Prevalence and Extent of Atherosclerosis in Adolescents and Young Adults:  Implications for Prevention From the Pathobiological Determinants of Atherosclerosis in Youth Study FREE

This article summarizes the natural history of aortic and coronary atherosclerosis among adolescents from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study, which was a multi-institutional study of atherosclerosis in 15- to 34-year-old, black and white men and women who underwent autopsy.^1- 2 In 1986, THE JOURNAL republished, as a landmark article, the 1953 report by Enos et al^3- 4 of atherosclerosis in young American soldiers killed in the Korean War. A perspective of this landmark article traced the history of atherosclerosis in young persons prior to this landmark article up until the beginning of the PDAY Study.⁵ The present report closes the loop from the landmark article by presenting final results from the PDAY Study on the natural history of atherosclerosis in youth and young adulthood as viewed from a study of gross specimens.

The PDAY Study focused on 15- to 34-year-old subjects because fatty streaks are prevalent and fibrous plaques begin to appear in this age group.^6- 7 Due to continued lipid deposition and proliferation of smooth muscle and connective tissue, fatty streaks and fibrous plaques increase in size and extent and some undergo qualitative changes. The most serious change is rupture, which exposes the blood to lipid-rich thrombogenic material and precipitates an occlusive thrombus, which in turn leads to myocardial infarction or sudden cardiac death.⁸ The PDAY Study encompassed the transition from innocuous fatty streaks to clinically significant fibrous plaques and attempted to determine the conditions associated with this process.

Previous PDAY reports have described selected aspects of the effects of age, sex, race, serum lipoprotein levels, smoking, hypertension, glycohemoglobin levels, and obesity on the gross extent and microscopic characteristics of atherosclerotic lesions in these subjects.^9- 16 In brief, the conditions that predict risk of clinically manifest coronary heart disease (CHD) are also associated with the extent and severity of atherosclerosis in youth. This article summarizes the natural history of the grossly detectable lesions of atherosclerosis in American youth and confirms the rapid progression of atherosclerosis in some young adults examined at autopsy between 1987 and 1994.

Detailed descriptions of methods have been published in earlier reports.^{1- 2,12- 14,16} Nine cooperating centers adopted a standard operating protocol and a manual of procedures to collect specimens and information and to submit them to central laboratories for processing, artery grading, and analysis.¹ Study subjects were persons aged 15 through 34 years who had died due to external causes and underwent autopsy in 1 of the cooperating medical examiners' laboratories between June 1, 1987, and August 31, 1994. Of the 3210 cases collected, 334 were excluded because they did not meet the study criteria. Of the 2876 cases included in this report, thoracic aortas were obtained from 2856, abdominal aortas from 2823, and right coronary arteries from 2788.

At the time of autopsy, the PDAY team bisected the descending thoracic and abdominal aorta longitudinally, prepared the right half for histological and chemical analyses, and fixed the left half in 10% neutral buffered formalin. The PDAY team opened and fixed the right coronary artery in the same manner as the aorta. The left anterior descending coronary artery was fixed by pressure perfusion for microscopic study. The left circumflex coronary artery was prepared for chemical and microscopic study.

Blood, liver, kidney tissue, and standardized arterial wall samples, including samples from the perfusion-fixed left anterior descending coronary artery, were also collected in this study. These samples were used to investigate the associations of atherosclerosis with the risk factors for adult CHD, which are reported elsewhere,^9,12- 16 and for studies of the microscopic features of aortic and coronary lesions including cellular, fibrous, and lipid-containing components.^10- 11

Collection centers shipped the left half of each aorta and the right coronary artery in a plastic bag to the central laboratory. The central laboratory stained the arteries with Sudan IV¹⁷ and then x-ray films were made.

Three pathologists, blinded to specimen source or other information, independently evaluated the stained 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.¹⁷ The sum of the percentages of surface involved with fibrous plaques, complicated lesions, and calcified lesions by gross visual grading was designated raised lesions. Consensus grading of lesions was the average of the 3 independent gradings.

The prevalence of cases with lesions was based on the recording by any of the pathologists of any nonzero value of percentage surface area involved from all lesion types except calcification. Prevalence also was computed based on 5% or greater surface area involved. Prevalence of calcified lesions was based on evaluation of the x-ray films.

