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A comparison of coronary and internal mammary arteries and implications of the results in the etiology of arteriosclerosis
April,
Schechter,
Wilson,
and Kong
American
ER, Stone NJ, Richardsion SM, Levy RI, Epstein SE: Limitations of the electrocardiogram in predicting coronary artery disease. N Engl J Med 293:367, 1975. 15. Cottrell JE, Wood FC: The effect of epinephrine in angina pectoris. Am J Med Sci 181:36, 1931. 16. Ritchie JL. Trobaueh- GB. , Hamilton GW: Mvocardial imaaing with Thallium-201 at rest and during exercise: Cornpar;son with coronary arteriography and resting and stress electrocardiography. Circulation 56:66, 1977. 17. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS: Real-time radionuclide tine-angiography in the non-invasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease. N Engl J Med 296:839, 1977.
Heart
1983
Journal
18. Guttler RB, Croxson MS, DeQuarttro VL, Warren DW, Otis CL, Nicoloff ST: Effects of thyroid hormone on plasma adenosine 3’, 5’-monophosphate production in man. Metabolism 26:1155, 1977. 19. Sullivan JM, Gorlin R: Effect of L-epinephrine on the coronary circulation in human subjects with and without coronary artery disease. Circ Res 21:919, 1967. 20. Horn HH, Teichholz LE, Cohn PF, Herman MV, Gorlin R: Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine. Circulation 49:1003, 1974.
A comparison of coronary and internal mammary arteries and i at&m of the results in the etiology of arterbsclerosis Comparison was made between the intimal thickening of the anterior descending branch of the left coronary artery and the internal mammary artery in 352 necropsy examinations. The coronary arteries showed severe intimal thickening, progressing in severity throughout life, whereas the internal mammary showed no more than slight changes at any age. These observations, together with the variation in severity of the changes in different portions of the same vessel, and the freedom from this disease of the smaller arteries throughout the body, strongly suggest that a local or anatomic factor is the dominant tnfluence in coronary artery disease. (AM HEART J 105:560, 1983.)
Frank H. Sims, M.B., Ch.B., Ph.D. Auckland,
New Zealand
Arteriosclerosis continues to be a lively subject of debate,‘e5 and new advances are being constantly reviewed.6-‘4 Fundamental issues are whether factors associated with the homogeneous circulating blood, such as generalized endothelial damage, lipids, platelets, hormones, antibodies, or toxins, can explain the features of arteriosclerosis in view of the specific anatomic distribution of the lesions,15-20 and the observation that certain vessels may carry blood for a whole lifetime without showing significant arterial disease. Any valid theory of arteriosclerosis
From School.
Pathology
Department,
Received accepted
for publication Nov. 16, 1981.
Aug.
*Reprint Auckland,
requests: Private
560
the
University
31, 1981;
Pathology Department, Bag, Auckland. New
revision Medical Zealand.
of
Auckland
received School,
Medical
Nov.
10, 1981;
University
of
must explain the freedom of these vessels from disease as well as the lesions in the affected arteries. Also to he explained is the development of irregular intimal thickening or plaques, a constant feature of advanced lesions in humans. In the investigation recorded here, the coronary and internal mammary arteries in 352 patients of all ages were compared. The internal mammary was chosen for the comparison because it is a systemic vessel of comparable size, situated in the thorax, and subject to the same intrathoracic respiratory pressure changes as the coronary vessels; it is surrounded by similar loose fibrofatty tissue, the lympathic drainage of which differs from that of the heart. Experience has shown that it rarely shows evidence of arterial disease. The results support the conclusion that local or anatomic factors are dominant in the etiology of coronary artery disease.
Volume Number
105 4
Comparison
of
coronary and mammary arteries relative to atherogenesis
661
Fig. 1. Cross sections of the anterior descendingbranch of the left coronary artery (top) and of the internal mammary artery (bottom) from the same patients. These individuals died suddenly from coronary artery insufficiency. (Coronary arteries ~14; mammary arteries x30.) A, Indian male aged 55. B, Indian male aged 40. C, Fijian male aged60; the mammary artery in this caseshowsalmost the maximum intimal thickening for this vessel seenin the whole seriesr’ = 0.5). D, Wall of the coronary artery of a Fijian male aged 22 who died from hemorrhagefollowing a stab wound. (X200.)
METHODS
Coronary and internal mammary arteries obtained at necropsy from 352 unselectedindividuals (181 Fijians, 144 Indians, and 27 of other racesEuropean and part European 12, Chinese and part Chinese 4, Rotoman 4, Solomon Islanders 3, Banaban 2, Samoan1, and Kiribati l), of agesvarying from newborn to 85 years, were compared histologically. The subjects were either patients who had died in the Colonial War Memorial Hospital, Suva, Fiji, or were accident and medicolegalcasesreferred by the coroner. From each, a block of tissue was removed from the anterior surface of the heart including the first part of the anterior descending branch of the left coronary artery. A block containing one internal mammary artery wasalsoexcised at the level of the second intercostal space. These were fixed in formalin, embedded in paraffin wax, sectioned 6 p in thickness, and stained with hematoxylin and eosin. Method of examination. The magnitude of the intimal thickening in the transversely sectionedarteries was meaSource
of material.
sured with a micrometer eyepiece and expressed as a fraction of the thickness of the media: thickness of intima/thickness of media = r, for the coronary arteries, and F’, for the internal mammary. When the intimal thickening was uneven, the average value for the whole circumference of the vesselwas recorded. In vesselswith marked intimal thickening and atrophy of the media, r valueswere calculated usingthe original thickness of the wall asrevealed by remaining traces of the internal elastic lamina. Uniformity of intimal thickening and edema of the media of each arterial wall were assessed as insignificant, mild, or severe. RESULTS Comparison
of intimal
thickening.
