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.

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.

Origin of atherosclerosis in childhood and adolescence.

Atherosclerosis begins in childhood as deposits of cholesterol and its esters, referred to as fatty streaks, in the intima of large muscular arteries. In some persons and at certain arterial sites, more lipid accumulates and is covered by a fibromuscular cap to form a fibrous plaque. Further changes in fibrous plaques render them vulnerable to rupture, an event that precipitates occlusive thrombosis and clinically manifest disease (sudden cardiac death, myocardial infarction, stroke, or peripheral arterial disease). In adults, elevated non-HDL-cholesterol concentrations, low HDL-cholesterol concentrations, hypertension, smoking, diabetes, and obesity are associated with advanced atherosclerotic lesions and increased risk of clinically manifest atherosclerotic disease. Control of these risk factors is the major strategy for preventing atherosclerotic disease. To determine whether these risk factors also are associated with early atherosclerosis in young persons, we examined arteries and tissue from approximately 3000 autopsied persons aged 15-34 y who died of accidental injury, homicide, or suicide. The extent of both fatty streaks and raised lesions (fibrous plaques and other advanced lesions) in the right coronary artery and in the abdominal aorta was associated positively with non-HDL-cholesterol concentration, hypertension, impaired glucose tolerance, and obesity and associated negatively with HDL-cholesterol concentration. Atherosclerosis of the abdominal aorta also was associated positively with smoking. These observations indicate that long-range prevention of atherosclerosis and its sequelae by control of the risk factors for adult coronary artery disease should begin in adolescence and young adulthood.

Medial thickenings of coronary artery and the aging risk factor for atherosclerosis.

The objective here is to inquire what kind of coronary artery is it that tends to acquire atheroma: When an atheroma is found somewhere in the specimen (YesA specimen), what do we see in the specimen far away from the atheroma? Previous studies found thicker intima in YesA specimens than in NoA specimens, but with equal numbers of smooth muscle cells (SMC's). Thickness per SMC strongly predicted atheroma, so much so that the risk factor age was fully explained statistically. This study now finds that the medial layer is also thicker in YesA specimens, and with medial SMC numbers equal to those in NoA specimens. Hence, the aging risk factor appears to induce excessive thickness per SMC as a generalized property throughout the whole specimen in the medial as well as intimal layers, with excessive production of collagenous matrix acting as an initial, rate limiting step in plaque formation. In the intima, atheroma tends to occur when average thickness per SMC exceeds the threshold value of 8.6 microm/SMC. The extreme high value found in the most severely affected medial sample was 4.2 microm/SMC, and this failure to approach the threshold could explain the medial resistance to fatty degenerations.

Medial thickness of coronary arteries as a correlate of atherosclerosis.

As coronary arteries grow older, they tend to acquire fibroplastic intimal thickenings. Those aging arteries that manifest the greatest fibroplasia are typically the ones that acquire atherosclerotic plaques with necrotic cores (YesA arteries); this is especially so if foam cell infiltration is also extensive. The present study finds that thicker media also distinguishes YesA from NoA specimens. Coronary arteries obtained at autopsy from males and females in eight populations, 16 groups altogether, were evaluated histologically for the YesA characteristics: intimal fibroplasia, foam cell infiltration, and medial thickness. The rankings of the 16 groups at ages 15-29 years persisted significantly into ages 30-69 years when looking at intimal fibroplasia, but not at foam cell infiltration. Medial thickness also yielded youthful population rankings that persisted into older groups, and the rankings were similar to those based on fibroplasia. Virtually all important correlations were obscured if intima:media ratios were employed, because the top and bottom numbers in the ratio typically move in parallel with each other across the meaningful group comparisons, thereby canceling each other.

Relationship of raised atherosclerotic lesions to fatty streaks in 19 location-race groups.

