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Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20
Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors a
a
a
Jack P. Strong MD , Gray T. Malcom PhD , William P. Newman III MD & Margaret C. a
Oalmann DrPH a
Address reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, New Orleans Published online: 02 Sep 2013.
To cite this article: Jack P. Strong MD, Gray T. Malcom PhD, William P. Newman III MD & Margaret C. Oalmann DrPH (1992) Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors, Journal of the American College of Nutrition, 11:sup1, 51S-54S, DOI: 10.1080/07315724.1992.10737984 To link to this article: http://dx.doi.org/10.1080/07315724.1992.10737984
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors Jack P. Strong, MD, Gray T. Malcom, PhD, William P. Newman, III, MD, and Margaret C. Oalmann, DrPH Department of Pathology, Louisiana State University Medical Center, New Orleans
Downloaded by [New York University] at 21:49 11 May 2015
Key words: atherosclerosis, childhood and youth, lesions, cholesterol, smoking This paper traces the development of knowledge concerning early lesions of atherosclerosis and the relationship to risk factors in children, youth, and young adults. Autopsy studies have shown that atherosclerosis begins in childhood with the appearance of aortic fatty streaks. Aortic fatty streaks of some degree are present in practically all individuals from every human population. Coronary fatty streaks begin to form in adolescence. Most persons 20-29 years of age have coronary fatty streaks of some degree, regardless of sex, race, or national origin. While fatty streaking is clinically harmless and potentially reversible, progression to fibrous plaques and more advanced lesions often leads to a critical stage of atherosclerosis in which clinical disease develops. Development of fibrous plaques begins in the 20s. The most recent studies of atherosclerosis in youth and young adults provide additional details to establish the relationship of these lesions to serum lipids and lipoproteins and other identified risk factors for atherosclerosis and coronary heart disease in adults. One report shows that microscopic counterparts of fatty streaks occur in the left anterior descending coronary artery in the majority of children 10-14 years of age. Over 5% have more advanced microscopic lesions at this age. Autopsy studies of youth have shown that serum total cholesterol and low-density lipoprotein cholesterol levels are strongly related to aortic fatty streaks and the very-low-density lipoprotein cholesterol levels are positively correlated to coronary artery fatty streaks. Finally, a definitive report indicates that serum lipoprotein cholesterol concentrations and smoking are important determinants of the early stages of atherosclerosis in adolescents and young adults.
Abbreviations: FH = familial hypercholesterolemia, HDL-C = high-density lip oprotein cholesterol, IAP = International Atherosclerosis Project, LDL-C = lowdensity lipoprotein cholesterol, PDAY = Pathobiological Determinants of Ath erosclerosis in Youth, VLDL-C = very-low-density lipoprotein cholesterol
INTRODUCTION
was a serendipitous result of the opportunity provided by a study of wound ballistics in battlefield casualties. It was reviewed in perspective when it was republished and the review article traced the history of studies of atherosclerosis in youth beginning in the earliest part of the 20th century [2]. The landmark article of Enos and colleagues had maximum impact because it was concerned with athero sclerotic lesions in the coronary arteries and because its findings were a complete surprise to the medical commu nity.
