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A family with myotonic dystrophy associated with diffuse cardiac conduction disturbances as demonstrated by His bundle electrocardiography
A family with myotonic dystrophy associated with diffuse cardiac conduction disturbances demonstrated by His bundle electrocardiography
as
In a family with myotonic dystrophy, three siblings showing ECG abnormalities were subjected to His bundle ECG studies. The duration of the disease ranged from 9 to 24 yearsAll three siblings had prolonged HV intervals (His-Purkinje conduction times) of 70 to 80 msec The sister with the shortest duration of the disease had second-degree atrioventricular (AV) nodal block as well as left posterior fascicular block, the younger brother had left anterior fascicular block, and the elder brother with the longest history had first-degree AV block without bundle branch or fascicular block. With regard to associated arrhythmias, however, the elder brother developed paroxysmal ventricular tachycardia, apparently due to reentry involving the right bundle branch system, whereas the younger brother and sister had sinus bradycardia alone. This study reveals the prevalence of diffuse conduction disturbances of the specialized conducting system in a family with myotonic dystrophy. (AM HEART J 111:85, 1988.)
Shuichi Hiromasa, M.D., Takayuki Ikeda, M.D., Kouji Kubota, M.D., Shigeo Takata, M.D., Nobu Hattori, M.D., Masao Nishimura, M.D.,* and Yoahio Watanabe, M.D.* Kunuzuwa, Ishikawa, Japan
Myotonic dystrophy is a neuromuscular disease with autosomal dominant transmission. Although this disease is characterized by rigidity and degeneration of the skeletal muscle, it is often accompanied by functional and anatomic derangements in the myocardium.1-3 Since such cardiac lesions tend to involve the specialized conducting system, development of abnormal impulse formation and conduction is frequent.z-16 Since the introduction of His bundle electrography in man, numerous investigators have carried out detailed studies on such conduction abnormalities.6-6v lz-14s l7 Regarding clinical electrophysiologic studies on a family afllicted with this hereditary disease, however, only two reports have so far been published; by Josephson et al.,7 who studied a father and son; and by Hawley et al.,18 who studied 30 patients with myotonic dystrophy and 17 From the First Medicine. Received accepted
Department
for publication July 15, 1985.
of Medicine, March
Kanazawa
6, 1985; revision
Reprint requests: Shuichi Hiromasa, M.D., The Medicine, Kanamwa University School of Medicine, 920, Japan. *Cardiovascular Toyoake, Aichi,
Institute, Japan.
Fujita
Gakwn
University
University received
School
June
of
18, 198&
First Department of Kanazawa, Ishikawa School
of Medicine,
unaffected family members in a total of 18 families with noninvasive His bundle recording. Hence, in this paper, we will present the results of His bundle electrographic studies of three siblings with this disease who showed various ECG abnormalities. METHODSAND
RESULTS
As shown in Fig. 1, the diagnosis of myotonic dystrophy was made on three members of this family. The proband or case No. 1 (K.K., a 42-year-old man) was the second son; case No. 2 (T.K., a 41-year-old woman) was the eldest daughter; and case No. 3 (S.K., a 38-year-old man) was the third son. It is not known whether any of their parents or grandparents were afllicted with this disease, and the cause of deaths of these individuaIs also could not be clearly identified. The eldest son is said to be in good health, but has not been studied for the presence or absence of this disease. The second daughter had no signs of myotonic dystrophy in the skeletal muscle, and her ECG was normal although echocardiographic studies revealed the presence of mitral valve prolapse. Rigidity and atrophy of the facial and thenar muscles were first noted subjectively at the age of 18 years in case No. 1, at 32 years in case No. 2, and at 28 years in case No. 3, respectively, but the patients did not seek medical advice for this problem. Approximately 1 year prior to his first visit to Kanaxawa University Hospital, case No. 1 started to experience
a5
86
Hiromasa
et al.
American
Pedigree
Table
I. Electrophysiologic Case
q
=Male 0 =Femde I-@ -Myotonic $Mitral
Dystrophy Valve Prolapse
/ =Deceased
Fig. 1. Pedigree of the present family with myotonic dystrophy. The question mark indicates lack of information regarding the presence or absence of this disease.
attacks of palpitation at an average frequency of once a week. These episodes often lasted up to 30 minutes, and both their onset and termination were sudden, as was clearly noted by the patient. Because of the progressively aggravating nature of such attacks, he came to the hospital in August, 1980. On physical examination, the patient presented with the so-called myotonic face, with clear atrophy of muscle of the neck, face, temporal region, and jaws. Grip myotonia of the thenar muscles, percussion myotonia of the tongue, and other associated symptoms (including a cataract, frontal baldness, and testicular atrophy) all led to the diagnosis of myotonic dystrophy. Inquiries into his family history brought to our attention his younger brother and sister, who were subsequently diagnosed as having the same disease. Echocardiographic examinations revealed the presence of mitral valve prolapse in all three. Since their ECGs showed various abnormalities, clinical electrophysiologic studies using His bundle electrography were performed after obtaining informed consent from each patient. All studies were performed with the patients in the nonsedated, postabsorptive state. Three to four multipolar electrode catheters (interpolar distance, 10 mm) were introduced percutaneously and were positioned in the heart under fluoroscopic guidance at the high right atrium, His bundle, and right ventricular apex and, in case No. 1, at the left ventricular apex as well, to record the potentials of the high and low right atrium, His bundle, and right and left ventricles. The stimulation protocol included incremental high right atrial, left and right ventricular pacing, and programmed atrial and ventricular premature stimulation in sinus rhythm and at one or more drive cycle lengths. In order to induce the ventricular tachycardia, paired extrastimuli with coupling intervals of ZOO to 400 msec were introduced during basic ventricular pacing. Case No. 1. The 12-lead ECG made on the patient’s first visit (August 16, 1980) is reproduced in Fig. 2, Zeft, which demonstrates a normal sinus rhythm. There was firstdegree atrioventricular (AV) block with a PR interval of 0.22 second. Fig. 2, right, shows the ECG recorded during an attack of palpitation on September 3,198O. A tachycardia at the rate of 1Wmin is present, with wide QRS complexes of left bundle branch block configuration.
no.
