Histopathology of the Conduction System in Sudden Death from Coronary Heart Disease By J. T. LIE, M.D. SUMMARY
Sudden cardiac death (SCD) has been attributed to the development of lethal dysrhythmias in coronary heart disease victims, and several recent autopsy surveys showed that 10 to 50% of SCD patients had unsuspected acute myocardial infaretion (AMI). The present study concerned histopathologic findings of the conduction system in 49 SCD (within six hours of the onset of acute symptoms) patients; 39 with established AMI (group A) and ten without (group B). Both groups showed high incidence of cardiomegaly, significant coronary artery disease affecting one or more vessels, and acute myocardial ischemia detectable by specific histological criteria. Stenosis of nutrient vessels of the conduction system was present in about 50% of the atrioventricular (A-V) node arteries and about 25% of the sinoatrial (SA) node arteries in both groups of SCD patients. Nonspecific "degenerative" changes (fibrosis, fatty infiltration, or both) of the conduction tissue, which might or might not represent results of old ischemic injury, also occurred with similar frequencies. Acute changes (infarction, hemorrhage) of the A-V node and bundle branches were found only in two group A patients, both had massive septal infarction. Thus, the conduction tissue appeared more resistant to ischemic injury and was overtly damaged only on rare occasions in fatal AMI. The scarcity of acute lesions in the conduction system itself suggested that lethal dysrhythmia in SCD was probably due to electrical instability of the acutely ischemic contractile myocardium rather than a direct injury to the specialized tissue of the heart.
Additional Indexing Words: Cardiac dysrhythmia Myocardial infarction
Coronary artery disease Autopsy study
Myocardial isehemia Atrioventricular node infaretion
evidence supports the notion that ventricular fibrillation or cardiac asystole is the most important mechanism of pre-hospital and hospital SCD,3 whether the lethal cardiac arrhythmia is associated with acute or specific lesions of the conduction system has not been documented. Because of this unsettled question, a study was carried out to determine the histopathology of the conduction system in 49 SCD, some with and some without unsuspected AMI.
THE MOST DISTURBING FINDING of any inquiry into the natural history of coronary heart
disease is the alarmingly high incidence of sudden cardiac death (SCD); epidemiological studies, both here and abroad, have repeatedly shown that, in about 40 to 70% of all deaths due to coronary heart disease, the victims died outside of a hospital or were dead on arrival.' For a cohort of patients with myocardial infarction, there are as many deaths within the first 24 hours as during the next five years.4 Recent pathologic studies have not only reaffirmed the prevalence of severe coronary atherosclerosis in SCD, but also revealed that 10 to 50% of the victims had unsuspected acute myocardial infarction (AMI),"10 and an even higher proportion had inapparent early myocardial ischemia.` Although electrophysiologic
Patients and Methods The 49 SCD were selected from a larger group of 120 patients previously reported,8 composed of all 39 patients with histologically demonstrable acute myocardial infarcts (group A) and ten of the remaining 81 patients without acute infarcts (group B). The patients, 35 men (mean age: 57 years) and 14 women (mean age: 62 years), died suddenly within six hours of the onset of acute symptoms. All but four deaths were witnessed. Sixty-eight percent (33/49) of the patients died at home, 12% (6/49) at work, 8% (4/49) at various sporting events either as participants or spectators, and 12% (6/49) in the ambulance or a hospital emergency room. Physical activity immediately preceding the terminal event was described as strenuous in only 14% (7/49) and moderate, mild, or none (resting) in the remainder. Resuscitations including defibrillation were attempted in the attended patients, but not all electrocardiographic monitoring records preceding the terminal event were available. In every instance, a complete autopsy examination had
From the Departments of Pathology, Mayo Clinic, Rochester, Minnesota, and Royal Melbourne Hospital, Melbourne, Australia. Supported in part by a Grant-in-Aid (71-200) from the Victor Hurley Medical Research Fund, Royal Melbourne Hospital. Dr. Lie is presently Associate Professor of Pathology, Baylor College of Medicine, Houston, Texas. Address for reprints: J. T. Lie, M.D., Department of Pathology, Baylor College of Medicine, 1200 Moursund, Houston, Texas 77025. Received July 11, 1974; revision accepted for publication November 19, 1974. 446
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CONDUCTION SYSTEM IN SUDDEN DEATH
447
Table 1 Major Cardiac Findings in Sudden Death from Coronary Heart Disease Group*
Number of patients
cardiomegaly (> 350 g)
A B Total
39 10 49
27 (69%) 7 (70%) 34 (69%)
*A: with recent myocardial
Significant coronary artery
diseaset
Recent coronary
thrombosist
Healed myocardial infarcts
34t (87%) 9t (90%) 43 (88%)
7 (18%) 2 (20%) 9 (18%)
18 (46%) 4 (40%) 22 (45%)
Acute myocardial
ischemia§ 33 (85c%) 8 (80%) 41 (84%,)
infarcts; B: without recent myocardial infarcts.
tDetermined by histologic aging to be less than 24 hours old. Number with 75% or greater luminal narrowing of one or more major epicardial coronary arteries. §Determined by positive HBFP staining and myofibrillar degeneration.
excluded
of death. The
noncoronary causes
gross
and
arteries and the described in detail pre-
microscopic examination of the
coronary
heart were conducted as viously.6' 12, 13 The methods of studying the conduction
system were similar to those described by Lev.'14 15 About three to five sinoatrial (SA) and six to nine atrioventricular
(A-V) conduction tissue blocks were prepared for histologic examination. Special care was directed to the correct sequence of tissue blocks during processing so that the topography of the conduction tissue could be reconstructed. From these tissue blocks, every fortieth and the adjacent 5-7,u sections were stained by hematoxylin-eosin (H&E), elastic van Gieson (ELVG) or Movat's pentachrome, and the nonenzymatic hematoxylin basic fuchsin-picric acid or HBFP stains.'6 All intervening sections were kept available for examination when needed. An average of 200 to 350 sections of the conduction system were examined per patient. Cardiomegaly was defined as heart weight exceeding the maximum of a normal range related to the body weight,'7 and in most instances, this meant heart weight exceeding 350 g. Significant coronary artery disease was defined as 75% or greater luminal narrowing due to atherosclerotic plaques, estimated from the vessel's cross-sectional appearance. Myocardial infarcts were dated histologically in the H&E stained sections, classified as acute (up to four weeks) and old (over four weeks), according to the criteria described by Mallory et al.'8 Infarcts involving the inner one-third to onehalf of the ventricular wall thickness were regarded as subendocardial, and those extending to 75% or full thickness as transmural.
