Sex differences in coronary atherosclerosis during the pre- and postmenopausal period: The Tampere Sudden Death Study.

BACKGROUND AND AIMS: Women are believed to be protected from coronary heart disease (CHD) by the effects of estrogen but detailed studies on the vessel wall level are missing. We aimed to measure sex differences in atherosclerosis during the premenopausal and postmenopausal periods directly at the coronary arteries. METHODS: We analyzed statistics for sex differences in CHD mortality in Finland in 2020. Coronary atherosclerosis was measured using computer-assisted morphometry in 10-year age groups of 185 white Caucasian women and 515 men from the Tampere Sudden Death Study. RESULTS: CHD mortality was rare in both women and men before 50 years of age. After 50 years of age, male mortality increased rapidly, with women reaching equal levels in the oldest age groups. In the autopsy series, there were no differences in fatty streak, fibrotic or calcified plaque areas, nor in the plaque area or stenosis percentage in coronary arteries between premenopausal women and men in the same age group. The plaque area remained 25 % smaller in both coronaries in postmenopausal women aged 51-70 years compared to men. In the oldest postmenopausal group (≥70 years), plaque area reached the level of men. In the postmenopausal period, coronary stenosis in the left anterior descending (LAD) artery remained lower among women. CONCLUSION: We did not detect any major sex-difference in coronary atherosclerosis in the premenopausal period when women are considered to be protected from CHD. However, in line with CHD mortality statistics, postmenopausal women showed a slower speed of coronary atherosclerosis development compared to men.

CRP gene variation affects early development of Alzheimer's disease-related plaques.

INTRODUCTION: We used the Tampere Autopsy Study (TASTY) series (n = 603, age 0-97 yrs), representing an unselected population outside institutions, to investigate the pathogenic involvement of inflammation in Alzheimer's disease-related lesions. METHODS: We studied senile plaque (SP), neurofibrillary tangles (NFT) and SP phenotype associations with 6 reported haplotype tagging single nucleotide polymorphisms (SNPs) in the CRP gene. CRP and Aß immunohistochemistry was assessed using brain tissue microarrays. RESULTS: In multivariate analyses (age- and APOE-adjusted), non-neuritic SP were associated with the high-CRP TA-genotype (3.0% prevalence) of rs3091244 and CA-genotype (10.8%) of rs3093075 compared to common genotypes. Conversely, the low-CRP C allele (39.3%) of rs2794521 reduced the risk of harbouring early non-neuritic SP, compared to the TT genotype. CRP haplotype TAGCC (high) associated with non-neuritic SP, whereas haplotype CCGCC offered protection. TT genotypes (high) of rs3091244 and rs1130864 were associated with CRP staining. There were no associations between SNPs or haplotypes and NFT. CRP staining of the hippocampal CA1/2 region correlated with Aß staining. CONCLUSIONS: CRP gene variation affects early SP development in prodromal Alzheimer's disease, independent of APOE genotype.

Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age.

OBJECTIVE: To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community-dwelling normal population. METHODS: This neuropathological study used both silver staining and A beta immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out-of-hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems. RESULTS: Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE epsilon 4-carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of epsilon 4-carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55-27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group. INTERPRETATION: The brain changes associated with AD may already begin developing early in middle age, especially among APOE epsilon 4 carriers.

Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

AIMS: The interleukin 18 (IL-18) gene has a single nucleotide promoter region (-137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors. METHODS AND RESULTS: TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78-7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39-29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-gamma mRNA (P = 0.004). CONCLUSION: Hypertension interacts with IL-18 gene promoter -137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.

A device for measuring sternal bone connectivity using vibration analysis techniques.