The effects of sex, race, and 5-year age group on percentage surface area involved with lesions were analyzed using analysis of variance.¹⁸ The prevalence of cases involved with lesions was analyzed using multiple logistic regression.¹⁹

Macroscopic color transparencies and black-and-white prints of aortas and right coronary arteries on each case were sent to the Laboratory of Vascular Diseases at Ohio State University, Columbus, where an automated image processing system mapped the topographic distribution of atherosclerotic lesions in each artery as described previously.^20- 22 The image of the aorta and right coronary artery in 35-mm slides was digitized and transformed to standard templates. The standard templates were generated from the average location of the anatomical landmarks, such as ostia or branches of other arteries. The digitized images were used to compute lesion prevalence (percentage) at each pixel location and to generate maps. This process was performed for fatty streaks as identified by Sudan IV staining and raised atherosclerotic lesions as identified by pathologists at the Louisiana State University Medical Center, New Orleans.

Table 1 shows the 2876 cases listed by sex, race, 5-year age group, and circumstances of death. The most frequent cause of death in white subjects was accidents; in black subjects, homicide. The mean percentage of intimal surface area involved with atherosclerotic lesions did not differ significantly among the causes of death within sex or race groups (results not shown). Therefore, all analyses were performed by pooling individuals dying of all causes.

Table 2 shows the percentage of intimal surface area involved with atherosclerotic lesions by sex, race, and 5-year age groups for each arterial segment. Mean percentage of area involved with total lesions increased with age (P<.001) and was greater in blacks than in whites in all arterial segments (P<.001). Mean percentage of total lesion area was greater in men than in women for the thoracic aorta (P = .004) and less in men than in women for the abdominal aorta (P<.001). For the right coronary artery, men had greater total surface involvement than women (P<.001).

Mean percentage of area involved with raised lesions also increased with age (P<.001) in all arterial segments but did not differ greatly between blacks and whites in any of the arterial segments. Men and women had a similar extent of raised lesions in both aortic segments, but men had more extensive raised lesions than women (P<.001) in the right coronary artery. Although there were a few statistically significant interactions among sex, race, and age in their effects on extent and prevalence of lesions, these interactions were small and considered not to be biologically important.

Figure 1 illustrates the percentage of surface area involved with fatty streaks and raised lesions, which combine to form total surface area involved with lesions, by age, sex, and race. Fatty streaks account for the race difference (blacks more than whites) in all arterial segments. While fatty streaks also account for the sex difference in percentage of surface area involved in the aorta (thoracic, men more than women; abdominal, women more than men), raised lesions account for the sex difference in the right coronary artery; men have a greater extent of advanced lesions than women. The right coronary artery has a smaller percentage of surface involved with atherosclerotic lesions than either the thoracic or abdominal aorta, but a much greater proportion of lesions in the coronary artery are advanced lesions than in the thoracic or abdominal aorta.

Table 3 shows the prevalence of any atherosclerotic lesions and the prevalence of lesions involving more than 5% of the intimal surface area. All subjects in this study had lesions in the abdominal aorta, and all except 2 white men had lesions in the thoracic aorta. Prevalence of lesions in the right coronary artery increased from about 60% in the youngest age group to greater than 80% in men and approximately 70% in women in the 30- to 34-year age group (P<.001).

The prevalence of total lesions involving 5% or more of the arterial surface was greater in women than men in the abdominal aorta (P = .01) and was greater in blacks than whites in the right coronary artery (P<.001).

The prevalence of raised lesions, whether measured as any lesions or lesions involving 5% or more of the arterial surface area, increased with age in all arterial segments of all sex and race groups. Prevalence of raised lesions by both measures was greater in the right coronary arteries of men than in those of women (P≤.003), but there were no differences in prevalence in the right coronary arteries between blacks and whites.

Table 4 shows the prevalence of lesions divided into fatty streaks, fibrous plaques, complicated lesions, and calcified lesions. Although complicated and calcified lesions were rare among these cases, all race-sex groups with subjects aged 30 to 34 years had some cases with calcified lesions in the abdominal aorta and right coronary artery, and all race-sex groups with subjects aged 30 to 34 years had some cases with complicated lesions, except for the right coronary artery in white women.

Figure 2 shows the topographic distribution and prevalence of fatty streaks and raised lesions in the thoracic and abdominal aorta and Figure 3 shows the right coronary artery by 5-year age groups for people (black and white, men and women) aged 15 to 34 years. Some regions of the arteries were lesion prone, while others were lesion resistant. These prevalence maps also show the differences in the propensity to develop raised or advanced lesions among the 3 arteries.

