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The vasculature of the atrioventricular conduction system in heart block
The vasculature system in heart
of the atrioventricular block
conduction
Arthur J. Kennel, M.D. Jack L. Titus, M.D. Ben D. McCallister, M.D. Raymond D. Pruitt, M.D. Rochester, M&an.
F
ibrosis of the bifurcating portion of the bundle of His and proximal portions of the right and left bundle branches is the pathologic lesion found most often in chronic complete heart block.‘e4 Yater and associates5t6 attributed this lesion to “stress and strain” and Lev3 ascribed it to “wear and tear,” but its pathogenesis has not been precisely defined. Disease of the coronary arteries, especially those arteries supplying the atrioventricular conduction system, has been implicated in the pathogenesis of both acute and chronic disturbances in atrioventricular (A-V) conduction, particularly since coronary artery disease is common at older ages when chronic heart block is most frequent. In this study, the condition of the artery to the A-V node and its parent artery of origin, and the morphologic features of the A-V node, common bundle of His, and the origins of the left and right bundle branches were examined in instances of disturbed A-V conduction and in cases with apparently normal A-V conduction. Materials
and
methods
The hearts of 19 adults-9 associated with some type of heart block and 10 with From the Mayo Clinic and Mayo Foundation. Received for publication June 16, 1972. Reprint requests to: Section of Publications,
Vol. 85, No. 5, pp. 593-600
May, 1973
normal rhythm and conduction (“controls”)-were studied. In all cases, ample documentation of cardiac rhythm and conduction before death and complete medical records were available for review. The specific requirements for inclusion in the study were: (1) availability of one or more 12-lead electrocardiograms obtained within a few days of death; and (2) availability of adequate clinical, cardiovascular examination within a few days of death. Autopsies were complete in all patients. No patient had chronic disease resulting in significant weight loss. Of the 10 control hearts, 8 were from men and 2 were from women; ages of the controls ranged from 47 to 83 years, with a mean of 65 years. The 9 hearts from patients with A-V block were from 6 men and 3 women; the ages of these patients ranged from 31 to 81 years, with a mean of 63 years. A composite method of gross morphologic, radiologic, and histologic examination of the coronary arterial and venous systems and the A-V conduction system was used for examination of the unembalmed hearts. In each, after the heart had been weighed, a plain roentgenogram was made of the intact specimen to detect calcifica-
Rochester. Mayo
Clinic,
Minn. Rochester.
Minn.
55901.
American Heart Journal
593
594
Am. Heart J. May, 1973
Kennel et al.
tion. Selective, pressure-controlled injections of color-coded barium sulfate were made into the right and left coronary arterial, systems according to the following method: The injection pressures ranged from 100 to 150 mm. Hg and were maintained for 10 minutes; the injection mass was Chromopaque* (25 ml.), Micropaque* (25 Gm.), gelatin (1.5 Gm.), and water (20 ml.); the right heart chambers and venous system were filled with gelatin solution (10 per cent) under water pressure (5 cm.); and immediately thereafter the entire specimen was immersed in ice-cold Kaiserling I solution for 1 to 2 hours, a pressure of 100 mm. Hg being maintained on the coronary artery cannulae. Stereoscopic roentgenograms (multiple views) were then made of the injected specimen with 22 calibration wires (diameter range, 25 p to 4 mm.) placed adjacent to the heart. The major epicardial coronary arteries were cross-sectioned and serially examined (intervals, 2 to 3 mm.), and routine and selected segments were prepared for histologic study. A large tissue block, containing the proximal parts of the A-V conduction system and the A-V-node artery, was then removed and x-rayed. This block contained the ostium of the coronary sinus, the A-V node and common bundle of His, the adjacent portions of the atria1 septum with the approaches to the A-V node, the septal leaflet of the tricuspid valve, the central fibrous body and membranous septum, the crest of the ventricular septum, the origins and proximal portions of the right and left bundle branches (for about 1 cm.), the A-V-node artery in its entirety, and a segment of the parent coronary artery from which the A-V-node artery originated. The tissue was further fixed in formalin and impregnated with paraffin. The large tissue blocks from two of the first specimens studied were serially sectioned and every fortieth histologic section was mounted and stained, with further examination of intervening sections as required. With subsequent specimens, histologic sections were made from serial tissue blocks of the original large block, which was cut into serial blocks immediately on removal from melted paraffin. The thickness of the *Damancy
and
Co.. Ltd..
Ware-Herts.
England.
serial blocks (1 to 2 mm.) was designed to approximate the luminal diameter of the artery. Additional sections of the small blocks, including serial sections, were prepared as needed. The thickness of all histologic sections was 7 p. The stains routinely used were hematoxylin and eosin, Lawson’s elastic stain with a van Gieson counterstain, and the Mallory-Heidenhain stain. Quantitative studies of the histologic sections were done with an upright projection microscope and planimetry. The external and internal (luminal) diameters of the A-V-node artery, both at its origin and within or near the bulk of the node, and the two dimensions of the A-V node in that section exhibiting the greatest cross-sectional area were measured. A mean of two or more measurements was tabulated for vessels that were not circular. Results Cardiac diagnoses. The findings referable to weight and cardiac diagnosis are summarized in Table I. There were three instances of chronic first degree heart block, two of acute complete heart block complicating acute myocardial infarction, and four of chronic complete heart block. Most of the hearts were enlarged, with the largest ones being in the chronic complete heart block group. Congestive heart failure was most common in the latter group. None of the 4 subjects with chronic heart block had coronary heart disease. Of the 10 “control” cases, 8 had evidence of coronary arterial disease. Histologic jindings. Morphologic findings referable to the A-V conduction system are summarized in Table II. Abnormalities of the conduction system were evident in 5 of the “control” cases; the abnormalities were focal lesions of the bundle branches (slight fibrosis of the right bundle branch [RBB] in 2, slight fibrosis of both bundle branches in one, and recent focal necroses of the left bundle branch [LBB] in 2 hearts). None of these lesions completely disrupted the involved branch. Of the 3 cases of chronic first degree heart block, the A-V conduction system was normal in one and noninterruptive, focal lesions of the LBB (one case) and the His bundle (one case) were found in the other 2. One of the 2 patients with
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The atrioventriculur
Table I. Findings
in atrioventricular
conduction system in heart block
59s
block Heart
block
-_____--__-“COntrOlS”* (n= 10)
Heart weight, mean (Gm.) Heart condition Anatomically normal Pathologic lesions Coronary disease Acute infarct Old infarct Idiopathic cardiomyopathy Cardiomyopathymyotonic dystrophy Calcification, aortic and mitral annuli Myocarditis Interstitial fibrosis Congestive failure
First degree, chronic (n = 3)
432 (350-670)t
0
412 (450-575)t
__-Third degree, acute (n = 2) 440 (370~510)I
Third chronic
degree, (n = 4)
548 (420-700)t
0
0
0
1 l$ 11
2 0
0 0 0
1
0
0
4
0
0
0 0 0 1
0 0 0 0
*Normal rhythm and conduction. tRawe. tsame case. QMassive anteroseptal infarct in both.