OBJECTIVES: Stability of bone splitting sternotomy is essential for normal healing after open cardiac surgery. Mechanical vibration transmittance may offer a means for early detection of separation of bone (diastasis) in the sternotomy and prevent further complications. This article describes the technical implementation and validation of vibration analysis-based prototype device built for measuring sternal bone connectivity after sternotomy. METHODS: An in-house built measurement system, sternal vibration device, consisting of actuator, sensor, and main controller and signal acquisition unit was designed and manufactured. The system was validated, and three different test settings were studied in mockups (polylactide rods in ballistic gel) and in two human sternums: intact, stable wire fixation, and unstable wire fixation with a gap mimicking bone diastasis. The transmittance of vibration stimulus across the median sternotomy was measured. RESULTS: The validation showed that the force produced by the actuator was stable, and the sensor could be calibrated to precisely measure the acceleration values. The vibration transmittance response to material cut and sternotomy was evident and detectable in the 20 Hz to 2 kHz band. The transmittance decreased when the connectivity between the sternal halves became unstable. The trend was visible in all the settings. CONCLUSION: Technical solutions and description of validation process were given. The device was calibrated, and the vibration transmittance analysis differentiated intact and cut polylactide rod. In the sternum, intact bone, wire fixation with exact apposition, and with a gap were identified separately. Although further studies are needed to assess the accuracy of the method to detect different levels of diastases, the method appears to be feasible.

Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease.

INTRODUCTION: Cerebral hypoperfusion caused by large vessel atherosclerosis has been suggested to be associated with the pathogenesis of sporadic Alzheimer's disease (AD). Atherosclerosis and AD share risk factors such as age, diabetes, hypercholesterolemia, hypertension and apolipoprotein E epsilon4 (APOE epsilon4) allele. We studied the association between atherosclerosis of the circle of Willis (CW) and AD neuropathology in a large autopsy sample. METHODS: The present study comprised a consecutive autopsy series (n = 466) representing noninstitutionalized general population aged 50 years and over (mean 70.8, SD 11.5 years). The atherosclerosis of CW was scored semiquantitatively and the amyloid plaque (AP) load in the frontal cortex and the number of neurofibrillary tangles (NFT) in the hippocampus were measured. RESULTS: In a linear regression model, AP percentage area was associated with age (p < 0.0001) and APOE epsilon4 allele (p < 0.0001), but not with CW score (p = 0.70) or gender (p = 0.11). Similarly, the NFT count was predicted only by age (p > 0.0001), and not by CW score (p = 0.36), gender (p = 0.41) or APOE epsilon4 allele (p = 0.072). CONCLUSION: Our results suggest that cerebral large vessel atherosclerosis is not in direct association with APs or NFTs - hallmarks of AD neuropathology.

Asbestos fibers in para-aortic and mesenteric lymph nodes.

BACKGROUND: Asbestos fibers are known to accumulate in lung parenchyma and thoracic lymph nodes, but their presence and translocation into the extrapulmonary tissues need clarification. We assessed the presence of asbestos in the para-aortic (PA) and mesenteric (ME) lymph nodes. METHODS: PA and ME lymph nodes and lung tissue from 17 persons who underwent medicolegal autopsy for suspicion of asbestos-related disease and from five controls were analyzed for asbestos fibers using transmission electron microscopy. RESULTS: High concentrations of amphibole asbestos fibers were detected in several lung tissue samples and in the respective PA and ME lymph nodes. The mean concentration for the 10 persons with a lung asbestos content of >/=1 million fibers/g of dry tissue (f/g) was 0.85 (<0.05-4.36) million f/g in the PA lymph nodes and 0.55 (<0.02-2.86) million f/g in the ME lymph nodes. The respective mean values for the 12 persons with a lung asbestos concentration of <1 million f/g were 0.07 for the PA lymph nodes and 0.03 million f/g for the ME nodes. The lung asbestos burden that predicted the detection of asbestos in abdominal lymph nodes was 0.45 million f/g. CONCLUSIONS: In addition to their accumulation in lung tissue, asbestos fibers also collect in the retroperitoneal and the mesenteric lymph nodes. Even low-level occupational exposure results in the presence of crocidolite, amosite, anthophyllite, tremolite, or chrysotile in these abdominal lymph nodes. Our results support the hypothesis of lymph drainage as an important translocation mechanism for asbestos in the human body.

