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The anatomic substrate for the sick sinus syndrome in adolescence
CASE REPORTS
The Anatomic Substrate for the Sick Sinus Syndrome in Adolescence
SAROJA AARON ROBERT
BHARATI,
MD,
NORDENBERG, BAUERNFIEND,
FACC MD,
FACC
MD
MD, FACC ARNALDO G. CARVALHO, MD, FACC KENNETH ROSEN, MD, FACC MAURICE LEV, MD, FACC’
JACOB
P. VARGHESE,
Chicago, Illinois
From the Congenital Heart Disease Research and Training Center, Hektoen Institute for Medical Research, Chicago, Illinois; the Department of Pathology, Northwestern University Medical School, Evanston, Illinois; the Pritzker School of Medicine, University of Chicago; the Chicago Medical School, University of Health Sciences; Loyola University, Stritch School of Medicine; the Section of Cardiology, Department of Medicine and the Department of Pathology, Abraham Lincoln School of Medicine, University of Illinois; and the Departments of Pediatrics, Medicine and Pathology, Rush Medical College, Chicago, Illinois; the Department of Medicine of the Johns Hopkins Hospital, Baltimore, Maryland; and the Polyclinic Medical Center, Harrisburg, Pennsylvania. This work was supported by Grants HL 0760516, HL 16794 and HL 23566 and Training Grant 07387 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received January 15, 1980, accepted February 1, 1980. ’ Career Investigator and Educator, Chicago Heart Association, Chicago, Illinois. Address for reprints: Saroja Bharati, MD, Congenital Heart Disease Research and Training Center, Hektoen Institute for Medical Research, 637 South Wood Street, Chicago, Illinois 60612.
This is a study of the conduction system of two adolescent boys, one 16 and the other 17 years of age, who had prolonged unexptalned sinus nodal dysfunction. The first patient had sinus pauses up to 2.5 seconds in duration, absence of persistent sinus bradycardia and prolonged sinus nodal recovery time of 3,451 ms. He died suddenly. Pathologic study of the conduction system revealed degeneration and fibrosis of the approaches to the sinoatrial (S-A) and atrioventrlcular (A-V) nodes and the atrial preferential pathways. The second patient had a 1 year history of persistent sinus bradycardia (30 to 60 beats/min) and prolonged slnus nodal recovery time of 3,725 ms. He died of acute viral hepatitis. Pathologic study of the conduction system revealed fatty inflttration of the approaches to the S-A and A-V nodes and the atrial preferential pathways. In summary, the approaches to the S-A and A-V nodes and the atrial preferential pathways were altered by fibrosis in Case 1 and by fatty infiltration in Case 2, both of unknown origin. The S-A node itself was not significantly involved in either case.
The sick sinus syndrome is usually encountered in the elderly. However, recent reports describe sinus nodal dysfunction in children and adolescents.l-l2 This dysfunction often complicates surgical correction of congenital heart .disease. 13,14In the latter instance, pathologic examination may reveal surgical trauma to the sinoatrial (S-A) node or internodal pathways. The idiopathic sick sinus syndrome is relatively rare in children and adolescents and there have been no previous pathologic reports concerning the anatomic substrate of this disorder. In this report, we describe the findings in two adolescent boys with electrophysiologically documented sinus nodal dysfunction. Both boys subsequently died (one suddenly), allowing an opportunity for pathologic examination of the heart. In both cases, serial section of the conduction system demonstrated a pathologic substrate for the occurrence of the sick sinus syndrome. Case Reports Case 1 This boy had a harsh systolic murmur at birth and at age 11 months underwent
cardiac catheterization, which revealed a left to right shunt at the ventricular level. By the time the boy was 6 years old, the murmur was no longer audible and at age 13 a second cardiac catheterization revealed no abnormalities. The patient was asymptomatic except for a single brief syncopal episode, associated with convulsions, at age 5 years. At age 13, the boy was referred to the Johns Hopkins Hospital for evaluation of bradyarrhythmias. After that time, he failed to keep his medical appointments, but was reported to have pulse rates of 70 to 90 beats/min during school examinations. He died suddenly at age 16.
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“I “6 FIGURE 1. Case 1. Leads I, II, Ill, VI and Vg from resting electrocardiogram taken at age 13. Short runs of supraventricular tachycardia (probably multifocal atrial tachycardia) are followed by pauses of 1.5 to 1.7 seconds terminated by junctional escape beats. Left axis deviation is also evident.
Review of electrocardiographic and electrophysiologic data: Right ventricular hypertrophy was demonstrated on
electrocardiograms taken prior to age 4 l/2 years. At age 2 years, sinus tachycardia, interrupted by sinus pauses of 1.3 to 1.4 seconds, was evident. Electrocardiograms taken at 7 l/2 and 8 l/2 years showed normal sinus rhythm. At age 13, the following were noted: brief runs of supraventricular tachycardia, followed by pauses of 1.5 to 1.7 seconds, terminated by junctional escape beats (Fig. 1 and 2) with rates of 40 to 50 beats/min. At age 14 years, the patient undcmcent electrophysiologic studies. These revealed a junctional escape rhythm (cycle
length 1,040 ms) that controlled
both the atria and the ven-
tricles (H-V interval 40 ms). The sinoatrial recovery time, determined by atria1 pacing, was 3,780 ms (Fig. 2). After administration of 0.8 mg of atropine, the cycle length of the junctional rhythm decreased to 585 ms and the sinoatrial recovery time to 940 ms (Fig. 2). Postmortem findings: The pathologic diagnoses, excluding the findings in the heart, were (1) acute passive congestion of the visceral organs, and (2) abnormal origin of the right subclavian artery (originating distal to the left subclavian artery), which coursed in front of the trachea to the right side. Heart: gross examination: The heart was enlarged and weighed 325 g. All chambers were hypertrophied and enlarged. The internal architecture of the right atrium was abnormal (Fig. 3). There was no sharp line of demarcation between the sinus venarum receiving the superior vena cava and the right atria1 appendage. The ventricular septum at its base presented a small ventricular septal defect measuring 1 mm in greatest dimension. This defect was situated beneath the junction of the right and posterior aortic cusps and opened into the right side at the junction of the right atrium and ventricle in an area devoid of tricuspid valve tissue. On the left ventricular side it was surrounded by thickened endocardium. The aortic valve consisted of three cusps with a slight separation of the cusps at the commissures. Microscopic examination: methods: The S-A and atrioventricular (A-V) nodes and their approaches, the A-V bundle and bundle branches up to the muscle of Lancisi were serially sectioned and every fifth section was retained. The remainder of the bundle branches up to the region of the moderator band were serially sectioned and every 10th section was retained. These were consecutively stained with hematoxylin-eosin. Weigert-van Gieson and Gomori trichrome stains. The atria1 preferential pathways were serially sectioned and every 20th section was retained. The remainder of the heart was cut into blocks and two sections were taken from each block. The atrial preferential pathways and the remainder of the heart were alternately stained with hematoxylin-eosin and Weigert-van Gieson stains. in this manner 898 sections were studied. This manner of examination of the heart has previously been reported.15J6
FIGURE 2. Case 1. Determination of sinoatrial recovery times (SART) by atrial pacing. Shown in each panel are electrocardiographic lead II (L2) and high right atrial (HRA) and His bundle (HBE) electrograms. Time (T) spikes (bottom of each panel) are at 10 ms intervals. Before administration of atropine (top panel) the sinoatrial recovery time was 3,780 ms; after administration of 0.8 mg of atropine (bottom panel), it was 940 ms. Cl = cycle length.
