Edward E. Herderick

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.

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.

Increase in atherosclerosis and adventitial mast cells in cocaine abusers: An alternative mechanism of cocaine-associated coronary vasospasm and thrombosis

Coronary vasospasm has been implicated as a cause of myocardial ischemia and sudden cardiac death in cocaine abusers. However, the mechanism or mechanisms remain unknown. Autopsy records (n = 5,871) from the medical examiners files at Baltimore, Maryland and northern Virginia were examined and 495 persons (8.4%) were identified with positive toxicologic findings for cocaine. Of these, six subjects (1.2%) had total thrombotic occlusion, involving primarily the left anterior descending coronary artery. The mean number of adventitial mast cells per coronary segment and the degree of atherosclerosis were determined. These observations were compared with findings in age- and gender-matched subjects who died from cocaine overdose and in patients who had sudden cardiac death (acute thrombosis) without a history of illicit drug abuse. There were significantly more mast cells in subjects with cocaine-associated thrombosis than in the other groups. The number of mast cells showed a significant correlation with the degree of cross-sectional luminal narrowing (r = 0.68) in subjects with cocaine-associated thrombosis but not in subjects with sudden death due to thrombosis (r = 0.34, p less than 0.03). Subjects with cocaine-associated thrombosis also had significant coronary atherosclerosis without plaque hemorrhage (five had one or more vessels with greater than 75% cross-sectional area luminal narrowing) despite a mean age of 29 +/- 2 years. These findings suggest that adventitial mast cells may potentiate atherosclerosis and vasospasm, thrombosis and premature sudden death in long-term cocaine abusers.

Hypercholesterolemia in the Rabbit Induced by Feeding Graded Amounts of Low-Level Cholesterol: Methodological Considerations Regarding Individual Variability in Response to Dietary Cholesterol and Development of Lesion Type

While a number of studies have presented detailed examinations of lesion development in the cholesterol-fed rabbit, individual variability in response to cholesterol feeding and type of lesion produced relative to the degree of cholesterol exposure is not well defined. This study analyzed such critical parameters in an attempt to further characterize the model and establish a baseline for future testing of treatments targeted at limiting atherosclerosis. For these experiments, male New Zealand White rabbits were fed atherogenic diets consisting of 0.05%, 0.10%, 0.15%, 0.20%, or 0.25% cholesterol dissolved in 6% peanut oil for 31 to 32 weeks. Raising dietary cholesterol from 0.05% to 0.15% resulted in a less than twofold stepwise increase in total plasma cholesterol (TPC) exposure (area under plasma cholesterol versus time curve), whereas further increases in cholesterol intake resulted in an exponential four- to fivefold increase in TPC exposure. Regression analysis of TPC exposure with aortic sudanophilia demonstrated a threshold of approximately 5000 cholesterol weeks; below this limit lesions were minimal, and above this value the degree of plaque correlated with TPC exposure. Furthermore, a wide biological variability occurred among rabbits with respect to individual responsiveness to dietary cholesterol. In the aorta, various types of plaques, from fatty streaks to atheromatous lesions, were observed, depending on the degree of cholesterol intake. Diets consisting of < 0.15% cholesterol resulted in the development of fatty streak lesions, while transitional lesions and atheromatous plaques were mostly found with higher cholesterol feeding. Coronary artery atherosclerosis was present in > 50% of animals fed diets > or = 0.15% cholesterol. Despite the level of TPC exposure, coronary lesions in epicardial vessels were generally the fibrous type, whereas intramyocardial arteries demonstrated predominantly intimal foam cells. In conclusion, by adjusting dietary cholesterol intake and selecting rabbits with a similar responsiveness to cholesterol, the overall cholesterol exposure can be more closely controlled to minimize the inherent individual variability among animals in this model. The nature of the target lesion must also be carefully considered, because the efficacy of some treatments may depend on the type of atherosclerotic plaque.

Gene Expression Phenotypes of Atherosclerosis

Objective—Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues. Methods and Results—We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility. We find gene expression signatures that relate to each of these disease measures and are reliable and robust in predicting the classification for new samples with >93% in each analysis. The genes that provide the predictive power include many previously suspected to play a role in atherosclerosis and additional genes without prior association with atherosclerosis. Conclusion—Hence, we are reporting a novel method for generating a molecular phenotype of disease and then identifying genes whose discriminatory capability strongly implicates their potential roles in human atherosclerosis.

