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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:95-106

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:95-106.)
© 1997 American Heart Association, Inc.

Articles

Effects of Serum Lipoproteins and Smoking on Atherosclerosis in Young Men and Women

Henry C. McGill, Jr; C. Alex McMahan; Gray T. Malcom; Margaret C. Oalmann; Jack P. Strong; for the PDAY Research Group

the Southwest Foundation for Biomedical Research, San Antonio, Tex (H.C.M.); the University of Texas Health Science Center, San Antonio (H.C.M., C.A.M.); and Louisiana State University Medical Center, New Orleans (G.T.M., M.C.O., J.P.S.).

Correspondence to Henry C. McGill, Jr, MD, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail hmcgill@icarus.sfbr.org.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowAppendix
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Atherosclerosis begins in childhood and progresses from fatty streaks to raised lesions in adolescence and young adulthood. A cooperative multicenter study (Pathobiological Determinants of Atherosclerosis in Youth [PDAY]) examined the relation of risk factors for adult coronary heart disease to atherosclerosis in 1079 men and 364 women 15 through 34 years of age, both black and white, who died of external causes and were autopsied in forensic laboratories. We quantitated atherosclerosis of the aorta and right coronary artery as the extent of intimal surface involved by fatty streaks and raised lesions and analyzed postmortem serum for lipoprotein cholesterol and thiocyanate (as an indicator of smoking). The extent of intimal surface involved with both fatty streaks and raised lesions increased with age in all arterial segments of all sex and race groups. Women had a greater extent of fatty streaks in the abdominal aorta than men, but women and men had about an equal extent of raised lesions. Women and men had a comparable extent of fatty streaks in the right coronary artery, but women had about half the extent of raised lesions. Blacks had a greater extent of fatty streaks than whites, but blacks and whites had a similar extent of raised lesions. VLDL plus LDL cholesterol concentration was associated positively and HDL cholesterol was associated negatively with the extent of fatty streaks and raised lesions in the aorta and right coronary artery. Smoking was associated with more extensive fatty streaks and raised lesions in the abdominal aorta. All three risk factors affected atherosclerosis to about the same degree in both sexes and both races. Primary prevention of atherosclerosis by controlling these adult coronary heart disease risk factors is applicable to young men and women and to young blacks and whites.


Key Words: atherosclerosis • youth • lipoproteins • smoking • sex • race


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowAppendix
down arrowReferences
 
Atherosclerosis begins in childhood with deposits of cholesterol and its esters in arterial intimal macrophages and smooth muscle cells to form lesions known as fatty streaks.1 2 3 In young adulthood, some fatty streaks are converted into raised lesions by the continued accumulation of intracellular and extracellular lipid and the formation of a fibromuscular intimal cap.4 5 6 7 As individuals enter middle age, raised lesions increase in size by continued accumulation of lipid and become susceptible to rupture of the fibromuscular cap and overlying endothelium, an event leading to occlusive thrombosis and ischemic injury to the heart, brain, or extremity.8 9

Epidemiological studies identified a number of conditions, commonly known as "risk factors," that predicted the probability that an individual would develop one of the clinical manifestations of atherosclerosis.10 Risk factors also are associated with preclinical atherosclerotic lesions in middle-aged and older adults.11 Control of risk factors by changes in lifestyle or by drugs has become the major strategy for primary and secondary prevention of coronary heart disease.12

Whether primary prevention of adult coronary heart disease should begin in youth has been controversial because the influence of the risk factors on atherosclerosis in its early stages was not known. Plasma cholesterol levels, lipoprotein profiles, blood pressures, and smoking vary among children and adolescents, although within lower ranges than among adults.13 Plasma cholesterol concentrations measured during life were associated with fatty streaks in a few adolescents and young adults.14

The 10-year lag in coronary heart disease death rates among women compared with men15 also has raised doubts about whether risk factor control should apply to young women as well as to young men. However, coronary heart disease is the most frequent cause of death in women,15 and the effects of risk factors on coronary heart disease in adult women are generally similar to those in men.16

In 1985, investigators organized a multicenter cooperative study (Pathobiological Determinants of Atherosclerosis in Youth [PDAY]) of the relation of cardiovascular risk factors to atherosclerosis in accident, homicide, and suicide victims who were 15 through 34 years of age. A preliminary report showed that lipoprotein cholesterol levels and smoking affected atherosclerosis in 390 black and white men.17 Completion of the collection phase of the study in 1994 provided a larger number of men and a substantial number of women for analysis. The results confirm and extend the previous observations in men and show that the risk factors also affect atherosclerosis in young women.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowAppendix
down arrowReferences
 
Study Design
Fifteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and information and to submit them to central laboratories for analysis. A statistical coordinating center received all data pertaining to each case from the collection centers and central laboratories.

Subjects
Study subjects were persons 15 through 34 years of age who died of external causes (accidents, homicides, or suicides) within 72 hours after injury and were autopsied within 48 hours after death in one of the cooperating forensic laboratories. Age and race were obtained from death certificates. Persons of races other than black or white and those with congenital heart disease, Down's syndrome, the acquired immunodeficiency syndrome, or hepatitis were excluded. We collected 3210 subjects from June 1, 1987, through August 31, 1994. Of these, 334 did not meet the study criteria. Of the 2876 accepted subjects, 1506 had measurements of VLDL plus LDL cholesterol (VLDL+LDL-C), HDL cholesterol (HDL-C), and thiocyanate that met study criteria. Because we previously showed a strong association of lesions with elevated glycohemoglobin (>=8%),18 we did not include 4 subjects with missing glycohemoglobin and 59 with glycohemoglobin >=8%. The remaining 1443 subjects were used in this analysis. The Institutional Review Board of each participating center approved the use of tissue, blood, and data from the human subjects in this study.

Distribution of Subjects by Cause of Death
Overall, about 1/3 of the subjects died of accidents; 1/2, of homicide; and 1/10th, of suicide. Among white men, accidents accounted for about 1/2 the deaths, while among black men and women, homicide accounted for about 3/4 of the deaths. Suicide was the cause of death in about 1/7th of the white men and women but in only about 1/20th of the black men and women. Analyses of lesions, risk factors, and cause of death category showed that the associations of the lesions and risk factor variables were consistent across cause of death. Therefore, all cause of death categories were pooled for analysis of race, sex, and risk factor effects.

