Atherosclerosis in youth.

BACKGROUND: Coronary heart disease (CHD) and the related diseases due to atherosclerosis continue to be major public health problems in the industrialized countries and are likely to become serious problems in the developing countries. Treatment of end stage disease has improved, and risk factor modification has succeeded in reducing risk among adults. However, the age at which to begin risk factor control for long-range primary prevention is controversial. METHODS: A multicenter cooperative study, Pathobiological Determinants of Atheroscle-rosis in Youth (PDAY), was organized in 1985 to examine the relationship of the risk factors for adult CHD to preclinical atherosclerotic lesions in youth. Fourteen participating centers collected arteries, blood, other tissue, and data from 3,000 persons 15-34 years of age who died from external causes and were autopsied in forensic laboratories. Central laboratories evaluated atherosclerosis in the aorta and coronary arteries, measured lipoproteins and thio-cyanate (for smoking) in serum, glycohemo-globin in red blood cells (for blood glucose), thickness of small renal arteries (for hypertension), and body mass index (for obesity). The data were analyzed to determine the progression of atherosclerosis with age in both sexes and the association of the risk factors with atherosclerotic lesions. RESULTS: Raised lesions of the coronary arteries, the advanced lesions of atherosclerosis that lead directly to CHD, are associated positively with non-HDL cholesterol concentration, hypertension, obesity (in men), and blood glucose concentration; and inversely, with HDL cholesterol concentration. Smoking affects predominantly the abdominal aorta. CONCLUSIONS: These results suggest that long-range prevention of CHD should begin in adolescence or at least in young adulthood with control of the major established risk factors for adult CHD.

Immunolocalization of apolipoproteins in aortic atherosclerosis in American youths and young adults: findings from the PDAY study.

The immunohistochemical distribution of apolipoproteins in the abdominal aortas of 142 men, 15-34 years of age, collected in a cooperative multicenter study group (Pathobiological Determinants of Atherosclerosis in Youth) was examined in relationship to serum VLDL+LDL+HDL cholesterol levels. ApoB deposits were limited to the intima of specimens with intimal fibro cellular thickening or atherosclerotic lesions. Apo A-I, E and J were observed in both the intima and media of the aortas with intimal lesions. The pattern of apoJ distribution was similar to that of apoA-I and E. The distribution patterns of these apolipoproteins in these young adults were very similar to those in adults and old men seen in an earlier study. The extent of apolipoprotein distribution in the intima and media increased with age and the stage of atherosclerosis development, but was not correlated significantly with serum VLDL+LDL or HDL cholesterol levels. The infiltration of lipoprotein particles into the aortic wall seems to be more strongly associated with the progression of intimal lesions rather than with serum cholesterol levels.

Histopathological modifications of early atherosclerotic lesions by risk factors--findings in PDAY subjects.

To investigate whether histopathological modifications on early atherosclerotic lesions differ according to risk factors, we compared the histological findings of arteries obtained from a multicenter study in the USA (Pathobiological Determinants of Atherosclerosis in Youth, PDAY) with the antemortem risk factors. The materials comprised aortas and left anterior descending (LAD) coronary arteries of 140 male subjects. Measurements of intimal thickness, classification of intimal lesions, and density of foam cells and intimal fibrosis at the determined sites of LAD and aorta were evaluated. In both arteries, intimal thickness of hypertensives was greater than the normotensives with no definite proliferation of foam cells. In aortas, hypercholesterolemia was associated with an increase in foam cells, but not with an increase in intimal thickness. HDL-C value correlated inversely with number of foam cells in both the arteries, and the degree of intimal thickness in LADs, where early appearance of advanced lesion such as preatheroma and atheroma, was also indicated in the low HDL-C group. Smokers had less number of foam cells in both the arteries and more intensive intimal fibrosis in LAD than non-smokers. Our study suggests that there are several ways to advanced atherosclerotic lesions by risk factors.

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/m(2)) 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.

Lipoproteins and atherosclerosis in children: an early marriage?

