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Aims The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries. Methods We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries. Results A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA2DS2-VASc categories: 0–1 (72.8% vs 60.3%), 2–3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11–4.23) vs 4.08 (3.91–4.26), p value = .147] and [0.98 (0.73–1.32) vs 1.02 (0.93–1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32–2.09) vs 1.01 (0.93–1.10), p value

BackgroundNeurological, visual and hearing deviations have been observed in the offspring of parents with schizophrenia. This study test whether children to parents hospitalized with schizophrenia have increased the likelihood of childhood neurological disorder.MethodsAmong all parents in Sweden born 1950–1985 and with offspring born 1968–2002: 7107 children with a parent hospitalized for schizophrenia were compared to 172 982 children with no parents hospitalized for schizophrenia or major depression, as well as to 32 494 children with a parent hospitalized for major depression as a control population with another severe psychiatric outcome. We estimated relative risks (RR) and two-sided 95% confidence intervals calculated from Poisson regression.ResultsChildren to parents with schizophrenia were more likely than controls to have been hospitalized before the age of 10 with a diagnosis of cerebral palsy, RR = 1.76 (95% CI: 1.15–2.69); epilepsy, RR = 1.78 (95% CI: 1.33–2.40), combined neurological disease, RR = 1.33 (95% CI: 1.11–1.60) and certain diseases of the eye, RR = 1.92 (95% CI: 1.17–3.15) and ear, RR = 1.18 (95% CI: 1.05–1.32). Similar disease-risk-pattern was found for children to parents hospitalized with a diagnosis of major depression. A specific risk increase for strabismus RR = 1.21 (95%CI: 1.05–1.40) was found for off-spring with parental depression.ConclusionsCompared with children to healthy parents, children to parents with schizophrenia have increased risk of a variety of neurological disorders as well as visual and hearing disorders at an early age. The risk increase was not specific to schizophrenia but was also seen in children to parents with a diagnosis of major depression.

Background Physical activity plays a pivotal role in the development of disability and may modify the negative effect of vascular risk factors on progression of both cardio and cerebrovascular disorders. The aim of this study was to evaluate the activity level in people with age-related white matter changes as identified on magnetic resonance imaging (MRI) in relation to motor performance, cognition and perceived health. Methods Data came from the first year follow up of one participating centers of the LADIS study. Fifty one subjects were first enrolled in the study. Complete first year follow up data was available for 41 subjects. Information on comorbidity, physical activity level, physical function, cognition, level of white matter changes and perceived health was collected. Physical activity level was classified with a yes or no question and with the Frenchay Activities Index (FAI). Results Only 36% of the subjects in this study were physically active according to the yes/no question. 27.5% of the subjects were active according to the FAI score which evaluates the everyday activities. Being active discriminated subjects with better physical function. Subjects active according to the FAI score had a higher cognitive level (p ≤ 0.01), lower comorbidity (p = 0.02) and performed better on all motor function tasks as assessed by walking speed (p ≤ 0.01) and the Short Physical Performance battery (SPPB) (p ≤ 0.01). Conclusions Being physically active seems to be a long term protective factor. In our study, the majority of subjects with Age Related White Mattter Changes (ARWMC) with no or mild Instrumental Activity of Daily Living (IADL) disability did not attain recommended level of activity at first year follow up. Whether or not increasing physical activity may slow down cognitive decline and lessen development of disability in physically inactive subjects with manifest ARWC remains to be studied. Trial registration: not applicable.

The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort.We evaluated 988 stroke-free participants (mean age 66 ± 8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression.Plaque was present in 56% of the study population. Among those with plaque, the mean ± SD plaque area was 19.40 ± 20.46 mm² and thickness 2.30 ± 4.45 mm. The mean ± SD total HDL-C was 46 ± 14 mg/dl, HDL2-C 14 ± 8 mg/dl, and HDL3-C 32 ± 8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta = -0.26 at the 75th percentile, p = 0.001 and beta = -0.32 at the 90th percentile, p = 0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta = 0.02 at the 90% percentile, p = 0.003). HDL-C was associated with plaque area (per mg/dl: beta = -0.18 at the 90th percentile, p = 0.01), but only among Hispanics.In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke.