Dissection and Preservation of Arteries
The pathologist removed the aorta from a point 2 cm proximal to the ligamentum arteriosum to a point 2 cm distal from the iliac bifurcation. Branching arteries were severed close to the aortic wall, and adventitial fat was removed by sharp dissection. The PDAY technician opened the aorta along a line on the dorsal surface midway between the orifices of the intercostal and lumbar arteries, rinsed the intimal surface with Hank's modified balanced salt solution, and flattened it with the adventitial surface downward. The PDAY technician then split the aorta longitudinally along a line on the ventral surface that bisected the celiac, superior mesenteric, and inferior mesenteric ostia; prepared the right half for other studies, including histochemical and chemical analyses; and placed the left half on cardboard with the adventitia downward. The left half was covered with absorbent cotton and fixed in 10% neutral buffered formalin in a flat pan for 48 hours.

The PDAY technician opened the right coronary artery along the epicardial surface from its origin to the point at which it turned downward along the posterior interventricular sulcus with blunt-point microdissecting scissors, dissected it from the heart, removed the epicardial fat, rinsed the intimal surface with Hank's modified balanced salt solution, and fixed it in the same manner as the aorta. The other main branches of the coronary arteries were prepared for other studies.

The collection centers placed each aorta and coronary artery in a plastic bag with 10% formalin and shipped accumulated tissues to the central laboratory each month. The central laboratory stained the arteries with Sudan IV and packaged each artery with its identification number in a transparent plastic bag with a slight excess of 10% formalin.19

Grading Arterial Specimens
Pathologists, blinded to demographic, clinical, and pathological observations, evaluated the right coronary arteries and left halves of the aortas. They visually estimated the extent of intimal surface involved with fatty streaks, fibrous plaques, complicated lesions, and calcified lesions by procedures developed in the International Atherosclerosis Project.19 A fatty streak was a flat or slightly elevated intimal lesion stained by Sudan IV and without other underlying changes. A fibrous plaque was a firm, elevated, intimal lesion, sometimes partially or completely covered by sudanophilic deposits. A complicated lesion was a plaque with hemorrhage, thrombosis, or ulceration. A calcified lesion was an area in which calcium was detectable, either visually or by palpation, without overlying hemorrhage, ulceration, or thrombus. The sum of the percentages of surface involved with fibrous plaques, complicated lesions, and calcified lesions by gross visual grading was designated "raised lesions." Raised lesions were predominantly fibrous plaques. Consensus grading of lesions was the average of independent gradings by three pathologists. Intraobserver variability was assessed by repeated independent gradings of coded specimens randomly interspersed among new specimens.

For percent intimal surface area involved with fatty streaks, the intraclass correlation coefficients among the grades of the three pathologists were .81 for the thoracic aorta, .78 for the abdominal aorta, and .83 for the right coronary artery. For percent intimal surface area involved with raised lesions, the intraclass correlation coefficients among the grades of the three pathologists were .63 for the thoracic aorta, .74 for the abdominal aorta, and .80 for the right coronary artery.

Blood
Blood collected at autopsy from the aorta, heart, or vena cava was centrifuged. Frozen serum and cells were shipped to the central laboratory for analyses.

Lipoprotein Cholesterol
We measured serum cholesterol and HDL-C after precipitation of other lipoproteins with heparin MnCl2 by the cholesterol oxidase method.20 The coefficient of variation for blind duplicate analyses of serum cholesterol was 1.3%; for HDL-C, 5.2%. The non–HDL-C concentration, or the VLDL+LDL-C concentration, was obtained by subtraction. Several studies have demonstrated that postmortem levels of serum cholesterol and lipoproteins were representative of premortem levels.21 22 23 24 However, because emergency medical teams often administer large quantities of intravenous fluids to some individuals immediately before death from violent causes, we excluded all serum values from the statistical analysis when serum cholesterol was <2.59 mmol/L (100 mg/dL).

Thiocyanate
We measured color produced by the thiocyanate–ferric nitrate complex after treatment of trichloroacetic acid filtrates of serum with ferric nitrate.25 The coefficient of variation for blind duplicate analyses was 5.5%. A smoker was defined as having a serum thiocyanate level >=90 µmol/L.

Statistical Analysis
We analyzed associations of sex, race, 5-year age group, VLDL+LDL-C, HDL-C, and smoking status with percent arterial intimal surface involved with lesions by multiple linear regression analysis.26 The linear model included main effects and two-factor interactions. We applied a logit transformation to the proportion of surface area involved with lesions.27 A small constant (0.001) was added to avoid the logarithm of zero. We applied a logarithmic transformation to the serum lipoprotein concentrations. The prevalence of smoking and the prevalence of having raised lesions were analyzed by use of logistic regression.28 Tests of hypotheses used the likelihood ratio test. For simplicity and clarity, we present selected results in 10-year age groups and by lowest, middle, and highest thirds of VLDL+LDL-C and HDL-C concentrations.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
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 down arrowAppendix
down arrowReferences
 
Serum and Lipoprotein Cholesterol Concentrations
Table 1Down shows the mean total serum cholesterol and lipoprotein cholesterol concentrations. Women have slightly higher HDL-C levels than men (P=.0701). Whites have higher total serum cholesterol (P=.0081) and VLDL+LDL-C (P=.0001) levels than blacks; but blacks have higher HDL-C levels (P=.0006). Total serum cholesterol increases with age, and the increase is greater for whites than for blacks (race-by-age interaction, P=.0229). VLDL+LDL-C (P=.0016) and HDL-C (P=.0052) increase with age.


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  		Table 1. Serum Lipid and Lipoprotein Concentrations by Sex, Race, and Age

Smoking Prevalence
About half the subjects older than 20 years of age are smokers as indicated by serum thiocyanate concentration, and the prevalence of smoking in both races and both sexes approaches 60% in the 30-to-34-year age group (Table 1Up). Smoking prevalence is lower in men than in women 15 to 19 years of age, greater in men than in women 20 to 24 years of age, and about equal in men and women 25 to 34 years of age (sex-by-age interaction, P=.0200).

Age, Sex, and Race Effects on Atherosclerosis
Table 2Down shows the extent of fatty streaks and raised lesions by 5-year age groups, race, and sex. These values are adjusted for VLDL+LDL-C concentration, HDL-C concentration, and smoking and show the effects of sex and race independent of any sex or race differential in lipoprotein cholesterol levels or smoking prevalence.


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  		Table 2. Percent Intimal Surface Area Involved With Lesions by Sex, Race, and Age Adjusted for VLDL+LDL Cholesterol, HDL Cholesterol, and Smoking Status

In the thoracic aorta, fatty streaks (P=.0146) and raised lesions (P=.0001) increase with age in all sex and race groups. Blacks have more extensive fatty streaks than whites (P=.0001) and more extensive raised lesions (P=.0670).