acute heart block complicating acute massive anteroseptal infarction had regained normal conduction before death and the A-V conduction system was morphologically normal; the other patient had acute heart block for 7 days before death and the distal bundle of His and the bundle branches showed severe fibrosis that morphologically antedated the acute infarct (Fig. 1). All four cases of chronic complete heart block had severe, interruptive lesions of the A-V conduction system. The lesions were fibrotic or fibrocalcific processes; in 3 hearts,
these
were
confined
to the distal,
bifurcating part of the common bundle and the origins of both bundle branches (Fig. 2), and in the fourth heart the entire node, His bundle, and origins of the bundle branches were replaced. Generally, the LBB seemed more extensively affected than the RBB. A-V noda arteries. Mild to moderate degrees of luminal narrowing, with loss of 10 to 40 per cent of the original lumen, were found in the A-V nodal arteries of patients with heart block and of the *‘controls” (Table III). Such lesions were virtually al-
ways confined to the proximal part (1 to 5 mm.) of the artery and were invariably associated with more extensive lesions of the parent artery at, and proximal to, the origin of the nodal vessel. Beyond this, the nodal artery, including that segment within or near the A-V node, was either free of disease or only minimally involved. Isolated vascular diseaseconfined to the A-V nodal artery was not observed. When luminal narrowing of the coronary arteries as an index of vascular diseasewas considered, there were no apparent differences between the control casesand the group with heart block (Table III). There was less luminal narrowing of the A-V node artery, its parent coronary artery, and the major epicardial coronary arteries in the hearts of the heart block group than in the hearts of the “control” subjects with coronary heart disease. Vasculur anastomoses. Many arterial anastomoses were found in the region of the A-V node, common bundle of His, and origins of the bundle branches. The general vascular arrangement, which is well known, was as follows: The A-V node artery origi-
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Fig. 1. Old nonspecific fibrotic changes of atrioventricular conduction system in acute complete heart block complicating acute anteroseptal myocardial infarction. Top: Distal bundle of His (B) and origin of left bundle branch (point of arrow,) are fibrotic. T is tricuspid leaflet and VS is ventricular septum with pale area to lower left of infarction. (MalloryHeidenhain. Original magnification X 18.) Battam: RBB in proximal subendocardial portion is replaced by fibrous tissue. Right ventricular cavity is below. (Mallory-Heidenhain. Original magnification X.50.)
nated from a U-shaped curve of its parent artery at the crux of the heart and coursed directly to the region of the A-V node in the lower part of the atria1 septum. In the vicinity of the A-V node, this artery divided into many branches, several of which passed toward the apex through the annulus fibrosus into the ventricular septum; here they anastomosed extensively with branches of both the anterior septal perforating branch of the left anterior descending coronary artery and the posterior septal branches of the posterior descending coronary artery, and with the subendocardial plexus of the left ventricle. In the atria1 septum, the nodal artery anastomosed with other atria1 branches. These anastomoses were present in normal and abnormal hearts, but were more prominent in cases of severe stenosing coronary artery disease
Fig. 2. Atrioventricular conduction system in chronic complete heart block. Top: Fibrotic interruption (point of unlabeled arrow) of LBB at origin from bundle of His (B); VS is muscular ventricular septum. (Mallory-Heidenhain. Original magnification X22.) Bcttom: Section more distal to that pictured in top view: Bundle of His (B) was severely fibrotic and LBB was completely fibrotic (point of arrow); VS is muscular ventricular septum. This histologic section is approximately 5 mm. distal to that shown in top view. (Mallory-Heidenhain. Original magnification X 22.)
of the major epicardial coronary arteries. A prominent venous system, mainly sinuto the A-V soidal,7 in close relationship node and bundle of His, was found consistently in both normal and abnormal hearts. Discussion
Consideration of these findings requires brief review of previous reports. Since the identification of the common atrioventricular (A-V) bundlesnsand the A-V nodelo with its artery, the ramus septi fibrosi,” the myogenic basis of A-V conduction has become well established12-15 despite dissent.16*17nlorphologic features of the A-V conduction system such as the presence of fatty tissue,18aging changes,lg and venous
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Table I I. Morphologic
The atrioventriculur
$ndings
in A-V conduction
conduction system in heart block
system in A - T, block Heart
block
___-___-~“ControlsO*
(n= A-V node Normal Abnormal His bundle Normal Abnormal Right bundle branch Normal Abnormal Left bundle branch Normal Abnormal Right and left bundle branch Abnormal
10)
597
____----
First degree, chronic (n = 3)
Third
degree,
acute (n = 2)
Third degree, chronic (n = 4)
10 0
3 0
2 0
3 It
10 0
2 1 (part fibrofatty replacement)$
1 1 (fibrosis)#
0 4 (fibrosis and/or calcification)
7 2 (both, slight fibrosis)
3 0
2 0
0 4 (fibrosis and/or calcification)
7 2 (both, focal necrosis)
2 1 (focal vacuolization)
2 0
0 4 (fibrosis and/or calcification)
1 (both branches, slight fibrosis)
0
0
4 (fibrosis and/or calcification)
*Normal rhythm and conduction. tGranulomatous myocarditis with destruction of all of A-V conduction tPartia1 fibrofatty replacement; myotonic dystrophy. $Severe fibrosis of His bundle histologically antedating acute infarct.
channels’ have been described. In acquired, nonsurgical chronic complete heart block,1-6~20-27 the most frequent pathologic lesions were fibrosis of the distal, bifurcating portion of the His bundle and fibrosis of the bundle branches at or near their origins. Coronary artery disease long has been suspected to be pathogenetically significant in severe bradycardia** and heart block.zgJO Diseaseof the artery to the A-V node31and small intramural coronary arteries32 hsa been specifically implicated in acquired complete heart block, but Davies and coworkers33 found coronary disease to be responsible in only 8 of 53 cases; in all 8 septal infarction had destroyed the bundle branches. Similarly, Harper and co-workers34found “ . . . poor correlation between specific vascular pathology and histologic changes in the major conduction pathways, except when related to fresh vascular occlusive disease.” Acute, often transient, complete heart block when associated with acute myocardial infarction is due to coro-
system.
nary heart disease.35l36 Although the block is most commonly associated with posterior myocardial infarction,35 which may imply a lesion of the right coronary artery, the risk that the acute block will be permanent seemsto be greater when there is an anteroseptal infarction, which usually is related to disease of the left anterior descending coronary artery. 36 A-V conduction disturbances also have been observed in a variety of serious systemic diseases,37-42 and in some cases, lesions of the artery to the A-V node were present and presumed to be causally related to the A-V conduction disturbance. In consideration of correlative electrophysiologic-morphologic studies, certain anatomic features require notation. Since the fascicles making up the left bundle branch arise from the common bundle of His over a relatively long distance, a precise definition of the junction between the bundle of His and the bundle branches is difficult. For this study, we considered the common bundle of His to end when the fibers of the
598
Table III.
