Familial Congenital Sinus Rhythm Anomalies: Clinical and Pathological Correlations SAROJA BHARATI, BORYS SURAWICZ.* HUMBERTO J. VIDAILLET, JR.,** and MAURICE LEV From tbe Congenital Heart and Conduction System Center, Tbe Heart Institute for Children, Christ Hospital and Medical Center Oak Lawn, Illinois; Department of Pathology, Rush Medical College, Rush Presbyterian St. Lukes Medical Center, Chicago. Illinois; "Indiana University, Krannert Institute of Cardiology, Indianapolis, Indiana; and "'Marshfield Medical Center, Marshfield, Wisconsin
BHARATI, S., ET AL.: Familial Congenital Sinus Rhythm Anomalies: Clinical and Pathological Correlations. We describe pathological abnormalities in a 72-year-old nnale member of a family with a congenital absence 0/ sinus rhythm and a tendency to develop atria] fihrillation at an early age, and in a 54year-old female member 0/ a famiJy with cardiomyopathy and progressive conduction system disease manifested by first-degree atrioventricular {AV} block, left bundle branch block, and atrial arrhythmias. Both patients died suddenly. The absence of sinus rhythm in case 1 could be explained by marked atrophy, degeneration, and isolation of the sinoatrial (SA) node. The SA node was also diseased in the member 0/the other family with atrial arrhythmias. Additional common features in both cases included; fatty metamorphosis and degenerative changes of the approaches to the SA node, the atrial preferential fibers, and the approaches to the AV node, a small AV node, degenerative changes of the bundle branches, and floppy AV valves. These findings shoiv that the pathological substrate of familial supraventricular arrhythmias consists of a diffuse involvement of the entire conduction system, bearing resemblance to pathological findings in elderly subjects with acquired sick sinus syndrome. (PACE, Vol. 15, November, Part r 1992} familial congenital absence of sinus rhythm, famiJial cardiomyopathy with arrhythmias, familial firstdegree atrioventricular block, familial progressive conduction system disease, sudden death, pathology of the conduction system
Introduction Although familial atrial arrhythmias and familial first-degree atrioventricular (AV) block have been documented in the clinical literature, there is a paucity of pathological substrates for these entities. This is the first histologic examination of two hearts including the conduction system, one of a member of a family with congenital absence of sinus rhythm, and another of a member
Address for reprints: Saroja Bharati, M.D.. Congenital Heart and Conduction System Center, 11745 Southwest Highway, Palos Heights, IL 60463. Kax; (708] 361-8673. Received March 23,1992; revision May 12,1992; accepted June 5, 1992.
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of a family with cardiomyopathy, congenital firstdegree AV block associated with development of atrial arrhythmias, and left bundle branch block. Both subjects died suddenly.
Case 1 Clinical History This was a 72-year-old white male, member of the second generation in a family with congenital absence of sinus rhythm who collapsed upon rising from a chair and could not be resuscitated. Atrial fibrillation, at first paroxysmal and later chronic, had been present for the past 18 years but was only mildly incapacitating. This subject was IV-14 in the 1988 report enti-
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tied, "Follow-up of the family with congenital absence of sinus rhythm."^ The clinical aspects of this family were originally reported in 1960.^ In addition to the absence of sinus rhythm and atrial tachyrhythmias, the siblings had a dilated pulmonary artery. The genealogy of the present case can be summarized as follows: The condition was inherited from the patient's mother who lived up to age 71, but was known to have a slow heart rate and atrial fibrillation during the last 20 years of her life. In each of the four siblings of the second generation (mother's offspring), permanent atrial fibrillation became established at ages ranging from 54 to 67 years. Among four members of the third generation, three had documented slow supraventricular ectopic rhythms and tachycardia-bradycardia syndrome, and one of them required pacemaker implantation. One member died suddenly at the age of 27 years. In three of the four members of the fourth generation, slow supraventricular ectopic rhythms had been documented since infancy. However, one member had sinus rhythm. Paroxysmal atrial fibrillation was symptomatic in two, and presyncopal sensation occurred in one family member.
lus, the membranous septum, and the base of the aortic valve. The latter showed marked aging changes. The left coronary ostium emerged ahove the supravalvular ridge. All three major coronary artery branches were markedly thickened and calcified, with high grade stenosis. Microscopic Examination of the Gonduction System
Heart: Gross Examination
Methodology. Blocks containing the sinoatrial (SA) node and its approaches, the AV node and its approaches, the AV hundle [penetrating, branching, and bifurcating portions], and the beginning of the bundle branches up to the region of the moderator band were serially sectioned, and every 20th section for case 1 and every 10th section for case 2 was retained. The block containing the atrial preferential pathways (atrial septum) was serially sectioned, and every 40th section was retained. The block containing the peripheral conduction system (distal hundle branches) was likewise serially sectioned, and every 40th section was retained. The remainder of the heart was cut into blocks, and two sections were taken from each block. All sections were alternately stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner, a total of 2,298 sections for case 1 and 2,596 sections for case 2 were examined. The sections were then compared with similar aged group normal conduction system. Findings.
