Extent and Composition of Coronary Lesions and Degree of Cardiac Hypertrophy in Relation to Abdominal Fatness in Men Under 40 Years of Age
Abstract The relationship of the extent and composition of coronary lesions and the degree of cardiac hypertrophy to anthropometric indicators of abdominal fatness and the amount of intra-abdominal fat was investigated in a group of 32 forensic autopsy cases that consisted of sudden deaths from violent causes of previously healthy men under 40 years of age. Body height and weight, waist and hip circumferences, and the thickness of the subscapular and abdominal subcutaneous fat were measured; the body mass index (BMI) and waist-to-hip ratio (WHR) were calculated; and omental, mesenteric, and perirenal fat deposits and the heart were weighed. The degree of coronary narrowing was determined visually, and the extent of coronary lesions was measured by planimetry. The thickness of the intima and intima-media was measured by computerized image analysis. Intimal macrophage foam cells and smooth muscle cells were detected by immunohistochemistry. Significant positive correlations were found between WHR and the overall degree of coronary narrowing and the intima-media thicknesses of the left anterior descending artery and right coronary artery when adjusted for age. Intima-media thickness was also related to tertiles of WHR. Heart weight indexed to height2.7 showed a significant positive correlation with BMI, waist circumference, WHR, and the size of intra-abdominal fat deposits, of which WHR was the best predictor of mild cardiac hypertrophy. The results indicate that the severity of clinically silent lesions in the atherosclerosis-prone regions of the coronary arteries is associated with WHR in young male individuals who also have mild myocardial hypertrophy associated with abdominal fatness and an accumulation of intra-abdominal fat. These associations between fat distribution and early cardiovascular changes point to a powerful need for preventive action with respect to weight gain in young men to alleviate progression of the lesions.
- Received March 29, 1996.
- Accepted July 4, 1996.
A previous study of forensic autopsy cases indicates that BMI, waist circumference, subscapular fat thickness, and perirenal fat weight have significant positive associations with the severity of coronary narrowings and myocardial hypertrophy in men who did not have any premortem evidence of cardiovascular disease.1 The degree of coronary artery stenosis was assessed visually according to the method of Champ and Coghill,2 who introduced a schematic diagram representing a percentage reduction in cross-sectional area of the coronary arteries. This method is preferable to a simpler categorization into mild, moderate, and severe degrees of stenosis,2 but microscopy and planimetric methods would probably be more specific when investigating early atherosclerotic changes in young individuals. The degree of less severe lesions can often be underestimated when only a visual method is used.3
Many clinical studies have shown that coronary events and hypertension are associated with abdominal accumulation of fat,4 5 6 7 8 and there is also angiographic evidence that clinically significant coronary narrowings are associated with abdominal obesity.9 10 As the previous autopsy series examined at our department showed a clear association between the degree of previously undiagnosed coronary narrowings, BMI, and abdominal fatness, we designed a new prospective autopsy study in which the subjects would be younger men with no history of cardiovascular abnormalities and in which a detailed examination of the composition of the coronary lesions would be carried out. The purpose was to find out whether the overall extent of early atherosclerotic lesions and their precursors in the coronary arteries is associated with abdominal accumulation of fat in young males and whether abdominal fatness is related to more advanced lesions in the typical arteriosclerosis-prone regions of the coronary tree. In addition, the relationships between the heart and anthropometric indicators of overweight and abdominal fatness and the size of intra-abdominal fat deposits were examined to see which of these would be the best predictors of mild myocardial hypertrophy in young men.
The material was collected from medico-legal autopsies performed at the Department of Forensic Medicine, University of Oulu, Finland, during 1995 and 1996. Thirty-two males from 18 to 40 years of age (median 31 years) were examined. The subjects were not reported to have suffered from coronary artery disease, hypertension, lipid disorders, or any other cardiovascular disease. Chronic alcoholics, diabetics, and individuals with other chronic diseases or with marked changes in body structure, eg, severe crush injuries, or marked changes in body weight were also excluded. The cases consisted of violent deaths from accidental causes, homicide, or suicide.