Age W Age of onset (yr) A-A (600-1000 msec)* SACT (50-125 msec) SRT (<1400 msec) PA (20-55 msec) AH (50-140 msec) HV (35-55 msec) Wenckebach point (<140 bpm) At-ERP (170-300 msec) At-FRP (180.330 msec) AVN-ERP (230-390 msec) AVN-FRP (330-500 msec) V-ERP (170-290 msec) V-FRP (170-290 msec) AV block Fascicular block VT
findings
Jm~.wy, 1986 Heart Journal
of three siblings 1
2
3
42 18 896 117 1310 25 130 70 133
41 32 650 85 1020 20 210 80 100
38 28 660 105 1050 25 140 75 130
360 380 380 500 240 270 lo -
230 280 320 520 210 240 2O LP
240 260 330 450 190 230
+
-
-
-
lo
LA
A-A = spontaneous sinus cycle length SACT = sinoatrial conduction time; SRT = sinus node recovery time; PA = intra-atria1 conduction time; AH = intranodal conduction time; HV = His-Purkinje conduction time; At = atrial; AVN = atriaventricular nodak V = ventricular; ERP = effective refractory period; FRP = functional refractory period; AV = atrioventricular; LP = left posterior; LA = left anterior; VT = ventricular tachycardia. *Numbers in parentheses indicate normal values.
Although the atrial activity cannot be clearly identified, apparent presence of AV dissociation with occasional normalization of the QRS, possibly due to ventricular capture by sinus impulses (e.g., beat 1 in lead VJ, suggests a ventricular tachycardia originating in the right ventricle. On the His bundle electrogram (Fig. 3), the PA interval (or the intra-atria1 conduction time) measured 25 msec, and the AH interval (or the intranodal conduction time) measured 130 msec, both being within normal limits. The HV interval (or the His-Purkinje conduction time) was, however, prolonged to 70 msec, indicating that the firstdegree AV block observed resulted from a depressed His-Purkinje conduction. Other variables obtained by the His bundle recording are summarized in Table I. It is noted that both the effective and functional refractory periods of the atria were prolonged, whereas the AV nodal and ventricular refractory periods were within normal limts. In order to confirm the diagnosis of paroxysmal ventricular tachycardia, provocation of tachycardia with right ventricular stimulation was attempted. In Fig. 4, the right ventricular apex was initially driven at a basic cycle length of 600 msec for seven beats (S), followed by paired extrastimuli (&, SJ, with coupling intervals of 300 msec. This resulted in a successful induction of tachycardia with a QRS configuration similar to that during the spontaneous attack, as was shown in Fig. 2, right. Although the R-R interval manifested some fluctuations during the tachycardia, the ventricular rate was approximately 26O/min.
Volume 111 Number 1
Conduction
in myotonic
dystrophy
87
s5593
S5!56.16 Fig. 2. Twelve-lead ECGs of case No. 1 during sinus rhythm tachycardia (right).
There was AV dissociation, with an atria1 rate of 68/min. Since the excitation of the right ventricular apex preceded that of the left ventricular apex by 70 to 80 msec, right ventricular origin of this tachycardia was substantiated. On the His bundle recording, t.he H deflection became identifiable in the middle portion of Fig. 4, following right ventricular apical activation by approximately 30 msec. In the last two beats, however, the H spike almost coincided with the apical electrogram. Hence, this tachycardia may have originated from the proximal right bundle branch region. As the tachycardia, was both induced and terminated (not shown) by premature ventricular stimulation, reentry appears to be a likely mechanism, Case No. 2. A 12-lead ECG of this patient reproduced in Fig. 5 reveals sinus bradycardia at the rate of 47lmin, with second-degree AV block of type 1 variety causing occasional appearance of an AV junctional escape beat. The presence of right axis deviation (QRS axis = +130 degrees) suggests the possibility of left posterior fascicular block. Low voltage QRS complexes are noted in the precordial leads. During the clinical electrophysiologic studies, there was only first-degree AV block (Fig. 3, middle row). The PA interval was normal at 20 msec, whereas the AH and HV intervals were both abnormally prolonged, measuring 210 and 80 msec, respectively. The lowest rate of right atria1 pacing causing Wenckebach type of conduction block (so-called Wenckebach point) was lOO/min. The AV nodal functional refractory period was prolonged to 520 msec, whereas the AV nodal effective refractory period was within norma limits at 320 msec.
disturbances
{left) and paroxysmal ventricular
From these observations, case No. 2 appeared to have a diffuse conduction system disease, involving both the AV node and the intraventricular conducting system (especially the left posterior fascicle). Case No. 3. Fig. 6 shows a 12-lead gCG of the younger brother. There is a sinus bradycardia at the rate of 53/min. The PR interval measures 0.24 second, showing firstdegree AV block. A frontal QRS axis of -50 degrees suggests left anterior fascicular block. The His bundle electrogram reproduced in Fig. 3, bottom, reveals normal PA and AH intervals of 25 and 140 msec, respectively. The HV interval is prolonged to 75 msec. Other electrophysiologic parameters were mostly within normal limits (Table I). These findings suggest that, in this case, the AV nodal function is normal, whereas His-Purkinje conduction is depressed, especially in the left anterior fascicle. DISCUSSION
When myotonia and atrophy of the skeletal muscle in the face, neck, and extremities are accompanied by a cataract, frontal baldness, and gonadal atrophy, myotonic dystrophy can be diagnosed easily. It is said, however, that the development of these pathognomonic symptoms is often preceded by myocardial involvement,lv K s*6vv lg and that the latter may very well explain the occurrence of sudden death in certain patients afllicted with this disease.m Thus, identification of cardiac lesions may aid in earlier diagnosis of myotonic dystrophy on one
88
Hiromasa
et al.
