Atherosclerosis-like lesions of the aortic valve are common in adults of all ages: a necropsy study.

OBJECTIVE: To determine the presence and size of atherosclerosis-like lesions in aortic valves of unselected adults of all ages. DESIGN: Necropsy study. SETTING: Departments of Forensic Medicine and Pathology at the University of Oulu and the Oulu University Hospital in Finland. SUBJECTS: 48 consecutive unselected adult subjects (15 subjects aged 20-40 years, 17 aged 41-60, and 16 aged >or= 61) undergoing necropsy. MAIN OUTCOME MEASURES: Detection of the presence of atherosclerosis-like lesions and mineralisation in aortic valves, and morphometrical measurement of the size of lesions. RESULTS: None of the necropsy subjects had aortic stenosis and only two subjects had macroscopic calcification of the aortic valve. Of 48 subjects, however, 45 had an atherosclerosis-like subendothelial thickening above the elastic lamina on the aortic side of at least one of the valve leaflets. Of 15 young subjects aged 20-40 years, eight had a lesion in the right coronary cusp of the aortic valve and 12 had a lesion in at least one of the three aortic valve leaflets. Of 17 middle aged subjects, 16 had an early lesion in the right coronary cusp and all had a lesion in at least one of the valve leaflets. In the oldest age group, all 16 subjects had a lesion in every valve leaflet. The mean lesion area in the three valve leaflets varied from 0.1-0.2 mm(2) in young subjects, 0.5-0.8 mm(2) in middle aged, and 1.3-2.3 mm(2) in elderly subjects (p < 0.001). Microscopic calcification in the right coronary cusp of the aortic valve was observed in 12 of 17 middle aged and 14 of 16 elderly subjects but only in one young subject. CONCLUSIONS: Atherosclerosis-like lesions in the aortic valve are prevalent in adults of all age groups, including young subjects aged 20-40 years, suggesting that the disease process leading to aortic stenosis is common, often beginning in early adulthood.

Suicides in persons suffering from rheumatoid arthritis.

OBJECTIVE: To assess the demographic and psychosocial profiles of patients with rheumatoid arthritis (RA) who committed suicide. Two control groups were used: osteoarthritis (OA) and suicide victims with neither RA nor OA. METHOD: A study based on a prospective, 13-yr follow-up database with linkage to national hospital discharge registers of all suicides (1296 males, 289 females) committed during the years 1988-2000 in the province of Oulu situated in northern Finland. RESULTS: Females were significantly over-represented among RA patients who committed suicide (52.6% RA women vs 17.3% women with neither RA nor OA). Comorbid depressive disorders preceded suicides in 90% of the female RA patients. Before their suicide, 50% of the female RA patients (vs 11% of the male RA patients) had experienced at least one suicide attempt. The method of suicide was violent in 90% of the RA females. RA males were less often depressive, but committed suicide after experiencing shorter periods of RA and fewer admissions than females. CONCLUSION: Attempted suicides and especially depression in female RA patients should be taken more seriously into account than previously in clinical work so that the most appropriate psychiatric treatment can be provided for such patients.

Measurement of the striatal dopamine transporter density and heterogeneity in type 1 alcoholics using human whole hemisphere autoradiography.

Dopaminergic mechanisms are involved in the positive reinforcing and addicting effects of alcohol. Positron emission tomography (PET) and single photon emission tomography (SPET) studies have indicated alterations in striatal dopamine transporters (DAT) and in presynaptic dopamine (DA) function in alcoholics, although also contradictory results have been reported. Normal variations in blood flow, metabolism, and receptor densities are apparently important to brain function. Such variations are known to decrease during pathophysiological processes, such as epilepsy, whereas normal receptor distributions are broadly heterogenous. We evaluated the densities and heterogeneities of striatal DAT in 8 adult-onset, Cloninger type I alcoholics and 10 controls using [125I]N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta- (4'-methylphenyl)nortropane ([125I]PE2I) as a ligand for human postmortem whole hemisphere autoradiography, which provided high resolution images of the brain when compared with in vivo PET and SPET. The mean density and heterogeneity of DAT were markedly lower in the alcoholics. A significant linear correlation existed between DAT density and heterogeneity, as well as between DAT densities in the nucleus accumbens and in the dorsal striatum (caudate and putamen) in alcoholics, but not consistently in controls. The observed low DAT density and heterogeneity in the dorsal striatum suggest that type 1 alcoholics may have a dysfunctional DA system. These data indicate that human whole hemisphere autoradiography with the analysis of binding heterogeneity may be a relevant tool to measure pathological processes in the brain.