In the abdominal aorta, women have more extensive fatty streaks than men (P=.0001), and the excess of lesions in women becomes greater with increasing age (sex-by-age interaction, P=.0135). Raised lesions increase in extent sixfold to ninefold from the 15-to-19-year age group to the 30-to-34-year age group (P=.0001). White women have more extensive raised lesions than white men, but black women have less extensive raised lesions than black men (sex-by-race interaction, P=.0526).

Lesions in the right coronary artery present a pattern different from that in the aorta. The extent of fatty streaks increases about threefold to fourfold from the 15-to-19-year age group to the 30-to-34-year age group (P=.0001); there is no sex difference; and blacks have more extensive fatty streaks than whites (P=.0001). The extent of raised lesions increases about threefold from the youngest to the oldest age group (P=.0001); there is no race difference; and raised lesions are more extensive in men than in women (P=.0001).

Because raised lesions in the thoracic aorta are minimal, risk factor effects in the thoracic aorta are almost exclusively on fatty streaks, and atherosclerotic lesions in the thoracic aorta rarely cause clinical disease, we focused subsequent comparisons of the effects of risk factors by sex and race on the abdominal aorta and the right coronary artery. To show the effects of the risk factors between the sexes, we present values for men and women after adjusting for race, and to show the effects of risk factors between the two races, we present values for blacks and whites after adjusting for sex.

Sex Effects
Fig 1Down compares lesions between men and women in 5-year age groups after adjustment for race, VLDL+LDL-C and HDL-C levels, and smoking. In the abdominal aorta, women have more extensive fatty streaks than men (Fig 1ADown; P=.0001), and the difference between men and women changes with age (sex-by-age interaction, P=.0135). Men and women have a nearly equal extent of raised lesions in the abdominal aorta (Fig 1BDown). In contrast, in the coronary artery, men and women have a similar extent of fatty streaks (Fig 1CDown), but men have more extensive raised lesions than women (Fig 1DDown; P=.0001). Men have an almost twofold greater involvement with raised lesions than women in the 30-to-34-year age group. Women lag behind men in the development of raised lesions by about 5 years.



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  		Figure 1. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) in men ({square}) and women ({blacksquare}) by 5-year age groups. All values are adjusted for race, VLDL+LDL cholesterol and HDL cholesterol concentrations, and smoking. In the abdominal aorta, women have more extensive fatty streaks than men but equally extensive raised lesions. In contrast, in the right coronary artery, women have equally extensive fatty streaks but less raised lesions. Standard error ({top}) is indicated.

VLDL+LDL-C Effects by Sex
Fig 2Down compares the extent of lesions by thirds of VLDL+LDL-C concentration (low, <2.79 mmol/L [108 mg/dL]; medium, 2.79 to 3.88 mmol/L [108 to 150 mg/dL]; and high, >3.88 mmol/L [150 mg/dL]), sex, and 10-year age groups. VLDL+LDL-C affects fatty streaks in both the abdominal aorta and the right coronary artery (Fig 2A and 2CDownDown; P=.0001) and raised lesions (Fig 2B and 2DDownDown) in the abdominal aorta (P=.0456) and right coronary artery (P=.0417). Although women have more extensive fatty streaks than men in the abdominal aorta, the increase attributable to VLDL+LDL-C is greater for men than for women (sex-by–VLDL+LDL-C interaction, P=.0319). VLDL+LDL-C affects raised lesions in both arteries to about the same degree in men and women (sex-by–VLDL+LDL-C interactions, P=.6171 and P=.2095). VLDL+LDL-C affects fatty streaks in both arteries more in the older age groups than in the younger age groups (age-by–VLDL+LDL-C interactions, P<.0055). VLDL+LDL-C also affects raised lesions more in the older age groups (age-by–VLDL+LDL-C interactions, P=.0064 and P=.0767 for the abdominal aorta and right coronary artery, respectively).



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  		Figure 2. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of men ({square}) and women ({blacksquare}) by 10-year age groups and thirds of VLDL+LDL cholesterol (VLDL+LDL-C) concentration (low, <2.79 mmol/L [108 mg/dL]; medium, 2.79 to 3.88 mmol/L [108 to 150 mg/dL]; and high, >3.88 mmol/L [150 mg/dL]). All values are adjusted for race, HDL cholesterol (HDL-C), and smoking. Sex differences are similar to those displayed in Fig 1Up. Effect of VLDL+LDL-C is similar in men and women. Standard error ({top}) is indicated.

HDL-C Effects by Sex
A similar analysis of HDL-C and lesions (Fig 3Down) shows that the HDL-C level (low, <1.11 mmol/L [43 mg/dL]; medium, 1.11 to 1.55 mmol/L [43 to 60 mg/dL]; and high, >1.55 mmol/L [60 mg/dL]) is negatively associated with fatty streaks in both arteries (Fig 3A and 3CDownDown; P=.0001 and P=.0015 for the abdominal aorta and right coronary artery, respectively). The negative association of HDL-C with fatty streaks in the abdominal aorta is stronger in the older age groups (Fig 3ADown; age-by–HDL-C interaction, P=.0022). The effect on fatty streaks and raised lesions is about the same in both sexes (no sex-by–HDL-C interaction). There is a negative association of HDL-C with raised lesions in the right coronary artery of the older age groups (age-by–HDL-C interaction, P=.0066).



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  		Figure 3. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of men ({square}) and women ({blacksquare}) by 10-year age groups and thirds of HDL cholesterol (HDL-C) concentration (low, <1.11 mmol/L [43 mg/dL]; medium, 1.11 to 1.55 mmol/L [43 to 60 mg/dL]; and high, >1.55 mmol/L [60 mg/dL]). All values are adjusted for race, VLDL+LDL cholesterol, and smoking. Sex differences are similar to those displayed in Fig 1Up. Effect of HDL-C on lesions is similar in men and women. Standard error ({top}) is indicated.

Smoking Effects by Sex
Smoking affects both fatty streaks (P=.0046) and raised lesions (P=.0001) in the abdominal aorta (Fig 4A and 4BDownDown). The effect on raised lesions is present to a small degree in the 15-to-24-year age group but is particularly strong (twofold to threefold) in the 25-to-34-year age group (age-by-smoking interaction, P=.0001). The effect is similar in men and women. There is no effect of smoking on the extent of either fatty streaks or raised lesions in the right coronary artery (Fig 4C and 4DDownDown).



