Henry C. McGill

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.

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.

Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study

We could prevent 90% of heart attacks. Such a claim would have seemed outrageous in the 1960s, as the coronary heart disease (CHD) epidemic reached new heights and accounted for one third of all deaths in the United States and most other developed countries.1 The identification of conditions that predicted the probability of CHD (known as “risk factors”) stimulated hope that modification of these risk factors would reduce the frequency of CHD. Long before this idea was validated in clinical trials, individual physicians2,3 and voluntary health agencies4 began in the 1960s to promote the concept to the public. Many individuals accepted the idea, and many physicians adopted the recommendations in their practices. The US CHD mortality rate declined to approximately half its former level by 1990.5 The associated favorable changes in risk factors accounted for about half of this decline, whereas improved treatment of CHD accounted for the other half.6 The extent and severity of atherosclerosis also declined during this period.7,8 CHD mortality continued to decline after 1990 but at a slower rate, and CHD remained the leading cause of death in the United States.9 A convergence of evidence from diverse sources in the last 2 decades now indicates that the claim that we can prevent 90% of CHD should no longer be thought of as outrageous but as achievable. For example, the absence of the major established CHD risk factors at 50 years of age has been shown to indicate a 90% lower lifetime risk (to age 95 years) for men and a 79% lower risk for women.10,* Subjects in several large cohorts without any of the major risk factors who were followed up for 16 to 22 years had 77% to 92% lower (men) or 79% lower (women) …

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.

Nuclear uptake of sex steroid hormones in the cardiovascular system of the baboon.

Cardiac and arterial tissues of six male and six female adult baboons were examined for nuclear uptake of tritiated 5-a-dihydrotestosterone (3H-DHT) or tritiated estradiol-17/S (H-E2) by autoradiography.3H-DHT uptake occurred in nuclei of most atrial and ventricular myocardial fibers, no cardiac interstitial tissues, some arterial endothelial cells, most smooth muscle cells of the intima and inner arterial media, and a few smooth muscle cells of the outer arterial media. 3H-E2 uptake occurred in nuclei of a few atrial and ventricular myocardial fibers, many cardiac interstitial cells, occasional arterial endothelial cells, a few smooth muscle cells of the intima and inner arterial media, smooth muscle cells of the outer arterial media, and nearly all adventitial cells. These observations are consistent with other autoradiographic and biochemical findings which indicate that the heart and major arteries of several mammalian species contain androgen and estrogen receptors in distinctive patterns of distribution among muscle and connective tissue cells. Circ Res 48: 238-244, 1981

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.

Relationship of lipoprotein cholesterol concentrations to experimental atherosclerosis in baboons.

For 26 months, we fed 60 baboons a high saturated fat, high cholesterol diet that contained very low concentrations of four common pesticides (chlordane, parathlon, dlazlnon, and carbofuran). We detected no effect of pesticides on body weight, serum llpld, or Iipoprotein cholesterol concentrations, or experimental atherosclerosis. We then examined the associations of serum llpld and Iipoprotein cholesterol concentrations {predictor variables) with arterial lesions (naponto variables). Among predictor variables, very low density Iipoprotein plus low density Iipoprotein cholesterol concentration showed a positive association with fatty streaks in the aorta and its major branches, Including the coronary arteries, while high density Iipoprotein cholesterol concentration showed a consistently negative association. The very low density Iipoprotein plus low density llpoproteln/hlgh density Iipoprotein cholesterol ratio was more highly associated with lesions than was either value alone. These results are consistent with epidemlologic evidence suggesting that high density Iipoprotein cholesterol concentration Is Inversely related to probability of developing clinically manifest atherosclerotic disease.

Effects of estrogen and progesterone on plasma lipoproteins and experimental atherosclerosis in the baboon (Papio sp.).

We determined the effect of estrogen and progesterone on plasma cholesterol and lipoprotein cholesterol concentrations and on arterial lesions in 24 ovariectomized and hysterectomized baboons fed a high-cholesterol/high-saturated-fat diet. These baboons were divided into four groups: untreated control (C); estrogen, 100 micrograms/kg/week injected i.m. (E); progesterone, 3 mg/kg/day (P); and estrogen plus progesterone (E + P). The treatment regimen continued for 18 months. Cholesterol levels in plasma and lipoproteins were measured before hormone treatment and at 3, 10, and 18 months of treatment. Postheparin plasma lipoprotein lipase (LPL) activity was also measured during the treatment. After 18 months of hormone treatment, baboons were necropsied and arterial lesions were measured. Hormone treatment significantly influenced plasma cholesterol (P greater than C greater than [E + P] greater than E) and very low density lipoprotein plus low density lipoprotein (VLDL + LDL) cholesterol (P greater than C greater than [E + P] greater than E), with very little effect on high density lipoprotein (HDL) cholesterol concentration. The E + P group had a significantly higher HDL cholesterol concentration than did the P group. The (VLDL + LDL)/HDL cholesterol ratios in the E and E + P groups were significantly lower than those in the P and C groups. LPL activities were significantly lower in the E group compared with those in the E + P and P groups. Hormone treatment significantly influenced lesions in four (innominate, carotid, iliac, and abdominal aorta) of seven arteries. The P group had the most fatty streaks, and the E + P group had the least.(ABSTRACT TRUNCATED AT 250 WORDS)