Arthur W. Zieske

Obesity Accelerates the Progression of Coronary Atherosclerosis in Young Men

Background—Obesity is a risk factor for adult coronary heart disease and is increasing in prevalence among youths as well as adults. Results regarding the association of obesity with atherosclerosis are conflicting, particularly when analyses account for other risk factors. Methods and Results—The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study collected arteries, blood, and other tissue from ≈3000 persons aged 15 to 34 years dying of external causes and autopsied in forensic laboratories. We measured gross atherosclerotic lesions in the right coronary artery (RCA), American Heart Association (AHA) lesion grade in the left anterior descending coronary artery (LAD), serum lipid concentrations, serum thiocyanate (for smoking), intimal thickness of renal arteries (for hypertension), glycohemoglobin (for hyperglycemia), and adiposity by body mass index (BMI) and thickness of the panniculus adiposus. BMI in young men was associated with both fatty streaks and raised lesions in the RCA and with AHA grade and stenosis in the LAD. The effect of obesity (BMI>30 kg/m2) on RCA raised lesions was greater in young men with a thick panniculus adiposus. Obesity was associated with non-HDL and HDL (inversely) cholesterol concentrations, smoking (inversely), hypertension, and glycohemoglobin concentration, and these variables accounted for ≈15% of the effect of obesity on coronary atherosclerosis in young men. BMI was not associated with coronary atherosclerosis in young women although there was trend among those with a thick panniculus adiposus. Conclusions—Obesity is associated with accelerated coronary atherosclerosis in adolescent and young adult men. These observations support the current emphasis on controlling obesity to prevent adult coronary heart disease.

Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis

Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.

Morphologic Findings of Coronary Atherosclerotic Plaques in Diabetics A Postmortem Study

Objective—Coronary atherosclerotic plaque composition of diabetic subjects and localization of receptor for advanced glycation end products (RAGE) and its ligands have not been extensively studied. Method and Results—Hearts from diabetic subjects and age, race, and sex-matched nondiabetic subjects dying suddenly were examined. Coronary arteries were dissected and lesions were evaluated for plaque burden, necrotic core size, and inflammatory infiltrate. The expression of RAGE, the RAGE-binding protein (S100-A12, EN-RAGE), and cell death (apoptosis) were also determined. Lesions from type II diabetic subjects had larger mean necrotic cores (P= 0.01) and greater total and distal plaque load (P <0.001) than nondiabetic subjects. Necrotic core size correlated positively with diabetic status, independent of other risk factors. Intimal staining for macrophages, T-cells, and HLA-DR was also significantly greater in diabetic subjects (P =0.03, P =0.003, and P <0.0001), respectively. The association of increased macrophage infiltrate was independent of cholesterol levels and patient age. Expression of RAGE and EN-RAGE was significantly greater in diabetic subjects (P =0.004) and was associated with apoptotic smooth muscle cells and macrophages. Conclusion—In sudden coronary death, inflammation and necrotic core size play a greater role in the progression of atherosclerosis in diabetic subjects. The expression of RAGE and EN-RAGE may further compromise cell survival and promote plaque destabilization.

Elevated C-Reactive Protein Values and Atherosclerosis in Sudden Coronary Death Association With Different Pathologies

Background—Elevations in serum C-reactive protein measured by high-sensitivity assay (hs-CRP) have been associated with unstable coronary syndromes. There have been no autopsy studies correlating hs-CRP to fatal coronary artery disease. Methods and Results—Postmortem sera from 302 autopsies of men and women without inflammatory conditions other than atherosclerosis were assayed for hs-CRP. There were 73 sudden deaths attributable to atherothrombi, 71 sudden coronary deaths with stable plaque, and 158 control cases (unnatural sudden deaths and noncardiac natural deaths without conditions known to elevate CRP). Atherothrombi were classified as plaque ruptures (n=55) and plaque erosion (n=18); plaque burden was estimated in each heart. Total cholesterol, high-density lipoprotein cholesterol, diabetes, smoking history, and body mass index were also determined. Immunohistochemical stains for CRP and numbers of thin cap atheromas per heart were quantitated in coronary deaths with hs-CRP in the highest and lowest quintiles. The median hs-CRP was 3.2 &mgr;g/mL in acute rupture, 2.9 &mgr;g/mL in plaque erosion, 2.5 &mgr;g/mL in stable plaque, and 1.4 &mgr;g/mL in controls. Mean log hs-CRP was higher in rupture (P <0.0001), erosion (P =0.005), and stable plaque (P =0.0003) versus controls. By multivariate analysis, atherothrombi (P =0.02), stable plaque (P =0.003), and plaque burden (P =0.03) were associated with log hs-CRP independent of age, sex, smoking, and body mass index. Mean staining intensity for CRP of macrophages and lipid core in plaques was significantly greater in cases with high hs-CRP than those with low CRP (P =0.0001), as were mean numbers of thin cap atheromas (P <0.0001). Conclusions—hs-CRP is significantly elevated in patients dying suddenly with severe coronary artery disease, both with and without acute coronary thrombosis, and correlates with immunohistochemical staining intensity and numbers of thin cap atheroma.

Associations of Coronary Heart Disease Risk Factors With the Intermediate Lesion of Atherosclerosis in Youth

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.

BACKGROUND 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). CONCLUSIONS -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.