HRA HBE
Fig. 3. His bundle electrograms recorded in the presence of a normal sinus rhythm from case No. 1 (top), case No. 2 (middle), and case No. 3 (bottom). RV = right ventricular LV = left ventricular electrogram; electrogram; HRA = high right atrial electrogram; HBE = His bundle electrogram; A = atrial deflection; H = His bundle deflection; V = ventricular deflection.
hand, and provide us with a clue in assessing its prognosis on the other. Such myocardial involvement would manifest itself either as a mechanical derangement (e.g., congestive heart failure) or as an electrical abnormality (ECG changes). Based on their observation of 29 cases, Grndahl et al4 stated that the incidence of mechanical derangement was rather low (7 % ), whereas the incidence of electrical abnormalities was much higher (68%). In the present family, no one has so far developed heart failure, although four out of five siblings have mitral vaIve prolapse. Whether the latter is etiologically related to myotonic dystrophy is still uncertain,
American
January, 1996 Heart Journal
despite a report suggesting this possibility.1c The high incidence of this condition in the present family may partly be attributed to the routine use of noninvasive, echocardiographic studies in recent years. Regarding electrical derangements, three out of the four members of this family showed ECG abnormalities. According to a review of existing literature by Church: ECG abnormalities were noted in 202 out of 236 cases, but only 45 of 269 cases had subjective symptoms related to the cardiovascular system. Similarly, of our three cases, only one (case No. 1) developed palpitation, while the other two were asymptomatic from the cardiovascular standpoint. The prolonged HV intervals in these three cases, ranging from 70 to 80 msec, suggest a generalized depression of conduction in all the fascicles of the intraventricular conducting system. Indeed, case No. 2 showed left posterior fascicular block, and case No. 3, left anterior fascicular block. Case No. 2 had an additional conduction disturbance in the AV node, as evidenced by the occurrence of intermittent second-degree intranodal block and the prolonged functional refractory period. These observations are in keeping with the available literature. For instance, Komajda et all3 reported that in 12 cases of myotonic dystrophy, conduction disorder was noted within the AV node in two, in the main His bundle in three, and below the His bundle in nine. High-grade or third-degree AV block has been reported in rare instances.5,g, l8 Of the numerous factors known to adversely afIect AV conduction,21 serum electrolytes and blood pH levels were all within normal limits in the present cases. With regard to the presence of ischemic heart disease, coronary cineangiography was not carried out. However, both resting and exercise ECGs were devoid of ischemic ST-T changes. Furthermore, it has been reported that the degree of coronary atherosclerosis in patients with myotonic dystrophy is not different from that in age- and sex-matched control subjects4 Thus the possibility of intraventricular conduction disorder resulting from ischemic heart disease appears remote. Based on these considerations, the AV and intraventricular conduction disturbances observed in the present cases are most likely due to a direct involvement of the specialized conducting system by the dystrophic process. On light microscopic examination, the cardiac tissue from cases of myotonic dystrophy usually shows nonspecific histologic changes including irreguhrrities in cell size: hypertrophy,17*zo fiber disarray?14 uneven nuclei: increased interstitial fibrosis,17* z”and interstitial fatty infiltration.l? Electron microscopic
volume 111 Number 1
Conduction
disturbances
in rnyotonic
dystrophy
09
Case 1
Fig. 4. Paroxysmal ventricular tachycardia induced by programmed stimulation of the right ventricle. Basic cycle length (S&) was 600 msec, and the coupling intervals of paired extrastimuli (SISz and S$&) were 300 msec. other abbreviations are identical to those in Fig. 3.
Sf3i.6.29 Fig. 5. A 1%lead ECG (top) and a lead II record (bottom) from atrioventricular block of the Wenckebach variety and an atrioventricular noted.
studies have often revealed various abnormalities, even in those hearts showing no significant changes on light microscopy. I7 For instance, irregularity, indistinctness, and partial loss of the sarcolemma,22 degeneration of the myofibril, swelling and degeneration of the mitochondria? l7 and marked vacuolation of the sarcoplasmic reticulum22 have been observed. Although not directly demonstrated by endomyocardial biopsy in the present cases, these histopathologic changes would damage the ionic channels of the sarcolemma, increase the intracellular resistivity, and impair cell-to-cell electrical coupling, thereby causing those electrophysiologic abnormaIities described above.
case No. junctional
2. A second-degree escape rhythm are
According to the literature, cardiac rhythm disturbances often observed in myotonic dystrophy include sinus bradycardia, sick sinus syndrome, atrial tachycardia, atrial flutter or fibrillation, and ventricular premature systoles.5s 14sI792oThe incidence of ventricular tachycardia and fibrillation, however, is said to be low, and Church5 found only one case of each in the 236 patients having this disease. In the present family, cases No. 2 and 3 showed sinus bradycardia, and sick sinus syndrome cannot be definitely ruled out by the presence of normal sinus node recovery time alone. Further studies should be done for a final diagnosis. The attacks of paroxysmal ventricular tachycardia noted in case No. 1 were
90
Hiromasa
--
..-
et al.
...
..-.
-2-J..
American
-.
aR VM .-- ~..--..-..-.-.-A......-!
---.
Fig.
6.
A 12-lead
ECG from case No. 3.
January< 1986 lieart Journal
conducting system in a father and son. Recently, Hawley et al.18 studied 30 patients with myotonic dystrophy and 17 unaffected family members in a total of 18 families, by noninvasive His bundle recording. They reported that if one patient with myotonic dystrophy was found to have heart block or arrhythmia, it should be expected in other members of his family afllicted with this disease.18 A similarly high incidence of conduction disturbances and abnormal impulse formation was found in the present family. For instance, paroxysmal ventricular tachycardia was noted in the eldest son (case No. l), who had the longest duration of this disease, or 24 years. This case, however, had only a mild intraventricular conduction delay without showing patterns of bundle branch or fascicular block. On the other hand, his sister (case No. 2), having the shortest duration of the disease (9 years), showed the most marked conduction disorder, with second-degree intra-AV nodal block and left posterior fascicular block. These observations indicate that AV and intraventricular conduction disturbances due to the dystrophic lesions involving the cardiac tissue may not progress linearly with time. A similar finding was reported by Hawley et al.,18 who concluded that the HV interval was not correlated with the duration of myotonic dystrophy. Likewise, the extent of the skeletal muscle symptoms was similar in the three present cases, despite the marked differences in the duration of this disease. Finally, the youngest daughter has so far not shown any signs of myotonic dystrophy and has a normal ECG, although she too has mitral valve prolapse. A close observation of this patient appears mandatory to detect possible development of this disease in the future. REFERENCES
considered to arise from the right ventricle. It is quite possible that the various pathophysiologic changes mentioned above sufficiently depressed conduction in the right bundle branch system to produce an area of unidirectional block and a reentry circuit. Although mitral valve prolapse was noted in all the present cases-and it is known that this condition is often accompanied by ventricular arrhythmias-the possibility of mitral valve prolapse playing a role in generating ventricular tachycardia in case No. 1 is considered remote, as the tachycardia apparently originated in the right bundle branch system. Regarding clinical electrophysiologic studies carried out on two or more members of a family afbicted with myotonic dystrophy, Josephson et al? found extensive conduction disturbances in the AV
1. Kohn NN, Faires JS, Rodman T: Unusual manifestations due to involvement of involuntary muscle in dystrophia myotonica. N Engl J Med 271:1179, 1964. JC: Electrocardiographic abnormali2. Payne CA, Greenfield ties associated with myotonic dystrophy. AM HEART J 65:436, 1963. Griffith TW: On myotonia. Q J Med 5:229, 1912. Grndahl G, Thulesius 0, Enestrom S, Dehlin 0: The heart in myotonic disease. Acta Med Stand 176:479, 1964. Church SC: The heart in myotonia atrophica. Arch Intern Med 119:176, 1967. Uemura N, Tanaka H, Niimura T, Hashiguchi N, Yoshimura M, Terashi S, Kanehisa Tz Electrophysiological and histological abnormalities of the heart in myotonic dystrophy. AM HEART J 66:616, 1973. ME, Caracta AR, Gallagher JJ, Damato AN: Site 7. Josephson of conduction disturbances in a family with myotonic dystrophy. Am J Cardiol 32:114, 1973. 8. Griggs RC, Davis RJ, Anderson DC, Dove JTz Cardiac conduction in myotonic dystrophy. Am J Med 59:37, 1975. SD, Colmers RA, Hurst JW: Myotonia dystrophica: 9. Clementa Ventricular arrhythmias, intraventricular conduction abnor-
"d"nw Ill Number 1
10. 11. 12.