After the age of 3
years, no coronary vessel was free from intimal thickening, and in the older age groups, r values varied from one to more than 10. By contrast, intimal thickening of the internal mammary artery
562
Sims
American
IN TERNAL
MAMMARY
ARTERIES
AGE (years
(n =209)
April, 1983 Heart Journal
Range of f’ values
1
2. The percentage of patients in the different age groups having no significant intimal thickening (r’ < 0.1) of the internal mammary artery (cross-hatched columns) and the rangeof intimal thickening of the internal mammary artery at different ages (dotted lines). Thickness of intima/Thickness of media = r’. Fig.
(r’ < 0.1) until the fifth decade, and even at its maximum in the seventh decade it was in no case more than 0.6. When the intimal thickening of the coronary artery was pronounced, the inner zone nearest to the lumen was relatively acellular and had a looser, more edematous structure, as seen in histologic sections. Fig. 1, A to C illustrates the contrasting findings in representative pairs of vessels from the same subjects, and Fig. 2 shows graphically the mammary artery results from the whole series. Intimal thickening in the internal mammary artery had the same histologic characteristics as those seen in the early stages of intimal thickening of the coronary vessels. It was sometimes asymmetric as in the coronary arteries. was insignificant
Relationship of intimal thickening vessels to death from cardiovascular
of the coronary disease. Fig. 3
shows the relationship of the percentage of subjects dying from acute coronary artery insufhciency to intimal thickening of the anterior descending branch of the left coronary artery. This cause of
death was highly probable when F was greater than 5 and almost certain for r values greater than 8. There was no instance of death attributable to acute heart failure when F was less than 2. The natural history of intimal thickening. Intimal thickening of the coronary artery began at or before birth and reached a mean value of F = 0.6 for the age group 2 to 3 years. Progress slowed during the subsequent 25 years, and the mean for the third decade reached only the value F = 1.45 (Table I). During the fourth decade, however, there was a pronounced increase (mean r = 3.64) suggesting strongly that intimal thickening advances with increasing speed after the third decade. The range of r values increased also with each age group and showed a sudden expansion in the fourth decade, so that many individuals over the age of 30 years had values greater than 5. In this decade deaths from coronary artery disease were beginning to occur (17 % of the total) in individuals with greater than average intimal thickening of their coronary vessels. The mean F values for subsequent decades remained
Volume
105
Number
4
Comparison
of coronary
and mammary
arteries
relative
to atherogenesis
563
from colvnary insufficicc
70.n.113
n:
60.
r values Fig. 3. The percentage of sudden deaths from coronary artery insufficiency in patients with different r values (the numbers of patients in each group are indicated).
Table
1. Mean r values by race and sex (number of patients in each group is given in parenthesis)
Male Fijians
Age group =?3 > 3-10 > 10-20 > 20-30 > 30-40 > 40-50 > 50-60 > 60-70 > 70-80 > 80 r = Thickness
0.48 1.12 1.30 2.03 4.12 3.74 5.59 4.25 4.0
(33) (7) (12) (11) (18) (14) (16) (4) (3) -
of intima
of coronary
Female Fijians
Male Indians
Female Indians
Combined males
Combined females
Total Fijian and Indian subjects
0.23 (25) 0.85 (4)
0.17 1.0 1.0 1.25 4.80 4.84 5.53 4.5 4.0 4.5
0.12 0.13 1.21 1.12 1.53 3.88 1.75 7.0
0.39 1.11 1.17 1.60 4.43 4.41 5.55 4.36 4.0 4.5
0.19 0.61 1.21 1.19 1.89 3.76 3.15 5.6 2.5 -
0.30 0.89 1.18 1.45 3.64 4.19 4.93 4.88 3.79 4.5
1.6 2.6 3.67 3.40 5.25 2.5
(2) (5) (6) (11) (4) (I) -
artery/thickness
(13) (1) (9) (13) (15) (8) (21) (3) (3) (2)
of media of coronary
in the same general range, 4 to 5, and showed no very
significant trend, probably because of the continuing loss of individuals with high r values. The average r values for females were less than those for males, particularly in the younger age groups in both Fijians and Indians, a finding consis-
(15) (2) (6) (12) (10) (5) (2) (1) -
(46) (8) (21) (24) (33) (22) (37) (7) (6) (2)
(40) (6) (6) (14) (15) (11) (13) (5) (1)
(86) (14) (27) (38) (48) (33) (50) (12) (7) (2)
artery.