Age-dependent association of gut bacteria with coronary atherosclerosis: Tampere Sudden Death Study.

BACKGROUND: The gut microbiome is thought to remain stable into old age. Gut bacteria and their translocation may play a role in the development of coronary heart disease (CHD) by modulating cholesterol levels and immune responses, as well as by producing toxic metabolites and bacterial endotoxins. The association of changes in the gut microbiome with the severity of coronary atherosclerosis and the ability of gut bacteria themselves to translocate into coronary plaques has not been studied. MATERIALS AND METHODS: As a part of the Tampere Sudden Death Study, we measured age-dependent changes in the relative ratios of major intestinal bacterial communities (Bacteroides species [spp.], the Clostridium leptum group, the Clostridium coccoides group, Bifidobacterium spp., Enterobactericeae, Lactobacillus spp.) and Streptococcus spp. in both feces and coronary plaques of the same male autopsy cases (n = 67, age range 44-95) using real-time quantitative PCR (qPCR). The area of coronary atherosclerotic lesions were measured by computer-assisted morphometry. Fecal bacterial DNA measurements from healthy volunteers served as a control for gut bacterial analyses of autopsy cases. The relative amount of bacterial DNA in a sample was determined with the comparative Cq method. RESULTS: The relative ratios of fecal Lactobacillus spp., Bifidobacterium spp., the Clostridium coccoides group, and Bacteroides spp. did not differ between controls and autopsy cases and showed no age-dependence. In contrast, the ratios of the Clostridium leptum group, Enterobactericeae, and Streptococcus spp. increased with age. Elevated relative ratios of fecal Enterobactericeae associated with a larger coronary plaque fibrotic area (p = 0.001), and the Clostridium leptum group with a larger calcification area (p = 0.015). Intestinal bacterial DNA could be amplified in 67.6% of the coronary plaques, the most common being Streptococcus spp. (41.0%), followed by Enterobactericeae (12.1%), Clostridium leptum (2.4%), and Lactobacillus spp. (2.4%). The percentages of Streptococcus spp. DNA decreased, and those of Enterobactericeae increased in coronary plaques along with age. CONCLUSIONS: DNA of the Clostridium leptum group and pathogenic Enterobactericeae increase in the gut microbiome with age and can be detected in the same individual's coronary plaques along with pathogenic Streptococcus spp., associating with more severe coronary atherosclerosis.

Vibration transmittance measures sternotomy stability - a preliminary study in human cadavers.

BACKGROUND: Stability is essential for the normal healing of a sternotomy. Mechanical vibration transmittance may provide a new means of early detection of diastasis in the sternotomy and thus enable the prevention of further complications. We sought to confirm that vibration transmittance detects sternal diastasis in human tissue. METHODS: Ten adult human cadavers (8 males and 2 females) were used for sternal assessments with a device constructed in-house to measure the transmittance of a vibration stimulus across the median sternotomy at the second, third, and fourth costal cartilage. Intact bone was compared to two fixed bone junctions, namely a stable wire fixation and an unstable wire fixation with a 10 mm wide diastasis mimicking a widely rupturing sternotomy. A generalized Linear Mixed Model with the lme function was used to determine the ability of the vibration transmittance device to differentiate mechanical settings in the sternotomy. RESULTS: The transmitted vibration power was statistically significantly different between the intact chest and stable sternotomy closure, stable and unstable closure, as well as intact and unstable closure (t-values and p-values respectively: t = 6.87, p < 0.001; t = 7.41, p < 0.001; t = 14.3, p < 0.001). The decrease of vibration transmittance from intact to stable at all tested costal levels was 78%, from stable to unstable 58%, and from intact to unstable 91%. The vibration transmittance power was not statistically significantly different between the three tested costal levels (level 3 vs. level 2; level 4 vs. level 2; level 4 vs. level 3; t-values and p-values respectively t = - 0.36, p = 0.723; t = 0.35, p = 0.728; t = 0.71, p = 0.484). CONCLUSIONS: Vibration transmittance analysis differentiates the intact sternum, wire fixation with exact apposition, and wire fixation with a gap. The gap detection capability is not dependent on the tested costal level. The method may prove useful in the early detection of sternal instability and warrants further exploration.

Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis.

The apolipoprotein E (APOE) epsilon4 allele is associated with elevated cholesterol and risk of atherosclerosis. However, its role in ischemic stroke (IS) remains controversial. We investigated a possible link between IS or the severity of intracranial atherosclerosis and the APOE promoter polymorphisms -219G/T and +113G/C, involved in regulating APOE transcription. We genotyped subjects from a multicentric Belgian case-control study, including 237 middle-aged patients with IS due to small- or large-vessel atherosclerotic stroke and 326 ethnicity- and gender-matched controls and a Finnish autopsy series of 1004 non-stroke cases, who had received a quantitative score of atherosclerosis in the circle of Willis. The APOE epsilon4+ genotype did not associate with IS, but was related to more severe intracranial atherosclerosis score in men (5.4 vs 4.6, P=0.044). Within the most common APOE epsilon3/epsilon3 genotype group, the risk of IS associated with the G-allele of the tightly linked -219G/T (OR=6.2; 95% CI: 1.6-24.3, P=0.009) and +113G/C (OR=7.1; 95% CI: 1.7-29.9, P=0.007) promoter polymorphisms. There was no difference in the severity of intracranial atherosclerosis between -219G/G genotype carriers and non-carriers. This study suggests a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE epsilon4+ genotype did not predict the risk of IS but was associated with severity of subclinical intracranial atherosclerosis in men on the autopsy study. In contrast, the promoter variants were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS.

Age-dependent association between hepatic lipase gene C-480T polymorphism and the risk of pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

OBJECTIVE: We investigated the association between hepatic lipase (HL) C-480T polymorphism and the risk of acute myocardial infarction (AMI) as well as pre-hospital sudden cardiac death (SCD). METHODS: Seven hundred sudden or unnatural pre-hospital deaths of middle-aged (33-70 years, mean 53 years) Caucasian Finnish men were subjected to detailed autopsy (Helsinki Sudden Death Study). Genotype data were obtained for 682 men. RESULTS: In logistic regression analysis with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, men with the TT genotype had an increased risk for SCD and AMI compared to CC carriers (OR=3.0, P=0.011; and OR=3.7, P=0.003). There was a significant age-by-genotype interaction (P<0.05) on the risk of SCD. Compared to CC genotype carriers, the association between the TT genotype and SCD was particularly strong (P=0.001) among men <53 years of age, but this association was non-significant among older men. This was mainly due to a strong association between the TT genotype and AMI due to severe coronary disease in the absence of thrombosis. Carriers of the TT genotype were more likely to have severe coronary stenoses (> or =50%) than men with the CT or CC genotype (P=0.019). CONCLUSIONS: The results suggest that HL C-480T polymorphism is a strong age-dependent risk factor of SCD in early middle-aged men.

C-reactive protein in vulnerable coronary plaques.

BACKGROUND: An increased level of serum C-reactive protein (CRP) is a known prognostic factor for acute coronary events and sudden cardiac death, and it is associated with coronary calcification. CRP is expressed in coronary arteries, but its role in the development of coronary plaques is unclear. AIM: To investigate CRP immunoreactivity in relation to the severity of coronary artery disease and plaque morphology in human left anterior descending coronary arteries (LAD). METHODS: A prospective, consecutive autopsy series of 66 patients (mean age 63.4 years) in Tampere University Hospital, Tampere, Finland. RESULTS: CRP immunoreactivity was seen in 59% of the cases. In logistic regression analysis with age, sex and body mass index as confounders, CRP immunoreactivity in LAD was associated with >50% stenosis and plaque calcification. All three cases with acute coronary thrombosis due to rupture or erosion of the plaque showed a clear immunopositive reaction. CRP-positive cells were never detected in normal arteries, but were often found in early fibrous plaques (75%) and almost invariably present in the shoulder area of plaques with necrotic core (96%). CRP immunoreactivity adjacent to calcified areas in more stable plaques (71%) was less consistent with one-third of these plaques showing no immunoreactivity. CONCLUSIONS: CRP immunoreactivity is associated with the progression of atherosclerosis, and especially with unstable coronary plaques. The immunoreactivity could cease at the stable calcified stages of atherosclerosis.