SUMMARY: Atherosclerosis was graded by gross inspection of Sudan-stained arterial intimal surfaces estimating percent surface involved by raised lesions (R), fatty streaks (F), and no lesions (N). The right coronary artery and abdominal aorta of over 20,000 cases, 25-69 years of age, from 19 location-race groups were used. Cases were classed by sex, broad cause of death categories, and age. Raised lesions expressed as a percentage of all types of lesions was found at each age to have approximately a constant ratio to the percentage surface involved with all types of lesions. This was true over the range of surface involvement within age, sex, and cause of death classes, but between classes the ratio was not constant. Comparisons among location-race groups indicated marked differences in mean involvement by all types of lesions and by raised lesions expressed as a percentage of all lesions. The variation among groups in the fraction of raised among lesions was found to be partly related to parallel variability in average involvement by all types of lesions. However, some groups stood out as having too much or too little of raised lesions for their degree of involvement by all types of lesions. For instance Manila had extensive raised lesions with little fatty streaking while Bogota had more fatty streaking but not so much of raised lesions. In the sequence N yields F yields R, Class A causes act at both stages of atherogenesis while Class B causes act at stage I or stage II but not both. Class A and Class B causes both revealed important variation among location-race, sex, and cause of death groups.

Variations in human aortic fatty streaks among geographic locations.

Histologic features of aortic fatty streaks were examined in male subjects aged 10-39 from Guatemala, Jamaica Negro, Durban Bantu, New Orleans Negro, New Orleans white, Lima and Santiago. These groups were selected from the 19 available in the IAP (International Atherosclerosis Project) because they represented the greatest contrasts between the exten of fatty streaks in the young and raised lesions in the elders. Among these seven groups the extent of raised lesions in the older subjects was significantly but weakly correlated with the type of fatty streaks in the young as measureed by lesion thickness, content of demonstrable lipid, numbers of foam and spindle cells. The severity of leukocytic infilitration and prevalence of foci of necrosis in fatty streaks however, correlated strongly with raised lesions (rank r equals 0.90). We interpret this to imply that the presence of leukocytes and of foci of necrosis in the fatty streak marks its propensity to progress into raised lesions. If this formulation is correct, then the presence of both features in the histology of fatty streaks could be used as a marker in future studies of factors bearing upon the emergence of raised lesions out of fatty streaks.

Relationship of advanced atherosclerosis lesions to fibrous plaques in 19 location-race groups.

Aortas and coronary arteries from 23,000 autopsies of 19 location-race groups (L/R) were graded for % surface fatty streaks (FS), fibrous plaques (FP) and advanced lesions (AL = calcified, hemorrhagic, ulcerated, or thrombotic). Cases were classed by age (24-34, 35-44, 45-54, 55-64, and 65-69), sex, L/R, broad cause of death category (C/D; athero = related to atherosclerosis; basal = all other), and % surface raised lesions (RL = FP + AL). AL was converted to "advanced among lesions" (AaR = AL divided RL) because AaR was found on the average within each subgroup of subjects to hold a nearly constant ratio to RL (i.e. AaR : RL = K, an empirical constant). This ratio was different for each age (older greater than younger), C/D (athero greater than basal), and sex (M greater than F) subgroup and for coronary vs. aorta, thus requiring 5 X 2 X 2 X 2 = 40 values of K to describe the pools of subjects. The values of K were essentially same for all 19 location-race groups. If it be assumed that advanced lesions arise only be evolution from fibrous plaques, then the speed of this evolution up to each specified age is measured by K, in the sense that at a particular age larger K implies faster evolution. On the average, the rate of evolution in this sense was found to be the same in all location-race groups. Within groups a large variability of K among individuals was found, and this variation remains unexplained. However, across location-race boundaries no such variability was found, and this implies that the magnitude of K is not under control of geographically variable factors.

Relationship of raised atherosclerotic lesions to fatty streaks in coronary heart disease and hypertension.

The abdominal aortas and right coronary arteries removed during autopsies were gathered from over 18,000 subjects in 19 location-race groups. Sudanstained intimal surfaces were graded for the percent as raised lesions (R) and fatty streaks (F). The proportions of all types of lesions (ATL = F + R) that were raised (RaL = R divided by ATL) were examined. The difference between the observed RaL (in subjects having atherosclerosis-related conditions) and the expected RaL (in age-, sex-, and ATL-matched subjects without such conditions) measured the excess of RaL, which by inference indicated the tendency for an excess of raised lesions to be produced in place of fatty streaks. In cases of coronary heart disease (CHD), a large excess of RaL was found consistently on the average. The coronary arteries and aortas of hypertensive subjects, compared with those of nonhypertensives, had only a small and inconsistent excess of RaL. Both CHD and hypertension were characterized by a marked tendency for severe involvement by ATL, including extensive fatty streaks, leaving only small remnants of normal intima. Some factors (Class A) act to form fatty streaks and also to continue advancing them into raised lesions. Once the fatty streaks are formed, some new factors (Class B2) convert them into raised lesions. We concluded that hypertension is almost, if not entirely, a Class A type of atherogenic agent, and that CHD is promoted by exceptionally strong effects of both A and B2 types of causation. This conclusion exposes a biological priniciple that, if the assumptions of the model are true, is of considerable importance: Some of the more important causes of atherosclerosis (Class B causes) begin to act only after the fatty streaks have formed.

