Copyright 1981 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

AMERICA JOUIAL or EPIDEMIOLOGY Vol. 113, o. 4 Copyright 1981 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Printed m USA. COMMUITY PATHOLOGY OF ATHEROSCLEROSIS AD COROARY HEART DISEASE: POST MORTEM SERUM CHOLESTEROL AD EXTET OF COROARY ATHEROSCLEROSIS MARGARET C. OALMA, 1 GRAY T. MALCOM, 1 VIVIA T. TOCA, J MIGUEL A. GUZMA," AD JACK P. STROG 1 Oalmann, M. C. (Louisiana State U. Medical Center, 1542 Tulane Avenue, ew Orleans, LA 70112), G. T. Malcom, V. T. Toca, M. A. Guzman, and J. P. Strong. Am J Epidemiol 1981 ;113:396-403. Little Is known about the direct relationship between serum cholesterol and the extent of coronary atherosclerosis In human populations even though the association of serum cholesterol levels with risk of developing coronary heart disease (CHD) is well documented. The results of this study of men 25-44 years of age, residents of Orleans Parish, Louisiana, show a significant relationship between post mortem serum cholesterol levels and extent of more advanced lesions (raised lesions) in the coronary arteries In 110 autopsied white men, but not In the cases of 221 autopsied black men. When disease categories comprising CHD cases and non-chd cases (fyasal group) were evaluated, the racial difference In the cholesterol-lesion associations persisted. The reason for the racial difference In the observed cholesterol-lesion association Is not clear. Additional research, where younger age groups are Included, and considering earlier lesions and other risk factors In different environments may help In clearing this question. atherosclerosis; cholesterol; coronary disease Little is known about the direct re- death due to coronary disease, are prelationship between serum cholesterol sumably due to a combination of factors levels and the extent of atherosclerosis in including the amount and distribution of the coronary artery wall in human popu- coronary atherosclerosis, the size and lations, even though the association of work load of the heart, mechanisms reserum cholesterol levels with the risk of lated to the occlusive episode and sequeldeveloping clinically significant coronary ae such as cardiac arrhythmias (9-12). heart disease (CHD) is well documented For the proper understanding of the dis- (1 8). The clinical end points for CHD, ease process, it is important to establish such as myocardial infarction or sudden whether the risk factors for clinically Received for publication July 16, 1980, and in 4 Institute) de utricion de Centro America y final form September 22, 1980. Panama, Guatemala City, Guatemala, CA. Abbreviations: CHD, coronary heart disease; This research was supported by Grant o. RCL, raised coronary lesions. Departments of Pathology and Public Health HL08974 from the ational Heart, Lung, and Blood Institute, ational Institutes of Health, US Public and Preventive Medicine, Louisiana State Univer- Health Service, Bethesda, MD. sity Medical Center, 1542 Tulane Avenue, ew Or- The authors wish to acknowledge the assistance of leans, LA 70112 (address for reprint requests). William P. ewman EEL M.D., William A. Rock, Department of Medical Technology, School of Al- M.D., and Richard E. Tracy, M.D., Ph.D., for their lied Health Professions and Department of Pathol- assistance in evaluating the coronary atheroscleroogy, Louisiana State University Medical Center, sis and for categorizing cases into disease categories; ew Orleans, LA. Karen Cantrelle for preparation of the tables and ' Department of Pathology, Louisiana State Uni- figure; and Irene S. Melerine for preparation of the versity Medical Center, ew Orleans, LA. manuscript. 396

SERUM CHOLESTEROL AD COROARY ATHEROSCLEROSIS 397 overt CHD, such as serum lipid levels, are related to the development of atherosclerosis per se or other factors in the pathogenesis of CHD. A community pathology study of atherosclerosis, CHD, and sudden death has provided an opportunity to investigate the relationship between post mortem serum cholesterol levels and the extent of atherosclerotic lesions in the coronary arteries as determined in specimens obtained at autopsy. Information from this study and findings from epidemiologic cardiovascular studies which incorporate autopsy follow-up to evaluate the extent of atherosclerotic lesions at autopsy may help in elucidating the relation of serum cholesterol to