with the reduced incidence of death from coronary insufficiency in females. Intimal thickening in Indian males also appeared to increase more rapidly with age than was the case with Fijian males. The risk of sudden death from coronary artery disease was found to be twice as great in Indian as tent
564
American
Sims
II. Percentageof patients showingasymmetry of the intimal thickening of the anterior descending branch of the left coronary artery and percentageshowing edemaof the media Table
Moderate No. in Age group
each group
> ‘n2-12A2
19
> %2-2 > 2-3 > 3-10 >lO-20 > 20-30 > 30-40 > 40-50 > 50-60 > 60-70 > 70-80 > 80
13 9 14 27 40 49 33 52 16 8 3
or severe edema of the media (%I
Pronounced Asymmetry (%I
47 57 40 70 83 93 80 85 82 69 17 0
0 0 0 0 0
10 22 18 46 44 38 33
compared with Fijian males in a recent survey.21 With increasing age and r values, a considerable proportion of the coronary arteries showed markedly asymmetric intimal thickening (Table II) as has been described by other investigators.22T23 Changes in the media. The media of the coronary arteries showed edema in a high proportion of vessels from subjects over the age of 10 years (Fig. 1, D, and Table II). There was obvious separation of the smooth muscle cells and increased interstitial fluid in the media. This was not associated simply with circulatory failure during the terminal illness, since it was also found in patients dying suddenly by accident. When there was gross intimal thickening, the media tended to show atrophic changes and a reduced thickness. Edema of the media in such cases tended to be less prominent or absent. Changes in the adventitia and surrounding tissue. In the sections from the anterior
fibrofatty
surface of the heart in which the fibrofatty tissue surrounding the coronary artery was well displayed, one or more large lymphatic trunks were seen in the vicinity of the artery in approximately 50% of cases. In the age group 0 to 10 years, of those individuals showing greater than average intimal thickness, fewer showed large lymphatic channels (32 % ) compared with those having less than average intimal thickness (46%). DISCUSSION Relationohip
of intimal
thickening
This study has demonstrated
to arterial
marked
disease.
differences
April, tS83 Heart Journal
between the internal mammary and coronary arteries in the progress of intimal thickening with increasing age, and has shown that if there is no intimal thickening there is no arterial disease. Other workers have drawn attention to these differences, and observations have been published on the radial and tibial arteries.15-20 These vessels may be similar in size to the coronary arteries. They have a similar histologic structure, and when intimal thickening develops they show the same appearance of the thickened intima as that seen in early coronary disease. There is no reason to suppose that they respond in a different manner to the appropriate stimuli. Theories which depend on a general property, cellular or humoral, of the circulating blood cannot explain the observed facts. It has already been shown that arteries which normally do not develop the typical changes of arteriosclerosis may do so under special circumstances, for example, arteries involved in an inflammatory process24 or those surrounded by infiltrating tumor cells. 25 Thickness of the wall of the vessel would also appear to be important,24 since intimal thickening is more severe the thicker the wall of the vessel (for example, aorta and great vessels), and tends to be absent in the peripheral portions of the same vessels. The evidence is therefore convincing that intimal thickening is a general response of the arterial wall to a local factor or factors. The coronary arteries are affected early and more severely than most arteries of comparable size, and there is little doubt that intimal thickening is the fundamental basis of coronary artery insufficiency. While coronary artery spasm has been established as a rare cause of death,26s 27most patients who die from acute cardiac insufficiency show extensive coronary artery disease28-33as was the case in this study. Progress of intimal thickening with age. The rapid progress of intimal thickening in the early years of life has been well recorded by others.34-3g The changes in the mean values of intimal thickening of the coronary vessels with increasing age suggest that the values for each individual could be represented by an S-shaped curve. Since it is unlikely that intimal thickening, once formed, will regress significantly, those with a high initial rate will be likely to continue at an early age into the critical area of r values greater than 5, while those fortunate enough to have a slow rate of intimal thickening are likely to live to a much greater age before coronary artery disease becomes critical for survival. The inclination of these S-shaped curves means that a slight reduc-
Volume Number
105 4
Comparison
of
coronary and mammary arteries relative to atherogenesis
tion in the rate will result in a considerable increase in the age at which coronary artery insufficiency may become apparent. Rate of intimal thickening lute thickness of the intima.