tablished infarcts and in the subendocardium. Only occasional hearts showed positive HBFP staining of the conduction fibers. Healed or old infarcts (fibrous scars) were present in about half of the patients (46% and 40%). The histological age of acute infarcts in group A patients ranged from less than 12 hours to 28 days; two-thirds (26/39) were more than 12 hours old. Subendocardial infarcts outnumbered transmural infarcts by the ratio of 2:1 (table 2). About one-half (19/39) of the infarcts were antero-septal, one-third (13/39) were postero-septal, and the remainder (7/39) were
antero-septo-posterior.
Conduction System
Table 3 summarizes the histopathologic findings of the conduction system. Intimal thickening with significant luminal narrowing occurred commonly in the nutrient vessels of the conduction system, affecting the SA node artery in about 25% of cases and the A-V nodal artery in about 50% of cases. Although there was no recent thrombosis of the conduction system nutrient vessels, A-V node necrosis was seen in two group A patients, both had thrombosis of the right
Results
Table 2
Major Cardiac Findings
Age and Type of Myocardial Infarcts in Sudden Cardiac
The 49 SCD hearts in this study, irrespective of whether AMI was present (group A) or absent (group B), shared many common anatomic characteristics (table 1). All hearts had a right preponderant coronary artery distribution and showed a comparable high incidence of cardiomegaly (69% and 70%) and significant coronary artery disease affecting one or more vessels (87% and 90%). Recent coronary thrombosis was uncommon (18% and 20%). Early myocardial ischemia (less than six hours), identified in the conventional H&E stained histologic sections by myofibrillar degeneration'9 and by positive HBFP staining reaction (figs. 1 and 2), was present in the majority of cases (85% and 80%), mainly around es-
Death Histologic age of infarct*
6-12 hours 13 - 24 hours 25 - 48 hours 3- 7 days 8 - 14 days 15 - 28 days Total
Number of casest
Type of infarct$
13 (0): 12 (2): 3 (0): 7 (3): 3 (1):
4 TM 9 SE 5 TM 7 SE 0 TM 3 SE 2 TM 5 SE 2 TM 1 SE 0 TM 1 SE 13 TM 26 SE
1(1): 39 (7):
*Determined by the criteria of Mallory et al.'8 tNumbers in parentheses indicate cases with coronary thrombosis. tTM = transmural infarct; SE = subenldocardial infarct.
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48
LIE
.1
,
4,.>f;
s s
t
:;5,'
Figure 1 An example of inapparent early myocardial ischemia SCD. Left panel) Histologically normal myocardium in the conventiontal in
(liematoxylin-eosin stain, X 100). Right panel) Consecutive serial section of the same myocardium, showing positive HBFP staining (seen here as black staining) indicative of
stained section
early myocardial ischemia (Hematoxylin-basic fuchsin-picric acid stain,
X
100).
artery and massive acute myocardial infarction involving the ventricular septum. In one patient
coronary
associated with embolic obstruction of the A-V node artery and hemorrhage in the peripheral left bundle branch (fig. 3); in another, with marked narrowing of the A-V node (fig. 4) and infarction of this
Figure 2 Myofibrillar degeneration, indicative of acute ischemic injury, in the heart of a patient with sudden coronary death. Note the eosinophilic and irregularly spaced transverse "contraction hands" and the more lightly stained granular cytoplasm (Hematoxylineosin stain, 256). X
was
the right bundle branch (fig. 5). No acute lesion of the SA node or the A-V bundle was seen in either group A or group
B patients.
T;'able 3 Histopathology of the Conduction System in Sudden Death from Coronary Heart Disease
Conducietion system Significant disease
Number
Groulp
of patients*
of nutrient vessels SA novle A-V nodle artery artery
Type of
dliseaset
MA node
Disease of specialized fibers A-V X-V R bundle nodle
Bundle branch L
R + L
4 5 1
1
A: With infarets
Aiitero-septal
19 (3)
)
9t
Postero-septal
13 (2)
3
5
7 (2)
2
4
1.0 (2)
3
6
N: F: A:
N:
Antero-septo-post.erior
F: A: N: F: A: N:
B: Without infarets
Total
13
49 (9)
24
F: A: N: F:
A:
16 3 9 10 4 0 6
12
6 1 5
3
13 6 0
2 0
S3 0
4
2
2
1
8 0 3 3 1 6
9 0 3
4 0 1
2 0 1
4 0 7
2 0 1 0 0 2
2 0 2
1 1 2
40
4 0 26
3 0 27
0 8
3 0 9
0 5
9 0
21 2
22 0
4 0
14 1
7 1
1 0 8
2 0
(1
*Numbers in parenitheses indicate cases with coronary thrombosis. tN: normal; F: fibrosis, fatt.y replacement and vascularization; A: acuite infarction and/or hemorrhage. tIncluding one case in which ani emnboluis was present in the A-V node artery. Abbreviations: SA = sinoatrial; A-V atrioventricullar. =
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CONDUCTION SYSTEM IN SUDDEN DEATH
. 'r-. -'
449
,- r\t
Figure 3 I evft bulndle branrch (12313) int a SC!) Fopv panel1) hIemorrhazge in the lewft bunrdle branlch (between2 arrow2s). S intfarctefd ventriculalr septutu (Hernactoxysliri-evosinl stalin, X 60). Bosttcom pantel) Higher niagnlifi cationt of thwe boxe area showinrg hemorrhage an1d nivoyc2ttolusis of the necrostic LBI3 fibers (hl-ernatoxylin eoJsin stainl, X
160C).