13.
14.
15.
Conduction
malities, atrioventricular block and Stokes-Adams attacks successfully treated with permanent transvenous pacemaker. Am J Cardiol 37:933, 1976. Litchfield JA: A-V dissociation in dystrophia myotonica. Br Heart J 15:375, 1953. Roberts NK, Cabeen WR, Perloff JK: The cardiac disease of myotonic muscular dystrophy. Am J Cardiol 47:421, 1981. Prvstowskv ELC. Roses AD, Galla!zher J: The - EN. Pritchett natural history of conduction system disease in myotonic muscular dystrophy as determined by serial electrophysiologic studies. Circulation 60:1360, 1979. Komajda M, Frank R, Vedel J, Fontaine G, Petitot JC, Grosgogeat Y: Intracardiac conduction defects in dystrophia myo&ica. Br Heart J 43:315, 1980. Atarashi H. Saito H. Aoki H. Havakawa H: A case of myotonic dystrophy associated with sick sinus syndrome. Jpn Circ J 45:763, 1981. Gottdiener JS, Hawley RJ, Gay JA, DiBianco R, Fletcher RD, Engel WK: Left ventricular relaxation, mitral valve prolapse, and intracardiac conduction in myotonia atrophica. AM HEART J 104:77, 1982.
disturbances
in myotonic
dystrophy
16. Cannon PJz The heart and lungs in myotonic muscular dystrophy. Am J Med 32:765, 1962. 17. Motta J, Guilleminault C, Billingham M, Barry W, Mason Jz Cardiac abnormalities in myotonic dystrophy. Am J Med 67:467, 1979. 18. Hawley RJ, Gottdiener JS, Gay JA, Engel WK: Families with myotonic dystrophy with and without cardiac involvement. Arch Intern Med 143:2134, 1983. 19. Petkovich NJ, Dunn M, Reed W: Myotonia dystrophica with A-V dissociation and Stokes-Adams attacks. AM HEART J 68:391,
1964.
Fisch C, Evans Pw The heart in dystrophia myotonica: Report of an autopsied case. N Engl J Med 251:527, 1954. 21. Watanabe Y, Nishimura M Atrioventricular conduction disturbance. Membr 7:184, 1982. 22. Bulloch RT, Davis JL, Hara Mz Dystrophia myotonica with heart block. A light and electron microscopic study. Arch Path01 84:130, 1967. 23. Wei JY, Bulkley BH, Schaeffer AH, Greehe HL, Reid PR Mitral valve prolapse syndrome and recurrent ventricular tachyarrhythmias. Ann Intern Med 89:6, 1978. 20.
HLA-DR3 antigen linkage in patients with hypertrophic obstructive cardiomyopathy In order to investigate if genetic factors could be involved in the pathogenesis of hypertrophic obstructive cardiomyopathy, we determined HLA-A, HLA-B, HLA-C, and HLA-DR specificities in 12 Italian patients affected with the disease and in healthy family members of one of them. HLA-DR3 was found in 50% of patients as compared to 17.1% of normal control subjects (p = 0.023, relative risk = 4.82)The two relatives also had HLA-DR3 antigen and, in addition, showed equivocal signs of hypertrophy at echocardiographic examination. Thus hypertrophic obstructive cardiomyopathy is associated with genes in the HLA-DR region, and immunogenetic factors could be involved in the pathogenesis of the disease. Furthermore, the minimal target organ abnormalities in “healthy” relatives could represent a subclinical stage of the disease. (AM HEART J 111:91, 1986.)
Silvana Fiorito, Maria Purpura,
M.D., Camille Autore, M.D., Pier Vincenzo Fragola, M.D., M.D.,* Asst. Prof. Dario Cannata,** and Prof. Mario Sangiorgi.**
Rome, Italy
Hypertrophic cardiomyopathy (HCM) is a disorder of heart muscle of unknown origin that is classified into two subtypes: an obstructive form (HOCM) and a nonobstructive one (HNCM). Previous studies
From
Ca&dra
V Pat&gia
Medica,
Universiti
di Roma “La
*Centro N&on& Trasfwione Sangue (C.R.1.); **Diparhnento ina Interna, II Universit& di Roma “Tar Vergata.” Received
for publication
Reprint Umberto
requesk Silvana Fiorito, I, 00161 Rome, Italy.
June
10, 1985; accepted M.D.,
Sapienza”; di Medic-
July 3, 1985.