as a function
of the abso-
In addition to the above findings, other evidence suggests that the thicker the intima becomes the more rapidly it increases in thickness. In this study there was an increasing degree of asymmetry in the intima of the coronary vessels with age (Table II). This is the same process as plaque development. Such surface irregularities would be consistent with a process in which the rate of thickening increased as a function of the intimal thickness. The histologic appearance of the severely thickened intima also strongly suggested accelerating progress, since the luminal margin was relatively acellular (Fig. 1, A to C) and showed tissue edema with separation of the collagen fibers. Such a concept is implicit in the theory of arteriosclerosis already advanced.24 The thicker the intima becomes, the slower will be the rate of diffusion of protein and other macromolecules through the arterial wall into the surrounding lymphatics. The protein concentration of the innermost zone of the intima will therefore tend to be progressively higher and persistent edema of this zone more certain. Observations on patients less than 3 years of age suggest that the early rapid phase of intimal thickening seen at this time may be related to delay in the development of the cardiac lymphatic system. The importance of the lymphatic drainage of the heart has been demonstrated by Miller et a1.40and Pick et a1.,41who have shown in many experiments on dogs that impairment of the lymphatic drainage from the heart reduces the rate of healing of a myocardial infarction and causes increased fibrosis of the myocardium. Also Feola et al.42 have shown that drainage of cardiac lymph alleviates the myocardial changes produced by ischemic injury. The high protein content of cardiac lymph43 suggests that the lymphatic drainage of the heart may well be marginal. Nakata and ShionoyaM showed that obstruction of the microcirculation of the vasa vasorum and the lymphatics of the aorta resulted in intimal thickening similar in histologic appearance to the arterial lesions of humans. Edema of the media of the arterial wall was noted in this series in more than 50% of the coronary artery sections from patients over the age of 5 years. This would be anticipated if there were limitation of the lymphatic drainage from the arterial wall. When the intima becomes grossly thickened, it might be expected that edema would be prominent in the
565
luminal zone of the intima but less obvious in the more peripherally situated media. This was an observed trend in the group of arteries studied. Genetic factor in intlmal thickening. A number of recent publications45-50 offer substantial evidence that the dominant factor or factors which determine the rate of intimal thickening in a given individual are inborn, like any of the other inherited characteristics. REFERENCES
5. 6. 7. 8. 9.
10. 11. 12. 13.
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19. 20.
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23.
MC Michael J: Fats and arterial disease. AM HEART J 98:409, 1979. Mann JI: Fata and atheroma: A retrial. Br Med J 1:732, 1979. Smith EB: Molecular interactions in human atherosclerotic plaques. Am J Path01 88:665, 1977. Bailar JC: Cause and effect in epidemiology. What do we know about hypertriglyceridaemia? N Engl J Med 302:1417, 1980. Lipids, platelets, and atherosclerosis (editorial). Lancet 1:464, 1980. Levene CI: Atherosclerosis-disease of old age or infancy? J Clin Path01 31 suppl (R Co11 Pathol): 12:165, 1978. Ross R, Glomset J, Harker L: Response to injury and atherogenesis. Am J Path01 88:675, 1977. Benditt EP. Gown AM: Atheroma: The arterv wall and the environment. Int Rev Exp Path01 21:55, 1986. Groszek E, Grundy SM: The possible role of the arterial microcirculation in the pathogenesis of atherosclerosis. J Chron Dis 33:679, 1980. Copley AL: Fibrin(ogen), platelets and a new theory of atherogenesis. Thromb Res 14:249, 1979. Lewis B: Hypothesis into theory-the development of aetiological concepts of ischaemic heart disease: A review. J R Sot Med 71:809, 1978. Rissanen AM: Familial occurrence of coronary heart disease: Effect of age at diagnosis. Am J Cardiol 44:60, 1979. Bjorkerud SU: Mechanisms of atherosclerosis. In Ioachim HL, editor: Pathobiology annual. New York, 1979, Raven Press, p 277. Kadish JL: Fibrin and atherogenesis-a hypothesis. Atherosclerosis 33:409, 1979. Dock W: The predilection of atherosclerosis for the coronary arteries. JAMk 31~875, 1946. Wilens SL: The nature of diffuse intimal thickening of arteries. Am J Path01 27:825, 1951. Duff GL, MC Millan GC: Pathology of atherosclerosis. Am J Med 11:92, 1951. Sappington SW, Cook HS: Radial artery changes in comparison with those of the coronary and other arteries. Am J Med Sci 192:822, 1936. Sappington SW, Hornett JA: Tibia1 artery changes in comparison with those of the radial and coronary arteries. Am J Med Sci 201:862, 1941. Movat HZ, More RH, Haust MD: The diffuse intimal thickening of the human aorta with aging. Am J Path01 34:1023, 1958. Sims FH, Singh K, Singh M, Singh K: The prevalence of coronary heart disease in the two major racial groups in Fiji. Fiji Med J 9:54, 1981. Hartman JD: Structural changes within the media of coronary arteries related to intimal thickening. Am J Path01 89:13, 1977. Horie T, Sekiguchi M, Hirosawa K: Coronary thrombosis in the pathogenesis of acute myocardial infarction. Histopathological study of coronary arteries in 108 necropsied cases using serial section. Br Heart J 40:153,. 1978. ”
