This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McGill, H. C. Articles by Strong, J. P. Search for Related Content PubMed PubMed Citation Articles by McGill, H. C., Jr Articles by Strong, J. P. Related Collections Primary prevention Risk Factors Epidemiology

(Circulation. 2000;102:374.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Association of Coronary Heart Disease Risk Factors With Microscopic Qualities of Coronary Atherosclerosis in Youth

Henry C. McGill, Jr, MD; C. Alex McMahan, PhD; Arthur W. Zieske, MD; Richard E. Tracy, MD; Gray T. Malcom, PhD; Edward E. Herderick, BS; Jack P. Strong, MD; for the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group

From the Department of Pathology, The University of Texas Health Science Center at San Antonio (H.C.M., C.A.M.) and Southwest Foundation for Biomedical Research (H.C.M.), San Antonio, Tex; the Department of Pathology, Louisiana State University Medical Center, New Orleans (A.Z.W., R.E.T., G.T.M., J.P.S.); and the Biomedical Engineering Center, Ohio State University, Columbus (E.E.H.).

Correspondence to Henry C. McGill, Jr, MD, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail jstron{at}lsumc.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—This study examined whether atherosclerosis in young people is associated with the risk factors for clinical coronary heart disease (CHD).

Methods and Results—Histological sections of left anterior descending coronary arteries (LADs) from 760 autopsied 15- to 34-year-old victims of accidents, homicides, and suicides were graded according to the American Heart Association (AHA) system and computerized morphometry. Risk factors (dyslipoproteinemia, smoking, hypertension, obesity, impaired glucose tolerance) were assessed by postmortem measurements. Approximately 2% of 15- to 19-year-old men and 20% of 30- to 34-year-old men had AHA grade 4 or 5 (advanced) lesions. No 15- to 19-year-old women had grade 4 or 5 lesions; 8% of 30- to 34-year-old women had such lesions. Approximately 19% of 30- to 34-year-old men and 8% of 30- to 34-year-old women had atherosclerotic stenosis 40% in the LAD. AHA grade 2 or 3 lesions (fatty streaks), grade 4 or 5 lesions, and stenosis 40% were associated with non-HDL cholesterol 4.14 mmol/L (160 mg/dL). AHA grade 2 or 3 lesions were associated with HDL cholesterol <0.91 mmol/L (35 mg/dL) and smoking. AHA grade 4 or 5 lesions were associated with obesity (body mass index 30 kg/m²) and hypertension (mean arterial pressure 110 mm Hg).

Conclusions—Young Americans have a high prevalence of advanced atherosclerotic coronary artery plaques with qualities indicating vulnerability to rupture. Early atherosclerosis is influenced by the risk factors for clinical CHD. Long-range prevention of CHD must begin in adolescence or young adulthood.

Key Words: atherosclerosis • coronary disease • risk factors • youth

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The major strategy to prevent coronary heart disease (CHD) has been to control risk factors that predict the probability of developing clinical disease.¹ The success of these efforts² encourages continued efforts directed toward risk factor control,³ but the age at which such efforts should begin, particularly efforts to control serum lipid levels, remains controversial.⁴

The risk factors for CHD are associated with the extent and severity of atherosclerosis in adults >35 years old,⁵ but until recently, we did not know whether the risk factors were also associated with the early lesions of atherosclerosis in younger people. In 1985, investigators organized a multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), to determine the relation of cardiovascular risk factors to atherosclerosis in victims of accidents, homicides, or suicides who were 15 to 34 years old.⁶ Previous PDAY reports showed that the gross extent of lesions of the right coronary artery and aorta was associated with the risk factors for CHD (male sex, high non-HDL cholesterol, low HDL cholesterol, smoking, hypertension, obesity, and impaired glucose tolerance).^{7 8 9} However, each of these gross lesion classes is microscopically heterogeneous, and some lesion qualities are associated with the likelihood of plaque rupture and arterial thrombosis.^{10 11} The relations of the risk factors to the qualitative characteristics associated with lesion progression and vulnerability to rupture would provide additional information with which to assess the need for risk factor modification in young people.