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Conduction system: S-A node: There was a slight increase in connective tissue in the lower part of the node (Fig. 4, top) with a slight infiltration of mononuclear cells. An occasional arteriole was thickened. The epicardium likewise showed a slight mononuclear cell infiltration. The S-A nodal artery showed no changes. Approaches to the S-A node: All of the approaches had enlarged cells, which were pale-staining and somewhat vacuolated. There was a diffuse marked increase of connective tissue at the lower pole of the S-A node, focally in the upper pole (Fig. 4, bottom) and in general in the transitional zone with the atria. Atria1 preferential pathways: Diffuse fibrosis of the anterior, middle and inferior preferential pathways was seen (Fig. 5, left) with marked swelling and vacuolization of the cells. The S-A nodal artery arose from the left circumflex artery and showed no changes. Approaches to the A-V node: These cells were markedly swollen with diffuse fibrosis (Fig. 5, right). In addition there was occasional infiltration of mononuclear cells. The sinusoids and lymphatics were dilated. A-V node: Moderate fibrosis with focal eosinophilia of cells was present. A-V bundle, penetrating: This was markedly septated (Fig. 6, left). Swelling in some cells with pale cytoplasm and vacuolization were noted. Branching bundle: This again was markedly septated with marked vacuolization of the cells of the left side. Minimal fibrosis was also present. Left bundle branch: The cells showed increased vacuolization. There was moderate fibrosis, which increased more distally. The left bundle branch was disrupted at the bifurcation (Fig. 6, right) with vacuolization of the remaining cells. These findings were more evident in the anterior than in the posterior radiation. Right bundle branch: Increased vacuolization of cells was noted, and moderate fibrosis was seen in the region of the closing ventricular septal defect. More distally, there was slight fibrosis. Peripheral Purkinje cells: Moderate fibrosis was present on both sides. Vacuolar degeneration of the Purkinje cells with focal mononuclear and neutrophilic infiltration was present on the left side.
ET AL.
(1.3 mg/ml), but endocrinologic investigations and hepatic enzyme levels were normal. Electrophysiologic studies were performed at St. John’s Hospital, Springfield, Illinois at this time (see later). The patient was treated with corticosteroids and sublingual isoproterenol and his symptoms were alleviated despite persistence of bradycardia. Nine months later, he presented with hepatitis (hepatitis B surface antigenpositive). He lapsed into hepatic coma and died. Electrocardiographic and electrophysiologic data: Electrocardiograms at rest revealed left axis deviation, low voltage in the limb leads and marked sinus bradycardia (30 to 32 beata/min) (Fig. 7). After administration of atropine, 0.02 mg/kg, and propranolol, 0.1 mg/kg, intrinsic heart rate was slower than normal at 74 beats/min. (Normal range for age 15 years: 94 to 115 beats/min). With exercise, sinus rate increased to 150 beatslmin. Electrophysiologic studies revealed marked sinus bradycardia (cycle length 1,532 ms). P-A, A-H and H-V intervals were normal (16,72 and 50 ms, respectively). Type 1 second degree block occurred in the A-V node at an atrial paced rate of 150 beats/min. Sinoatrial recovery time was 3,725 ms (corrected recovery time 2,445 ms) (Fig. 8). Atria1 extrastimulus testing during sinus rhythm yielded a calculated sinoatria1 recovery time of 46 ms. Atria1 extrastimulus testing at a paced cycle length of 600 ms revealed normal atria1 and A-V node1 refractory periods, and a prolonged left bundle branch effective refractory period of 470 ms. Postmortem examination: Aside from the findings in the heart, the pathologic diagnosis was acute viral hepatitis, type B, with massive central necrosis of liver cells (massive agonal necrosis of the renal cortical parenchyma secondary to shock).
Summit of the ventricular septum and central fibrous body: Marked fibrosis of the myocardium and endocardial
fibroelastosis were present in the region of the ventricular septal defect. The sinusoids of the right ventricular side were enlarged. The central fibrous body was thickened. Left atrium: The myocardium was infiltrated with mononuclear cells. The left circumflex artery passed through the atria1 myocardium instead of the A-V groove. Left ventricle: There was a focal infiltration of mononuclear cells. Right atrium: The myocardial cells showed diffuse swelling and vacuolization, with a fine infiltration of mononuclear cells. The roof was markedly fibrotic. Right uentricle: The myocardial cells showed irregular staining and swelling. Some small arteries were slightly thickened. Case 2 This boy was in good health until age 15 years, when he failed to attend school because of easy fatigability and dizziness. Physical examination revealed bradycardia (30 to 50 beats/min) and orthostatic hypotension. Hospital evaluation revealed neutropenia and slight indirect hyperbilirubinemia
venarum is not sharply demarcated from the atrial appendage. L = limbus; PC = posterior crest: RA = right atrium: RV = right ventricle; SVC = entry of superior vena cava into right atrium; TV = tricuspid
valve.
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Heart: gross examination: The heart was enlarged and weighed 372 g. All the cardiac chambers were hypertrophied and enlarged, but all four valves were normal. An increased amount of fat was seen externally in most parts of the epicardium (Fig. 9). The coronary ostia and the coronary circulations were normal. Microscopic examination: methods: The S-A and A-V nodes and their approaches and the bundle and the bundle branches up to the level of the moderator band were serially sectioned and every 10th section was retained. The atria1 preferential pathways were likewise serially sectioned and every 20th section was retained. The remainder of the heart
was cut into blocks and two sections were taken from each block. Consecutive sections of the S-A node, A-V node and bundle and the bundle branches were stained with hematoxylin-eosin, Weigert-van Gieson and Gomori trichrome stains. The remainder of the heart was stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner 826 sections were examined. Conduction system: S-A node: There was a slight increase in connective tissue (Fig. 10) with a fine infiltration of mononuclear cells. The S-A nodal artery showed no changes. Approaches to the S-A node: An increase in fat tissue was present (Fig. 11, left) with degenerative changes in the fat with
FIGURE 4. Case 1. Top, sinoatrial (S-A) node and approaches. Bottom, superior approaches to S-A node showing marked fibrosis. Ap = approaches to sinoatrial node; SA = sinoatrial node. (Both panels, Weigert-van Gieson stain X45, reduced by 20 percent.)
