Atherosclerosis In Youth Research Articles

Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

The raised fatty streak (fatty plaque) is the gross term for the lesion intermediate between the juvenile (flat) fatty streak and the raised lesion of atherosclerosis. We measured the percentage of intimal surface involved with flat fatty streaks, raised fatty streaks, and raised lesions in the aortas and right coronary arteries of 2876 autopsied persons aged 15 through 34 years who died of external causes. Raised fatty streaks were present in the abdominal aortas of approximately 20% of 15- to 19-year-old subjects, and this percentage increased to approximately 40% for 30- to 34-year-old subjects. Raised fatty streaks were present in the right coronary arteries of approximately 10% of 15- to 19-year-old subjects, and this percentage increased to approximately 30% for 30- to 34-year-old subjects. The percent intimal surface involved with raised fatty streaks increased with age in both arteries and was associated with high non-high density lipoprotein (HDL) and low HDL cholesterol concentrations in the abdominal aorta and right coronary artery, with hypertension in the abdominal aorta, with obesity in the right coronary artery of men, and with impaired glucose tolerance in the right coronary artery. Associations of risk factors with raised fatty streaks became evident in subjects in their late teens, whereas associations of risk factors with raised lesions became evident in subjects aged >25 years. These results are consistent with the putative transitional role of raised fatty streaks and show that coronary heart disease risk factors accelerate atherogenesis in the second decade of life. Thus, long-range prevention of atherosclerosis should begin in childhood or adolescence.

Association of Coronary Heart Disease Risk Factors with microscopic qualities of coronary atherosclerosis in youth.

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 > or =40% in the LAD. AHA grade 2 or 3 lesions (fatty streaks), grade 4 or 5 lesions, and stenosis > or =40% were associated with non-HDL cholesterol > or =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 > or =30 kg/m(2)) and hypertension (mean arterial pressure > or =110 mm Hg). -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.

Intimal Thickness and Layering, and Smooth Muscle Cell Phenotypes in Aorta of Youth

Proneness to the lesions of atherosclerosis varies along the length and circumferential topography of the aorta. Smooth muscle cells, in particular those of the ‘modulated’ synthetic phenotype which are able to proliferate and synthesize matrix proteins, are considered to play an important role in lesion progression. We report on a study of the aortic intima at a lesion-prone site from abdominal aorta and a lesion-resistant site from thoracic aorta in young humans to determine (1) whether the histologic structure and the smooth muscle cell composition show quantitative differences between lesion-prone and lesion-resistant aortic sites; (2) whether there are gender differences, and (3) whether any differences increase in degree with increasing age in this young population. Material for this study was obtained as part of the NIH-funded multicenter study on Pathobiological Determinants of Atherosclerosis in Youth (PDAY) from autopsies of male and female subjects between the ages of 15 and 34, victims of unexpected sudden death, usually from trauma. The samples consisted of strips of abdominal and thoracic aorta, all derived from the same anatomical sites standardized in the PDAY studies. The thickness of total intima (TI) and its elastic hyperplastic (EH) layer was measured. Smooth muscle cells of all types (SMC) and separately those of the synthetic phenotype (SynSMC) were quantified in each site using immunohistochemical procedures in replicate sections of uniform thickness. The intima of the atherosclerotic lesion-prone dorsal half of the abdominal aorta (AD) shows significant differences from the lesion-resistant ventral half of thoracic aorta (TV) in that (1) its EH layer is significantly thicker; (2) its EH layer has a comparatively higher number of both total SMC and SynSMC, even when adjusted for intimal thickness, and (3) the age-related increase in thickness of both TI and EH layer of AD is much greater than that of TV.

