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The neglected coronary atherosclerosis
Atherosclerosis, 47 (1983) 215-229 Elsevier Scientific Publishers Ireland.
215 Ltd.
The Neglected Coronary Atherosclerosis C. Velican
and Doina
Velican
Instiiule of Internal Medicine, Colentina Hospital, 72202 Bucharest 10 (Romama) (Received 3 September, 1982) (Revised, received 10 November, 1982) (Accepted 27 December, 1982)
Summary A study of the natural history of coronary heart disease by means of gross inspection and light microscopy, carried out on 640 subjects aged l-50 years who had died of violent accidents, revealed a grossly neglected coronary atherosclerosis. It included fibromuscular plaques, intimal necrotic areas and incorporated microthrombi present in the longitudinally opened main coronary arteries but not visible to the naked eye, and some atherosclerotic lesions visible to the naked eye but present in branch vessels unopened or not removed during routine autopsy. There were approximately 500 grossly neglected intimal necrotic areas and approximately 120 grossly neglected incorporated microthrombi; from a total of 809 atherosclerotic plaques 261 (32%) were grossly neglected. The topographic distribution and the number of neglected and non-neglected atherosclerotic plaques, in successive age groups, were analyzed. A small subsample, including 32 patients 52-79 years old, dead of coronary heart disease, was used to demonstrate the importance of the detection of, obstructive atherosclerotic lesions in some usually unopened or not removed branch vessels for a realistic anatomo-clinic-cardioangiographic and ECG correlation. Key words:
Anatomo-clinical correlations - Coronary atherosclerosis - Gross inspection - Light microscopy - Method-dependent limits - Undetected lesions - Unopened branch vessels
Introduction A post mortem study on the natural history of coronary heart disease [l-6] was commenced in 1973 in our laboratory. We adopted the definition and classification of atherosclerotic lesions of the WHO [7] and the ‘Standard Operating Protocol’ used by the International Atherosclerosis Project [8,9]. According to this, the 0021-9150/83/$03.00
0 1983 Elsevier Scientific
Publishers
Ireland,
Ltd.
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atherosclerotic involvement in Sudan-stained segments of the coronary arteries was ‘measured’ by unaided visual estimation. This method requires only systematic observation, estimation of the surface area involving fatty streaks, fibrous plaques and complicated lesions, and recording. We gradually realized that the major problems in coronary heart disease arose from the degree of narrowing of the lumen of the coronary arteries, and not from the extent of the intimal surface involved with fatty streaks and raised lesions. In an attempt to improve the quality of anatomo-clinic-cardioangiographic and ECG correlations, as well as precision in diagnosis and the extent of information, from 1975 we systematically compared data furnished by macro- and microscopic examinations of similar topographic sites of the coronary tree. This complex method allowed us to reveal that (a) using only gross inspection we constantly overlooked the presence of early atherosclerotic lesions in the longitudinally opened vessels, occurring as fibromuscular plaques, intimal necrotic areas and incorporated microthrombi. Among the early atherosclerotic lesions, only the fatty streaks were clearly visualized grossly after Sudan staining; (b) macroscopic examination of the coronary arteries could not offer information on the pattern and rate of progression of fibromuscular plaques, intimal necrotic areas and incorporated microthrombi toward fibronecrotic or fibrohyaline plaques, or on the main pathogenetic mechanisms involved in the onset of atherosclerotic lesions of possible clinical significance; (c) some branch vessel unopened during gross inspection might appear, on light-microscopic examination, severely narrowed by atherosclerotic plaques and/or by an excessive intimal thickening. These observations led progressively to the individualization of a grossly neglected coronary atherosclerosis, as presented. Material and Methods Coronary arteries of 640 subjects aged l-50 years, who had died of violent accident were examined. This unselected population sample of Bucharest was used to delineate the light-microscopic features, extension and importance of the neglected coronary atherosclerosis in apparently healthy subjects. This material was supplemented with 32 hospitalized patients aged 52-79 years (24 males and 8 females) who died of myocardial infarction and sudden cardiac arrest without obstructive lesions in the main coronary arteries. This small selected subsample was used to reveal the light-microscopic features, extension and importance of the neglected coronary atherosclerosis in patients with clinical manifestations of coronary heart disease. Using scissors with blunt points, a gross dissection of the coronary bed was performed in each heart up to the 1.O- 1.5 mm level of the external vessel diameter. The smaller branch vessels were investigated only microscopically. Examination of the coronary arteries began at and included the aortic ostia and extended distally along the epicardial traject of the three main vessels, as far as they could be traced. The right coronary artery was investigated from its origin to the area of the posterior interventricular groove or some distance beyond this along the groove between the left atrium and ventricle. The following branches of the right coronary
217
artery were also investigated. The sinus node artery, its origin appearing at the superior cave-atria1 junction. It ran in the direction opposite to the conus branch, i.e. cranially and dorsally and to the right, along the anterior wall of the right atrium below the right auricular appendage. It ascended on the anterior wall of the left atrium to reach the ostium of the superior vena cava. In approximately one third of cases the sinus node artery arose from the proximal segment of the circumflex artery, a few millimetres beyond its origin. The atrioventricular node artery, appearing as a rather slender vessel at or about the level of the U-curve at the crux cordis. It ran in a cranial direction toward the posterior and superior portion of the interventricular septum. The posterior descending artery occurred as the major terminal branch of the right coronary artery, arising at or immediately before the level of the crux cordis. Its course toward the apex could be followed in the posterior interventricular sulcus; this vessel was opened longitudinally whenever its external diameter was more than 1.O-1.5 mm. We also removed the right marginal artery coursing along the acute margin of the heart, for light-microscopic examination. The anterior descending artery was investigated grossly from its origin to the apex, along the anterior interventricular groove. Both first diagonal artery and first septal artery arose from the anterior descending artery in the proximal 20 mm of the anterior interventricular groove. In some cases the external diameter of the first diagonal artery was equal to or exceeded that of the parent vessel. Usually, the first diagonal artery was present in the angle subtended by the anterior descending and circumflex arteries, running in a caudal direction toward the apex. In contrast, the first septal artery arose at about a 90” angle and ran along the septum from front to back and in a caudal direction. Generally, only the more cranial septal artery was well demonstrable, being of greater length and calibre than the lower septal vessels. Its identification was aided by the characteristic branching from the anterior descending artery (it entered the septum at a right angle and exhibited a straight course). The circumflex artery was investigated from its origin until it was too small to dissect. This vessel ran in the atrioventricular groove in the direction of the crux and was often difficult to find, being buried deep in fat, particularly in the posterior atrioventricular sulcus. The circumflex artery appeared as the vessel of the coronary tree exhibiting the most variable origin, feature and topography. In more than one-third of the subjects investigated it was very short or long, narrow or large and as a coronary artery with or without important branch vessels. The origin of the circumflex artery was also variable: from the left main coronary artery, from the right coronary artery or directly from the aorta. In our material only 371 subjects (58%) showed a more or less similar branching anatomical pattern, arbitrarily termed by us ‘the common type of distribution’ of the coronary arteries. The remainder, 269 subjects (42%) exhibited deviations from this common type, some of them associated with an accelerated atherosclerotic involvement [lo]. Samples were removed at centimeters intervals from the origin of the main coronary arteries: 5-7 samples along the course of the anterior descending artery; 2-4 samples along the course of the circumflex artery; and 6-10 samples along the