The clinical sequelae of atherosclerosis—myocardial infarction, cerebral infarction (thrombo atherosclerotic), atherosclerotic aortic aneurysms, and peripheral vascular disease—generally occur in middle-aged and older adults. It is now clear that this atherosclerotic process has its beginning in childhood and further develops in adoles cence and early adulthood. In 1955, Enos, Holmes, and Byer described the high frequency of grossly visible lesions in the coronary arteries of young US soldiers killed in the Korean War [1]. This remarkable study, republished in the Journal of the American Medical Association in 1988 as a landmark article,
Earlier studies in the United States and Europe had recognized the importance of early development of athero sclerosis in the aorta [3-7], but there were no systematic, quantitative studies until the 1950s. Holman, McGill,
Presented at the 32nd Annual Meeting/Symposium of the American College of Nutrition, Clearwater Beach, FL, Oct. 11-14, 1991. Address reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, 1901 Perdido St., New Orleans, LA 70112. Journal of the American College of Nutrition, Vol. 11, No. S, 51S-54S (1992) Published by the American College of Nutrition 51S
Lesions of Atherosclerosis in Childhood
Downloaded by [New York University] at 21:49 11 May 2015
Strong, and Geer systematically studied the early aortic lesions in young persons aided by gross fat staining of arterial specimens in 526 necropsied individuals from 140 years of age in New Orleans. All autopsied patients >3 years of age had at least minimal sudanophilic fatty streaks [8]. Strong and McGill in 1962 published information on the natural history of coronary atherosclerosis based on quantitative evaluation of lesions in the coronary arteries from 548 autopsies of deceased subjects 1-69 years of age in New Orleans [9]. Fatty streaks began to occur in the second decade and were almost universal to some extent after age 20. Fibrous plaques first were evident in some cases in the second decade of life and increased in fre quency and extent in subsequent decades. These early quantitative studies in New Orleans led to the concept of the natural history of atherosclerosis illustrated by Figure 1. Russell Holman, a pioneer investigator of atheroscle rosis in youth, posed the question whether atherosclerosis was a pediatrie nutrition problem. Holman presented this provocative statement to the 9th International Congress of Pediatrics in 1959 and published his ideas in 1961, iden tifying atherosclerosis as a pediatrie problem [10]. Holman's colleagues, Strong and McGill, in 1969 responded to the provocative question in their analyses of young cases from the International Atherosclerosis Project (IAP) [11]. Findings from the IAP, in which over 23,000 sets of aortas and coronary arteries were collected and evaluated from persons autopsied in 14 countries (persons aged 10-69 years), are beyond the scope of this review [12,13]. How ever, the subset of younger autopsied subjects (n = 4,737) with an age range of 10-39 years from six of the geographic ethnic subgroups of the IAP were the basis for a special analysis [11]. Strong and McGill found from these analyses that at age 10 almost all aortas from all groups were positive for aortic fatty streaks. Coronary fatty streaks, while not as frequent as aortic fatty streaks, occurred in some cases from each geographic ethnic group even in the 10-14-year age group. Fatty streaks were universally present in coro nary arteries in persons over age 20 in New Orleans and occurred in approximately 90% of persons in other groups by age 30. This study clearly confirmed Holman's assertion that atherosclerosis is a pediatrie problem since aortic fatty streaks develop extensively in childhood, coronary fatty streaks begin to form in adolescence, and the development of fibrous plaques begins in the 20s.
SYSTEMATIC MICROSCOPIC STUDIES OF ARTERIAL LESIONS IN YOUNG SUBJECTS While some of the studies cited above reported histo logie features of lesions in the young, none was as intensive
52S
as recent studies by Stary [14,15] who systematically stud ied, by light and electron microscopy, unopened pressure perfusion fixed left coronary arteries of 691 male and female subjects dying between full-term birth and 39 years of age. The techniques used were designed to assess the earliest microscopic changes of atherosclerosis. Over 50% of children aged 10-14 years had lesions characterized by accumulations of macrophage foam cells, lipid-containing smooth muscle cells, and thinly scattered extracellular lipid. These changes represent the microscopic counterpart of gross fatty streaks. Approximately 8% of the subjects 10-14 years of age had more advanced lesions with larger accumulations of extracellular lipid. These were either lesions that were thought to be in transition or that had features of the atherosclerotic plaques which are known to be associated with clinical disease in adults. These micro scopic studies clearly indicate a progression from fatty streaks through intermediate or transitional lesions to atheromatous lesions (comparable to fibrous plaques by gross classification) in a defined segment of left anterior coronary artery predisposed to clinically significant lesions.