Data on the cases were collected from the medical records and police records. The police records included a standard form, in which the results of scene investigations; interviews with family members (when existing); and information on diseases, alcohol consumption, and medication were presented. The medical records were obtained from the hospitals and/or medical reception centers, and these contained the essential health information available for each individual. Heavy alcohol consumption was not reported in the records of any individual included in the series. Information on smoking habits was available in very few cases, and quantitative estimates of the number of cigarettes smoked or of passive exposure to cigarette smoke proved impossible to obtain. None of the individuals had received any long-term medication, and only occasional use of analgesics or sleeping pills or short treatments with antibiotics were mentioned in the medical records of some individuals.
The following measurements were made by two autopsy technicians trained for the purpose: height (cm), weight (kg), waist circumference (cm), hip circumference (cm), and thickness of the abdominal and subscapular subcutaneous fat (mm). The levels for measuring the circumferences and fat thicknesses were based on the same skeletal reference points as used for clinical purposes.11 The cadavers were lying naked in supine position on the autopsy table during the procedure. BMI (weight divided by height squared) and WHR were calculated from the measurements.
The greater omentum was excised free from intra-abdominal tissues, mesenteric fat was excised free from the gut, and perirenal fat was removed from both sides. All fat deposits were weighed fresh.
Heart and Coronary Arteries
The heart was removed according to a systematic autopsy protocol, by cutting through the root of the aorta and other great vessels proximal to the atria, and washed externally. Blood clots were removed from the chambers, and the heart was then weighed. The heart weight was indexed to height2.7 (heart weight/height2.7) in each individual. This is a modification of the method presented by de Simone et al,12 in which the left ventricular mass obtained by echocardiography was indexed to height2.7 (left ventricular mass/height2.7) to minimize the effect of body size on the evaluation of left ventricular hypertrophy.
The coronary arteries were opened longitudinally and the left and right coronary arteries excised along the line around the orifices of the left main trunk and the RCA. Left and right coronary arteries were then removed en bloc so that the smaller branches were also excised free of the surrounding tissue as far as possible with the naked eye. The degree of coronary narrowing was visually estimated in the LM, LAD, CX, and RCA separately. A numerical value was given for each artery according to the following criteria: 0, no detectable lesions; 1, stenosis 20% or less; 2, stenosis 20% to 40%; 3, stenosis 40% to 60%; 4, stenosis 60% to 80%; and 5, stenosis >80%. The total score for each individual was obtained from the sum of the scores in the four arteries (maximum score, 20). Each artery was then trimmed free from the surrounding muscle and fat tissue, placed intimal surface upwards on a piece of cardboard, and fixed in 10% neutral formalin for 24 hours. Transversely cut samples ≈2 mm thick were taken from the lesion-occupied region of the LM, LAD, CX, and RCA. All samples from vessels with no visible lesions were taken from the proximal parts of the LAD, CX, and RCA. The length of the LM was very variable, being extremely short in some cases, and therefore the samples were taken either from the lesion site or from the middle of the vessel in the case of a macroscopically normal left main trunk.
The arteries were then stained overnight at room temperature with Sudan IV.13 The total area of the vessels and the areas of the red lipid-stained lesions and more advanced lesions with or without positive staining were measured planimetrically (Ushikata Area-Curvimeter X-plan 360d, Ushikata Mfg Co, Ltd). The total area covered by the lesions was calculated, and the percentage of the intima involved by the lesions was determined according to the following formula: (Intimal Area Covered by Lesions/Total Intimal Area)×100.
Histology and Immunohistochemistry
The paraffin-embedded coronary artery samples, sectioned transversely at 5 μm, were stained by the Verhoeff-Masson trichrome method,14 in which collagen appears green, smooth muscle red, and elastic fibers black. Intimal macrophage foam cells were detected immunohistochemically with the monoclonal mouse anti-human antibody HAM56 (Dako) and smooth muscle cells with a monoclonal mouse anti-human smooth muscle actin antibody (Dako).