The heart was hypertrophied and enlarged, weighing 650 g. All chambers of the heart were enlarged, and their walls were thickened. The eustachian and thebesian valves were absent, The sulcus terminalis and the endocardium of the right atrium were markedly thickened and whitened. The tricuspid orifice was enlarged, and the tricuspid valve was markedly thickened and redundant from the line of closure to the edge. The pulmonary trunk was aneurysmally dilated, with marked atherosclerosis. The endocardium of the left atrium was thickened, and the mitral valve was enlarged. The posterior leaflet of this valve was large, markedly thickened, and redundant from annulus to the edge. There was considerable thickening and atherosclerosis of the summit of the ventricular septum, involving the aortic-mitral annu-
SA Node. This consisted of a small remnant of SA nodal cells infiltrated with mononuclear cells (Fig. 1). The remnant of the SA node consisted of atrophic nodal fibers with marked fibrosis (Fig. lC), and spotty infiltration with mononuclear cells. The amount of the SA nodal tissue was estimated to be < TO of the SA nodal tissue for a comparable age. Approaches to the SA Node. This showed marked fatty metamorphosis, mononuclear cell infiltration, and hypertrophy and atrophy of cells. There was marked fibrosis with marked thickening and inflammation of the epicardium and endocardium, and considerable fibrosis of the nerves. Many atrial cells underwent degeneration and atrophy but some were hypertrophied.
Postmortem Examination This was limited to heart and lungs. There was marked pulmonary edema.
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Figure 1. Case 1. Hisfologic charocteristics of our present case. SA node. (Panei A) Weigerf-rnn Gieson stain x 30. (Panels B and C) Hemaloxyiin-eosin stain. (Panel B) x 150. (Panel C) x 262.5. Arrows point to the fragmented SA node in panels B and CF = fat: Fi = fibrosis: M = myocardium; H ^ remnant o/ SA node,
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Atrial Preferentiai Pathways. There was marked fatty metamorphosis with moderate chronic inflammation. The endocardium was hypertrophied. Some cells of the pathways were degenerated and associated with marked fibroelastosis throughout. Some arteries showed fibrosis with intimal narrowing. There was also marked muscular thickening of veins. Hypertrophy and atrophy of the atrial cells and fibrosis of nerves were apparent. Summit of the Ventricular Septum. This showed marked fibrosis, focal degeneration of cells, focal thickening of veins, and moderate infiltration of mononuclear cells. The ventricular septum was thickened, with small areas of calcification. Tricuspid VaJve. This revealed marked fibrous thickening at the base, with fibrosis of the proximalis, elastosis of the spongiosa, and with vacuolization and mononuclear cell infiltration at the base. Mitral Vaive. This also showed gross thickening at the base with fatty metamorphosis, increased thickening of fibrosa, and elastosis of the distalis. Approaches to the AV Node. This revealed marked fatty metamorphosis with moderate fibrosis. AV Node. This was smaller than normal, and consisted of relatively few nodal cells. There was fatty metamorphosis, moderate-to-marked mononuclear cell infiltration, and considerable fibrosis. The node was almost isolated by the fat from the surrounding atrial musculature (Fig. 2). AV Bundle: Penetrating Portion. This revealed moderate mononuclear cell infiltration, fibrosis, focal thickening of the veins, and large empty spaces. AV BundJe: Branching Portion. This showed marked mononuclear cell infiltration and a small area of calcification. The amount of empty space formation, chronic inflammation, and fatty metamorphosis was moderate to marked (Fig. 3A), There was marked increase in the number of thinwalled vessels. Left Bundle Branch. Only a fragment of this structure was present amid fibrosis and empty spaces (Fig. 3B). Marked fibrosis also involved the distal part of the left bundle branch.
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Figure 2. Case 1. Isoiation of the AV node /rom (he approaches by/at. Hematoxylin-eosin stain x 105. A ^ atrium; C = centrai /ibrous body; F ^ /at; N ^ AV node.
Bight BundJe Branch. The beginning showed marked elastosis and moderate mononuclear cell infiltration. Fatty metamorphosis was also apparent with an increase in empty spaces. At the end of the second portion, there was marked atrophy of the right bundle branch (Fig. 4). Right Atrium and Rigiit Ventricle. There was marked fibrosis and fatty metamorphosis of the right atrium and marked chronic epicarditis with marked fatty metamorphosis of the right ventricle, Marked sclerosis with narrowing of the coronary arteries was noted. The right ventricular myocardium showed marked fibrosis and focal myocarditis, Left Atrium and Left Ventricle. The left atrium showed marked fibrosis. Chronic epicarditis of the left ventricle was present, with marked fibrosis, focal infiltration of mononuclear cells.
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LBB
K
Figure 3. Case 1. Space formation, fatty metamorphosis, and chronic in/Iammation of the AV bundle and branching portions. (Ponel A] Hematoxylin-eosin sfain x GO. fPanel BJ Weigert-van Gieson stain x 30. Arrows point to the loss of ceils in the bundle and linear/ormations in panels A and B and loss of left bundle branch fibers in pane] B. B ^ branching bundle; F ^ fat; LBB — left bundle branch; V — ventricular myocardium.
focal myocarditis, and acute focal degeneration of the myocardium. Posterior Septum; Apex. Marked focal fibrosis and fatty metamorphosis were present. Anatomical Diagnosis (1) Familial congenital absence of sinus rhythm history. (2) Atherosclerotic three vessel coronary artery disease with calcification. (3) Cardiomegaly (hypertrophy and dilatation of all chambers). (4) Floppy tricuspid and mitral valves. Microscopic Diagnosis (1) Remnant of SA node with few nodal cells remaining; marked fatty metamorphosis, atrophy, and marked fihrosis.