SERUM CHOLESTEROL LEVELS AND ARTERIAL LESIONS IN YOUNG PEOPLE The relationship of serum lipid levels to clinical disease cannot easily be evaluated in children because clinically significant coronary heart disease does not occur in chil dren except in unusual conditions such as familial hypercholesterolemia (FH) [16]. Myocardial infarction has been reported in young children with homozygous FH and frequently causes death before age 20 [17]. Only recently have serum lipid levels been directly related to the extent of early arterial lesions of atheroscle rosis in children. Investigators in the Bogalusa Heart Study, an epidemiologie study of cardiovascular risk factors in children in the biracial community of Bogalusa, LA, first assessed the relationship of risk factors to early atheroscle rotic lesions in the aorta and coronaries of a relatively small number of deceased subjects 7-34 years of age [18,19]. Aortic fatty streaks were significantly related to antemortem levels of both total cholesterol and low-density lipoprotein cholesterol (LDL-C) independent of race, sex, and age, and were negatively correlated with the ratio of high-density lipoprotein cholesterol (HDL-C) to LDL-C + very-low-density lipoprotein cholesterol (VLDL-C). Coro nary artery fatty streaks were positively correlated with levels of VLDL-C. In a later analysis from the Bogalusa Heart Study with additional subjects, there was a signifi cant relationship of LDL-C to coronary artery fatty streaks; furthermore, there were significant relationships between
VOL. 11, NO. S
Lesions of Atherosclerosis in Childhood
70·
Myocardial mfarct
Cerebral infarct
Gangrene of . extremities
Abdominal aortic aneurysrr
60
50clinical
§1>
40
■S
ç·
Si. 30
horizon Calcification Complicated lesion hemorrhage, ulcération, thrombosis
of atherosclerotic lesions in the arteries, along with other "postmortem risk factor variables." The recent preliminary report on arterial lesions and selected risk factors from the PDAY study is based on the evaluation of arterial specimens and blood samples from 390 autopsied male subjects [22]. Intimai surface involve ment with atherosclerotic lesions in both aortic and right coronary artery was positively associated with serum VLDL + LDL-C concentration and was negatively asso ciated with serum HDL-C concentration. The serum thiocyanate concentration, a marker for smoking, was strongly associated with the prevalence of raised lesions, particularly in the abdominal aorta. These associations indicate that serum lipoprotein cholesterol concentrations and smoking are important determinants of the early stages of atherosclerosis in adolescents and young adults.
Downloaded by [New York University] at 21:49 11 May 2015
Fibrous plaque
20
CONCLUDING STATEMENT Fatty streak
10
0 Fig. 1. The natural history of atherosclerosis. [Modified from McGill H, Geer JC, Strong JP: Natural history of human atherosclerosis lesions. In Sandier M, Bourne GH (eds): "Ath erosclerosis and Its Origin." New York: Academic, 1963.]
LDL-C levels and the prevalence of both aortic and coro nary artery fibrous plaques [20].
PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH A detailed and extensive study to investigate directly the possible causes of precocious atherosclerosis in adoles cents and young adults, "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)," led by Robert W. Wissler of the University of Chicago, involves 14 labora tories in the United States collaborating to evaluate coro nary arteries, aortas, and specimens of blood and other tissue from over 1,500 15- to 34-year-old autopsied trau matic death victims [21]. As part of the PDAY investiga tion, serum lipid and lipoprotein concentrations are meas ured in postmortem serum, and smoking habits are as sessed by measuring levels of thiocyanate in serum. The postmortem serum lipid variables and thiocyanate levels are being tested for relationship to the extent and severity
We are continuing to learn more about the natural history and progression of atherosclerosis in the aorta and coronary arteries. This increasing knowledge, coupled with the ongoing study of how generally recognized risk factors for adult cardiovascular disease influence the development of lesions in young people, will provide important infor mation about the atherosclerotic process. With this infor mation the appropriate recommendations and control pro grams might be initiated to prevent the sequelae of athero sclerosis in later life.
ACKNOWLEDGMENTS Supported in part by Grant Nos. HL33746 and HL45720 from the National Heart, Lung, and Blood In stitute and the National Institutes of Health, Bethesda, MD.