Smoking and atherosclerosis in youth

Coronary heart disease is the most common cause of death in the US. Studies have demonstrated that smoking is a major risk factor for coronary heart disease and that a positive relationship occurs between smoking and aortic and coronary atherosclerosis in adults. In 1985, a multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was organized to study atherosclerosis in trauma victims 15–34 years of age. Reports from this study have demonstrated that smoking is strongly associated with the prevalence and extent of grossly visible raised lesions in the abdominal aorta but only weakly associated with similar lesions in the right coronary artery. Coronary arteries from 50 smokers and 50 non-smokers were classified microscopically using a system developed by the American Heart Association in order to determine the stage at which smoking affects atherosclerosis. Smokers had over twice as many advanced lesions, types IV and V, as non-smokers (32 vs 14%) and fewer early lesions, types I, II, III, as non-smokers (38 vs 62%). The prevalence of advanced or types IV and V lesions (32%) was over twice that of intermediate or type III lesions (14%) in smokers. The opposite relationship was observed in non-smokers (14 vs 26%). This observation suggest that intermediate lesions progress rapidly into advanced lesions in smokers and that intima formerly having early lesions is replaced by intima with raised lesions.

Stability of apolipoprotein(a) isoform phenotype to postmortem conditions

Studies, such as the one entitled Pathobiological Determinants of Atherosclerosis in Youth or PDAY, have investigated the relationship of atherosclerotic lesions with lipid and lipoprotein risk factors. However, it is possible that proteolytic hydrolysis during the postmortem period could alter protein components of lipoproteins. Apo(a) is the defining protein of Lp(a), a lipoprotein associated with risk of cardiovascular disease. Apo(a) proteins are highly polymorphic for size and we simulated, using baboon tissues, the postmortem conditions for the PDAY study in order to determine their effects on apo(a) phenotypes. The bulk of the postmortem samples (93%) were correctly phenotyped and showed little or no evidence of degradation. Thus, apo(a) isoform size phenotypes can be determined in postmortem samples, although with caution.

Lipid and apolipoprotein predictors of atherosclerosis in youth: apolipoprotein concentrations do not materially improve prediction of arterial lesions in PDAY subjects. The PDAY Research Group.

We compared serum lipid and apolipoprotein predictors of atherosclerosis in cases from the multicenter study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY). The lipid measures included HDL cholesterol (HDL-C) and non-HDL-C, and the apolipoprotein measures included concentrations of apoA1, apoB, and Lp(a), and sizes of the apo(a) proteins. We tested whether the apolipoprotein measures predicted atherosclerotic lesions as well as the more traditional lipid measures. We estimated extent of lesions as fatty streaks or raised lesions (fibrous plaques, complicated or calcified lesions) in 3 sites: thoracic aorta, abdominal aorta, and right coronary artery. Neither apoA1 nor apoB measures were as strongly or consistently correlated with extent of lesions as the corresponding lipid measure (HDL-C and non-HDL-C, respectively). Beyond the basic model that included sex, age, race, smoking status, hypertension, and the lipid measures, apoA1 and apoB added only an average 1.3% increased explanatory ability to the model, whereas HDL-C plus non-HDL-C added an average 2.5%. The results suggest that the traditional lipid measures are more useful than apolipoprotein measures for detecting young persons at high risk of precocious atherosclerosis. Because of large racial differences, the two Lp(a)-related measures, Lp(a) concentrations and apo(a) size, were evaluated in blacks and whites separately. Under these circumstances, neither of the Lp(a)-related measures was strongly or consistently correlated with extent of lesions.

Usefulness of electron beam tomography in adolescents and young adults with heterozygous familial hypercholesterolemia.