I Clinica
Medica,
Policlinico
have reported that HCM is often familial and an autosomal dominant pattern of inheritance has been well documented, mainly in the obstructive form of the disease. In order to investigate if genetic factors could be involved in the pathogenesis of HCM, several studies have been performed in recent years to examine human major histocompatibility complex in patients &e&d with the disease. Hi&compatibility leukocyte-antigens (HLA) typing revealed no significant differences in frequencies of HLA class I antigens (A, B, and C) 91
as
In a family with myotonic dystrophy, three siblings showing ECG abnormalities were subjected to His bundle ECG studies. The duration of the disease ranged from 9 to 24 yearsAll three siblings had prolonged HV intervals (His-Purkinje conduction times) of 70 to 80 msec The sister with the shortest duration of the disease had second-degree atrioventricular (AV) nodal block as well as left posterior fascicular block, the younger brother had left anterior fascicular block, and the elder brother with the longest history had first-degree AV block without bundle branch or fascicular block. With regard to associated arrhythmias, however, the elder brother developed paroxysmal ventricular tachycardia, apparently due to reentry involving the right bundle branch system, whereas the younger brother and sister had sinus bradycardia alone. This study reveals the prevalence of diffuse conduction disturbances of the specialized conducting system in a family with myotonic dystrophy. (AM HEART J 111:85, 1988.)
Shuichi Hiromasa, M.D., Takayuki Ikeda, M.D., Kouji Kubota, M.D., Shigeo Takata, M.D., Nobu Hattori, M.D., Masao Nishimura, M.D.,* and Yoahio Watanabe, M.D.* Kunuzuwa, Ishikawa, Japan
Myotonic dystrophy is a neuromuscular disease with autosomal dominant transmission. Although this disease is characterized by rigidity and degeneration of the skeletal muscle, it is often accompanied by functional and anatomic derangements in the myocardium.1-3 Since such cardiac lesions tend to involve the specialized conducting system, development of abnormal impulse formation and conduction is frequent.z-16 Since the introduction of His bundle electrography in man, numerous investigators have carried out detailed studies on such conduction abnormalities.6-6v lz-14s l7 Regarding clinical electrophysiologic studies on a family afllicted with this hereditary disease, however, only two reports have so far been published; by Josephson et al.,7 who studied a father and son; and by Hawley et al.,18 who studied 30 patients with myotonic dystrophy and 17 From the First Medicine. Received accepted
Department
for publication July 15, 1985.
of Medicine, March
Kanazawa
6, 1985; revision
Reprint requests: Shuichi Hiromasa, M.D., The Medicine, Kanamwa University School of Medicine, 920, Japan. *Cardiovascular Toyoake, Aichi,
Institute, Japan.
Fujita
Gakwn
University
University received
School
June
of
18, 198&
First Department of Kanazawa, Ishikawa School
of Medicine,
unaffected family members in a total of 18 families with noninvasive His bundle recording. Hence, in this paper, we will present the results of His bundle electrographic studies of three siblings with this disease who showed various ECG abnormalities. METHODSAND
RESULTS
As shown in Fig. 1, the diagnosis of myotonic dystrophy was made on three members of this family. The proband or case No. 1 (K.K., a 42-year-old man) was the second son; case No. 2 (T.K., a 41-year-old woman) was the eldest daughter; and case No. 3 (S.K., a 38-year-old man) was the third son. It is not known whether any of their parents or grandparents were afllicted with this disease, and the cause of deaths of these individuaIs also could not be clearly identified. The eldest son is said to be in good health, but has not been studied for the presence or absence of this disease. The second daughter had no signs of myotonic dystrophy in the skeletal muscle, and her ECG was normal although echocardiographic studies revealed the presence of mitral valve prolapse. Rigidity and atrophy of the facial and thenar muscles were first noted subjectively at the age of 18 years in case No. 1, at 32 years in case No. 2, and at 28 years in case No. 3, respectively, but the patients did not seek medical advice for this problem. Approximately 1 year prior to his first visit to Kanaxawa University Hospital, case No. 1 started to experience
a5
86
Hiromasa
et al.
American
Pedigree
Table
I. Electrophysiologic Case
q
=Male 0 =Femde I-@ -Myotonic $Mitral
Dystrophy Valve Prolapse
/ =Deceased
Fig. 1. Pedigree of the present family with myotonic dystrophy. The question mark indicates lack of information regarding the presence or absence of this disease.
attacks of palpitation at an average frequency of once a week. These episodes often lasted up to 30 minutes, and both their onset and termination were sudden, as was clearly noted by the patient. Because of the progressively aggravating nature of such attacks, he came to the hospital in August, 1980. On physical examination, the patient presented with the so-called myotonic face, with clear atrophy of muscle of the neck, face, temporal region, and jaws. Grip myotonia of the thenar muscles, percussion myotonia of the tongue, and other associated symptoms (including a cataract, frontal baldness, and testicular atrophy) all led to the diagnosis of myotonic dystrophy. Inquiries into his family history brought to our attention his younger brother and sister, who were subsequently diagnosed as having the same disease. Echocardiographic examinations revealed the presence of mitral valve prolapse in all three. Since their ECGs showed various abnormalities, clinical electrophysiologic studies using His bundle electrography were performed after obtaining informed consent from each patient. All studies were performed with the patients in the nonsedated, postabsorptive state. Three to four multipolar electrode catheters (interpolar distance, 10 mm) were introduced percutaneously and were positioned in the heart under fluoroscopic guidance at the high right atrium, His bundle, and right ventricular apex and, in case No. 1, at the left ventricular apex as well, to record the potentials of the high and low right atrium, His bundle, and right and left ventricles. The stimulation protocol included incremental high right atrial, left and right ventricular pacing, and programmed atrial and ventricular premature stimulation in sinus rhythm and at one or more drive cycle lengths. In order to induce the ventricular tachycardia, paired extrastimuli with coupling intervals of ZOO to 400 msec were introduced during basic ventricular pacing. Case No. 1. The 12-lead ECG made on the patient’s first visit (August 16, 1980) is reproduced in Fig. 2, Zeft, which demonstrates a normal sinus rhythm. There was firstdegree atrioventricular (AV) block with a PR interval of 0.22 second. Fig. 2, right, shows the ECG recorded during an attack of palpitation on September 3,198O. A tachycardia at the rate of 1Wmin is present, with wide QRS complexes of left bundle branch block configuration.
no.