Therefore, in 760 PDAY cases, we evaluated the microscopic qualities of lesions at a standard site in the left anterior descending coronary artery (LAD) by the American Heart Association (AHA) grading system^{12 13} and measured the cross-sectional area of the potential arterial lumen occupied by these lesions as an indicator of stenosis. The association of these lesions with the risk factors for CHD is the subject of this report.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Design
Fifteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and data and to submit them to central laboratories for analysis.⁶ A statistical coordinating center received all data pertaining to each case.

Subjects
Study subjects were persons 15 through 34 years of age who died of external causes (accidents, homicides, or suicides) within 72 hours of injury and were autopsied within 48 hours in one of the cooperating forensic laboratories. Age and race were obtained from the death certificate. We collected 2876 acceptable cases from June 1, 1987, to August 31, 1994. For 760 cases, we had measurements of all risk factors, histological sections of a standard segment of the LAD, and digitized images from these sections. Fifty-two percent of the subjects were black, and 26% were women. The Institutional Review Board of each cooperating center approved this study.

Risk Factor Measurements
Methods of measuring CHD risk factors and the limitations of these measurements have been presented in previous publications^{7 8 9} and are summarized in Table 1, which also shows the prevalence of each risk factor in the 760 PDAY subjects included in this study.

View this table: [in this window] [in a new window]   Table 1. Risk Factors, Samples, Analyses, Classification, and Prevalence in the PDAY Study

Preparation of the LAD
PDAY investigators ligated the left circumflex and right coronary arteries close to their origins and removed them for other studies. They perfused the left main coronary artery and the LAD with 10% buffered formalin at a pressure of 100 mm Hg (130 cm H₂O) for 30 minutes while the heart lay in a formalin bath. The left main coronary arteries and LADs were then dissected from the heart and shipped to a central laboratory.

A technician cut a 5-mm transverse block from the LAD bounded on its proximal edge by the distal flow divider of the left main and left circumflex arteries. The proximal half of the bisected block was sectioned on a freezing microtome and stained with oil red O, and the distal half was embedded in paraffin and stained with Gomori’s trichrome aldehyde fuchsin (GTAF). This site was selected because of its susceptibility to clinically significant atherosclerotic lesions,¹⁴ particularly in young persons.¹⁵ The AHA grade at this site was associated with the extent of lesions in the entire right coronary artery (Kendall’s =0.324 for association with right coronary artery fatty streaks, =0.311 with right coronary artery raised lesions, P=0.0001). This finding supports the use of this single site in the LAD as representative of atherosclerosis in the entire coronary artery system. Therefore, to have statistical power to detect associations with the risk factors, we quantified selected histological and structural characteristics of this single site of maximum susceptibility in a large number of individuals rather than measuring more points in a smaller number of individuals.

Grading Histological Characteristics
Two pathologists (H.C.M. and A.W.Z.) graded the GTAF- and oil red O–stained sections according to the AHA classification system.^{12 13} The criteria are described briefly in Table 2. Differences were resolved by discussion, and the consensus grade was used in the statistical analyses.

View this table: [in this window] [in a new window]   Table 2. Criteria for AHA Lesion Classification System and Correspondence With Classification of Gross Arterial Specimens

Computerized Morphometry
A central laboratory scanned the GTAF-stained sections at a resolution of 1024x1024 pixels by 24-bit full color and displayed the image on a color monitor. The operator manually identified the luminal border, the internal elastic lamina (IEL), and the external elastic lamina (EEL). If the IEL or the EEL was broken, the operator drew a smooth curve between the 2 ends. The operator then measured the lengths of the EEL and IEL and the cross-sectional areas of the intima and media. Because some of the sections were flattened transversely during sectioning, we assumed that the EEL was a circle and calculated the total artery cross-sectional area. The maximum potential lumen area was calculated by subtracting the measured medial area from the calculated area within the EEL. A case was classified as having atherosclerotic stenosis if the ratio of measured intimal area to maximum potential lumen area was 40% and the AHA grade was 3. We chose 40% as the definition of stenosis because compensatory remodeling is believed to occur up to this level.¹⁶ All cases with AHA grade 0, 1, or 2 were considered to have adaptive intimal thickening (a "normal" structure¹⁷ ) or minimal atherosclerosis and not to have atherosclerotic stenosis.