Interleukin-1 receptor antagonist, interleukin-6, and C-reactive protein as predictors of mortality in nonagenarians: the vitality 90+ study.

BACKGROUND: Inflammation plays a major role in both aging and chronic disease. Longitudinal studies in very old people can improve our understanding of these processes. We investigated blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and their combinations as predictors of mortality in nonagenarians. METHODS: This is a prospective population-based study including both community-dwelling and institutionalized nonagenarians enrolled in the Vitality 90+ Study. Altogether 285 persons participated in the baseline interview and gave blood. Information on chronic disease was drawn from health center registers. Data on mortality over 4 years were obtained from the Population Register Center. In Cox proportional hazards models, chronic disease and major risk factors were adjusted for. RESULTS: Plasma levels of IL-1ra, IL-6, and CRP were higher in persons who died during the follow-up than in those who survived. When sex, education, cardiovascular disease, diabetes, cancer, history of infections, high density lipoprotein cholesterol, Mini-Mental State Examination, body mass index, smoking status, and exercise were adjusted for, only IL-1ra was a significant predictor of mortality (hazard ratio [HR] 2.12; 95% confidence interval [CI], 1.24-3.62). Persons in the upper tertiles of both CRP and IL-1ra (HR 2.72; 95% CI, 1.25-6.00), or in the upper tertile of all three markers (HR 2.34; 95% CI, 1.23-4.61), had higher mortality than those who were not in the upper tertile in any of the markers. CONCLUSIONS: IL-1ra is a powerful prognostic marker in very old people. Our results implicate its role in the complex interaction between inflammatory markers in aging and disease.

Interleukin-6 modulates plasma cholesterol and C-reactive protein concentrations in nonagenarians.

OBJECTIVES: To establish whether the relationship between interleukin-6 (IL-6) and plasma lipid and C-reactive protein (CRP) concentrations is different in Finnish nonagenarians than in middle-aged subjects with lower inflammatory status. DESIGN: Cross-sectional. SETTING: Observational cohort study concentrating on the oldest old. PARTICIPANTS: Nonagenarians (n=291, mean age+/-standard deviation 90+/-1; 68 men, 223 women) who lived in the Tampere municipality in southern Finland and a middle-aged control population from the same area (n=227, aged 44+/-8). MEASUREMENTS: Plasma high sensitive CRP and lipid concentrations were analyzed using an automatic analyzer and IL-6 levels using enzyme-linked immunosorbent assay. RESULTS: Plasma concentrations of IL-6 (4.39+/-5.25 vs 1.88+/-1.98 pg/mL) and CRP (3.54+/-4.98 vs 1.53+/-1.91 mg/L) were significantly higher in nonagenarians than in middle-aged subjects (P<.001). In nonagenarians, plasma CRP levels increased (P<.001) and plasma total cholesterol (P=.006), low-density lipoprotein cholesterol (P=.02), and high-density lipoprotein cholesterol (P=.002) levels decreased according to IL-6 quartiles. In middle-aged subjects, similar associations were not found. CONCLUSION: The relationship between IL-6 and plasma CRP and cholesterol levels in nonagenarians with enhanced systemic inflammation differs from that of middle-aged subjects.

Association of the endothelial nitric oxide synthase gene polymorphism with risk of coronary artery disease and myocardial infarction in middle-aged men.