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Sims Sims FH: The mechanism of intimal thickening in arteriosclerosis. Med Hypotheses 4:388, 1978. Sims FH: The arterial wall in malignant disease. Atherosclerosis 32:445, 1979. Lown B, De Silva RA: Is coronary arterial spasm a risk factor for coronary atherosclerosis? Am J Cardiol45:901, 1980. Rissanen V: Sudden coronary death and coronary artery disease. A clinicopathological appraisal. Cardiology 64:289, 1979. Harris PJ, Behar VS, Conley MJ, Harrell FE, Lee KL, Peter RH, Kong Y, Rosati RA: The prognostic significance of 50% coronary stenosis in medically treated patients with coronary artery disease. Circulation 62:240, 1980. Matova EE: Atherosclerosis and sudden death. Bull WHO 53~527, 1976. Virmani R, Roberts WC: Quantification of coronary arterial narrowing and of left ventricular myocardial scarring in healed myocardial infarction with chronic eventually fatal congestive cardiac failure. Am J Med 68:831, 1980. Horie M, Inoue M, Ohgitani N, Tsujioka K, Abe H, Fukiu S, Minamino T: Size and severity of coronary narrowing and infarct size in man. Br Heart J 44:271, 1980. Roberts WC, Jones AA: Quantitation of coronary arterial narrowing at necropsy in sudden coronary death. Am J Cardiol 44:39, 1979. Rissanen V, Romo M, Siltanen P: Prehospital sudden death from ischaemic heart disease: A post mortem study. Br Heart J 40:1025, 1978. Velican D, Velican C: Study of fibrous plaques occurring in the coronary arteries of children. Atherosclerosis 33:201, 1979. Rapola J, Pesonen E: Coronary artery changes in newborn babies. Acta Path01 Microbial Stand (A) 85:286, 1977. Schornagel HE: Intimal thickening in the coronary arteries in infants. Arch Path01 62:427, 1956. Gillot P: Les alterations histologiques des coronaires foetales et infantiles. Acta Cardiol(Brux) 17:145, 1962.
American
April, 1983 Heart Journal
Moon HD: Coronary arteries in fetuses, infants and juveniles. Circulation 16:263,-1957. 39. Neufeld HN. Waeenvoort CA. Edwards JE: Coronarv arteries in fetuses, infants, juveniles,’ and young adults. Lab Invest 11:837, 1962. 40. Miller AJ, Pick R, Katz LN: The importance of the lymphatits of the mammalian heart: Experimental observations and some speculations. Circulation 29:485, 1964. 41. Pick R, Miller AJ, Glick G: Myocardial pathology after cardiac venous and lymph flow obstruction in the dog. AM 38.
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Feola M, Merklin R, Cho S, Brockman SK: The terminal pathway of the lympathic system of the human heart. Ann Thorac Surg 24:531, 1977. Key1 MJ, Dowel1 RT, Yunice AA: Comparison of renal and cardiac lymph constituents. Lymphology 13:158, 1980. Nakata Y, Shionoya S: Structure of lymphatics in the aorta and the periaortic tissues, and vascular lesions caused by disturbance of the lymphatics. Lymphology 12:18, 1979. Holmes DR, Kennel AJ, Smith HC, Gordon H, Moore SB: Coronary artery disease in twins. Br Heart J 45:193, 1981. Nora JJ, Lortscher RN, Spangler RD, Nora AH, Kimberling WJ: Genetic-epidemiological study of early-onset ischaemic heart disease. Circulation 61:503, 1980. Rissanen AM. Nikkila EA: Aeareeation of coronarv risk factors in families of men with fatal and non-fatal coronary heart disease. Br Heart J 42:373, 1979. Anderson AJ, Loeffler RF, Barboriak JJ, Rimm AA: Occlusive coronary artery disease and parental history of myocardial infarction. Prev Med 8:419. 1979. Voldaver Z, Kahn HA, Neufeld HN: The coronary arteries in early life in three different ethnic groups. Circulation 39:541, 1969. Pesonen E, Norio R, Sarna S: Thickenings in the coronary arteries in infancy as an indication of genetic factors in coronary heart disease. Circulation 51:218, 1975.
Schechter,
Wilson,
and Kong
American
ER, Stone NJ, Richardsion SM, Levy RI, Epstein SE: Limitations of the electrocardiogram in predicting coronary artery disease. N Engl J Med 293:367, 1975. 15. Cottrell JE, Wood FC: The effect of epinephrine in angina pectoris. Am J Med Sci 181:36, 1931. 16. Ritchie JL. Trobaueh- GB. , Hamilton GW: Mvocardial imaaing with Thallium-201 at rest and during exercise: Cornpar;son with coronary arteriography and resting and stress electrocardiography. Circulation 56:66, 1977. 17. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS: Real-time radionuclide tine-angiography in the non-invasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease. N Engl J Med 296:839, 1977.
Heart
1983
Journal
18. Guttler RB, Croxson MS, DeQuarttro VL, Warren DW, Otis CL, Nicoloff ST: Effects of thyroid hormone on plasma adenosine 3’, 5’-monophosphate production in man. Metabolism 26:1155, 1977. 19. Sullivan JM, Gorlin R: Effect of L-epinephrine on the coronary circulation in human subjects with and without coronary artery disease. Circ Res 21:919, 1967. 20. Horn HH, Teichholz LE, Cohn PF, Herman MV, Gorlin R: Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine. Circulation 49:1003, 1974.