Because of the success of secondary prevention of coronary events by intense risk factor modification, a more precise measure of atherosclerosis in youth would have great clinical value both in the design of clinical trials for the demonstration of the usefulness of coronary disease prevention early in life and in guiding therapy. Identification of calcium in coronary arteries by electron beam tomography has been associated with severity of atherosclerosis in adults. Twenty-nine youths 11 to 23 years old with familial hypercholesterolemia (average LDL cholesterol, 5.95 mmol/L) underwent electron beam tomography as well as comprehensive risk factor assessment with measurement of total cholesterol, triglycerides, HDL cholesterol, lipoprotein (a), apolipoprotein E phenotype, blood pressure, body mass index, and history of tobacco use. Significant coronary calcium was identified in 7 of 29 subjects. Increased body mass index was significantly associated with the presence of coronary calcium (25.3 versus 20.6 kg/m2, P<0.03). No other risk factors were associated with the presence of coronary calcium. Coronary calcium, uncommonly identified before the fourth decade, was found in a significant percentage of adolescents and young adults with familial hypercholesterolemia. Overweight may increase the likelihood of coronary calcium being present in individuals already at high risk.

Determinants of atherosclerosis in the young

A multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth, examined the relation of the risk factors for adult coronary artery disease to atherosclerosis in nearly 3,000 persons, aged 15–34 years, who died from accidents, homicides, and suicides and were autopsied in forensic laboratories. Very-low-density lipoprotein (VLDL) plus low-density lipoprotein (LDL) cholesterol levels were positively, and high-density lipoprotein (HDL) cholesterol levels were negatively, associated with both fatty streaks and raised lesions in the aorta and right coronary artery, particularly after age 25. Elevated glycohemoglobin levels were associated with raised lesions throughout the 15–34-year age span. Body mass index was associated with both fatty streaks and raised lesions of the right coronary artery in men but not in women. Smoking was associated with a 3-fold increase in raised lesions of the abdominal aorta in the 25–34-year age group. Women lagged after men in the extent of raised lesions in the right coronary artery by about 5 years, but the effects of risk factors in women, except for adiposity, were similar to those in men. The risk factors for adult coronary artery disease accelerate atherogenesis in the teenage years and their effects are amplified in young adulthood, 20–30 years before coronary artery disease becomes clinically manifest. Long-range prevention of adult coronary artery disease will require control of the risk factors early in life.

Risk Factors and Progression of Atherosclerosis in Youth

“The Pathobiological Determinants of Atherosclerosis in Youth” (PDAY), a unique research program initiated in 1985, has now developed into a detailed and comprehensive 15-center investigation of the arteries of more than 3,000 young persons who died between 15 and 34 years of age (Appendix A). The main objectives of this highly organized multicenter study are to compare the quantitatively evaluated risk factors for coronary heart disease including blood lipid values, evidence of smoking, indices of hypertension, tendency toward diabetes, etc., with the results of macroscopic and microscopic quantitation of severity and with microscopic components of developing atherosclerotic lesions in these young people. 1-5 This commentary will summarize some of the results which have been published in more than 75 full-length reports, with emphasis on the results obtained because of the unusual and frequently unique features of the study’s protocol, which was developed during a 10-year period before the study began. 6-17 Reported findings can be divided into two categories. Results in the first category are derived from the gross evaluation of the extent and severity of lesions. 18-28 Computer-assisted mapping was also applied to raised lesions traced out by the pathologists. 28,29 The second category of reported results comes from detailed micromorphometric, microchemical, and immunohistochemical quantitative data based on the major microscopic components and the classification of each lesion. 30-39 In fact, as the study progressed, it became possible to classify the four major types of intermediate lesions that are associated with different rates of progression of the atherosclerotic process in the aortas and coronary arteries of these young people as well as with certain risk factors. 40,41 Because lesions tend to increase in extent, numbers, and severity with age, it is assumed that this in-depth quantitative analysis of the atherosclerosis found in each of these cases from the 15–34 age group may give new insights into why some young people’s plaques seem to progress rapidly with age while others’ remain almost stationary, as well as a comparison of progression in various parts of the arterial tree. 20,22,30,42 Results of the study reflect the state of atherosclerosis development in young people living in the USA late in the 20th century. All case material came from forensic autopsies on young individuals who had no evidence of chronic debilitating disease and who succumbed suddenly to traumatic or other fatal episodes. The intervals between death and refrigeration of the body, as well as performance of the autopsy, were generally short. This has made it possible for the tissues and cells to be studied using a number of pathobiological methods appropriate for well-preserved human tissues. 31-41 In order to insure an adequate and representative autopsy population, nine of the centers selected, approved, and funded functioned as “collecting centers.” All nine are geographically and/or organizationally related to forensic laboratories where state and local regulations make it possible to collect and utilize small samples of tissue for research purposes. Most of the principal investigators leading the 15 centers have a long-standing interest and a record of productivity in the field of atherosclerosis research with an emphasis on the artery wall and the pathogenesis of atherosclerotic lesions. 5 Centers were selected during a period of approximately two years (1983–85) of intensive preliminary meetings of potential principal investigators. The overall plans took shape over a 10-year period (1975–85) during which a carefully prepared and detailed protocol as well as a detailed manual of procedures for the study were developed. 5,34,36 Furthermore, during this period the steering committee developed a standardized sampling strategy and procedures based on the results of an NIH-funded preliminary study by Dr. Frederick Cornhill, Director of the Biomedical Engineering Center at Ohio State University, and Dr. Herbert Stary, Professor of Pathology at Louisiana State University. This preliminary study established the patterns of lesion location most likely to develop in the aorta 5,29 and helped establish the best sites to study in the proximal coronary arteries. This commentary will conclude with a list of major opportunities for future studies afforded by the accumulated data and the currently unused PDAY samples of arteries and other tissues.