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(2) Marked fatty metamorphosis of approaches to SA node, with marked fibrosis and atrophy of atrial cells, and fibrosis of nerves. (3) Marked fatty metamorphosis, chronic inflammation, and fibroelastosis of atrial preferential pathways. (4) Marked fibrosis of summit of the ventricular septum with calcification. (5) Fatty metamorphosis and fibrosis of the approaches to the AV node, (6} Small AV node isolated from its approaches. (7) Fatty metamorphosis, mononuclear cell infiltration, and fibrosis of the AV node. (8) Space formation, chronic inflammation, and fatty metamorphosis of the AV bundle. (9) Marked atrophy of the beginning of the left bundle branch.
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History
She was diagnosed to have familial cardiomyopathy and at age 47 (1982] underwent cardioversion for atrial flutter. She was later diagnosed to have sick sinus syndrome with chronic atrial flutter, and a permanent pacemaker was implanted for conduction system disease with syncope. She had ventricular arrhythmias that were induced during the electrophysiological studies but these were not sustained in nature. Postmortem Examination
Heart: Gross Examination The heart weighed 450 g. The right atrium and ventricle were enlarged and their walls were thickened. The coronary sinus was enlarged and received a left superior vena cava. There was marked fatty infiltration in the coronary sinus area, the region of the approaches to the AV node, the AV node proper, and the central fibrous body. The atrial component of the membranous part of the ventricular septum was large. Also, the tricuspid orifice and the tricuspid valve were large. There was thickening and redundancy of both leaflets of the mitral valve (Fig. 5). The membranous septum Figure 4. Case 1. Right bundle branch showing marked atrophy. Weigert-van Gieson stain x 150. Arrows point to the atrophied second part of the right bundle branch intramyocardiaily. V - ventricular myocardium.
(10) Marked atrophy of the right bundle branch peripherally. (11) Marked chronic epicarditis and focal fibrosis of the right and left ventricles.
Case 2 Clinical History This was a 54-year-oId woman who died suddenly. She was one of the seven siblings with a diagnosis of progressive conduction system disease manifested initially by first-degree AV block and by subsequent development of left bundle branch block and atrial arrhythmias, followed hy deterioration of left ventricular function.
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Figure 5. Case 2. Gross picture of the left atrium (LA) and left ventricle (LVj showing thickening and redundancy of both mitral leaflets. MV ^ mitraJ valve.
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was enlarged. The left ventricle was hypertrophied. The aortic valve was sclerotic. The coronary arteries were mildly sclerotic and slightly narrowed. Microscopic Examination SA Node. This showed paucity of nodal cells. The node was almost completely isolated from the atrial ceils (Fig. 6). The amount of elastic tissue was diminished and there were foci of fibrosis. Approaches to the SA Node. Marked fibrosis and fatty metamorphosis were present. Thrombi and occasional hemorrhages were noted in the arteries. The epicardium was infiltrated with monouuclear cells. AtriaJ Preferential Pathivays. Marked fatty metamorphosis was noted. The nerves showed marked fibrosis, and some were infiltrated with mononuclear cells. Summit of VentricuJar Septum. Marked fibrosis was present, especially on the left side. AV Node. This was almost isolated from the surrounding myocardium with marked fatty metamorphosis. The node was almost absent. AV Bundle; Penetrating Portion. Marked fatty metamorphosis was noted in penetrating portion (Fig. 7), with empty space formation and elastosis in the branching portion. The bundle hegan on the left side and had a rightward course. Bifurcation. Space formation and moderate fatty metamorphosis were evident. Left Bundle Branch. Marked fibrosis with marked degenerative changes resulted in near destruction of the left hundle branch (Fig. 8]. Right Bundle Branch. This was large at the beginning but more distally showed marked elastosis with space formation. However, it remained intact until the end. Mitral Valve. There was a marked increase in the fihrosa. Tricuspid Valve. This was markedly thickened with a large fibrous prong. There was a marked increase in fibrosa. flight Ventricle. Marked fatty metamorphosis was present. Left Ventricle. Marked fatty metamorphosis in both atria and ventricles with marked fibrosis were evident.
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Figure 6. Case 2. SA node showing marked fibrosis and fatty metamorphosis. The node is almost completely separated from the atrial musculature. Hematoxylineosin stain X 30. At = atriai musculature; F ^ fat; N = AV node.
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Figure 7. Case 2. AV hund]e, penetrating portion, showing marked fatty metamorphosis. Weigert-van Gieson stain X 85. B = hundle; C ^ centra]/ibrous body: F -
fat.
Figure 8. Case 2 showing marked degeneration and near destruction of the left bundle branch. HematoxyJin-eosin stain x 150. Arrows point to the left bundle branch. VS ^ ventricular septum.
Anatomical Diagnosis (1) Familial cardiomyopathy. (2) Floppy mitral valve. (3) Separation of SA node from atrial musculature. (4) Almost absence of the AV node and isolation from the atrial musculature with marked fatty infiltration. (5) Fatty metamorphosis of AV bundle. (6) Marked fibrosis of the left bundle branch. (7) Marked fatty metamorphosis and fibrosis of the ventricles.