Morphometric Measurements on Coronary Artery Samples
Only those sections in which all the layers were completely visible without any distortion or other damage produced by tissue processing were chosen for morphometric analysis. Multiple sections were made from each paraffin-embedded tissue block to get acceptable material. The thickness of the intimal layer was first measured in the samples in which the intima was of a normal appearance or had only diffuse thickening. In the samples with more advanced lesions, the internal elastic membrane showed variable degrees of destruction, so that the exact limit of the intimal and medial layer was no longer visible in many of the samples. We therefore decided to measure the combined thickness of intima and media in each sample to compare the results between cases. All the measurements were made at 40× magnification on a microscope connected to a computerized image analysis system (Imaging Research Inc, Brock University, St Catherines, Canada). The results represent means of at least five measurements on each vessel.
All the analyses were performed using the Statistical Package for the Social Sciences (SPSS) software.15 Many of the variables (age, BMI, coronary narrowing, percentage of intima covered by lesions, intra-abdominal fat weights, intima-media thicknesses of LM and RCA, subscapular fat thickness, and waist circumference) showed some skewness in their distribution, and therefore logarithmic transformed values were calculated. A small constant (0.01) was added to the coronary narrowing score and to the percentage of coronary plaques to avoid the logarithm of zero. Normal distributions were achieved with the exception of coronary narrowing score and the percentage of intimal plaques, which still remained somewhat skewed. Pearson correlation coefficients were calculated between age and the other variables, between two variables after controlling for age as a covariate, and between the various cardiac parameters. Tertiles of WHR and intra-abdominal fat weight were calculated, the cutoff points being 0.84 and 0.94 for WHR and 700 g and 1200 g for intra-abdominal fat (sum of mesenteric, omental, and perirenal fat weights). An analysis of covariance with age as a covariate was used to compare the means of coronary intima-media thicknesses across tertiles of WHR and the means of heart weight/height2.7 across tertiles of WHR and intra-abdominal fat. In addition, stepwise multiple linear regression analysis was used to show which of the indicators of abdominal obesity would be the best predictor of cardiac hypertrophy. The regression model included heart weight/height2.7 as a dependent variable and age, BMI, waist circumference, WHR, abdominal fat, and the sum weight of the intra-abdominal fat deposits as independent variables. The significance level for entry was .05 and for removal .01.
The descriptive statistics, including means, SDs, and ranges, are presented in Table 1⇓. BMI varied over a wide range, and consequently the variation in the circumferences and fat-tissue measurements was also wide. The coronary lesions were generally mild, especially in the youngest individuals. In five cases, no fatty streaks or dots were seen at all, and the average proportion of the intimal surface of the coronary arteries covered by fatty streaks or more advanced macroscopically visible lesions was 4.7%. There were four cases in which >20% of the intimal surface was affected.
The proximal part of the LAD was most often affected (25 cases), followed by the RCA (19 cases), where lesions were also frequently found in the more distal parts of the vessel. There were 11 individuals who had more advanced lesions than only fatty streaks on visual inspection, but only in 2 cases was the most severe lesion detected in the LAD visually estimated to cause at least 50% luminal narrowing. The intima-media was thickest in the LM, followed by the LAD, RCA, and finally CX (Table 1⇑). The thickness of the intima in macroscopically normal arteries varied from 90 to 340 μm in the LAD, for example, and the combined intima-media thickness from 211 to 545 μm. A typical example of the structure and dimensions of a normal LAD is shown in Fig 1⇓. Many of the macroscopically normal arteries showed diffuse thickening of the intimal layer with marked smooth muscle proliferation, an example of which is given in Fig 2⇓. There were variable amounts of macrophage foam cells in the fatty streaks and raised lesions, and the plaques with an intima-media thickness exceeding 1000 μm usually had a lipid core. A raised lesion with a lipid core is shown, together with the dimensions of the plaque, in Fig 3⇓.
Age had significant positive correlations with the degree of coronary narrowing (r=.498, P<.001) and with the intima-media thickness of the CX (r=.376, P<.05) and RCA (r=.387, P<.05) but not with the percentage of coronary plaques in the left coronary artery, the RCA, or the whole coronary tree. Waist circumference, WHR, subscapular subcutaneous fat thickness, and the weights of the intra-abdominal fat deposits also had significant positive correlation with age (r=.402, P<.05 for waist circumference; r=.499, P<.01 for WHR; r=.430, P<.05 for subscapular fat; and r=.598, P<.001 for the sum weight of intra-abdominal fat deposits), but BMI, body weight, and height were not significantly associated with age.