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macrophages. There was a fine infiltration of mononuclear cells throughout the myocardium, including the epicardium. Atria1 preferential pathways: The superior pathway was markedly infiltrated with fat (Fig. 11, right) with marked degeneration of the fat with macrophages. Mononuclear cells had infiltrated throughout the myocardium. The nerves of the epicardium were infiltrated with mononuclear cells and the nerve ganglia had degenerated. The S-A nodal artery was normal. Approaches to the A-V node: Fatty infiltration was present throughout. There was considerable infiltration of mononuclear cells and fibrosis in the myocardium. A-V node: This was small and infiltrated with mononuclear cells. Penetrating bundle: This was normal. Branching bundle: A moderate amount of fibrosis was present with slight infiltration of mononuclear cells. Left bundle branch: Fibrosis was present at its jtiction with the main bundle. Mononuclear cell infiltration was also present, which increased toward the periphery of the left bundle branch. The radiations showed a marked infiltration of mononuclear cells. Right bundle branch: Slight fibrosis was present in the first part, but became moderate in the second part. The third part showed a marked infiltration of mononuclear cells. Central fibrous body: This was markedly thickened.
Summit of the ventricular septum: Mononuclear cell infiltration was marked anteriorly. ln addition arteriolceclerosis and fibrosis were present. Some large arterioles showed necrotic changes. Myocardium: A moderate amount of mononuclear cell infiltration was present in both the atria and ventricles. This was accompanied by a moderate amount of perivascular fibrosis and arteriolar and venular degeneration. Infiltration of fat was present in the right ventricle with degeneration of fat cells.
Discussion Anatomic basis for sick sinus syndrome: Sinus nodal dysfunction in young people has previously been reported. However, the anatomic basis for sinus dysfunction is unknown. Our two cases shed some light on this problem. In evaluating the cause of this chronically present sick sinus syndrome only chronic changes can be taken into account. In Case 1, sinus nodal dysfunction was documented when the patient was 2 and 6 years old, but thereafter there was no evidence of such dysfunction until age 14. This problem was complicated by the fact that the patient had a closing ventricular septal defect. The anatomic finding that might conceivably be related to this
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FIGURE 5. Case 1. Left, junction of inferior interatrial tract and inferior approacnes to A-V nooe (coronary smus regton), snowing marked tibrosis. Right, superior approaches to A-V node showing marked fibrosis. CFB = central fibrous body. T = thebesian valve. (Both panels, Weigert-van Gieson stain X45, reduced by 23 percent.)
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FIGURE 6. Case 1. Left, bundle of His, showing marked septation and fragmentation. Arrows point to bundle Right, left bundle branch (LBB) cut off from bundle(B). CFB = central fibrous body; F = fibroelastosis; TV = tricuspid valve; V = ventricular septum; VSD = ventricular septal defect. (Both panels, Weigert-van Gieson stain X30 [left] and Xl3 [rlght], reduced by 24 percent.)
dysfunction was fibrosis of the approaches to the S-A node, of the atria1 preferential pathways and of the approaches to the A-V node. What is the cause of this fibrosis? We do not know. An interesting minor abnormality in the formation of the superior part of the right atrium may be related to it. It is possible that long-standing hypertrophy and
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Rhythm
m
AVR
AVL
enlargement of the atria secondary to hypertrophy and enlargement of the ventricles due to a left to right shunt at the ventricular level may have produced the fibrosis. In Case 2, sinus nodal dysfunction was documented 1 year before the patient’s death. The anatomic basis for this dysfunction conceivably lies in the fatty infil-
AVF
,Strip FIGURE 7. Case 2. Twelve standard electrocardiographic leads (too) and a lead II rhythm strip (bottom) taken at age 15. Left axis deviation, low voltage in the limb leads and marked sinus bradycardia (31 beats/min) are evident.
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FIGURE 8. Case 2. Determination of sinus nodal recovery time. Shown are Frank leads X, Y and 2 as well as a high right atria1 electrogram (HRA). Time lines are at 1 second intervals. After atria1 pacing (S) at a cycle length of 545 ms (rate 110 beatslmin), sinus nodal recovery time was 3,725 ms. (Corrected sinus nodal recovery time was 2,445 ms.)
tration of the approaches to the S-A node, of the atria1 preferential pathways and of the approaches to the A-V node. What is the cause of this fatty infiltration, which involved not only the aforementioned areas, but also the entire subepicardial region: Again, we do not know. Fatty infiltration is either a replacement of degenerated tissue or is the cause of such degeneration.17-lg In a youth of 15, it is distinctly abnormal to have such fatty infiltration. There are many instances of fatty infiltration or lipomatosis of the atria1 septum associated with arrhythmias.20-25 However, it is clear that in both cases the so-called sick sinus syndrome was due to pathologic changes not in the S-A node, but in the approaches to the S-A node and the atria1 preferential pathways and perhaps in the approaches to the A-V node. We are dealing with an atria1 disease, not a S-A nodal disease. In both cases there was chronic pathologic change in the more distal as well as in the proximal part of the conduction system. In Case 1 this can be ascribed to the closing ventricular septal defect, with its concomitant fibrosis and fibroelastosis in the surrounding areas. However, in Case 2 the only anatomic changes that might affect the more distal part of the conduction system are the enlargement of the central fibrous body and the fibrosis and arteriolosclerosis of the summit of the ventricular septum. These changes might conceivably be due to sclerosis of the left side of the cardiac skeleton occurring in a young person.16 The finding of distal disease in the conduction system in the sick sinus syndrome in older people is well known.26-4e Such findings in young people are equally important in assessing the value of pacemaker implantation and in making a general prognosis. We have previously stated41 that conduction system studies in the sick sinus syndrome should include studies of the S-A node and its approaches, the atria1 preferential pathways, the approaches to the A-V node, the A-V bundle, bundle branches and the Purkinje nets as well as the remainder of the heart. The value of such studies is borne out by these two cases. Because our
knowledge of the anatomic basis of the so-called sick sinus syndrome is fragmentary, only complete studies from many laboratories will yield useful data in elucidating the problem. Clinical features: The cause of sudden death in Case 1 is very likely related to the sick sinus syndrome. The patient was repeatedly asked to return for examination after age 13 to evaluate the necessity for a pacemaker, but he refused to do so. From the clinical standpoint, our two cases had important features in common. Each patient had a relative paucity of symptoms. In neither were symptoms thought to be severe enough to necessitate permanent pacing. Electrophysiologic studies in both revealed
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FIGURE 10. Case 2. Sinoatrial (SA) node showing slight fibrosis. (Weigert-van Gieson stain X45, reduced by 2 1 percent.)