REFERENCES 1. Enos WF Jr, Beyer JC, Holmes RH: Pathogenesis of coronary disease in American soldiers killed in Korea. JAMA 158:912— 914, 1955. 2. Strong JP: Coronary atherosclerosis in soldiers. A clue to the natural history of atherosclerosis in young. JAMA 256:28632866, 1986. 3. Klotz O, Manning MF: Fatty streaks in the intima of arteries. J Pathol Bacteriol 16:211, 1911. 4. Saltykow S: Jugendliche und beginnende atherosklerose. Aertze 45:1057-1089, 1915. 5. Mönckeberg JG: Über die atherosklerose der Kombatten (nach Obduktionsbefunde). Zentralbl Herz Gefasskrankheiten 7:7-10, 1915.
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Downloaded by [New York University] at 21:49 11 May 2015
Lesions ofAtherosclerosis in Childhood 6. Zinserling WD: Untersuchungen über atherosklerose. I. Über die aorta-Verfettung bei kindern. Virchows Arch [Pathol Anat] 255:677-705, 1925. 7. Zeek P: Juvenile arteriosclerosis. Arch Pathol 10:417-446, 1930. 8. Holman RL, McGill HC, Strong JP, Geer JC: The natural history of atherosclerosis. The early aortic lesions as seen in New Orleans in the middle of the 20th century. Am J Pathol 34:209-235, 1958. 9. Strong JP, McGill HC: The natural history of coronary ath erosclerosis. Am J Pathol 40:37-49, 1962. 10. Holman R: Atherosclerosis—A pediatrie nutrition problem? Am J Clin Nutr 9:565-569, 1961. 11. Strong JP, McGill HC: The pediatrie aspects of atherosclero sis. J Atheroscler Res 9:251-265, 1969. 12. McGill HC Jr (ed): "The Geographic Pathology of Athero sclerosis." Baltimore: Williams and Wilkins, 1968. 13. Tejada CJ, Strong JP, Montenegro MR, Restrepo C, Solberg LA: Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest 18:509-526, 1968. 14. Stary HC: Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arterioscle rosis 9(Suppl 1):I-19-1-32, 1989. 15. Stary HC: The sequence of cell and matrix changes in athero sclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J 1 l(Suppl E):3-19, 1990. 16. Mabuchi H, Koizumi J, Shimizu M, Takeda R, the Hokuriku FH-CHD Study Group: Development of coronary heart dis
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17.
18.
19.
20.
21. 22.
ease in familial hypercholesterolemia. Circulation 79:217224, 1989. Goldstein JL, Brown MS: Familial hypercholesterolemia. In Scriver CR, Beaudet AL, Sly SW, Valle D (eds): "The Meta bolic Basis of Inherited Disease," 6th ed. New York: McGrawHill, pp 1215-1250, 1989. Newman WP III, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, Williamson GD, Webber LS, Ber enson GS: Relationship of serum lipoprotein levels and sys tolic blood pressure to early atherosclerosis. The Bogalusa Heart Study. N Engl J Med 314:128-144, 1986. Freedman DS, Newman WP III, Tracy RE, Voors AW, Srinivasan SR, Webber LS, Restrepo C, Strong JP, Berenson GS: Black-white differences in aortic fatty streaks in adoles cence and early adulthood: The Bogalusa Heart Study. Cir culation 77:856-864, 1988. Newman WP III, Wattigney W, Berenson GS: Autopsy stud ies in United States children and adolescents: relationship of risk factors to atherosclerotic lesions. Ann NY Acad Sci 623:16-25, 1991. Wissler RW: USA multicenter study of pathobiology of ath erosclerosis in youth. Ann NY Acad Sci 623:26-39, 1991. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group: Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentration and smoking: a preliminary report from the PDAY Research Group. JAMA 264:3018-3024, 1990.
Received December 1991; revision accepted January 1992.
VOL. 11, NO. S
Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20
Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors a
a
a
Jack P. Strong MD , Gray T. Malcom PhD , William P. Newman III MD & Margaret C. a
Oalmann DrPH a
Address reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, New Orleans Published online: 02 Sep 2013.