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course of the right coronary artery. In addition the left main coronary artery was separately sampled, as well as the main branching areas and the proximal segment of the main branch vessels. In selected cases (subjects dead of coronary heart disease), the ventricular myocardium was sliced transversely in approximately IO-mm thick slices from the apex to within 20 mm of the atrioventricular groove. Each slice was examined to identify acute myocardial infarction, aneurysm, ruptures, pathological changes in the endocardium and mural thrombi. Acute myocardial infarction was defined as an area of ischemia and necrosis which measured at least 10 mm in any one dimension; old or healed infarcts were considered areas of granulation tissue or fibrous scars measuring at least 10 mm in any one dimension. In the absence of evident infarction and coronary artery obstruction, random samples of the full thickness of the ventricular wall were taken from the heart slices in a spiral step-wise manner, from the apex to the base of the heart. Finally, in a few cases, samples were removed from myocardial areas including the sinoatrial and atrioventricular nodes [ill. After fixation in Carnoy’s fluid, the coronary artery specimens and the selected myocardial samples were embedded in paraffin wax and cut at 4 pm thick. All tissue sections were stained routinely with resorcin fuchsin (1 h) followed by alcian blue (2 h). They were also occasionally stained with hematoxylin-eosin, Van Gieson’s picrofuchsin, Masson’s and Mallory’s trichromes and by Lendrum’s method for fibrin [ 121. The lumen of the vessel present in each tissue section was measured with the aid of a micrometer eyepiece, the units of the micrometer being transformed into microns. The degree of encroachment of lesions or of the thickened intima was estimated in terms of percentage narrowing. The reference point for luminal diameter reduction was the lumen of a similar area of the coronary tree, free of lesions and/or abnormal intimal thickening, belonging to a subject with a similar age, sex and branching anatomical pattern. The distance recorded was that from the internal elastic membrane or intima/media frontier on one side to the internal elastic membrane or intima/media frontier on the other side. An atherosclerotic lesion or a very thick intima was termed ‘obstructive’ only if it narrowed more than 75% of the arterial lumen. Results The importance and extent of the neglected coronary atherosclerosis in successive age groups, from children up to mature adults 50 years old, was deduced from the ratios of: (i) cases with atherosclerotic plaques, intimal necrotic areas, incorporated microthrombi and fatty streaks revealed by gross inspection versus those revealed by light microscopy; (ii) total number of atherosclerotic lesions occurring as atherosclerotic plaques, intimal necrotic areas, incorporated microthrombi and fatty streaks revealed by gross inspection versus that revealed by light microscopy. Among the various types of early lesions only the fatty streak could not be included in the neglected coronary atherosclerosis, since it was easily and constantly revealed on routine autopsy in Sudan-stained coronary segments. In contrast, the fibromuscular plaques, the intimal necrotic areas and the incorporated microthrombi were con-
219
Fig. 1. Three early lesions which represent the main morphological substratum of the grossly neglected coronary atherosclerosis: the fibromuscular plaques (left), the intimal necrotic areas (middle, arrow) and the incorporated microthrombi (right). Resorcin fuchsin-alcian blue, X 120 (reduced by l/3).
sistently included in the grossly neglected coronary only on light-microscopic examination (Fig. 1).
atherosclerosis,
being
detected
The grossly undetected lesions Table 1 shows that of the 640 apparently healthy subjects aged l-50 years, dead of violent accidents, 289 (45%) exhibited on light-microscopic examination intimal necrotic areas and 89 (14%) incorporated microthrombi. In the coronary arteries of all these 640 subjects there were approximately 500 intimal necrotic areas and 120 incorporated microthrombi undetected by gross inspection. In young and mature adults a limited number of these grossly undetected lesions became visible to the
TABLE
1
CASES (W) AGED MICROTHROMBI
l-50 YEARS WITH INTIMAL NECROTIC AREAS AND INCORPORATED UNDETECTED BY GROSS INSPECTION AND REVEALED BY LIGHT MI-
CROSCOPY Age groups
Total cases studied
(yr)
I- 5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50
63 81 66 59 69 72 56 54 58 62 Total
640
Cases with intimal necrotic areas
Cases with incorporated microthrombi
Total
B
Total
%
2.46 6.06 13.55 33.33 55.55 71.42 83.92 94.82 96.77
1 1 2 5 6 12 10 12 18 22
1.58 1.23 3.03 8.47 10.14 13.88 17.85 22.22 31.03 35.48
0 2 4 8 23 40 50 47 55 60 289
89
220
TABLE 2 NUMBER OF CASES WITH CORONARY ATHEROSCLEROTIC CORONARY ATHEROSCLEROTIC PLAQUES, AS REVEALED AND LIGHT MICROSCOPY (LM) Age groups (yr)
Total cases studied
Number of cases with atherosclerotic plaques
Number sclerotic Total
GI total
LM total
(%)
(a)
63 81
0
0
0
11-15
66
0
16-20
59
0
21-25
69
26-30
72
31-35
56
36-40
54
41-45
58
46-50
62
14 (20.28) 22 (30.55) 26 (46.42) 31 (57.40) 46 (79.3 I) 59 (95.16)
2 (2.46) 3 (4.54) 7 (11.86) 20 (28.98) 30 (41.66) 33 (58.92) 36 (66.66) 51 (87.93) 60 (96.77)
198
242
l- 5 6-10
Total
640
of coronary plaques GI
PLAQUES AND NUMBER OF BY GROSS INSPECTION (GI)
athero-
LM
GI/LM ratio
3
0
3
10
0
10
21
0
21
63
40
63
0.63
98
62
98
0.63
108
71
108
0.65
120
88
120
0.73
177
122
177
0.68
209
165
209
0.78
809
548
809
unaided eye, this particular evolution being reflected by the existence of intermediate, transitional stages between intimal necrotic areas and fibronecrotic plaques and between incorporated microthrombi and fibrohyaline plaques. Table 2 shows that the first aspects of evolution of atherosclerotic plaques from undetected lesions to lesions visible to the naked eye could be demonstrated in the coronary arteries of subjects aged 21-25 years. This table also shows the age-related distribution of all types of atherosclerotic plaques in the neglected and non-neglected coronary atherosclerosis. Of the 640 subjects aged l-50 years, 242 (38%) exhibited atherosclerotic plaques on light-microscopic examination and only 198 (3 1 W) on gross inspection. From the total 809 plaques revealed by light microscopy in the unselected population sample examined, only 549 were also recorded grossly. This means that 261, or 32% of the existing plaques remained undetected even after Sudan staining, owing to the limits of the unaided visual estimation. They represented approximately one third of all atherosclerotic plaques visualized in the coronary arteries of 640 children, adolescents, young and mature adults up to 50
221 TABLE
3
NUMBER OF CORONARY ATHEROSCLEROTIC MAIN CORONARY ARTERIES, AS REVEALED MICROSCOPY (LM) Sites selected
IN SELECTED SITES OF THE INSPECTION (GI) AND LIGHT
Age WJUP~ (~0 l-5 GI
Origin of the left main coronary artery Left main coronary artery Origin of the anterior descending artery Proximal segment of the anterior descending artery Distal segment of the anterior descending artery Origin of the circumflex artery Proximal segment of the circumflex artery Distal segment of the circumflex artery Origin of the right coronary artery Proximal segment of the right coronary artery Distal segment of the right coronary artery
PLAQUES BY GROSS
0
6-10
-
LM
GI