Am. Heart J. May, 1973
Kennel et al.
Coronary
artery disease in A-V block: Mean luminal
“Controls”* (n = 8)
A-V nodal artery Parent coronary artery, proximal to A-V node artery Combined findings in proximal left anterior descending coronary artery, left circumflex coronary artery, and right coronary artery
*Normal rhythm and conduction but with coronary tone cake had acute thrombotic occlusion proximal iBoth bases had complete occlusion of left anterior
,_---_-_--~~. : First degree, chronic (n = 3)
decrease, percentage Heart block ~~.__-------Third degree, acute (n = 2)
__._____ ’
Third chronic
degree (n = i)
9
0
10
4
61
37t
50
30
59
36
551
47
heart disease. to &V-node artery. descendinn artery.
right bundle branch and those of the left bundle branch were distinctly separated, that is, the bifurcation of the common bundle was completed. For assessment of vasculature, filling of the vessels and fixation under standardized conditions minimized artifacts, facilitated measurements, and improved identification of arterial and venous channels. Stereoscopic roentgenography enhanced the over-all assessment of the vasculature. Interpretation of findings by comparison with age-matched “controls” is required. The simple coincidence of coronary artery disease and of heart block with pathologic lesions of the A-V conduction system, especially in older ages, alone cannot be taken to indicate a casual relationship of the former to the latter. Our findings support the conclusion of Lev and Unger,lM3 Lenegre,4 Yater and associates,5s6 and Daviesz4 that the majority of cases of chronic complete heart block are not caused by coronary artery disease. For this majority, the pathogenesis of the lesions causing the block has not been established. Instances of acute complete heart block complicating acute myocardial infarction bear the same relationship to coronary artery disease as does the acute infarction. Like Davies and co-workers,33 we found acute heart block with morphologic lesions of the A-V conduction system in anteroseptal myocardial infarction associated with disease of the left anterior descending coronary artery. The need for caution in ascribing a cause and effect
relationship between disease of a specific artery and a major disturbance of A-V conduction was exemplified by the presence of acute occlusion of the distal right coronary artery and the proximal A-V nodal artery in a patient who had an acute posteroseptal myocardial infarct, but continued to manifest only first degree heart block after infarction. While coronary arterial disease primarily involves the major epicardial coronary arteries, commonly the origin of the A-V nodal artery also is involved, apparently as an extension of the process in the parent artery. In this study the incidence of such a lesion in the A-V nodal artery was about as common (9 per cent) in the “controls” as in cases of either acute (10 per cent) or chronic (2 per cent) third degree heart block. The same general statement pertains to disease of the first anterior septal perforating branch of the left anterior descending coronary artery which makes major contributions to the collateral circulation of the A-V conduction system. From this study, we cannot confirm that disease of intramural small arteries32 and isolated disease of the A-V nodal artery31 are major factors in chronic complete heart block. It is interesting that ischemic necrosis of the bundle branches in the septum and of the atria1 myocardium adjacent to the A-V node was found without ischemic necrosis of the A-V node itself being identified. One case had minor ischemic morphologic abnormalities of the common bundle of His;
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The atrioventricular
this patient, with normal coronary arteries, had diffuse infarction of all cardiac chambers associated with prolonged shock, secondary to blood loss after valvular surgery. Heart block did not occur. Several anatomic features of the vasculature of the proximal parts of the A-V conduction system might confer some form of relative immunity to ischemic insult on the specialized tissues.43These include the relatively large and constant arterial supply to this region, the fact that the nodal artery is an atria1 artery and perhaps less subject to the systolic-diastolic phasic flow of the left ventricular arteries, the presence in this area of many anastomoses between the nodal artery and branches from both right and left coronary systems and from extracoronary vessels, and the possible beneficial effects conferred by the venous sinusoids of Truex and Schwartz.? Summary
and
conclusions
The morphology of the atrioventricular (A-V) node, common bundle of His, origins of the bundle branches, and their vasculature was studied by stereoscopic arteriography and histology in 9 instances of disturbed A-V conduction and 10 “control” hearts with normal rhythm and A-V conduction. In some hearts from both groups, mild to moderate luminal narrowing of the first few millimeters of the A-V-node artery was found ; such lesions always were associated with more severe disease of the parent coronary artery proximal to the A-V-node artery. Neither in severity nor in distribution were these vascular lesions in the 9 casesof heart block different from the vascular lesions in the 8 of 10 agematched “control” subjects in whom coronary artery disease was present. Isolated disease of the A-V nodal artery was not found in either group. Severe fibrosis of the bifurcating portion of the bundle of His and the origins of the bundle branches was present in 3 subjects with chronic complete heart block, one of which had calcification of the aortic and mitral annuli that impinged on the common bundle. A fourth case of chronic complete heart block was related to granulomatous myocarditis that involved all parts of the A-V conduction system. Myocardial infarction was not present in any of these four
conduction system in heart block
599