Population-based data on serum adiponectin levels, an adipocytokine secreted from adipose tissue, are lacking, particularly across race-ethnic groups. Studies have suggested an inverse association between adiponectin and vascular risk factors, but data are limited and inconsistent. We examined the cross-sectional association between adiponectin, vascular risk factors and race-ethnicity in the population-based Northern Manhattan Study (NOMAS).Blood samples, anthropomorphics, and vascular risk factors were collected at baseline. Multivariable linear regression analysis was conducted with log-transformed adiponectin as the dependent variable.Adiponectin was measured among 2900 participants (age 69±10 years, body mass index (BMI) 28.0±5.6, 37% male, 21% white, 53% Hispanic, 24% black). The mean adiponectin was 11.4±6.2 μg/mL (median=9.8, range=2.1-53.3). After multivariable adjustment, adiponectin levels were greatest among whites, followed by Hispanics, and lowest among blacks. Lower adiponectin levels were observed in participants with the following characteristics: Male, former smoking, hypertension, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), metabolic syndrome, moderate alcohol use, elevated waist circumference, BMI, estimated glomerular filtration rate (eGFR), triglycerides, low-density lipoprotein cholesterol (LDL-C), lower high-density lipoprotein cholesterol (HDL-C), and younger age. Obesity was a stronger risk factor for decreased adiponectin among blacks than among whites or Hispanics. The associations for several vascular risk factors, including hypertension, triglycerides, and low HDL-C, with low adiponectin were stronger among individuals who were not obese than among those who were obese.Adiponectin levels were lower among blacks and Hispanics and among those with various vascular risk factors, and greater with older age. The association between BMI and adiponectin varied across race-ethnic groups. Investigation of whether differences in body fat distribution may explain race-ethnic differences in adiponectin is needed.

Background and Purpose— Recent drug trials have challenged the high-density lipoprotein-cholesterol (HDL-C) antiatherosclerotic hypothesis, suggesting that total level of HDL-C may not be the best target for intervention. HDL-C subfractions may be better markers of vascular risk than total levels of HDL-C. The objective of this cross-sectional study was to investigate the relationship between HDL2-C and HDL3-C fractions and carotid intima-media thickness (cIMT) in the population-based Northern Manhattan Study. Methods— We evaluated 988 stroke-free participants (mean age, 66±8 years; 60% women; 66% Hispanic, and 34% non-Hispanic) with available data on HDL-C subfractions using precipitation method and cIMT assessed by a high-resolution carotid ultrasound. The associations between HDL-C subfractions and cIMT were analyzed by multiple linear regression models. Results— The mean HDL2-C was 14±8 mg/dL, HDL3-C 32±8 mg/dL, and the mean total HDL-C was 46±14 mg/dL. The mean cIMT was 0.90±0.08 mm. After controlling for demographics and vascular risk factors, HDL2-C and total HDL-C were inversely associated with cIMT (per 2 SDs, β=−0.017, P =0.001 and β=−0.012, P =0.03, respectively). The same inverse association was more pronounced among those with diabetes mellitus (per 2SDs, HDL2-C: β=−0.043, P =0.003 and HDL-C: β=−0.029, P =0.02). HDL3-C was not associated with cIMT. Conclusions— HDL2-C had greater effect on cIMT than HDL3-C in this large urban population. The effect of HDL2-C was especially pronounced among individuals with diabetes mellitus. More research is needed to determine antiatherosclerotic effects of HDL-C subfractions and their clinical relevance.