After adjusting for age, the degree of coronary narrowing and the intima-media thicknesses of the LAD and RCA showed significant positive correlations with WHR (r=.461, P<.01 for coronary narrowing; r=.455, P<.01 for LAD; and r=.441, P<.05 for RCA), but there were no other statistically significant associations between the coronary parameters and BMI or other measures of body fatness. The intima-media thicknesses of the LAD and RCA varied significantly over the tertiles of WHR (Figs 4⇓ and 5⇓).
Correlations between the various coronary measures were generally positive and significant: Coronary narrowing was positively correlated with the percentage of intimal plaques (r=.363, P<.05) and with intima-media thickness of LAD (r=.572, P<.01), CX (r=.522, P<.01), and RCA (r=.676, P<.001). Many coronary variables were also positively correlated with heart weight/height2.7 (r=.521, P<.01 for coronary narrowing; r=.451, P<.01 for intima-media thickness of LM; r=.490, P<.01 for LAD; r=.390, P<.05 for CX; and r=.513, P<.01 for RCA).
Heart weight varied from 244 g to 515 g (mean 367 g) or from 50 to 109 g/m2.7 (mean 75) when indexed to height2.7 (Table 1⇑), and these both had a significant positive correlation with age (r=.651, P<.001 for heart weight and r=.766, P<.001 for heart weight/height2.7). After adjusting for age, the BMI, waist circumference, WHR, subscapular fat thickness, and all intra-abdominal fat deposits had significant positive associations with heart weight/height2.7 (Table 2⇓), which in turn varied significantly over the tertiles of WHR (Fig 6⇓) and of intra-abdominal fat (Fig 7⇓). Multiple stepwise regression analysis showed that alongside age, WHR was the best predictor of heart weight/height2.7 (r=.873, P<.001 for WHR and r=.762, P<.001 for age).
The present autopsy results did not reveal any significant correlation between the various measures of atherosclerosis and BMI in the age group from 18 to 40 years, which is in accordance with the results of Joseph et al3 for individuals under 35 years of age. On the other hand, McGill et al16 reported a significant association between BMI and the extent of fatty streaks and raised lesions in the RCA in persons aged under 34 years. McGill et al16 also found a positive association between the thickness of the panniculus adiposus and the extent of atherosclerotic lesions in the RCA, whereas in our present study the correlations between the different measures of coronary atherosclerosis and abdominal subcutaneous fat thickness were not significant. This finding could be because of methodological differences, as McGill et al used visual estimation of the area covered by the lesions and also because of their much larger sample size (1532 cases) and different ethnic background of the individuals studied. These previous studies did not investigate the relationship between anthropometric indicators of central obesity and coronary pathology in young men, however, whereas the present series of autopsies on trauma victims revealed an association between increased WHR and the severity of lesions in the arteriosclerosis-prone regions of the coronary tree.
The overall extent of lipid-containing sudanophilic lesions and more complicated lesions on the intimal surface of the coronary arteries was not associated with intra-abdominal fat accumulation in men under 40 years of age, but increased WHR was related to the severity of lesions in the proximal part of the LAD and to the degree of changes in the RCA. The proximal segment of the LAD has been described previously as a typical arteriosclerosis-prone region, whereas the RCA has been reported to be involved distally as frequently as proximally in younger individuals.3 Our autopsy findings regarding the LAD and RCA point to a considerable risk effect of male abdominal fatness on lesion development in the vulnerable regions of the coronary tree.
There is much variation in the methods and technical details in autopsy studies in which atherosclerotic changes are quantified.2 3 16 17 The percentage of luminal narrowing was not estimated planimetrically in the present series, as it was in the work of Joseph et al,3 for instance, but we consider that the combination of planimetry of the coronary intimal surface and computerized measurements of lesion thickness, together with visual evaluation by experienced pathologists, histological appearance, and immunohistochemical characteristics, gives a representative picture of the severity of the changes. The summary score of total coronary narrowing does not differentiate a few advanced lesions from many smaller lesions, and therefore it is better to use multiple parameters and microscopic evaluation, especially when early coronary changes are examined. It is, however, noteworthy that in the present study the total narrowing score had positive associations with the intima-media thicknesses measured.