Statistical Analyses
For statistical analysis, the AHA grades were placed into 3 combined categories. We analyzed the prevalence of grades 0 or 1, 2 or 3, and 4 or 5 using polytomous logistic regression.^{18 19} Using grade 0 or 1 as the reference group, we constructed logits for comparing grades 2 or 3 with 0 or 1 and for comparing grades 4 or 5 with 0 or 1. The regression model included the effects of sex, race, 5-year age group, non-HDL cholesterol, HDL cholesterol, smoking, hypertension, obesity, and impaired glucose tolerance. We analyzed the prevalence of cases with atherosclerotic stenosis 40% using binary logistic regression with the same model.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Prevalence of Lesions by AHA Grade in the LAD
Figure 1 shows the prevalence of each grade of LAD lesions by 5-year age groups and sex. No lesions with hemorrhage or thrombosis (AHA grade 6) were encountered. There were no significant differences by race (black versus white; results not shown). There was a progressive increase in the frequency of advanced lesions with age in both sexes. Grade 4 or 5 lesions were present in 2.4% of 15- to 19-year-old men and in 20.3% of 30- to 34-year-old men. There were no grade 4 or 5 lesions among 15- to 19-year-old women, and grade 4 or 5 lesions were present in 7.8% of 30- to 34-year-old women.

View larger version (17K): [in this window] [in a new window]   Figure 1. Prevalence of AHA grades in LAD by sex and 5-year age group. Women, ; men, ; error bar=SE.

Prevalence of Atherosclerotic Stenosis
Figure 2 shows the prevalence of atherosclerotic stenosis 40% in men and women by 5-year age groups. Men 15 to 19 years old occasionally (3.2%) had stenosis by this definition, and the prevalence increased with age to 18.8% in the 30- to 34-year age group. Women had no stenosis (40%) before age 25, and had <50% the prevalence of men in the 30- to 34-year age group.

View larger version (12K): [in this window] [in a new window]   Figure 2. Prevalence of atherosclerotic stenosis 40% in LAD by sex and 5-year age group. Women, ; men, ; error bar=SE.

Prevalence of Risk Factors
Table 1 gives the prevalence of each of the risk factors. Only 22.4% of these adolescents and young adults had no risk factors as defined in Table 1, whereas 42.7% had 1 risk factor and 34.9% had 2 risk factors.

Associations of Risk Factors With Lesion Grades and Stenosis
Table 3 presents the odds ratios for the associations of the risk factors with coronary artery lesions, and Figures 3 and 4 illustrate the effects of these associations on the prevalence of lesions. The odds ratios do not depend on prevalence of lesions and could apply to a population with a prevalence of lesions different from that in the PDAY sample. The odds ratios for risk factor effects in Table 3 are presented for AHA grade 2 or 3 versus grade 0 or 1, AHA grade 4 or 5 versus grade 0 or 1, and stenosis 40% versus stenosis <40%. The odds ratio for a grade 4 or 5 lesion versus a grade 2 or 3 lesion can be estimated by dividing the odds ratio for a grade 4 or 5 lesion versus a grade 0 or 1 lesion (Table 3, column 4) by the odds ratio for a grade 2 or 3 lesion versus a grade 0 or 1 lesion (Table 3, column 2). Odds ratios for risk factor combinations can be estimated as the product of the odds ratios for the individual risk factors.

View this table: [in this window] [in a new window]   Table 3. Odds Ratios for Risk Factor Effects Adjusted for Other Risk Factors and 5-Year Age Group

View larger version (23K): [in this window] [in a new window]   Figure 3. Estimated prevalence of AHA grades in LAD by high () vs normal () non-HDL cholesterol concentration (top); low () vs normal () HDL cholesterol concentration (middle); smoking () vs nonsmoking () status (bottom); and 5-year age group, adjusted for race, sex, and other risk factors (Table 1).

View larger version (24K): [in this window] [in a new window]   Figure 4. Estimated prevalence of AHA grades in LAD by hypertensive () vs nonhypertensive () status (top); body mass index 30 () vs body mass index <30 () (middle); glycohemoglobin 8% () vs glycohemoglobin <8% () (bottom); and 5-year age group, adjusted for race, sex, and other risk factors (Table 1).

