Pathobiological Determinants of Atherosclerosis in Youth (PDAY)
Condition: Cardiovascular Diseases; Atherosclerosis; Heart Diseases; Coronary Disease; Coronary Arteriosclerosis
MeSH terms: Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Disease; Coronary Artery Disease; Arteriosclerosis; Myocardial Ischemia
Study type: Observational

Summary: 
      To conduct a multicenter prevalence survey for characterizing pathologically the extent of
      atherosclerosis in the aortas and coronary arteries of young persons dying from accidental
      causes, suicide, or homicide.
    

Detailed description: 
      BACKGROUND:

      The International Atherosclerosis Project (IAP) quantified atherosclerosis of the aorta and
      coronary arteries in over 31,000 persons age 10 to 69 who died between 1960 and 1965 in
      fifteen cities and countries throughout the world. The IAP established that the average
      severity of atherosclerosis differed widely in many parts of the world and that the
      differences correlated with mortality from ischemic heart disease. It also demonstrated that
      the fatty streaks of childhood were prevalent and severe in both boys and girls. Fibrous
      plaques generally first appeared between the ages of 20 and 30 and in proportion to the
      prevalence of ischemic disease in the adult population. Since the results of the IAP were
      first published in 1968, research into atherosclerosis has changed greatly from gross and
      microscopic morphological methods to manipulation of experimental animals, in vitro culture
      of arterial wall cells, and the application of micro-chemical, physical chemical, and
      immunological techniques to tissues.

      The use of these newer techniques made it possible to test the hypothesis that a series of
      changes in the fatty streak between the ages of fifteen and twenty-five lead to the typical
      fibrous plaque and to test the hypothesis that lesions other than fatty streaks precede and
      may progress to fibrous plaques. The study also tested associations of the established risk
      factors for atherosclerosis with early stages of lesion progression as seen in young persons.

      The protocol for this study served as the basis of the protocol developed by the World Health
      Organization (WHO) Committee on Pathobiological Determinants of Atherosclerosis in Youth. It
      was planned to incorporate this study into the WHO study so that cross-cultural and
      geographic factors could be evaluated in populations with higher and lower incidence of
      atherosclerosis.

      DESIGN NARRATIVE:

      A common protocol was followed for collecting risk factor data and coronary arteries and
      aortas from approximately 1,000 autopsies per year for three years. Specimens were collected
      and preserved in a standardized way at each collection center. Data management and
      statistical analysis were conducted at the University of Texas in San Antonio. The unit at
      Louisiana State University was composed of three central laboratories: the lipid biochemistry
      center; the coronary heart disease risk factor center; and a gross morphology center. The
      morphometry central laboratory was located at Ohio State University. Administration and
      coordination were directed from the University of Chicago and the University of Illinois.

      In addition to serving as collection centers, many of the centers carried out individual
      research projects. At the University of Alabama in Birmingham, two separate but related
      investigations were conducted: Dr. Miller analyzed the various collagens by solubilizing them
      as peptide fractions and isolating the peptides via chromatography; Dr. Gay used monoclonal
      antibodies to define the distribution of the various collagens in atheromatous lesions. At
      the West Virginia University under Dr. Jagannathan, there were studies on isomeric fatty
      acids and proteoglycans. Dr. Reichenbach at the University of Washington studied the
      distribution of immunocytochemical markers of smooth muscle cell differentiation and
      leukocyte subpopulations in the coronary arteries as well as searched for viral DNA in
      plaques. At Baylor, the three-dimensional distribution of lipid inclusions, macrophages, and
      smooth muscle cells in coronary arteries were determined by digital fluorescence. Dr. Mergner
      of the University of Maryland collected specimens in the immediate autopsy program which
      provided specimens free of autolysis. He also performed transmission and scanning electron
      microscopy, X-ray microanalysis, lipid analysis, and immunofluorescence and immunoperoxidase
      procedures to define calcium content and cytoskeletal components. Dr. Virmani at Vanderbilt
      determined the role of biogenic amines such as histamine, serotonin, and catecholamines in
      atherosclerosis and correlated the content of amines with the presence of mast cells in the
      adventitia.

      In 1988, two regular research grants were awarded as part of this multicenter study. The
      grant at the Southwest Foundation for Biomedical Research determined the genotypes for each
      subject with respect to restriction fragment length polymorphisms in apolipoprotein and LDL
      receptor genes using Southern blot analyses of DNA from liver samples sent from each
      collection center. It also typed the subjects for apo E isoform genotypes using
      oligonucleotide probes. The grant at Ohio State University correlated 3-D coronary axial
      geometry and pathology.

      Some of the major questions addressed by the study included: whether some or all fatty
      streaks progressed to fibrous plaques and the transitional lesions; the morphometric and
      biochemical lesion changes indicated by progression; the frequency and features of insudative
      and proliferative lesions which may portend progressive disease; sex differences in lesions;
      whether immune complexes or viral infections were implicated.

      In FY 1991, six grants were awarded under the title "Risk Factors in Early Human
      Atherogenesis" (RFEHA). The purpose was to extend the ongoing PDAY and to : obtain an
      adequate number of female cases so that risk factor associations could be accurately detected
      and studied; to increase the power of the study in general to detect associations of risk
      factors with raised lesions, which began to appear in this age group; and to increase the
      power of the study to detect genetic influences on atherosclerosis. REFHA added 1,400 new
      specimens to the 1,800 cases already collected in PDAY to achieve approximately 3,000 total
      specimens. Emphasis was placed on female cases and those that provided the best opportunity
      to study transition lesions between fatty streaks and fibrous plaques.

      In 1998, the NHLBI awarded R24HL60808 for five years to provide and maintain an archive of
      human cardiovascular and other tissues which can be used by other United States and
      international investigators to study human atherosclerosis. The investigators, as part of
      PDAY and RFEHA, have assembled autopsy material (mostly of aorta and coronary artery, but
      with other tissues including liver, serum, and adipose tissue) from over 3,000 Black and
      white males and females. These were from autopsies on individuals ages 15 to 34 and obtained
      within 48 hours of death. The grant for the cardiovascular specimen and data library was
      renewed through July 2007.