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Hyperplasia of coronary intima in young males in relation to development of coronary heart disease in adults
International Journal of Cardiology 76 (2000) 57–64 www.elsevier.com / locate / ijcard
Hyperplasia of coronary intima in young males in relation to development of coronary heart disease in adults a, b a a Valentin S. Zhdanov *, Nils H. Sternby , Iraida P. Drobkova , Igor E. Galakhov a
Department of Cardiovascular Pathology, Russian Cardiology Complex, 121552 Moscow, Russian Federation b Department of Pathology, Lund University, Malmo University Hospital, S-20502 Malmo, Sweden Received 12 August 1999; received in revised form 5 July 2000; accepted 4 September 2000
Abstract The aim of the investigation was to study structural features of coronary arteries in young males which may influence the development of stenosing coronary atherosclerosis in older age. We studied the coronary arteries from 84 males, 10–39 years old, who died from accidents in Moscow, Malmo and Riga, and 98 males aged 40 and above from Moscow who died from coronary heart disease (71 cases) or other diseases (27 cases). In children and young males from all three cities, musculo-elastic hyperplasia of the coronary intima took place constantly but with different degrees of expression; a strict relationship of the intimal thickness and age was observed. Histometric investigations of the right coronary artery showed that in young males of Riga, in comparison with those of Malmo, the intima was significantly thicker both outside (69.662.8 and 58.262.5 mm) and within the area of cushion like thickening (118.864.0 and 101.963.8 mm), they had more extended cushion-like thickening of intima (42.663.0 and 30.863.3% to the length of the artery circumference) and destroyed parts of the internal elastic lamina (28.361.9 and 19.161.7% of its length). In males older than 40 years, severe coronary atherosclerosis and stenosis was also significantly more common in Riga than in Malmo. Our data indicate that with age the intimal musculo-elastic hyperplasia in the coronary arteries is transformed to a fibro–elastic layer. The thickness of this layer in the presence of stenosing plaques (.75% of arterial lumen) was much greater than in the presence of plaques with stenoses less than 50% (188.16 7.3 and 69.864.5 mm, respectively). Conclusion: The development of stenosing coronary atherosclerosis is closely related to the degree of musculo-elastic intimal hyperplasia in childhood and young age. The formation of a fibro–elastic layer in the coronary intima decreases the ability of the artery to dilate during the development of atherosclerosis. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Coronary arteries; Intimal hyperplasia; Coronary stenosis; Coronary heart disease; Children; Young males
1. Introduction Stenosis of the coronary arteries is an important factor in the development of coronary heart disease. Stenosis is observed significantly more often in the coronary arteries than in other arteries [1]. In most investigations, coronary stenosing is closely related to the degree of coronary atherosclerosis, but occasion*Corresponding author. Tel.: 17-95-4146582; fax: 17-95-4152962. E-mail address: [email protected] (V.S. Zhdanov).
ally there is a discrepancy between the amount of atherosclerotic changes in the coronary arteries and the prevalence of stenosis. Moreover, the development of atherosclerosis in different arteries can be accompanied also with dilatation of their lumen, it is found when atrophy and destruction of vessel wall elements, especially in the media, occurs [2,3]. Different populations vary in susceptibility to development of coronary stenosis and therefore also development of coronary heart disease [3–6]. The role of structural peculiarities of the coronary
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00369-7
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V.S. Zhdanov et al. / International Journal of Cardiology 76 (2000) 57 – 64
arteries in the development of coronary stenosis is insufficiently investigated. These peculiarities are first of all expressed in the development of coronary intimal hyperplasia which is noted already in children and before the appearance of atherosclerotic changes [1,7–13]. The aim of this investigation is to study the role of some structural changes of the coronary arteries in children and young males and their possible relation to the development of coronary stenosis in atherosclerosis in later life.