Men had greater odds of grade 2 or 3 lesions (P=0.0044), grade 4 or 5 lesions (P=0.0236), and stenosis (P=0.0285) (Table 3, row 1). Men had an 60% higher prevalence of grade 4 or 5 lesions than women (Figure 1). The higher prevalence of advanced lesions in men could not be explained by differences in risk factors.

High non-HDL cholesterol concentrations were associated with greater odds of grade 2 or 3 lesions (P=0.0003), grade 4 or 5 lesions (P=0.0054), and stenosis (P=0.0013) (Table 3, row 2) and with 60% higher prevalence of grade 4 or 5 lesions (Figure 3).

Low HDL cholesterol concentrations were associated with greater odds of grade 2 or 3 lesions (P=0.0341) (Table 3, row 3) and with 30% higher prevalence of grade 4 or 5 lesions (Figure 3).

Smoking was associated with greater odds of grade 2 or 3 lesions (P=0.0475) (Table 3, row 4) and higher prevalence of grade 2 or 3 lesions, whereas there was little difference in the prevalence of grade 4 or 5 lesions in smokers compared with nonsmokers (Figure 3).

Hypertension was associated with greater odds of grade 4 or 5 lesions (P=0.0589) (Table 3, row 5) and with a higher prevalence of grade 4 or 5 lesions (Figure 4).

Obesity was associated with greater odds of grade 4 or 5 lesions (P=0.0138) (Table 3, row 6) and of atherosclerotic stenosis (P=0.0303). Obese persons had a higher prevalence of grade 4 or 5 lesions at all ages (Figure 4).

Impaired glucose tolerance was not significantly associated with LAD lesion grade (P0.2043; Table 3, row 7), although the odds ratios and prevalences (Figure 4) suggest a substantial effect. The lack of statistical significance is most likely a result of the low prevalence of impaired glucose tolerance in these young persons and the resulting small numbers of cases.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Summary of Results
Severe atherosclerotic lesions (AHA grade 4 or 5) causing stenosis occur at a standard site of the proximal LAD in a few 15- to 19-year-old men and in 20% of 30- to 34-year-old men. The prevalence of similar lesions in 30- to 34-year-old women is <50% that of men. High non-HDL cholesterol concentrations are associated with a higher prevalence of atherosclerosis (both AHA grades 2 or 3 and 4 or 5) and atherosclerotic stenosis 40%. Low HDL cholesterol levels and smoking are associated with greater prevalence of AHA grade 2 or 3 lesions. Hypertension and obesity are associated with greater prevalence of AHA grade 4 or 5 lesions, and obesity also is associated with atherosclerotic stenosis 40%.

Comparison With Other Studies
The associations of risk factors with the histological qualities of LAD lesions are similar to the associations of risk factors with the extent of lesions in the right coronary artery and the abdominal aorta.^{7 8 9} Impaired glucose tolerance is not significantly associated with LAD lesion grade, whereas it was significantly associated with the extent of raised lesions in the right coronary artery.⁹ The lack of statistical significance is probably a result of the smaller number of cases examined in this histological study.

A detailed comparison of the PDAY results with atherosclerosis in Korean War battle casualties is not possible because Enos et al²⁰ used different methods to assess atherosclerosis and did not report ages in detail. We would expect to find a lower prevalence of stenosis in PDAY cases, because we assessed stenosis at only 1 site. Stary²¹ reported the prevalence of coronary artery lesions in 1160 persons from birth to 29 years of age by a grading system similar to the AHA system. For comparable age and sex groups, the prevalence of advanced lesions (AHA grade 4 or 5) we found in PDAY cases is 25% to 50% the prevalence reported by Stary in multiple coronary artery sections. As with the Korean War battle casualties, this difference may be partly a result of our having examined only 1 site. There also may have been a secular trend in the severity of atherosclerosis between the 3 periods of collection (Enos et al, circa 1950–53; Stary, 1979–86; PDAY, 1987–1994).