Atherosclerosis in Young People: The Value of the Autopsy for Studies of the Epidemiology and Pathobiology of Disease

In this issue of The American Journal of Pathology we publish a summary of the major results of a research project initiated in 1985. Titled “The pathobiological determinants of atherosclerosis in youth” (PDAY), the study was directed by Drs. R. W. Wissler of the University of Chicago and J. P. Strong of Louisiana State University and involved 14 centers. Investigators examined material obtained from forensic autopsies of more than 3000 individuals between the ages of 15 and 34. These individuals had no evidence of cardiovascular or other chronic disease; most died as a result of trauma. Although more than 75 papers based on this material have already been published, I feel that it is useful to compile a summary of these observations. In their paper, Wissler et al 1 outline the protocols developed for the project, highlight its more significant results, and present some important guidelines for the prevention of cardiovascular disease in young people. I also want to emphasize the essential role that forensic autopsies played in these studies. There has been much debate about the role of the autopsy in present-day medical practice, teaching, and research. Rosai has argued that to be a tool of real value rather than an exercise in tradition, autopsies need to be done selectively and efficiently, yielding final diagnoses rapidly so that findings can be integrated meaningfully with clinical data, as is the case for surgical specimens. 2 Asking specific questions before an autopsy is performed permits the collection of material that can best answer these questions and can be used for further studies involving biochemical and molecular techniques. These were the goals of the PDAY research program protocols. The project has been very successful in reaching these goals using tissues obtained at autopsy as the basis for correlations of morphological, biochemical, and epidemiological data. The next phase of the project will, I hope, extend these studies to the analysis of molecular markers of atherosclerosis derived from recent studies in humans and animal models. The new studies should aim to establish precise pathogenetic mechanisms that determine the progression of atherosclerosis in young people. As stated by Wissler et al, “the results of the (PDAY) study reflect the state of atherosclerosis development in young people living in the U.S.A. late in the 20th century.” Among the many important findings reported, I call your attention to these: 1. All U.S. teenagers sampled had fatty streaks in some segment of their arterial system. 2. Intermediate lesions (fatty plaques) developed from fatty streaks in the aorta and coronary with wide age variation but the extent of the lesions increased steadily from 15 to 34 years, as measured in 5-year age-group intervals. 3. Raised lesions were detected earlier in the aorta than in coronary arteries; lesions containing lipids were present in the aorta of 15- to 20-year-old individuals. 4. The presence of coronary artery lesions having concentric microarchitecture and a large number of inflammatory cells was correlated with the presence of circulating immune complexes. 5. Obesity was a positive risk factor for the development of vascular lesions. 6. Raised lesions in the abdominal aorta were greatly increased in smokers in the 25–34 age group. 7. Smoking and hypertension had the greatest effect on the development of advanced plaques in young adults (approximately 6-fold and 4-fold increased incidence, respectively). 8. Ten percent of the individuals in this study had advanced atherosclerosis consisting of plaques with necrotic fat-filled centers and fibrous caps. Approximately 80% of these individuals were smokers. It is debatable whether the presence of fatty streaks in individuals 15 to 34 years of age has pathogenetic importance for the development of atherosclerosis. However, it is truly alarming that 10% of individuals in this age group had advanced atherosclerosis. There is no reason to believe there was a bias in the selection of cases for study. Indeed, I agree with Wissler et al that the PDAY cases represent a random sample of U.S. youth. Do all individuals with advanced lesions have gene mutations known to predispose one to atherosclerosis? Answers to this question and many others remain to be determined. The material used in the PDAY project is available to the scientific community through the administrative center at Louisiana State University. I hope that publication of the paper by Wissler et al will further increase the use of this material for scientific investigation of the causes and progression of atherosclerosis.

