Histological changes and risk factor associations in type 2 atherosclerotic lesions (fatty streaks) in young adults.

OBJECTIVES: The purpose of this study was to investigate which histological changes associated with risk factors could contribute to the progression from the initial atherosclerotic lesions including fatty streaks to the advanced lesions. METHODS: We examined the associations of histomorphometric findings in the determined anatomical sites of mid-thoracic aortas (TAs) and left anterior descending coronary arteries (LADs) with major risk factors for atherosclerosis, using a young autopsied series from the the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. The histological classification by the American Heart Association was graded for 1013 TAs and 1009 LADs. Histometric study, including immunohistochemistry, was performed in type 2 lesions (fatty streaks) of TAs from 59 subjects and LADs from 45 ones. RESULTS: For the progression from the initial lesions into the advanced atherosclerotic lesions, the most effective lipid profiles were low plasma HDL-C in TA and elevated serum non-HDL-C in LAD. This lipid profile of each artery correlated with number or density of intimal smooth muscle cell-derived foam cells, respectively. The serum concentration of non-HDL-C correlated with macrophage foam cells in TAs. Hypertension and hyperglycemia were associated with increase of intimal area and/or collagen content in both arteries, but not with either types of foam cell proliferation. Smoking correlated with increased collagen content in TAs. CONCLUSION: There were histologically different ways of progressing from fatty streaks to advanced atherosclerotic lesions depending on the risk factors. For the atherosclerosis progression from type 2 lesions to advanced lesions, increase in number of smooth muscle cell-derived foam cells could be an important indicator.

Heparin cofactor II in atherosclerotic lesions from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study.

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin) that has been shown to be a predictor of decreased atherosclerosis in the elderly and protective against atherosclerosis in mice. HCII inhibits thrombin in vitro and HCII-thrombin complexes have been detected in human plasma. Moreover, the mechanism of protection against atherosclerosis in mice was determined to be the inhibition of thrombin. Despite this evidence, the presence of HCII in human atherosclerotic tissue has not been reported. In this study, using samples of coronary arteries obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, we explore the local relationship between HCII and (pro)thrombin in atherosclerosis. We found that HCII and (pro)thrombin are co-localized in the lipid-rich necrotic core of atheromas. A significant positive correlation between each protein and the severity of the atherosclerotic lesion was present. These results suggest that HCII is in a position to inhibit thrombin in atherosclerotic lesions where thrombin can exert a proatherogenic inflammatory response. However, these results should be tempered by the additional findings from this, and other studies, that indicate the presence of other plasma proteins (antithrombin, albumin, and alpha(1)-protease inhibitor) in the same localized region of the atheroma.

Thieno[2,3-c]isoquinolin-5-one, a potent poly(ADP-ribose) polymerase inhibitor, promotes atherosclerotic plaque regression in high-fat diet-fed apolipoprotein E-deficient mice: effects on inflammatory markers and lipid content.

We recently showed that poly(ADP-ribose) polymerase (PARP) is activated within atherosclerotic plaques in an animal model of atherosclerosis. Pharmacological inhibition of PARP or reduced expression in heterozygous animals interferes with atherogenesis and may promote factors of plaque stability, possibly reflecting changes in inflammatory and cellular factors consistent with plaque stability. The current study addresses the hypothesis that pharmacological inhibition of PARP promotes atherosclerotic plaque regression. Using a high-fat diet-induced atherosclerosis apolipoprotein E(-/-) mouse model, we demonstrate that administration of the potent PARP inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), when combined with a regular diet regimen during treatment, induced regression of established plaques. Plaque regression was associated with a reduction in total cholesterol and low-density lipoproteins. Furthermore, plaques of TIQ-A-treated mice were highly enriched with collagen and smooth muscle cells, displayed thick fibrous caps, and exhibited a marked reduction in CD68-positive macrophage recruitment and associated foam cell presence. These changes correlated with a significant decrease in expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1, potentially as a result of a robust reduction in tumor necrosis factor expression. The PARP inhibitor appeared to affect cholesterol metabolism by affecting acyl-coenzymeA/cholesterol acyltransferase-1 expression but exerted no effect on cholesterol influx or efflux as assessed by an examination of the ATP-binding cassette transporter-1 and the scavenger receptor-A expression levels in the different experimental groups. In accordance, PARP inhibition may prove beneficial not only in preventing atherogenesis but also in promoting regression of preexisting plaques.

Associations of arterial tissue lipids with coronary heart disease risk factors in young people.