A comparison of coronary and internal mammary arteries and i at&m of the results in the etiology of arterbsclerosis Comparison was made between the intimal thickening of the anterior descending branch of the left coronary artery and the internal mammary artery in 352 necropsy examinations. The coronary arteries showed severe intimal thickening, progressing in severity throughout life, whereas the internal mammary showed no more than slight changes at any age. These observations, together with the variation in severity of the changes in different portions of the same vessel, and the freedom from this disease of the smaller arteries throughout the body, strongly suggest that a local or anatomic factor is the dominant tnfluence in coronary artery disease. (AM HEART J 105:560, 1983.)
Frank H. Sims, M.B., Ch.B., Ph.D. Auckland,
New Zealand
Arteriosclerosis continues to be a lively subject of debate,‘e5 and new advances are being constantly reviewed.6-‘4 Fundamental issues are whether factors associated with the homogeneous circulating blood, such as generalized endothelial damage, lipids, platelets, hormones, antibodies, or toxins, can explain the features of arteriosclerosis in view of the specific anatomic distribution of the lesions,15-20 and the observation that certain vessels may carry blood for a whole lifetime without showing significant arterial disease. Any valid theory of arteriosclerosis
From School.
Pathology
Department,
Received accepted
for publication Nov. 16, 1981.
Aug.
*Reprint Auckland,
requests: Private
560
the
University
31, 1981;
Pathology Department, Bag, Auckland. New
revision Medical Zealand.
of
Auckland
received School,
Medical
Nov.
10, 1981;
University
of
must explain the freedom of these vessels from disease as well as the lesions in the affected arteries. Also to he explained is the development of irregular intimal thickening or plaques, a constant feature of advanced lesions in humans. In the investigation recorded here, the coronary and internal mammary arteries in 352 patients of all ages were compared. The internal mammary was chosen for the comparison because it is a systemic vessel of comparable size, situated in the thorax, and subject to the same intrathoracic respiratory pressure changes as the coronary vessels; it is surrounded by similar loose fibrofatty tissue, the lympathic drainage of which differs from that of the heart. Experience has shown that it rarely shows evidence of arterial disease. The results support the conclusion that local or anatomic factors are dominant in the etiology of coronary artery disease.
Volume Number
105 4
Comparison
of
coronary and mammary arteries relative to atherogenesis
661
Fig. 1. Cross sections of the anterior descendingbranch of the left coronary artery (top) and of the internal mammary artery (bottom) from the same patients. These individuals died suddenly from coronary artery insufficiency. (Coronary arteries ~14; mammary arteries x30.) A, Indian male aged 55. B, Indian male aged 40. C, Fijian male aged60; the mammary artery in this caseshowsalmost the maximum intimal thickening for this vessel seenin the whole seriesr’ = 0.5). D, Wall of the coronary artery of a Fijian male aged 22 who died from hemorrhagefollowing a stab wound. (X200.)
METHODS
Coronary and internal mammary arteries obtained at necropsy from 352 unselectedindividuals (181 Fijians, 144 Indians, and 27 of other racesEuropean and part European 12, Chinese and part Chinese 4, Rotoman 4, Solomon Islanders 3, Banaban 2, Samoan1, and Kiribati l), of agesvarying from newborn to 85 years, were compared histologically. The subjects were either patients who had died in the Colonial War Memorial Hospital, Suva, Fiji, or were accident and medicolegalcasesreferred by the coroner. From each, a block of tissue was removed from the anterior surface of the heart including the first part of the anterior descending branch of the left coronary artery. A block containing one internal mammary artery wasalsoexcised at the level of the second intercostal space. These were fixed in formalin, embedded in paraffin wax, sectioned 6 p in thickness, and stained with hematoxylin and eosin. Method of examination. The magnitude of the intimal thickening in the transversely sectionedarteries was meaSource
of material.
sured with a micrometer eyepiece and expressed as a fraction of the thickness of the media: thickness of intima/thickness of media = r, for the coronary arteries, and F’, for the internal mammary. When the intimal thickening was uneven, the average value for the whole circumference of the vesselwas recorded. In vesselswith marked intimal thickening and atrophy of the media, r valueswere calculated usingthe original thickness of the wall asrevealed by remaining traces of the internal elastic lamina. Uniformity of intimal thickening and edema of the media of each arterial wall were assessed as insignificant, mild, or severe. RESULTS Comparison
of intimal
thickening.
After the age of 3
years, no coronary vessel was free from intimal thickening, and in the older age groups, r values varied from one to more than 10. By contrast, intimal thickening of the internal mammary artery
562
Sims
American
IN TERNAL
MAMMARY
ARTERIES
AGE (years
(n =209)
April, 1983 Heart Journal
Range of f’ values
1
2. The percentage of patients in the different age groups having no significant intimal thickening (r’ < 0.1) of the internal mammary artery (cross-hatched columns) and the rangeof intimal thickening of the internal mammary artery at different ages (dotted lines). Thickness of intima/Thickness of media = r’. Fig.