- -
-
11-15 LM
-
16-20
GI
LM
GI
LM
0 0
0 0
0 0
0 0
0 0
0
0 0
0
0
2
0
4
I
0
0
0
0
0
5
6
0
0
0
0
0
0
0
0
0
1
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
years old. The fact that 1 out of every 3 plaques was overlooked grossly could account for the greater number of plaques per subject revealed on microscopic than on macroscopic examination of similar topographic sites. The ratio of total number of plaques versus total number of subjects with plaques, varied between 3.00 and 3.48 according to data furnished by light microscopy and between 2.65 and 2.85 according to data furnished by gross inspection. In the material investigated there were microscopically more than 3 plaques per subject and grossly less than 3 plaques per subject. microscopy at the bifurcation area of the left main coronary artery about 20 years earlier than the first grossly visible lesions. Table 3 also shows that there were 3 plaques in 81 children aged 6-10 years, 10 plaques in 66 children and juveniles aged 11-15 years, and 21 plaques in 59 adolescents aged 16-20 years, all undetected by gross inspection. Starting from the age group 21-25-years old, plaques were visualized both macro- and microscopically, but the number revealed by light microscopy
222
Age groups(yr) 26-30
21-25 GI
31-35
41-45
36-40
LM
GI
LM
GI
LM
0 0
0 0
0
1 1
0
0
1
2 2
5
I
11
13
12
10
17
16
20
0
0
0
3
4
6
LM
GI
LM
GI
LM
1 1
2 2
2 3
3 6
4 8
5 10
14
12
14
14
18
18
20
11
14
16
18
21
25
28
30
2
5
7
5
7
I
9
16
18
8
11
6
9
6
8
8
10
8
10
8
6
10
6
10
10
12
16
20
18
21
0
0
0
0
1
3
2
4
2
4
3
5
5
5
8
10
I
11
7
9
8
12
12
14
7
10
8
10
8
10
10
12
14
18
14
16
4
7
5
7
8
10
10
12
11
14
14
16
-
GI
46-50
remained consistently greater in successive age groups than that revealed grossly. This is also strengthened by the age-dependent evolution of the ratio of plaques revealed by light microscopy versus plaques revealed grossly. The respective ratio varied between 1.58 (age group 26-30-years old) and 1.30 (age group 46-50-years old). This demonstrates the persistence, even in mature adults, of grossly undetected atherosclerotic plaques. The unopened branch vessels Table 4 shows that the first atherosclerotic plaques were visualized microscopically in the main branch vessels of the coronary arteries in subjects aged 21-25 years, in the proximal segment of the first diagonal, or first septal, or posterior descending arteries. Ten years later at similar topographic points, we revealed raised lesions if the respective branch vessels were opened during routine autopsy. Table 4 also shows that in branch vessels such as the second diagonal, left and right marginal, sinus node and atrioventricular node arteries, the presence of atherosclerotic
223 TABLE 4 NUMBER OF CORONARY ATHEROSCLEROTIC PLAQUES IN THE MAIN OF THE CORONARY ARTERIES, AS REVEALED BY GROSS INSPECTION MICROSCOPY (LM) Main branch
vessels
Age groups (yr) l-5 GI
First diagonal artery Second diagonal artery First septal artery Left marginal artery Sinus node artery Right marginal artery Atrioventricular node artery Posterior descending artery
BRANCH VESSELS (GI) AND LIGHT
6-10 LM
0
0
0
0
11-15
16-20
GI
LM
GI
LM
GI
LM
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0
0 0
0 0
0 0
0 0
0 0
plaques was revealed only microscopically, these branch vessels being unopened during gross inspection. Figs. 2-4 illustrate such occasional findings, in apparently healthy subjects dead of violent accidents. A more important involvement of the branch vessels of the coronary artery was visualized in the small selected subsample dead of coronary heart disease and aged 52-79 years. In this small selected subsample we could not find lumen-compromising complicated lesions, even in the
Fig. 2. The posterior descending artery of an apparently healthy 34-year-old male subject who a car accident. A grossly neglected atherosclerotic plaque, narrowing up to 80% of the vessel extending longitudinahy more than 2 mm along the artery course. The posterior descending not opened during routine autopsy but removed for light-microscopic examination. Resorcin cian blue, X65.
had died in lumen and artery was fuchsin-al-
224
Age groups (~0 21-25 ~
26-30 ____
31-35 ~
36-40 ~
41-45 ~
46-50
GI
LM
GI
LM
GI
LM
GI
LM
GI
LM
GI
LM
0 0 0 0 0 0
I 0 2 0 0 0
0 0 0 0 0 0
4 0 5 1 0 0
1 0 2 0 0 0
4 1 4 1 0 1
1 0 4 0 0 0
4 1 6 1 1 1
3 0 7 0 0 0
I 2 11 2 2 2
5 0 8 0 0 0
8 2 12 2 2 3
0 0
0 2
0 0
0 3
0 3
0 5
0 3
0 6
0 6
1 11
0 9
2 13
Fig. 3. The left marginal artery of an apparently healthy 42-year-old male subject who had died in a car accident. A grossly neglected atherosclerotic plaque narrowing up to 75% of the vessel lumen and extending more than 1.5 mm along the artery course. The left marginal artery was not opened during routine autopsy, but removed for light-microscopic examination. Resorcin fuchsin-alcian blue, x 65.
Fig. 4. The right marginal artery of an apparently healthy 47-year-old male subject who had died in a car accident. A grossly neglected atherosclerotic plaque narrowing up to 60% of the vessel lumen and extending more than 1.5 mm along the artery course. The right marginal artery was not opened during routine autopsy, but removed for light-microscopic examination. Resorcin fuchsin-alcian blue, ~65.
225
Fig. 5. The arteries supplying the conduction system (left, the sinoatrial node artery; right, the atrioventricular node artery) involved by grossly neglected atherosclerotic lesions. A 52-year-old woman with severe bradycardia, bigeminy and atrioventricular block, followed by cardiac arrest. Absence of myocardial infarction and lumen-compromising lesions in the three main coronary arteries. Left: severe narrowing of the lumen of the artery supplying the sinoatrial node, whereas the proximal segment of the right coronary did not show atherosclerotic involvement, but only a moderate intimal thickening. Right: severe narrowing of the lumen of the artery supplying the atrioventricular node, whereas the terminal segment of the right coronary artery did not show pathologic changes. Resorcin fuchsin-alcian blue, x 40.
Fig. 6. A grossly neglected obstructive lesion, blocking more than 80% of the lumen of the artery supplying the atrioventricular node, revealed on light-microscopic examination within the proximal 2 mm of the vessel course. A 58-year-old women who manifested syncopal episodes, followed by chest pain. The ECG showed left bundle branch block. She died with ventricular arrhythmia. The conduction system was partly replaced by fibrous connective tissue. Pathological examination revealed the absence of myocardial infarction and stenotic lesions in the main coronary arteries. Resorcinfuchsin-alcian blue, x 40.
Fig 7. A grossly neglected obstructive lesion, blocking more than 75% of the lumen of the artery supplying the sinoatrial node, revealed on light-microscopic examination within the proximal 2 mm of the vessel course. A 54-year-old man with persistent thoracic pain resistant to nitroglycerin. The ECG showed ST shifts of the ischemic type. He died with ventricular fibrillation. Pathological examination revealed the absence of myocardial infarction and lumen-compromising lesions in the main coronary arteries. We could not detect the vessel supplying the atrioventricular node. Resorcin fuchsin-alcian blue, x 65.
presence of fresh myocardial infarcts, in the left main coronary artery, anterior descending artery, circumflex artery and right coronary artery. On the other hand obstructive intimal thickenings or atherosclerotic plaques were present in the first septal artery in 7 patients (22%) in the posterior descending artery in 7 patients (22%), in the first diagonal artery in 5 patients (16%) and in the branches supplying the conduction system in 3 patients (9%). In the absence of stenosis in the main
Fig. 8. A grossly neglected obstructive lesion, blocking more than 75% of the lumen of the first septal artery and extending more than 2 mm along the vessel course. A 69-year-old woman with a history of angina pectoris and ECG evidence of infarction. Pathological examination showed a fresh myocardial infarct in the interventricular septum, in the area supplied by the obstructed artery. Lumen-compromising lesions were absent from the main coronary arteries. A narrow and very short posterior descending artery was present. Resorcin fuchsin-al&n blue, x 65.
