LAH block + LAH block + LAH + RBBB block + LAH + RBBB
A-H
tf-V
100 80 92 119 123 125 110 91 156 140 160 50-120
52 50 39 61 49 55 59 75 72 60 61 35-55
Responseto Atrial Tachypacing Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach Wenckebach
at at at at at at at
140 beats/min 140 beats/min 140 beats/min 140 beats/min 140 beats/mm 140 beats/min 140 beats/min
at at at at
130 beats/min, 130 beats/min, 120 beats/min, 120 beats/min,
2:l A-V 2:1A-V 2:l A-V 2:l A-V
block block block block
at at at at
150 beats/min 150 beats/min 130 beats/min 130 beats/min
...
__. NOTE: l” A-V block denotes first degree atrioventricular block(P-R interval > 0.20); LAH = left anterior hemiblock; RBBB = right bundle branch block. The A-H interval reflects conduction through the A-V node (proximal conduction); the H-V interval reflects conduction through the His and Purkinje pathways (distal conduction); Wenckebach response to atrial tachypacing was above the His bundle and hence A-V nodal in each case.
July 1975
The American Journal of Medlclne
Volume 59
39
CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRIGGS
TABLE
iii
Effect of Treatment Interval
ET AL.
of Myotonia on P-R-
Change ininterval During Age (yr)
Control
Quinine
25 35 40 21 40 58 30 29 40 58 39 61 42
0.170 0.160 0.165 0.190 0.200 0.215 0.200 0.190 0.185 0.250 0.215 0.220 0.190
0 0 +0.010 0 +0.005 +0,015 0 +0.015 +0.020 0 +0.010 0 -0.015
Increased
Decreased
Procainamide Chronic 0 +0.010 +0.020 +0.005 +0.045 +0.010 +0.030 +0.040 +0.020
Not given +0.010 +0.020 +0.020
6/13(significant 11/13(signifi-
at 0.10 level)
cant at 0.001
l/13
level) None
Diphenylhydantoin -0.030 -0.035 -0.015 -0.050 +0.005 -0.005 0 -0.010 -0.025 Not given -j-o.005 Not given Not given 2/10
7/10 (significantat 0.02level)
duction abnormalities in addition to first degree heart block (Table II). These patients had a Wenckebach phenomenon with failure of His bundle depolarization at rates less than 140 beats/min and 2: 1 A-V block at rates of 130 to 150 beatslmin (Figure 2). A comparison of the effects of quinine, procainamide and diphenylhydantoin therapy (Table Ill) showed that, although all three agents appeared to be equally effective in the treatment of myotonia, procainamide lengthened the P-R interval (5 to 45 msec) in 12 of 13 patients whereas diphenylhydantoin shortened the P-R interval in 8 of 10 patients ( 5 to 50 msec). These differences were significant at the 0.001 and 0.02 level, respectively. Quinine also lengthened the P-R interval in 6 of 13 patients, but the difference in length was less (5 to 10 msec) and the difference from base line values did not reach significance for the group as a whole (P = 0.10). In the last four patients studied, drug levels were determined and were in the therapeutic range for each agent except diphenylhydantoin which was low in one patient (quinine 4.0 to 4.9 mg/liter; procainamide 4.2 to 6.0 mg/liter; diphenylhydantoin 5.0 to 21 mg/ liter). No episode of a higher degree of block was detected by routine electrocardiography during shortterm administration of quinine, procainamide or diphenylhydantoin or by the 6 hour electrocardiographic monitoring during long-term procainamide or diphenylhydantoin therapy. Intravenous diphenylhydantoin (8 mg/kg) given to
40
July 1975
The Anwrkan
Journal of Medkkre
Volume 59
four patients during His bundle electrocardiography (Cases 1, 3, 8 and 11) produced only slight changes in the H-V interval (-10, i-3, -6, -t-3 msec, respectively). Blood levels were not monitored during intravenous administration of diphenylhydantoin. Larger doses were not given, and several patients were unable to tolerate the intravenous administration because of pain at the injection site. Subsequent experience demonstrated that the administration of diphenylhydantoin via a central venous catheter obviated the discomfort and permitted administration of the agent. COMMENTS This study confirms the high incidence of conduction abnormality in patients with myotonic dystrophy [2] and emphasizes the fact that first degree heart block (P-R interval > 0.20) is frequently present before other clinical features lead to diagnosis. (We have considered 0.20 as the upper limit of normal for the P-R interval. As others have pointed out [ 121, this limit may be high and an even greater proportion of patients niay have conduction abnormalities.) Seven of the 13 patients detected in the course of family screening