Significance of Gross Fatty Streaks and Grade 1 or 2 Microscopic Lesions
The ubiquity of the fatty streak²² has led some investigators to conclude that the fatty streak does not represent the initial stage of atherosclerosis.²³ However, a continuous progression of lesions from grade 2 coronary artery lesions can be traced through successive age groups to clinically significant grade 4 or 5 plaques.^{12 13 21} Results presented here show that the prevalence of grade 2 lesions, corresponding to a gross fatty streak, is associated with the risk factors for clinical CHD, just as the gross extent of fatty streaks is associated with those risk factors. Therefore, it is reasonable to expect that control of risk factors in young persons would retard the progression of the fatty streak and thereby retard the occurrence of CHD.

Significance of Stenosis
Stenosis is measured in these fixed arteries as the percentage of potential lumen inside the IEL that is occupied by normal intima and atherosclerotic lesion(s). Our measure of stenosis may not correspond with stenosis measured by angiography. Furthermore, our measure of stenosis may not indicate true functional stenosis, because many of the grade 4 or 5 lesions are associated with distended arterial walls and appear to be undergoing the adaptive remodeling described by Glagov et al.¹⁶ The clinical significance of grade 4 or 5 lesions is probably more closely related to their susceptibility to plaque rupture and its sequelae.

Plaque Vulnerability
The major criterion for AHA grade 4 or 5 atherosclerotic plaques is the presence of a large core of lipid and necrotic debris lying beneath a fibromuscular cap.¹³ This core, which is softer than the fibrous cap,²⁴ is also the hallmark of a plaque vulnerable to rupture and thrombotic occlusion.^{10 11 25 26} Other changes associated with plaque rupture and thrombosis are thinning and macrophage infiltration of the fibrous cap,^{27 28} both of which may be accelerated by continued lipid accumulation. Thus, a substantial proportion of these young individuals have coronary artery lesions that are vulnerable to rupture and thrombosis and have the potential to precipitate CHD.^{29 30}

Implications for Early Primary Prevention
There is little or no controversy regarding hygienic measures to control smoking, obesity, hypertension, and hyperglycemia in young persons, but there is controversy regarding how early in life serum cholesterol levels should be a matter of concern.^{1 31 32 33 34} The results presented here show that 1 of 5 young men between the ages of 30 and 34 has 1 advanced atherosclerotic plaque that has probably developed over the preceding decade and show that such lesions are associated with the CHD risk factors, including elevated non-HDL cholesterol. These observations indicate the need for risk factor modification early in life. If these susceptible individuals wait for the first CHD event, 25% or more will die unexpectedly and suddenly outside the hospital.^{35 36} The survivors will be at greatly increased risk of recurrence, and aggressive lipid lowering offers at best only 40% risk reduction over 5 years.³⁷

The high prevalence of risk factors in the PDAY sample (Table 1) and in living children and adolescents^{38 39} indicates that a large number of young people are at risk of precocious atherosclerosis and eventual CHD. Thus, there is considerable potential for risk factor reduction, with resulting prevention or retardation of severe atherosclerosis and clinical CHD. Although changing the behavior of young people is a difficult task, available information indicates that the earlier the cardiovascular risk factors are modified, the greater the potential for deferring the onset of CHD. Prevention of CHD is, indeed, a pediatric problem.⁴⁰

	Acknowledgments

 
The PDAY Research Group: Participating institutions and the supporting grants from the National Heart, Lung, and Blood Institute and other sources are as follows. University of Alabama, Birmingham, HL-33733, HL-33728. Albany Medical College, Albany, NY, HL-33765. Baylor College of Medicine, Houston, Tex, HL-33750. University of Chicago, Chicago, Ill, HL-33740, HL-45715. The University of Illinois, Chicago, HL-33758. Louisiana State University Medical Center, New Orleans, HL-33746, HL-45720. University of Maryland, Baltimore, HL-33752, HL-45693. Medical College of Georgia, Augusta, HL-33772. University of Nebraska Medical Center, Omaha, HL-33778. The Ohio State University, Columbus, HL-33760, HL-45694. Vanderbilt University, Nashville, Tenn, HL-33770, HL-45718. Southwest Foundation for Biomedical Research, San Antonio, Tex, HL-39913; gift of Peter and Beth Dahlberg. The University of Texas Health Science Center at San Antonio, San Antonio, HL-33749, HL-45719. West Virginia University Health Sciences Center, Morgantown, HL-33748.

	Footnotes

 
Reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, 1901 Perdido St, New Orleans, LA 70112-1393.