227
coronary arteries, valid anatomo-clinic-cardioangiographic were established based on the presence of obstructive branch vessels. Figs. 5-8 demonstrate this.
and ECG correlations lesions in grossly unopened
Discussion The prevalent trend in studying human atherosclerosis is oversimplification: an oversimplified standard operating protocol to record atherosclerotic lesions (visual estimation of the longitudinally opened main coronary arteries stained with Sudan dyes); an oversimplified classification of lesions (non-raised and raised); an oversimplified concept of the natural history of atherosclerosis (fatty streaks + fibrous plaques + complicated lesions); an oversimplified form of the pathogenetic sequence (conversion of fatty streaks to fibrous plaques). The main objective of these over-simplified methods, classifications and concepts was to offer procedures easy to apply, which avoid undue demands upon the time and resources of the pathologist and which offer information that can be computed. Because of this, all atherosclerotic lesions existing outside the longitudinally opened main coronary arteries are inevitably overlooked, since they do not fit with the surface area ‘decided’ to be grossly estimated. The standard operating protocol of the IAP [8], for instance, recommends one ‘to exclude from the study all branches of the right coronary artery’ and does not give any specific indication on atherosclerotic involvement of the first diagonal and first septal arteries. Also types of early atherosclerotic lesions other than fatty streaks are overlooked by this method, since they are not visible to the naked eye. Consequently, in the IAP-study [9], the intimal surface covering fibromuscular plaques, intimal necrotic areas and incorporated microthrombi was recorded as ‘normal intima’. The grossly neglected coronary atherosclerosis, analyzed in this study, includes lesions present in the longitudinally opened left main coronary artery, anterior descending artery, circumflex artery and right coronary artery undetected by the naked eye and lesions present in the branch vessels of these main coronary arteries unopened or not removed during routine autopsy. The existence of this grossly neglected coronary atherosclerosis must be taken into consideration in all studies dealing with: (i) the feature of early atherosclerotic lesions; (ii) the lesions which characterize pediatric coronary atherosclerosis; (iii) the temporal and spatial relations between early and advanced atherosclerotic lesions; (iv) the main pathogenetic mechanisms of atherosclerosis; (v) the relationships between coronary bed obstruction, on the one hand, and myocardial infarcts, myocardial electrical instability, syncopal episodes and sudden cardiac arrest on the other. The results in this paper demonstrate that a grossly undetected obstructive lesion in the vessels supplying the conduction system might be more important for anatomo-clinic-angiocardiographic and ECG correlations in subjects with coronary heart disease than the extent of intimal surface of the main coronary arteries involved with fatty streaks and raised lesions. This assumption is also valid in respect to the presence of obstructive lesions in the first septal, first diagonal and posterior descending arteries, usually unopened during routine autopsy and not
228
removed for light-microscopic examination. The sinus node artery, which supplies the sinoatrial
node with its dominant
effect
on cardiac pacemaker function, is not difficult to grossly detect. In many studies of the pharmacology of the automaticity of the sinus node, the sinus node artery was used to deliver drugs, hormones and other chemical agents to the node [ 13-151. Its light-microscopic examination in all cases with severe electrical instability of the myocardium is required. Cases illustrated by Figs. 5 and 7 demonstrate this well. Our results also suggest that pathologists must routinely open and remove for light-microscopic examination the first aeptal artery (see Fig. 8). It supplies 30% of [ 171 and represents the main the total left ventricle [16], 15% of the total myocardium source of collateral circulation when obstructive lesions exist in the posterior descending artery [ 181. This may help to explain the particular importance attributed to the first septal artery in cardiac surgery, reflected by the increasing number of procedures for its direct or indirect grafting [ 191. In many cases, the stenosed septal artery was of a large enough calibre to warrant revascularization [20,21]. This means that, like the main coronary arteries, the first septal vessel may be larger than 1.5 mm distal to stenosis. Similar examples could be given concerning the first diagonal and posterior descending branches (see Fig. 2), both susceptible to develop obstructive atherosclerotic lesions and thus to be involved in the clinical manifestations of coronary heart disease. Acknowledgements The authors wish to express their sincere gratitude to Professor Dr.M. Terbancea, Director of the Institute of Forensic Medicine of Bucharest and to Dr. Maria Anghelescu, C. Petrescu and Silvia Bude, for kindly providing the material used in this study. The authors also wish to acknowledge the skilled technical assistance of Maria Bogovici, Margareta Teodorescu and Silvia Chelaru. References 1 Velican, D. and Velican, C., Study of fibrous plaques occurring in the coronary arteries of children, Atherosclerosis, 33 (1979) 201. 2 Velican, D. and Velican, C., Atherosclerotic involvement of the coronary arteries of adolescents and young adults, Atherosclerosis, 36 (1980) 449. 3 Velican, C. and Velican, D., Incidence, topography and light microscopic feature of coronary atherosclerotic plaques in adults 26-35 years old, Atherosclerosis, 35 (1980) 11. 4 Velican, C. and Velican, D., The percursors of coronary atherosclerotic plaques in subjects up to 40 years old, Atherosclerosis, 37 (1980) 33. 5 Velican, D. and Velican, C., Comparative study on age-related changes and atherosclerotic involvement of the coronary arteries of male and female subjects up to 40 years old, Atherosclerosis, 38 (1981) 39. 6 Velican, C. and Velican, D., Coronary intimal necrosis occurring as an early stage of atherosclerotic involvement, Atherosclerosis, 39 (1981) 479. 7 World Health Organization, Classification of Atherosclerotic Lesions (WHO Technical Report Series, No. 143). World Health Organization, Geneva, 1957, p. 20. 8 Guzman, A.M., McMahan, CA., McGill, H.C., et al., Selected methodological aspects of the International Atherosclerosis Project, Lab. Invest., 18 (1968) 479.
229
9 McGill, H.C. (Ed.), The Geographic Pathology of Atherosclerosis, The Williams and Wilkins Company, Baltimore, MD, 1968, pp. 19-37. 10 Velican, D. and Vehcan, C., Accelerated atherosclerosis in subjects with some minor deviations from the common type of distribution of human coronary arteries, Atherosclerosis, 40 (1981) 309. 11 Hudson, R.E.B., The human conducting system and its examination, J. Clin. Path., 16 (1963) 492. 12 Lendrum, A.C., Fraser, D.S. Sliders, W. and Henderson, R., Studies on the character and staining of fibrin, J. Clin. Path., 15 (1962) 401. 13 James, T.N. and Nadeau, R.A., Direct perfusion of the sinus node - An experimental model for pharmacologic and electrophysiologic studies of the heart. Henry Ford Hosp. Bull., 10 (1962) 21. 14 James, T.N. and Nadeau, R.A., Sinus bradycardia during injection directly into the sinus node artery. Amer. J. Physiol., 204 (1963) 9. 15 White, C.W., Marcus, M.L. and Abboud, F.M., Distribution of coronary artery flow to the coronary right atrium and sinoatrial node, Circ. Res., 40 (1977) 342. 16 McAlpine, W.A., Heart and Coronary Arteries, Springer-Verlag, Heidelberg, 1975, pp. 15 1- 162. 17 James, R.S. and Burch, G.E., Blood supply of the human interventricular septum. Circulation, 17 (1958) 391. 18 Stoney, W.S., Vernon, R.P., Alford, W.C., et al., Revascularization of the septal artery, J. Thorac. Cardiovasc. Surg., 21 (1976) 2. 19 Bedard, P., Keon, W.J., Brais, M. and Goldstein, W., First septal artery - Direct or indirect grafting, Cardiovasc. Surg. (Supp. to Circulation), 62 (1980) I - 116. 20 Keon, W.J., Expectation of myocardial revascularization, Canad. Med. Ass. J., 118 (1978) 408. 21 Bedard, P., Keon, W.J., Brais, M. and Goldstein, W., Direct revascularization of the septal artery. Canad. J. Surg., 23 (1980) 11.