Relation of a postmortem renal index of hypertension to atherosclerosis and coronary artery size in young men and women. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

In a cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth, we measured atherosclerosis of the aorta and right coronary artery (RCA) in 2403 black and white men and women 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories. We measured the diameter of the opened, flattened, and fixed RCA and the diameter, intimal thickness, intimal cross-sectional area, medial thickness, and medial cross-sectional area of the pressure-perfused, fixed left anterior descending (LAD) coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure during life, we classified the cases as normotensive (mean arterial pressure < 110 mm Hg) or hypertensive (mean arterial pressure > or = 110 mm Hg). The prevalence of hypertension by age, sex, and race corresponded closely with that measured in a survey of the living population. Hypertension had little or no effect on fatty streaks. Hypertension was associated with more extensive raised lesions in the abdominal aortas and RCAs of blacks > 20 years of age and in the RCAs of whites > 25 years of age. At all ages, women had less extensive raised lesions in the RCAs than did men, but the effect of hypertension on raised lesions was similar to that in men. Adjustment for serum lipoprotein cholesterol levels and smoking in a subset of cases yielded results similar to those obtained without adjustment. Hypertension was associated with larger diameters of the RCA and LAD coronary artery and with larger cross-sectional intimal and medial areas of the LAD coronary artery. Hypertension augments atherosclerosis in both men and women primarily by accelerating the conversion of fatty streaks to raised lesions beginning in the third decade of life, and the effect of hypertension increases with age.

Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association.

The Framingham Heart Study has contributed importantly to understanding of the causes of coronary heart disease (CHD), stroke, and other cardiovascular diseases. Framingham research has helped define the quantitative and additive nature of these causes or, as they are now called, “cardiovascular risk factors.”1 The National Cholesterol Education Program (NCEP)2 3 has made extensive use of Framingham data in developing its strategy for preventing CHD by controlling high cholesterol levels. The NCEP guidelines2 3 adjust the intensity of cholesterol-lowering therapy with absolute risk as determined by summation of risk factors. The National High Blood Pressure Education Program (NHBPEP) has set forth a parallel approach for blood pressure control. In contrast to the NCEP,2 however, earlier NHBPEP reports issued through the Joint National Committee4 did not match the intensity of therapy to absolute risk for CHD. “Normalization” of blood pressure is the essential goal of therapy regardless of risk status. Blood pressure–lowering therapy is carried out as much for prevention of stroke and other cardiovascular complications as for reduction of CHD risk. Nonetheless, risk assessment could be important for making decisions about type and intensity of therapy for hypertension. Thus, the most recent Joint National Committee report5 gives more attention to risk stratification for adjustment of therapy for hypertension. Although Framingham data have already been influential in the development of national guidelines for risk factor management, the opportunity may exist for both cholesterol and blood pressure programs to draw more extensively from Framingham results when formulating improved risk assessment guidelines and recommending more specific strategies for risk factor modification. The American Heart Association has previously used Framingham risk factor data to prepare charts for estimating CHD risk. Framingham investigators of the National Heart, Lung, and Blood Institute prepared the original charts and have now revised …