atherosclerosis and the process leading to CHD. MATERIALS AD METHODS This report is based on results from an autopsy sample of all black men and white men, 25 44 years of age, who resided and died in Orleans Parish, Louisiana, USA, between October 1, 1968, and December 31, 1972. Of the 1011 male residents who died in the parish and composed the target population, 781 were autopsied and either a total or partial set of specimens was obtained in 579 cases admitted to the study. The most common cause of failure in identifying cases admissible to the study was discrepancy between the age or place of residence reported at the time of autopsy and that recorded on the death certificate, while consideration of a technical nature prevented collection of all intended specimens in every study case. The collection of data and specimens followed standard procedures previously described in detail by Guzman et al. (13), Rock et al. (14), and Oalmann et al. (15). This report, however, relates only to post mortem serum cholesterol findings and the extent of atherosclerotic lesions in the coronary arteries. Thirty-one cases (21 blacks and 10 whites) did not have coronary atherosclerotic measurements because of post mortem decomposition or trauma to the arteries, or because the prosector cut the arteries. One hundred sixty-seven cases (108 blacks and 59 whites) did not have post mortem serum cholesterol determinations because of trauma with massive blood loss, burns, post mortem decomposition, blood hemolysis, and large amounts of intravenous fluids immediately prior to death. Seventy-two cases (54 blacks and 18 whites) that had post mortem serum cholesterol levels below 100 mg/dl most of them (88 per cent) dying during surgery, in a postoperative status, or of protracted wasting terminal disease were excluded when serum cholesterollesion associations were studied, to avoid possible biases (16-18) that may have conditioned these values. These cases, on the average, were thinner, had higher mean liver lipids, lower renal hypertensive indices (19, 20) and were less involved with coronary raised lesions than the group of cases included in the analyses. The three main branches of the coronary arteries were injected, x-rayed, removed from the heart, opened longitudinally, flattened on cardboard, fixed in formalin, stained with Sudan IV, and packed in plastic bags identified by randomly assigned four-digit code numbers. Five especially trained pathologists followed a standardized procedure (13, 21) and under controlled conditions visually estimated the extent of intimal surface affected by atherosclerotic lesions. Raised coronary lesions, the measure of atherosclerotic involvement used in this study, is the mean percentage of intimal surface of the three coronary arteries with fibrous plaques, complicated and calcified lesions; when combined, these are a measure of advanced lesions of atherosclerosis. The five pathologists also evaluated independently the hearts and aortas, resolved disagreements by consensus, and assigned a cause of death for each case in the study after review of all pertinent in-

398 OALMA, MALCOM, TOCA, GUZMA AD STROG formation. Arterial lesion involvement for the consensus grading is defined as the average of the pathologists' gradings after eliminating outliers using procedures described by Dixon and Massey (22). Post mortem serum cholesterol levels were determined by the method of Abell et al. (23) on blood samples taken from the inferior vena cava. The mean of blind duplicate determinations for each sample was used for data analysis. The correlation coefficient for the two samples was 0.999 for white men and 0.998 for black men. RESULTS Four broad disease diagnostic categories are considered in the analysis of the data: forty men died with CHD; 52 died with related disease (stroke, hypertension, diabetes or chronic renal disease); seven were classified as uncertain CHD deaths even after extensive study; and 480 who died from other conditions, including 274 deaths due to trauma, were considered as a basal group of deaths. The distribution, by race and broad diagnostic category, of the 579 cases initially admitted to the study is presented in table 1. These data show a higher proportion of CHD deaths (p = 0.05) in whites than in blacks, while the proportion of deaths with CHD-related disease is higher (p = 0.05) in blacks than in whites. The two races