Moderate to marked degrees of fibrosis, myocytolyss, fatty replacement and vascularization of the specialized fibers of the conduction system (fig. 6) were not uncommon. These nonspecific "'degenerative" changes were just as prevalent in SCD patients with AMI (group A n) as in those without
Figure 4 Acute lesionis in a SCD patient with massive antero-septo-posterior AIL. Fop panel) Irnfarcted A-V node (TAVN) and mairked intinial thickening of the A-V node artery (A). CF/B = centralfibrous body; V = cvenouis channel (Hematoxylin-eosini stain7, X 25). Bottoni panel) Higher magnification of the boxed area showing necrotic
conidtiction fibers, marked polymcorphonuclear itnfiltrate, and organized thrombus in the vein (V) with ani eccentric residual li rrien (IIemriatoxylin-eosin stainz, X 60).
(group B), and affecting, in decreasing order of frequency, proximal segments of the bundle branches, the A-V bundle, the A-V node and the SA node (table 3). In general, fibrosis and fibrofatty replacement of the conduction tissue were more common in patients after the fifth decade of life. Discussion A comparison of this study and our previous anatomic studies of coronary victims12 13 showed that there were no specific histopathologic lesions of the Figure 5 Right btundle branch in the same SCD shown in figure 4. Left panel) N\ecrosis of the right bundle branch (between arrows) in the midst of infarcted ventricuilar septum. T = tricuspid valve (Hematoxylin-eosin stain, X 40). Right panel) Hligher magnification of the boxed area showing necrotic RBB fibers and inflammatory infiltrate (Hernatoxylin-eosini stain, X 100).
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450
LIE
Figure 6 Nonspecific degenerative changes of the conduction tissue in SCD. Top left panel) Fibrosis and fatty itmfiltrationr of the A-VX7 node. CFB = central fibrous body. Top right panel) Septatefibrosis of the His b undle (HJB) with mynyocltolysis.Bottoin left pianel) Almost completely sclerotic His btundle (HIB) w ith fibrosis of the proximal segment of the left buindle b ranch (LBB) and cornpletefibrotus interruption of the right buindle branchi (RBB). Bottom right panel) Fibrosis of t/hc Il is buindle (LIB), right butndle branch (RBB) and left bunidle branch (LBB). Hematoxylini-eosini stain, all X 40. Circulation, Volume 51. March 1975 Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2015
CONDUCTION SYSTEM IN SUDDEN DEATH
conduction system peculiar to SCD, and a seemingly intact conduction system did not preclude the development of lethal cardiac arrhythmias. Irrespective of whether death occurred suddenly or while under hospital care for myocardial infarction, acute ischemic necrosis of the conduction tissue was an exceptional finding. Only two of our 49 SCD patients had acute injury to the conduction tissue, affecting the A-V node and the peripheral bundle branches (figs. 3-5). In both instances, the patients had massive AMI involving the ventricular septum. Nonspecific "degenerative" changes (fibrosis, fatty infiltration, or both) of the conduction system, which might or might not represent previous ischemic injury, were just as common in patients who died suddenly as in those who did not (table 3), and just as common in patients who died in sinus rhythm as in those who had various types of conduction disturbances.'3 These changes occurred more commonly in SCD and AMI patients after the fifth decade of life, and thus might well be only manifestation of aging. Indeed, studies by Lev20 21 and Davies22' 23 have clearly demonstrated that with aging there was progressive increase of collagen and fatty replacement of the conduction tissue in patients who had died of noncardiovascular diseases. The lack of a specific finding of acute lesions in the conduction system of the vast majority of SCD was compatible with the proposed mechanism of the terminal event, namely ventricular fibrillation or cardiac asystole, but in no way excluded the possibility of bradyarrhythmias occurring shortly before death. Although there is, to our knowledge, no published anatomical study of the cardiac conduction system in SCD, it has been well documented in the literature that, in patients with established AMI, even marked conduction disturbances are frequently not accompanied by significant lesions of the cardiac conduction system.24 27 In posterior AMI with complete heart block, extensive to total necrosis of the A-V node was seen in two out of nine patients in the series reported by Blondeau,24 in none of Sutton and Davies' ten patients,25 and in only three of the 36 patients studied by Ekelund et al.27 These same authors describe a higher incidence of ischemic necrosis of the bundle branches in patients with anterior AMI complicated by complete A-V block. Hackel et al.26 have suggested several factors which may explain the lack of histologically demonstrable acute lesions of the conduction system in patients with clinically documented heart blocks complicating AMI, including higher glycogen content and lower oxygen consumption of the conduction tissue of the heart as compared with the contractile myocardium. Hackel et al.26 attribute the possible mechanism of transient conduction defects in AMI to altered ionic milieu, the release of