Age W Age of onset (yr) A-A (600-1000 msec)* SACT (50-125 msec) SRT (<1400 msec) PA (20-55 msec) AH (50-140 msec) HV (35-55 msec) Wenckebach point (<140 bpm) At-ERP (170-300 msec) At-FRP (180.330 msec) AVN-ERP (230-390 msec) AVN-FRP (330-500 msec) V-ERP (170-290 msec) V-FRP (170-290 msec) AV block Fascicular block VT
findings
Jm~.wy, 1986 Heart Journal
of three siblings 1
2
3
42 18 896 117 1310 25 130 70 133
41 32 650 85 1020 20 210 80 100
38 28 660 105 1050 25 140 75 130
360 380 380 500 240 270 lo -
230 280 320 520 210 240 2O LP
240 260 330 450 190 230
+
-
-
-
lo
LA
A-A = spontaneous sinus cycle length SACT = sinoatrial conduction time; SRT = sinus node recovery time; PA = intra-atria1 conduction time; AH = intranodal conduction time; HV = His-Purkinje conduction time; At = atrial; AVN = atriaventricular nodak V = ventricular; ERP = effective refractory period; FRP = functional refractory period; AV = atrioventricular; LP = left posterior; LA = left anterior; VT = ventricular tachycardia. *Numbers in parentheses indicate normal values.
Although the atrial activity cannot be clearly identified, apparent presence of AV dissociation with occasional normalization of the QRS, possibly due to ventricular capture by sinus impulses (e.g., beat 1 in lead VJ, suggests a ventricular tachycardia originating in the right ventricle. On the His bundle electrogram (Fig. 3), the PA interval (or the intra-atria1 conduction time) measured 25 msec, and the AH interval (or the intranodal conduction time) measured 130 msec, both being within normal limits. The HV interval (or the His-Purkinje conduction time) was, however, prolonged to 70 msec, indicating that the firstdegree AV block observed resulted from a depressed His-Purkinje conduction. Other variables obtained by the His bundle recording are summarized in Table I. It is noted that both the effective and functional refractory periods of the atria were prolonged, whereas the AV nodal and ventricular refractory periods were within normal limts. In order to confirm the diagnosis of paroxysmal ventricular tachycardia, provocation of tachycardia with right ventricular stimulation was attempted. In Fig. 4, the right ventricular apex was initially driven at a basic cycle length of 600 msec for seven beats (S), followed by paired extrastimuli (&, SJ, with coupling intervals of 300 msec. This resulted in a successful induction of tachycardia with a QRS configuration similar to that during the spontaneous attack, as was shown in Fig. 2, right. Although the R-R interval manifested some fluctuations during the tachycardia, the ventricular rate was approximately 26O/min.
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87
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S5!56.16 Fig. 2. Twelve-lead ECGs of case No. 1 during sinus rhythm tachycardia (right).
There was AV dissociation, with an atria1 rate of 68/min. Since the excitation of the right ventricular apex preceded that of the left ventricular apex by 70 to 80 msec, right ventricular origin of this tachycardia was substantiated. On the His bundle recording, t.he H deflection became identifiable in the middle portion of Fig. 4, following right ventricular apical activation by approximately 30 msec. In the last two beats, however, the H spike almost coincided with the apical electrogram. Hence, this tachycardia may have originated from the proximal right bundle branch region. As the tachycardia, was both induced and terminated (not shown) by premature ventricular stimulation, reentry appears to be a likely mechanism, Case No. 2. A 12-lead ECG of this patient reproduced in Fig. 5 reveals sinus bradycardia at the rate of 47lmin, with second-degree AV block of type 1 variety causing occasional appearance of an AV junctional escape beat. The presence of right axis deviation (QRS axis = +130 degrees) suggests the possibility of left posterior fascicular block. Low voltage QRS complexes are noted in the precordial leads. During the clinical electrophysiologic studies, there was only first-degree AV block (Fig. 3, middle row). The PA interval was normal at 20 msec, whereas the AH and HV intervals were both abnormally prolonged, measuring 210 and 80 msec, respectively. The lowest rate of right atria1 pacing causing Wenckebach type of conduction block (so-called Wenckebach point) was lOO/min. The AV nodal functional refractory period was prolonged to 520 msec, whereas the AV nodal effective refractory period was within norma limits at 320 msec.
disturbances
{left) and paroxysmal ventricular
From these observations, case No. 2 appeared to have a diffuse conduction system disease, involving both the AV node and the intraventricular conducting system (especially the left posterior fascicle). Case No. 3. Fig. 6 shows a 12-lead gCG of the younger brother. There is a sinus bradycardia at the rate of 53/min. The PR interval measures 0.24 second, showing firstdegree AV block. A frontal QRS axis of -50 degrees suggests left anterior fascicular block. The His bundle electrogram reproduced in Fig. 3, bottom, reveals normal PA and AH intervals of 25 and 140 msec, respectively. The HV interval is prolonged to 75 msec. Other electrophysiologic parameters were mostly within normal limits (Table I). These findings suggest that, in this case, the AV nodal function is normal, whereas His-Purkinje conduction is depressed, especially in the left anterior fascicle. DISCUSSION
When myotonia and atrophy of the skeletal muscle in the face, neck, and extremities are accompanied by a cataract, frontal baldness, and gonadal atrophy, myotonic dystrophy can be diagnosed easily. It is said, however, that the development of these pathognomonic symptoms is often preceded by myocardial involvement,lv K s*6vv lg and that the latter may very well explain the occurrence of sudden death in certain patients afllicted with this disease.m Thus, identification of cardiac lesions may aid in earlier diagnosis of myotonic dystrophy on one
88
Hiromasa
et al.
