Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.

Human mitochondrial DNA polymerase, encoded by POLG, contains a polyglutamine tract encoded by a CAG microsatellite repeat. Analysis of POLG genotypes in different populations identified an association between absence of the common, ten-repeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia.

Diurnal and weekly rhythms of health-related variables in home recordings for two months.

Several telecare systems for long-term monitoring of the well-being of patients at home have been developed as an aid in healthcare and to reduce hospitalization costs. Most of the systems have been designed to measure only one or two variables. Because well-being is a combination of both psychological and physiological wellness, there is a need to monitor several psychophysiological variables simultaneously in out-of-hospital conditions for a long period. To understand better the variability of patients' wellness-related variables in long-term recordings, the knowledge of the normal variation in health-related variables in healthy people is necessary. In our study, 14 healthy working middle-aged men were studied daily for 24 h and periods of 50 to 79 days. The variables measured were beat-to-beat heart rate, motor activity, blood pressure, body weight, and temperature. At night respiratory frequency, time of movements, amount of quiet sleep, and ballistocardiographic respiratory variation were also measured. Heart rate variability in the waking period was calculated later (standard deviation of the 5 min average of the successive normal to normal beat to beat intervals). Daily self-reported well-being, activities, and consumption of alcohol were monitored by keeping a behavioral diary. After normalizing the physiological data, the diurnal and weekly variability was calculated for each variable. In several variables the most notable diurnal and weekly variability was found between working time and free time. In conclusion, diurnal and weekly rhythms in several wellness-related physiological and psychological variables were identified, depending on working and free-time in healthy middle-aged men.

Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study.

BACKGROUND: Apolipoprotein E (apoE) polymorphism is one of the genetic determinants of serum cholesterol values. The apoE epsilon4 allele has been associated with advanced coronary heart disease (CHD) diagnosed by angiography, but the role of the apoE genotype in atherosclerosis has not been confirmed at vessel-wall level, nor is any age-dependent effect of the apoE genotype on the development of CHD known. METHODS AND RESULTS: The right and left anterior descending coronary arteries (RCA and LAD) and the aorta from 700 male autopsy cases (Helsinki Sudden Death Study) in 1981-1982 and 1991-1992 (average age 53 years, range 33 to 70 years) were stained for fat, and all areas covered with fatty streaks, fibrotic plaques, and complicated lesions were measured. In the RCA and LAD, the apoE genotype was significantly associated with the area of total atherosclerotic lesions in men <53 years old but not with that in older men (P=0.0085 and P=0.041, respectively, for age-by-genotype interaction). Men <53 years old with the epsilon4/3 genotype showed 61% larger total atherosclerotic lesion area in the RCA (P=0.0027) and 26% larger area in the LAD (P=0.12) than did men with the epsilon3/3. The apoE epsilon4/3 was also associated with atherosclerotic lesions in the abdominal (P=0.014) and thoracic (P=0.12) aorta, but this effect, unlike that of the coronary arteries, was not age-related. CONCLUSIONS: In men, the apoE epsilon4 allele is a significant genetic risk factor for coronary atherosclerosis in early middle age. This suggests that at older age, other known risk factors of CHD play a more important role in the atherosclerotic process than apoE polymorphisms.

Glycoprotein IIIa Pl(A1/A2) polymorphism and sudden cardiac death.

OBJECTIVES: We studied the association of the Pl(A1/A2) polymorphism with coronary thrombosis, myocardial infarction (MI) and sudden cardiac death (SCD) in autopsied victims of sudden death. BACKGROUND: Sudden cardiac death is one of the leading symptoms of coronary heart disease in early middle age. Platelet glycoprotein (GP)IIb/IIIa fibrinogen receptors play a key role in coronary thrombosis and MI. Pl(A1/A2) polymorphism of the gene for GPIIIa has been previously studied in hospital MI patients. Significance of the Pl(A1/A2) polymorphism in victims of SCD is not known. METHODS: The Pl(A1/A2) polymorphism was studied in the Helsinki Sudden Death Study comprising 700 autopsied middle-aged white Finnish men (33 to 70 years, mean 53 years) who suffered sudden or violent out-of-hospital death. RESULTS: Prevalence of the A2 allele decreased with age in the series. This decrease was observed among victims of SCD (n = 281) but not in men who died violently (n = 258) or of other diseases (n = 127). Of SCD victims below 50 years, 39.7% were carriers of the A2 allele compared with 28.3% among men under 50 who died of other causes (odds ratio [OR] 2.5, p = 0.01). Men with acute fatal coronary thrombosis (n = 39) were more often (OR 3.4, p < 0.01) carriers of the A2 allele than were men (n = 242) with SCD in the absence of acute coronary thrombosis (48.7% vs. 24.4%, respectively). In addition, men with MI and recent or old thrombosis (n = 67) were more often (OR 3.6, p = 0.005) carriers of the A2 allele than were men (n = 123) with MI in the absence of thrombosis (44.8% vs. 20.3%, respectively). These associations were especially strong in men under 60. CONCLUSIONS: Our results suggest that the A2 allele of the Pl(A1/A2) polymorphism of GPIIIa is a major risk factor of coronary thrombosis and may be one important predictor of SCD in early middle age.

Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study.

Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged >/=53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype.

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology.

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.

Prognosis of diastolic and systolic orthostatic hypotension in older persons.

BACKGROUND: Orthostatic hypotension (OH) predicts mortality in hypertensive persons with diabetes mellitus, but no increase in mortality has been found among random samples of home-dwelling persons with OH. We examined the risks of nonvascular and vascular deaths according to different definitions of OH among home-dwelling elderly persons. SUBJECTS AND METHODS: The study population consisted of all persons aged 70 years or older living in 5 rural municipalities (N=969), of whom 833 (86%) participated. Orthostatic tests were successfully carried out in 792 persons by nurse examiners. Orthostatic hypotension was defined as a systolic blood pressure (BP) drop of 20 mm Hg or more or a diastolic BP drop of 10 mm Hg or more 1 minute or 3 minutes after standing up. Nonvascular and vascular deaths during the follow-up period were recorded. Data on diseases, symptoms, medications, the results of clinical examinations and tests, functional ability, and health behavior were collected at the beginning of the follow-up period. RESULTS: Of the sample, 30% had OH: the prevalence of systolic OH 1 minute and 3 minutes after standing up was 22% and 19%, respectively; that of diastolic OH 1 minute and 3 minutes after standing up was 6% for each. No differences in the occurrence of nonvascular deaths were found according to any of these definitions. By Cox multivariate regression analysis, the hazard ratio of vascular death associated with a diastolic BP reduction of 1 mm Hg 1 minute after standing up was 1.02 (P=.03), adjusted for systolic BP postural changes at 1 and 3 minutes and a diastolic BP change at 3 minutes. Adjusted for other significant factors associated with vascular death, the hazard ratio for vascular death associated with diastolic OH 1 minute after standing up was 2.04 (95% confidence interval, 1.01-4.15). The corresponding hazard ratio for systolic OH 3 minutes after standing up was 1.69 (95% confidence interval, 1.02-2.80). Using a cutoff point of 7 mm Hg or greater for a diastolic BP change 1 minute after standing up, the hazard ratio for vascular death was highest: 2.20 (95% confidence interval, 1.23-3.93). By logistic regression analysis, the baseline associates of diastolic OH 1 minute after standing up were dizziness when turning the neck (odds ratio [OR], 2.44), the use of a calcium antagonist (OR, 2.31), the use of a diuretic medication (OR, 2.29), a high systolic BP (OR, 2.23), and a low body mass index (OR, 2.26). The baseline associates of systolic OH 3 minutes after standing up were male sex (OR, 1.52), diabetes mellitus (OR, 1.92), a high systolic BP (OR, 2.91), and a low body mass index (OR, 1.68). CONCLUSIONS: The presence of diastolic OH 1 minute and systolic OH 3 minutes after standing up predict vascular death in older persons. They differ from each other in their prevalence and in several associates, suggesting different pathophysiologic backgrounds. Clinicians should prescribe vasodilating and volume-depleting medications with caution for elderly persons with diastolic OH 1 minute after standing up. Appropriate treatment of hypertension might be the best means to manage the different types of OH with poor vascular prognoses.

Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin.