451
lysosomal enzymes by leukocytes, or hypersensitive vagal reflexes following ischemic injury to the myocardium. Because of the vulnerability of ischemic myocardium to ventricular fibrillation, our finding of positive HBFP staining and myofibrillar degeneration, both of which are histologic markers of acute injury to the myocardium,'6' 19 in the hearts of about 80% of SCD is highly significant. This observation correlates well with the clinical finding of electrocardiographic changes of myocardial ischemia in about threequarters of successfully resuscitated "would-be SCD" survivors,28-30 and with the postmortem detection of lowered potassium/sodium ionic ratios in coronary heart disease victims who had no histologically demonstrable AMI.3M By the use of similar histochemical methods, Lee et al.32 have also been able to define "early" or "inapparent ischemic injury consistently, involving or surrounding the conduction tissue of the heart in an experimental pig model of sudden death from severe coronary atherosclerosis. In their experiment, electrocardiographic equipment was placed in close proximity and terminal electrocardiograms were obtained in some of the swine within a few minutes after the first recognizable signs of illness. The terminal electrocardiograms of 18 swine that died suddenly showed ventricular fibrillation in 13 cases and ventricular asystole in five animals.32 If myocardial ischemia, not necessarily directly involving the conduction tissue of the heart, is the anatomical basis of SCD manifested by electrical instability and the development of ventricular fibrillation, then the tedious histologic study of the conduction system may not be as revealing as has been anticipated in the clinicopathologic correlation of SCD.33 While the mechanism which precipitates the seemingly abrupt onset of fatal myocardial ischemia may be multifactorial,34 it seems more profitable to continue the search for more sensitive and reliable histopathologic markers of acute injury to the myocardium. 6', 19, 35, 36 References 1. MCNEILLY RH, PEMBELRTON J: Duration of the last attack in 998 fatal cases of coronary artery disease and its relation to possible cardiac resuscitation. Br Med J 3: 139, 1968 2. FULTON M, JULIAN DG, OLIVER MF: Sudden death and myocardial infarction. Circulation 40 (suppl IV): IV-182, 1969 3. BONDERANT S: Problems of the pre-hospital phase of acute myocardial infarction. Am J Cardiol 24: 612, 1969 4. KULLER L: Sudden death in arteriosclerotic heart disease: The case for preventive medicine. Am J Cardiol 24: 617, 1969 5. LOVELL RRH, PRINEAS RJ: Mechanisms of sudden death and their implications for prevention and management. Prog Cardiovasc Dis 13: 482, 1971 6. LIE JT, TITUS JL: Inapparent early myocardial ischemia in
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452 sudden death from coronary heart disease. Proceedings of the Fifth Asian Pacific Congress of Cardiology, Singapore, October 8-13, 1972, p 542
21.
7. TITUS JL, OXMAN HA, CONNOLLY DC, NOBREGA FT: Sudden unexpected death as the initial manifestation of coronary
22.
heart disease: Clinical and pathological observation. Singapore Med J 14: 291, 1973 8. SCOTT RF, BRIGGS TS: Pathologic findings in pre-hospital deaths due to coronary atherosclerosis. Am J Cardiol 29: 782, 1972 9. LIBERTHSON RR, NAGEL EL, HIRSCHMAN JC, NUSSENFELD SR, BLACKBOURNE BD, DAVIS JH: Pathophysiologic observations
23.
24.
in prehospital ventricular fibrillation and sudden cardiac death. Circulation 49: 790, 1974
25.
10. FRIEDMAN M, MANWARING JH, ROSENMAN RH, DONLON G, ORTEGA P, GRUBE SM: Instantaneous and sudden deaths: Clinical and pathological differentiation in coronary heart
26.
11.
12. 13. 14.
15.
16. 17. 18.
19.
20.
disease. JAMA 225: 1319, 1973 LIE JT, TITUS JL: Pathology of the myocardium and the conduction system in sudden coronary death. In AHA Symposium on Sudden Coronary Death Outside Hospital, Spring Hill, Minneapolis, October 10-13, 1974 HUNT D, LIE JT, VOHRA J, SLOMAN G: Histopathology of heart block complicating acute myocardial infarction: Correlation with the His bundle electrogram. Circulation 48: 1252, 1973 LIE JT, HUNT D: The cardiac conduction system in acute myocardial infarction: A clinicopathological correlation. Aust NZ J Med 4: 331, 1974 LEV M, WIDRAN J, ERICKSON EE: A method for the histopathologic study of the atrioventricular node, bundle, and branches. Arch Pathol 52: 73, 1951 LEV M, WATNE AL: Method for routine histopathologic study of human sinoatrial node. Arch Pathol 57: 168, 1954 LIE JT, HOLLEY KE, KAMPA WR, TITUS JL: New histochemical method for morphologic diagnosis of early stages of myocardial ischemia. Mayo Clin Proc 46: 319, 1971 SMITH HL: The relation of the weight of the heart to weight of the body, and of the weight of the heart to age. Am Heart J 4: 79, 1928-29 MALLORY GK, WHITE PD, SALCEDO-SALGAR J: The speed of healing of myocardial infarction: A study of the pathologic anatomy in seventy-two cases. Am Heart J 18: 647, 1939 REICHENBACH DD, BENDITT EP: Catecholamines and cardiomyopathy: The pathogenesis and potential importance of myofibrillar degeneration. Human Pathol 1: 125, 1970 ERICKSON EE, LEX M: Aging changes in the human
27. 28.
29. 30. 31. 32.
33. 34.
35. 36.