The PDAY Study: natural history, risk factors, and pathobiology. Pathobiological Determinants of Atherosclerosis in Youth.

The PDAY Study: natural history, risk factors, and pathobiology. Pathobiological Determinants of Atherosclerosis in Youth.

In vivo action of 15-lipoxygenase in early stages of human atherogenesis.

Oxidative modification of low density lipoprotein has been suggested as patho-physiologically relevant process in atherogenesis and the lipid peroxidizing enzyme 15-lipoxygenase may be involved. For experimental evidence on the in vivo action of this enzyme in the time course of plaque formation we analyzed the lipid extracts of lesional areas representing various stages of human atherogenesis for the occurrence of specific 15-lipoxygenase products. In advanced human lesions the degree of oxygenation of the lesion lipids measured as hydroxy linoleic acid/linoleic acid ratio varied between 0.2 and 3.2%. Here an unspecific pattern of oxygenated lipids that did not differ from the pattern formed during copper-catalyzed LDL oxidation was detected. In both cases an enantiomer ratio (S/R-ratio) of 13-hydroxy-9Z,11E-octadecadienoic acid (13-HODE) of approximately 1:1 was found. In young human lesions which were obtained from the collection of the pathological determinants of atherosclerosis in youth (PDAY) program the hydroxy linoleic acid/linoleic acid ratio was much smaller (variation between 0.05 and 0.6%), and a significant share of specific 15-lipoxygenase products was detected (S/R-ratio of 13-hydroxy linoleic acid of 54 +/- 3.1/46 +/- 3.1 [mean +/- SD]). These data suggest that the 15-lipoxygenase is enzymatically active on endogenous substrates in young human lesions and thus, may be of patho-physiological importance for early atherogenesis. In advanced human plaques the 15-lipoxygenase may be functionally silent and specific lipoxygenase products formed in earlier stages may be decomposed or superimposed by large amounts of nonenzymatic lipid peroxidation products.

Atherosclerosis in youth: are hypertension and other coronary heart disease risk factors already at work?

The purposes of this review were to describe the natural history of atherosclerosis in youth, discuss the role of adult coronary heart disease (CHD) risk factors in the development of atherosclerosis-particularly in the young- and present the relationship between atherosclerosis and hypertension. Evidence is presented that, by age 15 years, 100% of the youth have aortic atherosclerosis and about one-half have coronary atherosclerosis. Risk factors for adult CHD, including lipoproteins, smoking, glycohemoglobin (a marker for diabetes), obesity, and hypertension, are associated with extent and prevalence of atherosclerosis in young people. Hypertension seems to play its role mainly by converting early atherosclerotic lesions (fatty streaks) to more advanced lesions (raised lesions).

Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. The PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth.

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 postmorterm 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.

Relation of a postmortem renal index of hypertension to atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