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  		Figure 4. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of men ({square}) and women ({blacksquare}) by 10-year age groups and nonsmoking (N) or smoking (S). All values are adjusted for race, VLDL+LDL cholesterol, and HDL cholesterol. Sex differences are similar to those displayed in Fig 1Up. Effect of smoking on lesions is similar in men and women. Standard error ({top}) is indicated.

Risk Level Effects by Sex
Fig 5Down compares the combined effects of the three risk factors on lesions between men and women. The low risk level is defined as the lowest third of VLDL+LDL-C, the highest third of HDL-C, and no smoking; the high risk level is defined as the highest third of VLDL+LDL-C, lowest third of HDL-C, and smoking. Low and high risk levels have similar effects on the extent of both types of lesions in men and women. As noted previously, however, women lag behind men in the development of raised lesions in the right coronary artery (Fig 5DDown).



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  		Figure 5. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of men ({square}) and women ({blacksquare}) by 10-year age groups and risk level. "Low" risk is defined as lowest third of VLDL+LDL cholesterol (VLDL+LDL-C), highest third of HDL cholesterol (HDL-C), and nonsmoking. "High" risk is defined as the highest third of VLDL+LDL-C, lowest third of HDL-C, and smoking. All values are adjusted for race. Effects of the combined risk factors are similar in men and women. Standard error ({top}) is indicated.

Race Effects
Blacks have more extensive fatty streaks than whites in both the abdominal aorta and the right coronary artery (Fig 6Down; P=.0001). Blacks and whites have similar extents of raised lesions and similar associations of lesions with age (no race-by-age interaction).



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  		Figure 6. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of whites ({square}) and blacks ({blacksquare}) by 5-year age groups. All values are adjusted for sex, VLDL+LDL cholesterol, HDL cholesterol, and smoking. Blacks have more extensive aortic and coronary artery fatty streaks than whites but have about equally extensive raised lesions. Standard error ({top}) is indicated.

VLDL+LDL-C Effects by Race
The associations of lesions with VLDL+LDL-C are similar among blacks and whites (no race-by–VLDL+LDL-C interaction; results not shown).

HDL-C Effects by Race
The associations of lesions with HDL-C are similar among whites and blacks (no race-by–HDL-C interaction) except for the hint of a slightly stronger negative association with abdominal aortic fatty streaks in whites (race-by–HDL-C interaction, P=.0824; results not shown).

Smoking Effects by Race
The associations of lesions with smoking status are similar among blacks and whites (no race-by-smoking interaction) except for a stronger effect of smoking on abdominal aortic fatty streaks in whites (race-by-smoking interaction, P=.0439; results not shown).

Risk Level Effects by Race
The two risk levels, defined as in Fig 5Up, affect lesions similarly in blacks and whites (Fig 7Down).



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  		Figure 7. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of whites ({square}) and blacks ({blacksquare}) by 10-year age groups and risk level as defined in Fig 5Up. All values are adjusted for sex. Effects of the combined risk factors are similar in whites and blacks. Standard error ({top}) is indicated.

Risk Level Effects by Age
Fig 8Down shows the effects of the two risk levels, defined as in Fig 5Up, in all subjects by 5-year age groups adjusted for race and sex. There is little or no increase in lesions with age at the low risk level before 30 years of age. An excess of aortic and coronary fatty streaks associated with the high risk level begins in the 15-to-19-year age group and becomes greater in successive age groups (except for aortic fatty streaks, which are replaced by raised lesions in the 30-to-34-year group). An excess of raised lesions associated with the high risk level emerges in the 25-to-29-year age group and becomes substantial in the 30-to-34-year age group.



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  		Figure 8. Extent of fatty streaks and raised lesions in the abdominal aorta (A and B) and right coronary artery (C and D) of all subjects by 5-year age groups and low ({square}) and high ({blacksquare}) risk levels as defined in Fig 5Up. All values are adjusted for race and sex. The difference in fatty streaks begins in the 15-to-19-year age group; the difference in raised lesions begins in the 25-to-29-year age group. Standard error ({top}) is indicated.

Risk Level Effects on Raised Lesion Prevalence
The prevalence of raised lesions of any extent (ie, any value greater than zero) in both the abdominal aorta and right coronary artery increases with age (P=.0001). The prevalence of raised lesions in the right coronary artery is greater in men than in women (P=.0001). There is no difference in prevalence between the two races. VLDL+LDL-C is positively associated with prevalence in both the abdominal aorta (P=.0137) and the right coronary artery (P=.0036). The negative association of HDL-C with prevalence in the right coronary artery is greater in the older age groups (age-by–HDL-C interaction, P=.0194). In the abdominal aorta, smoking is associated with prevalence in all age groups (P=.0001), and the effect becomes larger with increasing age (age-by-smoking interaction, P=.0388). In the right coronary artery, there is no significant effect of smoking on the prevalence of raised lesions of any extent greater than zero; however, male smokers have a greater prevalence of raised lesions involving 5% or more of the intimal surface than male nonsmokers (P=.0356; results not shown).

Fig 9Down compares the prevalence of raised lesions in the abdominal aorta (Fig 9ADown) and right coronary artery (Fig 9BDown) by risk level as defined in Fig 5 and 5UpUp-year age groups. The prevalence of raised lesions in both arteries at the low risk level lags about 5 years behind the prevalence at the high risk level.



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  		Figure 9. Prevalence of raised lesions in the abdominal aorta (A) and right coronary artery (B) by 5-year age groups and risk level as defined in Fig 5Up. All values are adjusted for sex and race. Effect of the combined risk factors on raised lesions in the abdominal aorta begins in the 15-to-19-year age group; on raised lesions in the right coronary artery, in the 20-to-24-year age group. Standard error ({top}) is indicated.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowAppendix
down arrowReferences
 
Summary of Results
In the abdominal aorta, young women have more extensive fatty streaks than men but the same extent of raised lesions. In the right coronary artery, young women have the same extent of fatty streaks as men but much less extensive raised lesions. Young blacks have more extensive fatty streaks in both the abdominal aorta and right coronary artery than whites but the same extent of raised lesions. VLDL+LDL-C concentration is associated positively with both fatty streaks and raised lesions in the abdominal aorta and right coronary artery; HDL-C concentration is associated negatively with lesions in both arteries; and smoking is associated positively with fatty streaks and raised lesions in the abdominal aorta. The effects of VLDL+LDL-C and HDL-C concentrations and smoking are similar in men and women and are similar in blacks and whites. Race and sex differences in atherosclerotic lesions are not explained by differences in lipoprotein cholesterol levels or smoking.