Nitric oxide (NO), formed by endothelial constitutive nitric oxide synthase (eNOS) maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. The eNOS gene harbours a common polymorphism in intron 4 (4a/b), and some clinical studies have suggested an association of the rare a-allele with coronary artery disease (CAD) and myocardial infarction (MI). However, contradictory results have also been reported. We studied associations of eNOS polymorphism with CAD and MI in two prospective autopsy series comprising altogether 700 Caucasian Finnish men, who died suddenly. In ANCOVA, no significant differences in areas of atherosclerotic lesions and coronary stenosis percentages were found between men carrying the a-allele (ba+aa) compared with those homozygous for the b-allele. Subjects with the a-allele had significantly lower risk of MI (odds ratio 0.44, 95% confidence interval 0.25-0.77, P=0.004) compared with those carrying the bb genotype. Men with the a-allele also tended to have coronary thrombosis less often (odds ratio 0.43, 95% confidence interval 0.18-1.01, P=0.055). The eNOS gene 4a/b polymorphism was not associated with the extent of coronary atherosclerosis, but the a-allele of the variant seems to protect to some degree against the development of MI.

Fatal kavalactone intoxication by suicidal intravenous injection.

Kavalactones are a group of compounds found in kava, a beverage or extract prepared from the rhizome of the kava plant (Piper methysticum). Traditionally kava extracts have been used for their anxiolytic and sedative properties. Sales of kava extracts were severely restricted or prohibited in European countries in 2002 following several cases of serious hepatotoxicity. Here we report a case where high concentrations of kavalactones and ethanol were detected in post mortem femoral blood. An injection needle with a 10-mL syringe containing 7.5 mL of slightly yellowish liquid was found next to the victim, and there were numerous needle prints on both lower arms following the venous tracks. No evidence of other cause of death was found in the medico-legal investigation. The case was therefore classified as suicide using an injection of kavalactones intravenously together with alcohol poisoning.

Association of paraoxonase-1 M55L genotype and alcohol consumption with coronary atherosclerosis: the Helsinki Sudden Death Study.

High-density lipoprotein (HDL) level is inversely correlated with coronary heart disease risk. Paraoxonase-1 (PON1) is an HDL-associated anti-atherogenic enzyme. The activity of PON1 is affected by the methionine for leucine substitution at position 55 (M55L) and increased during regular moderate alcohol consumption, consistent with increased HDL cholesterol concentration. We related the PON1 M55L genotypes to the extent of atherosclerosis in left anterior descending coronary artery (LAD) in alcohol abstainers (0-1 g of alcohol/day), moderate consumers (1-36 g of alcohol/day) and drinkers (> 36 g of alcohol/day). The study subjects included an autopsy series of total of 700 middle-aged Finnish men from the Helsinki Sudden Death Study. The LAD was stained for fat and the areas covered with fatty streaks and fibrotic and complicated plaques were measured. Data on coronary artery disease risk factors were obtained from relatives or close friends of the deceased. Compared to the LL homozygotes, carriers of the M55 allele tended to have larger areas of atherosclerotic lesions, the size of which decreased dose-dependently by reported alcohol consumption. Moderate consumers carrying the M55 allele had significantly larger complicated plaques compared to the LL homozygotes drinking as much (P = 0.009). Among the M55 allele carriers, drinkers showed significantly smaller areas of fatty streaks compared to abstainers (P = 0.042) and moderate consumers (P < 0.001) (for the PON1 genotype by alcohol interaction, P = 0.078). Similarly, drinkers with the M55 allele also had statistically significantly smaller areas of complicated lesions than moderate consumers with the M55 allele (P < 0.0001) (for the PON1 genotype by alcohol interaction, P = 0.009). The areas of atherosclerotic lesions in LAD appear to be dependent on the amount of alcohol consumption, especially in men carrying the PON1 M55 allele.

Coronary artery calcification is related to functional polymorphism of matrix metalloproteinase 3: the Helsinki Sudden Death Study.