A monoclonal antibody that recognizes hyaluronic acid binding region of aorta proteoglycans.

A chondroitin sulfate-dermatan sulfate proteoglycan was isolated from bovine aorta intima by extraction of the tissue with 4 M guanidine hydrochloride. The proteoglycan was purified by CsCl isopycnic centrifugation followed by gel filtration and ion exchange chromatography. A monoclonal antibody C8F4 was developed to this core protein. The characteristics and specificity of the antibody were studied by an enzyme-linked immunosorbent assay (ELISA) using an alkaline phosphatase conjugated antibody (goat anti-mouse IgG). The antibody binding to the core protein was found specific and optimal at pH 7.0. The antibody recognizes either intact chondroitin sulfate-dermatan sulfate proteoglycan monomer, chondroitinase ABC digested monomer or chemically deglycosylated proteoglycan. Free chondroitin sulfates, keratan sulfate and hyaluronic acid did not compete for the antigenic sites in ELISA. Limited hydrolysis of the core protein by trypsin resulted in three peptides and only the peptide with a molecular weight M(r) = 40,000 was found capable of binding to hyaluronic acid. The antibody C8F4 recognized this hyaluronic acid binding peptide but did not recognize the other two peptides suggesting that the epitope(s) for this antibody is in the hyaluronic acid-binding region of the core protein. The antibody recognized the core proteins from bovine nasal cartilage proteoglycan and human aorta proteoglycan but did not recognize bovine aorta link protein, bovine serum albumin, human serum albumin, human transferrin, collagen Type I and fibronectin. The antibody was found useful to localize proteoglycans in atherosclerotic lesions in human aorta by immunohistochemical techniques.

The relation of atherosclerotic lesions to antemortem and postmortem lipid levels: the Bogalusa Heart Study.

Although postmortem lipid levels have been used as surrogates for levels during life, it is uncertain whether atherosclerotic lesions are related similarly to antemortem and postmortem lipid values. In a sample of 23 children and young adults who had been examined for cardiovascular disease risk factors and subsequently died from violent causes, we examined the relation of (a) postmortem lipid levels to values obtained 1 to 14 years earlier, and (b) atherosclerotic lesions to antemortem and postmortem lipid levels. Postmortem levels of triglycerides and very-low-density lipoprotein cholesterol (VLDLC) were higher than levels during life, but postmortem levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDLC) and high-density lipoprotein cholesterol (HDLC) were related to antemortem levels (rs > 0.40). After excluding eight persons who likely received large volumes of intravenous fluids before death, the within-person variability between antemortem and postmortem levels of LDLC and HDLC was similar to the antemortem variability. Furthermore, the relation of atherosclerotic lesions to antemortem and postmortem lipid levels differed only slightly for TC, LDLC and HDLC. In contrast, lesions in the coronary arteries showed the strongest association with antemortem VLDLC levels, but were not associated with postmortem VLDLC levels. Despite the very small number of subjects, our results suggest that if intravenous fluids are not administered before death, postmortem levels of TC, LDLC and HDLC are fairly representative of levels during life. Postmortem levels of VLDLC or triglycerides, however, should not be used as surrogates for antemortem levels.

Histologic features of atherosclerosis and hypertension from autopsies of young individuals in a defined geographic population: the Bogalusa Heart Study.

Histologic features of arterial intima have been quantified at autopsy by morphometric methods in 66 individuals aged 6-30 years, in whom cardiovascular risk factors had been measured prospectively prior to death. Measures of serum cholesterol were found to correlate significantly with the extent of foam cell infiltration seen in paraffin sections and the intensity of lipid staining in frozen sections of the abdominal and thoracic segments of the aorta. A similar correlation in the coronary arteries was weak and inconsistent. Blood pressure was significantly correlated with foam cells and stainable lipid in the abdominal but not the thoracic segment of the aorta. A similar correlation in the coronary arteries was significant, but only in males, and most consistently in the black males. Intimal thickness of the coronary arteries showed sporadic and weak correlations with blood pressure and lipids; however, a strong and consistent correlation was seen between coronary intimal thickness and hyalinization of renal arterioles. With many statistical tests carried out on a limited data set, some particular details are, no doubt, spuriously significant; however, some persistent patterns are beginning to emerge. The reproducible findings support the concept that prospective measurements of blood pressure and serum lipids are associated with a degree of structural characteristics present in children and young adults. Moreover, the observed structural characteristics, specifically the deposition of lipids in the intima of coronary arteries and aorta, are likely to reflect variations in the rates of progression of atherosclerosis.