cases. Each of two instances of acute complete heart block had occlusion of the left anterior descending coronary artery and massive anteroseptal myocardial infarction. The regions of the A-V node and common bundle usually are supplied by the artery to the A-V node. This artery is always present and participates in many intercoronary, intracoronary, and extracoronary anastomoses. Venous sinusoids are prominent around the node and common bundle. These anatomic features may contribute to the apparent lack of pathologic change in the A-V conduction system in coronary heart disease. REFERENCES P. N.: The pathology of 1. Lev, M., and Unger, the conduction system in acquired heart disease I. Severe atrioventricular block, Arch. Pathol. 60502, 1955. of complete atrioven2. Lev, M.: The pathology tricular block, Progr. Cardiovasc. Dis. 6:317, 1964. M.: The conduction system, in Gould, 3. Lev, S. E., editor: Pathology of the heart and blood vessels, ed. 3, Springfield, Ill., 1968, Charles C Thomas, Publisher, p. 180. J. : Les lesions du systi.me de His 4. Lenegre, Tawara dans les blocs auriculo-ventriculaires d’un haut degre, Cardiologia 46:261, 1965. W. M., and Willius, F. A.: Heart-block 5. Yater, showing multiple transitions associated with convulsive syncope: Report of a case with detailed histopathological study, AM. HEART 1. 4:280, 1929: 6. Vnter. ----- , W. M.. and Cornell. V. H.: Heart block due to calcareous lesions of the bundle of His: Review and report of a case with detailed histopathologic study, Ann. Intern. Med. 8:777, 1935. R. C., and Schwartz, M. J.: Venous sys7. Truex, tem of the myocardium with special reference to the conduction system, Circulation 4:881, 1951. des embryonalen 8. His, W., Jr.: Die Thatigkeit Herzens und deren Bedeutung fur die Lehre von der Herzbewegung beim Erwachsenen, Arb. Med. Klin., 1893, p. 14. on the structure and 9. Kent. A. F. S.: Researches function of the mammalian heart, J. Physiol. (Land.) 14:233, 1893. Das Reizleitungssystem des S.: 10. Tawara, Saueetierherzens: Eine anatomisch-histologische St&e tiber das atrioventricularbundel und die Purkinjeschen Faden, Jena, 1906, Gustav Fischer Verlag. G.: Ueber die Gefassversorgung des 11. Haas, Reizleitungssystems des Herzens, Anat. Hefte 43:627, 1911. 12. Widran, J., and Lev, M.: The dissection of the node, bundle and bundle atrioventricular
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branches in the human heart, Circulation 4:863, 1951. James, T. N.: Morphology of the human atrioventricular node, with remarks pertinent to its electrophysiology, AM. HEART J. 62:756, 1961. Truex, R. C., and Smythe, M. Q.: Recent observations on the human cardiac conduction system, with special considerations of the atrioventricular node and bundle, in Taccardi, B., and Marchetti, G., editors: International symposium on the electrophysiology of the heart, New York, 1965, Pergamon Press, p. 177. Titus, J. L., Daugherty, G. W., and Edwards, J. E.: Anatomy of the normal human atrioventricular conduction system, Am. J. Anat. 113:407, 1963. Glomset, D. J., and Glomset, A. T. A.: A morphologic study of the cardiac conduction system in ungulates, dog, and man. Part I. The sinoatrial node, AM. HEART J. 20:389, 1940. Wensing, C. J. G.: Evidence for neurogenic conduction in the mammalian heart, Nature (Lond.) 207:1375, 1965. Bullard, H. H.: On the occurrence and physiological significance of fat in the muscle fibers of the normal myocardium and the atrioventricular system: interstitial granules (mitochondria) and phospholipines in cardiac muscle, Am. J. Anat. 19:1, 1916. Erickson, E. E., and Lev, M.: Aging changes in the human atrioventricular node, bundle, and bundle branches, J. Gerontol. i’:l, 1952. Aschoff, L.: A discussion on some aspects of heart-block, Br. Med. J. 2:1103, 1906. Barr, I.: Case of Stokes-Adams disease. ~, Br. Med: J. 2:1122, 1906. Fahr: Uber die musk&ire Verbindung zwischen Vorhof und Ventrikel (das Hissche Btindel) im normalen Herzen und beim Adams-Stokesschen Symptomkomplex, Virchows Arch. [Pathol. Anat.] 188:562, 1907. Moenckeberg, J. G.: Untersuchungen iiber das Atrioventrikularbundel im menschlichen Herzen, Jena, 1908, Gustav Fischer Verlag. Davies, M. J.: A histological study of the conduction system in complete heart block, J. Pathol. 94:351, 1967. Lumb, G., and Shacklett, R. S.: Human cardiac conduction tissue lesions, Am. J. Pathol. Xi:41 1, 1960. Zoob, M., and Smith, K. S.: The aetiology of complete heart-block, Br. Med. J. 2:1149, 1963. Storstein, 0.: Treatment of heart block from a clinical viewpoint, Acta Med. Stand. 183:559, 1968. Worthington, W. C., Sr.: Remarkable slowness of pulse, Lancet 2:336, 1841.
29.
Oppenheimer, A., and Oppenheimer, B. S.: Three cases of Adams-Stokes syndrome with histological findings, Arch. Intern. Med. 13:957, 1914. 30. G&audel, E.: The mechanism of the heart and its anomalies: anatomical and electrocardiographic studies (English translation by L. F. Bishop), Baltimore, 1930, Williams & Wilkins Company. 31. Mahaim, I.: Les maladies organiques du faisceau de His-Tawara, Paris, 1931, Masson & Cie. 32. Knieriem, H.-J., and Effert, S.: Morphologische Befunde beim kompletten Herzblock, Klin. Wochenschr. 44:349, 1966. 33. Davies, M. J., Redwood, D., and Harris, A.: Heart block and coronary artery disease, Br. Med. J. 3:342, 1967. 34. Harper, J. R., Harley, A., Hackel, D. B., and Estes, E. H., Jr.: Coronary artery disease and major conduction disturbances: A pathologic study designed to correlate vascular and conduction system abnormalities with electrocardiogram, AM. HEART J. i’7:411, 1969. 35. James, T. N.: The coronary circulation and conduction system in acute myocardial infarction, Progr. Cardiovasc. Dis. 10:410, 1968. 36. Sutton, R., and Davies, M.: The conduction system in acute myocardial infarction complicated by heart block, Circulation 38:987, 1968. 37. James, T. N., Rupe, C. E., and Monto, R. WV.: Pathology of the cardiac conduction system in systemic lupus erythematosus, Ann. Intern. Med. 63:402, 1965. 38. Lev, M., Landowne, M., Matchar, J. C., a2 Wagner, J. A.: Systemic scleroderma with complete heart block: Report of a case with comprehensive study of the conduction system, Au. HEART J. 72:13, 1966. 39. James, T. N., and Birk, R. E.: Pathology of the cardiac conduction system in polyarteritis nodosa, Arch. Intern. Med. 117:561, 1966. 40. James, T. N.: Pathology of the cardiac conduction system in amyloidosis, Ann. Intern. Med. 65:28, 1966. 41. James, T. N., and Monto, R. W.: Pathology of the cardiac conduction system in thrombotic thrombocytopenic purpura, Ann. Intern. Med. 65:37, 1966. 42. Thomson, A. M. P.: Dystrophia cordis myotonica studied by serial histology of the pacemaker and conducting system, J. Pathol. 96:285, 1968. 43. Kennel, A. J., and Titus, J. L.: The vasculature of the human atrioventricular conduction system, Mayo Clin. Proc. 47:.562, 1972.
of the atrioventricular block
conduction
Arthur J. Kennel, M.D. Jack L. Titus, M.D. Ben D. McCallister, M.D. Raymond D. Pruitt, M.D. Rochester, M&an.
