Richard E. Tracy

ASSOCIATION BETWEEN MULTIPLE CARDIOVASCULAR RISK FACTORS AND ATHEROSCLEROSIS IN CHILDREN AND YOUNG ADULTS

BACKGROUNDnIn adults, cardiovascular risk factors reinforce each other in their effect on cardiovascular events. However, information is scant on the relation of multiple risk factors to the extent of asymptomatic atherosclerosis in young people.nnnMETHODSnWe performed autopsies on 204 young persons 2 to 39 years of age, who had died from various causes, principally trauma. Data on antemortem risk factors were available for 93 of these persons, who were the focus of this study. We correlated risk factors with the extent of atherosclerosis in the aorta and coronary arteries.nnnRESULTSnThe extent of fatty streaks and fibrous plaques in the aorta and coronary arteries increased with age. The association between fatty streaks and fibrous plaques was much stronger in the coronary arteries (r=0.60, P<0.001) than in the aorta (r=0.23, P=0.03). Among the cardiovascular risk factors, body-mass index, systolic and diastolic blood pressure, and serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as a group, were strongly associated with the extent of lesions in the aorta and coronary arteries (canonical correlation [a measure of the association between groups of variables]: r=0.70; P<0.001). In addition, cigarette smoking increased the percentage of the intimal surface involved with fibrous plaques in the aorta (1.22 percent in smokers vs. 0.12 percent in nonsmokers, P=0.02) and fatty streaks in the coronary vessels (8.27 percent vs. 2.89 percent, P=0.04). The effect of multiple risk factors on the extent of atherosclerosis was quite evident. Subjects with 0, 1, 2, and 3 or 4 risk factors had, respectively, 19.1 percent, 30.3 percent, 37.9 percent, and 35.0 percent of the intimal surface covered with fatty streaks in the aorta (P for trend=0.01). The comparable figures for the coronary arteries were 1.3 percent, 2.5 percent, 7.9 percent, and 11.0 percent, respectively, for fatty streaks (P for trend=0.01) and 0.6 percent, 0.7 percent, 2.4 percent, and 7.2 percent for collagenous fibrous plaques (P for trend=0.003).nnnCONCLUSIONSnThese findings indicate that as the number of cardiovascular risk factors increases, so does the severity of asymptomatic coronary and aortic atherosclerosis in young people.

Risk Factors and Atherosclerosis in Youth Autopsy Findings of the Bogalusa Heart Study

The Collaborative Pathology Study is one of the most impressive programs of the Bogalusa Heart Study. Attempts are made to obtain complete and uniform necropsy coverage of all decreased young people who may have been examined in the Bogalusa Heart Study. Since 1978, autopsy specimens have been collected from 190 deaths, representing 65% of all known deaths in the study age category. The relation of antemortem risk factors for cardiovascular disease to early atherosclerotic lesions in the aorta and coronary arteries was assessed in those individuals previously examined in the Bogalusa Heart Study (N = 59). Aortic fatty streaks were strongly related to both total and low-density lipoprotein (LDL) cholesterol (r = 0.62, P < 0.0001 for each association), and were inversely correlated with the ratio of high-density lipoprotein (HDL) cholesterol to LDL plus very-low-density lipoprotein (VLDL) cholesterol (r = -0.29, P < 0.01). Coronary artery fatty streaks were associated with elevated total cholesterol, LDL cholesterol, VLDL cholesterol, and systolic blood pressure. Higher levels of LDL and VLDL cholesterol, triglycerides, systolic and diastolic blood pressure, and a lower ratio of HDL to LDL plus VLDL were found in those people with coronary artery fibrous plaques. Microscopy offered additional information about the characteristics of the aortic and coronary arterial intimal disease. Histologic observations have confirmed some of the relationships indicated with gross observations and show the complexity of this disease process. These findings emphasize the importance of an approach to preventive cardiology early in life.