2. Material and methods Coronary arteries were investigated in two groups of 142 Moscow males: one group of 44 practically healthy males, 10–39 years of age who died from accidents, and the second group of 98 males, 40–69 years of age who died from coronary heart disease (71 cases) or other diseases (27 cases). All these coronary arteries were collected in 1995–1999. In both groups the proximal parts of coronary arteries were studied on cross microscopic sections with 0.5 cm interval. In the old Moscow group histometrical studies of coronary arteries with severe (.75%) or moderate (,50%) stenoses of their lumen were performed. The initial area of arterial lumen was determined by using the internal elastic lamina as peripheral limit, and the remaining area of the lumen by measuring the internal intimal surface; these data were the base for calculation of the degree of coronary stenosis. Besides, the thickness of the fibrous or fibro–elastic layer at the base of the plaques and outside of them was measured. In the young group of males, the thickness of coronary intima was investigated along of the whole vessel circumference. In previous repeated epidemiological studies of atherosclerosis on autopsy material [6], we noticed significant differences in the development of coronary atherosclerosis and stenosis in males of Malmo and Riga over a 25-year period. In Malmo males, atherosclerosis diminished during this period, but in Riga males, it increased significantly. It was therefore of interest to study coronary arteries in young males of these populations to determine if there were differences in their structure that might help to explain the
different rate of development of coronary atherosclerosis and stenosis. The studied coronary arteries from Malmo and Riga were collected almost 10 years ago and kept in formalin in plastic bags at Moscow Center for studying the epidemiology of atherosclerosis. A standard section of the right coronary artery (1 cm from its origin) was examined by histometrical methods in practically healthy 20–39 year-old males from these two cities (20 cases from each city). The following parameters of the arteries were measured: the maximal thickness (in microns) of cushion-like thickening of the intima (the most prominent local parts of hyperplased intima), the extent of these cushion-like thickening (in percent of the artery circumference), the intimal thickness outside places of cushion-like thickenings, the length of the destroyed internal elastic lamina (in percent of the artery circumference), and the degree of intimal lipid infiltration (in percent to the whole surface of intima in histological sections). The microscopic sections were stained with haematoxylin–eosin, oil red 0 (for fat), orcein (elastic fibers), and Masson’s trichrome staining (connective tissue). Histometrical investigations of the coronary arteries were performed with the help of the ocular-micrometer and the microscopic analysis system (Morphomat 30, Opton, West Germany). Data are reported as a mean6standard error. To ascertain the significance of the received data the two-tailed Student’s t-test was used.
3. Results The proximal parts of the coronary arteries in Moscow 10–39 year-old males showed intimal hyperplasia of varying degree (Fig. 1). A strict relationship dependence of the thickness of the coronary intima and age was observed. The mean thickness of intima in the proximal part of the right coronary artery in the age of 10–19 years was equal to 72 mm (n55, range: 9–120), in the age 20–29 years 132611.5 mm (n519, range: 22–210), in the age 30–39 years 187610.8 mm (n520, range: 62–283). Slight degree of hyperplasia (thickness of intima less or equal to the thickness of media) was present in 17 of 44 cases (38.7%), moderate degree of intimal hyperplasia (up to double thickness of the media) —
V.S. Zhdanov et al. / International Journal of Cardiology 76 (2000) 57 – 64
Fig. 1. Slight and sometimes moderate degree of intimal hyperplasia in the right coronary artery in a male of 33 years, who died from trauma. Hyperelastosis of intima is marked (Orcein stain: 340).
in 21 cases (47.7%), and severe degree of intimal hyperplasia (more than double the thickness of the media) in six cases (13.6%). Coronary arteries with even severe degree of intimal hyperplasia showed macroscopically only an insignificant thickening of the wall, or occasionally flat white–yellow plaques. Histometric investigations of the right coronary artery (Table 1) showed that young males from Riga,
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in comparison with those from Malmo, had significantly thicker intima both outside and within areas of so-called cushion-like (localized) thickenings. They had also greater extent of cushion-like thickenings and greater destroyed parts of the internal elastic lamina. The lipid infiltration of the coronary intima was practically the same in males of both cities. The basic cellular elements in the hyperplastic intima are smooth muscle cells. They are usually organized as a compact layer, and unlike medial smooth muscle cells have a longitudinal and not a circular arrangement. The extracellular matrix in the hyperplastic intima was rich in collagen and elastic fibers, which compose a dense net. The typical changes of the internal elastic lamina in such areas were numerous defects and splitting with newly formed elastic fibers. The development of intimal hyperplasia was usually observed around the whole circumference of the coronary arteries. However it did not develop the same in different segments of the arteries. Even in arteries with severe degree of intimal hyperplasia, there were areas of only moderate or slight intimal hyperplasia, and this did create a picture of so-called musculo–fibrous or musculo–elastic plaques (Fig. 2). It was found in 9% of the studied cases. In the deep layers of such plaques sometimes small necroses developed. A lipid component in the intimal hyperplasia and in the musculo–elastic plaques in the coronary arteries of children was present, but not significant in most cases. There were mainly extracellular small-graine lipid particles along the fibrous structures and only a few fat-containing cells, but in adults, the areas of the coronary arteries with severe degree of hyperplasia often contained a lot of extraand intracellular lipids both in the superficial and in the deep layers of the intima. Many coronary athero-
Table 1 Histometric characteristics of structural peculiarities of intima in right coronary artery in young males (20–39 years) in Malmo and Riga a Town
Malmo Riga P-value a
Mean thickness of intima outside of CT (mm) 58.262.5 69.662.8 ,0.01
Mean thickness of CT (mm)
101.963.8 118.864.0 ,0.01
Extent of CT (% of the artery circumference) 30.863.3 42.663.0 ,0.05
Extent of destroyed parts of IEM (% of the artery circumference) 19.161.7 28.361.9 ,0.01
Data are mean6standard error of the mean. CT, cushion-like thickenings of coronary arteries. IEM, internal elastic membrane.