had first degree heart block. The occurrence of cardiac abnormalities prior to other symptoms of the disorder has been noted in individual cases [5, lo], and in one series [ 131 several relatives had no signs of myotonic dystrophy. The youngest. such patient was a 2 year old with left axis deviation [5]. Also of note is the report of Wolintz et al. [ 141 of cardiac arrhythmias occurring 17 years prior to diagnosis at age 3 1. We did not detect any family member in this study who had first degree heart block and no other evidence of myotonic dystrophy, and thus the electrocardiographic abnormalities may be of limited value in family detection studies since slit lamp and electromyographic studies detect over 95 per cent of cases [ 151. Conduction abnormalities are not common in other forms of muscular dystrophy [ 161 or in other myotonic disorders [ 11, and thus conduction abnormalities are of supportive value in the diagnosis of myotonic dystrophy. Since many of the patients with first degree heart block had few symptoms referable to skeletal muscle, myotonic dystrophy should be considered in the differential diagnosis of patients with this abnormality on the electrocardiogram. His bundle electrocardiography revealed the H-V interval to be abnormal in seven of nine patients with first degree heart block. This prolongation of the interval from onset of the H spike to ventricular activation suggests that in these patients there is disease in all three fascicles of the ventricular conducting system. It is also possible, although less likely, that delay
CARDIAC
in the His bundle could contribute The
development
of
higher
to the prolongation.
degrees
of
block
ob-
served during atrial tachypacing may reflect abnormality in conduction above the His bundle since the A-H interval was prolonged in these patients. Although Wenckebach and 2:l A-V block can develop at rates below 140 beats/min, the occurrence of this response only in patients with severe intranodal disease supports involvement of the entire conducting system in many of these patients. In a recently published study of His bundle electrocardiography in a single family with myotonic dystrophy, conduction abnormalities were noted throughout the His-Purkinje system [ 171 Pathologic study of the S-A and A-V node and the His and Purkinje fibers has been performed in only two cases of myotonic dystrophy [6,18]. In a carefully studied patient [ 181, changes were observed in the A-V node and in both the right and left bundle branches, but they were not thought to be complete enough to disrupt conduction. However, atrial arrhythmias rather than conduction disturbances were prominent. In the only case with conduction abnormalities similar to ours, “Purkinje tissue was normal” [S]. This was in a 60 year old man who had right bundle branch block and left axis deviation but who may not have had heart block. The diffuse involvement which we are postulating, therefore, awaits pathologic confirmation. Since the conduction abnormalities occurred in our patients irrespective of age and have occurred in other young patients [5], it seems unlikely that the changes result from atherosclerosis. Moreover, since the abnormalities appear to be widespread, it seems unlikely that they reflect focal infarction secondary to vascular disease [ 191. Complete heart block has been noted in patients with myotonic dystrophy [ 14,18,20-231, and we have observed three patients with complete heart block of abrupt onset [24]. The high incidence of sudden death in myotonic dystrophy has been attributed to sudden arrhythmia [ 11. One aim of this investigation was to find parameters which might be of predictive value in determining which patients with myotonic dystrophy are particularly prone to the development of higher degrees of block. It has been suggested in conditions other than muscular dystrophy that the presence of bifascicular block (e.g.,right bundle branch block and left anterior hemiblock) may warrant consideration of pacemaker implantation [25]. There are no data, however, to indicate how likely such patients with myotonic dystrophy are to progress to complete heart block. Although atrial tachypacing did demonstrate abnormalities, the 6 hour electrocardiographic monitoring did not detect intermittent higher degrees of block. None of the patients
CONDUCTION IN MYOTONIC
that we have followed of their conduction
DYSTROPHY--GRIGGS
ET AL.