OBJECTIVE: To examine the associations of the coronary heart disease (CHD) risk factors with lipid composition of arterial tissue in 397 autopsied subjects 15-34 years of age from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. METHODS AND RESULTS: We measured esterified cholesterol, free cholesterol, and phospholipid in the left circumflex coronary artery and two segments of the abdominal aorta, one of which is more susceptible to advanced atherosclerosis than the other, and also measured the major CHD risk factors. Non-HDL cholesterol concentration was positively associated, and HDL cholesterol concentration was negatively associated, with tissue lipids in the left circumflex coronary artery and the abdominal aorta. Hypertension was positively associated with tissue lipids in both arteries. Hyperglycemia was associated with tissue lipids in the left circumflex coronary artery and smoking with lipids in the abdominal aorta. PDAY risk scores summarize the effects of the CHD risk factors on advanced atherosclerosis. These risk scores, computed from the mutable risk factors, were associated with tissue lipids in the left circumflex coronary artery and both segments of the abdominal aorta. CONCLUSIONS: The CHD risk factors are associated with lipids in arterial tissue just as they are associated with gross and microscopic lesions. These results support the proposal that early control of risk factors is likely to prevent or delay progression of atherosclerosis and prevent or delay the onset of CHD.

Histological topographical comparisons of atherosclerosis progression in juveniles and young adults.

BACKGROUND: The histologically topographic comparisons on atherosclerosis progression among three anatomical sites, mid-thoracic and lower abdominal aorta and left anterior descending coronary artery (LAD) were performed using a young population (age 15-34 years) from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. METHODS AND RESULTS: The histological classification based on the American Heart Association grading scheme showed that in the thoracic aorta type 2 lesions (numerous macrophage foam cells with fine particles but no pools of extracellular lipid) appeared in the first 10-year age group, with no significant change in prevalence in the next 10 years. Lesions greater than type 2 were rarely seen in the thoracic aorta. Although type 2 lesions appeared later in the LAD than in the aorta, the lesions within the LAD progressed rapidly to more advanced lesions (types 4 and 5) or atheroma. Lesion development in the abdominal aorta was intermediate to lesion development in the thoracic aorta and the LAD. CONCLUSIONS: The most striking topographic difference on lesion progression among the three anatomical sites was the vulnerability of type 2 lesions to progress into advanced lesions. The histology study, including immunohistochemistry limited to the type 2 lesions suggested that lesion progression was related to the intimal thickness and the amount of collagen but not to the number of macrophage foam cells.

Comparison of coronary heart disease risk factors in autopsied young adults from the PDAY Study with living young adults from the CARDIA study.

BACKGROUND: Disease is sometimes best studied by examination of tissue obtained from autopsied individuals. Results derived from autopsied persons are considered biased because many factors influence the decision to perform an autopsy, and variables measured postmortem may be affected by changes immediately prior to death and emergency medical treatment. METHODS: The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study measured coronary heart disease risk factors postmortem in autopsied young adults 23-34 years of age dying from external causes (accidents, homicides, suicides). The Coronary Artery Risk Development in Young Adults (CARDIA) study measured risk factors in living subjects of similar ages. RESULTS: Within sex, race, and age groups, the differences in body mass index between PDAY and CARDIA were significant but small. The prevalences of hyperglycemia/diabetes within sex, race, and age groups were similar in PDAY and CARDIA; overall, blacks in PDAY, but not in CARDIA, had a higher prevalence than whites. Serum lipoprotein concentrations were slightly and significantly higher and significantly more variable in PDAY subjects than in CARDIA subjects; the greater variability was interpreted as due primarily to emergency medical treatment. Prevalences of smoking and hypertension were substantially higher in PDAY subjects. CONCLUSIONS: Although there were statistically significant differences, the overall similarity of the risk factors in the two studies supports the validity of investigating associations of risk factors measured postmortem with anatomically determined arterial lesions in autopsied young adults dying from external causes. The greater variability in postmortem serum measurements attenuates but does not obscure associations.

PDAY risk score predicts advanced coronary artery atherosclerosis in middle-aged persons as well as youth.