To cite this article: Jack P. Strong MD, Gray T. Malcom PhD, William P. Newman III MD & Margaret C. Oalmann DrPH (1992) Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors, Journal of the American College of Nutrition, 11:sup1, 51S-54S, DOI: 10.1080/07315724.1992.10737984 To link to this article: http://dx.doi.org/10.1080/07315724.1992.10737984
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Early Lesions of Atherosclerosis in Childhood and Youth: Natural History and Risk Factors Jack P. Strong, MD, Gray T. Malcom, PhD, William P. Newman, III, MD, and Margaret C. Oalmann, DrPH Department of Pathology, Louisiana State University Medical Center, New Orleans
Downloaded by [New York University] at 21:49 11 May 2015
Key words: atherosclerosis, childhood and youth, lesions, cholesterol, smoking This paper traces the development of knowledge concerning early lesions of atherosclerosis and the relationship to risk factors in children, youth, and young adults. Autopsy studies have shown that atherosclerosis begins in childhood with the appearance of aortic fatty streaks. Aortic fatty streaks of some degree are present in practically all individuals from every human population. Coronary fatty streaks begin to form in adolescence. Most persons 20-29 years of age have coronary fatty streaks of some degree, regardless of sex, race, or national origin. While fatty streaking is clinically harmless and potentially reversible, progression to fibrous plaques and more advanced lesions often leads to a critical stage of atherosclerosis in which clinical disease develops. Development of fibrous plaques begins in the 20s. The most recent studies of atherosclerosis in youth and young adults provide additional details to establish the relationship of these lesions to serum lipids and lipoproteins and other identified risk factors for atherosclerosis and coronary heart disease in adults. One report shows that microscopic counterparts of fatty streaks occur in the left anterior descending coronary artery in the majority of children 10-14 years of age. Over 5% have more advanced microscopic lesions at this age. Autopsy studies of youth have shown that serum total cholesterol and low-density lipoprotein cholesterol levels are strongly related to aortic fatty streaks and the very-low-density lipoprotein cholesterol levels are positively correlated to coronary artery fatty streaks. Finally, a definitive report indicates that serum lipoprotein cholesterol concentrations and smoking are important determinants of the early stages of atherosclerosis in adolescents and young adults.
Abbreviations: FH = familial hypercholesterolemia, HDL-C = high-density lip oprotein cholesterol, IAP = International Atherosclerosis Project, LDL-C = lowdensity lipoprotein cholesterol, PDAY = Pathobiological Determinants of Ath erosclerosis in Youth, VLDL-C = very-low-density lipoprotein cholesterol
INTRODUCTION
was a serendipitous result of the opportunity provided by a study of wound ballistics in battlefield casualties. It was reviewed in perspective when it was republished and the review article traced the history of studies of atherosclerosis in youth beginning in the earliest part of the 20th century [2]. The landmark article of Enos and colleagues had maximum impact because it was concerned with athero sclerotic lesions in the coronary arteries and because its findings were a complete surprise to the medical commu nity.
The clinical sequelae of atherosclerosis—myocardial infarction, cerebral infarction (thrombo atherosclerotic), atherosclerotic aortic aneurysms, and peripheral vascular disease—generally occur in middle-aged and older adults. It is now clear that this atherosclerotic process has its beginning in childhood and further develops in adoles cence and early adulthood. In 1955, Enos, Holmes, and Byer described the high frequency of grossly visible lesions in the coronary arteries of young US soldiers killed in the Korean War [1]. This remarkable study, republished in the Journal of the American Medical Association in 1988 as a landmark article,
Earlier studies in the United States and Europe had recognized the importance of early development of athero sclerosis in the aorta [3-7], but there were no systematic, quantitative studies until the 1950s. Holman, McGill,
