Association of Carotid Plaque Morphology and Glycemic and Lipid Parameters in the Northern Manhattan Study

Low Gray-Scale Median (GSM) index is an ultrasonographic parameter of soft, lipid rich plaque morphology that has been associated with stroke and cardiovascular disease (CVD). We sought to explore the contribution of the modifiable and not-modifiable cardiovascular risk factors (RFs) to vulnerable plaque morphology measured by the low GSM index. A total of 1,030 stroke-free community dwelling individuals with carotid plaques present (mean age, 71.8 ± 9.1; 58% women; 56% Hispanic, 20% Non-Hispanic Black, 22% Non-Hispanic White) were assessed for minimum GSM (min GSM) using high-resolution B-mode carotid ultrasound. Multiple linear regression models were used to evaluate the association between RFs and minGSM after adjusting for sociodemographic characteristics. Within an individual, median plaque number was 2 (IQR: 1–3) and mean plaque number 2.3 (SD: 1.4). Mean minGSM was 78.4 ± 28.7 (IQR: 56–96), 76.3 ± 28.8 in men and 80 ± 28.5 in women; 78.7 ± 29.3 in Hispanics participants, 78.5 ± 27.2 in Non-Hispanic Black participants, and 78.2 ± 29 in Non-Hispanic white participants. In multivariable adjusted model, male sex (β = −5.78, p = 0.007), obesity BMI (β = −6.92, p = 0.01), and greater levels of fasting glucose (β = −8.02, p = 0.02) and LDL dyslipidemia (β = −6.64, p = 0.005) were positively associated with lower minGSM, while presence of glucose lowering medication resulted in a significant inverse association (β = 7.68, p = 0.04). Interaction (with p for interaction <0.1) and stratification analyses showed that effect of age on minGSM was stronger in men (β = −0.44, p = 0.03) than in women (β = −0.20, p = 0.18), and in individuals not taking glucose lowering medication (β = −0.33, p = 0.009). Our study has demonstrated an important contribution of glycemic and lipid metabolism to vulnerable, low density or echolucent plaque morphology, especially among men and suggested that use of glucose lowering medication was associated with more fibrose-stable plaque phenotype (greater GSM). Further research is needed to evaluate effects of medical therapies in individuals with vulnerable, low density, non-stenotic carotid plaques and how these effects translate to prevention of cerebrovascular disease

Cigarette Smoking and Carotid Plaque Echodensity in the Northern Manhattan Study

BACKGROUND: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multi-ethnic 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 to 5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a 2-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; CI, 1.42–3.83), quintile 4 (OR=2.05; CI, 1.19–3.51), and quintile 5 (OR=2.13; CI, 1.27–3.56) but not in quintile 3 (OR=1.18; 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; CI, 1.00–2.12), quintile 3 (OR=1.56; CI, 1.09–2.24), quintile 4 (OR=1.66; CI, 1.13–2.42), and quintile 5 (OR=1.73; CI, 1.19–2.51), but not in quintile 1 (OR=1.05; CI, 0.72–1.55). CONCLUSIONS: A non-linear, Vshaped like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at 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 only echodense plaques when compared against never smokers. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events

Shape Abnormalities of the Caudate Nucleus Correlate with Poorer Gait and Balance: Results from a Subset of the LADIS Study

Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in fronto-striatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter changes (WMC) on MRI 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

Risk profile, antithrombotic treatment and clinical outcomes of patients in Nordic countries with atrial fibrillation - results from the GARFIELD-AF registry

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 CHA(2)DS(2)-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 Conclusion: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable.</p

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Cell death in atherosclerosis