FIGURE 11. Case 2. Left, approaches to sinoatrial node showing marked fatty rnrrrrrarronor myocararum. nrgnr, ratty rntrnratronor superror rnternooat pathway. Arrows point to fatty infiltration. (Both panels, Gomori trichrome stain X45, reduced by 12 percent.)
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marked prolongation of the sinus nodal recovery time. Both patients also had a significant functional component to sinus bradycardia, as manifested by marked facilitation of the sinus rate after administration of atropine in Case 1 and by demonstration of normal sinus nodal response to exercise in Case 2. The clinicians caring for both patients believed their disorder to be an example of obscure (idiopathic) sinus nodal dysfunction, not related to any apparent organic heart disease. Therapy: This study has little to suggest regarding the therapy of the sick sinus syndrome in children and adolescents because there are no means of judging the functional significance of pathologically demonstrated conduction system lesions. From our studies of conduction diseases in adults, it is clear that advanced and often subtotal destruction of major portions of the conduction system is consistent with preservation of normal electrophysiologic function.42 In our Case 1, it
is possible that implantation of a permanent pacemaker might have prevented sudden death (if sudden death was bradyarrhythmic). Permanent pacing would not have prevented the death of Patient 2, who died of fulminant hepatitis. It is not clear what the natural history of sinus nodal disease in this boy would have been if he had not died of hepatitis. Clinical implications: It is difficult to draw definitive clinical inferences from the pathologic study of these two cases. The disease process responsible for the pathologic findings in both cases is obscure. However, the two cases underline the importance of careful noninvasive (and perhaps invasive) evaluation for the presence of organic heart disease in young patients with the sick sinus syndrome. Further electrophysiologic and pathologic correlation, including complete studies of the entire conduction system in children and young adults with this syndrome, should allow further understanding of this disorder.
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& Stratton, 1958:3. 18. Cameron OR. Pathology of the Cell. Springfield, IL: Charles C Thomas, 1951:316-28. 19. Anderson WAD, Kissane JM. Pathology. Vol 1. St. Louis: CV Mosby, 19771742. 20. Bharati S, Bauernfiend R, Scheinman M, et al. Congenital abnormalities of the conduction system in two patients with tachyarrhythmias. Circulation 1979;59:593-606. 21. Balsaver AM, Morales AR, Whftehouse FW. Fat infiltration of myocardium as a cause of cardiac conduction defect. Am J Cardiol 1967;19:261-5. 22. Ross CF, Belton EM. A case of isolated cardiac lipidosis. Br Heart J 1968;30:726-8. 23. Page DL. Lipomatous hypertrophy of the cardiac interatrial septum; its development and probable clinical significance. Hum Pathol 1970;1:151-63. 24. Hutter AM Jr, Page DL. Atrial arrhythmias and lipomatous hypertrophy of the cardiac interatrial septum. Am Heart J 1971;82: 16-21. 25. Anbe DT, Fine G. Cardiac lymphangioma and lipoma: report of a case of simultaneous occurrence in association with lipomatous infiltration of the myocardium and cardiac arrhythmia. Am Heart J 1973;86:227-35. 26. Schneider MD, Roller DH, Morganroth J, Josephson ME. The syndromes of familial atrioventricular block with sinus bradycardia: prognostic indices, electrophysiologic and histopathologic correlates. Eur J Cardiol 1978;7:337-51. 27. Massie B, Scheinman MM, Peters R, Desai J, Hirschfeld D, D’Young J. Clinical and electrophysiologic findings in patients with paroxysmal slowing of the sinus rate and apparent Mobitz type II atrioventricular block. Circulation 1978;58:305-14. 28. Mandel WJ, Jordan JL, Yamaguchi I. The sick sinus syndrome. Adv Cardiol 1978;22:71-9. 29. Santinf M, Dfnl P, Di Mascolo R, Mastni V. Conduction disturbances associated with the sick sinus node syndrome. Study of 15 cases with His bundle electrogram. G ltal Cardiol 1976;6:786-91. 30. Toyama J. Clinical studies on the sick sinus syndrome. Jpn Circ J 1976;40:203-7. 31. Mdtha~ PB, Flewy G, Caspl G, Faivle D’Arcy F, Henlln A, DlMateo J. Troubles de la conduction sino-auriculaire et auriculo-ventriculaire dans la maladie de steinert. Arch Mal Coeur 1976;69: 547-52. 32. Sinker D, Parameswaran R, Goldberg H. Sinus and A-V nodal dysfunction following myocardial infarction. J Electrocardiol 1975;8:281-3. 33. Dfghton DH. Sinoatrial block autonomic influences and clinical
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assessment. Br Heart J 1975;37:321-5. 34. Waxman WB, Catching JD, Felderhof CH, Downar E, Silver MD, Abbot MM. Familial atrioventricular heart block. An autosomal dominant trait. Circulation 1975;51:226-233. 35. Sarachek NS, Leonard JJ. Familial heart block and sinus bradycardia. Classification and natural history. Am J Cardiol 1972;29: 451-a. 36. Lev M, Kinare SG, Pick A. The pathogenesis of atrioventricular block in coronary disease. Circulation 1970;42:409-25. 37. Bharati S, Lev M, Denes P, et al. Infiltrative cardiomyopathy with conduction disease and ventricular arrhythmia: electrophysiologic and pathologic correlations. Am J Cardiol 1980;45: 163-73. 38. Rosen KM, Rahlrntoola SH, Bharatl S, Lev M. Bundle branch block with intact atrioventricular conduction. Electrophysiologic and pathologic correlations in three cases. Am J Cardiol 1973;32:
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783-93. 39. Bharati S, Lev M, Dhingra R, et al. Pathologic correlations in three cases of bilateral bundle branch disease with unusual electrophysiologic manifestations in two cases. Am J Cardiol 1976;38: 508-18. 40. Rosen KM, Rahimtoola SH, Gunnar RM, Lev M. Transient and persistent atrial standstill with His bundle lesions: electrophysiologic and pathologic correlations. Circulation 1971;44:220-36. 41. Kaplan BY, Laqendorf R, Lev M, Pick A. Tachycardia-bradycardia syndrome (so-called “sick sinus syndrome”): pathology, mechanisms and treatment. Am J Cardiol 1973;31:497-508. 42. Rosen KM, Wu D, Kanakis C Jr, Denes P, Bharatl S, Lev M. Return of normal conductionafter paroxysmal heart block: report of a case with major discordance of electrophysiological and pathological findings. Circulation 1975;51:197-204.