We examined serum total osteocalcin (TOC), carboxylated osteocalcin (COC), and their ratio (COC/TOC) by one-step two-site immunofluorescent assays in 87% (n = 792) of all home-dwelling persons of 70 years or older living in a defined area in northern Finland. Other baseline subject-related risk factors of fractures were assessed by postal questionnaires, interviews, clinical examinations, and tests. During a 5-year follow-up period, all falls and fractures (n = 106) were recorded by regular phone calls and by examining all the medical records yearly. Serum TOC and COC concentrations increased with advancing age and were higher in women than in men, but corresponding differences were not found in the case of COC/TOC. The adjusted relative risk of fracture was elevated in association with low (< or =-1 SD from the mean) COC; hazard ratio (HR, 95% CI) 2.00 (1.20-3.36) and low COC/TOC; HR 5.32 (3.26-8.68), the relative risk being highest in the population older than 80 years; and HR 7.02 (2.42-20.39). The predictive value of low COC/TOC lasted 3 years. The multivariable-adjusted relative risk of hip fracture (n = 26) in regard to low COC/TOC ratio was 3.49 (1.12-10.86), as compared with the persons who did not suffer hip fractures. Our results suggest that serum COC concentrations and, more strongly, COC/TOC, predict the occurrence of fractures in older community-dwelling adults. The risk of fracture associated with low COC/TOC equals the hip fracture risk previously verified for concomitant high serum undercarboxylated OC concentrations and low bone mineral density.

Fibrinogen gene promoter -455 A allele as a risk factor for lacunar stroke.

BACKGROUND AND PURPOSE: Elevated fibrinogen levels are suggested to increase the risk of myocardial infarction and stroke. Carriers of the A allele of the fibrinogen -455G/A polymorphism have increased plasma fibrinogen levels. We studied the association of this polymorphism with stroke subtype in the Stroke Aging Memory (SAM) cohort. METHODS: The SAM cohort comprises 486 consecutive patients 55 to 85 years of age who, 3 months after ischemic stroke, completed a detailed stroke assessment. Stroke subtypes were examined with MRI. -455G/A genotype was determined by polymerase chain reaction. MRI and genotype data were available for the 299 patients who constitute the present study population. RESULTS: Genotype distributions were 64.9% (GG), 31.8% (GA), and 3.3% (AA). In a logistic regression model with age, sex, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, myocardial infarction, arrhythmia, atrial fibrillation, peripheral arterial disease, and smoking as possible confounders, there was a significant association between A+ genotype and >or=3 lacunar infarcts (odds ratio [OR], 2.57; 95% CI, 1.23 to 5.36; P=0.01). Hypertensive patients carrying the A allele had increased risk (OR, 4.24; 95% CI, 1.29 to 13.99; P=0.02) for >or=3 lacunar infarcts. A similar increase in risk was observed among smokers with the A+ genotype (OR, 2.67; 95% CI, 0.92 to 7.77; P=0.07). CONCLUSIONS: Stroke patients carrying the A allele of the Bbeta-fibrinogen -455G/A polymorphism frequently presented with multiple lacunar infarcts. This association was stronger among hypertensives and smokers. These associations suggest that the A allele may predispose to atherothrombotic events in cerebrovascular circulation.

Ubiquinol-10 and total peroxyl radical trapping capacity of LDL lipoproteins during aging: the effects of Q-10 supplementation.

Evidence is rapidly accumulating that oxidative modification of low density lipoprotein (LDL) may play an important role in the pathogenesis of atherosclerosis. In this study we measured the total peroxyl radical trapping capacity of human plasma LDL phospholipids (TRAPLDL) with a luminescent method. The study was carried out with 70 healthy volunteers, aged 28-77. In males an age-related decrease in TRAPLDL was observed. In the age group under 50 years the mean TRAPLDL was 31.36 +/- 1.45 pmol peroxyl radicals/nmol Pi; among those over 50 years it was significantly lower at 26.67 0.94 pmol/nmol Pi. As regards the components of TRAPLDL, the concentration of LDL-ubiquinol did not change and a non-significant decrease in the LDL-tocopherol concentration was detected with age. In females, the mean TRAPLDL, LDL-ubiquinol-10 and tocopherol concentrations did not differ between the age groups. When 17 of the participants were given coenzyme Q10 (Q10) supplementation, 100 mg/day, a highly significant increase in LDL-ubiquinol concentration was detected. Our results indicate that LDL antioxidant defenses tend to decrease with age in the Finnish male population. The decline is most significant in males under 50 years; in older age groups the values remain stable at a low level. Q10 supplementation doubles the number of ubiquinol-10-containing LDL molecules and may therefore have an inhibitory effect on LDL oxidation.