atrioventricular node, bundle, and bundle branches. J Gerontol 7: 1, 1952 LEV M: Aging changes in the human sinoatrial node. J Gerontol 9: 1, 1954 DAVIES M, HARRIS A: Pathological basis of primary heart block. Br Heart J 31: 219, 1969 DAVIES MJ, POMERANCE A: Quantitative study of aging changes in the human sinoatrial node and internodal tracts. Br Heart J 34: 150, 1972 BLONDEAU M, RIzzow P, LENEGRE J: Les troubles de la conduction auriculo-ventriculaire dans L'infarctus myocardique recent. II. Etude anatomique. Arch Mal Coeur 54: 1104, 1961 SUTTON R, DAVIES M: The conduction system in acute myocardial infarction complicated by heart block. Circulation 38: 987, 1968 HACKEL DB, WAGNER G, RATLIFF NB, CIES A, ESTES EH: Anatomic studies of the cardiac conduction system in acute myocardial infarction. Am Heart J 83: 77, 1972 EKELUND L-G, MOBERG A, OLSSON AG, ORo L: Recent myocardial infarction and the conduction system: A clinicopathological correlation. Br Heart J 34: 774, 1972 ALVAREZ H, WILLS RE, COBB LA: Sudden cardiac death: Physiologic observations and therapeutic implications. Am J Cardiol 31: 116, 1973 BAUM RS, ALVAREZ H, COBB LA: Mechanisms of out-ofhospital sudden cardiac death and their prognostic significance. Circulation 45: 153, 1973 LIBERTHSON RR, HIRSCHNIAN JC, NUSSENFELD SR, NAGEL EL: Prognostic implications of the initial post defibrillation heart rate and rhythm. Circulation 45: 485, 1973 MCVIE J: Postmortem detection of inapparent myocardial infarction. J Clin Pathol 23: 203, 1970 LEE KT, LEE WM, HAN J, JARMOLYCH J, BISHOP MB, GOEL BJ: Experimental model for study of "sudden death" from ventricular fibrillation or asystole. Am J Cardiol 32: 62, 1973 SCHWvARTZ CJ, WALSH WJ: The pathologic basis of sudden death. Prog Cardiovasc Dis 13: 465, 1971 RAAB W: The nonvascular metabolic myocardial vulnerability factor in "coronary heart disease:'' Fundamentals of pathogenesis, treatment, and prevention. Am Heart J 66: 685, 1963 BOUCHARDY B, MAJNO G: Histopathology of early myocardial infarcts: A new approach. Am J Pathol 74: 301, 1974 HOCH-LICETI C, LAN CW: Morphology and frequency of early myocardial damage in various diseases. Am J Clin Pathol 62: 455, 1974
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Histopathology of the conduction system in sudden death from coronary heart disease. J T Lie Circulation. 1975;51:446-452 doi: 10.1161/01.CIR.51.3.446 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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Sudden cardiac death (SCD) has been attributed to the development of lethal dysrhythmias in coronary heart disease victims, and several recent autopsy surveys showed that 10 to 50% of SCD patients had unsuspected acute myocardial infaretion (AMI). The present study concerned histopathologic findings of the conduction system in 49 SCD (within six hours of the onset of acute symptoms) patients; 39 with established AMI (group A) and ten without (group B). Both groups showed high incidence of cardiomegaly, significant coronary artery disease affecting one or more vessels, and acute myocardial ischemia detectable by specific histological criteria. Stenosis of nutrient vessels of the conduction system was present in about 50% of the atrioventricular (A-V) node arteries and about 25% of the sinoatrial (SA) node arteries in both groups of SCD patients. Nonspecific "degenerative" changes (fibrosis, fatty infiltration, or both) of the conduction tissue, which might or might not represent results of old ischemic injury, also occurred with similar frequencies. Acute changes (infarction, hemorrhage) of the A-V node and bundle branches were found only in two group A patients, both had massive septal infarction. Thus, the conduction tissue appeared more resistant to ischemic injury and was overtly damaged only on rare occasions in fatal AMI. The scarcity of acute lesions in the conduction system itself suggested that lethal dysrhythmia in SCD was probably due to electrical instability of the acutely ischemic contractile myocardium rather than a direct injury to the specialized tissue of the heart.
Additional Indexing Words: Cardiac dysrhythmia Myocardial infarction
Coronary artery disease Autopsy study
Myocardial isehemia Atrioventricular node infaretion
evidence supports the notion that ventricular fibrillation or cardiac asystole is the most important mechanism of pre-hospital and hospital SCD,3 whether the lethal cardiac arrhythmia is associated with acute or specific lesions of the conduction system has not been documented. Because of this unsettled question, a study was carried out to determine the histopathology of the conduction system in 49 SCD, some with and some without unsuspected AMI.
THE MOST DISTURBING FINDING of any inquiry into the natural history of coronary heart
disease is the alarmingly high incidence of sudden cardiac death (SCD); epidemiological studies, both here and abroad, have repeatedly shown that, in about 40 to 70% of all deaths due to coronary heart disease, the victims died outside of a hospital or were dead on arrival.' For a cohort of patients with myocardial infarction, there are as many deaths within the first 24 hours as during the next five years.4 Recent pathologic studies have not only reaffirmed the prevalence of severe coronary atherosclerosis in SCD, but also revealed that 10 to 50% of the victims had unsuspected acute myocardial infarction (AMI),"10 and an even higher proportion had inapparent early myocardial ischemia.` Although electrophysiologic
Patients and Methods The 49 SCD were selected from a larger group of 120 patients previously reported,8 composed of all 39 patients with histologically demonstrable acute myocardial infarcts (group A) and ten of the remaining 81 patients without acute infarcts (group B). The patients, 35 men (mean age: 57 years) and 14 women (mean age: 62 years), died suddenly within six hours of the onset of acute symptoms. All but four deaths were witnessed. Sixty-eight percent (33/49) of the patients died at home, 12% (6/49) at work, 8% (4/49) at various sporting events either as participants or spectators, and 12% (6/49) in the ambulance or a hospital emergency room. Physical activity immediately preceding the terminal event was described as strenuous in only 14% (7/49) and moderate, mild, or none (resting) in the remainder. Resuscitations including defibrillation were attempted in the attended patients, but not all electrocardiographic monitoring records preceding the terminal event were available. In every instance, a complete autopsy examination had
From the Departments of Pathology, Mayo Clinic, Rochester, Minnesota, and Royal Melbourne Hospital, Melbourne, Australia. Supported in part by a Grant-in-Aid (71-200) from the Victor Hurley Medical Research Fund, Royal Melbourne Hospital. Dr. Lie is presently Associate Professor of Pathology, Baylor College of Medicine, Houston, Texas. Address for reprints: J. T. Lie, M.D., Department of Pathology, Baylor College of Medicine, 1200 Moursund, Houston, Texas 77025. Received July 11, 1974; revision accepted for publication November 19, 1974. 446
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CONDUCTION SYSTEM IN SUDDEN DEATH
447
Table 1 Major Cardiac Findings in Sudden Death from Coronary Heart Disease Group*
Number of patients
cardiomegaly (> 350 g)
A B Total
39 10 49
27 (69%) 7 (70%) 34 (69%)
*A: with recent myocardial
Significant coronary artery
diseaset
Recent coronary
thrombosist
Healed myocardial infarcts
34t (87%) 9t (90%) 43 (88%)
7 (18%) 2 (20%) 9 (18%)
18 (46%) 4 (40%) 22 (45%)
Acute myocardial
ischemia§ 33 (85c%) 8 (80%) 41 (84%,)
infarcts; B: without recent myocardial infarcts.