Extent of intima occupied by lipids (% to the extent of whole intima) 22.562.3 25.462.9 NS
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Fig. 2. Irregular severe degree of intimal hyperplasia in the left anterior descending coronary artery with formation of fibro–muscular plaque in a male of 38 years (Orcein stain: 340).
sclerotic plaques in young people show evidence of being developed on the basis of intimal hyperplasia. The amount of smooth muscle cells was decreasing gradually with age in the hyperplastic intima and there was an increase of the number of elastic and collagen fibers. Such an evolution of intimal hyperplasia with accumulation of lipids and appearance of necroses can lead to the formation of an atherosclerotic fibro–lipid plaque, which hardly differ from classic atherosclerotic plaque. Comparative investigations of proximal parts of the coronary arteries with severe (.75%) and moderate (,50%) stenosing atherosclerotic plaques were performed separately. Severe coronary stenoses were marked in subjects older than 40 years, who died from coronary heart disease (71 cases); moderate coronary stenoses — in subjects, who died from other diseases (27 cases). Atherosclerotic plaques in both groups were classified as fibro–lipid with some variations in the expression of fibrous and lipid components. The plaques causing severe coronary stenosis were complicated (the presence of calcinosis, haemorrhages, thrombosis) in 93% of cases (in 66 of
71 subjects). Such changes in the atherosclerotic plaques giving only moderate stenosis of coronary lumen were found only in 22.2% of cases (in six of 27 subjects). There was a lot of variation in the quantitative contents of lipids in the plaques in both groups. The most significant difference between severe and moderately stenosing atherosclerotic plaques was the thickness of the fibrous or fibro–elastic layer at the base of the plaques. In cases with severe stenosing plaques, these layers were pronounced at the base of the plaques and found around the whole circumference of the artery (Figs. 3 and 4). The average thickness of that layer in coronary arteries with severe stenosing plaques was 188.167.3 mm, while in arteries with moderately stenosing plaques it was 69.864.5 mm (P,0.001). Non-stenosing plaques sometimes were located directly on the media, in which dystrophic changes develop and the media became thin. It was accompanied by protruding of the arterial wall in such place, but even when these plaques were large, the size of lumen did not change, i.e., a stenosis did not develop.
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4. Discussion
Fig. 3. Stenosing atherosclerotic plaque in the left anterior descending coronary artery in a male of 59 years, who died from coronary heart disease. At the base of the plaque there is a thick fibro–elastic layer, the internal elastic membrane is destroyed, the external elastic membrane is thickened. (Orcein stain: (a) 340; (b) 3100).
The development of a musculo–elastic layer in the intima of the coronary arteries is observed already during the first year of life. In children of this age the myo-intimal hyperplasia was noted in 74.5% of the cases [10,14]. In older persons coronary intimal hyperplasia is marked in 90% of the cases [11,12,15,16]. The highest degree of intimal hyperplasia is present in the left anterior descending coronary artery and intimal hyperplasia is more pronounced in males than in females. The prevalence and expression of intimal hyperplasia in the different coronary arteries is the same as the prevalence and expression of atherosclerosis in males and females in these arteries [8–12,16]. Some authors consider that coronary intimal hyperplasia is an adaptation phenomenon, but at the same time it is related to the development of coronary atherosclerosis [1,7,9– 13,17,18]. The relation between lipoidosis and the development of fibro–lipid plaques in the coronary arteries is very much influenced by the state of the coronary intima. Intimal lipoidosis often precedes and practically determines the development of plaques in the arteries; this is especially typical for the development of plaques in the arteries with light degree of intimal hyperplasia [19]. For the development of fibro–lipid plaques in expressed intimal hyperplasia there was another succession of events: the fibrous or fibro– muscular component in such plaques was formed before but not after lipoidosis. This explains the very early appearance of plaques in the coronary arteries [16,19]. Intimal musculo–elastic coronary hyperplasia has a direct relation not only to the development of atherosclerosis, but also to coronary stenosis. It is connected with the transformation in adults of the musculo–elastic hyperplasia of intima into the fibro– muscular or fibrous layer. The thickness of the latter can often exceed the thickness of coronary media. The formation of such powerful layer in coronary intima is usually observed around the whole circumference of arteries that predisposes to the development of stenosing athersclerosis Moreover, severe degrees of intimal hyperplasia can itself provoke a reduction of the arterial lumen up to 50–70% [11,12]. Taking into account that intimal hyperplasia mostly is
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Fig. 4. A thick fibro–elastic layer at the base of stenosing plaques in patients who died from coronary heart disease. The internal elastic membrane is differently preserved: (a) it is destroyed on more part of its extent; (b) it is practically wholly preserved. (Orcein stain: 3100).
composed of smooth muscle cells and elastic fibers, it can be the cause of spasm in the coronary arteries. In some cases of sudden coronary death, especially of young people, there is severe intimal hyperplasia in the coronary arteries [11].