Matrix metalloproteinase 3 (MMP3) is expressed in human coronary atherosclerotic lesions and is known to be involved in degradation of the plaque and to be co-localized with calcium and fibrin deposits in advanced lesions, indicating a possible role of MMP3 in arterial calcification. The MMP3 gene promoter polymorphism leads to low promoter activity 6A6A, intermediate promoter activity 5A6A and high promoter activity 5A5A genotypes. To determine whether these genotypes predict the extent of atherosclerosis we investigated their association with different types of coronary lesions in an autopsy series of 300 middle-aged white Finnish men (aged 35-69 years) from the Helsinki Sudden Death Study (HSDS). Areas of the coronary wall covered with different atherosclerotic lesions were measured and MMP3 genotypes were determined by PCR and minisequencing. In men >/=53 years the mean area of calcified lesion in the most severely affected coronary artery was significantly associated with the MMP3 genotype (P=0.029). Subjects with high promoter activity genotypes had on average larger calcified lesion areas than those with the low-activity genotype. The MMP3 genotype (P=0.025) persisted as an independent predictor of mean calcified lesion area after stepwise adjustment for age, BMI, hypertension, diabetes, number of affected vessels and smoking. These data provide evidence that the proposed effect of MMP3 in the process of atherogenesis may be modified by the MMP3 genotype.

Use of hospitals at age 90. A population-based study.

People live longer than ever before, and the rapidly growing population of the oldest-old are increasingly frequent users of health care services. To determine the extent and causes of hospital care in the population aged 90, we examined the hospital discharge registers for the annual cohorts of Tampere residents born in 1907-1910 at age 90. The basic population consisted of 1077 people, 20.6% of who were men and 79.4% women. Close on one-fifth or 18.7% of this group died during the year under review. During this year, 43.2% of men and 50.3% of women had been admitted to hospital. Men spent significantly fewer days in hospital than women: the mean length of stay for men was 19 days, for women 46 days. Of the 90-year olds, 6.7% were permanently staying in hospitals. The most common diagnoses at discharge were cardiovascular diseases, infections, psychiatric diseases including dementia, and trauma. Of those who had been admitted to hospital once or more within the year, 31.7% died during the follow-up time, while the figure for those not admitted was only 6.2%. People aged 90 are an important group of hospital users. In the future, hospitals need to be prepared to provide adequate care for the most common diseases affecting the growing population of the oldest-old.

Age-dependent interaction of apolipoprotein E gene with eastern birthplace in Finland affects severity of coronary atherosclerosis and risk of fatal myocardial infarction--Helsinki Sudden Death Study.

BACKGROUND: Mortality from coronary heart disease (CHD) has been constantly higher in eastern late settlement regions compared to western early settlements in Finland, unrelated to classical risk factors. In line with this, eastern birthplace was an age-dependent predictor of severe coronary atherosclerosis and pre-hospital sudden coronary death among male residents of Helsinki. We investigated a possible interaction of apolipoprotein E (APOE) gene with birthplace on the risk of myocardial infarction (MI) and coronary atherosclerosis. METHOD: APOE genotypes were analyzed in the Helsinki Sudden Death Study series comprising out-of-hospital deaths among males aged 33-70 years (n = 577), who were born in high (east, n = 273) or low (west, n = 304) CHD mortality area. RESULTS: Eastern-born men ≤ 55 years carried 30% more often (P = 0.017) and older men 40% less often (P = 0.022) the APOE ϵ4 allele compared to western-born men (P = 0.003 for birthplace-by-age interaction). In multivariate analysis, the ϵ4 allele associated with the risk of out-of-hospital MI (odds ratio 2.58; 95% CI 1.20-5.55; P = 0.016) only in eastern-born men and with advanced atherosclerosis in both regions of origin, respectively. CONCLUSIONS: Birthplace-bound risk of CHD was age-dependently modified by APOE ϵ4 allele, suggesting genetic differences in CHD susceptibility between early and late settlement regions in Finland and providing one explanation for the eastern high mortality.