Received September 20, 1999; revision received February 11, 2000; accepted February 21, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. National Cholesterol Education Program. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023.[Medline] [Order article via Infotrieve]
   
2. Hunink MGM, Goldman L, Tosteson ANA, et al. The recent decline in mortality from coronary heart disease, 1980–1990: the effect of secular trends in risk factors and treatment. JAMA. 1997;277:535–542.[Abstract]
   
3. Kuller LH. Future in lipid and lipoprotein research: from preventing clinical disease to preventing elevated risk factors. Atherosclerosis. 1994;108(suppl):S143–S156.
   
4. Davidoff F. Evangelists and snails redux: the case of cholesterol screening. Ann Intern Med. 1996;124:513–514.[Free Full Text]
   
5. Solberg LA, Strong JP. Risk factors and atherosclerotic lesions: a review of autopsy studies. Arteriosclerosis. 1983;3:187–198.[Abstract/Free Full Text]
   
6. Wissler RW. USA multicenter study of the pathobiology of atherosclerosis in youth. Ann N Y Acad Sci. 1991;623:26–39.
   
7. McGill HC Jr, McMahan CA, Malcom GT, et al, for the PDAY Research Group. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. Arterioscler Thromb Vasc Biol. 1997;17:95–106.[Abstract/Free Full Text]
   
8. McGill HC Jr, McMahan CA, Tracy RE, et al, for the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Relation of a postmortem renal index of hypertension to atherosclerosis and coronary artery size in young men and women. Arterioscler Thromb Vasc Biol. 1998;18:1108–1118.[Abstract/Free Full Text]
   
9. McGill HC Jr, McMahan CA, Malcom GT, et al, Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Arterioscler Thromb Vasc Biol. 1995;15:431–440.[Abstract/Free Full Text]
   
10. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1–17.
    
11. Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol. 1997;17:1859–1867.[Free Full Text]
    
12. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994;89:2462–2478.[Abstract/Free Full Text]
    
13. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1995;15:1512–1531.[Abstract/Free Full Text]
    
14. Montenegro MR, Eggen DA. Topography of atherosclerosis in the coronary arteries. Lab Invest. 1968;18:586–593.[Medline] [Order article via Infotrieve]
    
15. Stary HC. Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children. Atherosclerosis. 1987;64:91–108.[Medline] [Order article via Infotrieve]
    
16. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–1375.[Abstract]
    
17. Stary HC, Blankenhorn DH, Chandler AB, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb. 1992;12:120–134.[Free Full Text]
    
18. Agresti A. Analysis of Ordinal Categorical Data. New York, NY: John Wiley & Sons; 1984.
    
19. Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons; 1989.
    
20. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea: preliminary report. JAMA. 1953;152:1090–1093.
    
21. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 1989;9(suppl 1):I-19–I-32.
    
22. McGill HC Jr. Fatty streaks in the coronary arteries and aorta. Lab Invest. 1968;18:560–564.[Medline] [Order article via Infotrieve]
    
23. Stehbens WE. The epidemiological relationship of hypercholesterolemia, hypertension, diabetes mellitus and obesity to coronary heart disease and atherogenesis. J Clin Epidemiol. 1990;43:733–741.[Medline] [Order article via Infotrieve]
    
24. Loree HM, Tobias BJ, Gibson LJ, et al. Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thromb. 1994;14:230–234.[Abstract/Free Full Text]
    
25. Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med. 1998;129:1050–1060.[Abstract/Free Full Text]
    
26. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850.[Free Full Text]
    
27. Falk E. Why do plaques rupture? Circulation. 1992;86(suppl III):III-30–III-42.
    
28. Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994;90:775–778.[Abstract/Free Full Text]
    
29. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276–1282.[Abstract/Free Full Text]
    
30. Burke AP, Farb A, Malcom GT, et al. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA. 1999;281:921–926.[Abstract/Free Full Text]
    
31. Garber AM, Browner WS, Hulley SB. Clinical guideline, part 2: cholesterol screening in asymptomatic adults, revisited. Ann Intern Med. 1996;124:518–531.[Abstract/Free Full Text]
    
32. Hulley SB, Newman TB, Grady D, et al. Should we be measuring blood cholesterol levels in young adults? JAMA. 1993;269:1416–1419.[Abstract]
    
33. American College of Physicians. Clinical guideline, part 1: guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults. Ann Intern Med. 1996;124:515–517.[Abstract/Free Full Text]
    
34. LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Circulation. 1990;81:1721–1733.[Free Full Text]
    
35. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol. 1985;5(suppl 6):141B–149B.
    