do not differ in the proportion of deaths assigned to the basal group, and the number of cases in the uncertain CHD category is clearly insufficient for a valid race comparison. The mean percentage of the coronary intima involved with raised lesions (RCL), by diagnostic category and race, is presented in table 2 for the 548 cases from which it was possible to obtain the coronary arteries. There is no evidence of racial differences in the extent of intimal involvement with raised lesions within disease categories, although, over the combined disease categories, whites have more raised lesions in the coronaries than blacks. In both races, however, the percentage of intimal surface of the coronaries with raised lesions is greater in the CHD category than in either the related disease or basal categories. As illustrated in table 3, the mean post mortem serum cholesterol levels for all cases in this study, after excluding the values <100 mg/dl, as well as for the cases in the based groups, were somewhat higher but quite similar to the serum cholesterol levels determined in a blood donor study (17) carried out in our laboratory. There is no evidence of an age dependence of the serum cholesterol levels in either race within the narrow 20-year age range considered in this study. The mean post mortem serum cholesterol levels determined in the sample of autopsied men studied are presented by disease diagnostic category and race in table 4. The mean serum cholesterol level TABLB 1 Distribution of the 579 autopsied men initially admitted to the study by broad disease category and race, Orleans Parish, Louisiana, 1968-1972 Diagnostic category % % % Coronary heart disease Uncertain coronary heart disease Related Basal 20 2 43 325 5.1 0.5 11.0 83.4 20 5 9 155 10.6 2.6 4.8 82.0 40 7 52 480 6.9 1.2 9.0 82.9 390 10O.O 189 100.0 579 100.0

SERUM CHOLESTEROL AD COROARY ATHEROSCLEROSIS 399 TABLE 2 percentage of the coronary intima involved with raised atherosclerotic lesions, in a sample of 548* autopsied men, by broad disease category and race, Orleans Parish, Louisiana, 1968 1972 Diagnostic category Coronary heart disease Uncertain coronary heart disease Related Basal 20 2 41 306 369 49.6 3.3 20.3 6.1 10.0 5.7 2.3 3.2 0.6 0.6 20 3 8 148 179 56.0 20.1 15.4 7.6 13.6 * Coronary arteries were not obtained or not evaluated in 21 black and in 10 white cases. See text. TABLE 3 serum cholesterol levels (mgldl) in adult males in two ew Orleans, Louisiana, studies Study Blood donor* Community pathologyt All cases Basal cases 76 228 186 187 199 201 4.1 4.0 4.4 39 112 88 189 225 211 4.4 10.2 4.5 0.8 0.8 Restrepo et al. (17). t Excluding 167 cases without serum cholesterol determinations and 72 cases that were below 100 mg/dl. See text. TABLE 4 post mortem serum cholesterol levels (mgldl) in a sample of 340* autopsied men, by broad disease category and race, Orleans Parish, Louisiana, 1968-1972 Diagnostic category Coronary heart disease Uncertain coronary heart disease Related Basal 10 2 30 186 228 229 241 176 201 199 17.1 42.5 9.9 4.4 4.0 15 4 5 88 112 279 275 270 211 225 5.6 7.2 6.9 * Excluding 167 cases without serum cholesterol determinations and 72 cases that were below 100 mg/dl. See text 26.5 46.5 40.3 6.9 7.2 for the white CHD cases (279 mg/dl) is groups. On the other hand, there was no significantly higher (t = 3.42; p =s 0.001) difference in the serum cholesterol levels than the mean serum cholesterol level for of CHD and basal groupings for black the white basal cases (211 mg/dl), and males, but the mean value for the related similar to the mean values for the uncer- disease group was significantly lower tain and related categories in spite of the than the corresponding value for either limited number of cases in these two the CHD (t = 2.68;p = 0.025) or the basal