F
ibrosis of the bifurcating portion of the bundle of His and proximal portions of the right and left bundle branches is the pathologic lesion found most often in chronic complete heart block.‘e4 Yater and associates5t6 attributed this lesion to “stress and strain” and Lev3 ascribed it to “wear and tear,” but its pathogenesis has not been precisely defined. Disease of the coronary arteries, especially those arteries supplying the atrioventricular conduction system, has been implicated in the pathogenesis of both acute and chronic disturbances in atrioventricular (A-V) conduction, particularly since coronary artery disease is common at older ages when chronic heart block is most frequent. In this study, the condition of the artery to the A-V node and its parent artery of origin, and the morphologic features of the A-V node, common bundle of His, and the origins of the left and right bundle branches were examined in instances of disturbed A-V conduction and in cases with apparently normal A-V conduction. Materials
and
methods
The hearts of 19 adults-9 associated with some type of heart block and 10 with From the Mayo Clinic and Mayo Foundation. Received for publication June 16, 1972. Reprint requests to: Section of Publications,
Vol. 85, No. 5, pp. 593-600
May, 1973
normal rhythm and conduction (“controls”)-were studied. In all cases, ample documentation of cardiac rhythm and conduction before death and complete medical records were available for review. The specific requirements for inclusion in the study were: (1) availability of one or more 12-lead electrocardiograms obtained within a few days of death; and (2) availability of adequate clinical, cardiovascular examination within a few days of death. Autopsies were complete in all patients. No patient had chronic disease resulting in significant weight loss. Of the 10 control hearts, 8 were from men and 2 were from women; ages of the controls ranged from 47 to 83 years, with a mean of 65 years. The 9 hearts from patients with A-V block were from 6 men and 3 women; the ages of these patients ranged from 31 to 81 years, with a mean of 63 years. A composite method of gross morphologic, radiologic, and histologic examination of the coronary arterial and venous systems and the A-V conduction system was used for examination of the unembalmed hearts. In each, after the heart had been weighed, a plain roentgenogram was made of the intact specimen to detect calcifica-
Rochester. Mayo
Clinic,
Minn. Rochester.
Minn.
55901.
American Heart Journal
593
594
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Kennel et al.
tion. Selective, pressure-controlled injections of color-coded barium sulfate were made into the right and left coronary arterial, systems according to the following method: The injection pressures ranged from 100 to 150 mm. Hg and were maintained for 10 minutes; the injection mass was Chromopaque* (25 ml.), Micropaque* (25 Gm.), gelatin (1.5 Gm.), and water (20 ml.); the right heart chambers and venous system were filled with gelatin solution (10 per cent) under water pressure (5 cm.); and immediately thereafter the entire specimen was immersed in ice-cold Kaiserling I solution for 1 to 2 hours, a pressure of 100 mm. Hg being maintained on the coronary artery cannulae. Stereoscopic roentgenograms (multiple views) were then made of the injected specimen with 22 calibration wires (diameter range, 25 p to 4 mm.) placed adjacent to the heart. The major epicardial coronary arteries were cross-sectioned and serially examined (intervals, 2 to 3 mm.), and routine and selected segments were prepared for histologic study. A large tissue block, containing the proximal parts of the A-V conduction system and the A-V-node artery, was then removed and x-rayed. This block contained the ostium of the coronary sinus, the A-V node and common bundle of His, the adjacent portions of the atria1 septum with the approaches to the A-V node, the septal leaflet of the tricuspid valve, the central fibrous body and membranous septum, the crest of the ventricular septum, the origins and proximal portions of the right and left bundle branches (for about 1 cm.), the A-V-node artery in its entirety, and a segment of the parent coronary artery from which the A-V-node artery originated. The tissue was further fixed in formalin and impregnated with paraffin. The large tissue blocks from two of the first specimens studied were serially sectioned and every fortieth histologic section was mounted and stained, with further examination of intervening sections as required. With subsequent specimens, histologic sections were made from serial tissue blocks of the original large block, which was cut into serial blocks immediately on removal from melted paraffin. The thickness of the *Damancy
and
Co.. Ltd..
Ware-Herts.
England.
serial blocks (1 to 2 mm.) was designed to approximate the luminal diameter of the artery. Additional sections of the small blocks, including serial sections, were prepared as needed. The thickness of all histologic sections was 7 p. The stains routinely used were hematoxylin and eosin, Lawson’s elastic stain with a van Gieson counterstain, and the Mallory-Heidenhain stain. Quantitative studies of the histologic sections were done with an upright projection microscope and planimetry. The external and internal (luminal) diameters of the A-V-node artery, both at its origin and within or near the bulk of the node, and the two dimensions of the A-V node in that section exhibiting the greatest cross-sectional area were measured. A mean of two or more measurements was tabulated for vessels that were not circular. Results Cardiac diagnoses. The findings referable to weight and cardiac diagnosis are summarized in Table I. There were three instances of chronic first degree heart block, two of acute complete heart block complicating acute myocardial infarction, and four of chronic complete heart block. Most of the hearts were enlarged, with the largest ones being in the chronic complete heart block group. Congestive heart failure was most common in the latter group. None of the 4 subjects with chronic heart block had coronary heart disease. Of the 10 “control” cases, 8 had evidence of coronary arterial disease. Histologic jindings. Morphologic findings referable to the A-V conduction system are summarized in Table II. Abnormalities of the conduction system were evident in 5 of the “control” cases; the abnormalities were focal lesions of the bundle branches (slight fibrosis of the right bundle branch [RBB] in 2, slight fibrosis of both bundle branches in one, and recent focal necroses of the left bundle branch [LBB] in 2 hearts). None of these lesions completely disrupted the involved branch. Of the 3 cases of chronic first degree heart block, the A-V conduction system was normal in one and noninterruptive, focal lesions of the LBB (one case) and the His bundle (one case) were found in the other 2. One of the 2 patients with
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The atrioventriculur
Table I. Findings
in atrioventricular
conduction system in heart block
59s
block Heart
block
-_____--__-“COntrOlS”* (n= 10)
Heart weight, mean (Gm.) Heart condition Anatomically normal Pathologic lesions Coronary disease Acute infarct Old infarct Idiopathic cardiomyopathy Cardiomyopathymyotonic dystrophy Calcification, aortic and mitral annuli Myocarditis Interstitial fibrosis Congestive failure
First degree, chronic (n = 3)
432 (350-670)t
0
412 (450-575)t
__-Third degree, acute (n = 2) 440 (370~510)I
Third chronic
degree, (n = 4)
548 (420-700)t
0
0
0
1 l$ 11
2 0
0 0 0
1
0
0
4
0
0
0 0 0 1
0 0 0 0
*Normal rhythm and conduction. tRawe. tsame case. QMassive anteroseptal infarct in both.