Is there an unidentified defence mechanism against infection in human plasma?

The total peroxyl radical scavenging capacity (TRAP) of human plasma was measured from pneumonia patients and controls. TRAP and its main components, ascorbic acid, alpha-tocopherol, uric acid or protein thiol groups, were unaltered, but the concentration of unidentified antioxidants in pneumonia patients was significantly reduced. Our results indicate that human plasma may contain so far unidentified antioxidants depleted in infection.

New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus.

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have investigated oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary excretion of 8-OHdG from 24 h urine samples of 81 NIDDM patients 9 years after the initial diagnosis and of 100 non-diabetic control subjects matched for age and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in NIDDM patients than in control subjects (68.2 +/- 39.4 microg vs. 49.6 +/- 37.7 microg, P = 0.001). High glycosylated hemoglobin was associated with a high level of urinary 8-OHdG. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in NIDDM patients.

Age-related changes in the peroxyl radical scavenging capacity of human plasma.

Aging and the diseases that typically follow with increasing age, notably atherosclerosis and cancer, are often proposed to be involved in increased oxidative stress. Animal studies, on the other hand, show no clear-cut pattern of age-related changes in enzymatic antioxidant defences. In this study we have demonstrated that total peroxyl radical scavenging antioxidant capacity (TRAP) in human plasma changes with age. We also found that among the antioxidants in human plasma there exists a major fraction of so far unidentified antioxidant(s). A chemiluminescent TRAP assay was used to determine the presence of peroxyl radical scavenging antioxidants in human plasma. The material consisted of 87 healthy volunteers, aged 20-96 years, who used no regular medication, vitamins, or trace elements. In females, total antioxidant capacity increased significantly during the life span. The increase in TRAP was mainly due to unidentified antioxidants. In males, TRAP increased until age 51-74, and then significantly decreased. The decrease observed among males was also due to the sharp decline in the concentration of unidentified antioxidants.

The effect of short-term fasting, apolipoprotein E gene polymorphism, and sex on plasma lipids.

The effect of 1 wk of supervised fasting on plasma lipid concentrations in subjects with different apolipoprotein E (apo E) phenotypes was studied in 58 healthy free-living volunteers. The participants consumed an 870-kJ(208 kcal)/d liquid diet containing fruit and berry juices, tea, and water. The decline in plasma total cholesterol during 1 wk of fasting was 0.46 mmol/L in women and 0.35 mmol/L in men. The decreases were significant in both women and men. The response patterns of plasma total cholesterol were not significantly different between the sexes. In men, the changes in plasma low-density-lipoprotein cholesterol during the fast differed significantly (P = 0.0181) between the apo E phenotypes, whereas in women there were no differences due to phenotype (P = 0.695). The magnitude of the change in plasma triacylglycerol during the fast was different between the sexes (P = 0.0099). The changes in plasma triacylglycerols differed significantly between apo E phenotype groups in men (P = 0.0295) but not in women (P = 0.0661). Statistical comparison between different apo E phenotypes was performed with and without the small apo E3,2+E2,2 group, with essentially similar results. During fasting, plasma high-density-lipoprotein cholesterol concentrations decreased slightly but not significantly. The study shows significant differences in the associations of apo E alleles and sex on plasma lipid responses during fasting and illustrates the importance of gene-diet interactions in the regulation of lipid metabolism in humans.

Head injuries and cognitive decline among older adults: a population-based study.

OBJECTIVE: To examine the relationship between minor and major head injuries caused by fall accidents and cognitive decline among a cohort of adults age 70 years or older (n = 588). BACKGROUND: Even a mild brain injury may affect cognitive functions. Among older adults, results from case-control studies suggest that the occurrence of head injury is positively associated with the onset of AD. METHODS: The shortened version of the Mini-Mental State Examination (sMMSE) was performed and a set of demographic and clinical variables were collected at the beginning of the study. All falls were recorded during a period of 2.5 years, after which the sMMSE tests were repeated. The risk of falls causing head injury in terms of a defined cognitive decline was examined during another follow-up period of approximately 2.5 years. RESULTS: There was no association between the occurrence of minor head injuries and decline in sMMSE scores. A positive relationship existed between the occurrence of major head injuries and a decline in sMMSE scores. The risk of cognitive decline increased linearly as higher cut-off points were used to define the decline in sMMSE scores-with relative risks (95% CI) of 0.94 (0.47 to 1.90), 1.35 (0.64 to 2.85), 1.75 (0.78 to 3.91), 2.38 (1.02 to 5.52), and 3.72 (1.64 to 8.44)-for a decline of > or =1, > or =2, > or =3, > or =4, and > or =5 points in the sMMSE score. The high risk remained unchanged after adjustment for other potential factors contributing to cognitive decline or dementia. The risk factors associated with falls causing major head injury during the second follow-up period were high age, OR (95% CI) 3.58 (1.87 to 6.85); use of psychotropic medication, 2.04 (1.09 to 3.83); diagnosis of hypertension, 1.80 (0.96 to 3.37); and decline in sMMSE score of >5 points, 2.41 (0.86 to 6.76). CONCLUSIONS: Our results suggest that the occurrence of major head injury increases the risk of cognitive decline. The cause of cognitive decline may be dementia, but this assumption remains to be elucidated in future studies.