The Anatomic Substrate for the Sick Sinus Syndrome in Adolescence
SAROJA AARON ROBERT
BHARATI,
MD,
NORDENBERG, BAUERNFIEND,
FACC MD,
FACC
MD
MD, FACC ARNALDO G. CARVALHO, MD, FACC KENNETH ROSEN, MD, FACC MAURICE LEV, MD, FACC’
JACOB
P. VARGHESE,
Chicago, Illinois
From the Congenital Heart Disease Research and Training Center, Hektoen Institute for Medical Research, Chicago, Illinois; the Department of Pathology, Northwestern University Medical School, Evanston, Illinois; the Pritzker School of Medicine, University of Chicago; the Chicago Medical School, University of Health Sciences; Loyola University, Stritch School of Medicine; the Section of Cardiology, Department of Medicine and the Department of Pathology, Abraham Lincoln School of Medicine, University of Illinois; and the Departments of Pediatrics, Medicine and Pathology, Rush Medical College, Chicago, Illinois; the Department of Medicine of the Johns Hopkins Hospital, Baltimore, Maryland; and the Polyclinic Medical Center, Harrisburg, Pennsylvania. This work was supported by Grants HL 0760516, HL 16794 and HL 23566 and Training Grant 07387 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received January 15, 1980, accepted February 1, 1980. ’ Career Investigator and Educator, Chicago Heart Association, Chicago, Illinois. Address for reprints: Saroja Bharati, MD, Congenital Heart Disease Research and Training Center, Hektoen Institute for Medical Research, 637 South Wood Street, Chicago, Illinois 60612.
This is a study of the conduction system of two adolescent boys, one 16 and the other 17 years of age, who had prolonged unexptalned sinus nodal dysfunction. The first patient had sinus pauses up to 2.5 seconds in duration, absence of persistent sinus bradycardia and prolonged sinus nodal recovery time of 3,451 ms. He died suddenly. Pathologic study of the conduction system revealed degeneration and fibrosis of the approaches to the sinoatrial (S-A) and atrioventrlcular (A-V) nodes and the atrial preferential pathways. The second patient had a 1 year history of persistent sinus bradycardia (30 to 60 beats/min) and prolonged slnus nodal recovery time of 3,725 ms. He died of acute viral hepatitis. Pathologic study of the conduction system revealed fatty inflttration of the approaches to the S-A and A-V nodes and the atrial preferential pathways. In summary, the approaches to the S-A and A-V nodes and the atrial preferential pathways were altered by fibrosis in Case 1 and by fatty infiltration in Case 2, both of unknown origin. The S-A node itself was not significantly involved in either case.
The sick sinus syndrome is usually encountered in the elderly. However, recent reports describe sinus nodal dysfunction in children and adolescents.l-l2 This dysfunction often complicates surgical correction of congenital heart .disease. 13,14In the latter instance, pathologic examination may reveal surgical trauma to the sinoatrial (S-A) node or internodal pathways. The idiopathic sick sinus syndrome is relatively rare in children and adolescents and there have been no previous pathologic reports concerning the anatomic substrate of this disorder. In this report, we describe the findings in two adolescent boys with electrophysiologically documented sinus nodal dysfunction. Both boys subsequently died (one suddenly), allowing an opportunity for pathologic examination of the heart. In both cases, serial section of the conduction system demonstrated a pathologic substrate for the occurrence of the sick sinus syndrome. Case Reports Case 1 This boy had a harsh systolic murmur at birth and at age 11 months underwent
cardiac catheterization, which revealed a left to right shunt at the ventricular level. By the time the boy was 6 years old, the murmur was no longer audible and at age 13 a second cardiac catheterization revealed no abnormalities. The patient was asymptomatic except for a single brief syncopal episode, associated with convulsions, at age 5 years. At age 13, the boy was referred to the Johns Hopkins Hospital for evaluation of bradyarrhythmias. After that time, he failed to keep his medical appointments, but was reported to have pulse rates of 70 to 90 beats/min during school examinations. He died suddenly at age 16.
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“I “6 FIGURE 1. Case 1. Leads I, II, Ill, VI and Vg from resting electrocardiogram taken at age 13. Short runs of supraventricular tachycardia (probably multifocal atrial tachycardia) are followed by pauses of 1.5 to 1.7 seconds terminated by junctional escape beats. Left axis deviation is also evident.
Review of electrocardiographic and electrophysiologic data: Right ventricular hypertrophy was demonstrated on
electrocardiograms taken prior to age 4 l/2 years. At age 2 years, sinus tachycardia, interrupted by sinus pauses of 1.3 to 1.4 seconds, was evident. Electrocardiograms taken at 7 l/2 and 8 l/2 years showed normal sinus rhythm. At age 13, the following were noted: brief runs of supraventricular tachycardia, followed by pauses of 1.5 to 1.7 seconds, terminated by junctional escape beats (Fig. 1 and 2) with rates of 40 to 50 beats/min. At age 14 years, the patient undcmcent electrophysiologic studies. These revealed a junctional escape rhythm (cycle
length 1,040 ms) that controlled
both the atria and the ven-
tricles (H-V interval 40 ms). The sinoatrial recovery time, determined by atria1 pacing, was 3,780 ms (Fig. 2). After administration of 0.8 mg of atropine, the cycle length of the junctional rhythm decreased to 585 ms and the sinoatrial recovery time to 940 ms (Fig. 2). Postmortem findings: The pathologic diagnoses, excluding the findings in the heart, were (1) acute passive congestion of the visceral organs, and (2) abnormal origin of the right subclavian artery (originating distal to the left subclavian artery), which coursed in front of the trachea to the right side. Heart: gross examination: The heart was enlarged and weighed 325 g. All chambers were hypertrophied and enlarged. The internal architecture of the right atrium was abnormal (Fig. 3). There was no sharp line of demarcation between the sinus venarum receiving the superior vena cava and the right atria1 appendage. The ventricular septum at its base presented a small ventricular septal defect measuring 1 mm in greatest dimension. This defect was situated beneath the junction of the right and posterior aortic cusps and opened into the right side at the junction of the right atrium and ventricle in an area devoid of tricuspid valve tissue. On the left ventricular side it was surrounded by thickened endocardium. The aortic valve consisted of three cusps with a slight separation of the cusps at the commissures. Microscopic examination: methods: The S-A and atrioventricular (A-V) nodes and their approaches, the A-V bundle and bundle branches up to the muscle of Lancisi were serially sectioned and every fifth section was retained. The remainder of the bundle branches up to the region of the moderator band were serially sectioned and every 10th section was retained. These were consecutively stained with hematoxylin-eosin. Weigert-van Gieson and Gomori trichrome stains. The atria1 preferential pathways were serially sectioned and every 20th section was retained. The remainder of the heart was cut into blocks and two sections were taken from each block. The atrial preferential pathways and the remainder of the heart were alternately stained with hematoxylin-eosin and Weigert-van Gieson stains. in this manner 898 sections were studied. This manner of examination of the heart has previously been reported.15J6
FIGURE 2. Case 1. Determination of sinoatrial recovery times (SART) by atrial pacing. Shown in each panel are electrocardiographic lead II (L2) and high right atrial (HRA) and His bundle (HBE) electrograms. Time (T) spikes (bottom of each panel) are at 10 ms intervals. Before administration of atropine (top panel) the sinoatrial recovery time was 3,780 ms; after administration of 0.8 mg of atropine (bottom panel), it was 940 ms. Cl = cycle length.