Discussion In our patient 1, the histologic examination of the conduction system documented for the first
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time the pathological substrate of the familial absence of sinus rhythm. The examination showed nearly complete absence of SA nodal tissue with only a few cells scattered within the degenerated atrial tissue. Other pertinent findings included: marked fatty infiltration and degenerative changes, atrophy and hypertrophy of the approaches to the SA and AV nodes, fatty metamorphosis of the atria, and a small AV node. The almost absence of the sinus node and the small AV node are most likely of congenital etiology. Fat, fibrosis. and atrophy in other parts of the conduction system and the heart represent the acquired changes. The relationship of the floppy mitral and tricuspid valves to familial absence of sinus rhythm is unclear. There were no autopsies on the previous two deaths in the family and the clinical
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examination and the cardiac catheterization did not suggest evidence of mitral valve prolapse. The clinical features of the family in case 1 have been reported.^-^ Slow heart rate and irregular rhythm were present since birth; symptoms frequently occurred in the later twenties and thirties, and most subjects developed atrial fibrillation at a variable age. Only one subject with the disease died suddenly. Clinically, the third and fourth generation members with bradycardia appeared to be more symptomatic at a younger age than their parents. This may be related to a less efficient function of the escape pacemaker. In patient 2, a case of familial cardiomyopathy and familial arrhythmia was associated with abnormal SA node, AV node, AV bundle, left bundle branch, and a floppy mitral valve. Other findings in common with case 1 were; (1) the enlarged heart; (2) fatty infiltration and fibrosis of the SA node, AV node, their approaches, and the atrial preferential pathways; (3) almost absent AV node; (4) involvement of the distal conduction system; (5) familial occurrence and autosomal dominance; (6) progression in both to atrial fibrillation and flutter; and (7) sudden death. The above findings in our two cases suggest the presence of a familial genetic trait responsible for conduction tissue abnormalities involving the SA and AV nodes, and probably the peripheral conduction system. Several pathological abnormalities may be incriminated in sudden death that occurred in both cases. These include; (1) Fibrosis of the ventricular septum with focal degeneration. (2) Hypertrophied heart. (3) Focal myocarditis. (4) Marked fatty metamorphosis and degeneration of the AV bundle. (5) Marked fibrosis of the left bundle branch and atrophy of the distal portion of the right bundle branch. The distal part of the conduction system in our two cases showed marked pathological abnormalities, a finding that could have played a role in the sudden death in both cases. The findings in the two cases in this report resemble a previously published case of familial
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arrhythmia^ in a 40-year-old female from a family with sinus node disease, atrial standstill, AV dissociation, first-degree AV ventricular block, atrial fibrillation, sinus bradycardia with AV block, bundle branch block, and bidirectional tachycardia. This patient is still alive. However, her mother who had atrial fibrillation and complete AV block died suddenly. Four members of the family died suddenly before the age of 35 with atrial fibrillation without AV block, or first-degree AV ventricular block, persistent sinus bradycardia, wandering atrial pacemaker, and multiple atrial premature beats. Altogether, three members of the first generation, four members of the second generation, and eight members of the fourth generation had the above ECG abnormalities. The pathological findings in the approaches to the SA node, atrial preferential pathways, approaches to the AV node, and the AV node were similar to the previously studied patients with sick sinus syndrome in the elderly and in the adolescent.*-^ However, unlike the almost complete absence of SA nodal fibers in our case 1, the SA node was present but showed an increase in connective tissue^ in patients with sick sinus syndrome in adolescence. On the other hand, sick sinus syndrome in the elderly was associated with small vessel disease, amyloidosis, and fibro-fatty degeneration of the elastic and collagen fibers of the SA node." Also, marked pathological abnormalities of the AV bundle and the distal conduction system in our two patients were similar to the previously described changes in the distal conduction system in sick sinus syndrome.''•^ Thus, the common pathological features of the absent sinus rhythm and sick sinus syndrome include; [1) coronary artery disease with or without infarction; (2] development of atrial fibrillation; (3) disease of the distal conduction system (AV bundle and bundle branches); and (4) occurrence of sudden death. In summary, the two patients have a certain similarity. Both have abnormal SA and AV nodes with further abnormalities in the conduction system. The maximum pathology in the first case is in the SA and the AV nodes. The maximum pathology in the second case is in the AV node but also in other parts of the conduction system. They are both described together because they are familial. The theme that is promulgated is that there are
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congenital familial abnormalities in the conduction system. These abnormalities may be somewhat different from one case to another but they are both familial in nature. The acquired changes probably are related not only to aging but also to the chronic nature of the arrhythmias both patients had for many years (patient 1: 72 years; and patient 2: 54 years). The familial occurrence of ar-
rhythmias in both patients suggest that there is a tendency for a genetically weak or a tendency for a vulnerable conduction system in some families that may predispose or accelerate the acquired pathological changes with time. The fact that both had mitral valve prolapse does not necessarily imply that this is the basis of the conduction system abnormalities in these cases.
References 1. Surawicz B, Hariman RJ. Follow-up of the family with congenital absence of sinus rhythm. Am J Cardiol 1988: 61:467-469. 2. Bacos |M, Eagan IT, Orgain ES. Congenital familial nodal rhythm. Circulation 1960: 22:887-895. 3. Amat-y-Leon F. Racki AJ, Denes P, et al. Familial atrial dysrhythmia with A-V hlock. Circulation 1974; 50:1097-1104.