CSF and MRI findings in patients with acute herpes zoster.

OBJECTIVE: To explore MRI and CSF findings in patients with herpes zoster (HZ) and to correlate the findings with clinical manifestations of the disease. METHODS: Fifty immunocompetent patients (mean age, 59 years; range, 17 to 84 years) with HZ of fewer than 18 days duration participated. None had clinical signs of meningeal irritation, encephalitis, or myelitis. In 42 patients (84%), the symptoms constituted pain and rash only. Six patients (12%) had motor paresis, and three patients (6%) had ocular complications. One to three CSF samples were obtained from 46 patients (the first sampling taken 1 to 18 days from onset of rash), and 16 patients (all with either trigeminal or cervical HZ) underwent MRI of the brain. The clinical follow-up continued at least 3 months. RESULTS: CSF was abnormal in 28/46 patients (61%): pleocytosis (range, 5 to 1,440 microL) was detected in 21, elevated protein concentration in 12, varicella zoster virus (VZV) DNA in 10, and immunoglobulin G antibody to VZV in 10. These changes were more common in patients with acute complications, although they did not predict development of postherpetic neuralgia (PHN). In 9/16 patients (56%), MRI lesions attributable to HZ were seen in the brainstem and cervical cord. At 3 months, 5/9 patients (56%) with abnormal MRI had PHN, whereas none of the 7 patients with no HZ-related lesions on MRI had any remaining pain. CONCLUSIONS: Subclinical extension of viral inflammation into the CNS occurs commonly in HZ. This finding may have implications for treatment of HZ and prevention of various associated complications.

Postprandial plasma lipoprotein changes in relation to apolipoprotein E phenotypes and low density lipoprotein size in men with and without coronary artery disease.

Postprandial lipoprotein metabolism may play a role in the etiology of premature coronary artery disease (CAD). To determine whether apolipoprotein E (apo E) polymorphism and the size of low density lipoprotein (LDL) influence postprandial lipemia we studied 39 healthy men and 35 men with CAD. Venous blood samples were obtained before an oral fat load and 3, 5 and 7 h thereafter. Total cholesterol and high density lipoprotein (HDL) cholesterol concentrations did not change in either group during the fat load, but triglycerides increased more markedly in CAD patients compared with controls independently of apo E phenotypes. There was a positive correlation between the size of LDL and the concentration of HDL cholesterol (r = 0.541, P < 0.001); conversely, an inverse correlation was observed between LDL size and the level of fasting triglycerides (r = -0.582; P < 0.001). The patients with CAD had significantly smaller LDL particles (25.89 +/- 0.56 nm) than in controls (26.21 +/- 0.63 nm) (P < 0.05). The increase in triglyceride levels during the fat load was highest in CAD patients with a small size of LDL particles (< 25.5 nm) and lowest in controls with large LDL (> 25.5 nm). Our results suggest that the magnitude of the triglyceride response is a better indicator of CAD risk than the fasting triglyceride concentration. The best model in our logistic regression analysis selected as significant risk factors the change of triglyceride concentration from the baseline at 5 h after a fat meal and HDL cholesterol. This model classified 83% of the subjects correctly.

Apolipoprotein E polymorphism and atherosclerosis: association of the epsilon4 allele with defects in the internal elastic lamina.