acute heart block complicating acute massive anteroseptal infarction had regained normal conduction before death and the A-V conduction system was morphologically normal; the other patient had acute heart block for 7 days before death and the distal bundle of His and the bundle branches showed severe fibrosis that morphologically antedated the acute infarct (Fig. 1). All four cases of chronic complete heart block had severe, interruptive lesions of the A-V conduction system. The lesions were fibrotic or fibrocalcific processes; in 3 hearts,
these
were
confined
to the distal,
bifurcating part of the common bundle and the origins of both bundle branches (Fig. 2), and in the fourth heart the entire node, His bundle, and origins of the bundle branches were replaced. Generally, the LBB seemed more extensively affected than the RBB. A-V noda arteries. Mild to moderate degrees of luminal narrowing, with loss of 10 to 40 per cent of the original lumen, were found in the A-V nodal arteries of patients with heart block and of the *‘controls” (Table III). Such lesions were virtually al-
ways confined to the proximal part (1 to 5 mm.) of the artery and were invariably associated with more extensive lesions of the parent artery at, and proximal to, the origin of the nodal vessel. Beyond this, the nodal artery, including that segment within or near the A-V node, was either free of disease or only minimally involved. Isolated vascular diseaseconfined to the A-V nodal artery was not observed. When luminal narrowing of the coronary arteries as an index of vascular diseasewas considered, there were no apparent differences between the control casesand the group with heart block (Table III). There was less luminal narrowing of the A-V node artery, its parent coronary artery, and the major epicardial coronary arteries in the hearts of the heart block group than in the hearts of the “control” subjects with coronary heart disease. Vasculur anastomoses. Many arterial anastomoses were found in the region of the A-V node, common bundle of His, and origins of the bundle branches. The general vascular arrangement, which is well known, was as follows: The A-V node artery origi-
596
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Kennel et al.
Fig. 1. Old nonspecific fibrotic changes of atrioventricular conduction system in acute complete heart block complicating acute anteroseptal myocardial infarction. Top: Distal bundle of His (B) and origin of left bundle branch (point of arrow,) are fibrotic. T is tricuspid leaflet and VS is ventricular septum with pale area to lower left of infarction. (MalloryHeidenhain. Original magnification X 18.) Battam: RBB in proximal subendocardial portion is replaced by fibrous tissue. Right ventricular cavity is below. (Mallory-Heidenhain. Original magnification X.50.)
nated from a U-shaped curve of its parent artery at the crux of the heart and coursed directly to the region of the A-V node in the lower part of the atria1 septum. In the vicinity of the A-V node, this artery divided into many branches, several of which passed toward the apex through the annulus fibrosus into the ventricular septum; here they anastomosed extensively with branches of both the anterior septal perforating branch of the left anterior descending coronary artery and the posterior septal branches of the posterior descending coronary artery, and with the subendocardial plexus of the left ventricle. In the atria1 septum, the nodal artery anastomosed with other atria1 branches. These anastomoses were present in normal and abnormal hearts, but were more prominent in cases of severe stenosing coronary artery disease
Fig. 2. Atrioventricular conduction system in chronic complete heart block. Top: Fibrotic interruption (point of unlabeled arrow) of LBB at origin from bundle of His (B); VS is muscular ventricular septum. (Mallory-Heidenhain. Original magnification X22.) Bcttom: Section more distal to that pictured in top view: Bundle of His (B) was severely fibrotic and LBB was completely fibrotic (point of arrow); VS is muscular ventricular septum. This histologic section is approximately 5 mm. distal to that shown in top view. (Mallory-Heidenhain. Original magnification X 22.)
of the major epicardial coronary arteries. A prominent venous system, mainly sinuto the A-V soidal,7 in close relationship node and bundle of His, was found consistently in both normal and abnormal hearts. Discussion
Consideration of these findings requires brief review of previous reports. Since the identification of the common atrioventricular (A-V) bundlesnsand the A-V nodelo with its artery, the ramus septi fibrosi,” the myogenic basis of A-V conduction has become well established12-15 despite dissent.16*17nlorphologic features of the A-V conduction system such as the presence of fatty tissue,18aging changes,lg and venous
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Table I I. Morphologic
The atrioventriculur
$ndings
in A-V conduction
conduction system in heart block
system in A - T, block Heart
block
___-___-~“ControlsO*
(n= A-V node Normal Abnormal His bundle Normal Abnormal Right bundle branch Normal Abnormal Left bundle branch Normal Abnormal Right and left bundle branch Abnormal
10)
597
____----
First degree, chronic (n = 3)
Third
degree,
acute (n = 2)
Third degree, chronic (n = 4)
10 0
3 0
2 0
3 It
10 0
2 1 (part fibrofatty replacement)$
1 1 (fibrosis)#
0 4 (fibrosis and/or calcification)
7 2 (both, slight fibrosis)
3 0
2 0
0 4 (fibrosis and/or calcification)
7 2 (both, focal necrosis)
2 1 (focal vacuolization)
2 0
0 4 (fibrosis and/or calcification)
1 (both branches, slight fibrosis)
0
0
4 (fibrosis and/or calcification)
*Normal rhythm and conduction. tGranulomatous myocarditis with destruction of all of A-V conduction tPartia1 fibrofatty replacement; myotonic dystrophy. $Severe fibrosis of His bundle histologically antedating acute infarct.
channels’ have been described. In acquired, nonsurgical chronic complete heart block,1-6~20-27 the most frequent pathologic lesions were fibrosis of the distal, bifurcating portion of the His bundle and fibrosis of the bundle branches at or near their origins. Coronary artery disease long has been suspected to be pathogenetically significant in severe bradycardia** and heart block.zgJO Diseaseof the artery to the A-V node31and small intramural coronary arteries32 hsa been specifically implicated in acquired complete heart block, but Davies and coworkers33 found coronary disease to be responsible in only 8 of 53 cases; in all 8 septal infarction had destroyed the bundle branches. Similarly, Harper and co-workers34found “ . . . poor correlation between specific vascular pathology and histologic changes in the major conduction pathways, except when related to fresh vascular occlusive disease.” Acute, often transient, complete heart block when associated with acute myocardial infarction is due to coro-
system.
nary heart disease.35l36 Although the block is most commonly associated with posterior myocardial infarction,35 which may imply a lesion of the right coronary artery, the risk that the acute block will be permanent seemsto be greater when there is an anteroseptal infarction, which usually is related to disease of the left anterior descending coronary artery. 36 A-V conduction disturbances also have been observed in a variety of serious systemic diseases,37-42 and in some cases, lesions of the artery to the A-V node were present and presumed to be causally related to the A-V conduction disturbance. In consideration of correlative electrophysiologic-morphologic studies, certain anatomic features require notation. Since the fascicles making up the left bundle branch arise from the common bundle of His over a relatively long distance, a precise definition of the junction between the bundle of His and the bundle branches is difficult. For this study, we considered the common bundle of His to end when the fibers of the
598
Table III.