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Conduction system: S-A node: There was a slight increase in connective tissue in the lower part of the node (Fig. 4, top) with a slight infiltration of mononuclear cells. An occasional arteriole was thickened. The epicardium likewise showed a slight mononuclear cell infiltration. The S-A nodal artery showed no changes. Approaches to the S-A node: All of the approaches had enlarged cells, which were pale-staining and somewhat vacuolated. There was a diffuse marked increase of connective tissue at the lower pole of the S-A node, focally in the upper pole (Fig. 4, bottom) and in general in the transitional zone with the atria. Atria1 preferential pathways: Diffuse fibrosis of the anterior, middle and inferior preferential pathways was seen (Fig. 5, left) with marked swelling and vacuolization of the cells. The S-A nodal artery arose from the left circumflex artery and showed no changes. Approaches to the A-V node: These cells were markedly swollen with diffuse fibrosis (Fig. 5, right). In addition there was occasional infiltration of mononuclear cells. The sinusoids and lymphatics were dilated. A-V node: Moderate fibrosis with focal eosinophilia of cells was present. A-V bundle, penetrating: This was markedly septated (Fig. 6, left). Swelling in some cells with pale cytoplasm and vacuolization were noted. Branching bundle: This again was markedly septated with marked vacuolization of the cells of the left side. Minimal fibrosis was also present. Left bundle branch: The cells showed increased vacuolization. There was moderate fibrosis, which increased more distally. The left bundle branch was disrupted at the bifurcation (Fig. 6, right) with vacuolization of the remaining cells. These findings were more evident in the anterior than in the posterior radiation. Right bundle branch: Increased vacuolization of cells was noted, and moderate fibrosis was seen in the region of the closing ventricular septal defect. More distally, there was slight fibrosis. Peripheral Purkinje cells: Moderate fibrosis was present on both sides. Vacuolar degeneration of the Purkinje cells with focal mononuclear and neutrophilic infiltration was present on the left side.
ET AL.
(1.3 mg/ml), but endocrinologic investigations and hepatic enzyme levels were normal. Electrophysiologic studies were performed at St. John’s Hospital, Springfield, Illinois at this time (see later). The patient was treated with corticosteroids and sublingual isoproterenol and his symptoms were alleviated despite persistence of bradycardia. Nine months later, he presented with hepatitis (hepatitis B surface antigenpositive). He lapsed into hepatic coma and died. Electrocardiographic and electrophysiologic data: Electrocardiograms at rest revealed left axis deviation, low voltage in the limb leads and marked sinus bradycardia (30 to 32 beata/min) (Fig. 7). After administration of atropine, 0.02 mg/kg, and propranolol, 0.1 mg/kg, intrinsic heart rate was slower than normal at 74 beats/min. (Normal range for age 15 years: 94 to 115 beats/min). With exercise, sinus rate increased to 150 beatslmin. Electrophysiologic studies revealed marked sinus bradycardia (cycle length 1,532 ms). P-A, A-H and H-V intervals were normal (16,72 and 50 ms, respectively). Type 1 second degree block occurred in the A-V node at an atrial paced rate of 150 beats/min. Sinoatrial recovery time was 3,725 ms (corrected recovery time 2,445 ms) (Fig. 8). Atria1 extrastimulus testing during sinus rhythm yielded a calculated sinoatria1 recovery time of 46 ms. Atria1 extrastimulus testing at a paced cycle length of 600 ms revealed normal atria1 and A-V node1 refractory periods, and a prolonged left bundle branch effective refractory period of 470 ms. Postmortem examination: Aside from the findings in the heart, the pathologic diagnosis was acute viral hepatitis, type B, with massive central necrosis of liver cells (massive agonal necrosis of the renal cortical parenchyma secondary to shock).
Summit of the ventricular septum and central fibrous body: Marked fibrosis of the myocardium and endocardial
fibroelastosis were present in the region of the ventricular septal defect. The sinusoids of the right ventricular side were enlarged. The central fibrous body was thickened. Left atrium: The myocardium was infiltrated with mononuclear cells. The left circumflex artery passed through the atria1 myocardium instead of the A-V groove. Left ventricle: There was a focal infiltration of mononuclear cells. Right atrium: The myocardial cells showed diffuse swelling and vacuolization, with a fine infiltration of mononuclear cells. The roof was markedly fibrotic. Right uentricle: The myocardial cells showed irregular staining and swelling. Some small arteries were slightly thickened. Case 2 This boy was in good health until age 15 years, when he failed to attend school because of easy fatigability and dizziness. Physical examination revealed bradycardia (30 to 50 beats/min) and orthostatic hypotension. Hospital evaluation revealed neutropenia and slight indirect hyperbilirubinemia
venarum is not sharply demarcated from the atrial appendage. L = limbus; PC = posterior crest: RA = right atrium: RV = right ventricle; SVC = entry of superior vena cava into right atrium; TV = tricuspid
valve.
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Heart: gross examination: The heart was enlarged and weighed 372 g. All the cardiac chambers were hypertrophied and enlarged, but all four valves were normal. An increased amount of fat was seen externally in most parts of the epicardium (Fig. 9). The coronary ostia and the coronary circulations were normal. Microscopic examination: methods: The S-A and A-V nodes and their approaches and the bundle and the bundle branches up to the level of the moderator band were serially sectioned and every 10th section was retained. The atria1 preferential pathways were likewise serially sectioned and every 20th section was retained. The remainder of the heart
was cut into blocks and two sections were taken from each block. Consecutive sections of the S-A node, A-V node and bundle and the bundle branches were stained with hematoxylin-eosin, Weigert-van Gieson and Gomori trichrome stains. The remainder of the heart was stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner 826 sections were examined. Conduction system: S-A node: There was a slight increase in connective tissue (Fig. 10) with a fine infiltration of mononuclear cells. The S-A nodal artery showed no changes. Approaches to the S-A node: An increase in fat tissue was present (Fig. 11, left) with degenerative changes in the fat with
FIGURE 4. Case 1. Top, sinoatrial (S-A) node and approaches. Bottom, superior approaches to S-A node showing marked fibrosis. Ap = approaches to sinoatrial node; SA = sinoatrial node. (Both panels, Weigert-van Gieson stain X45, reduced by 20 percent.)