Visceral fat and coronary pathology in male adolescents.

OBJECTIVE: To find out whether coronary atherosclerotic lesions and their precursors in male adolescents are associated with the amount of mesenteric and omental fat. SUBJECTS: A series of 40 forensic autopsy cases of ante-mortem healthy boys of 13-19 y of age were investigated. METHODS: Body height and weight, waist and hip circumferences and the thickness of the abdominal subcutaneous fat were measured, the body mass index (BMI) and waist-to-hip ratio (WHR) were calculated, and omental and mesenteric fat deposits were weighed. The intimal surface of the coronary arteries covered by lesions was measured by planimetry, and the thickness of the intima was measured by computerized image analysis. Intimal macrophage foam cells and smooth muscle cells were detected by immunohistochemisty, and macrophages were quantified. RESULTS: The intima thickness of the left anterior descending artery (LAD) and in the thickest lesion varied significantly across the tertiles of visceral fat when adjusted for age, being highest when the sum weight of omental and mesenteric fat exceeded 358 g. The intima thickness of the circumflex artery (CX) varied significantly across the tertiles of waist circumference when adjusted for age. No statistically significant associations with other indicators of obesity were found. Macrophage foam cells were present in the lesions and their maximal density/mm(2) correlated significantly with intima thickness in the LAD and CX. The maximal density of macrophages in CX and the right coronary artery (RCA) and in the thickest lesion varied significantly across the tertiles of visceral fat when adjusted for age, being highest when the amount of fat exceeded 358 g. The macrophage density also varied significantly across the tertiles of waist circumference in all vessels. CONCLUSIONS: The results indicate that early macrophage-rich coronary lesions are associated with increased amounts of visceral fat in adolescent male individuals. This emphasizes the importance of effective prevention of weight gain in individuals with a tendency to accumulate visceral fat at an early age.

Dopamine D(2)/D(3)-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics.

Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. We evaluated the densities of DA D(2)/D(3) receptors and transporters in the nucleus accumbens and amygdala of post-mortem human brains by using [(125)l]epidepride and [(125)I]PE2I as radioligands in whole hemispheric autoradiography of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean binding of [(125)I]epidepride to DA D(2)/D(3) receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and [(125)I]PE2I binding to DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. Our results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function.

Characterization of gamma-aminobutyrate type A receptors with atypical coupling between agonist and convulsant binding sites in discrete brain regions.

Gamma-ainobutyric acid type A (GABA(A)) receptor ionophore ligand t-[35S]butylbicyclophosphorothionate ([35S]TBPS) was used in an autoradiographic assay on brain cryostat sections to visualize and characterize atypical GABA-insensitive [35S]TBPS binding previously described in certain recombinant GABA(A) receptors and the cerebellar granule cell layer. Picrotoxinin-sensitive but 1-mM GABA-insensitive [35S]TBPS binding was present in the rat cerebellar granule cell layer, many thalamic nuclei, subiculum and the internal rim of the cerebral cortex, amounting in these regions up to 6% of the basal binding determined in the absence of exogenous GABA. Similar binding properties were detected also in human and chicken brain sections. Like the GABA-sensitive [35S]TBPS binding, GABA-insensitive binding was profoundly decreased by pentobarbital, pregnanolone, loreclezole and Mg2+. The binding was reversible and apparently dependent on Cl- ions. Localization of the GABA-insensitive [35S]TBPS binding was not identical to that of high-affinity [3H]muscimol binding and diazepam-insensitive [3H]Ro 15-4513 binding, two previously established receptor subtype-dependent binding heterogeneities in the rat brain. The present study reveals a component of the GABA-ionophore enriched in the thalamus and cerebellar granule cells, possibly representing poorly desensitized or desensitizing receptors.

Dopamine-transporter density in nucleus accumbens of type-1 alcoholics.

We have shown that alcoholic patients have a lower number of dopamine transporters in the nucleus accumbens, which mediates the rewarding effects of addictive drugs. Thus, certain dopaminergic agents may be beneficial in the treatment of alcohol withdrawal and in the long-term treatment of alcoholism with selective use.

Does alcohol drinking have an influence on suicides in cancer sufferers? A population-based study of 1515 suicide victims.