Characteristics of the plaque under a coronary thrombus

Young men dying suddenly and autopsied by the coroner sometimes have coronary thrombosis at a relatively early stage of arteriosclerosis. The plaques under such thrombi often have a complex of features, a) rupture, b) hemorrhage, c) medial destruction, d) nodular collections of foam cells, e) calcification, f) cellular infiltrates of the fibrous cap, fibrous base and adventitia, and g) a newly described kind of phagocytic activity at the boundary between the necrotic core and the fibrous base of the plaque. Commonplace innocuous plaques in most middle and old aged subjects without heart disease also often have some of these features. What structural characteristics might distinguish rare thrombogenic from commonplace innocuous plaques? Twenty-one thrombotic plaques from 18 cases of sudden coronary heart disease (CHD) death were histologically compared with 129 nonthrombotic plaques from these same 18 cases, 85 plaques from 23 cases of CHD death due to arteriosclerotic occlusion, and 94 plaques from 22 cases having no CHD. Plaques with thrombosis all had necrotic cores; plaques for comparison with these were therefore chosen all to have necrotic cores. Rupture and hemorrhage were found in 90% of thrombotic plaques, with mixing of plaque gruel and blood in the thrombus. Medial destruction, foam cells and calcification (features c, d, and e) were commonplace in all types of plaques. Small-cell infiltrates and atherophagocytosis (features f or g) were found in 72–94% of the 21 thrombotic plaques, but only in 18–24% of the 94 not CHD plaques. The necrotic core, characterized by crystalline cholesterol, appears to incite cellular responses in some plaques but not others; those responses distinguish thrombogenesis. The findings imply that thrombogenicity and its accompanying plaque cellularity are incited not by cholesterol, but by some trace or minor component of the plaque gruel of the necrotic core. The possibility of testing these hypotheses by practical methods has been shown to be feasible.

Cardiovascular Risk Factors and Hyalinization of Renal Arterioles at Autopsy The Honolulu Heart Program

Nephrosclerosis, commonly found in subjects with hypertension and diabetes, is marked by hyalinization of arterioles and fibroplasia of small arteries in the renal cortex. Cardiovascular risk factors that predicted subsequent hyalinization of renal arterioles at autopsy were identified, using data from the Honolulu Heart Program, a prospective epidemiological study of cardiovascular disease (CVD) in Japanese-American men. Among 8006 participants at baseline, 1381 died between 1965 and 1982; 285 of these had a protocol autopsy, and 150 had assessments of arteriolar hyalinization from renal tissue. Subjects were categorized into four groups on the basis of the number of hyalinized arterioles per square centimeter of renal tissue, and CVD risk factor levels and proportions were compared across these groups with the use of general linear models and logistic regression. Multivariate assessment using logistic regression demonstrated that diastolic blood pressure (DBP) and glucose level were positively associated and alcohol intake was negatively associated with an elevated degree of renal arteriolar hyalinization, independent of other CVD risk factors. The odds ratios for elevated hyalinization associated with a 10-mm Hg increase in DBP, a 20-mg/dL increase in glucose level, and a 30-mL/d increase in alcohol intake were 1.97 (95% confidence interval [CI] = 1.24-3.12), 1.23 (95% CI = 1.07-1.41), and 0.24 (95% CI = 0.11-0.55), respectively. Associations were similar when prevalent cases of CVD were excluded and when autopsy selection bias was taken into account. Renal arteriolar hyalinization was also more strongly associated with atherosclerosis in the larger cerebral vessels (Spearmans r = .59, P < .001) than in the coronary arteries (r = .16, P = .073) and aorta (r = .24, P = .022). Hyalinization was significantly related to cardiovascular-renal mortality, and this association was accounted for by other CVD risk factors. These findings suggest that blood pressure, glucose level, and alcohol intake are independent predictors of hyalinization in renal arterioles and that this type of renal vasculopathy may be a marker for atherosclerosis in other vascular regions, particularly the cerebral vessels. The protective association involving alcohol and the possibility that renal arteriolar hyalinization may be an indicator of cerebral atherosclerosis may warrant investigation in other populations.

Coronary heart disease in young black and white males in New Orleans: Community Pathology Study☆

The biracial population of New Orleans has a high overall mortality rate, high coronary heart disease (CHD) mortality rate, and high autopsy rate. In the New Orleans Community Pathology Study we investigated atherosclerosis and CHD in all deceased males aged 25 to 44 years, with major focus on the 52% of subjects from whom heart and arterial specimens were collected and evaluated according to standardized procedures. Morphologic correlates of CHD are the same in young black and white males. CHD mortality and mortality from cerebral hemorrhage, hypertensive heart disease, chronic renal disease, and diabetes are greater in young black males than young white males. Age, serum cholesterol, and hypertension were identified as important associated factors in the atherosclerotic process, as well as in CHD. The extent of coronary lesions seems to have decreased between 1960-1964 and 1969-1978 in young white males but not in blacks. Racial differences in coronary lesion involvement in non-CHD deaths are smaller than in our earlier studies.