Comparative histometric investigations of stenosing and non-stenosing atherosclerotic plaques in the coronary arteries have shown definite differences in the thickness of fibrous or fibro–elastic layer at the base of the plaques as well as outside them. This
V.S. Zhdanov et al. / International Journal of Cardiology 76 (2000) 57 – 64
layer was significantly thicker in stenosing than in non-stenosing plaques. The formation of a fibrous or a fibro–elastic layer in the depth of the intima and at the base of a plaque is related to the evolution of a musculo–elastic hyperplasia of the coronary intima. The presence of such layer at the base of plaques leads to a limitation of the widening ability of coronary arteries during the development of atherosclerosis. Just as the development of coronary intimal hyperplasia occurs already in childhood, the inclination to coronary stenoses in atherosclerosis is also formed already in childhood. Some other data also points to the significance of intimal hyperplasia in the development of coronary stenosis. Coronary stenosis is mostly marked in the proximal parts of the arteries, i.e. in the parts with the most severe intimal hyperplasia. It is also more frequent in males than in females, and correlates with the greater prevalence of coronary heart disease in males. Epidemiological pathomorphological investigations of different groups of children and adults have shown a direct relation between intimal hyperplasia in the coronary arteries of children and the development of atherosclerosis and prevalence of coronary heart disease in adults [1,4,5]. For this reason, some authors suppose that the development of intimal hyperplasia in coronary arteries is determined by genetic factors [1,4,5,10,16]. Investigations of prevalence and expression of intimal hyperplasia in the coronary arteries of children during the first year of life did not show any essential relation between such hyperplasia and some cardiovascular risk factors (arterial hypertension, diabetes mellitus, smoking, obesity) in their mothers [10,16], but such relationships in some parameters of the newborns have been reported. Thus, Barker [20] noticed a direct relationship between the size of a foetus and the prevalence of coronary heart disease and cerebral insults in persons of medium and older age; a greater prevalence of these diseases was noted in persons who were small at birth.
5. Conclusion In childhood and young age, the development of musculo–elastic hyperplasia of the intima takes place in the coronary arteries. With age, fibrosis of the
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hyperplastic intima occurs with formation of a fibrous or fibro–elastic layer. Stenosing of the coronary lumen in atherosclerosis depends to a large degree from the thickness of this layer in the coronary intima, including of the base of the atherosclerotic plaque: the average thickness of this layer in severely stenosing plaques was much greater than in moderately stenosing plaques. The formation of stenosing coronary atherosclerosis, which is the cause of coronary heart disease, is thus closely related to hyperplastic changes of the intima in children and persons of young age.
Acknowledgements The study was performed with the support of the Russian Academy of Medical Sciences, the Royal Swedish Academy of Sciences and the Swedish Heart and Lung Foundation.
References [1] Vikhert AM, Zhdanov VS, Matova EE, Aptekar SG. Geographical pathology of atherosclerosis. In: New Delhi: Oxonian Press, 1987, pp. 1–183. [2] Almagor B, Leon MB, Bartorell AL et al. Media severely diseased coronary arteries: guidelines for new interventional procedures. J Am Coll Cardiol 1989;13(2):194A. [3] Hermiller JB, Tanaglia AN, Kisslo KB et al. In vivo validation of compensatory enlargement of atherosclerosis coronary arteries. Am J Cardiol 1993;71:665–8. [4] Vlodaver Z, Kahn HA, Neufeld HN. The coronary arteries in early life in three different ethnic groups. Circulation 1964;29:541–50. [5] Neufeld HN, Schneeweiss A. Coronary artery disease in infants and children, Philadelphia: Lea Febiger, 1983. [6] Zhdanov VS, Sternby NH, Vikhert AM, Galakhov IE. Development of atherosclerosis over a 25-year period: an epidemiological autopsy study in males of 11 towns. Int J Cardiol 1999;68:95–106. [7] Wolkoff K. Ueber die atherosclerose der coronararterien des Herzens. Beitr Pathol Anat 1929;82:555–96. [8] Velican D, Velican C. Atherosclerotic involvement of the coronary arteries of adolescents and young adults. Atherosclerosis 1980;36:449–60. [9] Velican C, Velican D. Study of coronary intimal thickening. Atherosclerosis 1985;56:331–44. [10] Sultanaliev AA. Comparative study of the intima diffuse thickening of the heart coronary arteries in children of the first year of life in the cities of Moscow Frunze and Yakutsk, Arch Patologii (in Russian) 1986;XLVIII(4):38–44. [11] Angelini A, Thiene G, Frescura C, Baroldi G. Coronary arterial wall and atherosclerosis in youth (1–20 years): a histologic study in Northern Italian population. Int J Cardiol 1990;28:361–70.