36. Traven ND, Kuller LH, Ives DG, et al. Coronary heart disease mortality and sudden death: trends and patterns in 35- to 44-year-old white males, 1970–1990. Am J Epidemiol. 1995;142:45–52.[Abstract/Free Full Text]
    
37. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]
    
38. Berenson GS, Srinivasan SR, Nicklas TA, et al. Cardiovascular risk factors in children and early prevention of heart disease. Clin Chem. 1988;34(suppl):B115–B122.
    
39. Lauer RM, Connor WE, Leaverton PE, et al. Coronary heart disease risk factors in school children: the Muscatine study. J Pediatr. 1975;86:697–706.[Medline] [Order article via Infotrieve]
    
40. Van Horn L, Greenland P. Prevention of coronary artery disease is a pediatric problem. JAMA. 1997;278:1779–1780.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				J. A Nettleton, M. B Schulze, R. Jiang, N. S Jenny, G. L Burke, and D. R Jacobs Jr A priori-defined dietary patterns and markers of cardiovascular disease risk in the Multi-Ethnic Study of Atherosclerosis (MESA) Am. J. Clinical Nutrition, July 1, 2008; 88(1): 185 - 194. [Abstract] [Full Text] [PDF]

				A. Moran, D. R. Jacobs Jr, J. Steinberger, L. M. Steffen, J. S. Pankow, C.-P. Hong, and A. R. Sinaiko Changes in Insulin Resistance and Cardiovascular Risk During Adolescence: Establishment of Differential Risk in Males and Females Circulation, May 6, 2008; 117(18): 2361 - 2368. [Abstract] [Full Text] [PDF]

				H. C. McGill Jr, C. A. McMahan, and S. S. Gidding Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study Circulation, March 4, 2008; 117(9): 1216 - 1227. [Full Text] [PDF]

				S. S. Gidding, C. A. McMahan, H. C. McGill, L. A. Colangelo, P. J. Schreiner, O. D. Williams, and K. Liu Prediction of Coronary Artery Calcium in Young Adults Using the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Risk Score: The CARDIA Study Arch Intern Med, November 27, 2006; 166(21): 2341 - 2347. [Abstract] [Full Text] [PDF]

				C. A. McMahan, S. S. Gidding, G. T. Malcom, R. E. Tracy, J. P. Strong, H. C. McGill Jr, and for the Pathobiological Determinants of Atheroscle Pathobiological Determinants of Atherosclerosis in Youth Risk Scores Are Associated With Early and Advanced Atherosclerosis Pediatrics, October 1, 2006; 118(4): 1447 - 1455. [Abstract] [Full Text] [PDF]

				M Egred, G Viswanathan, and G K Davis Myocardial infarction in young adults Postgrad. Med. J., December 1, 2005; 81(962): 741 - 745. [Abstract] [Full Text] [PDF]

				A. W. Zieske, R. P. Tracy, C. A. McMahan, E. E. Herderick, S. Homma, G. T. Malcom, H. C. McGill Jr, J. P. Strong, and for the Pathobiological Determinants of Atheroscle Elevated Serum C-Reactive Protein Levels and Advanced Atherosclerosis in Youth Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1237 - 1243. [Abstract] [Full Text] [PDF]

				C. A. McMahan, S. S. Gidding, Z. A. Fayad, A. W. Zieske, G. T. Malcom, R. E. Tracy, J. P. Strong, H. C. McGill Jr, and for the Pathobiological Determinants of Atheroscle Risk Scores Predict Atherosclerotic Lesions in Young People Arch Intern Med, April 25, 2005; 165(8): 883 - 890. [Abstract] [Full Text] [PDF]

				H. C. McGill Jr and C. A. McMahan Starting Earlier to Prevent Heart Disease JAMA, November 5, 2003; 290(17): 2320 - 2322. [Full Text] [PDF]