Comparison of Lipid and Lipoprotein Concentrations With Those From Living Populations
We compared the total serum cholesterol levels shown in Table 1Up with those for comparable age, sex, and race groups reported from the Lipid Research Clinics Prevalence Study,29 the Coronary Artery Risk Development in Young Adults study,30 the National Health and Nutrition Examination Survey,31 and the Johns Hopkins Precursors Study.32 Total serum cholesterol in the PDAY subjects ranged from 7% lower to 12% higher than the levels reported for those groups. Among most groups for which HDL-C values were available, the levels for PDAY subjects were nearly identical; the only exception was that in the National Health and Nutrition Examination Survey, 20- to-34-year-old black and white men combined had HDL-C levels 13% lower than PDAY subjects. In view of the variations in time ({approx}20 years), location, numbers of subjects, inability to obtain fasting blood samples from PDAY subjects, and the potential effects of hemodilution or hemoconcentration after traumatic injuries, we consider values from PDAY subjects to be remarkably similar to those reported from surveys of living persons.

Smoking Prevalence
About half the PDAY subjects over 20 years of age are smokers, as indicated by serum thiocyanate concentration (Table 1Up), and the prevalence approaches 60% in both races and both sexes in the 30-to-34-year age group. This figure is {approx}50% higher than the prevalence reported in some surveys that depended on self-reported cigarette smoking33 but is only slightly higher than figures reported in other surveys.34 Reasons for a higher prevalence in PDAY subjects include the association of smoking with deaths from accidents and suicides35 36 ; secular trends, because the rate of decrease of smoking among young persons was declining (and may have been rising in some groups) when these subjects were being collected37 ; and the higher estimates of prevalence derived from objective indicators of smoking compared with those derived from self-reported smoking status.38

Study Limitations
Inclusion of subjects in this study was influenced by decisions of the medical examiner or coroner regarding which deaths would be autopsied and which subjects could be entered into this study. This decision was influenced by resources, local laws, and circumstances surrounding the death. These subjects do not represent a random sample of the living population of 15- through 34-year-old persons, but they do represent a sample from which arterial tissues can be obtained for quantitative measurement of atherosclerosis and a sample not biased by natural causes of death. The proportions of homicides are slightly higher than, accidental deaths are slightly lower than and suicides are similar to proportions in 1991 national mortality statistics for black and white men and women.39 The associations of lesions with risk factors were consistent across cause of death categories. Therefore, despite the potentially biased nature of the sample, we conclude that the relation of risk factors to atherosclerotic lesions in this sample of autopsied subjects represents the relation that exists in the population of young persons.

Because of within-subject biological variation in the risk factor variables, the single measurements available for each subject in this study should reflect long-term averages less precisely than the multiple measurements that would be possible in living subjects. Hemodilution and hemoconcentration, which do not occur in all subjects, introduce additional variation. These variations in the risk factor variables are expected to reduce or degrade associations of serum lipoproteins and smoking with atherosclerosis.40 41 The estimates of associations of serum lipoproteins and smoking with atherosclerosis reported here are likely to be underestimates of the true associations.

Comparison With Previous Results
These results are similar to those reported previously from 390 men (subjects also included in this analysis).17 The results are also similar to those reported from the Bogalusa Heart Study.14 42 43 44 The Bogalusa Heart Study included a small number of women but not enough to permit analyses by sex. We know of no other studies of the relation of risk factors to atherosclerosis in young women.

Sex Effects
The lower incidence of coronary heart disease in premenopausal women compared with that in men of similar ages was one of the first observations about predictors of disease risk, but the sex differential remains poorly explained.45 The sex differential in raised lesions begins early in life in the coronary arteries; there is little or no sex differential in raised lesions of the abdominal aorta; and the sex differential is attenuated in nonwhite races.1 46 The present study is consistent with previous results and shows that differences in three of the major risk factors for adult coronary heart disease do not explain the sex differential in lesions (Table 2Up and Fig 1Up).

Risk Factor Effects by Sex
A possible explanation of the sex differential is that arteries of women and men may respond differently to the risk factors. Shurtleff47 showed that the independent contribution of each risk factor to coronary heart disease incidence in Framingham men and women was approximately the same, except that cigarette smoking had a greater effect on relative risk in men than in women. The results of the present study, displayed in Figs 2 through 5UpUpUpUp, show that VLDL+LDL-C and HDL-C levels and smoking affect both fatty streaks and raised lesions in both men and women. This observation indicates that risk factor reduction is likely to benefit women as well as men.

Excess of Fatty Streaks in Women
As previously reported, young women have more extensive aortic fatty streaks than men.46 48 This excess is not accounted for by differences in serum lipoprotein levels or smoking. VLDL+LDL-C has slightly less effect on abdominal aortic fatty streaks in women than in men. There is no sex-by–HDL-C or sex-by-smoking interaction for fatty streaks in either the abdominal aorta or the right coronary artery. This peculiar excess of fatty streaks in young women remains unexplained but is clearly related to conditions other than the lipoprotein profile or smoking.

Race Effects and Interactions
The results comparing lesions between races confirm and extend the observation, made many times before,1 46 48 49 that young blacks have more extensive aortic and coronary artery fatty streaks than young whites (Table 2Up and Fig 6Up). In a small number of subjects from the Bogalusa Heart Study, serum lipoproteins, blood pressure, and obesity did not account for the excess of fatty streaks in blacks compared with whites.50 The PDAY study adds a much larger number of subjects with lipoprotein measurements and shows that neither serum lipoproteins nor smoking accounts for the excess of fatty streaks in blacks. The excess of fatty streaks in blacks is not paralleled by a similar excess of raised lesions.

In a subset of PDAY subjects, a polymorphism in the apolipoprotein B gene (resulting in insertion or deletion of three amino acids in the 27–amino acid signal peptide) was associated with fatty streaks in blacks but not in whites.51 Other genetic differences between blacks and whites that account for the racial difference in susceptibility to fatty streaks are likely.

Secular Trend in Raised Lesions in Blacks
Despite the excess of fatty streaks in blacks, there is no difference between blacks and whites in raised lesions of the abdominal aorta or right coronary artery (Table 2Up and Fig 6Up). This finding differs from earlier results that showed less extensive raised lesions in blacks than in whites.1 46 48 The extent of raised lesions in the coronary arteries of young New Orleans white men decreased between 1960 through 1964 and 1968 through 1972, and the extent in blacks remained the same, so blacks and whites from the later period (1968 through 1972) had a similar extent of raised lesions.52 53 The present results indicate that this equalization in raised lesions between blacks and whites is not limited to the New Orleans population but has occurred in other areas of the United States.