215 Ltd.
The Neglected Coronary Atherosclerosis C. Velican
and Doina
Velican
Instiiule of Internal Medicine, Colentina Hospital, 72202 Bucharest 10 (Romama) (Received 3 September, 1982) (Revised, received 10 November, 1982) (Accepted 27 December, 1982)
Summary A study of the natural history of coronary heart disease by means of gross inspection and light microscopy, carried out on 640 subjects aged l-50 years who had died of violent accidents, revealed a grossly neglected coronary atherosclerosis. It included fibromuscular plaques, intimal necrotic areas and incorporated microthrombi present in the longitudinally opened main coronary arteries but not visible to the naked eye, and some atherosclerotic lesions visible to the naked eye but present in branch vessels unopened or not removed during routine autopsy. There were approximately 500 grossly neglected intimal necrotic areas and approximately 120 grossly neglected incorporated microthrombi; from a total of 809 atherosclerotic plaques 261 (32%) were grossly neglected. The topographic distribution and the number of neglected and non-neglected atherosclerotic plaques, in successive age groups, were analyzed. A small subsample, including 32 patients 52-79 years old, dead of coronary heart disease, was used to demonstrate the importance of the detection of, obstructive atherosclerotic lesions in some usually unopened or not removed branch vessels for a realistic anatomo-clinic-cardioangiographic and ECG correlation. Key words:
Anatomo-clinical correlations - Coronary atherosclerosis - Gross inspection - Light microscopy - Method-dependent limits - Undetected lesions - Unopened branch vessels
Introduction A post mortem study on the natural history of coronary heart disease [l-6] was commenced in 1973 in our laboratory. We adopted the definition and classification of atherosclerotic lesions of the WHO [7] and the ‘Standard Operating Protocol’ used by the International Atherosclerosis Project [8,9]. According to this, the 0021-9150/83/$03.00
0 1983 Elsevier Scientific
Publishers
Ireland,
Ltd.
216
atherosclerotic involvement in Sudan-stained segments of the coronary arteries was ‘measured’ by unaided visual estimation. This method requires only systematic observation, estimation of the surface area involving fatty streaks, fibrous plaques and complicated lesions, and recording. We gradually realized that the major problems in coronary heart disease arose from the degree of narrowing of the lumen of the coronary arteries, and not from the extent of the intimal surface involved with fatty streaks and raised lesions. In an attempt to improve the quality of anatomo-clinic-cardioangiographic and ECG correlations, as well as precision in diagnosis and the extent of information, from 1975 we systematically compared data furnished by macro- and microscopic examinations of similar topographic sites of the coronary tree. This complex method allowed us to reveal that (a) using only gross inspection we constantly overlooked the presence of early atherosclerotic lesions in the longitudinally opened vessels, occurring as fibromuscular plaques, intimal necrotic areas and incorporated microthrombi. Among the early atherosclerotic lesions, only the fatty streaks were clearly visualized grossly after Sudan staining; (b) macroscopic examination of the coronary arteries could not offer information on the pattern and rate of progression of fibromuscular plaques, intimal necrotic areas and incorporated microthrombi toward fibronecrotic or fibrohyaline plaques, or on the main pathogenetic mechanisms involved in the onset of atherosclerotic lesions of possible clinical significance; (c) some branch vessel unopened during gross inspection might appear, on light-microscopic examination, severely narrowed by atherosclerotic plaques and/or by an excessive intimal thickening. These observations led progressively to the individualization of a grossly neglected coronary atherosclerosis, as presented. Material and Methods Coronary arteries of 640 subjects aged l-50 years, who had died of violent accident were examined. This unselected population sample of Bucharest was used to delineate the light-microscopic features, extension and importance of the neglected coronary atherosclerosis in apparently healthy subjects. This material was supplemented with 32 hospitalized patients aged 52-79 years (24 males and 8 females) who died of myocardial infarction and sudden cardiac arrest without obstructive lesions in the main coronary arteries. This small selected subsample was used to reveal the light-microscopic features, extension and importance of the neglected coronary atherosclerosis in patients with clinical manifestations of coronary heart disease. Using scissors with blunt points, a gross dissection of the coronary bed was performed in each heart up to the 1.O- 1.5 mm level of the external vessel diameter. The smaller branch vessels were investigated only microscopically. Examination of the coronary arteries began at and included the aortic ostia and extended distally along the epicardial traject of the three main vessels, as far as they could be traced. The right coronary artery was investigated from its origin to the area of the posterior interventricular groove or some distance beyond this along the groove between the left atrium and ventricle. The following branches of the right coronary
217
artery were also investigated. The sinus node artery, its origin appearing at the superior cave-atria1 junction. It ran in the direction opposite to the conus branch, i.e. cranially and dorsally and to the right, along the anterior wall of the right atrium below the right auricular appendage. It ascended on the anterior wall of the left atrium to reach the ostium of the superior vena cava. In approximately one third of cases the sinus node artery arose from the proximal segment of the circumflex artery, a few millimetres beyond its origin. The atrioventricular node artery, appearing as a rather slender vessel at or about the level of the U-curve at the crux cordis. It ran in a cranial direction toward the posterior and superior portion of the interventricular septum. The posterior descending artery occurred as the major terminal branch of the right coronary artery, arising at or immediately before the level of the crux cordis. Its course toward the apex could be followed in the posterior interventricular sulcus; this vessel was opened longitudinally whenever its external diameter was more than 1.O-1.5 mm. We also removed the right marginal artery coursing along the acute margin of the heart, for light-microscopic examination. The anterior descending artery was investigated grossly from its origin to the apex, along the anterior interventricular groove. Both first diagonal artery and first septal artery arose from the anterior descending artery in the proximal 20 mm of the anterior interventricular groove. In some cases the external diameter of the first diagonal artery was equal to or exceeded that of the parent vessel. Usually, the first diagonal artery was present in the angle subtended by the anterior descending and circumflex arteries, running in a caudal direction toward the apex. In contrast, the first septal artery arose at about a 90” angle and ran along the septum from front to back and in a caudal direction. Generally, only the more cranial septal artery was well demonstrable, being of greater length and calibre than the lower septal vessels. Its identification was aided by the characteristic branching from the anterior descending artery (it entered the septum at a right angle and exhibited a straight course). The circumflex artery was investigated from its origin until it was too small to dissect. This vessel ran in the atrioventricular groove in the direction of the crux and was often difficult to find, being buried deep in fat, particularly in the posterior atrioventricular sulcus. The circumflex artery appeared as the vessel of the coronary tree exhibiting the most variable origin, feature and topography. In more than one-third of the subjects investigated it was very short or long, narrow or large and as a coronary artery with or without important branch vessels. The origin of the circumflex artery was also variable: from the left main coronary artery, from the right coronary artery or directly from the aorta. In our material only 371 subjects (58%) showed a more or less similar branching anatomical pattern, arbitrarily termed by us ‘the common type of distribution’ of the coronary arteries. The remainder, 269 subjects (42%) exhibited deviations from this common type, some of them associated with an accelerated atherosclerotic involvement [lo]. Samples were removed at centimeters intervals from the origin of the main coronary arteries: 5-7 samples along the course of the anterior descending artery; 2-4 samples along the course of the circumflex artery; and 6-10 samples along the