Blood Pressure Related Separately to Parenchymal Fibrosis and Vasculopathy of the Kidney

The term nephrosclerosis is customarily used to designate a pathological entity that tends to characterize subjects with high blood pressure; it refers to a condition of diffuse fibrous replacement of renal substance secondary to ischemia from hypertension-related vascular injury. The features of parenchymal fibrosis can be distinguished from those of vasculopathies in tissue sections, parenchymal fibrosis being measured by assessing the degree of interstitial fibrosis and by counting obsolete glomeruli, while vasculopathies are measured by determining arterial intimal fibroplasia and by counting hyalinized arterioles. A series of 166 autopsies in subjects aged 25 to 92 years, selected because ample documentation of blood pressure was available, was assessed. One form of vasculopathy, arterial fibroplasia, is a better correlate of high blood pressure than is parenchymal fibrosis in this body of data. Cases with much vasculopathy and little parenchymal fibrosis occurred frequently, and these subjects were usually hypertensive. Cases with little vasculopathy and much parenchymal fibrosis were also encountered, but these subjects were usually not hypertensive. The suggested conclusion is that blood pressure relates less to the renoprival state of nephron loss than it does to renal ischemia in patients with nephrosclerosis.

Nephrosclerosis and aortic atherosclerosis from age 6 to 70 years in the United States and Mexico.

With increasing age, the thoracic aorta shows progressive fibroplastic intimal thickening, which is thought to be pre-atheromatous. A similar progressive intimal thickening in the renal cortical arteries is the distinguishing feature of the nephrosclerosis which underlies essential hypertension. Therefore, the earliest detectable youthful precursors of atherosclerosis and hypertension show strong morphological resemblances to each other. In this study, close statistical associations have been shown between the two types of arterial intimal fibroplasia. Both conditions show similar sigmoid growth curves from ages 6 to 70 years, thereby generating correlations across age groups ofr=0.99 in New Orleans andr=0.95 in Mexico City. Specimens gathered in New Orleans were found to have about 1.4 times greater arterial intimal thickening than specimens from Mexico City, and this excess was seen at all ages in both the aortas and the renal cortical arteries. It seems likely that intimai fibroplasia of arteries is reflecting similar biological principles at all levels of the vascular tree. Whatever etiological factors vary between New Orleans and Mexico City, those factors appear to act directly at a tissue level to promote the early precursors of atherosclerosis and of the nephrosclerosis that underlies hypertension.

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.

Renovasculopathies in elderly normotensives of Bombay, India

In essential hypertension, specific vasculopathies distinguish the kidney of nephrosclerosis. The severity of renovasculopathy can be measured histologically at autopsy. A previously determined equation uses the measurements to calculate mean blood pressure levels. That equation did not encompass elderly subjects with minimal vasculopathy, because they were deficient in the previous data set. Such subjects were abundant in a series of 86 autopsies conducted at the J.J. Hospital in Bombay. That newly reviewed series now provides many instances of normotension accompanying minimal vasculopathy at ages greater than 40-50 years. These conditions are seldom observed in the U.S.A. The newly examined elderly normotensives manifest degrees of renovasculopathy equivalent to those of youthful normotensives with comparable blood pressure levels. The elderly subjects who escaped a rise of blood pressure with age were those with long delayed progression of renovasculopathy; this may be the explanation for avoidance of hypertension in old age. The outcome places the J.J. Hospital patients among the populations of the world with the slowest rates of progression of hypertension.

PATHOLOGY OF SUDDEN CORONARY DEATH

Sudden and unexpected death from coronary heart disease has been a major health problem throughout the world, especially in industrialized countries. Although progress has been made in determining the pathogenetic sequence of events leading to coronary heart disease and sudden death, many aspects of the process are still unknown. In our experience, most of these sudden deaths occur outside of the hospital or very shortly after the persons arrival. Autopsy materials from typical hospital-based studies do not include much of the information needed for a more complete description of the natural history of the disease. Our team of investigators has been studying atherosclerosis, coronary heart disease, and sudden death from a high percentage of all 25-44-year-old men dying in a well-delineated geographic location during a specified time period. This community-wide survey was designed to include men dying both inside and outside of hospitals. A large number of heart specimens, collected from young men dying of all causes, was examined by a team of pathologists according to a standardized protocol which required objective evaluation of findings and uniform application of definitions. This report focuses on the findings in sudden and not-sudden deaths from coronary heart disease in this 10-year study.