Background and Purpuse: Cerebral White matter changes (WMC) are a frequent finding on CT and MRI scans of elderly individuals, particularly in those with vascular risk factors, cerberovascular disease, and cognitive impairment. Methods: 56 subjects were included in the study after the review of reports of more than 200 consecutive brain Computerized Tomography (CT) and magnetic resonance imaging (MRI) examinations from the out-patient and in-patient units of the Department of Geriatric Medicine at Karolinska University Hospital, Huddinge during 2001-2002. MRI was performed using a 1.5 T system and WMC lesions were graded 1-3 using a visual scale. Total-cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride (TG) levels were determined using enzymatic techniques after 12 hours overnight fasting. Apo E genotyping was performed as described. Results: Low HDL levels were associated with higher severity of WMC on MRI (p=0.002). Subjects with the Apo E4 allele had higher LDL (p=0.002) and apoB levels (p=0.005). The presence of the Apo E4 allele was higher in the group of subjects with severe WMC (grade 3). However, there was no statistically significant group difference in severity of WMC lesions between carriers and noncarriers of Apo E4 allele. Conclusions: Low HDL is strongly associated with adverse coronary and cerebrovascular outcomes. Our results indicate that low HDL levels are also associated with more severe WMC lesions on MRI. Dietary or medical adjustment of HDL levels could have important implications for treatment and prevention of cerebral WMC, cerebrovascular and neurodegenerative diseases such as stroke and dementia.

The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid beta-peptide (Abeta). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial alpha-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by beta- and gamma-secretase enzymes, which produces Abeta peptides. Currently, the diagnosis of probable or possible Alzheimer's disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet beta-secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet alpha-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of alpha- and beta-secretase in platelets may represent a useful surrogate marker of the balance between the two pathways of APP metabolism and be of importance for the diagnosis of AD. We therefore considered it of interest to develop assays of platelet alpha- and beta-secretase activities suitable for such clinical investigations. Application of these assays to a Swedish population failed to uncover an effect of AD or MCI on individual platelet secretase activities or the secretase ratio. However, we did observe an inverse correlation between plasma triacylglycerol levels and the secretase ratio. The results are discussed in the context of the clinical usefulness of the secretase ratio as a biochemical adjunct to the diagnosis of AD.

Background: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort. Methods: We analyzed 1,743 stroke-free participants (mean age 65.5 ± 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. Results: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34-3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00-2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55). Conclusions: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events.

Objective Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. Methods Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. Results There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. Conclusion Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population.

Background and Purpose— Adiponectin is an insulin-sensitizing plasma protein expressed in adipose tissue and suggested to play a role in atherosclerosis and cardiovascular disease. Data are lacking on the relationship between adiponectin and carotid intima-media thickness (IMT) in ethnically heterogeneous populations. We examined the relationship between adiponectin and IMT, a marker of atherosclerosis, in a multiethnic cohort study of stroke risk factors. Methods— Participants were from the Northern Manhattan Study (N=1522, mean age 66±9 years, 60% female, 20% black, 18% white, 60% Hispanic). Adiponectin was measured from baseline plasma samples and IMT was assessed by high-resolution B-mode carotid ultrasound. Regression models were used to examine the association between adiponectin, assessed continuously and in quartiles, and IMT controlling for demographics and vascular risk factors. Results— The mean adiponectin level was 10.3±5.2 μg/mL (median, 9.2 μg/mL; range, 2.3–53.3 μg/mL), and the mean IMT was 0.91±0.08 mm. Adiponectin was inversely associated with IMT, even after controlling for demographics and vascular risk factors. Individuals in the first quartile of adiponectin had mean IMT that was on average 0.02 mm greater than those in the top quartile. The relationship between adiponectin and IMT appeared to be stronger among those with diabetes. Conclusions— Our findings suggest that low adiponectin is associated with increased IMT in a multiethnic cohort and support a protective role for adiponectin in atherosclerosis.