HRA HBE
Fig. 3. His bundle electrograms recorded in the presence of a normal sinus rhythm from case No. 1 (top), case No. 2 (middle), and case No. 3 (bottom). RV = right ventricular LV = left ventricular electrogram; electrogram; HRA = high right atrial electrogram; HBE = His bundle electrogram; A = atrial deflection; H = His bundle deflection; V = ventricular deflection.
hand, and provide us with a clue in assessing its prognosis on the other. Such myocardial involvement would manifest itself either as a mechanical derangement (e.g., congestive heart failure) or as an electrical abnormality (ECG changes). Based on their observation of 29 cases, Grndahl et al4 stated that the incidence of mechanical derangement was rather low (7 % ), whereas the incidence of electrical abnormalities was much higher (68%). In the present family, no one has so far developed heart failure, although four out of five siblings have mitral vaIve prolapse. Whether the latter is etiologically related to myotonic dystrophy is still uncertain,
American
January, 1996 Heart Journal
despite a report suggesting this possibility.1c The high incidence of this condition in the present family may partly be attributed to the routine use of noninvasive, echocardiographic studies in recent years. Regarding electrical derangements, three out of the four members of this family showed ECG abnormalities. According to a review of existing literature by Church: ECG abnormalities were noted in 202 out of 236 cases, but only 45 of 269 cases had subjective symptoms related to the cardiovascular system. Similarly, of our three cases, only one (case No. 1) developed palpitation, while the other two were asymptomatic from the cardiovascular standpoint. The prolonged HV intervals in these three cases, ranging from 70 to 80 msec, suggest a generalized depression of conduction in all the fascicles of the intraventricular conducting system. Indeed, case No. 2 showed left posterior fascicular block, and case No. 3, left anterior fascicular block. Case No. 2 had an additional conduction disturbance in the AV node, as evidenced by the occurrence of intermittent second-degree intranodal block and the prolonged functional refractory period. These observations are in keeping with the available literature. For instance, Komajda et all3 reported that in 12 cases of myotonic dystrophy, conduction disorder was noted within the AV node in two, in the main His bundle in three, and below the His bundle in nine. High-grade or third-degree AV block has been reported in rare instances.5,g, l8 Of the numerous factors known to adversely afIect AV conduction,21 serum electrolytes and blood pH levels were all within normal limits in the present cases. With regard to the presence of ischemic heart disease, coronary cineangiography was not carried out. However, both resting and exercise ECGs were devoid of ischemic ST-T changes. Furthermore, it has been reported that the degree of coronary atherosclerosis in patients with myotonic dystrophy is not different from that in age- and sex-matched control subjects4 Thus the possibility of intraventricular conduction disorder resulting from ischemic heart disease appears remote. Based on these considerations, the AV and intraventricular conduction disturbances observed in the present cases are most likely due to a direct involvement of the specialized conducting system by the dystrophic process. On light microscopic examination, the cardiac tissue from cases of myotonic dystrophy usually shows nonspecific histologic changes including irreguhrrities in cell size: hypertrophy,17*zo fiber disarray?14 uneven nuclei: increased interstitial fibrosis,17* z”and interstitial fatty infiltration.l? Electron microscopic
volume 111 Number 1
Conduction
disturbances
in rnyotonic
dystrophy
09
Case 1
Fig. 4. Paroxysmal ventricular tachycardia induced by programmed stimulation of the right ventricle. Basic cycle length (S&) was 600 msec, and the coupling intervals of paired extrastimuli (SISz and S$&) were 300 msec. other abbreviations are identical to those in Fig. 3.
Sf3i.6.29 Fig. 5. A 1%lead ECG (top) and a lead II record (bottom) from atrioventricular block of the Wenckebach variety and an atrioventricular noted.
studies have often revealed various abnormalities, even in those hearts showing no significant changes on light microscopy. I7 For instance, irregularity, indistinctness, and partial loss of the sarcolemma,22 degeneration of the myofibril, swelling and degeneration of the mitochondria? l7 and marked vacuolation of the sarcoplasmic reticulum22 have been observed. Although not directly demonstrated by endomyocardial biopsy in the present cases, these histopathologic changes would damage the ionic channels of the sarcolemma, increase the intracellular resistivity, and impair cell-to-cell electrical coupling, thereby causing those electrophysiologic abnormaIities described above.
case No. junctional
2. A second-degree escape rhythm are
According to the literature, cardiac rhythm disturbances often observed in myotonic dystrophy include sinus bradycardia, sick sinus syndrome, atrial tachycardia, atrial flutter or fibrillation, and ventricular premature systoles.5s 14sI792oThe incidence of ventricular tachycardia and fibrillation, however, is said to be low, and Church5 found only one case of each in the 236 patients having this disease. In the present family, cases No. 2 and 3 showed sinus bradycardia, and sick sinus syndrome cannot be definitely ruled out by the presence of normal sinus node recovery time alone. Further studies should be done for a final diagnosis. The attacks of paroxysmal ventricular tachycardia noted in case No. 1 were
90
Hiromasa
--
..-
et al.
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..-.
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American
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aR VM .-- ~..--..-..-.-.-A......-!
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Fig.
6.
A 12-lead
ECG from case No. 3.
January< 1986 lieart Journal
conducting system in a father and son. Recently, Hawley et al.18 studied 30 patients with myotonic dystrophy and 17 unaffected family members in a total of 18 families, by noninvasive His bundle recording. They reported that if one patient with myotonic dystrophy was found to have heart block or arrhythmia, it should be expected in other members of his family afllicted with this disease.18 A similarly high incidence of conduction disturbances and abnormal impulse formation was found in the present family. For instance, paroxysmal ventricular tachycardia was noted in the eldest son (case No. l), who had the longest duration of this disease, or 24 years. This case, however, had only a mild intraventricular conduction delay without showing patterns of bundle branch or fascicular block. On the other hand, his sister (case No. 2), having the shortest duration of the disease (9 years), showed the most marked conduction disorder, with second-degree intra-AV nodal block and left posterior fascicular block. These observations indicate that AV and intraventricular conduction disturbances due to the dystrophic lesions involving the cardiac tissue may not progress linearly with time. A similar finding was reported by Hawley et al.,18 who concluded that the HV interval was not correlated with the duration of myotonic dystrophy. Likewise, the extent of the skeletal muscle symptoms was similar in the three present cases, despite the marked differences in the duration of this disease. Finally, the youngest daughter has so far not shown any signs of myotonic dystrophy and has a normal ECG, although she too has mitral valve prolapse. A close observation of this patient appears mandatory to detect possible development of this disease in the future. REFERENCES
considered to arise from the right ventricle. It is quite possible that the various pathophysiologic changes mentioned above sufficiently depressed conduction in the right bundle branch system to produce an area of unidirectional block and a reentry circuit. Although mitral valve prolapse was noted in all the present cases-and it is known that this condition is often accompanied by ventricular arrhythmias-the possibility of mitral valve prolapse playing a role in generating ventricular tachycardia in case No. 1 is considered remote, as the tachycardia apparently originated in the right bundle branch system. Regarding clinical electrophysiologic studies carried out on two or more members of a family afbicted with myotonic dystrophy, Josephson et al? found extensive conduction disturbances in the AV
1. Kohn NN, Faires JS, Rodman T: Unusual manifestations due to involvement of involuntary muscle in dystrophia myotonica. N Engl J Med 271:1179, 1964. JC: Electrocardiographic abnormali2. Payne CA, Greenfield ties associated with myotonic dystrophy. AM HEART J 65:436, 1963. Griffith TW: On myotonia. Q J Med 5:229, 1912. Grndahl G, Thulesius 0, Enestrom S, Dehlin 0: The heart in myotonic disease. Acta Med Stand 176:479, 1964. Church SC: The heart in myotonia atrophica. Arch Intern Med 119:176, 1967. Uemura N, Tanaka H, Niimura T, Hashiguchi N, Yoshimura M, Terashi S, Kanehisa Tz Electrophysiological and histological abnormalities of the heart in myotonic dystrophy. AM HEART J 66:616, 1973. ME, Caracta AR, Gallagher JJ, Damato AN: Site 7. Josephson of conduction disturbances in a family with myotonic dystrophy. Am J Cardiol 32:114, 1973. 8. Griggs RC, Davis RJ, Anderson DC, Dove JTz Cardiac conduction in myotonic dystrophy. Am J Med 59:37, 1975. SD, Colmers RA, Hurst JW: Myotonia dystrophica: 9. Clementa Ventricular arrhythmias, intraventricular conduction abnor-
"d"nw Ill Number 1
10. 11. 12.