tDetermined by histologic aging to be less than 24 hours old. Number with 75% or greater luminal narrowing of one or more major epicardial coronary arteries. §Determined by positive HBFP staining and myofibrillar degeneration.
excluded
of death. The
noncoronary causes
gross
and
arteries and the described in detail pre-
microscopic examination of the
coronary
heart were conducted as viously.6' 12, 13 The methods of studying the conduction
system were similar to those described by Lev.'14 15 About three to five sinoatrial (SA) and six to nine atrioventricular
(A-V) conduction tissue blocks were prepared for histologic examination. Special care was directed to the correct sequence of tissue blocks during processing so that the topography of the conduction tissue could be reconstructed. From these tissue blocks, every fortieth and the adjacent 5-7,u sections were stained by hematoxylin-eosin (H&E), elastic van Gieson (ELVG) or Movat's pentachrome, and the nonenzymatic hematoxylin basic fuchsin-picric acid or HBFP stains.'6 All intervening sections were kept available for examination when needed. An average of 200 to 350 sections of the conduction system were examined per patient. Cardiomegaly was defined as heart weight exceeding the maximum of a normal range related to the body weight,'7 and in most instances, this meant heart weight exceeding 350 g. Significant coronary artery disease was defined as 75% or greater luminal narrowing due to atherosclerotic plaques, estimated from the vessel's cross-sectional appearance. Myocardial infarcts were dated histologically in the H&E stained sections, classified as acute (up to four weeks) and old (over four weeks), according to the criteria described by Mallory et al.'8 Infarcts involving the inner one-third to onehalf of the ventricular wall thickness were regarded as subendocardial, and those extending to 75% or full thickness as transmural.
tablished infarcts and in the subendocardium. Only occasional hearts showed positive HBFP staining of the conduction fibers. Healed or old infarcts (fibrous scars) were present in about half of the patients (46% and 40%). The histological age of acute infarcts in group A patients ranged from less than 12 hours to 28 days; two-thirds (26/39) were more than 12 hours old. Subendocardial infarcts outnumbered transmural infarcts by the ratio of 2:1 (table 2). About one-half (19/39) of the infarcts were antero-septal, one-third (13/39) were postero-septal, and the remainder (7/39) were
antero-septo-posterior.
Conduction System
Table 3 summarizes the histopathologic findings of the conduction system. Intimal thickening with significant luminal narrowing occurred commonly in the nutrient vessels of the conduction system, affecting the SA node artery in about 25% of cases and the A-V nodal artery in about 50% of cases. Although there was no recent thrombosis of the conduction system nutrient vessels, A-V node necrosis was seen in two group A patients, both had thrombosis of the right
Results
Table 2
Major Cardiac Findings
Age and Type of Myocardial Infarcts in Sudden Cardiac
The 49 SCD hearts in this study, irrespective of whether AMI was present (group A) or absent (group B), shared many common anatomic characteristics (table 1). All hearts had a right preponderant coronary artery distribution and showed a comparable high incidence of cardiomegaly (69% and 70%) and significant coronary artery disease affecting one or more vessels (87% and 90%). Recent coronary thrombosis was uncommon (18% and 20%). Early myocardial ischemia (less than six hours), identified in the conventional H&E stained histologic sections by myofibrillar degeneration'9 and by positive HBFP staining reaction (figs. 1 and 2), was present in the majority of cases (85% and 80%), mainly around es-
Death Histologic age of infarct*
6-12 hours 13 - 24 hours 25 - 48 hours 3- 7 days 8 - 14 days 15 - 28 days Total
Number of casest
Type of infarct$
13 (0): 12 (2): 3 (0): 7 (3): 3 (1):
4 TM 9 SE 5 TM 7 SE 0 TM 3 SE 2 TM 5 SE 2 TM 1 SE 0 TM 1 SE 13 TM 26 SE
1(1): 39 (7):
*Determined by the criteria of Mallory et al.'8 tNumbers in parentheses indicate cases with coronary thrombosis. tTM = transmural infarct; SE = subenldocardial infarct.
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48
LIE
.1
,
4,.>f;
s s
t
:;5,'
Figure 1 An example of inapparent early myocardial ischemia SCD. Left panel) Histologically normal myocardium in the conventiontal in
(liematoxylin-eosin stain, X 100). Right panel) Consecutive serial section of the same myocardium, showing positive HBFP staining (seen here as black staining) indicative of
stained section
early myocardial ischemia (Hematoxylin-basic fuchsin-picric acid stain,
X
100).
artery and massive acute myocardial infarction involving the ventricular septum. In one patient
coronary
associated with embolic obstruction of the A-V node artery and hemorrhage in the peripheral left bundle branch (fig. 3); in another, with marked narrowing of the A-V node (fig. 4) and infarction of this
Figure 2 Myofibrillar degeneration, indicative of acute ischemic injury, in the heart of a patient with sudden coronary death. Note the eosinophilic and irregularly spaced transverse "contraction hands" and the more lightly stained granular cytoplasm (Hematoxylineosin stain, 256). X
was
the right bundle branch (fig. 5). No acute lesion of the SA node or the A-V bundle was seen in either group A or group
B patients.