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[12] Davies H. Atherogenesis and the coronary arteries in childhood. Int J Cardiol 1990;28:283–92. [13] Glagov S, Bassiouny HS, Giddens DP, Zarins CK. J Vascular Invest 1995;1:2–14. [14] Sultanaliev AA, Zhdanov VS. Lipoidosis of coronary arteries intima in newborn and children of the first year of life. Arch Patologii (in Russian) 1985;XLVII(10):36–42. [15] Stary HC, Chandler AB, Dinsmore RE et al. A definition of advanced types of atherosclerotic lesions and histological classification of atherosclerosis. Circulation 1995;92:1355–74. [16] Lasauskaite V, Tanganelli P, Bianciardi G et al. Histometric investigation of aorta and coronary arteries in young people of different geographic origins. WHO / ICFC Study of pathological determinants of atherosclerosis in youth (PBDAY study). Final report. WHO 1997:81–90.
[17] Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989;9(Suppl 1-19):1–32. [18] Tracy RE, Kissling GE. Age and fibroplasia as preconditions for atheronecrosis in human coronary arteries. Arch Pathol Lab Med 1987;111:957–63. [19] Zhdanov VC. Hyperplasia of the aorta and arteries intima in human atherogenesis. Arch Patologii (in Russian) 1998;60(6):8–13. [20] Barker DJP. Fetal origins of adult disease. Atherosclerosis 1997;134:11.
Hyperplasia of coronary intima in young males in relation to development of coronary heart disease in adults a, b a a Valentin S. Zhdanov *, Nils H. Sternby , Iraida P. Drobkova , Igor E. Galakhov a
Department of Cardiovascular Pathology, Russian Cardiology Complex, 121552 Moscow, Russian Federation b Department of Pathology, Lund University, Malmo University Hospital, S-20502 Malmo, Sweden Received 12 August 1999; received in revised form 5 July 2000; accepted 4 September 2000
Abstract The aim of the investigation was to study structural features of coronary arteries in young males which may influence the development of stenosing coronary atherosclerosis in older age. We studied the coronary arteries from 84 males, 10–39 years old, who died from accidents in Moscow, Malmo and Riga, and 98 males aged 40 and above from Moscow who died from coronary heart disease (71 cases) or other diseases (27 cases). In children and young males from all three cities, musculo-elastic hyperplasia of the coronary intima took place constantly but with different degrees of expression; a strict relationship of the intimal thickness and age was observed. Histometric investigations of the right coronary artery showed that in young males of Riga, in comparison with those of Malmo, the intima was significantly thicker both outside (69.662.8 and 58.262.5 mm) and within the area of cushion like thickening (118.864.0 and 101.963.8 mm), they had more extended cushion-like thickening of intima (42.663.0 and 30.863.3% to the length of the artery circumference) and destroyed parts of the internal elastic lamina (28.361.9 and 19.161.7% of its length). In males older than 40 years, severe coronary atherosclerosis and stenosis was also significantly more common in Riga than in Malmo. Our data indicate that with age the intimal musculo-elastic hyperplasia in the coronary arteries is transformed to a fibro–elastic layer. The thickness of this layer in the presence of stenosing plaques (.75% of arterial lumen) was much greater than in the presence of plaques with stenoses less than 50% (188.16 7.3 and 69.864.5 mm, respectively). Conclusion: The development of stenosing coronary atherosclerosis is closely related to the degree of musculo-elastic intimal hyperplasia in childhood and young age. The formation of a fibro–elastic layer in the coronary intima decreases the ability of the artery to dilate during the development of atherosclerosis. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Coronary arteries; Intimal hyperplasia; Coronary stenosis; Coronary heart disease; Children; Young males
1. Introduction Stenosis of the coronary arteries is an important factor in the development of coronary heart disease. Stenosis is observed significantly more often in the coronary arteries than in other arteries [1]. In most investigations, coronary stenosing is closely related to the degree of coronary atherosclerosis, but occasion*Corresponding author. Tel.: 17-95-4146582; fax: 17-95-4152962. E-mail address: [email protected] (V.S. Zhdanov).
ally there is a discrepancy between the amount of atherosclerotic changes in the coronary arteries and the prevalence of stenosis. Moreover, the development of atherosclerosis in different arteries can be accompanied also with dilatation of their lumen, it is found when atrophy and destruction of vessel wall elements, especially in the media, occurs [2,3]. Different populations vary in susceptibility to development of coronary stenosis and therefore also development of coronary heart disease [3–6]. The role of structural peculiarities of the coronary
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00369-7
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V.S. Zhdanov et al. / International Journal of Cardiology 76 (2000) 57 – 64
arteries in the development of coronary stenosis is insufficiently investigated. These peculiarities are first of all expressed in the development of coronary intimal hyperplasia which is noted already in children and before the appearance of atherosclerotic changes [1,7–13]. The aim of this investigation is to study the role of some structural changes of the coronary arteries in children and young males and their possible relation to the development of coronary stenosis in atherosclerosis in later life.