A risk score formula to estimate the probability of advanced atherosclerosis using coronary heart disease (CHD) risk factors was developed for persons 15-34 years of age by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. We applied the PDAY risk score to autopsied individuals from the Community Pathology Study (CPS), a different population that included middle-aged as well as young subjects. The PDAY risk score was associated with extent of raised lesions in the coronary arteries of CPS cases 15-34 years of age. The PDAY risk score computed from only the modifiable risk factors was associated with extent of raised lesions in the coronary arteries of subjects 35-54 years of age. The association of the PDAY risk score with lesions in 15-34 year old CPS subjects validates the PDAY risk score. The associations in both younger (15-34 years) and older (35-54 years) subjects suggest a seamless progression of the effects of the modifiable risk factors on atherosclerosis from 15 to 54 years of age. These results support the proposal that early control of risk factors is likely to prevent or delay the onset of CHD.

Aortic rhythmic wrinkling in youth: the PDAY study.

Transverse, white-streak 'wrinkles' in the aorta were first described as Querlinien (cross lines) or Wellenlinien (wave lines) in the German literature in the early 20th century. These rhythmic structures were previously thought to be artifacts of stretching and shrinkage of the aorta. Not until the 1970s was it proposed that the areas of rhythmic wrinkling (RW) might be part of the process of atherosclerosis. We analyzed 2,650 aortas from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study for prevalence, extent, and topographical distribution of these areas of RW. Furthermore, we investigated the possible relationship of RW to atherosclerotic sudanophilic stained 'fatty streaks' and elevated intimal lesions called 'raised lesions' (RL). This study provides evidence that (1) the prevalence of RW is fairly high in the aorta and occurs in a specific distribution in both the thoracic and abdominal aorta; (2) RW seems to precede the development of RL, with RL occurring in the same topographical areas as RW; and (3) RW may be associated with the subsequent development of advanced atherosclerosis, particularly raised lesions.

Pathobiological determinants of atherosclerosis in youth risk scores are associated with early and advanced atherosclerosis.

OBJECTIVES: Atherosclerosis begins in childhood and progresses during adolescence and young adulthood. The Pathobiological Determinants of Atherosclerosis in Youth Study previously reported risk scores to estimate the probability of advanced atherosclerotic lesions in young individuals aged 15 to 34 years using the coronary heart disease risk factors (gender, age, serum lipoprotein concentrations, smoking, hypertension, obesity, and hyperglycemia). In this study we investigated the relation of these risk scores to the early atherosclerotic lesions. METHODS: We measured atherosclerotic lesions in the left anterior descending coronary artery, right coronary artery, and abdominal aorta and the coronary heart disease risk factors in persons 15 to 34 years of age who died as a result of external causes and were autopsied in forensic laboratories. RESULTS: Risk scores computed from the modifiable risk factors were associated with prevalence of microscopically demonstrable lesions of atherosclerosis (American Heart Association grade 1) in the left anterior descending coronary artery and with the extent of the earliest detectable gross lesion (fatty streaks) in the right coronary artery and abdominal aorta. Risk scores computed from the modifiable risk factors also were associated with prevalence of lesions of higher degrees of microscopic severity (intermediate as well as advanced) in the left anterior descending coronary artery and with extent of lesions of higher degrees of severity (intermediate and raised lesions) in the right coronary artery and abdominal aorta. CONCLUSIONS: Risk scores calculated from traditional coronary heart disease risk factors to identify individual young persons with high probability of having advanced atherosclerotic lesions also are associated with earlier atherosclerotic lesions, including the earliest anatomically demonstrable atherosclerotic lesion. These results support lifestyle modification in youth to prevent development of the initial lesions and the subsequent progression to advanced lesions and, thereafter, to prevent or delay coronary heart disease.

Smoking is associated with advanced coronary atherosclerosis in youth.

Smoking is linked to atherosclerosis and coronary heart disease (CHD) in older adults. However, evidence that smoking affects coronary atherosclerosis in young people is incomplete. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study collected arteries, blood, and other tissues from persons 15 to 34 years of age dying of external causes and autopsied in forensic laboratories. Lesions in the proximal left anterior descending coronary arteries (LAD) from 1127 subjects were graded microscopically according to the American Heart Association criteria. Among individuals with advanced lesions (Grade 4 or 5), smokers had a greater prevalence of Grade 5 lesions than non-smokers (odds ratio 9.61, 95% confidence interval 2.34-39.57), a difference suggesting that smoking accelerates the transition from Grade 4 to Grade 5 lesions. This association occurred among both men and women, and among persons with and without other CHD risk factors. The difference in qualities of advanced lesions suggests that smoking possibly accelerates the transition from Grade 4 to Grade 5 lesions by promoting thrombosis and accretion on the intimal surface of the plaque.