13.
14.
15.
Conduction
malities, atrioventricular block and Stokes-Adams attacks successfully treated with permanent transvenous pacemaker. Am J Cardiol 37:933, 1976. Litchfield JA: A-V dissociation in dystrophia myotonica. Br Heart J 15:375, 1953. Roberts NK, Cabeen WR, Perloff JK: The cardiac disease of myotonic muscular dystrophy. Am J Cardiol 47:421, 1981. Prvstowskv ELC. Roses AD, Galla!zher J: The - EN. Pritchett natural history of conduction system disease in myotonic muscular dystrophy as determined by serial electrophysiologic studies. Circulation 60:1360, 1979. Komajda M, Frank R, Vedel J, Fontaine G, Petitot JC, Grosgogeat Y: Intracardiac conduction defects in dystrophia myo&ica. Br Heart J 43:315, 1980. Atarashi H. Saito H. Aoki H. Havakawa H: A case of myotonic dystrophy associated with sick sinus syndrome. Jpn Circ J 45:763, 1981. Gottdiener JS, Hawley RJ, Gay JA, DiBianco R, Fletcher RD, Engel WK: Left ventricular relaxation, mitral valve prolapse, and intracardiac conduction in myotonia atrophica. AM HEART J 104:77, 1982.
disturbances
in myotonic
dystrophy
16. Cannon PJz The heart and lungs in myotonic muscular dystrophy. Am J Med 32:765, 1962. 17. Motta J, Guilleminault C, Billingham M, Barry W, Mason Jz Cardiac abnormalities in myotonic dystrophy. Am J Med 67:467, 1979. 18. Hawley RJ, Gottdiener JS, Gay JA, Engel WK: Families with myotonic dystrophy with and without cardiac involvement. Arch Intern Med 143:2134, 1983. 19. Petkovich NJ, Dunn M, Reed W: Myotonia dystrophica with A-V dissociation and Stokes-Adams attacks. AM HEART J 68:391,
1964.
Fisch C, Evans Pw The heart in dystrophia myotonica: Report of an autopsied case. N Engl J Med 251:527, 1954. 21. Watanabe Y, Nishimura M Atrioventricular conduction disturbance. Membr 7:184, 1982. 22. Bulloch RT, Davis JL, Hara Mz Dystrophia myotonica with heart block. A light and electron microscopic study. Arch Path01 84:130, 1967. 23. Wei JY, Bulkley BH, Schaeffer AH, Greehe HL, Reid PR Mitral valve prolapse syndrome and recurrent ventricular tachyarrhythmias. Ann Intern Med 89:6, 1978. 20.
HLA-DR3 antigen linkage in patients with hypertrophic obstructive cardiomyopathy In order to investigate if genetic factors could be involved in the pathogenesis of hypertrophic obstructive cardiomyopathy, we determined HLA-A, HLA-B, HLA-C, and HLA-DR specificities in 12 Italian patients affected with the disease and in healthy family members of one of them. HLA-DR3 was found in 50% of patients as compared to 17.1% of normal control subjects (p = 0.023, relative risk = 4.82)The two relatives also had HLA-DR3 antigen and, in addition, showed equivocal signs of hypertrophy at echocardiographic examination. Thus hypertrophic obstructive cardiomyopathy is associated with genes in the HLA-DR region, and immunogenetic factors could be involved in the pathogenesis of the disease. Furthermore, the minimal target organ abnormalities in “healthy” relatives could represent a subclinical stage of the disease. (AM HEART J 111:91, 1986.)
Silvana Fiorito, Maria Purpura,
M.D., Camille Autore, M.D., Pier Vincenzo Fragola, M.D., M.D.,* Asst. Prof. Dario Cannata,** and Prof. Mario Sangiorgi.**
Rome, Italy
Hypertrophic cardiomyopathy (HCM) is a disorder of heart muscle of unknown origin that is classified into two subtypes: an obstructive form (HOCM) and a nonobstructive one (HNCM). Previous studies
From
Ca&dra
V Pat&gia
Medica,
Universiti
di Roma “La
*Centro N&on& Trasfwione Sangue (C.R.1.); **Diparhnento ina Interna, II Universit& di Roma “Tar Vergata.” Received
for publication
Reprint Umberto
requesk Silvana Fiorito, I, 00161 Rome, Italy.
June
10, 1985; accepted M.D.,
Sapienza”; di Medic-
July 3, 1985.
I Clinica
Medica,
Policlinico
have reported that HCM is often familial and an autosomal dominant pattern of inheritance has been well documented, mainly in the obstructive form of the disease. In order to investigate if genetic factors could be involved in the pathogenesis of HCM, several studies have been performed in recent years to examine human major histocompatibility complex in patients &e&d with the disease. Hi&compatibility leukocyte-antigens (HLA) typing revealed no significant differences in frequencies of HLA class I antigens (A, B, and C) 91