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macrophages. There was a fine infiltration of mononuclear cells throughout the myocardium, including the epicardium. Atria1 preferential pathways: The superior pathway was markedly infiltrated with fat (Fig. 11, right) with marked degeneration of the fat with macrophages. Mononuclear cells had infiltrated throughout the myocardium. The nerves of the epicardium were infiltrated with mononuclear cells and the nerve ganglia had degenerated. The S-A nodal artery was normal. Approaches to the A-V node: Fatty infiltration was present throughout. There was considerable infiltration of mononuclear cells and fibrosis in the myocardium. A-V node: This was small and infiltrated with mononuclear cells. Penetrating bundle: This was normal. Branching bundle: A moderate amount of fibrosis was present with slight infiltration of mononuclear cells. Left bundle branch: Fibrosis was present at its jtiction with the main bundle. Mononuclear cell infiltration was also present, which increased toward the periphery of the left bundle branch. The radiations showed a marked infiltration of mononuclear cells. Right bundle branch: Slight fibrosis was present in the first part, but became moderate in the second part. The third part showed a marked infiltration of mononuclear cells. Central fibrous body: This was markedly thickened.
Summit of the ventricular septum: Mononuclear cell infiltration was marked anteriorly. ln addition arteriolceclerosis and fibrosis were present. Some large arterioles showed necrotic changes. Myocardium: A moderate amount of mononuclear cell infiltration was present in both the atria and ventricles. This was accompanied by a moderate amount of perivascular fibrosis and arteriolar and venular degeneration. Infiltration of fat was present in the right ventricle with degeneration of fat cells.
Discussion Anatomic basis for sick sinus syndrome: Sinus nodal dysfunction in young people has previously been reported. However, the anatomic basis for sinus dysfunction is unknown. Our two cases shed some light on this problem. In evaluating the cause of this chronically present sick sinus syndrome only chronic changes can be taken into account. In Case 1, sinus nodal dysfunction was documented when the patient was 2 and 6 years old, but thereafter there was no evidence of such dysfunction until age 14. This problem was complicated by the fact that the patient had a closing ventricular septal defect. The anatomic finding that might conceivably be related to this
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FIGURE 5. Case 1. Left, junction of inferior interatrial tract and inferior approacnes to A-V nooe (coronary smus regton), snowing marked tibrosis. Right, superior approaches to A-V node showing marked fibrosis. CFB = central fibrous body. T = thebesian valve. (Both panels, Weigert-van Gieson stain X45, reduced by 23 percent.)
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FIGURE 6. Case 1. Left, bundle of His, showing marked septation and fragmentation. Arrows point to bundle Right, left bundle branch (LBB) cut off from bundle(B). CFB = central fibrous body; F = fibroelastosis; TV = tricuspid valve; V = ventricular septum; VSD = ventricular septal defect. (Both panels, Weigert-van Gieson stain X30 [left] and Xl3 [rlght], reduced by 24 percent.)
dysfunction was fibrosis of the approaches to the S-A node, of the atria1 preferential pathways and of the approaches to the A-V node. What is the cause of this fibrosis? We do not know. An interesting minor abnormality in the formation of the superior part of the right atrium may be related to it. It is possible that long-standing hypertrophy and
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enlargement of the atria secondary to hypertrophy and enlargement of the ventricles due to a left to right shunt at the ventricular level may have produced the fibrosis. In Case 2, sinus nodal dysfunction was documented 1 year before the patient’s death. The anatomic basis for this dysfunction conceivably lies in the fatty infil-
AVF
,Strip FIGURE 7. Case 2. Twelve standard electrocardiographic leads (too) and a lead II rhythm strip (bottom) taken at age 15. Left axis deviation, low voltage in the limb leads and marked sinus bradycardia (31 beats/min) are evident.
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FIGURE 8. Case 2. Determination of sinus nodal recovery time. Shown are Frank leads X, Y and 2 as well as a high right atria1 electrogram (HRA). Time lines are at 1 second intervals. After atria1 pacing (S) at a cycle length of 545 ms (rate 110 beatslmin), sinus nodal recovery time was 3,725 ms. (Corrected sinus nodal recovery time was 2,445 ms.)
tration of the approaches to the S-A node, of the atria1 preferential pathways and of the approaches to the A-V node. What is the cause of this fatty infiltration, which involved not only the aforementioned areas, but also the entire subepicardial region: Again, we do not know. Fatty infiltration is either a replacement of degenerated tissue or is the cause of such degeneration.17-lg In a youth of 15, it is distinctly abnormal to have such fatty infiltration. There are many instances of fatty infiltration or lipomatosis of the atria1 septum associated with arrhythmias.20-25 However, it is clear that in both cases the so-called sick sinus syndrome was due to pathologic changes not in the S-A node, but in the approaches to the S-A node and the atria1 preferential pathways and perhaps in the approaches to the A-V node. We are dealing with an atria1 disease, not a S-A nodal disease. In both cases there was chronic pathologic change in the more distal as well as in the proximal part of the conduction system. In Case 1 this can be ascribed to the closing ventricular septal defect, with its concomitant fibrosis and fibroelastosis in the surrounding areas. However, in Case 2 the only anatomic changes that might affect the more distal part of the conduction system are the enlargement of the central fibrous body and the fibrosis and arteriolosclerosis of the summit of the ventricular septum. These changes might conceivably be due to sclerosis of the left side of the cardiac skeleton occurring in a young person.16 The finding of distal disease in the conduction system in the sick sinus syndrome in older people is well known.26-4e Such findings in young people are equally important in assessing the value of pacemaker implantation and in making a general prognosis. We have previously stated41 that conduction system studies in the sick sinus syndrome should include studies of the S-A node and its approaches, the atria1 preferential pathways, the approaches to the A-V node, the A-V bundle, bundle branches and the Purkinje nets as well as the remainder of the heart. The value of such studies is borne out by these two cases. Because our
knowledge of the anatomic basis of the so-called sick sinus syndrome is fragmentary, only complete studies from many laboratories will yield useful data in elucidating the problem. Clinical features: The cause of sudden death in Case 1 is very likely related to the sick sinus syndrome. The patient was repeatedly asked to return for examination after age 13 to evaluate the necessity for a pacemaker, but he refused to do so. From the clinical standpoint, our two cases had important features in common. Each patient had a relative paucity of symptoms. In neither were symptoms thought to be severe enough to necessitate permanent pacing. Electrophysiologic studies in both revealed
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FIGURE 10. Case 2. Sinoatrial (SA) node showing slight fibrosis. (Weigert-van Gieson stain X45, reduced by 2 1 percent.)