Effects of Coronary Heart Disease Risk Factors on Atherosclerosis of Selected Regions of the Aorta and Right Coronary Artery

We examined topographic distributions of atherosclerosis and their relation to risk factors for adult coronary heart disease in right coronary arteries and abdominal aortas of more than 2000 autopsied persons 15 through 34 years of age. We digitized images of Sudan IV-stained fatty streaks and of manually outlined raised lesions and computed the percent surface area involved by each lesion in each of 6 regions of each artery. In abdominal aortas of 15- to 24-year-old persons, fatty streaks involve an elongated oval area on the dorsolateral intimal surface and another oval area in the middle third of the ventral surface. Raised lesions in 25- to 34-year-old persons involve an oval area in the distal third of the dorsolateral intimal surface. In other areas of the abdominal aortas of older persons, fatty streaks occur but raised lesions are rare. In the right coronary arteries of 15- to 24-year-old persons, fatty streaks are most frequent on the myocardial aspect of the first 2 cm. Raised lesions follow a similar pattern in 25- to 34-year-old persons. High non-HDL cholesterol and low HDL cholesterol concentrations are associated with more extensive fatty streaks and raised lesions in all regions of both arteries. Smoking is associated with more extensive fatty streaks and raised lesions of the abdominal aorta, particularly in the dorsolateral region of the distal third of the abdominal aorta. Hypertension is not associated with fatty streaks in whites or blacks but is associated with more extensive raised lesions in blacks. Risk factor effects on arterial regions that are vulnerable to lesions are approximately 25% greater than risk factor effects assessed over entire arterial segments. These risk factor effects on vulnerable sites emphasize the need for risk factor control during adolescence and young adulthood to prevent or delay the progression of atherosclerosis.

Effects of Nonlipid Risk Factors on Atherosclerosis in Youth With a Favorable Lipoprotein Profile

Background—The strong association between coronary heart disease and dyslipoproteinemia has often overshadowed the effects of the nonlipid risk factors–smoking, hypertension, obesity, and diabetes and impaired glucose tolerance–and even led to questioning the importance of these risk factors in the presence of a favorable lipoprotein profile. Methods and Results—A cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY), examined the relation of the nonlipid risk factors to atherosclerosis in 629 men and 227 women 15 to 34 years of age who died of external causes and who had a favorable lipoprotein profile (non-HDL cholesterol <4.14 mmol/L [<160 mg/dL] and HDL cholesterol ≥0.91 mmol/L [≥35 mg/dL]). In the abdominal aorta, smokers had more extensive fatty streaks and raised lesions than nonsmokers, and hypertensive blacks had more raised lesions than normotensive blacks. In the right coronary artery, hypertensive blacks had more raised lesions than normotensive blacks, obese men (body mass index ≥30 kg/m2) had more extensive fatty streaks and raised lesions than nonobese men, and individuals with impaired glucose intolerance had more extensive fatty streaks. Obese men had more severe lesions (American Heart Association grade 2 through 5) of the left anterior descending coronary artery. Conclusions—These substantial effects of the nonlipid risk factors on the extent and severity of coronary and aortic atherosclerosis, even in the presence of a favorable lipoprotein profile, support the need to control all cardiovascular risk factors.

NATURAL HISTORY AND RISK FACTORS OF ATHEROSCLEROSIS IN CHILDREN AND YOUTH: THE PDAY STUDY

The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study was organized to document the natural history of athersclerosis and to determine the relation of cardiovascular risk factors to atherosclerosis in young subjects. Pathology laboratories in 15 centers collected coronary arteries, aortas, and other tissues from over 3,000 subjects age 15 to 34 who died of external causes between 1987 and 1994. The extent, prevalence, and topography of arterial lesions were evaluated and risk factors were analyzed in a central laboratory. Postmortem risk factors included serum lipoproteins, serum thiocyanate (smoking), glycohemoglobin (diabetes), thickness of panniculus adiposus and body mass index (obesity), changes in small renal arteries (hypertension), and apoprotein isoforms. The PDAY study confirmed the origin of atherosclerosis in childhood, showed that progression toward clinically significant lesions may occur in young adulthood and demonstrated that the progression of atherosclerosis is strongly influenced by coronary heart disease (CHD) risk factors. Recent PDAY studies have shown that a significant number of advanced coronary artery lesions have microscopic qualities associated with susceptibility to rupture and that CHD risk factors are associated with the development of these characteristic microscopic qualities. The PDAY archive continues to provide an important resource for new investigators throughout the world that contribute to the understanding of atherosclerosis, the underlying cause of most cardiovascular disease and the leading cause of debilitating illness and death in this country. The PDAY findings emphasize the need to modify risk factors in young people to retard the development of atherosclerotic lesions, particularly clinically significant lesions. Thus, true primary prevention of atherosclerosis must being in childhood or early adolescence.

C-Peptide Colocalizes with Macrophages in Early Arteriosclerotic Lesions of Diabetic Subjects and Induces Monocyte Chemotaxis In Vitro

Objective—Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. This study tested the hypothesis that C-peptide might participate in atherogenesis in these patients. Method and Results—We demonstrate significantly higher intimal C-peptide deposition in thoracic artery specimens from young diabetic subjects compared with matched nondiabetic controls as determined by immunohistochemical staining. C-peptide colocalized with monocytes/macrophages in the arterial intima of artery specimen from diabetic subjects. In vitro, C-peptide stimulated monocyte chemotaxis in a concentration-dependent manner with a maximal 2.3±0.4-fold increase at 1 nmol/L C-peptide. Pertussis toxin, wortmannin, and LY294002 inhibited C-peptide–induced monocyte chemotaxis, suggesting the involvement of pertussis toxin-sensitive G-proteins as well as a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In addition, C-peptide treatment activated PI3K in human monocytes, as demonstrated by PI3K activity assays. Conclusion—C-peptide accumulated in the vessel wall in early atherogenesis in diabetic subjects and may promote monocyte migration into developing lesions. These data support the hypothesis that C-peptide may play an active role in atherogenesis in diabetic patients and suggest a new mechanism for accelerated arterial disease in diabetes.