2. Material and methods Coronary arteries were investigated in two groups of 142 Moscow males: one group of 44 practically healthy males, 10–39 years of age who died from accidents, and the second group of 98 males, 40–69 years of age who died from coronary heart disease (71 cases) or other diseases (27 cases). All these coronary arteries were collected in 1995–1999. In both groups the proximal parts of coronary arteries were studied on cross microscopic sections with 0.5 cm interval. In the old Moscow group histometrical studies of coronary arteries with severe (.75%) or moderate (,50%) stenoses of their lumen were performed. The initial area of arterial lumen was determined by using the internal elastic lamina as peripheral limit, and the remaining area of the lumen by measuring the internal intimal surface; these data were the base for calculation of the degree of coronary stenosis. Besides, the thickness of the fibrous or fibro–elastic layer at the base of the plaques and outside of them was measured. In the young group of males, the thickness of coronary intima was investigated along of the whole vessel circumference. In previous repeated epidemiological studies of atherosclerosis on autopsy material [6], we noticed significant differences in the development of coronary atherosclerosis and stenosis in males of Malmo and Riga over a 25-year period. In Malmo males, atherosclerosis diminished during this period, but in Riga males, it increased significantly. It was therefore of interest to study coronary arteries in young males of these populations to determine if there were differences in their structure that might help to explain the
different rate of development of coronary atherosclerosis and stenosis. The studied coronary arteries from Malmo and Riga were collected almost 10 years ago and kept in formalin in plastic bags at Moscow Center for studying the epidemiology of atherosclerosis. A standard section of the right coronary artery (1 cm from its origin) was examined by histometrical methods in practically healthy 20–39 year-old males from these two cities (20 cases from each city). The following parameters of the arteries were measured: the maximal thickness (in microns) of cushion-like thickening of the intima (the most prominent local parts of hyperplased intima), the extent of these cushion-like thickening (in percent of the artery circumference), the intimal thickness outside places of cushion-like thickenings, the length of the destroyed internal elastic lamina (in percent of the artery circumference), and the degree of intimal lipid infiltration (in percent to the whole surface of intima in histological sections). The microscopic sections were stained with haematoxylin–eosin, oil red 0 (for fat), orcein (elastic fibers), and Masson’s trichrome staining (connective tissue). Histometrical investigations of the coronary arteries were performed with the help of the ocular-micrometer and the microscopic analysis system (Morphomat 30, Opton, West Germany). Data are reported as a mean6standard error. To ascertain the significance of the received data the two-tailed Student’s t-test was used.
3. Results The proximal parts of the coronary arteries in Moscow 10–39 year-old males showed intimal hyperplasia of varying degree (Fig. 1). A strict relationship dependence of the thickness of the coronary intima and age was observed. The mean thickness of intima in the proximal part of the right coronary artery in the age of 10–19 years was equal to 72 mm (n55, range: 9–120), in the age 20–29 years 132611.5 mm (n519, range: 22–210), in the age 30–39 years 187610.8 mm (n520, range: 62–283). Slight degree of hyperplasia (thickness of intima less or equal to the thickness of media) was present in 17 of 44 cases (38.7%), moderate degree of intimal hyperplasia (up to double thickness of the media) —
V.S. Zhdanov et al. / International Journal of Cardiology 76 (2000) 57 – 64
Fig. 1. Slight and sometimes moderate degree of intimal hyperplasia in the right coronary artery in a male of 33 years, who died from trauma. Hyperelastosis of intima is marked (Orcein stain: 340).