Presented at the 32nd Annual Meeting/Symposium of the American College of Nutrition, Clearwater Beach, FL, Oct. 11-14, 1991. Address reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, 1901 Perdido St., New Orleans, LA 70112. Journal of the American College of Nutrition, Vol. 11, No. S, 51S-54S (1992) Published by the American College of Nutrition 51S
Lesions of Atherosclerosis in Childhood
Downloaded by [New York University] at 21:49 11 May 2015
Strong, and Geer systematically studied the early aortic lesions in young persons aided by gross fat staining of arterial specimens in 526 necropsied individuals from 140 years of age in New Orleans. All autopsied patients >3 years of age had at least minimal sudanophilic fatty streaks [8]. Strong and McGill in 1962 published information on the natural history of coronary atherosclerosis based on quantitative evaluation of lesions in the coronary arteries from 548 autopsies of deceased subjects 1-69 years of age in New Orleans [9]. Fatty streaks began to occur in the second decade and were almost universal to some extent after age 20. Fibrous plaques first were evident in some cases in the second decade of life and increased in fre quency and extent in subsequent decades. These early quantitative studies in New Orleans led to the concept of the natural history of atherosclerosis illustrated by Figure 1. Russell Holman, a pioneer investigator of atheroscle rosis in youth, posed the question whether atherosclerosis was a pediatrie nutrition problem. Holman presented this provocative statement to the 9th International Congress of Pediatrics in 1959 and published his ideas in 1961, iden tifying atherosclerosis as a pediatrie problem [10]. Holman's colleagues, Strong and McGill, in 1969 responded to the provocative question in their analyses of young cases from the International Atherosclerosis Project (IAP) [11]. Findings from the IAP, in which over 23,000 sets of aortas and coronary arteries were collected and evaluated from persons autopsied in 14 countries (persons aged 10-69 years), are beyond the scope of this review [12,13]. How ever, the subset of younger autopsied subjects (n = 4,737) with an age range of 10-39 years from six of the geographic ethnic subgroups of the IAP were the basis for a special analysis [11]. Strong and McGill found from these analyses that at age 10 almost all aortas from all groups were positive for aortic fatty streaks. Coronary fatty streaks, while not as frequent as aortic fatty streaks, occurred in some cases from each geographic ethnic group even in the 10-14-year age group. Fatty streaks were universally present in coro nary arteries in persons over age 20 in New Orleans and occurred in approximately 90% of persons in other groups by age 30. This study clearly confirmed Holman's assertion that atherosclerosis is a pediatrie problem since aortic fatty streaks develop extensively in childhood, coronary fatty streaks begin to form in adolescence, and the development of fibrous plaques begins in the 20s.
SYSTEMATIC MICROSCOPIC STUDIES OF ARTERIAL LESIONS IN YOUNG SUBJECTS While some of the studies cited above reported histo logie features of lesions in the young, none was as intensive
52S
as recent studies by Stary [14,15] who systematically stud ied, by light and electron microscopy, unopened pressure perfusion fixed left coronary arteries of 691 male and female subjects dying between full-term birth and 39 years of age. The techniques used were designed to assess the earliest microscopic changes of atherosclerosis. Over 50% of children aged 10-14 years had lesions characterized by accumulations of macrophage foam cells, lipid-containing smooth muscle cells, and thinly scattered extracellular lipid. These changes represent the microscopic counterpart of gross fatty streaks. Approximately 8% of the subjects 10-14 years of age had more advanced lesions with larger accumulations of extracellular lipid. These were either lesions that were thought to be in transition or that had features of the atherosclerotic plaques which are known to be associated with clinical disease in adults. These micro scopic studies clearly indicate a progression from fatty streaks through intermediate or transitional lesions to atheromatous lesions (comparable to fibrous plaques by gross classification) in a defined segment of left anterior coronary artery predisposed to clinically significant lesions.