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Kaplan BM, Langendorf R, Lev M. et al. Tachycardia-bradycardia syndrome (so-called "sick sinus syndrome"). Am J Cardiol 1973; 31:497-508. Bharati S, Nordenberg A, Bauernfeind R, et al. The anatomic suhstrate for the sick sinus syndrome in adolescence. Am J Cardiol 1980; 46;163-172.
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BHARATI, S., ET AL.: Familial Congenital Sinus Rhythm Anomalies: Clinical and Pathological Correlations. We describe pathological abnormalities in a 72-year-old nnale member of a family with a congenital absence 0/ sinus rhythm and a tendency to develop atria] fihrillation at an early age, and in a 54year-old female member 0/ a famiJy with cardiomyopathy and progressive conduction system disease manifested by first-degree atrioventricular {AV} block, left bundle branch block, and atrial arrhythmias. Both patients died suddenly. The absence of sinus rhythm in case 1 could be explained by marked atrophy, degeneration, and isolation of the sinoatrial (SA) node. The SA node was also diseased in the member 0/the other family with atrial arrhythmias. Additional common features in both cases included; fatty metamorphosis and degenerative changes of the approaches to the SA node, the atrial preferential fibers, and the approaches to the AV node, a small AV node, degenerative changes of the bundle branches, and floppy AV valves. These findings shoiv that the pathological substrate of familial supraventricular arrhythmias consists of a diffuse involvement of the entire conduction system, bearing resemblance to pathological findings in elderly subjects with acquired sick sinus syndrome. (PACE, Vol. 15, November, Part r 1992} familial congenital absence of sinus rhythm, famiJial cardiomyopathy with arrhythmias, familial firstdegree atrioventricular block, familial progressive conduction system disease, sudden death, pathology of the conduction system
Introduction Although familial atrial arrhythmias and familial first-degree atrioventricular (AV) block have been documented in the clinical literature, there is a paucity of pathological substrates for these entities. This is the first histologic examination of two hearts including the conduction system, one of a member of a family with congenital absence of sinus rhythm, and another of a member
Address for reprints: Saroja Bharati, M.D.. Congenital Heart and Conduction System Center, 11745 Southwest Highway, Palos Heights, IL 60463. Kax; (708] 361-8673. Received March 23,1992; revision May 12,1992; accepted June 5, 1992.
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of a family with cardiomyopathy, congenital firstdegree AV block associated with development of atrial arrhythmias, and left bundle branch block. Both subjects died suddenly.
Case 1 Clinical History This was a 72-year-old white male, member of the second generation in a family with congenital absence of sinus rhythm who collapsed upon rising from a chair and could not be resuscitated. Atrial fibrillation, at first paroxysmal and later chronic, had been present for the past 18 years but was only mildly incapacitating. This subject was IV-14 in the 1988 report enti-
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tied, "Follow-up of the family with congenital absence of sinus rhythm."^ The clinical aspects of this family were originally reported in 1960.^ In addition to the absence of sinus rhythm and atrial tachyrhythmias, the siblings had a dilated pulmonary artery. The genealogy of the present case can be summarized as follows: The condition was inherited from the patient's mother who lived up to age 71, but was known to have a slow heart rate and atrial fibrillation during the last 20 years of her life. In each of the four siblings of the second generation (mother's offspring), permanent atrial fibrillation became established at ages ranging from 54 to 67 years. Among four members of the third generation, three had documented slow supraventricular ectopic rhythms and tachycardia-bradycardia syndrome, and one of them required pacemaker implantation. One member died suddenly at the age of 27 years. In three of the four members of the fourth generation, slow supraventricular ectopic rhythms had been documented since infancy. However, one member had sinus rhythm. Paroxysmal atrial fibrillation was symptomatic in two, and presyncopal sensation occurred in one family member.
lus, the membranous septum, and the base of the aortic valve. The latter showed marked aging changes. The left coronary ostium emerged ahove the supravalvular ridge. All three major coronary artery branches were markedly thickened and calcified, with high grade stenosis. Microscopic Examination of the Gonduction System
Heart: Gross Examination
Methodology. Blocks containing the sinoatrial (SA) node and its approaches, the AV node and its approaches, the AV hundle [penetrating, branching, and bifurcating portions], and the beginning of the bundle branches up to the region of the moderator band were serially sectioned, and every 20th section for case 1 and every 10th section for case 2 was retained. The block containing the atrial preferential pathways (atrial septum) was serially sectioned, and every 40th section was retained. The block containing the peripheral conduction system (distal hundle branches) was likewise serially sectioned, and every 40th section was retained. The remainder of the heart was cut into blocks, and two sections were taken from each block. All sections were alternately stained with hematoxylin-eosin and Weigert-van Gieson stains. In this manner, a total of 2,298 sections for case 1 and 2,596 sections for case 2 were examined. The sections were then compared with similar aged group normal conduction system. Findings.
