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.