BACKGROUND: [corrected] We investigated whether alcohol drinking contributes to suicides in cancer sufferers when compared with non-cancer suicides. We also explored the suicide method used in cancer suicides. METHODS: The population-based, prospectively collected data sample consisted of 1515 completed suicides committed in the province of Oulu, Finland, during the period 1988-99. Victims who suffered from cancer were compared with other suicides. RESULTS: Cancer patients who committed suicide were significantly less commonly under the influence of alcohol than non-cancer suicide victims (84.8% vs 54.7%). Mental disorders were less prevalent among cancer patients than non-cancer patients. The cancer patients were significantly older and more often retired and a trend that a greater proportion of cancer suicide victims were male was noted. Shooting and poisoning were the most common suicide methods among cancer patients. CONCLUSION: An early recognition and evaluation of the extent of the suicidal tendencies among cancer patients is of great importance in clinical oncology, since preventive interventions would be effective especially for those without comorbid alcoholism at the time of the suicide.

Coronary atherosclerosis associated with body structure and obesity in 599 women aged between 15 and 50 years.

OBJECTIVE: Few data are available on the actual degree of coronary atherosclerosis or its relationship to body composition in young women. The present study was carried out to identify, with the help of simple indicators of obesity and body structure, those women under 50 y of age who have the most advanced coronary lesions. DESIGN: Autopsy reports were analysed including age, height, weight, abdominal subcutaneous fat thickness, heart weight, liver and kidney weights, coronary atherosclerosis, and ovarial status. SUBJECTS: Female cases of sudden unexpected death (n = 599) aged between 15 and 50 y autopsied in 1973-1995 were collected from the files of the Department of Forensic Medicine, University of Oulu, Finland. RESULTS: The percentage of individuals with coronary lesions was 50% in women over 41 years of age, 32% in women from 31 to 40, 17% in women from 21 to 30, and 6% in women under 20 y of age. 2.1% of the women had died from manifestations of coronary heart disease (CHD). The most severe lesions were found in women with body mass index (BMI) between 24.2 and 27.2 when adjusted for age, and when abdominal subcutaneous fat thickness exceeded 35 mm when adjusted for age and BMI. Heart weight indexed to body size increased with BMI and abdominal fat and was positively correlated with the degree of coronary atherosclerosis, which was also associated with short stature and high liver and kidney weights when adjusted for body size. CONCLUSION: Mild to moderate overweight, short stature, increased amounts of abdominal subcutaneous fat, increased components of fat free mass and myocardial hypertrophy are the physical characteristics that indicate more advanced coronary atherosclerosis in women under 50 y of age.

Extent and composition of coronary lesions in relation to fat distribution in women younger than 50 years of age.

To ascertain the relationship between the extent and composition of coronary arterial lesions and the regional distribution of fat in healthy women younger than 50 years of age, a series of 30 forensic autopsy cases were investigated. 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 and mesenteric fat deposits were weighed. The extent of coronary lesions was measured by planimetry, and the thickness of the intima-media was measured by computerized image analysis. Intimal macrophage foam cells and smooth muscle cells were detected by immunohistochemistry, and macrophages were quantified. The intima media thickness in the left anterior descending artery, circumflex artery, and right coronary artery varied significantly across the tertiles of WHR when age and BMI were adjusted, being highest when WHR exceeded 0.87. The thickest lesions also contained the largest numbers of macrophage foam cells. The intima-media thicknesses were highest with increased amounts of intraperitoneal fat. These results indicate that the severity of clinically silent coronary lesions in younger female individuals is associated with increased WHR and increased amounts of intraperitoneal fat. These results emphasize the importance of WHR as a coronary risk indicator in younger women.

Can degenerative aortic valve stenosis be related to persistent Chlamydia pneumoniae infection?