The heart was hypertrophied and enlarged, weighing 650 g. All chambers of the heart were enlarged, and their walls were thickened. The eustachian and thebesian valves were absent, The sulcus terminalis and the endocardium of the right atrium were markedly thickened and whitened. The tricuspid orifice was enlarged, and the tricuspid valve was markedly thickened and redundant from the line of closure to the edge. The pulmonary trunk was aneurysmally dilated, with marked atherosclerosis. The endocardium of the left atrium was thickened, and the mitral valve was enlarged. The posterior leaflet of this valve was large, markedly thickened, and redundant from annulus to the edge. There was considerable thickening and atherosclerosis of the summit of the ventricular septum, involving the aortic-mitral annu-
SA Node. This consisted of a small remnant of SA nodal cells infiltrated with mononuclear cells (Fig. 1). The remnant of the SA node consisted of atrophic nodal fibers with marked fibrosis (Fig. lC), and spotty infiltration with mononuclear cells. The amount of the SA nodal tissue was estimated to be < TO of the SA nodal tissue for a comparable age. Approaches to the SA Node. This showed marked fatty metamorphosis, mononuclear cell infiltration, and hypertrophy and atrophy of cells. There was marked fibrosis with marked thickening and inflammation of the epicardium and endocardium, and considerable fibrosis of the nerves. Many atrial cells underwent degeneration and atrophy but some were hypertrophied.
Postmortem Examination This was limited to heart and lungs. There was marked pulmonary edema.
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Figure 1. Case 1. Hisfologic charocteristics of our present case. SA node. (Panei A) Weigerf-rnn Gieson stain x 30. (Panels B and C) Hemaloxyiin-eosin stain. (Panel B) x 150. (Panel C) x 262.5. Arrows point to the fragmented SA node in panels B and CF = fat: Fi = fibrosis: M = myocardium; H ^ remnant o/ SA node,
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Atrial Preferentiai Pathways. There was marked fatty metamorphosis with moderate chronic inflammation. The endocardium was hypertrophied. Some cells of the pathways were degenerated and associated with marked fibroelastosis throughout. Some arteries showed fibrosis with intimal narrowing. There was also marked muscular thickening of veins. Hypertrophy and atrophy of the atrial cells and fibrosis of nerves were apparent. Summit of the Ventricular Septum. This showed marked fibrosis, focal degeneration of cells, focal thickening of veins, and moderate infiltration of mononuclear cells. The ventricular septum was thickened, with small areas of calcification. Tricuspid VaJve. This revealed marked fibrous thickening at the base, with fibrosis of the proximalis, elastosis of the spongiosa, and with vacuolization and mononuclear cell infiltration at the base. Mitral Vaive. This also showed gross thickening at the base with fatty metamorphosis, increased thickening of fibrosa, and elastosis of the distalis. Approaches to the AV Node. This revealed marked fatty metamorphosis with moderate fibrosis. AV Node. This was smaller than normal, and consisted of relatively few nodal cells. There was fatty metamorphosis, moderate-to-marked mononuclear cell infiltration, and considerable fibrosis. The node was almost isolated by the fat from the surrounding atrial musculature (Fig. 2). AV Bundle: Penetrating Portion. This revealed moderate mononuclear cell infiltration, fibrosis, focal thickening of the veins, and large empty spaces. AV BundJe: Branching Portion. This showed marked mononuclear cell infiltration and a small area of calcification. The amount of empty space formation, chronic inflammation, and fatty metamorphosis was moderate to marked (Fig. 3A), There was marked increase in the number of thinwalled vessels. Left Bundle Branch. Only a fragment of this structure was present amid fibrosis and empty spaces (Fig. 3B). Marked fibrosis also involved the distal part of the left bundle branch.
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Figure 2. Case 1. Isoiation of the AV node /rom (he approaches by/at. Hematoxylin-eosin stain x 105. A ^ atrium; C = centrai /ibrous body; F ^ /at; N ^ AV node.
Bight BundJe Branch. The beginning showed marked elastosis and moderate mononuclear cell infiltration. Fatty metamorphosis was also apparent with an increase in empty spaces. At the end of the second portion, there was marked atrophy of the right bundle branch (Fig. 4). Right Atrium and Rigiit Ventricle. There was marked fibrosis and fatty metamorphosis of the right atrium and marked chronic epicarditis with marked fatty metamorphosis of the right ventricle, Marked sclerosis with narrowing of the coronary arteries was noted. The right ventricular myocardium showed marked fibrosis and focal myocarditis, Left Atrium and Left Ventricle. The left atrium showed marked fibrosis. Chronic epicarditis of the left ventricle was present, with marked fibrosis, focal infiltration of mononuclear cells.
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LBB
K
Figure 3. Case 1. Space formation, fatty metamorphosis, and chronic in/Iammation of the AV bundle and branching portions. (Ponel A] Hematoxylin-eosin sfain x GO. fPanel BJ Weigert-van Gieson stain x 30. Arrows point to the loss of ceils in the bundle and linear/ormations in panels A and B and loss of left bundle branch fibers in pane] B. B ^ branching bundle; F ^ fat; LBB — left bundle branch; V — ventricular myocardium.
focal myocarditis, and acute focal degeneration of the myocardium. Posterior Septum; Apex. Marked focal fibrosis and fatty metamorphosis were present. Anatomical Diagnosis (1) Familial congenital absence of sinus rhythm history. (2) Atherosclerotic three vessel coronary artery disease with calcification. (3) Cardiomegaly (hypertrophy and dilatation of all chambers). (4) Floppy tricuspid and mitral valves. Microscopic Diagnosis (1) Remnant of SA node with few nodal cells remaining; marked fatty metamorphosis, atrophy, and marked fihrosis.