Insight into a bad omen for white men: coronary artery disease--the Bogalusa Heart Study.

Clinical experience of diagnostic and interventional procedures, including cardiac surgery, indicates a greater prevalence of coronary heart disease in white men than in other race-gender groups. Studies of children and young adults in the Bogalusa Heart Study have provided evidence that might account for this race-gender contrast. A variety of anthropometric and metabolic parameters influencing serum lipid and lipoprotein levels places white boys and young white men selectively at high risk for the development of atherosclerotic coronary artery disease. Obesity and greater central body fat, subtle aberrations in carbohydrate-lipid metabolic relations and variability in sex hormone profiles appear to underlie a trend to adverse lipoprotein changes in white men. A lower high-density lipoprotein cholesterol level and apolipoprotein A-l at puberty and a dramatic increase of low-density lipoprotein cholesterol are seen in young white men; such adverse changes identify them to be at greater risk. It is noteworthy that children whose fathers had myocardial infarction tend to be white. These children also have relatively high ratios of apolipoprotein B/apolipoprotein A-l and apolipoprotein B/low-density lipoprotein cholesterol. Studies of risk factors in children emphasize their importance in the early natural history of coronary artery disease. These findings show the need for beginning prevention of adult heart disease in childhood.

Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study).

Race and sex differences in aorta and coronary atherosclerotic lesions were studied in 150 persons aged 6 to 30 years. The intimal surface involvement with aorta fatty streaks was extensive, 0 to 71%, and greater in blacks than in whites (32 vs 20%, p less than 0.001). Coronary artery fatty streaks were more extensive in male than in female subjects (range 0 to 22%). Fibrous plaque lesions were present but not extensive in either the aorta (0 to 12%) or the coronary artery (0 to 24%) specimens. Lesions were more prevalent in male than in female persons, particularly white male subjects. The relation of fatty streaks to fibrous plaques was greater in the coronary vessels than in the aorta. In male subjects, aorta fatty streaks were strongly related to antemortem levels of total cholesterol, low-density lipoprotein cholesterol and ponderal index in white male subjects. Coronary artery fatty streaks in white male persons were significantly associated with serum triglycerides, very low density lipoprotein cholesterol, systolic and diastolic blood pressure and ponderal index. These results link antemortem risk factors to the development of atherosclerotic lesions and emphasize the need for preventive cardiology in early life.

Renovasculopathies of hypertension and the rise of blood pressure with age in blacks and whites.

Blood pressure increases with age in all US population groups that have been studies, but does so faster in African Americans. Evidence from extensive microscopic renal vascular studies at autopsy supports the view that blood pressure increases with age because of progressive fibroplasia of renal interlobular arteries and arterioles that leads to incrementally escalating renal ischemia. This process precedes the development of hypertension and progresses, on average, faster in African Americans compared with whites. The etiology for fibroplasia of the renal vasculature and the reasons for its faster progression in African Americans remains unknown.

Recent declines of hypertensive renovasculopathies in New Orleans blacks.

Some evidence indicates that renovasculopathies measured in paraffin sections of renal cortex obtained at autopsy might offer a general guide to prevailing mean blood pressure (MBP) in the averages of demographic groups. In this study, data on forensic autopsies done in New Orleans from 1968 to 1998 were retrieved from computer archives. Observations are confined to basal cases (ie, those with causes of death having no known correlation with hypertension and therefore, who can be taken as approximately representative of the sampled populations, although overt hypertensives may be underrepresented in such a series). MBP derived from renovasculopathies were used to follow birth date cohorts born around the years 1928, 1938, 1948, 1958, 1968, and 1978. Vasculopathy-derived MBP of white men and women increased with age in a stable pattern with no shifting of positions among the cohorts. This pattern offered a baseline for comparison with the data on blacks. Against this baseline, blacks displayed the highest MBP in the earliest cohort with stair-step declines in later born cohorts, and an abrupt decrease between the 1958 and 1968 cohorts. Data from National Health And Nutrition Examination Surveys are generally supportive of these conclusions, but are of uncertain significance because of severe downward drift due to method changes in the National Health And Nutrition Examination Survey III 1988-91 survey. The data analyzed here provide no direct evidence on the matter of whether we are gaining better blood pressure control in hypertensive individuals who really need it.