Am. Heart J. May, 1973
Kennel et al.
Coronary
artery disease in A-V block: Mean luminal
“Controls”* (n = 8)
A-V nodal artery Parent coronary artery, proximal to A-V node artery Combined findings in proximal left anterior descending coronary artery, left circumflex coronary artery, and right coronary artery
*Normal rhythm and conduction but with coronary tone cake had acute thrombotic occlusion proximal iBoth bases had complete occlusion of left anterior
,_---_-_--~~. : First degree, chronic (n = 3)
decrease, percentage Heart block ~~.__-------Third degree, acute (n = 2)
__._____ ’
Third chronic
degree (n = i)
9
0
10
4
61
37t
50
30
59
36
551
47
heart disease. to &V-node artery. descendinn artery.
right bundle branch and those of the left bundle branch were distinctly separated, that is, the bifurcation of the common bundle was completed. For assessment of vasculature, filling of the vessels and fixation under standardized conditions minimized artifacts, facilitated measurements, and improved identification of arterial and venous channels. Stereoscopic roentgenography enhanced the over-all assessment of the vasculature. Interpretation of findings by comparison with age-matched “controls” is required. The simple coincidence of coronary artery disease and of heart block with pathologic lesions of the A-V conduction system, especially in older ages, alone cannot be taken to indicate a casual relationship of the former to the latter. Our findings support the conclusion of Lev and Unger,lM3 Lenegre,4 Yater and associates,5s6 and Daviesz4 that the majority of cases of chronic complete heart block are not caused by coronary artery disease. For this majority, the pathogenesis of the lesions causing the block has not been established. Instances of acute complete heart block complicating acute myocardial infarction bear the same relationship to coronary artery disease as does the acute infarction. Like Davies and co-workers,33 we found acute heart block with morphologic lesions of the A-V conduction system in anteroseptal myocardial infarction associated with disease of the left anterior descending coronary artery. The need for caution in ascribing a cause and effect
relationship between disease of a specific artery and a major disturbance of A-V conduction was exemplified by the presence of acute occlusion of the distal right coronary artery and the proximal A-V nodal artery in a patient who had an acute posteroseptal myocardial infarct, but continued to manifest only first degree heart block after infarction. While coronary arterial disease primarily involves the major epicardial coronary arteries, commonly the origin of the A-V nodal artery also is involved, apparently as an extension of the process in the parent artery. In this study the incidence of such a lesion in the A-V nodal artery was about as common (9 per cent) in the “controls” as in cases of either acute (10 per cent) or chronic (2 per cent) third degree heart block. The same general statement pertains to disease of the first anterior septal perforating branch of the left anterior descending coronary artery which makes major contributions to the collateral circulation of the A-V conduction system. From this study, we cannot confirm that disease of intramural small arteries32 and isolated disease of the A-V nodal artery31 are major factors in chronic complete heart block. It is interesting that ischemic necrosis of the bundle branches in the septum and of the atria1 myocardium adjacent to the A-V node was found without ischemic necrosis of the A-V node itself being identified. One case had minor ischemic morphologic abnormalities of the common bundle of His;
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The atrioventricular
this patient, with normal coronary arteries, had diffuse infarction of all cardiac chambers associated with prolonged shock, secondary to blood loss after valvular surgery. Heart block did not occur. Several anatomic features of the vasculature of the proximal parts of the A-V conduction system might confer some form of relative immunity to ischemic insult on the specialized tissues.43These include the relatively large and constant arterial supply to this region, the fact that the nodal artery is an atria1 artery and perhaps less subject to the systolic-diastolic phasic flow of the left ventricular arteries, the presence in this area of many anastomoses between the nodal artery and branches from both right and left coronary systems and from extracoronary vessels, and the possible beneficial effects conferred by the venous sinusoids of Truex and Schwartz.? Summary
and
conclusions
The morphology of the atrioventricular (A-V) node, common bundle of His, origins of the bundle branches, and their vasculature was studied by stereoscopic arteriography and histology in 9 instances of disturbed A-V conduction and 10 “control” hearts with normal rhythm and A-V conduction. In some hearts from both groups, mild to moderate luminal narrowing of the first few millimeters of the A-V-node artery was found ; such lesions always were associated with more severe disease of the parent coronary artery proximal to the A-V-node artery. Neither in severity nor in distribution were these vascular lesions in the 9 casesof heart block different from the vascular lesions in the 8 of 10 agematched “control” subjects in whom coronary artery disease was present. Isolated disease of the A-V nodal artery was not found in either group. Severe fibrosis of the bifurcating portion of the bundle of His and the origins of the bundle branches was present in 3 subjects with chronic complete heart block, one of which had calcification of the aortic and mitral annuli that impinged on the common bundle. A fourth case of chronic complete heart block was related to granulomatous myocarditis that involved all parts of the A-V conduction system. Myocardial infarction was not present in any of these four
conduction system in heart block
599