Background —The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results —Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2±8.4% versus 23.9±21.1% of the plaque area, P P P P P P P P Conclusions —Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.

We determined whether plasma levels of circulating oxidized low-density lipoprotein (LDL; E06), immunoglobulin (Ig) G, and IgM autoantibodies binding to malonyldialdehyde-modified LDL (MDA-LDL) may predict cardiovascular events (CVEs). Patients (n = 123) with a previous myocardial infarction (MI) were included. The primary end point was defined as any of the following: cardiovascular death from any cause, nonfatal reinfarction or stroke, percutaneous coronary intervention, coronary artery bypass grafting, and hospitalization due to angina pectoris. There were 43 CVEs during the follow-up period of 8.4 ± 3.5 years. There was no significant difference in the levels of E06 and MDA-LDL IgG between the CVE and the event-free group. However, MDA-LDL IgM levels were significantly lower in patients in the CVE group (9524 ± 6326 relative light unit [RLU]) compared with the event-free (10 975 ± 5398 RLU) group ( P = .04). In conclusion, levels of MDA-LDL IgM were associated with an increased risk of CVE in patients with a previous MI.

To investigate, in a cohort of nondisabled elderly people, the association between urinary complaints and severity of age-related white matter changes (ARWMC).Cross-sectional data analysis from a longitudinal multinational study.The Leukoaraiosis And DISability Study, assessing ARWMC as an independent predictor of the transition from functional autonomy to disability in elderly subjects.Six hundred thirty-nine subjects (288 men, 351 women, mean age 74.1+/-5.0) with magnetic resonance imaging (MRI)-detected ARWMC of different severity.ARWMC severity was graded on MRI as mild, moderate, and severe (Fazekas scale). MRI assessment also included ARWMC volumetric analysis and the count of infarcts. Urinary complaints (nocturia, urinary frequency, urgency, incontinence) were recorded based on subjects' answers to four questions.In comparing the three ARWMC severity groups, there was a significant difference only in prevalence of urgency, with 16% of subjects in the mild severity group, 17% in the moderate severity group, and 25% in the severe group (P=.03). Adjusting for age, sex, lacunar and nonlacunar infarcts, diabetes mellitus, and use of diuretics, severe ARWMC retained an independent effect in the association with urinary urgency (odds ratio=1.74, 95% confidence interval=1.04-2.90, severe vs mild group). Subjects with urinary urgency also had higher ARWMC volumes (25.2, vs 20.4 mm(3) in those without urinary urgency; P.001). Urgency was confirmed to be associated with the severe degree of ARWMC, irrespective of complaints of memory, gait disturbances, or history of depression.In a cohort of nondisabled elderly people, severe ARWMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain.

The association between C-reactive protein (CRP) and future cardiovascular risk has been of particular interest during recent years. Oxidized low-density lipoprotein (ox-LDL) is another marker linking the immune system with the atherogenic process. The aim of this study was to examine whether ox-LDL and CRP were associated with endothelial function in peripheral resistance arteries. Twenty-five men with a previous hospital-diagnosed myocardial infarction were enrolled in the study. The exclusion criterion was a history of diabetes mellitus. IgG and IgM autoantibodies to malonyldialdehyde low-density lipoprotein (MDA-LDL) and high-sensitivity CRP (hs-CRP) were measured. Flow-mediated dilatation was measured in isolated resistance arteries from subcutaneous fat biopsies. Endothelial function test reflecting the maximum vessel dilatation in male subjects was inversely related to MDA-LDL IgG autoantibody levels (r = -0.6 and P = 0.003). Comparison of hs-CRP levels and of maximum vessel dilatation in males revealed also an inverse relation (r= -0.4 and P = 0.04). In conclusion, a clear correlation exists between flow-mediated dilatation in subcutaneous resistance arteries and plasma levels of MDA-LDL IgG autoantibody and CRP in male patients with coronary heart disease.

