Markers Of Plaque Stability Research Articles

The Relationship Between Coronary Calcification and the Natural History of Coronary Artery Disease

ObjectivesThe aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease. BackgroundCoronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy. MethodsThis analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques). ResultsCPV was strongly correlated with plaque volume (r = 0.780; p < 0.001) at baseline and with plaque progression (r = 0.297; p < 0.001); however, this association was reversed after accounting for plaque volume at baseline (r = –0.146; p < 0.001). In contrast, PCPV was an independent predictor of a reduction in plaque volume (r = –0.11; p < 0.001) in univariable and multivariable linear regression analyses. Patient-level analysis showed that high CPV was associated with incident major adverse cardiac events (hazard ratio: 3.01: 95% confidence interval: 1.58 to 5.72), whereas high PCPV was inversely associated with major adverse cardiac events (hazard ratio: 0.529; 95% confidence interval: 0.229 to 0.968) in multivariable analysis. ConclusionsCalcified plaque is a marker for risk of adverse events and disease progression due to its strong association with the total plaque burden. When considered as a percentage of the total plaque volume, increasing PCPV is a marker of plaque stability and reduced risk at both a lesion and patient level. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)

The Relationship Between Coronary Calcification And The Natural History Of Coronary Artery Disease

Introduction: Coronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and increases in response to medical therapy. The aim of the current study is to explore the impact of plaque calcification at a lesion and patient level on the natural history of coronary artery disease.

Differences in the association of total versus local coronary artery calcium with acute coronary syndrome and culprit lesions in patients with acute chest pain: The coronary calcium paradox

Background and aimsTotal coronary artery calcium (CAC) burden is associated with an increased cardiovascular risk, while local CAC may represent stable plaques. We determined differences in relationship of total CAC with acute coronary syndrome (ACS) and local CAC with culprit lesions in patients with suspected ACS. MethodsWe performed computed tomography (CT) for CAC and CT angiography to assess the presence of significant stenosis and high-risk plaque (positive remodeling, low CT attenuation, napkin-ring sign, spotty calcium) in 37 patients with ACS and 223 controls. Total and segmental Agatston scores were measured. Culprit lesions were assessed in subjects with ACS. ResultsPatients (n = 260) with vs. without ACS had higher total CAC score (median 229, 25th-75th percentile 75–517 vs. 27, 25th-75th percentile 0–99, p<0.001), higher prevalence of significant stenosis (78% vs. 7%, p<0.001) and high-risk plaque (95% vs. 59%, p<0.001). In those with ACS, culprit (n = 41) vs. non-culprit (n = 200) lesions, had similar segmental CAC score (median 22, 25th-75th percentile 4–71 vs. 14, 25th-75th percentile 0–51; p=0.37), but higher prevalence of significant stenosis (81% vs. 11%, p<0.001) and high-risk plaque (76% vs. 51%, p=0.005). Significant stenosis (odds ratio 40.2, 95%CI 15.6–103.9, p<0.001) and high-risk plaque (odds ratio 3.4, 95%CI 1.3–9.1, p=0.02), but not segmental CAC score (odds ratio 1.0, 95%CI 1.0–1.0, p=0.47), were associated with culprit lesions of ACS. ConclusionsTotal CAC burden was associated with ACS but segmental CAC was not associated with culprit lesions. Our findings suggest that total but not local CAC is a marker of ACS risk and support the hypothesis that extensive local CAC is a marker of plaque stability.

Plaque stabilizing effects of apolipoprotein A-IV

Background and aimsApolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo. MethodsPlaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD. ResultsIn the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity. ConclusionsApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.

Evaluation of Serum Pregnancy Associated Plasma Protein-A & Plasma D-Dimer in Acute Coronary Syndrome.