In a cooperative multicenter study, Pathobiological Determinants of Atherosclerosis in Youth, of 1164 young men 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories, we measured atherosclerosis of the aorta and the right coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure (MAP) during life, we classified the cases as either normotensive (MAP < 110 mm Hg) or hypertensive (MAP > or = 110 mm Hg). By this criterion, the prevalence of hypertension in blacks was 16%; in whites, 12%. Hypertension was associated directly with blood level of glycohemoglobin (an indicator of blood glucose concentration) and with body mass index (BMI) but inversely with thickness of the panniculus adiposus. Among hypertensive compared with normotensive cases, the extent of raised lesions (mainly fibrous plaques) was greater in the aortas of 30- to 34-year-old men and in the right coronary arteries of 25- to 34-year-old men. The prevalence of raised lesions involving 5% or more of the intimal surface was twofold greater in the aortas and right coronary arteries of hypertensive men throughout the 15-to-34-year age span of the study cases. The association of hypertension with raised lesions was not accounted for by adjusting for glycohemoglobin level, BMI, or thickness of the panniculus adiposus. Hypertension is associated with accelerated atherosclerosis in youth.

An Overview of the Quantitative Influence of Several Risk Factors on Progression of Atherosclerosis in Young People in the United States

This overview of the National Institutes of Health-supported, multicenter, investigator-initiated study of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) is designed to summarize the plan, approaches, and the expanding contribution of this unique research program, which is now in its tenth year. It traces for the first time the development, the organization, and the function of the many new features and facets that are being used to yield needed information on the relationships between the classic risk factors and the topography, severity, and the cellular and chemical reactions that influence the development of the early raised plaques. It has also helped establish the factors that influence the progression of the four major types of intermediate raised lesions that grossly are all similar, well delineated fatty plaques. Most of the observations are quantitative. A few glimpses into the unique findings that have been published are presented.

Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old).

An association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and aorta has been found by seroepidemiology and by demonstration of the organism in atheromata. Age-matched control tissue from persons without atherosclerosis was usually not available. We studied autopsy tissue from young persons, many with no atherosclerosis, to determine whether C. pneumoniae is present in atheroma in young persons with early atherosclerosis and to compare the findings in age- and sex-matched persons without atherosclerosis. A left anterior descending coronary artery sample, formalin-fixed, from 49 subjects, 15-34 years of age, from the multicenter study called Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was examined by immunocytochemistry and the polymerase chain reaction (PCR) for the presence of C. pneumoniae and by PCR for cytomegalovirus. A hematoxylin/eosin-stained section was used to determine disease present in the studied sample. Seven of the artery samples were found to have atheromatous plaque, 11 had intimal thickening, and 31 had no lesions. Eight of the samples were positive for C. pneumoniae by immunocytochemistry (n = 7) and/or PCR (n = 3). Six of the 7 (86%) atheroma, 2 of the 11 (18%) with intimal thickening, and none of the 31 normal-appearing coronary samples were positive. Four were positive by PCR for cytomegalovirus, 2 from diseased arteries and 2 from normal arteries. Examination of the adjacent left coronary artery sample with a fat stain found abnormalities in 25 of the patients, but 19 still showed no evidence of atherosclerosis as a result of either examination. Thus, C. pneumoniae is found in coronary lesions in young adults with atherosclerosis but is not found in normal-appearing coronary arteries of both persons with and without other evidence of atherosclerosis.

Detection and characterization of new mutations in the human angiotensinogen gene (AGT)

As part of the multicenter project entitled "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)," we are testing polymorphisms in candidate genes of atherosclerosis and hypertension for associations with arterial lesions in autopsied young persons. In this study, we used temperature gradient gel electrophoresis (TGGE) to type the Met235-->Thr polymorphism in exon 2 of the angiotensinogen gene (AGT) that is associated with essential hypertension in some human populations. In addition to Met235-->Thr, we detected and sequenced four other TGGE variants in exon 2 of AGT. These included two new amino acid substitutions (Thr209-->Ile and Leu211-->Arg) that were found only among black PDAY cases. The frequency of the Ile209 mutation was 0.002 and the frequency of the Arg211 was 0.006 in 260 black PDAY cases. The other two TGGE variants were Tyr248-->Cys and a T-->C substitution at nucleotide position 171 that had been identified in previous studies. We also developed restriction isotyping for rapid typing of each AGT variant using PCR amplification and digestion with diagnostic restriction enzymes.