Ischaemic stroke is pathogenetically heterogeneous, but there is strong evidence that genetic as well as environment factors contribute to the risk of the individual. Here we report the similar distribution of polymorphic markers of the lipoprotein lipase (LPL) gene in 128 patients with ischaemic stroke, 56 patients with carotid artery stenosis and 95 healthy control subjects, in spite of a significant influence of the Asn291-->Ser mutation on serum levels of triglycerides. We conclude that these LPL polymorphisms do not contribute greatly to the overall risk of ischaemic stroke in the general population.

Vascular risk factors such as hypertension and hypercholesterolemia during midlife increase the risk for Alzheimer's disease (AD). Treatment of hypercholesterolemia and other vascular risk factors may have great implications in the prevention of AD. Recent findings illustrate that the sterol metabolism in the brain is an active process, well controlled and regulated by 24-hydroxylase, an enzyme that is uniquely expressed in the brain. The use of statins in ischemic heart disease (IHD) has proven to be a phenomenal advance in pharmacological disease prevention and treatment. A growing body of evidence, suggest that statins exhibit additional benefits that are independent of their cholesterol-lowering actions. Statin treatment has also considerable effect in prevention of ischemic stroke. In animal models of ischemic stroke, statins have proven to reduce infarct size through up-regulation of endothelial nitric oxide synthases. Data from recent observational studies have revealed a potential role for statins in prevention of AD. The following review comments the processes leading to dementia including the involvement of cholesterol regulation, cerebral circulation and inflammation in development of dementia. The mechanisms by which statins may be beneficial in controlling these processes is discussed.

Epidemiological studies indicate that the risk of first ever stroke is strongly related to age. Based on the NASCET and ECST results, carotid endarterectomy (CEA) is a well-established indication for the prevention of ischemic stroke in patients with 70-99% symptomatic internal carotid artery (ICA) stenosis and in selective cases with moderate stenosis (50-69%). A recent analysis of data from the NASCET group, clearly demonstrates that elderly patients (age75 years) with symptomatic ICA stenosis benefit more from CEA compared to younger patients. However, the NASCET collaborators point out that the greater benefits achieved in patients older than 75 years compared to other age groups in the trial depends on the fact that CEA was performed on the elderly having a higher risk of ipsilateral ischemic stroke if treated medically and the lowest surgical risk. In order to obtain the treatment benefit reported, operation performed by skilled surgeons and meticulous medical screening of the elderly patients is recommended to exclude life-threatening conditions.

The aim of the present study was to analyze the frequency and mechanism of cell death in atherosclerotic plaques with a recent history ( 70% diameter reduction) undergoing carotid endarterectomy. In situ tailing nick translation of fragmented DNA, agarose gel electrophoresis of plaque DNA and electron microscopy were used to identify cell death by apoptosis (programmed cell death) and necrosis. The mean number of cell containing fragmented DNA in the plaques was 12.7 ± 3.5% (n=15). Focal accumulations of cells with DNA fragmentation occurred in the fibrous cap, at sites of rupture, close to lipid deposits and necrosis and was always accompanied by the presence of inflammatory cells. Electrophoretic separation of DNA isolated form part of plaques where the presence of DNA fragmentation had previously been demonstrated by in situ DNA nick translation resulted in multiple ladders of 180–200 base pairs characteristic of apoptosis. Electron microscopic analysis revealed presence of cells with morphological signs of degeneration in a frequency even higher than that found by in situ nick translation. Some of these cells had a characteristic apoptotic appearance with condensed chromatin and cytoplasm, but the large majority of the cells had an ultrastructure typical for cells undergoing cell death by necrosis with membrane disruption and swollen, disintegrating organelles. Thus, although apoptosis clearly takes place in atherosclerotic plaques necrosis appears to be a much more common mechanism for cell death. This may have negative consequences for plaque stability since cell death by necrosis induces a stronger inflammatory reaction than apoptotic cell death.