Relation of a Postmortem Renal Index of Hypertension to Atherosclerosis and Coronary Artery Size in Young Men and Women

In a cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth, we measured atherosclerosis of the aorta and right coronary artery (RCA) in 2403 black and white men and women 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories. We measured the diameter of the opened, flattened, and fixed RCA and the diameter, intimal thickness, intimal cross-sectional area, medial thickness, and medial cross-sectional area of the pressure-perfused, fixed left anterior descending (LAD) coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure during life, we classified the cases as normotensive (mean arterial pressure < 110 mm Hg) or hypertensive (mean arterial pressure > or = 110 mm Hg). The prevalence of hypertension by age, sex, and race corresponded closely with that measured in a survey of the living population. Hypertension had little or no effect on fatty streaks. Hypertension was associated with more extensive raised lesions in the abdominal aortas and RCAs of blacks > 20 years of age and in the RCAs of whites > 25 years of age. At all ages, women had less extensive raised lesions in the RCAs than did men, but the effect of hypertension on raised lesions was similar to that in men. Adjustment for serum lipoprotein cholesterol levels and smoking in a subset of cases yielded results similar to those obtained without adjustment. Hypertension was associated with larger diameters of the RCA and LAD coronary artery and with larger cross-sectional intimal and medial areas of the LAD coronary artery. Hypertension augments atherosclerosis in both men and women primarily by accelerating the conversion of fatty streaks to raised lesions beginning in the third decade of life, and the effect of hypertension increases with age.

Quantitative study of the rabbit aortic endothelium using vascular casts

A quantitative study of the en face size and shape of rabbit endothelial cells from the ventral mid-thoracic and ventral infrarenal abdominal aorta has been carried out in 6 rabbits. Photomicrographs were taken from vascular casts of the rabbit aorta and the endothelial cell outlines were analyzed quantitatively using a digitizer and digital computer. The morphology of the endothelial cells was described using 8 calculated parameters (area, perimeter, length, width, angle of orientation, width:length ratio, axis intersection ratio and shape index). The endothelial cells in both locations had the same surface area (P greater than 0.30); however, the cells in the abdominal aorta were longer (P less than 0.01) and narrower (P less than 0.01) than those in the thoracic aorta. This fact is reflected by the smaller value for the shape index and width : length ratio in the abdominal aorta (P less than 0.01). Cells in both the thoracic and abdominal aorta were aligned with the flow direction.

Topographic study of sudanophilic lesions in cholesterol-fed minipigs by image analysis.

A new morphometric technique using Image analysis has been developed to express the topographic distribution of atherosclerotic lesions in unambiguous statistical terms. Computer-stored Images of opened Sudan IV-stalned aortas and lilac and coronary arteries from hypercholesterolemic minipigs (n = 39) were used In this study. The Image processing methods included transformation of the data to standard templates, automated image segmentation, and creation of probabllity-of-occurrence maps. These maps have shown that sudanophilic lesions are localized with a characteristic topography along the aortas and lilac and coronary arteries. Areas of high probability are associated with the entrance regions of vessels and the lateral leading edges of the major flow dividers. Regions Immediately distal to large branches were found to be areas of low probability. Despite the association of areas of sudanophllia with entrance regions and branch points, a major portion of sudanophilic lesions was not associated with any orifice region (e.g., ductus scar, dorsolateral surface of abdominal aorta, and ventral surface of terminal aorta). The present study provides the necessary Information for the development of a rational sampling strategy for the experimental study of the distribution of localizing factors (e.g., hemodynamic, biochemical, cellular, mass transport, hlstological) and their relationships to putative atherogenic mechanisms.

Elevated Serum C-Reactive Protein Levels and Advanced Atherosclerosis in Youth

Objective—To determine the associations among serum C-reactive protein (CRP) concentration, age, sex, risk factors for coronary heart disease (CHD), and atherosclerosis in young people. Methods and Results—In 1244 subjects 15 to 34 years of age, we measured gross atherosclerotic lesions in the right coronary artery (RCA) and abdominal aorta (AA) and American Heart Association (AHA) lesion grade in the left anterior descending (LAD) coronary artery; serum CRP, lipoprotein cholesterol, and thiocyanate (for smoking) concentrations; intimal thickness of renal arteries (for hypertension); glycohemoglobin (for hyperglycemia); and body mass index (for obesity). Serum CRP levels increased with age, were higher in women than in men, and were positively related to obesity and hyperglycemia. Serum CRP ≥10 mg/L was associated with more extensive gross raised lesions in the RCA after age 25 and in the AA after age 30. Serum CRP ≥3 was associated with a greater prevalence of AHA grade 5 lesions in the proximal LAD coronary artery after age 25. The associations of CRP with lesions were independent of the traditional CHD risk factors. Conclusion—Serum CRP level is independently associated with advanced atherosclerosis in young persons.