in 21 cases (47.7%), and severe degree of intimal hyperplasia (more than double the thickness of the media) in six cases (13.6%). Coronary arteries with even severe degree of intimal hyperplasia showed macroscopically only an insignificant thickening of the wall, or occasionally flat white–yellow plaques. Histometric investigations of the right coronary artery (Table 1) showed that young males from Riga,
59
in comparison with those from Malmo, had significantly thicker intima both outside and within areas of so-called cushion-like (localized) thickenings. They had also greater extent of cushion-like thickenings and greater destroyed parts of the internal elastic lamina. The lipid infiltration of the coronary intima was practically the same in males of both cities. The basic cellular elements in the hyperplastic intima are smooth muscle cells. They are usually organized as a compact layer, and unlike medial smooth muscle cells have a longitudinal and not a circular arrangement. The extracellular matrix in the hyperplastic intima was rich in collagen and elastic fibers, which compose a dense net. The typical changes of the internal elastic lamina in such areas were numerous defects and splitting with newly formed elastic fibers. The development of intimal hyperplasia was usually observed around the whole circumference of the coronary arteries. However it did not develop the same in different segments of the arteries. Even in arteries with severe degree of intimal hyperplasia, there were areas of only moderate or slight intimal hyperplasia, and this did create a picture of so-called musculo–fibrous or musculo–elastic plaques (Fig. 2). It was found in 9% of the studied cases. In the deep layers of such plaques sometimes small necroses developed. A lipid component in the intimal hyperplasia and in the musculo–elastic plaques in the coronary arteries of children was present, but not significant in most cases. There were mainly extracellular small-graine lipid particles along the fibrous structures and only a few fat-containing cells, but in adults, the areas of the coronary arteries with severe degree of hyperplasia often contained a lot of extraand intracellular lipids both in the superficial and in the deep layers of the intima. Many coronary athero-
Table 1 Histometric characteristics of structural peculiarities of intima in right coronary artery in young males (20–39 years) in Malmo and Riga a Town
Malmo Riga P-value a
Mean thickness of intima outside of CT (mm) 58.262.5 69.662.8 ,0.01
Mean thickness of CT (mm)
101.963.8 118.864.0 ,0.01
Extent of CT (% of the artery circumference) 30.863.3 42.663.0 ,0.05
Extent of destroyed parts of IEM (% of the artery circumference) 19.161.7 28.361.9 ,0.01
Data are mean6standard error of the mean. CT, cushion-like thickenings of coronary arteries. IEM, internal elastic membrane.
Extent of intima occupied by lipids (% to the extent of whole intima) 22.562.3 25.462.9 NS
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Fig. 2. Irregular severe degree of intimal hyperplasia in the left anterior descending coronary artery with formation of fibro–muscular plaque in a male of 38 years (Orcein stain: 340).
sclerotic plaques in young people show evidence of being developed on the basis of intimal hyperplasia. The amount of smooth muscle cells was decreasing gradually with age in the hyperplastic intima and there was an increase of the number of elastic and collagen fibers. Such an evolution of intimal hyperplasia with accumulation of lipids and appearance of necroses can lead to the formation of an atherosclerotic fibro–lipid plaque, which hardly differ from classic atherosclerotic plaque. Comparative investigations of proximal parts of the coronary arteries with severe (.75%) and moderate (,50%) stenosing atherosclerotic plaques were performed separately. Severe coronary stenoses were marked in subjects older than 40 years, who died from coronary heart disease (71 cases); moderate coronary stenoses — in subjects, who died from other diseases (27 cases). Atherosclerotic plaques in both groups were classified as fibro–lipid with some variations in the expression of fibrous and lipid components. The plaques causing severe coronary stenosis were complicated (the presence of calcinosis, haemorrhages, thrombosis) in 93% of cases (in 66 of
71 subjects). Such changes in the atherosclerotic plaques giving only moderate stenosis of coronary lumen were found only in 22.2% of cases (in six of 27 subjects). There was a lot of variation in the quantitative contents of lipids in the plaques in both groups. The most significant difference between severe and moderately stenosing atherosclerotic plaques was the thickness of the fibrous or fibro–elastic layer at the base of the plaques. In cases with severe stenosing plaques, these layers were pronounced at the base of the plaques and found around the whole circumference of the artery (Figs. 3 and 4). The average thickness of that layer in coronary arteries with severe stenosing plaques was 188.167.3 mm, while in arteries with moderately stenosing plaques it was 69.864.5 mm (P,0.001). Non-stenosing plaques sometimes were located directly on the media, in which dystrophic changes develop and the media became thin. It was accompanied by protruding of the arterial wall in such place, but even when these plaques were large, the size of lumen did not change, i.e., a stenosis did not develop.
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4. Discussion
Fig. 3. Stenosing atherosclerotic plaque in the left anterior descending coronary artery in a male of 59 years, who died from coronary heart disease. At the base of the plaque there is a thick fibro–elastic layer, the internal elastic membrane is destroyed, the external elastic membrane is thickened. (Orcein stain: (a) 340; (b) 3100).