218
course of the right coronary artery. In addition the left main coronary artery was separately sampled, as well as the main branching areas and the proximal segment of the main branch vessels. In selected cases (subjects dead of coronary heart disease), the ventricular myocardium was sliced transversely in approximately IO-mm thick slices from the apex to within 20 mm of the atrioventricular groove. Each slice was examined to identify acute myocardial infarction, aneurysm, ruptures, pathological changes in the endocardium and mural thrombi. Acute myocardial infarction was defined as an area of ischemia and necrosis which measured at least 10 mm in any one dimension; old or healed infarcts were considered areas of granulation tissue or fibrous scars measuring at least 10 mm in any one dimension. In the absence of evident infarction and coronary artery obstruction, random samples of the full thickness of the ventricular wall were taken from the heart slices in a spiral step-wise manner, from the apex to the base of the heart. Finally, in a few cases, samples were removed from myocardial areas including the sinoatrial and atrioventricular nodes [ill. After fixation in Carnoy’s fluid, the coronary artery specimens and the selected myocardial samples were embedded in paraffin wax and cut at 4 pm thick. All tissue sections were stained routinely with resorcin fuchsin (1 h) followed by alcian blue (2 h). They were also occasionally stained with hematoxylin-eosin, Van Gieson’s picrofuchsin, Masson’s and Mallory’s trichromes and by Lendrum’s method for fibrin [ 121. The lumen of the vessel present in each tissue section was measured with the aid of a micrometer eyepiece, the units of the micrometer being transformed into microns. The degree of encroachment of lesions or of the thickened intima was estimated in terms of percentage narrowing. The reference point for luminal diameter reduction was the lumen of a similar area of the coronary tree, free of lesions and/or abnormal intimal thickening, belonging to a subject with a similar age, sex and branching anatomical pattern. The distance recorded was that from the internal elastic membrane or intima/media frontier on one side to the internal elastic membrane or intima/media frontier on the other side. An atherosclerotic lesion or a very thick intima was termed ‘obstructive’ only if it narrowed more than 75% of the arterial lumen. Results The importance and extent of the neglected coronary atherosclerosis in successive age groups, from children up to mature adults 50 years old, was deduced from the ratios of: (i) cases with atherosclerotic plaques, intimal necrotic areas, incorporated microthrombi and fatty streaks revealed by gross inspection versus those revealed by light microscopy; (ii) total number of atherosclerotic lesions occurring as atherosclerotic plaques, intimal necrotic areas, incorporated microthrombi and fatty streaks revealed by gross inspection versus that revealed by light microscopy. Among the various types of early lesions only the fatty streak could not be included in the neglected coronary atherosclerosis, since it was easily and constantly revealed on routine autopsy in Sudan-stained coronary segments. In contrast, the fibromuscular plaques, the intimal necrotic areas and the incorporated microthrombi were con-
219
Fig. 1. Three early lesions which represent the main morphological substratum of the grossly neglected coronary atherosclerosis: the fibromuscular plaques (left), the intimal necrotic areas (middle, arrow) and the incorporated microthrombi (right). Resorcin fuchsin-alcian blue, X 120 (reduced by l/3).
sistently included in the grossly neglected coronary only on light-microscopic examination (Fig. 1).
atherosclerosis,
being
detected
The grossly undetected lesions Table 1 shows that of the 640 apparently healthy subjects aged l-50 years, dead of violent accidents, 289 (45%) exhibited on light-microscopic examination intimal necrotic areas and 89 (14%) incorporated microthrombi. In the coronary arteries of all these 640 subjects there were approximately 500 intimal necrotic areas and 120 incorporated microthrombi undetected by gross inspection. In young and mature adults a limited number of these grossly undetected lesions became visible to the
TABLE
1
CASES (W) AGED MICROTHROMBI
l-50 YEARS WITH INTIMAL NECROTIC AREAS AND INCORPORATED UNDETECTED BY GROSS INSPECTION AND REVEALED BY LIGHT MI-
CROSCOPY Age groups
Total cases studied
(yr)
I- 5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50
63 81 66 59 69 72 56 54 58 62 Total
640
Cases with intimal necrotic areas
Cases with incorporated microthrombi
Total
B
Total
%
2.46 6.06 13.55 33.33 55.55 71.42 83.92 94.82 96.77
1 1 2 5 6 12 10 12 18 22
1.58 1.23 3.03 8.47 10.14 13.88 17.85 22.22 31.03 35.48
0 2 4 8 23 40 50 47 55 60 289
89
220
TABLE 2 NUMBER OF CASES WITH CORONARY ATHEROSCLEROTIC CORONARY ATHEROSCLEROTIC PLAQUES, AS REVEALED AND LIGHT MICROSCOPY (LM) Age groups (yr)
Total cases studied
Number of cases with atherosclerotic plaques
Number sclerotic Total
GI total
LM total
(%)
(a)
63 81
0
0
0
11-15
66
0
16-20
59
0
21-25
69
26-30
72
31-35
56
36-40
54
41-45
58
46-50
62
14 (20.28) 22 (30.55) 26 (46.42) 31 (57.40) 46 (79.3 I) 59 (95.16)
2 (2.46) 3 (4.54) 7 (11.86) 20 (28.98) 30 (41.66) 33 (58.92) 36 (66.66) 51 (87.93) 60 (96.77)
198
242
l- 5 6-10
Total
640
of coronary plaques GI
PLAQUES AND NUMBER OF BY GROSS INSPECTION (GI)
athero-
LM
GI/LM ratio
3
0
3
10
0
10
21
0
21
63
40
63
0.63
98
62
98
0.63
108
71
108
0.65
120
88
120
0.73
177
122
177
0.68
209
165
209
0.78
809
548
809
unaided eye, this particular evolution being reflected by the existence of intermediate, transitional stages between intimal necrotic areas and fibronecrotic plaques and between incorporated microthrombi and fibrohyaline plaques. Table 2 shows that the first aspects of evolution of atherosclerotic plaques from undetected lesions to lesions visible to the naked eye could be demonstrated in the coronary arteries of subjects aged 21-25 years. This table also shows the age-related distribution of all types of atherosclerotic plaques in the neglected and non-neglected coronary atherosclerosis. Of the 640 subjects aged l-50 years, 242 (38%) exhibited atherosclerotic plaques on light-microscopic examination and only 198 (3 1 W) on gross inspection. From the total 809 plaques revealed by light microscopy in the unselected population sample examined, only 549 were also recorded grossly. This means that 261, or 32% of the existing plaques remained undetected even after Sudan staining, owing to the limits of the unaided visual estimation. They represented approximately one third of all atherosclerotic plaques visualized in the coronary arteries of 640 children, adolescents, young and mature adults up to 50
221 TABLE
3
NUMBER OF CORONARY ATHEROSCLEROTIC MAIN CORONARY ARTERIES, AS REVEALED MICROSCOPY (LM) Sites selected
IN SELECTED SITES OF THE INSPECTION (GI) AND LIGHT
Age WJUP~ (~0 l-5 GI
Origin of the left main coronary artery Left main coronary artery Origin of the anterior descending artery Proximal segment of the anterior descending artery Distal segment of the anterior descending artery Origin of the circumflex artery Proximal segment of the circumflex artery Distal segment of the circumflex artery Origin of the right coronary artery Proximal segment of the right coronary artery Distal segment of the right coronary artery
PLAQUES BY GROSS
0
6-10
-
LM
GI
- -
-
11-15 LM
-
16-20
GI
LM
GI
LM
0 0
0 0
0 0
0 0
0 0
0
0 0
0
0
2
0
4
I
0
0
0
0
0
5
6
0