(r’ < 0.1) until the fifth decade, and even at its maximum in the seventh decade it was in no case more than 0.6. When the intimal thickening of the coronary artery was pronounced, the inner zone nearest to the lumen was relatively acellular and had a looser, more edematous structure, as seen in histologic sections. Fig. 1, A to C illustrates the contrasting findings in representative pairs of vessels from the same subjects, and Fig. 2 shows graphically the mammary artery results from the whole series. Intimal thickening in the internal mammary artery had the same histologic characteristics as those seen in the early stages of intimal thickening of the coronary vessels. It was sometimes asymmetric as in the coronary arteries. was insignificant
Relationship of intimal thickening vessels to death from cardiovascular
of the coronary disease. Fig. 3
shows the relationship of the percentage of subjects dying from acute coronary artery insufhciency to intimal thickening of the anterior descending branch of the left coronary artery. This cause of
death was highly probable when F was greater than 5 and almost certain for r values greater than 8. There was no instance of death attributable to acute heart failure when F was less than 2. The natural history of intimal thickening. Intimal thickening of the coronary artery began at or before birth and reached a mean value of F = 0.6 for the age group 2 to 3 years. Progress slowed during the subsequent 25 years, and the mean for the third decade reached only the value F = 1.45 (Table I). During the fourth decade, however, there was a pronounced increase (mean r = 3.64) suggesting strongly that intimal thickening advances with increasing speed after the third decade. The range of r values increased also with each age group and showed a sudden expansion in the fourth decade, so that many individuals over the age of 30 years had values greater than 5. In this decade deaths from coronary artery disease were beginning to occur (17 % of the total) in individuals with greater than average intimal thickening of their coronary vessels. The mean F values for subsequent decades remained
Volume
105
Number
4
Comparison
of coronary
and mammary
arteries
relative
to atherogenesis
563
from colvnary insufficicc
70.n.113
n:
60.
r values Fig. 3. The percentage of sudden deaths from coronary artery insufficiency in patients with different r values (the numbers of patients in each group are indicated).
Table
1. Mean r values by race and sex (number of patients in each group is given in parenthesis)
Male Fijians
Age group =?3 > 3-10 > 10-20 > 20-30 > 30-40 > 40-50 > 50-60 > 60-70 > 70-80 > 80 r = Thickness
0.48 1.12 1.30 2.03 4.12 3.74 5.59 4.25 4.0
(33) (7) (12) (11) (18) (14) (16) (4) (3) -
of intima
of coronary
Female Fijians
Male Indians
Female Indians
Combined males
Combined females
Total Fijian and Indian subjects
0.23 (25) 0.85 (4)
0.17 1.0 1.0 1.25 4.80 4.84 5.53 4.5 4.0 4.5
0.12 0.13 1.21 1.12 1.53 3.88 1.75 7.0
0.39 1.11 1.17 1.60 4.43 4.41 5.55 4.36 4.0 4.5
0.19 0.61 1.21 1.19 1.89 3.76 3.15 5.6 2.5 -
0.30 0.89 1.18 1.45 3.64 4.19 4.93 4.88 3.79 4.5
1.6 2.6 3.67 3.40 5.25 2.5
(2) (5) (6) (11) (4) (I) -
artery/thickness
(13) (1) (9) (13) (15) (8) (21) (3) (3) (2)
of media of coronary
in the same general range, 4 to 5, and showed no very
significant trend, probably because of the continuing loss of individuals with high r values. The average r values for females were less than those for males, particularly in the younger age groups in both Fijians and Indians, a finding consis-
(15) (2) (6) (12) (10) (5) (2) (1) -
(46) (8) (21) (24) (33) (22) (37) (7) (6) (2)
(40) (6) (6) (14) (15) (11) (13) (5) (1)
(86) (14) (27) (38) (48) (33) (50) (12) (7) (2)
artery.
with the reduced incidence of death from coronary insufficiency in females. Intimal thickening in Indian males also appeared to increase more rapidly with age than was the case with Fijian males. The risk of sudden death from coronary artery disease was found to be twice as great in Indian as tent
564
American
Sims
II. Percentageof patients showingasymmetry of the intimal thickening of the anterior descending branch of the left coronary artery and percentageshowing edemaof the media Table
Moderate No. in Age group
each group
> ‘n2-12A2
19
> %2-2 > 2-3 > 3-10 >lO-20 > 20-30 > 30-40 > 40-50 > 50-60 > 60-70 > 70-80 > 80
13 9 14 27 40 49 33 52 16 8 3
or severe edema of the media (%I
Pronounced Asymmetry (%I
47 57 40 70 83 93 80 85 82 69 17 0
0 0 0 0 0
10 22 18 46 44 38 33
compared with Fijian males in a recent survey.21 With increasing age and r values, a considerable proportion of the coronary arteries showed markedly asymmetric intimal thickening (Table II) as has been described by other investigators.22T23 Changes in the media. The media of the coronary arteries showed edema in a high proportion of vessels from subjects over the age of 10 years (Fig. 1, D, and Table II). There was obvious separation of the smooth muscle cells and increased interstitial fluid in the media. This was not associated simply with circulatory failure during the terminal illness, since it was also found in patients dying suddenly by accident. When there was gross intimal thickening, the media tended to show atrophic changes and a reduced thickness. Edema of the media in such cases tended to be less prominent or absent. Changes in the adventitia and surrounding tissue. In the sections from the anterior
fibrofatty
surface of the heart in which the fibrofatty tissue surrounding the coronary artery was well displayed, one or more large lymphatic trunks were seen in the vicinity of the artery in approximately 50% of cases. In the age group 0 to 10 years, of those individuals showing greater than average intimal thickness, fewer showed large lymphatic channels (32 % ) compared with those having less than average intimal thickness (46%). DISCUSSION Relationohip
of intimal
thickening
This study has demonstrated
to arterial
marked
disease.