SERUM CHOLESTEROL LEVELS AND ARTERIAL LESIONS IN YOUNG PEOPLE The relationship of serum lipid levels to clinical disease cannot easily be evaluated in children because clinically significant coronary heart disease does not occur in chil dren except in unusual conditions such as familial hypercholesterolemia (FH) [16]. Myocardial infarction has been reported in young children with homozygous FH and frequently causes death before age 20 [17]. Only recently have serum lipid levels been directly related to the extent of early arterial lesions of atheroscle rosis in children. Investigators in the Bogalusa Heart Study, an epidemiologie study of cardiovascular risk factors in children in the biracial community of Bogalusa, LA, first assessed the relationship of risk factors to early atheroscle rotic lesions in the aorta and coronaries of a relatively small number of deceased subjects 7-34 years of age [18,19]. Aortic fatty streaks were significantly related to antemortem levels of both total cholesterol and low-density lipoprotein cholesterol (LDL-C) independent of race, sex, and age, and were negatively correlated with the ratio of high-density lipoprotein cholesterol (HDL-C) to LDL-C + very-low-density lipoprotein cholesterol (VLDL-C). Coro nary artery fatty streaks were positively correlated with levels of VLDL-C. In a later analysis from the Bogalusa Heart Study with additional subjects, there was a signifi cant relationship of LDL-C to coronary artery fatty streaks; furthermore, there were significant relationships between
VOL. 11, NO. S
Lesions of Atherosclerosis in Childhood
70·
Myocardial mfarct
Cerebral infarct
Gangrene of . extremities
Abdominal aortic aneurysrr
60
50clinical
§1>
40
■S
ç·
Si. 30
horizon Calcification Complicated lesion hemorrhage, ulcération, thrombosis
of atherosclerotic lesions in the arteries, along with other "postmortem risk factor variables." The recent preliminary report on arterial lesions and selected risk factors from the PDAY study is based on the evaluation of arterial specimens and blood samples from 390 autopsied male subjects [22]. Intimai surface involve ment with atherosclerotic lesions in both aortic and right coronary artery was positively associated with serum VLDL + LDL-C concentration and was negatively asso ciated with serum HDL-C concentration. The serum thiocyanate concentration, a marker for smoking, was strongly associated with the prevalence of raised lesions, particularly in the abdominal aorta. These associations indicate that serum lipoprotein cholesterol concentrations and smoking are important determinants of the early stages of atherosclerosis in adolescents and young adults.
Downloaded by [New York University] at 21:49 11 May 2015
Fibrous plaque
20
CONCLUDING STATEMENT Fatty streak
10
0 Fig. 1. The natural history of atherosclerosis. [Modified from McGill H, Geer JC, Strong JP: Natural history of human atherosclerosis lesions. In Sandier M, Bourne GH (eds): "Ath erosclerosis and Its Origin." New York: Academic, 1963.]
LDL-C levels and the prevalence of both aortic and coro nary artery fibrous plaques [20].
PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH A detailed and extensive study to investigate directly the possible causes of precocious atherosclerosis in adoles cents and young adults, "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)," led by Robert W. Wissler of the University of Chicago, involves 14 labora tories in the United States collaborating to evaluate coro nary arteries, aortas, and specimens of blood and other tissue from over 1,500 15- to 34-year-old autopsied trau matic death victims [21]. As part of the PDAY investiga tion, serum lipid and lipoprotein concentrations are meas ured in postmortem serum, and smoking habits are as sessed by measuring levels of thiocyanate in serum. The postmortem serum lipid variables and thiocyanate levels are being tested for relationship to the extent and severity
We are continuing to learn more about the natural history and progression of atherosclerosis in the aorta and coronary arteries. This increasing knowledge, coupled with the ongoing study of how generally recognized risk factors for adult cardiovascular disease influence the development of lesions in young people, will provide important infor mation about the atherosclerotic process. With this infor mation the appropriate recommendations and control pro grams might be initiated to prevent the sequelae of athero sclerosis in later life.
ACKNOWLEDGMENTS Supported in part by Grant Nos. HL33746 and HL45720 from the National Heart, Lung, and Blood In stitute and the National Institutes of Health, Bethesda, MD.
REFERENCES 1. Enos WF Jr, Beyer JC, Holmes RH: Pathogenesis of coronary disease in American soldiers killed in Korea. JAMA 158:912— 914, 1955. 2. Strong JP: Coronary atherosclerosis in soldiers. A clue to the natural history of atherosclerosis in young. JAMA 256:28632866, 1986. 3. Klotz O, Manning MF: Fatty streaks in the intima of arteries. J Pathol Bacteriol 16:211, 1911. 4. Saltykow S: Jugendliche und beginnende atherosklerose. Aertze 45:1057-1089, 1915. 5. Mönckeberg JG: Über die atherosklerose der Kombatten (nach Obduktionsbefunde). Zentralbl Herz Gefasskrankheiten 7:7-10, 1915.
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