cases. Each of two instances of acute complete heart block had occlusion of the left anterior descending coronary artery and massive anteroseptal myocardial infarction. The regions of the A-V node and common bundle usually are supplied by the artery to the A-V node. This artery is always present and participates in many intercoronary, intracoronary, and extracoronary anastomoses. Venous sinusoids are prominent around the node and common bundle. These anatomic features may contribute to the apparent lack of pathologic change in the A-V conduction system in coronary heart disease. REFERENCES P. N.: The pathology of 1. Lev, M., and Unger, the conduction system in acquired heart disease I. Severe atrioventricular block, Arch. Pathol. 60502, 1955. of complete atrioven2. Lev, M.: The pathology tricular block, Progr. Cardiovasc. Dis. 6:317, 1964. M.: The conduction system, in Gould, 3. Lev, S. E., editor: Pathology of the heart and blood vessels, ed. 3, Springfield, Ill., 1968, Charles C Thomas, Publisher, p. 180. J. : Les lesions du systi.me de His 4. Lenegre, Tawara dans les blocs auriculo-ventriculaires d’un haut degre, Cardiologia 46:261, 1965. W. M., and Willius, F. A.: Heart-block 5. Yater, showing multiple transitions associated with convulsive syncope: Report of a case with detailed histopathological study, AM. HEART 1. 4:280, 1929: 6. Vnter. ----- , W. M.. and Cornell. V. H.: Heart block due to calcareous lesions of the bundle of His: Review and report of a case with detailed histopathologic study, Ann. Intern. Med. 8:777, 1935. R. C., and Schwartz, M. J.: Venous sys7. Truex, tem of the myocardium with special reference to the conduction system, Circulation 4:881, 1951. des embryonalen 8. His, W., Jr.: Die Thatigkeit Herzens und deren Bedeutung fur die Lehre von der Herzbewegung beim Erwachsenen, Arb. Med. Klin., 1893, p. 14. on the structure and 9. Kent. A. F. S.: Researches function of the mammalian heart, J. Physiol. (Land.) 14:233, 1893. Das Reizleitungssystem des S.: 10. Tawara, Saueetierherzens: Eine anatomisch-histologische St&e tiber das atrioventricularbundel und die Purkinjeschen Faden, Jena, 1906, Gustav Fischer Verlag. G.: Ueber die Gefassversorgung des 11. Haas, Reizleitungssystems des Herzens, Anat. Hefte 43:627, 1911. 12. Widran, J., and Lev, M.: The dissection of the node, bundle and bundle atrioventricular
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branches in the human heart, Circulation 4:863, 1951. James, T. N.: Morphology of the human atrioventricular node, with remarks pertinent to its electrophysiology, AM. HEART J. 62:756, 1961. Truex, R. C., and Smythe, M. Q.: Recent observations on the human cardiac conduction system, with special considerations of the atrioventricular node and bundle, in Taccardi, B., and Marchetti, G., editors: International symposium on the electrophysiology of the heart, New York, 1965, Pergamon Press, p. 177. Titus, J. L., Daugherty, G. W., and Edwards, J. E.: Anatomy of the normal human atrioventricular conduction system, Am. J. Anat. 113:407, 1963. Glomset, D. J., and Glomset, A. T. A.: A morphologic study of the cardiac conduction system in ungulates, dog, and man. Part I. The sinoatrial node, AM. HEART J. 20:389, 1940. Wensing, C. J. G.: Evidence for neurogenic conduction in the mammalian heart, Nature (Lond.) 207:1375, 1965. Bullard, H. H.: On the occurrence and physiological significance of fat in the muscle fibers of the normal myocardium and the atrioventricular system: interstitial granules (mitochondria) and phospholipines in cardiac muscle, Am. J. Anat. 19:1, 1916. Erickson, E. E., and Lev, M.: Aging changes in the human atrioventricular node, bundle, and bundle branches, J. Gerontol. i’:l, 1952. Aschoff, L.: A discussion on some aspects of heart-block, Br. Med. J. 2:1103, 1906. Barr, I.: Case of Stokes-Adams disease. ~, Br. Med: J. 2:1122, 1906. Fahr: Uber die musk&ire Verbindung zwischen Vorhof und Ventrikel (das Hissche Btindel) im normalen Herzen und beim Adams-Stokesschen Symptomkomplex, Virchows Arch. [Pathol. Anat.] 188:562, 1907. Moenckeberg, J. G.: Untersuchungen iiber das Atrioventrikularbundel im menschlichen Herzen, Jena, 1908, Gustav Fischer Verlag. Davies, M. J.: A histological study of the conduction system in complete heart block, J. Pathol. 94:351, 1967. Lumb, G., and Shacklett, R. S.: Human cardiac conduction tissue lesions, Am. J. Pathol. Xi:41 1, 1960. Zoob, M., and Smith, K. S.: The aetiology of complete heart-block, Br. Med. J. 2:1149, 1963. Storstein, 0.: Treatment of heart block from a clinical viewpoint, Acta Med. Stand. 183:559, 1968. Worthington, W. C., Sr.: Remarkable slowness of pulse, Lancet 2:336, 1841.
29.
Oppenheimer, A., and Oppenheimer, B. S.: Three cases of Adams-Stokes syndrome with histological findings, Arch. Intern. Med. 13:957, 1914. 30. G&audel, E.: The mechanism of the heart and its anomalies: anatomical and electrocardiographic studies (English translation by L. F. Bishop), Baltimore, 1930, Williams & Wilkins Company. 31. Mahaim, I.: Les maladies organiques du faisceau de His-Tawara, Paris, 1931, Masson & Cie. 32. Knieriem, H.-J., and Effert, S.: Morphologische Befunde beim kompletten Herzblock, Klin. Wochenschr. 44:349, 1966. 33. Davies, M. J., Redwood, D., and Harris, A.: Heart block and coronary artery disease, Br. Med. J. 3:342, 1967. 34. Harper, J. R., Harley, A., Hackel, D. B., and Estes, E. H., Jr.: Coronary artery disease and major conduction disturbances: A pathologic study designed to correlate vascular and conduction system abnormalities with electrocardiogram, AM. HEART J. i’7:411, 1969. 35. James, T. N.: The coronary circulation and conduction system in acute myocardial infarction, Progr. Cardiovasc. Dis. 10:410, 1968. 36. Sutton, R., and Davies, M.: The conduction system in acute myocardial infarction complicated by heart block, Circulation 38:987, 1968. 37. James, T. N., Rupe, C. E., and Monto, R. WV.: Pathology of the cardiac conduction system in systemic lupus erythematosus, Ann. Intern. Med. 63:402, 1965. 38. Lev, M., Landowne, M., Matchar, J. C., a2 Wagner, J. A.: Systemic scleroderma with complete heart block: Report of a case with comprehensive study of the conduction system, Au. HEART J. 72:13, 1966. 39. James, T. N., and Birk, R. E.: Pathology of the cardiac conduction system in polyarteritis nodosa, Arch. Intern. Med. 117:561, 1966. 40. James, T. N.: Pathology of the cardiac conduction system in amyloidosis, Ann. Intern. Med. 65:28, 1966. 41. James, T. N., and Monto, R. W.: Pathology of the cardiac conduction system in thrombotic thrombocytopenic purpura, Ann. Intern. Med. 65:37, 1966. 42. Thomson, A. M. P.: Dystrophia cordis myotonica studied by serial histology of the pacemaker and conducting system, J. Pathol. 96:285, 1968. 43. Kennel, A. J., and Titus, J. L.: The vasculature of the human atrioventricular conduction system, Mayo Clin. Proc. 47:.562, 1972.