Implications for Primary Prevention
The results of this study have implications for the age at which primary prevention of atherosclerosis by dietary modification should begin and whether primary prevention should apply to young women as well as to young men and to young blacks as well as to young whites.

Conservative groups (the "snails"54 ) conclude that measuring plasma cholesterol in children and adolescents and recommending fat-modified diets are inadvisable.55 56 57 58 59 60 61 This conclusion is based on imperfect tracking of plasma cholesterol; lack of evidence that control of plasma lipids retards progression of atherosclerosis in youth; the small effect of dietary modification on plasma lipids; impracticality of drug treatment for children; the long time before coronary heart disease actually occurs, particularly in women; and the rapid reduction in coronary heart disease risk by drug treatment of middle-aged hyperlipidemic subjects.

On the other hand, more aggressive groups (the "evangelists"54 ) recommend that plasma cholesterol should be measured in high-risk children and that all children older than 2 years of age should consume a diet low in total fat, saturated fat, and cholesterol62 63 64 65 similar to that recommended for adults.12 66 They note that atherosclerosis begins in childhood,1 48 that fat-modified diets lower LDL-C levels in 8- to 10-year-old children67 and lower plasma cholesterol levels in adolescent boys,68 and that plasma lipids are positively correlated with severity of adult atherosclerosis11 and clinically manifest coronary heart disease.69

A small number of subjects from the Bogalusa Heart Study14 and a larger number of subjects from the present PDAY study17 support the inference that plasma lipids in childhood and adolescence are associated with the extent and severity of atherosclerosis in children older than {approx}10 years of age and young men between 15 and 34 years of age. The results reported here show that serum lipoprotein levels, particularly the VLDL+LDL-C levels that are most susceptible to dietary fat and cholesterol intake, are associated with both fatty streaks and raised lesions in both the abdominal aorta and the right coronary artery and that these associations exist in both blacks and whites and in women as well as men.

There probably will never be a controlled clinical trial to determine whether controlling plasma cholesterol levels from childhood or adolescence will retard the onset and reduce the frequency of clinically manifest coronary heart disease in middle age, a level of proof required of most preventive regimens. However, the Johns Hopkins Precursors Study32 showed that the serum cholesterol level measured at 22 years of age predicted the risk of coronary heart disease up to 40 years later. The PDAY results suggest that the Johns Hopkins Study subjects who had high serum cholesterol levels at 22 years of age already had more extensive fatty streaks and raised lesions than those with low serum cholesterol levels.

The potential benefit of controlling VLDL+LDL-C levels among young adults is illustrated by Fig 2DUp. In 25- to 34-year-old men, raised lesions in the right coronary artery are about twice as extensive in those with VLDL+LDL-C levels in the highest third of the distribution as in those with VLDL+LDL-C levels in the lowest third. Men with VLDL+LDL-C levels in the lowest third have slightly more extensive coronary raised lesions than women with VLDL+LDL-C in the highest third. Between the ages of 49 and 82 years, the rate of coronary heart disease among men is about twice that among women,70 a relation that is approximately maintained over a wide range of LDL-C concentrations. If reducing VLDL+LDL-C levels among men to levels within the lowest third retards the rate at which raised lesions are formed to the rate experienced by young women, we can anticipate that the rate of coronary heart disease among men would be reduced to near the rate now experienced by women with VLDL+LDL-C in the upper part of the distribution. Retarding the rate at which raised lesions are formed in women would be expected to reduce their mortality from coronary heart disease below present levels.

The difference in extent of raised lesions between low- and high-risk groups (Fig 8B and 8DUpUp) begins to increase in subjects during the mid-20s, and the difference in prevalence (Fig 9Up) becomes apparent in the early 20s. Comparing the extent and prevalence of lesions by age for the low- and high-risk groups indicates that the low-risk group lags behind the high-risk group by about 5 years. Because the risk factors likely must be modified before the ages when these effects are observed, the findings suggest that risk factor modification should begin at least by the late teens.

These findings from the PDAY study strongly support modification of the risk factors in young people to retard the development of early atherosclerotic lesions, particularly raised lesions. We anticipate that risk factor modification would delay the development of lesions, an effect that in turn would delay correspondingly the onset of clinical coronary heart disease later in life.


*    Footnotes
 
Reprint requests to Jack. P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, 1901 Perdido St, New Orleans, LA 70112-1393. E-mail jstron@lsumc.edu.


*    Appendix
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 up arrowAbstract
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 *Appendix
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The PDAY Research Group
The investigators cooperating in the multicenter PDAY study are listed below.

Program Director: Jack P. Strong, MD, 1996 to date, and Robert W. Wissler, PhD, MD, 1985 through 1996.

Steering Committee: J. Fredrick Cornhill, DPhil; Henry C. McGill, Jr, MD; C. Alex McMahan, PhD; Gray T. Malcom, PhD; Margaret C. Oalmann, DrPH; and Jack P. Strong, MD.

Participating centers, principal and coinvestigators, and supporting grants from the National Heart, Lung, and Blood Institute: University of Alabama, Birmingham: Department of Medicine, Steffen Gay, MD (grant HL-33733), and Department of Biochemistry, Edward J. Miller, PhD (HL-33728); Albany (NY) Medical College: Assad Daoud, MD, and Adriene S. Frank, PhD (HL-33765); Baylor College of Medicine, Houston, Tex: Louis C. Smith, PhD (HL-33750); University of Chicago (Ill): Robert W. Wissler, PhD, MD; Dragoslava Vesselinovitch, DVM, MS; Akio Komatsu, MD, PhD; Yoshiaki Kusumi, MD; Toshinori Oinuma, MD; Alyna Chien, MA; Alexis Demopoulos, MD; Gertrud Friedman, BA; R. Timothy Bridenstine, MS; Robert J. Stein, MD; Robert H. Kirschner, MD; Manuela Bekermeier, ASCP; Blanche Berger, ASCP; and Laura Hiltscher, ASCP (HL-33740; HL-45715); University of Illinois, Chicago: Abel L. Robertson, Jr, MD, PhD; Robert J. Stein, MD; Edmund R. Donoghue, MD; Robert J. Buschmann, MD; and Yoshihisa Katsura, MD (HL-33758); Louisiana State University Medical Center, New Orleans: Jack P. Strong, MD; Gray T. Malcom, PhD; William P. Newman III, MD; Margaret C. Oalmann, DrPH; Richard E. Tracy, MD, PhD; Cynthia S. Zsembik, BS; DeAnne G. Gibbs, BS; and Dana A. Troxclair, MS (HL-33746 and HL-45720); University of Maryland, Baltimore: Wolfgang Mergner, MD, PhD; Catherine Cole, PhD; and J. Smialek, MD (HL-33752 and HL-45693); Medical College of Georgia, Augusta: A. Bleakley Chandler, MD; Raghunatha N. Rao, MD; D. Greer Falls, MD, Ross G. Gerrity, PhD; Benjamin O. Spurlock, BA; Kalish B. Sharma, MD; and Joel S. Sexton, MD (HL-33772); University of Nebraska Medical Center, Omaha: Bruce M. McManus, MD, PhD, and Jerry W. Jones, MD (HL-33778); Ohio State University, Columbus: J. Fredrick Cornhill, DPhil; William R. Adrion, MD; Patrick M. Fardel, MD; Brian Gara, MS; Edward Herderick, BS; and Larry R. Tate, MD (HL-33760 and HL-45694); Southwest Foundation for Biomedical Research, San Antonio, Tex: James E. Hixson, PhD (HL-39913); the University of Texas Health Science Center at San Antonio: C. Alex McMahan, PhD; Henry C. McGill, Jr, MD; Yolan Marinez, MA; and Thomas J. Prihoda, PhD (HL-33749 and HL-45719); Vanderbilt University, Nashville, Tenn: Renu Virmani, MD; James B. Atkinson, MD, PhD; and Charles W. Harlan, MD (HL-33770 and HL-45718); and West Virginia University Health Sciences Center, Morgantown: Singanallur N. Jagannathan, PhD, and James Frost, MD (HL-33748).