Physical activity and diet are closely associated with both obesity and cardiovascular status, but unfortunately there were no data available on these factors that could possibly explain much of the associations found in the present work. As it proved to be impossible to obtain reliable information on the duration and quantity of cigarette smoking, its confounding effect on both atherosclerosis and body fat distribution remained unclear. In the study of McGill et al16 smoking was not found to explain the association of adiposity and atherosclerosis in young individuals. Alcohol consumption is known to have a considerable effect on nutritional status18 and probably also on the risk of atherosclerosis.19 The actual level of habitual alcohol consumption was difficult to estimate here, although according to hospital and police records, none of the individuals had any drinking problems. No alcohol-related organ damage was found at autopsy, and no extremely high postmortem levels of blood alcohol typical of chronic heavy drinkers20 were detected. Thus, both antemortem and postmortem data are against excessive drinking in these individuals, but possible alcohol-related differences in the composition of coronary lesions or in body fat distribution cannot be ruled out entirely.
An age-dependent increase in waist circumference, WHR, and the size of intra-abdominal fat deposits was seen in the present series. All these have been reported to increase with age in clinical studies,11 21 but none of the intra-abdominal fat deposits reached the level of significance in the previous autopsy study at our department.1 This may have been because of the different age distributions in these two surveys, but it is also possible that once repeated excisions of mesenteric, omental, and perirenal fat had been performed, the measurements were more accurate.
Heart weight is known to increase with age and decrease in the elderly,22 and the age-related increase was also seen in the present individuals under 40 years old. No myocardial or valve diseases were found in any of these hearts, and the average heart weight was well below 420 g, which has been considered the upper normal limit in the Finnish population.23 Total heart weight is known to provide a good indication of left ventricular hypertrophy,22 but body size has to be taken into consideration when investigating the effect of overweight on the heart. Many investigators have normalized left ventricular weight or total heart weight for body weight or body surface area,3 12 but since de Simone et al12 showed that it is most appropriate to normalize left ventricular mass for height2.7, we used a modification in which left ventricular mass was replaced by total heart weight. As there were no signs of right ventricular abnormalities, chamber partition was regarded as unnecessary. In seven cases, heart weight exceeded 420 g, and in all of these, heart weight/height2.7 was over the average value of 75 g/m2.7, two of them exceeding 100 g/m2.7. Slightly elevated blood pressure, possibly associated with mild to moderate overweight (BMI 25.5 to 32.6), may have been the underlying mechanism of mild cardiac hypertrophy in these cases in spite of no clinical antemortem diagnosis of hypertension.
Heart weight indexed to height2.7 was clearly associated with waist circumference and the size of intra-abdominal fat deposits, which is in accordance with the earlier autopsy results obtained at our department.1 In the present series, WHR proved to be the best predictor of mild cardiac hypertrophy in addition to age, whereas previously the association between WHR and heart weight/height2.7 had not reached the level of statistical significance.1 The well-known age-induced changes in body composition24 may have been the reason for this, since the earlier series had included older men. This study also showed that mild cardiac hypertrophy and more advanced coronary lesions tended to appear together in young men.
The present autopsy results indicate that abdominal fatness, manifesting itself as increased WHR, is associated with mild cardiac hypertrophy and severity of coronary lesions in the atherosclerosis-prone regions of the coronary tree in men under 40 years of age without any signs of cardiovascular disease in their lifetime. These associations between fat distribution and early cardiovascular changes point to a powerful need for preventive actions with respect to weight gain in young men to alleviate progression of the lesions.
Selected Abbreviations and Acronyms
|BMI||=||body mass index|
|CX||=||left circumflex artery|
|LAD||=||left anterior descending artery|
|LM||=||left main artery|
|RCA||=||right coronary artery|
The authors wish to thank Marja-Leena Vahera and Mauno Lohvansuu for technical assistance at the autopsies and Marjut Paitsola, Vappu Vähäsarja, Esa Kerttula, and Taina Uusitalo for their assistance in the laboratory.
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