BACKGROUND: The cause of age-related degenerative (tricuspid) aortic valve calcification is largely unknown, but one typical characteristic is an active inflammatory process. The presence of Chlamydia pneumoniae in aortic valve stenosis was recently shown. OBJECTIVE: To test the hypothesis that if persistent C. pneumoniae infection plays an active role in the development of aortic stenosis, the organism can be detected in the healthy aortic valves of young persons. DESIGN: A cadaver study. SETTING: Oulu University Hospital, Oulu, Finland. SUBJECTS: 46 consecutive cadavers undergoing autopsy. MEASUREMENTS: Macroscopic and histologic pathology of aortic valves was determined. The presence of C. pneumoniae was determined by immunohistochemistry. RESULTS: 34 of 46 valves were macroscopically normal. Early lesions of aortic valve disease were found in 12 valves (no lesions in valves from persons 20 to 40 years of age [n = 15], 4 lesions in valves from persons 41 to 60 years of age [n = 16], and 8 lesions in valves from persons older than 60 years of age [n = 15]; P = 0.004). Fifteen of 34 normal valves (44%) and 10 of 12 valves with early lesions (83%) had positive results on staining for C. pneumoniae (P = 0.02). In persons older than 60 years of age, the chance of an early lesion was higher if the valve tested positive for C. pneumoniae (7 of 8 valves with C. pneumoniae infection compared with 1 of 7 valves without C. pneumoniae infection; P = 0.01). CONCLUSIONS: Chlamydia pneumoniae is frequently present in aortic valves and is associated with early lesions of aortic valve stenosis in elderly persons.

Expression of extracellular SOD and iNOS in macrophages and smooth muscle cells in human and rabbit atherosclerotic lesions: colocalization with epitopes characteristic of oxidized LDL and peroxynitrite-modified proteins.

Oxidative processes play an important role in atherogenesis. Because superoxide anion and nitric oxide (NO) are important mediators in vascular pathology, we studied the expression of extracellular superoxide dismutase (EC-SOD) and inducible nitric oxide synthase (iNOS) in human and rabbit atherosclerotic lesions by using simultaneous in situ hybridization and immunocytochemistry and EC-SOD enzyme activity measurements. We also analyzed the presence in the arterial wall of oxidized lipoproteins and peroxynitrite-modified proteins as indicators of oxidative damage and possible mediators in vascular pathology. EC-SOD and iNOS mRNA and protein were expressed in smooth muscle cells and macrophages in early and advanced lesions. The expression of both enzymes was especially prominent in macrophages. As measured by enzyme activity, EC-SOD was the major SOD isoenzyme in the arterial wall. EC-SOD activity was higher in highly cellular rabbit lesions but lower in advanced, connective tissue-rich human lesions. Despite the abundant expression of EC-SOD, malondialdehyde-lysine and hydroxynonenal-lysine epitopes characteristic of oxidized lipoproteins and nitrotyrosine residues characteristic of peroxynitrite-modified proteins were detected in iNOS-positive, macrophage-rich lesions, thus implying that malondialdehyde, hydroxynonenal, and peroxynitrite are important mediators of oxidative damage. We conclude that EC-SOD, iNOS, and the balance between NO and superoxide anion play important roles in atherogenesis. EC-SOD and iNOS are highly expressed in lesion macrophages. High EC-SOD expression in the arterial wall may be required not only to prevent deleterious effects of superoxide anion but also to preserve NO activity and prevent peroxynitrite formation. Modulation of arterial EC-SOD and iNOS activities could provide means to protect arteries against atherosclerotic vascular disease.

Extent and composition of coronary lesions and degree of cardiac hypertrophy in relation to abdominal fatness in men under 40 years of age.

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 height 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.

Coronary atherosclerosis and myocardial hypertrophy in relation to body fat distribution in healthy women: an autopsy study on 33 violent deaths.

OBJECTIVE: To determine the relationship between cardiovascular pathology and body fat distribution in healthy women with no ante mortem clinical evidence of cardiovascular disease. SUBJECTS: Thirty-three female forensic autopsy cases of sudden death from violent causes. METHODS: Body height and weight, the circumferences of the waist and hip and the thicknesses of the subscapular and abdominal subcutaneous fat were measured, and Body Mass Index (BMI) and Waist-to-Hip ratio (WHR) were calculated. Omental, mesenterial and perirenal fat deposits were weighted. Heart weight was indexed to height (2.7), the degree of coronary narrowing was determined in each artery, and myocardial collagen volume fraction and myocyte cross-sectional area were measured. RESULTS: The degree of coronary narrowing, heart weight in absolute terms and indexed to height (2.7), myocyte cross-sectional area and all the measures of obesity were significantly positively correlated with age. Regression of coronary narrowing on measures of obesity indicated that a quadratic model fitted the data for BMI, waist circumference and intra-abdominal fat better than a linear one. After adjusting for age, the degree of coronary narrowing was related to tertiles of BMI, waist circumference, WHR and intra-abdominal fat, the severity of the narrowing being most marked in the second tertile of BMI (24.0-31.0), waist circumference (80-96 cm) and intra-abdominal fat (500-1700 g), but in the third tertile of WHR (over 0.92). Regression on heart weight/height (2.7) on the aforementioned measures of obesity indicated a clearly linear association and heart weight indexed to height (2.7) was related to tertiles of BMI, waist circumference and WHR, and also to tertiles of intra-abdominal fat. CONCLUSIONS: The results suggest that body fatness and abdominal accumulation of fat are associated with the severity of coronary atherosclerosis and myocardial hypertrophy in women with no clinical evidence of cardiovascular disease, but the relationship between coronary lesions and BMI is not linear. Both coronary lesions and myocardial hypertrophy are more advanced as the numerical value for WHR increases in women. Future autopsy studies should be directed at young women with increased WHR in order to determine their risk of developing life-threatening lesions in the atherosclerosis-prone regions of the coronary tree.