In the thoracic aorta, the highest prevalence of fatty streaks occurred in the dorsal surface (>50%) while the ventral surface had few fatty streaks (<10%). The region of highest prevalence for fatty streaks was midway between successive pairs of intercostal ostia. The thoracic aorta was virtually spared of raised lesions even in the oldest age group (30-34 years: <4% raised lesions).

In the abdominal aorta, the frequency of fatty streaks was greater in the dorsal than in the ventral area, but lesion-prone and lesion-resistant regions were not as sharply defined as in the thoracic aorta. Regions of high prevalence occurred between pairs of lumbar ostia and in flow tracts to the celiac, superior mesenteric, renal, and inferior mesenteric arteries, while regions distal to the flow dividers of these ostia were spared. A region on the left dorsal surface of the abdominal aorta, originating at the level of the inferior mesenteric ostium and extending distally to the bifurcation, was the most prone to raised lesions.

In the right coronary artery, fatty streaks formed a pattern with the highest prevalence of lesions in the proximal region. The highest prevalence of raised lesions was in the first 2 cm of the vessel. This distribution confirms that there are also lesion-prone and lesion-resistant regions of the coronary artery.

For many years, investigators in the United States and abroad recognized the existence of atherosclerosis in children and adolescents, particularly in the aorta.^23- 27 The 1953 report of advanced lesions in the coronary arteries of young soldiers (average age, 22 years)³ surprised the medical community and focused attention on the potential importance of the childhood origin of atherosclerosis.

Holman and colleagues²⁸ in New Orleans had already initiated studies on the natural history of atherosclerosis in children before the 1953 report by Enos et al³ was published and confirmed the presence of fatty streaks in the aorta in the first decade of life²⁸ and in the coronary arteries in the second decade.²⁹ Fibrous plaques appeared in the second decade in both arteries. These early observations, coupled with the emerging evidence that dietary fat and cholesterol were important determinants of plasma cholesterol concentrations, which contributed to the progression of atherosclerosis, led Holman³⁰ to propose in 1959 that atherosclerosis was a pediatric nutrition problem. In subsequent years, evidence continued to show that atherosclerosis did begin in childhood.^31- 33 Strong and McGill⁶ examined the aortic and coronary artery lesions in 4737 persons, aged 10 to 39 years, from 6 geographic ethnic groups that represented a wide range in severity and extent of atherosclerosis. All aortas from all groups had fatty streaks. Fatty streaks were present in the coronary arteries of all subjects from New Orleans (a high atherosclerosis group) older than 20 years; and in 90% of the persons from other groups (all low atherosclerosis groups).⁶ Fibrous plaques appeared in a few coronary arteries before age 20 years, and prevalence and extent increased in the third and fourth decades.⁶

The PDAY results described in this report have confirmed and extended the previous observations concerning the ubiquity of fatty streaks in the abdominal aortas of adolescents and young adults and the frequency of fibrous plaques in the aortas and coronary arteries of young adults in a diverse sample of the US population during the current decade.

One of the objectives of the PDAY Study was to examine in greater depth the relationship of the fatty streak in young persons to the fibrous plaque and complicated lesions in older persons. The question of whether fibrous plaques arise from fatty streaks, or whether they arise independently of fatty streaks, has been a controversial issue in the pathogenesis of atherosclerosis. The PDAY results presented herein show that fatty streaks in some locations—the thoracic aorta and portions of the ventrolateral intimal surface of the abdominal aorta—are not likely to be replaced by raised lesions during the 15- to 34-year age period (Figure 2). On the other hand, the distribution pattern of raised lesions in the dorsolateral portion of the abdominal aorta (Figure 2) and the distribution pattern of raised lesions in the right coronary artery of older persons ( Figure 3) follow those of the distribution of fatty streaks in younger persons.