0
0
0
0
0
0
0
0
1
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
years old. The fact that 1 out of every 3 plaques was overlooked grossly could account for the greater number of plaques per subject revealed on microscopic than on macroscopic examination of similar topographic sites. The ratio of total number of plaques versus total number of subjects with plaques, varied between 3.00 and 3.48 according to data furnished by light microscopy and between 2.65 and 2.85 according to data furnished by gross inspection. In the material investigated there were microscopically more than 3 plaques per subject and grossly less than 3 plaques per subject. microscopy at the bifurcation area of the left main coronary artery about 20 years earlier than the first grossly visible lesions. Table 3 also shows that there were 3 plaques in 81 children aged 6-10 years, 10 plaques in 66 children and juveniles aged 11-15 years, and 21 plaques in 59 adolescents aged 16-20 years, all undetected by gross inspection. Starting from the age group 21-25-years old, plaques were visualized both macro- and microscopically, but the number revealed by light microscopy
222
Age groups(yr) 26-30
21-25 GI
31-35
41-45
36-40
LM
GI
LM
GI
LM
0 0
0 0
0
1 1
0
0
1
2 2
5
I
11
13
12
10
17
16
20
0
0
0
3
4
6
LM
GI
LM
GI
LM
1 1
2 2
2 3
3 6
4 8
5 10
14
12
14
14
18
18
20
11
14
16
18
21
25
28
30
2
5
7
5
7
I
9
16
18
8
11
6
9
6
8
8
10
8
10
8
6
10
6
10
10
12
16
20
18
21
0
0
0
0
1
3
2
4
2
4
3
5
5
5
8
10
I
11
7
9
8
12
12
14
7
10
8
10
8
10
10
12
14
18
14
16
4
7
5
7
8
10
10
12
11
14
14
16
-
GI
46-50
remained consistently greater in successive age groups than that revealed grossly. This is also strengthened by the age-dependent evolution of the ratio of plaques revealed by light microscopy versus plaques revealed grossly. The respective ratio varied between 1.58 (age group 26-30-years old) and 1.30 (age group 46-50-years old). This demonstrates the persistence, even in mature adults, of grossly undetected atherosclerotic plaques. The unopened branch vessels Table 4 shows that the first atherosclerotic plaques were visualized microscopically in the main branch vessels of the coronary arteries in subjects aged 21-25 years, in the proximal segment of the first diagonal, or first septal, or posterior descending arteries. Ten years later at similar topographic points, we revealed raised lesions if the respective branch vessels were opened during routine autopsy. Table 4 also shows that in branch vessels such as the second diagonal, left and right marginal, sinus node and atrioventricular node arteries, the presence of atherosclerotic
223 TABLE 4 NUMBER OF CORONARY ATHEROSCLEROTIC PLAQUES IN THE MAIN OF THE CORONARY ARTERIES, AS REVEALED BY GROSS INSPECTION MICROSCOPY (LM) Main branch
vessels
Age groups (yr) l-5 GI
First diagonal artery Second diagonal artery First septal artery Left marginal artery Sinus node artery Right marginal artery Atrioventricular node artery Posterior descending artery
BRANCH VESSELS (GI) AND LIGHT
6-10 LM
0
0
0
0
11-15
16-20
GI
LM
GI
LM
GI
LM
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0
0 0
0 0
0 0
0 0
0 0
plaques was revealed only microscopically, these branch vessels being unopened during gross inspection. Figs. 2-4 illustrate such occasional findings, in apparently healthy subjects dead of violent accidents. A more important involvement of the branch vessels of the coronary artery was visualized in the small selected subsample dead of coronary heart disease and aged 52-79 years. In this small selected subsample we could not find lumen-compromising complicated lesions, even in the
Fig. 2. The posterior descending artery of an apparently healthy 34-year-old male subject who a car accident. A grossly neglected atherosclerotic plaque, narrowing up to 80% of the vessel extending longitudinahy more than 2 mm along the artery course. The posterior descending not opened during routine autopsy but removed for light-microscopic examination. Resorcin cian blue, X65.
had died in lumen and artery was fuchsin-al-
224
Age groups (~0 21-25 ~
26-30 ____
31-35 ~
36-40 ~
41-45 ~
46-50
GI
LM
GI
LM
GI
LM
GI
LM
GI
LM
GI
LM
0 0 0 0 0 0
I 0 2 0 0 0
0 0 0 0 0 0
4 0 5 1 0 0
1 0 2 0 0 0
4 1 4 1 0 1
1 0 4 0 0 0
4 1 6 1 1 1
3 0 7 0 0 0
I 2 11 2 2 2
5 0 8 0 0 0
8 2 12 2 2 3
0 0
0 2
0 0
0 3
0 3
0 5
0 3
0 6
0 6
1 11
0 9
2 13
Fig. 3. The left marginal artery of an apparently healthy 42-year-old male subject who had died in a car accident. A grossly neglected atherosclerotic plaque narrowing up to 75% of the vessel lumen and extending more than 1.5 mm along the artery course. The left marginal artery was not opened during routine autopsy, but removed for light-microscopic examination. Resorcin fuchsin-alcian blue, x 65.
Fig. 4. The right marginal artery of an apparently healthy 47-year-old male subject who had died in a car accident. A grossly neglected atherosclerotic plaque narrowing up to 60% of the vessel lumen and extending more than 1.5 mm along the artery course. The right marginal artery was not opened during routine autopsy, but removed for light-microscopic examination. Resorcin fuchsin-alcian blue, ~65.
225
Fig. 5. The arteries supplying the conduction system (left, the sinoatrial node artery; right, the atrioventricular node artery) involved by grossly neglected atherosclerotic lesions. A 52-year-old woman with severe bradycardia, bigeminy and atrioventricular block, followed by cardiac arrest. Absence of myocardial infarction and lumen-compromising lesions in the three main coronary arteries. Left: severe narrowing of the lumen of the artery supplying the sinoatrial node, whereas the proximal segment of the right coronary did not show atherosclerotic involvement, but only a moderate intimal thickening. Right: severe narrowing of the lumen of the artery supplying the atrioventricular node, whereas the terminal segment of the right coronary artery did not show pathologic changes. Resorcin fuchsin-alcian blue, x 40.
Fig. 6. A grossly neglected obstructive lesion, blocking more than 80% of the lumen of the artery supplying the atrioventricular node, revealed on light-microscopic examination within the proximal 2 mm of the vessel course. A 58-year-old women who manifested syncopal episodes, followed by chest pain. The ECG showed left bundle branch block. She died with ventricular arrhythmia. The conduction system was partly replaced by fibrous connective tissue. Pathological examination revealed the absence of myocardial infarction and stenotic lesions in the main coronary arteries. Resorcinfuchsin-alcian blue, x 40.
Fig 7. A grossly neglected obstructive lesion, blocking more than 75% of the lumen of the artery supplying the sinoatrial node, revealed on light-microscopic examination within the proximal 2 mm of the vessel course. A 54-year-old man with persistent thoracic pain resistant to nitroglycerin. The ECG showed ST shifts of the ischemic type. He died with ventricular fibrillation. Pathological examination revealed the absence of myocardial infarction and lumen-compromising lesions in the main coronary arteries. We could not detect the vessel supplying the atrioventricular node. Resorcin fuchsin-alcian blue, x 65.
presence of fresh myocardial infarcts, in the left main coronary artery, anterior descending artery, circumflex artery and right coronary artery. On the other hand obstructive intimal thickenings or atherosclerotic plaques were present in the first septal artery in 7 patients (22%) in the posterior descending artery in 7 patients (22%), in the first diagonal artery in 5 patients (16%) and in the branches supplying the conduction system in 3 patients (9%). In the absence of stenosis in the main
Fig. 8. A grossly neglected obstructive lesion, blocking more than 75% of the lumen of the first septal artery and extending more than 2 mm along the vessel course. A 69-year-old woman with a history of angina pectoris and ECG evidence of infarction. Pathological examination showed a fresh myocardial infarct in the interventricular septum, in the area supplied by the obstructed artery. Lumen-compromising lesions were absent from the main coronary arteries. A narrow and very short posterior descending artery was present. Resorcin fuchsin-al&n blue, x 65.