Received June 19, 1996; accepted July 11, 1996.


*    References
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*References
 

  1. Strong JP, McGill HC Jr. The natural history of coronary atherosclerosis. Am J Pathol. 1962;40:37-49.
  2. McGill HC Jr, Geer JC, Strong JP. Natural history of human atherosclerotic lesions. In: Sandler M, Bourne GH, eds. Atherosclerosis and Its Origin. New York, NY: Academic Press Inc; 1963:39-65.
  3. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 1989;9(suppl I):I-19-I-32.
  4. Robertson WB, Geer JC, Strong JP, McGill HC Jr. The fate of the fatty streak. Exp Mol Pathol. 1963;suppl 1:28-39.
  5. Geer JC, McGill HC Jr, Robertson WB, Strong JP. Histologic characteristics of coronary artery fatty streaks. Lab Invest. 1968;18:565-570.[Medline] [Order article via Infotrieve]
  6. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. 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]
  7. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld, ME, Schwartz CJ, Wagner WD, Wissler RW. 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]
  8. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.
  9. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242-250,310-318.[Medline] [Order article via Infotrieve]
  10. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chronic Dis. 1978;31:201-306.[Medline] [Order article via Infotrieve]
  11. Solberg LA, Strong JP. Risk factors and atherosclerotic lesions: a review of autopsy studies. Arteriosclerosis. 1983;3:187-198.[Abstract/Free Full Text]
  12. National Cholesterol Education Program, National Heart, Lung, and Blood Institute National Institutes of Health. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Bethesda, Md: US Department of Health and Human Services; 1993. NIH publication 93-3095.
  13. Berenson GS, Srinivasan SR, Nicklas TA, Webber LS. Cardiovascular risk factors in children and early prevention of heart disease. Clin Chem. 1988;34:B115-B122.
  14. Newman WP III, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, Williamson GD, Webber LS, Berenson GS. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. N Engl J Med. 1986;314:138-144.[Abstract]
  15. Thom TJ. Cardiovascular disease mortality among United States women. In: Eaker ED, Packard BK, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary Heart Disease in Women; Proceedings of an NIH Workshop. New York, NY: Haymarket Doyma Inc; 1987:33-41.
  16. Tyroler HA, Eaker ED. Session I highlights: design and methods of epidemiologic studies of fatal and nonfatal coronary heart disease in women. In: Eaker ED, Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary Heart Disease in Women; Proceedings of an NIH Workshop. New York, NY: Haymarket Doyma Inc; 1987:2-6.
  17. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking: a preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. JAMA. 1990;264:3018-3024.[Abstract]
  18. McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP, and the 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]
  19. Guzman MA, McMahan CA, McGill HC Jr, Strong JP, Tejada C, Restrepo C, Eggen DA, Robertson WB, Solberg L. Selected methodologic aspects of the International Atherosclerosis Project. Lab Invest. 1968;18:479-497.[Medline] [Order article via Infotrieve]
  20. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475.[Abstract]
  21. Naumann HN. Postmortem liver function tests. Am J Clin Pathol. 1956;26:495-505.[Medline] [Order article via Infotrieve]
  22. Glanville JN. Post-mortem serum cholesterol levels. Br Med J. 1960;2:1852-1853.
  23. Enticknap JB. Lipids in cadaver sera after fatal heart attacks. J Clin Pathol. 1961;14:496-499.
  24. Hornick CA, Baker HN, Malcom GT, Newman WP, Roheim PS, Strong JP. Lipoproteins and apolipoproteins in postmortem serum. Mod Pathol. 1988;1:480-484.[Medline] [Order article via Infotrieve]
  25. Bowler RG. The determination of thiocyanate in blood serum. Biochem J. 1944;38:385-388.
  26. Draper NR, Smith H. Applied Regression Analysis. New York, NY: John Wiley & Sons; 1966:58-134.
  27. Carroll RJ, Ruppert D. Transformation and Weighting in Regression. New York, NY: Chapman and Hall; 1988:9-51.
  28. Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons; 1989:1-36.
  29. Lipid Research Clinics Population Studies Data Book, IA: The Prevalence Study—Aggregate Distributions of Lipids, Lipoproteins and Selected Variables in 11 North American Populations. Washington, DC: US Government Printing Office; 1980. NIH publication 80-1527.
  30. Donahue RP, Jacobs DR Jr, Sidney S, Wagenknecht LE, Albers JJ, Hulley SB. Distribution of lipoproteins and apolipoproteins in young adults: the CARDIA study. Arteriosclerosis. 1989;9:656-664.[Abstract/Free Full Text]
  31. Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bacharik PS, Briefel RR, Gordon DJ, Burt VL, Brown CD, Lippel K, Cleeman JI. Declining serum total cholesterol levels among US adults: the National Health and Nutrition Examination Surveys. JAMA. 1993;269:3002-3008.[Abstract]
  32. Klag MJ, Ford DE, Mead LA, He J, Whelton PK, Liang K-Y, Levine DM. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med. 1993;328:313-318.[Abstract/Free Full Text]
  33. CDC. Tobacco, alcohol, and other drug use among high school students, United States, 1991. Morb Mortal Wkly Rep. 1992;41:698-703.[Medline] [Order article via Infotrieve]
  34. Pirkle JL, Flegal KM, Bernert JT, Brody DJ, Etzel RA, Maurer KR. Exposure of the US population to environmental tobacco smoke: the Third National Health and Nutrition Examination Survey, 1988 to 1991. JAMA. 1996;275:1233-1240.[Abstract]