T;'able 3 Histopathology of the Conduction System in Sudden Death from Coronary Heart Disease
Conducietion system Significant disease
Number
Groulp
of patients*
of nutrient vessels SA novle A-V nodle artery artery
Type of
dliseaset
MA node
Disease of specialized fibers A-V X-V R bundle nodle
Bundle branch L
R + L
4 5 1
1
A: With infarets
Aiitero-septal
19 (3)
)
9t
Postero-septal
13 (2)
3
5
7 (2)
2
4
1.0 (2)
3
6
N: F: A:
N:
Antero-septo-post.erior
F: A: N: F: A: N:
B: Without infarets
Total
13
49 (9)
24
F: A: N: F:
A:
16 3 9 10 4 0 6
12
6 1 5
3
13 6 0
2 0
S3 0
4
2
2
1
8 0 3 3 1 6
9 0 3
4 0 1
2 0 1
4 0 7
2 0 1 0 0 2
2 0 2
1 1 2
40
4 0 26
3 0 27
0 8
3 0 9
0 5
9 0
21 2
22 0
4 0
14 1
7 1
1 0 8
2 0
(1
*Numbers in parenitheses indicate cases with coronary thrombosis. tN: normal; F: fibrosis, fatt.y replacement and vascularization; A: acuite infarction and/or hemorrhage. tIncluding one case in which ani emnboluis was present in the A-V node artery. Abbreviations: SA = sinoatrial; A-V atrioventricullar. =
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CONDUCTION SYSTEM IN SUDDEN DEATH
. 'r-. -'
449
,- r\t
Figure 3 I evft bulndle branrch (12313) int a SC!) Fopv panel1) hIemorrhazge in the lewft bunrdle branlch (between2 arrow2s). S intfarctefd ventriculalr septutu (Hernactoxysliri-evosinl stalin, X 60). Bosttcom pantel) Higher niagnlifi cationt of thwe boxe area showinrg hemorrhage an1d nivoyc2ttolusis of the necrostic LBI3 fibers (hl-ernatoxylin eoJsin stainl, X
160C).
Moderate to marked degrees of fibrosis, myocytolyss, fatty replacement and vascularization of the specialized fibers of the conduction system (fig. 6) were not uncommon. These nonspecific "'degenerative" changes were just as prevalent in SCD patients with AMI (group A n) as in those without
Figure 4 Acute lesionis in a SCD patient with massive antero-septo-posterior AIL. Fop panel) Irnfarcted A-V node (TAVN) and mairked intinial thickening of the A-V node artery (A). CF/B = centralfibrous body; V = cvenouis channel (Hematoxylin-eosini stain7, X 25). Bottoni panel) Higher magnification of the boxed area showing necrotic
conidtiction fibers, marked polymcorphonuclear itnfiltrate, and organized thrombus in the vein (V) with ani eccentric residual li rrien (IIemriatoxylin-eosin stainz, X 60).
(group B), and affecting, in decreasing order of frequency, proximal segments of the bundle branches, the A-V bundle, the A-V node and the SA node (table 3). In general, fibrosis and fibrofatty replacement of the conduction tissue were more common in patients after the fifth decade of life. Discussion A comparison of this study and our previous anatomic studies of coronary victims12 13 showed that there were no specific histopathologic lesions of the Figure 5 Right btundle branch in the same SCD shown in figure 4. Left panel) N\ecrosis of the right bundle branch (between arrows) in the midst of infarcted ventricuilar septum. T = tricuspid valve (Hematoxylin-eosin stain, X 40). Right panel) Hligher magnification of the boxed area showing necrotic RBB fibers and inflammatory infiltrate (Hernatoxylin-eosini stain, X 100).
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450
LIE
Figure 6 Nonspecific degenerative changes of the conduction tissue in SCD. Top left panel) Fibrosis and fatty itmfiltrationr of the A-VX7 node. CFB = central fibrous body. Top right panel) Septatefibrosis of the His b undle (HJB) with mynyocltolysis.Bottoin left pianel) Almost completely sclerotic His btundle (HIB) w ith fibrosis of the proximal segment of the left buindle b ranch (LBB) and cornpletefibrotus interruption of the right buindle branchi (RBB). Bottom right panel) Fibrosis of t/hc Il is buindle (LIB), right butndle branch (RBB) and left bunidle branch (LBB). Hematoxylini-eosini stain, all X 40. Circulation, Volume 51. March 1975 Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2015
CONDUCTION SYSTEM IN SUDDEN DEATH
conduction system peculiar to SCD, and a seemingly intact conduction system did not preclude the development of lethal cardiac arrhythmias. Irrespective of whether death occurred suddenly or while under hospital care for myocardial infarction, acute ischemic necrosis of the conduction tissue was an exceptional finding. Only two of our 49 SCD patients had acute injury to the conduction tissue, affecting the A-V node and the peripheral bundle branches (figs. 3-5). In both instances, the patients had massive AMI involving the ventricular septum. Nonspecific "degenerative" changes (fibrosis, fatty infiltration, or both) of the conduction system, which might or might not represent previous ischemic injury, were just as common in patients who died suddenly as in those who did not (table 3), and just as common in patients who died in sinus rhythm as in those who had various types of conduction disturbances.'3 These changes occurred more commonly in SCD and AMI patients after the fifth decade of life, and thus might well be only manifestation of aging. Indeed, studies by Lev20 21 and Davies22' 23 have clearly demonstrated that with aging there was progressive increase of collagen and fatty replacement of the conduction tissue in patients who had died of noncardiovascular diseases. The lack of a specific finding of acute lesions in the conduction system of the vast majority of SCD was compatible with the proposed mechanism of the terminal event, namely ventricular fibrillation or cardiac asystole, but in no way excluded the possibility of bradyarrhythmias occurring shortly before death. Although there is, to our knowledge, no published anatomical study of the cardiac conduction system in SCD, it has been well documented in the literature that, in patients with established AMI, even marked conduction disturbances are frequently not accompanied by significant lesions of the cardiac conduction system.24 27 In posterior AMI with complete heart block, extensive to total necrosis of the A-V node was seen in two out of nine patients in the series reported by Blondeau,24 in none of Sutton and Davies' ten patients,25 and in only three of the 36 patients studied by Ekelund et al.27 These same authors describe a higher incidence of ischemic necrosis of the bundle branches in patients with anterior AMI complicated by complete A-V block. Hackel et al.26 have suggested several factors which may explain the lack of histologically demonstrable acute lesions of the conduction system in patients with clinically documented heart blocks complicating AMI, including higher glycogen content and lower oxygen consumption of the conduction tissue of the heart as compared with the contractile myocardium. Hackel et al.26 attribute the possible mechanism of transient conduction defects in AMI to altered ionic milieu, the release of