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(2) Marked fatty metamorphosis of approaches to SA node, with marked fibrosis and atrophy of atrial cells, and fibrosis of nerves. (3) Marked fatty metamorphosis, chronic inflammation, and fibroelastosis of atrial preferential pathways. (4) Marked fibrosis of summit of the ventricular septum with calcification. (5) Fatty metamorphosis and fibrosis of the approaches to the AV node, (6} Small AV node isolated from its approaches. (7) Fatty metamorphosis, mononuclear cell infiltration, and fibrosis of the AV node. (8) Space formation, chronic inflammation, and fatty metamorphosis of the AV bundle. (9) Marked atrophy of the beginning of the left bundle branch.
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History
She was diagnosed to have familial cardiomyopathy and at age 47 (1982] underwent cardioversion for atrial flutter. She was later diagnosed to have sick sinus syndrome with chronic atrial flutter, and a permanent pacemaker was implanted for conduction system disease with syncope. She had ventricular arrhythmias that were induced during the electrophysiological studies but these were not sustained in nature. Postmortem Examination
Heart: Gross Examination The heart weighed 450 g. The right atrium and ventricle were enlarged and their walls were thickened. The coronary sinus was enlarged and received a left superior vena cava. There was marked fatty infiltration in the coronary sinus area, the region of the approaches to the AV node, the AV node proper, and the central fibrous body. The atrial component of the membranous part of the ventricular septum was large. Also, the tricuspid orifice and the tricuspid valve were large. There was thickening and redundancy of both leaflets of the mitral valve (Fig. 5). The membranous septum Figure 4. Case 1. Right bundle branch showing marked atrophy. Weigert-van Gieson stain x 150. Arrows point to the atrophied second part of the right bundle branch intramyocardiaily. V - ventricular myocardium.
(10) Marked atrophy of the right bundle branch peripherally. (11) Marked chronic epicarditis and focal fibrosis of the right and left ventricles.
Case 2 Clinical History This was a 54-year-oId woman who died suddenly. She was one of the seven siblings with a diagnosis of progressive conduction system disease manifested initially by first-degree AV block and by subsequent development of left bundle branch block and atrial arrhythmias, followed hy deterioration of left ventricular function.
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Figure 5. Case 2. Gross picture of the left atrium (LA) and left ventricle (LVj showing thickening and redundancy of both mitral leaflets. MV ^ mitraJ valve.
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was enlarged. The left ventricle was hypertrophied. The aortic valve was sclerotic. The coronary arteries were mildly sclerotic and slightly narrowed. Microscopic Examination SA Node. This showed paucity of nodal cells. The node was almost completely isolated from the atrial ceils (Fig. 6). The amount of elastic tissue was diminished and there were foci of fibrosis. Approaches to the SA Node. Marked fibrosis and fatty metamorphosis were present. Thrombi and occasional hemorrhages were noted in the arteries. The epicardium was infiltrated with monouuclear cells. AtriaJ Preferential Pathivays. Marked fatty metamorphosis was noted. The nerves showed marked fibrosis, and some were infiltrated with mononuclear cells. Summit of VentricuJar Septum. Marked fibrosis was present, especially on the left side. AV Node. This was almost isolated from the surrounding myocardium with marked fatty metamorphosis. The node was almost absent. AV Bundle; Penetrating Portion. Marked fatty metamorphosis was noted in penetrating portion (Fig. 7), with empty space formation and elastosis in the branching portion. The bundle hegan on the left side and had a rightward course. Bifurcation. Space formation and moderate fatty metamorphosis were evident. Left Bundle Branch. Marked fibrosis with marked degenerative changes resulted in near destruction of the left hundle branch (Fig. 8]. Right Bundle Branch. This was large at the beginning but more distally showed marked elastosis with space formation. However, it remained intact until the end. Mitral Valve. There was a marked increase in the fihrosa. Tricuspid Valve. This was markedly thickened with a large fibrous prong. There was a marked increase in fibrosa. flight Ventricle. Marked fatty metamorphosis was present. Left Ventricle. Marked fatty metamorphosis in both atria and ventricles with marked fibrosis were evident.
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Figure 6. Case 2. SA node showing marked fibrosis and fatty metamorphosis. The node is almost completely separated from the atrial musculature. Hematoxylineosin stain X 30. At = atriai musculature; F ^ fat; N = AV node.
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Figure 7. Case 2. AV hund]e, penetrating portion, showing marked fatty metamorphosis. Weigert-van Gieson stain X 85. B = hundle; C ^ centra]/ibrous body: F -
fat.
Figure 8. Case 2 showing marked degeneration and near destruction of the left bundle branch. HematoxyJin-eosin stain x 150. Arrows point to the left bundle branch. VS ^ ventricular septum.
Anatomical Diagnosis (1) Familial cardiomyopathy. (2) Floppy mitral valve. (3) Separation of SA node from atrial musculature. (4) Almost absence of the AV node and isolation from the atrial musculature with marked fatty infiltration. (5) Fatty metamorphosis of AV bundle. (6) Marked fibrosis of the left bundle branch. (7) Marked fatty metamorphosis and fibrosis of the ventricles.