				M. W. Massing, K. A. Foley, C. A. Sueta, M. Chowdhury, D. P. Biggs, C. M. Alexander, and R. J. Simpson Jr. Trends in Lipid Management Among Patients With Coronary Artery Disease: Has diabetes received the attention it deserves? Diabetes Care, April 1, 2003; 26(4): 991 - 997. [Abstract] [Full Text] [PDF]

				V. Biton, P. Levisohn, S. Hoyler, A. Vuong, and A. E. Hammer Lamotrigine Versus Valproate Monotherapy--Associated Weight Change in Adolescents With Epilepsy: Results From a Post Hoc Analysis of a Randomized, Double-Blind Clinical Trial J Child Neurol, February 1, 2003; 18(2): 133 - 139. [Abstract] [PDF]

				H. S. Starkman, G. Cable, V. Hala, H. Hecht, and C. M. Donnelly Delineation of Prevalence and Risk Factors for Early Coronary Artery Disease by Electron Beam Computed Tomography in Young Adults With Type 1 Diabetes Diabetes Care, February 1, 2003; 26(2): 433 - 436. [Abstract] [Full Text] [PDF]

				S. de Jongh, M. R. Lilien, J. op't Roodt, E. S. G. Stroes, H. D. Bakker, and J. J. P. Kastelein Early statin therapy restores endothelial function in children with familial hypercholesterolemia J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2117 - 2121. [Abstract] [Full Text] [PDF]

				S. de Jongh, L. Ose, T. Szamosi, C. Gagne, M. Lambert, R. Scott, P. Perron, D. Dobbelaere, M. Saborio, M. B. Tuohy, et al. Efficacy and Safety of Statin Therapy in Children With Familial Hypercholesterolemia: A Randomized, Double-Blind, Placebo-Controlled Trial With Simvastatin Circulation, October 22, 2002; 106(17): 2231 - 2237. [Abstract] [Full Text] [PDF]

				J. B. Meigs, M. G. Larson, R. B. D'Agostino, D. Levy, M. E. Clouse, D. M. Nathan, P. W. F. Wilson, and C. J. O'Donnell Coronary Artery Calcification in Type 2 Diabetes and Insulin Resistance: The Framingham Offspring Study Diabetes Care, August 1, 2002; 25(8): 1313 - 1319. [Abstract] [Full Text] [PDF]

				O. A Matvienko, D. S Lewis, M. Swanson, B. Arndt, D. L Rainwater, J. Stewart, and D L. Alekel A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men Am. J. Clinical Nutrition, July 1, 2002; 76(1): 57 - 64. [Abstract] [Full Text] [PDF]

				H. C. McGill Jr, C. A. McMahan, E. E. Herderick, A. W. Zieske, G. T. Malcom, R. E. Tracy, J. P. Strong, and for the Pathobiological Determinants of Atheroscle Obesity Accelerates the Progression of Coronary Atherosclerosis in Young Men Circulation, June 11, 2002; 105(23): 2712 - 2718. [Abstract] [Full Text] [PDF]

				K. Miura, H. Nakagawa, and P. Greenland Invited Commentary: Height-Cardiovascular Disease Relation: Where to Go from Here? Am. J. Epidemiol., April 15, 2002; 155(8): 688 - 689. [Full Text] [PDF]

				R. A. Kreisberg and A. Oberman Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 423 - 437. [Full Text] [PDF]

				K. O. Akosah, R. M. Cerniglia, P. Havlik, and A. Schaper Myocardial Infarction in Young Adults With Low-Density Lipoprotein Cholesterol Levels <= 100 mg/dL : Clinical Profile and 1-Year Outcomes Chest, December 1, 2001; 120(6): 1953 - 1958. [Abstract] [Full Text] [PDF]

				A. D Timmis Diabetes: Relationship to ischaemic heart disease Br. Med. Bull., October 1, 2001; 59(1): 159 - 172. [Abstract] [Full Text] [PDF]

				W. H. Briggs, J. D. Folts, H. E. Osman, and I. L. Goldman Administration of Raw Onion Inhibits Platelet-Mediated Thrombosis in Dogs J. Nutr., October 1, 2001; 131(10): 2619 - 2622. [Abstract] [Full Text] [PDF]

R. M. Robertson Women and Ca