The development of a musculo–elastic layer in the intima of the coronary arteries is observed already during the first year of life. In children of this age the myo-intimal hyperplasia was noted in 74.5% of the cases [10,14]. In older persons coronary intimal hyperplasia is marked in 90% of the cases [11,12,15,16]. The highest degree of intimal hyperplasia is present in the left anterior descending coronary artery and intimal hyperplasia is more pronounced in males than in females. The prevalence and expression of intimal hyperplasia in the different coronary arteries is the same as the prevalence and expression of atherosclerosis in males and females in these arteries [8–12,16]. Some authors consider that coronary intimal hyperplasia is an adaptation phenomenon, but at the same time it is related to the development of coronary atherosclerosis [1,7,9– 13,17,18]. The relation between lipoidosis and the development of fibro–lipid plaques in the coronary arteries is very much influenced by the state of the coronary intima. Intimal lipoidosis often precedes and practically determines the development of plaques in the arteries; this is especially typical for the development of plaques in the arteries with light degree of intimal hyperplasia [19]. For the development of fibro–lipid plaques in expressed intimal hyperplasia there was another succession of events: the fibrous or fibro– muscular component in such plaques was formed before but not after lipoidosis. This explains the very early appearance of plaques in the coronary arteries [16,19]. Intimal musculo–elastic coronary hyperplasia has a direct relation not only to the development of atherosclerosis, but also to coronary stenosis. It is connected with the transformation in adults of the musculo–elastic hyperplasia of intima into the fibro– muscular or fibrous layer. The thickness of the latter can often exceed the thickness of coronary media. The formation of such powerful layer in coronary intima is usually observed around the whole circumference of arteries that predisposes to the development of stenosing athersclerosis Moreover, severe degrees of intimal hyperplasia can itself provoke a reduction of the arterial lumen up to 50–70% [11,12]. Taking into account that intimal hyperplasia mostly is
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Fig. 4. A thick fibro–elastic layer at the base of stenosing plaques in patients who died from coronary heart disease. The internal elastic membrane is differently preserved: (a) it is destroyed on more part of its extent; (b) it is practically wholly preserved. (Orcein stain: 3100).
composed of smooth muscle cells and elastic fibers, it can be the cause of spasm in the coronary arteries. In some cases of sudden coronary death, especially of young people, there is severe intimal hyperplasia in the coronary arteries [11].
Comparative histometric investigations of stenosing and non-stenosing atherosclerotic plaques in the coronary arteries have shown definite differences in the thickness of fibrous or fibro–elastic layer at the base of the plaques as well as outside them. This
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layer was significantly thicker in stenosing than in non-stenosing plaques. The formation of a fibrous or a fibro–elastic layer in the depth of the intima and at the base of a plaque is related to the evolution of a musculo–elastic hyperplasia of the coronary intima. The presence of such layer at the base of plaques leads to a limitation of the widening ability of coronary arteries during the development of atherosclerosis. Just as the development of coronary intimal hyperplasia occurs already in childhood, the inclination to coronary stenoses in atherosclerosis is also formed already in childhood. Some other data also points to the significance of intimal hyperplasia in the development of coronary stenosis. Coronary stenosis is mostly marked in the proximal parts of the arteries, i.e. in the parts with the most severe intimal hyperplasia. It is also more frequent in males than in females, and correlates with the greater prevalence of coronary heart disease in males. Epidemiological pathomorphological investigations of different groups of children and adults have shown a direct relation between intimal hyperplasia in the coronary arteries of children and the development of atherosclerosis and prevalence of coronary heart disease in adults [1,4,5]. For this reason, some authors suppose that the development of intimal hyperplasia in coronary arteries is determined by genetic factors [1,4,5,10,16]. Investigations of prevalence and expression of intimal hyperplasia in the coronary arteries of children during the first year of life did not show any essential relation between such hyperplasia and some cardiovascular risk factors (arterial hypertension, diabetes mellitus, smoking, obesity) in their mothers [10,16], but such relationships in some parameters of the newborns have been reported. Thus, Barker [20] noticed a direct relationship between the size of a foetus and the prevalence of coronary heart disease and cerebral insults in persons of medium and older age; a greater prevalence of these diseases was noted in persons who were small at birth.
5. Conclusion In childhood and young age, the development of musculo–elastic hyperplasia of the intima takes place in the coronary arteries. With age, fibrosis of the
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hyperplastic intima occurs with formation of a fibrous or fibro–elastic layer. Stenosing of the coronary lumen in atherosclerosis depends to a large degree from the thickness of this layer in the coronary intima, including of the base of the atherosclerotic plaque: the average thickness of this layer in severely stenosing plaques was much greater than in moderately stenosing plaques. The formation of stenosing coronary atherosclerosis, which is the cause of coronary heart disease, is thus closely related to hyperplastic changes of the intima in children and persons of young age.
Acknowledgements The study was performed with the support of the Russian Academy of Medical Sciences, the Royal Swedish Academy of Sciences and the Swedish Heart and Lung Foundation.
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