differences
April, tS83 Heart Journal
between the internal mammary and coronary arteries in the progress of intimal thickening with increasing age, and has shown that if there is no intimal thickening there is no arterial disease. Other workers have drawn attention to these differences, and observations have been published on the radial and tibial arteries.15-20 These vessels may be similar in size to the coronary arteries. They have a similar histologic structure, and when intimal thickening develops they show the same appearance of the thickened intima as that seen in early coronary disease. There is no reason to suppose that they respond in a different manner to the appropriate stimuli. Theories which depend on a general property, cellular or humoral, of the circulating blood cannot explain the observed facts. It has already been shown that arteries which normally do not develop the typical changes of arteriosclerosis may do so under special circumstances, for example, arteries involved in an inflammatory process24 or those surrounded by infiltrating tumor cells. 25 Thickness of the wall of the vessel would also appear to be important,24 since intimal thickening is more severe the thicker the wall of the vessel (for example, aorta and great vessels), and tends to be absent in the peripheral portions of the same vessels. The evidence is therefore convincing that intimal thickening is a general response of the arterial wall to a local factor or factors. The coronary arteries are affected early and more severely than most arteries of comparable size, and there is little doubt that intimal thickening is the fundamental basis of coronary artery insufficiency. While coronary artery spasm has been established as a rare cause of death,26s 27most patients who die from acute cardiac insufficiency show extensive coronary artery disease28-33as was the case in this study. Progress of intimal thickening with age. The rapid progress of intimal thickening in the early years of life has been well recorded by others.34-3g The changes in the mean values of intimal thickening of the coronary vessels with increasing age suggest that the values for each individual could be represented by an S-shaped curve. Since it is unlikely that intimal thickening, once formed, will regress significantly, those with a high initial rate will be likely to continue at an early age into the critical area of r values greater than 5, while those fortunate enough to have a slow rate of intimal thickening are likely to live to a much greater age before coronary artery disease becomes critical for survival. The inclination of these S-shaped curves means that a slight reduc-
Volume Number
105 4
Comparison
of
coronary and mammary arteries relative to atherogenesis
tion in the rate will result in a considerable increase in the age at which coronary artery insufficiency may become apparent. Rate of intimal thickening lute thickness of the intima.
as a function
of the abso-
In addition to the above findings, other evidence suggests that the thicker the intima becomes the more rapidly it increases in thickness. In this study there was an increasing degree of asymmetry in the intima of the coronary vessels with age (Table II). This is the same process as plaque development. Such surface irregularities would be consistent with a process in which the rate of thickening increased as a function of the intimal thickness. The histologic appearance of the severely thickened intima also strongly suggested accelerating progress, since the luminal margin was relatively acellular (Fig. 1, A to C) and showed tissue edema with separation of the collagen fibers. Such a concept is implicit in the theory of arteriosclerosis already advanced.24 The thicker the intima becomes, the slower will be the rate of diffusion of protein and other macromolecules through the arterial wall into the surrounding lymphatics. The protein concentration of the innermost zone of the intima will therefore tend to be progressively higher and persistent edema of this zone more certain. Observations on patients less than 3 years of age suggest that the early rapid phase of intimal thickening seen at this time may be related to delay in the development of the cardiac lymphatic system. The importance of the lymphatic drainage of the heart has been demonstrated by Miller et a1.40and Pick et a1.,41who have shown in many experiments on dogs that impairment of the lymphatic drainage from the heart reduces the rate of healing of a myocardial infarction and causes increased fibrosis of the myocardium. Also Feola et al.42 have shown that drainage of cardiac lymph alleviates the myocardial changes produced by ischemic injury. The high protein content of cardiac lymph43 suggests that the lymphatic drainage of the heart may well be marginal. Nakata and ShionoyaM showed that obstruction of the microcirculation of the vasa vasorum and the lymphatics of the aorta resulted in intimal thickening similar in histologic appearance to the arterial lesions of humans. Edema of the media of the arterial wall was noted in this series in more than 50% of the coronary artery sections from patients over the age of 5 years. This would be anticipated if there were limitation of the lymphatic drainage from the arterial wall. When the intima becomes grossly thickened, it might be expected that edema would be prominent in the
565
luminal zone of the intima but less obvious in the more peripherally situated media. This was an observed trend in the group of arteries studied. Genetic factor in intlmal thickening. A number of recent publications45-50 offer substantial evidence that the dominant factor or factors which determine the rate of intimal thickening in a given individual are inborn, like any of the other inherited characteristics. REFERENCES
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