AIM: Describe the relationship between serum lipoproteins and the development of atherosclerosis in young subjects aged 15-34 years, and discuss the implications for prevention of coronary heart disease. DATA SYNTHESIS: Data from gross and microscopic evaluation of aorta and coronary arterial specimens as part of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study demonstrates that by the age of 15 years, all subjects have atherosclerosis. Lipoprotein risk factors for coronary heart disease are associated with the extent and prevalence of gross aortic and coronary atherosclerosis and with the development of microscopic coronary plaques that have qualities consistent with clinically significant lesions. Association of lipoprotein risk factors with intermediate type atherosclerotic lesions becomes evident in subjects in their late teens, whereas associations with raised lesions become evident in subjects greater than 25 years of age, consistent with a transitional role of intermediate lesion in the formation of advanced plaques. CONCLUSIONS: Atherosclerosis begins in childhood and a significant number of young people have advanced coronary artery plaques. Early atherosclerosis is accelerated by lipoprotein risk factors. Thus, long-range prevention of atherosclerosis should begin in childhood and should include measures to control hyperlipidemia.

Pathobiological determinants of atherosclerosis in youth (PDAY) cardiovascular specimen and data library.

In 1985, investigators organized a multi-center study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), to examine the relationships of cardiovascular risk factors to atherosclerosis involving more than 3,000 young persons 15 through 34 years of age who died of external causes. Reports from the PDAY group confirmed that atherosclerosis begins in the teens and showed that the progression of the lesions is strongly influenced by the same risk factors that predict risk of clinically manifest coronary disease in middle-aged adults. The results emphasize the need for early and aggressive control of all risk factors in young persons for long-range prevention of coronary heart disease and related diseases. Recent funding by the Louisiana Cancer and Lung Trust Fund (LCLTF) has assisted Pathology at Louisiana State University Health Sciences Center (LSUHSC) in the following objectives: (1) maintaining this national research resources; (2) making the unique specimens available to interested investigators; and (3) continuing support for studies at LSUHSC which investigate the effects of smoking on the development of atherosclerotic lesions.

Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

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. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth.

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.

Orthotopic human lung carcinoma xenografts in BALB/c mice immunosuppressed with anti-CD4 monoclonal antibodies and chronic alcohol consumption.

BACKGROUND: The role of the immune system in the surveillance of the body for cancer cells is well established. Human tumor cells do not survive in mice with intact immune systems, but they propagate in athymic nude mice. Presumably, the lack of a thymus gland and consequent loss of T lymphocytes results in a seriously compromised immune system without adequate cell-mediated immunity and tumor surveillance. In patients infected with the human immunodeficiency virus (HIV), a progressive loss of cell-mediated immunity is associated with the development of malignancies and opportunistic infections. This effect may be exacerbated in patients who chronically consume alcohol. METHODS: Normal and alcoholic BALB/c mice were treated with a monoclonal antibody to deplete CD4(+) lymphocytes before orthotopic implantation of human lung adenocarcinoma xenografts. Tumor volume and weight were measured and compared between groups. RESULTS: The authors' data show that a single treatment of anti-CD4 antibody causes almost complete depletion of CD4(+) lymphocytes and permits the formation of large intrapulmonary human nonsmall lung carcinoma xenografts in 100% of treated mice. All control animals injected with heat-denatured antibody failed to produce tumors. Chronic alcohol consumption by CD4-depleted mice resulted in larger tumors, compared with mice that did not receive ethanol in their diet (P = 0.05). CONCLUSIONS: Depletion of CD4(+) lymphocytes allows for the orthotopic growth of human lung adenocarcinoma xenografts in BALB/c mice. Furthermore, the consumption of alcohol reduces the ability of the impaired immune system to reject tumors.

Smoking and atherosclerosis in youth.