FIGURE 11. Case 2. Left, approaches to sinoatrial node showing marked fatty rnrrrrrarronor myocararum. nrgnr, ratty rntrnratronor superror rnternooat pathway. Arrows point to fatty infiltration. (Both panels, Gomori trichrome stain X45, reduced by 12 percent.)
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marked prolongation of the sinus nodal recovery time. Both patients also had a significant functional component to sinus bradycardia, as manifested by marked facilitation of the sinus rate after administration of atropine in Case 1 and by demonstration of normal sinus nodal response to exercise in Case 2. The clinicians caring for both patients believed their disorder to be an example of obscure (idiopathic) sinus nodal dysfunction, not related to any apparent organic heart disease. Therapy: This study has little to suggest regarding the therapy of the sick sinus syndrome in children and adolescents because there are no means of judging the functional significance of pathologically demonstrated conduction system lesions. From our studies of conduction diseases in adults, it is clear that advanced and often subtotal destruction of major portions of the conduction system is consistent with preservation of normal electrophysiologic function.42 In our Case 1, it
is possible that implantation of a permanent pacemaker might have prevented sudden death (if sudden death was bradyarrhythmic). Permanent pacing would not have prevented the death of Patient 2, who died of fulminant hepatitis. It is not clear what the natural history of sinus nodal disease in this boy would have been if he had not died of hepatitis. Clinical implications: It is difficult to draw definitive clinical inferences from the pathologic study of these two cases. The disease process responsible for the pathologic findings in both cases is obscure. However, the two cases underline the importance of careful noninvasive (and perhaps invasive) evaluation for the presence of organic heart disease in young patients with the sick sinus syndrome. Further electrophysiologic and pathologic correlation, including complete studies of the entire conduction system in children and young adults with this syndrome, should allow further understanding of this disorder.
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& Stratton, 1958:3. 18. Cameron OR. Pathology of the Cell. Springfield, IL: Charles C Thomas, 1951:316-28. 19. Anderson WAD, Kissane JM. Pathology. Vol 1. St. Louis: CV Mosby, 19771742. 20. Bharati S, Bauernfiend R, Scheinman M, et al. Congenital abnormalities of the conduction system in two patients with tachyarrhythmias. Circulation 1979;59:593-606. 21. Balsaver AM, Morales AR, Whftehouse FW. Fat infiltration of myocardium as a cause of cardiac conduction defect. Am J Cardiol 1967;19:261-5. 22. Ross CF, Belton EM. A case of isolated cardiac lipidosis. Br Heart J 1968;30:726-8. 23. Page DL. Lipomatous hypertrophy of the cardiac interatrial septum; its development and probable clinical significance. Hum Pathol 1970;1:151-63. 24. Hutter AM Jr, Page DL. Atrial arrhythmias and lipomatous hypertrophy of the cardiac interatrial septum. Am Heart J 1971;82: 16-21. 25. Anbe DT, Fine G. Cardiac lymphangioma and lipoma: report of a case of simultaneous occurrence in association with lipomatous infiltration of the myocardium and cardiac arrhythmia. Am Heart J 1973;86:227-35. 26. Schneider MD, Roller DH, Morganroth J, Josephson ME. The syndromes of familial atrioventricular block with sinus bradycardia: prognostic indices, electrophysiologic and histopathologic correlates. Eur J Cardiol 1978;7:337-51. 27. Massie B, Scheinman MM, Peters R, Desai J, Hirschfeld D, D’Young J. Clinical and electrophysiologic findings in patients with paroxysmal slowing of the sinus rate and apparent Mobitz type II atrioventricular block. Circulation 1978;58:305-14. 28. Mandel WJ, Jordan JL, Yamaguchi I. The sick sinus syndrome. Adv Cardiol 1978;22:71-9. 29. Santinf M, Dfnl P, Di Mascolo R, Mastni V. Conduction disturbances associated with the sick sinus node syndrome. Study of 15 cases with His bundle electrogram. G ltal Cardiol 1976;6:786-91. 30. Toyama J. Clinical studies on the sick sinus syndrome. Jpn Circ J 1976;40:203-7. 31. Mdtha~ PB, Flewy G, Caspl G, Faivle D’Arcy F, Henlln A, DlMateo J. Troubles de la conduction sino-auriculaire et auriculo-ventriculaire dans la maladie de steinert. Arch Mal Coeur 1976;69: 547-52. 32. Sinker D, Parameswaran R, Goldberg H. Sinus and A-V nodal dysfunction following myocardial infarction. J Electrocardiol 1975;8:281-3. 33. Dfghton DH. Sinoatrial block autonomic influences and clinical
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assessment. Br Heart J 1975;37:321-5. 34. Waxman WB, Catching JD, Felderhof CH, Downar E, Silver MD, Abbot MM. Familial atrioventricular heart block. An autosomal dominant trait. Circulation 1975;51:226-233. 35. Sarachek NS, Leonard JJ. Familial heart block and sinus bradycardia. Classification and natural history. Am J Cardiol 1972;29: 451-a. 36. Lev M, Kinare SG, Pick A. The pathogenesis of atrioventricular block in coronary disease. Circulation 1970;42:409-25. 37. Bharati S, Lev M, Denes P, et al. Infiltrative cardiomyopathy with conduction disease and ventricular arrhythmia: electrophysiologic and pathologic correlations. Am J Cardiol 1980;45: 163-73. 38. Rosen KM, Rahlrntoola SH, Bharatl S, Lev M. Bundle branch block with intact atrioventricular conduction. Electrophysiologic and pathologic correlations in three cases. Am J Cardiol 1973;32:
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783-93. 39. Bharati S, Lev M, Dhingra R, et al. Pathologic correlations in three cases of bilateral bundle branch disease with unusual electrophysiologic manifestations in two cases. Am J Cardiol 1976;38: 508-18. 40. Rosen KM, Rahimtoola SH, Gunnar RM, Lev M. Transient and persistent atrial standstill with His bundle lesions: electrophysiologic and pathologic correlations. Circulation 1971;44:220-36. 41. Kaplan BY, Laqendorf R, Lev M, Pick A. Tachycardia-bradycardia syndrome (so-called “sick sinus syndrome”): pathology, mechanisms and treatment. Am J Cardiol 1973;31:497-508. 42. Rosen KM, Wu D, Kanakis C Jr, Denes P, Bharatl S, Lev M. Return of normal conductionafter paroxysmal heart block: report of a case with major discordance of electrophysiological and pathological findings. Circulation 1975;51:197-204.