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Macrophage- and smooth muscle cell (SMC)-derived foam cells are typical constituents of human atherosclerotic lesions. At least three receptor systems have been characterized that could be involved in the development of foam cells: alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2 MR/LRP), scavenger receptor, and LDL receptor. We studied the expression of these receptors in human atherosclerotic lesions with in situ hybridization and immunocytochemistry. An abundant expression of alpha 2MR/LRP mRNA and protein was found in SMC and macrophages in both early and advanced lesions in human aortas. alpha 2MR/LRP was also present in SMC in normal aortas. Scavenger receptor mRNA and protein were expressed in lesion macrophages but no expression was found in lesion SMC. LDL receptor was absent from the lesion area but was expressed in some aortas in medial SMC located near the adventitial border. The results demonstrate that (a) alpha 2MR/LRP is, so far, the only lipoprotein receptor expressed in lesions SMC in vivo; (b) scavenger receptors are expressed only in lesion macrophages; and (c) both receptors may play important roles in the development of human atherosclerotic lesions.

Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.

The recruitment of monocyte-macrophages into the artery wall is one of the earliest events in the pathogenesis of atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) is a potent monocyte chemoattractant secreted by many cells in vitro, including vascular smooth muscle and endothelial cells. To test whether it is expressed in the artery in vivo, we used Northern blot analysis, in situ hybridization, and immunocytochemistry to study the expression of MCP-1 in normal and atherosclerotic human and rabbit arteries. Northern blot analysis showed that MCP-1 mRNA could be isolated from rabbit atherosclerotic lesions but not from the intima media of normal animals. Furthermore, MCP-1 mRNA was extracted from macrophage-derived foam cells isolated from arterial lesions of ballooned cholesterol-fed rabbits, whereas alveolar macrophages isolated simultaneously from the same rabbits did not express MCP-1 mRNA. MCP-1 mRNA was detected by in situ hybridization in macrophage-rich regions of both human and rabbit atherosclerotic lesions. No MCP-1 mRNA was found in sublesional medial smooth muscle cells or in normal arteries. By using immunocytochemistry, MCP-1 protein was demonstrated in human lesions, again only in macrophage-rich regions. Immunostaining of the serial sections with an antiserum against malondialdehyde-modified low density lipoprotein indicated the presence of oxidized low density lipoprotein indicated the presence of oxidized low density lipoprotein and/or other oxidation-specific lipid-protein adducts in the same areas that contained macrophages and MCP-1. We conclude that (i) MCP-1 is strongly expressed in a small subset of cells in macrophage-rich regions of human and rabbit atherosclerotic lesions and (ii) MCP-1 may, therefore, play an important role in the ongoing recruitment of monocyte-macrophages into developing lesions in vivo.

Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.

Oxidatively modified low density lipoprotein (LDL) exhibits several potentially atherogenic properties, and inhibition of LDL oxidation in rabbits decreases the rate of the development of atherosclerotic lesions. In vitro studies have suggested that cellular lipoxygenases may be involved in LDL oxidation, and we have shown previously that 15-lipoxygenase and oxidized LDL are present in rabbit atherosclerotic lesions. We now report that epitopes of oxidized LDL are also found in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions. Using in situ hybridization and immunostaining techniques, we also report that 15-lipoxygenase mRNA and protein colocalize to the same macrophage-rich areas. Moreover, these same lesions express abundant mRNA for the acetyl LDL receptor but no detectable mRNA for the LDL receptor. We suggest that atherogenesis in human arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase, leading to subsequent enhanced macrophage uptake, partly by way of the acetyl LDL receptor.