Coronary heart disease is the most common cause of death in the US. Studies have demonstrated that smoking is a major risk factor for coronary heart disease and that a positive relationship occurs between smoking and aortic and coronary atherosclerosis in adults. In 1985, a multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was organized to study atherosclerosis in trauma victims 15-34 years of age. Reports from this study have demonstrated that smoking is strongly associated with the prevalence and extent of grossly visible raised lesions in the abdominal aorta but only weakly associated with similar lesions in the right coronary artery. Coronary arteries from 50 smokers and 50 non-smokers were classified microscopically using a system developed by the American Heart Association in order to determine the stage at which smoking affects atherosclerosis. Smokers had over twice as many advanced lesions, types IV and V, as non-smokers (32 vs 14%) and fewer early lesions, types I, II, III, as non-smokers (38 vs 62%). The prevalence of advanced or types IV and V lesions (32%) was over twice that of intermediate or type III lesions (14%) in smokers. The opposite relationship was observed in non-smokers (14 vs 26%). This observation suggest that intermediate lesions progress rapidly into advanced lesions in smokers and that intima formerly having early lesions is replaced by intima with raised lesions.

Recombinant oncotoxin AR209 (anti-P185erbB-2) diminishes human prostate carcinoma xenografts.

PURPOSE: Prostate cancer is the most common malignancy of males in the United States. Although the overall survival rate for early stage prostate cancer is good, if cancer recurs following curative therapies there is no adequate salvage therapy. Systemic chemotherapy has never been associated with any meaningful improvement in overall survival or overall objective benefit. There is a need to develop novel therapies for prostate cancer. MATERIALS AND METHODS: Two prostatic cancer cell lines, DU-145 and PC-3, were grown as subcutaneous xenografts in athymic nude mice. The recombinant oncotoxin AR209, formerly OLX-209 [e23(Fv)PE38KDEL]), has the specificity of an anti-p185erbB-2 antibody contained within a single-chain antibody domain (e23Fv) coupled to a portion of the Pseudomonas exotoxin A (PE38KDEL). Using Western blot analysis, the cell lines were shown to express p185erbB-2. The mice received either 3 i.v. injections, one every 2 days, of the recombinant oncotoxin AR209 or PBS, or were implanted with osmotic pumps that delivered a constant s.c. amount of AR209 or PBS. RESULTS: The oncotoxin was effective in reducing the size of s.c. prostatic xenografts in athymic nude mice. The data demonstrated that small tumors (<200 mm.3) were effectively reduced in size. However, larger tumors (>500 mm.3) were not effectively diminished. CONCLUSIONS: This study provides preliminary evidence for the utility of a recombinant oncotoxin in the treatment of prostate carcinoma. Recombinant oncotoxins may be an effective clinical addition for the management of metastatic prostate lesions in patients treated with conventional therapy.

Aggressive administration of recombinant oncotoxin AR209 (anti-ErbB-2) in athymic nude mice implanted with orthotopic human non-small cell lung tumours.

Lung cancer remains a significant public health problem in the U.S.A. and will result in an estimated 160,400 deaths in 1997. This appalling number is due in large part to the lack of adequate treatment for tumours that are refractory to surgery with curable intent, or of an adequate salvage therapy for those patients who recur after surgical resection. Because non-small cell lung cancer is refractory to traditional chemotherapy, non-traditional therapies have been developed to treat patients with this disease. Recombinant oncotoxins have been designed to target cells that express certain proteins as part of their cellular membrane. One such oncotoxin, AR209 (formerly OLX-209 [e23(Fv)PE38KDEL]), has the specificity of an anti-ErbB-2 antibody contained within a single-chain antibody domain (e23v) coupled to a portion of the Pseudomonas exotoxin A (PE38KDEL). Previous studies demonstrate that this drug is capable of significantly reducing the size of orthotopic lung tumour xenografts. However, most of the treated mice developed tumours once therapy was removed. In this study, mice were treated aggressively using one of four drug treatment schedules. Mice were treated with either intravenous or subcutaneous injections of AR209 over a 2 week period. The data indicate that AR209 significantly reduced the size of tumours and upon microscopic analysis at necropsy, some mice were cured. However, despite the treatment schedule used, many mice contained residual tumour. Residual tumours expressed the ErbB-2 protein, indicating that more aggressive treatment with AR209 may have resulted in higher rates of cure.