The defects in the internal elastic lamina (IEL) have been proposed to be important for the migration of smooth muscle cells into the intima during atherosclerosis. We investigated the association of a genetic factor--apolipoprotein E (apoE) genotype--with the number of gaps in the IEL of the artery wall in 123 consecutive autopsy cases (90 male, 33 female) aged 18-93. At autopsy, the circumference of the IEL and the number of gaps in the IEL were measured in circular samples of the coeliac; (CA), superior mesenteric (SMA) and inferior mesenteric (IMA) arteries. In the series, the number of gaps per millimetre in the IEL of CA, SMA and IMA were associated with intimal thickening (P<0.0001, P=0.01 and P=0.005, respectively). In men, apoE genotype was significantly associated with the number of gaps in the IEL of the CA and IMA (P=0.033 and P=0.041, respectively). The carriers of epsilon4/3 or epsilon4/4 genotype had higher number of gaps in CA than the carriers of epsilon3/3 genotype (2.30+/-2.63 vs. 1.38+/-1.83 gaps/mm, P=0.035) and also higher number of gaps in IMA than the carriers of epsilon3/2 (2.18+/-1.71 vs. 0.66+/-0.60 gaps/mm, P=0.041). The results suggest that the apoE varepsilon4 allele may be involved with IEL fragmentation in men. This may be mediated through higher serum cholesterol associated with the varepsilon4 allele.

Women have a larger and less atherogenic low density lipoprotein particle size than men.

Some epidemiological studies have shown that serum total cholesterol increases with age. especially in women. On the other hand, the risk of coronary artery disease is smaller in women than in men. Earlier studies have shown that a small dense low density lipoprotein (LDL) is more atherogenic than a large LDL. We studied LDL size and apolipoprotein E (apo E) phenotypes in premenopausal and postmenopausal women and in men at the same age. In this study 342 subjects participating in a health screening study were examined. There were four subgroups: 40-year-old men (n = 85), 40-year-old women (n = 80), 70-year old men (n = 88) and 70-year-old women (n = 89). In the present study LDL size was larger (P < 0.01) in women (26.39 +/- 0.07 nm) than in men (25.95 +/- 0.07 nm). We found that LDL size correlated highly positively (r = 0.606; P < 0.001) with serum high density lipoprotein (HDL) concentration and inversely with serum triglyceride concentration (r = -0.627; P < 0.001). Measuring serum HDL cholesterol and triglycerides in health screening studies gives information indirectly about LDL size and its atherogenicity. Apo E phenotype was not significantly associated with serum triglycerides, but was associated with LDL size, LDL cholesterol, total cholesterol and HDL cholesterol. In our sample LDL size decreased and LDL cholesterol and total cholesterol increased according to the most prevalent apo E phenotypes in the order E2/3, E3/3, E3/4 and E4/4. Subjects with phenotype apo E4/4 had the smallest LDL size (25.70 +/- 0.19 nm), the highest total cholesterol (6.53 +/- 0.35 mmol/l) and the lowest HDL cholesterol values (1.28 +/- 0.04 mmol/l). We conclude that there was a significant interaction between sex and age in serum total cholesterol which was highest in older women. However, their LDL size was larger and their LDL is less atherogenic. Apo E phenotype had a significant influence on LDL size.

Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men.

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis and is also involved in lipid metabolism. Two biallelic polymorphisms within TNF gene locus-TNFA at the position -308 in the promoter region of the TNF gene and TNFB in the first intron of the lymphotoxin-alpha (LT-alpha) have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. We studied the association of these polymorphisms within the major histocompatibility complex (MHC) III region with coronary atherosclerosis and its manifestations. The autopsy series comprised 700 Caucasian Finnish men, aged 33-70 years (The Helsinki Sudden Death Study). Coronary stenosis and surface area of atherosclerotic changes (fatty streaks, fibrous plaques, complicated lesions and calcification) were measured and the presence of myocardial infarction and coronary thrombosis recorded. TNFA and TNFB genotypes were determined by the PCR-RFLP technique. The allele frequencies were TNFA1/TNFA2=0.88/0.12 and TNFB1/TNFB2=0.30/0.70. There was a strong linkage disequilibrium between the two polymorphisms. There were no differences in coronary stenosis and in the frequency of old or recent myocardial infarction or coronary thrombosis between men with different genotype status in either locus. Men with TNFA22 or TNFB11 genotype tended to have more fibrous lesions and calcification in their coronary arteries. TNFA and TNFB polymorphisms are unlikely to contribute to progression of atherosclerosis in a way clinically important.