Rupture of atherosclerotic lesions is recognized as the major cause of acute cerebrovascular and coronary syndromes. The characteristics of the typical vulnerable plaque include increased inflammatory cells at the shoulder region, a large lipid core, a thin fibrous cap with few collagen fibers and smooth muscle cells. The release of proteolytic enzymes produced by macrophages, generation of cytokines by T cells and death of smooth muscle cells in lesions may contribute to plaque instability. Oxidation of LDL in the vessel wall renders the LDL particles proinflammatory and cytotxic. However, the type of cell death occurring in vivo and the factors responsible for its' induction have remained equivocal. Cholesterol homeostasis is achieved through regulation of the uptake, synthesis and esterification of cholesterol. It has been recently shown that extrahepatic cells such as macrophages can eliminate intracellular cholesterol by enzymatic conversion into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. The sterol 27-hydroxylase is the enzyme responsible for the conversion of cholesterol to 27-oxygenated products. The introduction of statins, as potent inhibitors of HMG-CoA reductase has resulted in significant decrease in cardiovascular morbidity and mortality. Angiographic assessment has shown that improvement in arterial topographical morphology occurs slowly and only to a small extent (1-2%). These observations have led to the concept of plaque stabilisation, as a new strategy for prevention of acute cardiovascular syndromes. Advanced human carotid atherosclerotic plaques were characterized by a high frequency of degenerating smooth muscle cells with ongoing DNA fragmentation. The presence of DNA ladder suggested that some of these cells undergo apoptotic cell death, but electron microscopic analysis indicated that most dying cells in the plaque were in a state of oncosis. Analysis of the relation between DNA framentation and plaque cell composition demonstrated a significant association between degree of TUNEL positivity and T cell infiltration. High serum LDL cholesterol levels were associated with increased macrophage staining in atherosclerotic lesions. Degenerating cells were almost exclusively found in or very close to regions with strong oxidized LDL inummoreactivity. Exposure of smooth muscle cells to oxidized LDL induced cell death of a similar pattern found in atherosclerotic lesions. Sterol 27-hydroxylase functions as a defence towards accumulation of cholesterol in macrophages by enzymatic conversion of intracellular cholesterol into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. We found the sterol 27-hydroxylase immunoreactivity to be located primarily to macrophages and endothelial cells in humans atherosclerotic lesions. In humans, the sterol 27-hydroxylase mechanism is more active compared to other species such as the rabbit. A substantially lower amount of lipids, particularly oxidized LDL, T cells and macrophages and degenerating cells were observed in atherosclerotic lesions obtained from patients with advanced carotid artery stenosis treated with pravastatin for 3 months prior to carotid endarterectomy. The present findings support the hypothesis that oxidized LDL is highly toxic towards vascular smooth muscle cells and induces oncosis, a pattern found in dying smooth muscle cells and other cells in advanced human carotid plaques. Moreover, they indicate that pravastatin treatment may stabilise the plaque composition by reducing oxidized LDL, inflammation and number of degenerating cell in vivo in humans

Relation between Vascular Risk Factors and Carotid Plaque Cell Composition and Viability in Elderly Patients

Objectives: Carotid stenosis is a crucial cause of ischemic stroke. Recent studies suggest that one of the most important effects of lipid-lowering statins is to stabilize vulnerable plaques. However, it remains to be determined if this effect is secondary to the lowering of plasma cholesterol levels or due to a direct effect of statins on plaques stability. Design and main outcome measures: In this study we have analyzed if plaque cell composition and the frequency of apoptotic DNA fragmentation are related to cholesterol levels or any of the major risk factors for vascular disease. The study group consisted of 49 patients undergoing carotid endarterectomy. The plaques were stained by immunohistochemical and TUNEL techniques and scored semi quantitatively by a blinded observer. Results: Rupture sites contained significantly more TUNEL-positive cells and T-cells, but less smooth muscle cells than intact areas of the fibrous cap. Plaques from hypercholesterolemic patients were found to have less TUNEL-positive cells, but otherwise hypercholesterolemia, low HDL cholesterol, hypertension, diabetes and smoking did not influence plaque cell composition or the frequency of TUNEL-positive cells. Conclusions: Our observations suggest that there are no associations between major vascular risk factors and plaque cell composition. Accordingly, they favor the notion that the effects of statins are due to a direct effect on plaque structure rather than solely secondary to lowering of plasma cholesterol

Pravastatin inhibits pro-inflammatory effects of Alzheimer's peptide Abeta(1-42) in glioma cell culture in vitro.

Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer’s disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer’s peptide (Aβ1–42)-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1 mg ml−1) for 24 h were stimulated with 5 μM of freshly dissolved Aβ1–42 for the next 24 h. The pre-treatment of cells with pravastatin diminished the capacity of Aβ to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Aβ1–42 separately increased PPARγ activity, the combination of Aβ1–42 and pravastatin resulted in no effect on PPARγ expression. These data indicate that soluble forms of Aβ1–42, which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin

Modulation of inflammatory mediators and ppargammaand nfkappab expression by pravastatin in response to lipoproteins in human monocytes in vitro.

Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 mgr; M) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 mgr; g ml(minus sign1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins. Copyright 2002 Elsevier Science Ltd

Platelet Alpha- and Beta- Secretase Activities are not Significantly Affected by Dementia or Mild Cognitive Impairment in Swedish Patients.

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 β-peptide (Aβ). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial α-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by β- and γ- secretase enzymes, which produces Aβ peptides. Currently, the diagnosis of probable or possible Alzheimer\u27s disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet β- secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet α-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of α- and β-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 α- and β-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 (TAG) 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