400 OALMA, MALCOM, TOCA, GUZMA AD STROG groupings (t = 2.14; p =s 0.05). The two cases in the uncertain CHD group yielded the highest mean serum cholesterol value among blacks. Although the difference is not significant, possibly because of the limited number of cases, it should be noted that white CHD cases had higher mean post mortem serum cholesterol than the black CHD cases (279 vs. 229 mg/dl). In this sample of autopsied males, there is no evidence of a racial difference in post mortem serum cholesterol in the basal group (201 mg/dl for blacks and 211 mg/dl for whites). The mean serum cholesterol values, calculated for quartile groupings of the involvement with RCL of all cases, are presented for the two races in the form of bar diagrams in figure 1. In the black race, the mean serum cholesterol values 300-1 250-!»o-l 200-150 - 0-00-033 32 054-3" 34H4 > 14.00 did not show a consistent pattern of higher serum cholesterol values with increasing lesion involvement. The values were 190 ± 7.0 and 217 ± 8.6 in the first and fourth quartile groupings of RCL, respectively, suggesting at best only a moderate difference between the extreme quartiles of the distribution. In the white men, however, the increase in serum cholesterol levels with increasing involvement with RCL, although modest (198-212 mg/dl), is consistent through the first three quartiles, but dramatic and significant (t = 2.32; p = 0.025) from the third (212 ± 13.8) to the fourth (267 ± 16.9) quartile. The mean percentage of coronary involvement with raised lesions, calculated for quartile groupings of the post mortem cholesterol values of all cases are also ) 100-Ib2 I ISM U >245 <O 50 - O J BUCK. Ql WHITE l\dised Letting QturHks QIQ2Q5Q4 BLAOK WHITE Cholesterol Quartiks FIGUBB 1. cholesterol for quartiles (Q) of raised coronary lesions and mean raised lesions for quartiles of cholesterol by race in a sample of autopsied men, Orleans Parish, Louisiana, 1968-1972.

SERUM CHOLESTEROL AD COROARY ATHEROSCLEROSIS 401 presented by race in figure 1. In white males, the percentage of intimal surface involved with RCL increased from 9 ± 2.8 in the first to 23 ± 3.8 in the fourth quartile grouping by serum cholesterol values. The increase in per cent involvement with RCL, however, at best is only moderate through the first two quartile groupings by serum cholesterol values, and appears to occur abruptly in the third and fourth quartile groupings, when serum cholesterol values range in excess of 200 mg/dl. The increase in per cent involvement with RCL from low to high serum cholesterol quartile groupings in black men is uniform but very modest (7.5 ± 1.6 to 12.4 ± 2.8) and the fourth quartile mean for blacks is only slightly above the second quartile mean (10.1 ± 4.0) for white men. Correlation coefficients of the percentage of intima involved with RCL and serum cholesterol values were calculated for the various race and broad disease diagnostic groupings considered. The results (table 5) suggest a significant association between post mortem serum cholesterol values and extent of involvement with RCL in the case of white men (r = 0.353; p =s 0.01) without reference to cause of death. This association indicates that approximately 12 per cent (0.353 2 ) of the observed total variability is common to serum cholesterol values and per cent involvement of the coronaries with raised lesions. When the calculation of correlation coefficients is restricted to the basal group, the association between serum cholesterol and raised coronary lesions is still significant (r = 0.250; p * 0.05), but the estimate of common variance to lesions and cholesterol values is reduced to 6 per cent (0.250 2 ). There is no evidence of association between lesions and cholesterol values in our sample of autopsied black males, either when all cases are included in the calculations (r = 0.114) or when only the basal cases are considered (r = 0.112). The lesion-cholesterol correlations over the combined races are significant in both the basal group (r = 0.167; p = 0.01) and in the total autopsy sample (r = 0.247; p ^ 0.01). DISCUSSIO The age-race-specific mortality rates for the Orleans Parish population in the 25 44 years of age groups are greater than comparable figures for the United States in both the white and nonwhite groups. The nonwhite mortality rates in Orleans Parish, as is also the case for the nation, are higher than white rates in each disease category including CHD (24-26). The death rates that can be calculated from the observations in this study parallel the officially reported figures from the Bureau of Vital Statistics of the Louisiana Department of Health for the two racial groups. The distribution of deaths by disease category presented in table 1 occurs, as may be expected, with approximately the same proportion of deaths assigned to the basal group in both races but with a TABLE 5 Product moment correlations (r) between percentage of coronary intima involved with raised atherosclerotic lesions and post mortem serum cholesterol in a sample of autopsied men, Orleans Parish, Louisiana, 1968-1972 Diagnostic category* Basal 179 221 r 0.112 0.114 87 110 r 0.25Ot 0.353* * Excluding 72 cases with cholesterol below 100 mg/dl and cases with missing data. See text t p < 0.05. Xp 266 331 r 0.167* 0.247*