have thus far had progression
abnormalities
to higher degrees
of
block (12 to 24 months). A recently reported followup study of patients in whom right bundle branch block and left anterior hemiblock were detected as a chance electrocardiographic finding showed that only occasional patients progressed to complete heart block [25]. We are continuing to follow our patients with serial electrocardiographic evaluation. It remains to be determined whether His bundle electrocardiography or atrial tachypacing has any predictive value in patients with myotonic dystrophy. It is possible that use of induced extrasystoles as recently described [26] might give more information about the responsivity of the conducting system. Although quinine, procainamide and diphenylhydantoin are all known to effect cardiac conduction [8-lo], few investigators have considered these effects in treating myotonia. Procainamide has been demonstrated to prolong the A-H and H-V time on His bundle electrocardiography [8] of nondystrophic patients without conduction abnormalities whereas diphenylhydantoin has been known to shorten A-H time while not affecting the H-V interval [ 91. Munsat [ 271 in a double-blind study of the treatment with procainamide and diphenylhydantoin interval prolongation in three patients
of myotonia noted P-R during pro-
cainamide therapy but did not observe an effect with diphenylhydantoin. In our study, treatment of myotonia with procainamide was associated with a significant lengthening of the P-R interval, whereas during treatment with diphenylhydantoin the P-R interval was shortened. Quinine had an effect similar to procainamide, but the change was not statistically significant. Despite changes in cardiac conduction, there was no instance of an increase in the degree of heart block with any agent on routine or monitored electrocardiography. Blood levels obtained in four patients indicated that each agent was in the therapeutic range [ 281. Even the administration of diphenylhydantoin intravenously did not deleteriously effect the His bundle electrocardiogram in the four cases studied. Since the shortening of A-V conduction by diphenylhydantoin may be due to its autonomic actions [ 291, the difference between the agents may not reflect any true difference in effects on the cardiac conduction System. In three patients a slight shortening of the H-V interval was observed, but such shortening has not been seen in other studies with diphenylhydantoin [9]. It is possible that the diseased conduction system of these patients responded unexpectedly to the agent, but since the degree of shortening was small (3 to 10 msec) it may not be significant. In a comparison of the antimyotonic action of procainamide and diphenylhydantoin, Munsat [ 271 found
July 1975
The American Journal of Medicine
Volume 59
41
CARDIAC CONDUCTION IN MYOTONIC DYSTROPHY-GRICXS ET AL.
the agents to be of equal therapeutic effectiveness. Although our own study was not performed to answer this question in a double-blind fashion, each patient was treated with procainamide, diphenylhydantoin and quinine, and all three appeared effective in therapy of myotonia. More recently, conflicting reports [30,31] as to the efficacy of diphenylhydantoin for myotonia have appeared. As noted by others [ 11, many patients with myotonic dystrophy have only moderate or slight myotonia and in these subjects therapy of myotonia is not necessary and will not be helpful. Of our 13 study patients treated for myotonia only 5 have been maintained on thera-
py, despite objective improvement
in myotonia in 11.
Nonetheless, most patients with myotonic dystrophy deserve a trial of therapy for myotonia, and if these agents are of equal effectiveness, diphenylhydantoin may be preferable to quinine or procainamide because it does not appear to have a deleterious effect on cardiac conduction. ACKNOWLEDGMENT We thank Drs. David Kramer and Pravin Shah for their assistance and advice on this study, and Mr. Dennis Edwards and Mr. Ted Sun for technical assistance.
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