Nephrosclerosis in three cohorts of black and white men born 1925 to 1944, 1934 to 1953, and 1943 to 1962.

The prevailing levels of blood pressure among black and white men of ages 25 to 54 years were examined by two independent approaches in this study. Data on blood pressure obtained in national health surveys (National Health and Nutrition Examination Surveys, NHANES) do not show any appreciable upward or downward trend between 1960 and 1980 in men of these ages. The histologic examination of kidney samples obtained from coroner's autopsies offers an indirect way of estimating the levels of blood pressure that prevail in populations because of statistical relationships between nephrosclerosis and blood pressure. Samples of kidney tissues archived in New Orleans from 1968 to 1986 were evaluated by quantitative morphometry for the severity of the renovasculopathies that accompany high blood pressure. The outcome showed no significant secular trend among black and white men, confirming blood pressure survey findings that show no change in the hypertensive status of the population. The black-white difference in incipient signs of hypertension was seen to be well-established by ages 25 to 34 years in all cohorts of New Orleans subjects, as well as in the NHANES survey data. These result suggest that the adolescent and young adult ages are especially important in establishing the black-white difference in hypertension.

Blood pressure in people in Greenland assessed by measuring renovasculopathies of hypertension at autopsy.

Surveys taken of blood pressure in Greenland indicated prevailing levels similar to those in the USA. Morphometrically measured renovasculopathies in 88 autopsies confirmed blood pressure levels comparable to the survey findings. At clinic visits, the recorded blood pressures in 48 of the autopsies verified the morphometric conclusions (r = 0.559). By all three approaches, similar levels of blood pressure were determined for the population of Greenland. The agreements in outcome from these approaches serve to substantiate the validity of all three methods. The overall outcome verifies a previous report placing Greenland among the nations which experience rapid rise of blood pressure with age and high prevalence rates for hypertension.

Quantitation of hypertensive nephrosclerosis on an objective rational scale of measure in adults and children.

The development of a precise, mathematical relationship between blood pressure and renal microvascular abnormalities would be highly desirable. Such a relationship would require that abnormalities be quantitative on a rational scale. The dominant abnormality in nephrosclerosis occurs in arcuate and cortical arteries of 50 to 400 micron outer diameter. This abnormality consists of acquired inner layers of fibroplastic tissue accompanied by variable fibrosis or withering of the preexisting vessel wall. It is this pathologic variable of interest, the amount of fibroplasia, that can be measured by its thickness in a direction perpendicular to the arterial axis. A method for quantitating the fibroplasia is described. Use of this method in a series of 93 autopsies suggests two tentative conclusions. The outer diameter of 141 micron marks the size of artery in which fibroplasia best correlates with blood pressure. The linear function, mean blood pressure = 1.60 X microvascular lesions +79.7, with correlation coefficient 0.698, governs a relationship similar at all ages. This relationship can be used to compute expected blood pressure from measurements of microvascular abnormalities in kidneys obtained at autopsy. Because all ages include ages 14 to 21 years, the observations imply that the initial tissue changes of hypertensive disease occur early in life.

Declining density of intimal smooth muscle cells and age as preconditions for atheronecrosis in the basilar artery.

The aging basilar artery has some differences and some similarities when compared with the aorta and coronary arteries. As the non-necrotic intimal thickness increases over time, the number of smooth muscle cells reaches a steady state around age 25-30 years in the coronaries and aorta, but continues to increase in the basilar artery, even to 90 years of age. The numbers of cells per unit of tissue (the cell density) declines with age, and the patterns of decline are quantitatively similar in all three arterial segments. All arteries so far examined behave alike in showing that atheronecrosis emerges in those specimens that have sufficiently low density of intimal smooth muscle cells. These results identify low intimal cell density as a criterion for recognizing arteries that are prone to atheronecrosis. One possible explanation is that depopulation of the fibrotically thickened and aged intima, by spreading apart the smooth muscle cells with expanding matrix materials, could be the conditioning factor that brings about the intrusion of atheronecrosis.