402 OALMA, MALCOM, TOCA, GUZMA AD STROG higher proportion of CHD deaths among white men and a higher proportion of CHD-related causes among black men. The latter finding probably reflects the higher prevalence of hypertension among blacks (24, 27, 28). The fact that the mortality rates and the proportion of deaths by disease category assignment in our autopsy study are similar to those reported in the total population gives reasonable credibility to the results, provided that the limitations of studying autopsy samples (29, 30) are recognized. Furthermore, since the post mortem cholesterol levels in this study are similar to those reported in a blood bank study in ew Orleans (17), our results, even though based on a single determination, may reflect realistically the cholesterol values of the autopsied men studied. The measurement error and reliability of the visual method of grading lesions are well documented (13, 21) and their practical usefulness is demonstrated through fruitful utilization in many studies (31-34). Therefore, the basic conclusion of an association of serum cholesterol levels with the extent of involvement of the coronary arteries with atherosclerotic lesions per se among white men seems warranted. These results are in agreement with the conclusions of similar studies in Puerto Rico (33), Hawaii (35, 36) and Scandinavia (34, 37). This autopsy study, however, consistently failed to show clear-cut cholesterol-atherosclerotic lesion associations in black men. The reasons for the racial difference in the association pattern described are not clear. One possibility is that no single factor is uniquely responsible in the atherosclerosis and subsequent CHD process (36). A multiplicity of factors, not necessarily with atherogenic properties, interact and may be responsible for the final result. Under these conditions, it is not hard to conceive that different sets of risk factors (both atherogenic and nonatherogenic) may be responsible for the disease (CHD) in different environments. Thus, differences in the overall life styles of racial groups may result in different degrees of association among different sets of factors which, nevertheless, may eventually result in the same disease entity. The results of the present study may well be an example of this situation, for the direct association of serum cholesterol with the more advanced atherosclerotic lesions and CHD is clear in the case of white men but not so evident in the sample of black men. The usually higher prevalence of hypertension among blacks, documented by a higher mean renal hypertensive index in our autopsy sample, may partially account for this difference. Additional research is needed to clear these points. In particular, the study of younger age groups and of earlier lesions investigated in parallel with other risk factors in different environments may help in elucidating further this question. These studies, however, may be very time consuming because of the low frequency of CHD deaths at younger ages. REFERECES 1. Dawber TR, Kannel WB, Revotskie, et al. The epidemiology of coronary heart disease: The Framingham Inquiry. Proc R Soc Med 1962; 55:265-71. 2. McDonough JR, James C, Stulb SC, et al. Coronary heart disease among egroes and whites in Evans County, Ga. J Chronic Dis 1965;18: 443-68. 3. Dawber TR, Mcamara PM. Coronary heart disease: identification of susceptible individuals. In: Breast A, Moyer JH, eds. Atherosclerotic vascular disease. A Hahnemann symposium. ew York: Appleton-Century-Crofts, 1967:130-46. 4. Gordon T, Kannel WB. Premature mortality from coronary heart disease. The Framingham Study. JAMA 1971;215:1617-25. 5. Gordon T, Kannel WB. Predisposition to atherosclerosis in the head, heart, and legs. The Framingham Study. JAMA 1972;221:661-6. 6. Kato H, Tillotson J, ichaman MZ, et al. Epidemiologic studies on coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Serum lipids and diet. Am J Epidemiol 1973;97:372-85. 7. Ashley JR, Frantz W, Kannel WB. Relation of weight change to changes in atherogenic traits.

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