Discussion In our patient 1, the histologic examination of the conduction system documented for the first
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time the pathological substrate of the familial absence of sinus rhythm. The examination showed nearly complete absence of SA nodal tissue with only a few cells scattered within the degenerated atrial tissue. Other pertinent findings included: marked fatty infiltration and degenerative changes, atrophy and hypertrophy of the approaches to the SA and AV nodes, fatty metamorphosis of the atria, and a small AV node. The almost absence of the sinus node and the small AV node are most likely of congenital etiology. Fat, fibrosis. and atrophy in other parts of the conduction system and the heart represent the acquired changes. The relationship of the floppy mitral and tricuspid valves to familial absence of sinus rhythm is unclear. There were no autopsies on the previous two deaths in the family and the clinical
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examination and the cardiac catheterization did not suggest evidence of mitral valve prolapse. The clinical features of the family in case 1 have been reported.^-^ Slow heart rate and irregular rhythm were present since birth; symptoms frequently occurred in the later twenties and thirties, and most subjects developed atrial fibrillation at a variable age. Only one subject with the disease died suddenly. Clinically, the third and fourth generation members with bradycardia appeared to be more symptomatic at a younger age than their parents. This may be related to a less efficient function of the escape pacemaker. In patient 2, a case of familial cardiomyopathy and familial arrhythmia was associated with abnormal SA node, AV node, AV bundle, left bundle branch, and a floppy mitral valve. Other findings in common with case 1 were; (1) the enlarged heart; (2) fatty infiltration and fibrosis of the SA node, AV node, their approaches, and the atrial preferential pathways; (3) almost absent AV node; (4) involvement of the distal conduction system; (5) familial occurrence and autosomal dominance; (6) progression in both to atrial fibrillation and flutter; and (7) sudden death. The above findings in our two cases suggest the presence of a familial genetic trait responsible for conduction tissue abnormalities involving the SA and AV nodes, and probably the peripheral conduction system. Several pathological abnormalities may be incriminated in sudden death that occurred in both cases. These include; (1) Fibrosis of the ventricular septum with focal degeneration. (2) Hypertrophied heart. (3) Focal myocarditis. (4) Marked fatty metamorphosis and degeneration of the AV bundle. (5) Marked fibrosis of the left bundle branch and atrophy of the distal portion of the right bundle branch. The distal part of the conduction system in our two cases showed marked pathological abnormalities, a finding that could have played a role in the sudden death in both cases. The findings in the two cases in this report resemble a previously published case of familial
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arrhythmia^ in a 40-year-old female from a family with sinus node disease, atrial standstill, AV dissociation, first-degree AV ventricular block, atrial fibrillation, sinus bradycardia with AV block, bundle branch block, and bidirectional tachycardia. This patient is still alive. However, her mother who had atrial fibrillation and complete AV block died suddenly. Four members of the family died suddenly before the age of 35 with atrial fibrillation without AV block, or first-degree AV ventricular block, persistent sinus bradycardia, wandering atrial pacemaker, and multiple atrial premature beats. Altogether, three members of the first generation, four members of the second generation, and eight members of the fourth generation had the above ECG abnormalities. The pathological findings in the approaches to the SA node, atrial preferential pathways, approaches to the AV node, and the AV node were similar to the previously studied patients with sick sinus syndrome in the elderly and in the adolescent.*-^ However, unlike the almost complete absence of SA nodal fibers in our case 1, the SA node was present but showed an increase in connective tissue^ in patients with sick sinus syndrome in adolescence. On the other hand, sick sinus syndrome in the elderly was associated with small vessel disease, amyloidosis, and fibro-fatty degeneration of the elastic and collagen fibers of the SA node." Also, marked pathological abnormalities of the AV bundle and the distal conduction system in our two patients were similar to the previously described changes in the distal conduction system in sick sinus syndrome.''•^ Thus, the common pathological features of the absent sinus rhythm and sick sinus syndrome include; [1) coronary artery disease with or without infarction; (2] development of atrial fibrillation; (3) disease of the distal conduction system (AV bundle and bundle branches); and (4) occurrence of sudden death. In summary, the two patients have a certain similarity. Both have abnormal SA and AV nodes with further abnormalities in the conduction system. The maximum pathology in the first case is in the SA and the AV nodes. The maximum pathology in the second case is in the AV node but also in other parts of the conduction system. They are both described together because they are familial. The theme that is promulgated is that there are
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congenital familial abnormalities in the conduction system. These abnormalities may be somewhat different from one case to another but they are both familial in nature. The acquired changes probably are related not only to aging but also to the chronic nature of the arrhythmias both patients had for many years (patient 1: 72 years; and patient 2: 54 years). The familial occurrence of ar-
rhythmias in both patients suggest that there is a tendency for a genetically weak or a tendency for a vulnerable conduction system in some families that may predispose or accelerate the acquired pathological changes with time. The fact that both had mitral valve prolapse does not necessarily imply that this is the basis of the conduction system abnormalities in these cases.
References 1. Surawicz B, Hariman RJ. Follow-up of the family with congenital absence of sinus rhythm. Am J Cardiol 1988: 61:467-469. 2. Bacos |M, Eagan IT, Orgain ES. Congenital familial nodal rhythm. Circulation 1960: 22:887-895. 3. Amat-y-Leon F. Racki AJ, Denes P, et al. Familial atrial dysrhythmia with A-V hlock. Circulation 1974; 50:1097-1104.
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Kaplan BM, Langendorf R, Lev M. et al. Tachycardia-bradycardia syndrome (so-called "sick sinus syndrome"). Am J Cardiol 1973; 31:497-508. Bharati S, Nordenberg A, Bauernfeind R, et al. The anatomic suhstrate for the sick sinus syndrome in adolescence. Am J Cardiol 1980; 46;163-172.
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