227
coronary arteries, valid anatomo-clinic-cardioangiographic were established based on the presence of obstructive branch vessels. Figs. 5-8 demonstrate this.
and ECG correlations lesions in grossly unopened
Discussion The prevalent trend in studying human atherosclerosis is oversimplification: an oversimplified standard operating protocol to record atherosclerotic lesions (visual estimation of the longitudinally opened main coronary arteries stained with Sudan dyes); an oversimplified classification of lesions (non-raised and raised); an oversimplified concept of the natural history of atherosclerosis (fatty streaks + fibrous plaques + complicated lesions); an oversimplified form of the pathogenetic sequence (conversion of fatty streaks to fibrous plaques). The main objective of these over-simplified methods, classifications and concepts was to offer procedures easy to apply, which avoid undue demands upon the time and resources of the pathologist and which offer information that can be computed. Because of this, all atherosclerotic lesions existing outside the longitudinally opened main coronary arteries are inevitably overlooked, since they do not fit with the surface area ‘decided’ to be grossly estimated. The standard operating protocol of the IAP [8], for instance, recommends one ‘to exclude from the study all branches of the right coronary artery’ and does not give any specific indication on atherosclerotic involvement of the first diagonal and first septal arteries. Also types of early atherosclerotic lesions other than fatty streaks are overlooked by this method, since they are not visible to the naked eye. Consequently, in the IAP-study [9], the intimal surface covering fibromuscular plaques, intimal necrotic areas and incorporated microthrombi was recorded as ‘normal intima’. The grossly neglected coronary atherosclerosis, analyzed in this study, includes lesions present in the longitudinally opened left main coronary artery, anterior descending artery, circumflex artery and right coronary artery undetected by the naked eye and lesions present in the branch vessels of these main coronary arteries unopened or not removed during routine autopsy. The existence of this grossly neglected coronary atherosclerosis must be taken into consideration in all studies dealing with: (i) the feature of early atherosclerotic lesions; (ii) the lesions which characterize pediatric coronary atherosclerosis; (iii) the temporal and spatial relations between early and advanced atherosclerotic lesions; (iv) the main pathogenetic mechanisms of atherosclerosis; (v) the relationships between coronary bed obstruction, on the one hand, and myocardial infarcts, myocardial electrical instability, syncopal episodes and sudden cardiac arrest on the other. The results in this paper demonstrate that a grossly undetected obstructive lesion in the vessels supplying the conduction system might be more important for anatomo-clinic-angiocardiographic and ECG correlations in subjects with coronary heart disease than the extent of intimal surface of the main coronary arteries involved with fatty streaks and raised lesions. This assumption is also valid in respect to the presence of obstructive lesions in the first septal, first diagonal and posterior descending arteries, usually unopened during routine autopsy and not
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removed for light-microscopic examination. The sinus node artery, which supplies the sinoatrial
node with its dominant
effect
on cardiac pacemaker function, is not difficult to grossly detect. In many studies of the pharmacology of the automaticity of the sinus node, the sinus node artery was used to deliver drugs, hormones and other chemical agents to the node [ 13-151. Its light-microscopic examination in all cases with severe electrical instability of the myocardium is required. Cases illustrated by Figs. 5 and 7 demonstrate this well. Our results also suggest that pathologists must routinely open and remove for light-microscopic examination the first aeptal artery (see Fig. 8). It supplies 30% of [ 171 and represents the main the total left ventricle [16], 15% of the total myocardium source of collateral circulation when obstructive lesions exist in the posterior descending artery [ 181. This may help to explain the particular importance attributed to the first septal artery in cardiac surgery, reflected by the increasing number of procedures for its direct or indirect grafting [ 191. In many cases, the stenosed septal artery was of a large enough calibre to warrant revascularization [20,21]. This means that, like the main coronary arteries, the first septal vessel may be larger than 1.5 mm distal to stenosis. Similar examples could be given concerning the first diagonal and posterior descending branches (see Fig. 2), both susceptible to develop obstructive atherosclerotic lesions and thus to be involved in the clinical manifestations of coronary heart disease. Acknowledgements The authors wish to express their sincere gratitude to Professor Dr.M. Terbancea, Director of the Institute of Forensic Medicine of Bucharest and to Dr. Maria Anghelescu, C. Petrescu and Silvia Bude, for kindly providing the material used in this study. The authors also wish to acknowledge the skilled technical assistance of Maria Bogovici, Margareta Teodorescu and Silvia Chelaru. References 1 Velican, D. and Velican, C., Study of fibrous plaques occurring in the coronary arteries of children, Atherosclerosis, 33 (1979) 201. 2 Velican, D. and Velican, C., Atherosclerotic involvement of the coronary arteries of adolescents and young adults, Atherosclerosis, 36 (1980) 449. 3 Velican, C. and Velican, D., Incidence, topography and light microscopic feature of coronary atherosclerotic plaques in adults 26-35 years old, Atherosclerosis, 35 (1980) 11. 4 Velican, C. and Velican, D., The percursors of coronary atherosclerotic plaques in subjects up to 40 years old, Atherosclerosis, 37 (1980) 33. 5 Velican, D. and Velican, C., Comparative study on age-related changes and atherosclerotic involvement of the coronary arteries of male and female subjects up to 40 years old, Atherosclerosis, 38 (1981) 39. 6 Velican, C. and Velican, D., Coronary intimal necrosis occurring as an early stage of atherosclerotic involvement, Atherosclerosis, 39 (1981) 479. 7 World Health Organization, Classification of Atherosclerotic Lesions (WHO Technical Report Series, No. 143). World Health Organization, Geneva, 1957, p. 20. 8 Guzman, A.M., McMahan, CA., McGill, H.C., et al., Selected methodological aspects of the International Atherosclerosis Project, Lab. Invest., 18 (1968) 479.
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9 McGill, H.C. (Ed.), The Geographic Pathology of Atherosclerosis, The Williams and Wilkins Company, Baltimore, MD, 1968, pp. 19-37. 10 Velican, D. and Vehcan, C., Accelerated atherosclerosis in subjects with some minor deviations from the common type of distribution of human coronary arteries, Atherosclerosis, 40 (1981) 309. 11 Hudson, R.E.B., The human conducting system and its examination, J. Clin. Path., 16 (1963) 492. 12 Lendrum, A.C., Fraser, D.S. Sliders, W. and Henderson, R., Studies on the character and staining of fibrin, J. Clin. Path., 15 (1962) 401. 13 James, T.N. and Nadeau, R.A., Direct perfusion of the sinus node - An experimental model for pharmacologic and electrophysiologic studies of the heart. Henry Ford Hosp. Bull., 10 (1962) 21. 14 James, T.N. and Nadeau, R.A., Sinus bradycardia during injection directly into the sinus node artery. Amer. J. Physiol., 204 (1963) 9. 15 White, C.W., Marcus, M.L. and Abboud, F.M., Distribution of coronary artery flow to the coronary right atrium and sinoatrial node, Circ. Res., 40 (1977) 342. 16 McAlpine, W.A., Heart and Coronary Arteries, Springer-Verlag, Heidelberg, 1975, pp. 15 1- 162. 17 James, R.S. and Burch, G.E., Blood supply of the human interventricular septum. Circulation, 17 (1958) 391. 18 Stoney, W.S., Vernon, R.P., Alford, W.C., et al., Revascularization of the septal artery, J. Thorac. Cardiovasc. Surg., 21 (1976) 2. 19 Bedard, P., Keon, W.J., Brais, M. and Goldstein, W., First septal artery - Direct or indirect grafting, Cardiovasc. Surg. (Supp. to Circulation), 62 (1980) I - 116. 20 Keon, W.J., Expectation of myocardial revascularization, Canad. Med. Ass. J., 118 (1978) 408. 21 Bedard, P., Keon, W.J., Brais, M. and Goldstein, W., Direct revascularization of the septal artery. Canad. J. Surg., 23 (1980) 11.