Among the most persuasive evidence for the fatty streak being the precursor of the raised lesions is that derived from the microscopic examination of lesions of the coronary arteries. Stary,^34- 35 using light and electron microscopy of the unopened pressure perfusion-fixed left coronary arteries, studied 691 men and women who died between full-term birth and age 39 years to assess the earliest microscopic changes of atherosclerosis. More than 50% of children aged 10 to 14 years had lesions characterized by accumulations of macrophage foam cells, lipid-containing smooth muscle cells, and thinly scattered extracellular lipid. These changes represent the microscopic counterpart of gross fatty streaks. Approximately 8% of the subjects, aged 10 to 14 years, had lesions with larger accumulations of extracellular lipid that were thought to be in transition to fibrous plaques (ie, the lesions that are known to be associated with clinical disease in adults). These results indicate a progression from fatty streaks through intermediate or transitional lesions to atheromatous lesions (comparable with fibrous plaques by gross classification) in a defined segment of the left anterior descending coronary artery that is predisposed to clinically significant lesions.

Other evidence linking the fatty streak to the raised lesions includes topographic, chemical, physical chemical, and other histologic studies.^36- 44 These studies are consistent with Stary's^34- 35 demonstration of a continuous spectrum of lesions that begin with a collection of lipid-filled macrophages and progress to a lesion with a core of necrotic debris, extracellular lipid, and a fibromuscular cap, which is the typical raised lesion that directly leads to thrombotic occlusion and CHD. These results suggest that, although fatty streaks may be innocuous if they remain as such, under certain conditions and at certain anatomic sites, they represent the first stage of a process leading to clinical disease.

Secular Trends. In the International Atherosclerosis Project (1960-1964) and earlier studies of the natural history in New Orleans, white men consistently had more extensive coronary artery raised lesions than black men.^29,45 This pattern was altered in the Community Pathology Study of atherosclerosis in New Orleans in the 1970s. In 25- to 44-year-old men, the extent of raised coronary lesions was approximately the same in black and white subjects.^46- 48 Comparisons with the International Atherosclerosis Project results suggested that coronary atherosclerotic lesions had decreased in white men and remained relatively stable in black men.⁴⁹ In the PDAY Study, white and black young men have similar prevalence and mean extent of raised lesions in the right coronary artery. The decrease in coronary lesions in white men that may have been occurring between the 1960s and 1970s does not seem to be continuing.

Determinants of Atherosclerosis. Another major objective of the PDAY Study was to examine the relationship of the risk factors for adult CHD to atherosclerosis in persons younger than 35 years.⁵⁰ Studies begun in the 1980s showed that plasma lipoprotein concentrations, blood pressure, glucose tolerance, adiposity, and smoking habits were nearly as variable among children and adolescents as they were among adults.^51- 52 However, except for the reports of a few cases of precocious atherosclerosis and CHD in young persons with familial hypercholesterolemia,⁵³ their relationship to atherosclerosis was unknown. A small number of cases from the Bogalusa Heart Study showed associations of atherosclerosis with serum lipoprotein levels and blood pressure.^54- 55

The PDAY investigators have shown that very low-density lipoprotein and low-density lipoprotein cholesterol concentrations were positively and high-density lipoprotein cholesterol concentrations were negatively associated with both fatty streaks and raised lesions.^14,16 Smoking was associated with both fatty streaks and raised lesions in the abdominal aorta and with the prevalence of raised lesions in the right coronary artery.¹⁴ Elevated glycohemoglobin levels were associated with a substantial excess of fatty streaks and raised lesions in the right coronary artery and a lesser excess of raised lesions in the aorta.¹² Hypertension was associated with more extensive raised lesions but not with fatty streaks in both the aorta and right coronary artery.¹³ Body mass index was associated with more extensive raised lesions of the right coronary artery.¹³ Thus, not only does atherosclerosis begin in childhood, the risk factors for adult CHD and the other clinical syndromes resulting from atherosclerosis determine to a large degree its rate of progression.

Labarthe⁵⁶ recently suggested emphasizing the prevention of cardiovascular risk factors with the idea that the risk factors would become rare in the population, a result leading to less common and less extensive early atherosclerosis. This concept implies (1) primordial prevention as conceived by Strasser,⁵⁷ (2) an important focus on youth, (3) bridging of socially institutionalized gaps (childhood and adulthood, schools and workplace, pediatrics and adult medicine), (4) early markers for risk factors and retarding progression of risk factors, and (5) observational studies and intervention trials to determine effectiveness.⁵⁶ The PDAY results provide compelling support for the validity of this concept. This observational evidence is all we will have until noninvasive methods capable of detecting early raised lesions are available. True primary prevention of atherosclerosis, as contrasted with primary prevention of clinically manifest atherosclerotic disease, must begin in childhood or adolescence.