  35. Holme I, Helgeland A, Hjermann I, Leren P. The Oslo Study: social indicators, risk factors and mortality. In: Bostrom H, Ljungstedt N, eds. Medical Aspects of Mortality Statistics. Stockholm, Sweden: Almqvsit & Wiksell International; 1981:165-181.
  36. Grout P, Cliff KS, Harman ML, Machin D. Cigarette smoking, road traffic accidents and seat belt usage. Public Health. 1983;97:95-101.[Medline] [Order article via Infotrieve]
  37. Nelson DE, Giovino GA, Shopland DR, Mowery PD, Mills SL, Eriksen MP. Trends in cigarette smoking among US adolescents, 1974 through 1991. Am J Public Health. 1995;85:34-40.[Abstract/Free Full Text]
  38. Kornitzer M, Vanhemeldonck A, Bourdoux P, De Backer G. Belgian Heart Disease Prevention Project: comparison of self-reported smoking behaviour with serum thiocyanate concentrations. J Epidemiol Community Health. 1983;37:132-136.[Abstract]
  39. National Center for Health Statistics. Advance report of final mortality statistics, 1991. Mon Vital Stat Rep. 1993;42(suppl 2):1-52.
  40. McGill HC Jr, McMahan CA, Wene JD. Unresolved problems in the diet-heart issue. Arteriosclerosis. 1981;1:164-176.[Free Full Text]
  41. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease, I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774.[Medline] [Order article via Infotrieve]
  42. Newman WP III, Wattigney W, Berenson GS. Relationship of risk factors to atherosclerotic lesions. Ann N Y Acad Sci. 1991;623:16-25.[Medline] [Order article via Infotrieve]
  43. Freedman DS, Wattigney WA, Srinivasan S, Newman WP III, Tracy RE, Byers T, Berenson GS. The relation of atherosclerotic lesions to antemortem and postmortem lipid levels: the Bogalusa Heart Study. Atherosclerosis. 1993;104:37-46.[Medline] [Order article via Infotrieve]
  44. Tracy RE, Newman WP III, Wattigney WA, Berenson GS. Risk factors and atherosclerosis in youth: autopsy findings of the Bogalusa Heart Study. Am J Med Sci. 1995;310(suppl 1):S37-S41.
  45. McGill HC Jr, Stern MP. Sex and atherosclerosis. Atheroscler Rev. 1979;4:157-242.
  46. Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest. 1968;18:509-526.[Medline] [Order article via Infotrieve]
  47. Shurtleff D. Some characteristics related to the incidence of cardiovascular disease and death: Framingham Study, 18 year follow-up. In: Kannel WB, Gordon T, eds. An Epidemiological Investigation of Cardiovascular Disease, Section 30. Washington, DC: Government Printing Office; 1974. DHEW publication NIH 74-599.
  48. Holman RL, McGill HC Jr, 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. 1958;34:209-235.
  49. McGill HC Jr. Fatty streaks in the coronary arteries and aorta. Lab Invest. 1968;18:560-564.[Medline] [Order article via Infotrieve]
  50. Freeman DS, Newman WP III, Tracy RE, Voors AE, Srinivasan SR, Webber LS, Restrepo C, Strong JP, Berenson GS. Black-white differences in aortic fatty streaks in adolescence and early adulthood: the Bogalusa Heart Study. Circulation. 1988;77:856-864.[Abstract/Free Full Text]
  51. Hixson JE, McMahan CA, McGill HC Jr, Strong JP, and the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. ApoB insertion/deletion polymorphisms are associated with atherosclerosis in young black but not young white males. Arterioscler Thromb. 1992;12:1023-1029.[Abstract/Free Full Text]
  52. Strong JP, Guzman MA. Decrease in coronary atherosclerosis in New Orleans. Lab Invest. 1980;43:297-301.[Medline] [Order article via Infotrieve]
  53. Newman WP III, Guzman MA, Strong JP, Tracy, RE, Oalmann MC. Secular trends in atherosclerotic lesions: comparison of two studies of autopsied men conducted in different time periods. Mod Pathol. 1988;1:109-113.[Medline] [Order article via Infotrieve]
  54. Davidoff F. Evangelists and snails redux: the case of cholesterol screening. Ann Intern Med. 1996;124:513-514.[Free Full Text]
  55. Newman TB, Browner WS, Hulley SB. The case against childhood cholesterol screening. JAMA. 1990;264:3039-3043.[Abstract]
  56. Newman TB, Garber AM, Holtzman NA, Hulley SB. Problems with the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Arch Pediatr Adolesc Med. 1995;149:241-247.[Abstract]
  57. Olson RE. The dietary recommendations of the American Academy of Pediatrics. Am J Clin Nutr. 1995;61:271-273.[Free Full Text]
  58. American College of Physicians. 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]
  59. Garber AM, Browner WS, Hulley SB. Cholesterol screening in asymptomatic adults, revisited. Ann Intern Med. 1996;124:518-531.[Abstract/Free Full Text]
  60. Gaull GE, Giombetti T, Woo RWY. Pediatric dietary lipid guidelines: a policy analysis. J Am Coll Nutr. 1995;14:411-418.[Abstract]
  61. Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1993 update, II: lowering the blood total cholesterol level to prevent coronary heart disease. Can Med Assoc J. 1993;148:521-538.[Medline] [Order article via Infotrieve]
  62. Glueck CJ, McGill HC Jr, Shank RE, Lauer RM, for the Ad Hoc Committee of the Steering Committee for Medical and Community Program of the American Heart Association. Value and safety of diet modification to control hyperlipidemia in childhood and adolescence: a statement for physicians. Circulation. 1978;58(suppl A):381A-385A.
  63. Weidman W, Kwiterovich P Jr, Jesse MJ, Nugent E. Diet in the healthy child: Task Force Committee of the Nutrition Committee and the Cardiovascular Disease in the Young Council of the American Heart Association. Circulation. 1983;67(suppl A):1411A-1414A.
  64. American Academy of Pediatrics Committee on Nutrition. Statement on cholesterol. Pediatrics. 1992;90:469-473.