451
lysosomal enzymes by leukocytes, or hypersensitive vagal reflexes following ischemic injury to the myocardium. Because of the vulnerability of ischemic myocardium to ventricular fibrillation, our finding of positive HBFP staining and myofibrillar degeneration, both of which are histologic markers of acute injury to the myocardium,'6' 19 in the hearts of about 80% of SCD is highly significant. This observation correlates well with the clinical finding of electrocardiographic changes of myocardial ischemia in about threequarters of successfully resuscitated "would-be SCD" survivors,28-30 and with the postmortem detection of lowered potassium/sodium ionic ratios in coronary heart disease victims who had no histologically demonstrable AMI.3M By the use of similar histochemical methods, Lee et al.32 have also been able to define "early" or "inapparent ischemic injury consistently, involving or surrounding the conduction tissue of the heart in an experimental pig model of sudden death from severe coronary atherosclerosis. In their experiment, electrocardiographic equipment was placed in close proximity and terminal electrocardiograms were obtained in some of the swine within a few minutes after the first recognizable signs of illness. The terminal electrocardiograms of 18 swine that died suddenly showed ventricular fibrillation in 13 cases and ventricular asystole in five animals.32 If myocardial ischemia, not necessarily directly involving the conduction tissue of the heart, is the anatomical basis of SCD manifested by electrical instability and the development of ventricular fibrillation, then the tedious histologic study of the conduction system may not be as revealing as has been anticipated in the clinicopathologic correlation of SCD.33 While the mechanism which precipitates the seemingly abrupt onset of fatal myocardial ischemia may be multifactorial,34 it seems more profitable to continue the search for more sensitive and reliable histopathologic markers of acute injury to the myocardium. 6', 19, 35, 36 References 1. MCNEILLY RH, PEMBELRTON J: Duration of the last attack in 998 fatal cases of coronary artery disease and its relation to possible cardiac resuscitation. Br Med J 3: 139, 1968 2. FULTON M, JULIAN DG, OLIVER MF: Sudden death and myocardial infarction. Circulation 40 (suppl IV): IV-182, 1969 3. BONDERANT S: Problems of the pre-hospital phase of acute myocardial infarction. Am J Cardiol 24: 612, 1969 4. KULLER L: Sudden death in arteriosclerotic heart disease: The case for preventive medicine. Am J Cardiol 24: 617, 1969 5. LOVELL RRH, PRINEAS RJ: Mechanisms of sudden death and their implications for prevention and management. Prog Cardiovasc Dis 13: 482, 1971 6. LIE JT, TITUS JL: Inapparent early myocardial ischemia in
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452 sudden death from coronary heart disease. Proceedings of the Fifth Asian Pacific Congress of Cardiology, Singapore, October 8-13, 1972, p 542
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7. TITUS JL, OXMAN HA, CONNOLLY DC, NOBREGA FT: Sudden unexpected death as the initial manifestation of coronary
22.
heart disease: Clinical and pathological observation. Singapore Med J 14: 291, 1973 8. SCOTT RF, BRIGGS TS: Pathologic findings in pre-hospital deaths due to coronary atherosclerosis. Am J Cardiol 29: 782, 1972 9. LIBERTHSON RR, NAGEL EL, HIRSCHMAN JC, NUSSENFELD SR, BLACKBOURNE BD, DAVIS JH: Pathophysiologic observations
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in prehospital ventricular fibrillation and sudden cardiac death. Circulation 49: 790, 1974
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10. FRIEDMAN M, MANWARING JH, ROSENMAN RH, DONLON G, ORTEGA P, GRUBE SM: Instantaneous and sudden deaths: Clinical and pathological differentiation in coronary heart
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disease. JAMA 225: 1319, 1973 LIE JT, TITUS JL: Pathology of the myocardium and the conduction system in sudden coronary death. In AHA Symposium on Sudden Coronary Death Outside Hospital, Spring Hill, Minneapolis, October 10-13, 1974 HUNT D, LIE JT, VOHRA J, SLOMAN G: Histopathology of heart block complicating acute myocardial infarction: Correlation with the His bundle electrogram. Circulation 48: 1252, 1973 LIE JT, HUNT D: The cardiac conduction system in acute myocardial infarction: A clinicopathological correlation. Aust NZ J Med 4: 331, 1974 LEV M, WIDRAN J, ERICKSON EE: A method for the histopathologic study of the atrioventricular node, bundle, and branches. Arch Pathol 52: 73, 1951 LEV M, WATNE AL: Method for routine histopathologic study of human sinoatrial node. Arch Pathol 57: 168, 1954 LIE JT, HOLLEY KE, KAMPA WR, TITUS JL: New histochemical method for morphologic diagnosis of early stages of myocardial ischemia. Mayo Clin Proc 46: 319, 1971 SMITH HL: The relation of the weight of the heart to weight of the body, and of the weight of the heart to age. Am Heart J 4: 79, 1928-29 MALLORY GK, WHITE PD, SALCEDO-SALGAR J: The speed of healing of myocardial infarction: A study of the pathologic anatomy in seventy-two cases. Am Heart J 18: 647, 1939 REICHENBACH DD, BENDITT EP: Catecholamines and cardiomyopathy: The pathogenesis and potential importance of myofibrillar degeneration. Human Pathol 1: 125, 1970 ERICKSON EE, LEX M: Aging changes in the human
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Histopathology of the conduction system in sudden death from coronary heart disease. J T Lie Circulation. 1975;51:446-452 doi: 10.1161/01.CIR.51.3.446 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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