Acute coronary syndrome (ACS), a spectrum comprising unstable angina pectoris, ST Elevated Myocardial Infarction (STEMI) & Non ST Elevated Myocardial Infarction (NSTEMI) is the major cause of presentation in Emergency Department today. Though ECG and cardiac enzymes are used for diagnosis, they mislead the diagnosis sometimes and delay in treatment initiation. This leads us to search certain new parameters which reflect the pathophysiology of ACS. Markers of plaque stability like Pregnancy Associated Plasma Protein-A and D-Dimer, a marker of ongoing thrombosis are found to be better markers in early diagnosis. To evaluate the diagnostic competence of PAPP-A and D-Dimer in acute coronary syndrome over CK-MB and to compare with the inflammatory marker High Sensitive C-Reactive Protein (hs-CRP) which is associated with atherosclerosis. Fifty patients presenting with acute onset of chest pain to Emergency Department with or without ECG changes served as cases and 50 healthy people served as controls. Serum PAPP-A is measured by Enzyme Linked Immunosorbent Assay (ELISA), D-Dimer and hs-CRP by using Latex Turbidimetry method. A statistical significant difference of PAPP-A and D-Dimer was noted between the ACS and controls (p < 0.001) whereas CK-MB shows no much difference (p 0.09). Statistically significant positive correlation is noted between parameters. PAPP-A marker of plaque instability and D-Dimer marker of ongoing thrombosis are raised in acute coronary syndrome and thus can be considered as one of the marker in ACS for diagnosis.

Human Carotid Plaques With High Levels of Interleukin-16 Are Associated With Reduced Risk for Cardiovascular Events.

Interleukin-16 (IL-16) functions as a regulator of T-cell growth and acts as an inducer of cell migration. The aim of this study was to determine whether IL-16 measured in human carotid plaques was associated with symptoms (eg, stroke, transient ischemic attack, or amaurosis fugax), markers of plaque stability, and postoperative cardiovascular events. Plaques obtained from patients who had ≥1 cerebrovascular ischemic events within 1 month before endarterectomy (n=111) were compared with plaques from patients without symptoms (n=95). Neutral lipids, smooth muscle cell, and macrophage contents were evaluated histologically, and collagen, elastin, and caspase-3 activity were measured biochemically. IL-16, matrix metalloproteinases, and tissue inhibitors of metalloproteinases were measured in plaque homogenates using a multiplex immunoassay. IL-16, CD3, CD4, and FoxP3 mRNA expressions in carotid plaques were analyzed with quantitative real-time polymerase chain reaction. Carotid plaques from asymptomatic patients had higher levels of IL-16 mRNA. High plaque IL-16 protein levels (above median) were associated with reduced incidence of postoperative cardiovascular events during a mean follow-up of 21 months (hazard ratio, 0.47; 95% confidence interval, 0.22-0.99; P=0.047). IL-16 levels correlated with the plaque-stabilizing components: elastin, collagen, matrix metalloproteinase-2, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2 and FoxP3 mRNA. This study shows that high levels of IL-16 are associated with asymptomatic carotid plaques, expression of factors contributing to plaque stability, and decreased risk of new cardiovascular events during a 2-year period after surgery, suggesting that IL-16 might have a protective role in human atherosclerotic disease.

Markers of preclinical atherosclerosis and their clinical relevance.

The estimation of risk for atherosclerotic and cardiovascular events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical disease in individual subjects: blood markers of atherosclerosis and preclinical deterioration of the arterial wall. Elevated levels of several inflammatory mediators have been found in subjects with atherosclerosis. Increased basal levels of cytokines, the cell adhesion molecules, selectins and acute-phase reactants such as high sensitive C-reactive protein (hsCRP), fibrinogen, and serum amyloid A are related to an increased risk of cardiovascular events. For clinical purposes, the most promising inflammatory biomarker appears to be hsCRP. In the last decade, markers of plaque stability and unstable coronary artery disease have been sought. Further, markers of endothelial dysfunction, like circulating molecules as well as indicators of functional deterioration of the arterial wall were identified. It was shown that endothelial dysfunction is closely related to different risk factors of atherosclerosis, and to their intensity and duration. Intima-media thickness measurement has emerged as one of the methods of choice for determining the anatomic extent of preclinical atherosclerosis and for assessing cardiovascular risk.Determination of markers of preclinical atherosclerosis improve individual risk determination and could influence the decision of a clinician to intervene with medication and to use more aggressive treatment of risk factors in high risk subjects and in patients with atherosclerotic disease.

EVALUATION OF CALCIFICATION IN CAROTID ENDARTERECTOMY TISSUES WITH MICRO–COMPUTED TOMOGRAPHY IMAGING

Calcification in atherosclerotic plaque has been viewed as a marker of plaque stability, but whether calcification accumulates in specific anatomic sites in the carotid artery is unknown. In this study, we determined the burden and distribution of calcified lesions in carotid endarterectomy (CEA)

Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE*3-Leiden.CETP mice

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (−52%) in the aortic root, comparable to atorvastatin (−40%) and the combination of both drugs (−47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (−19%) comparable to atorvastatin (−19%) and the combination (−22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin.

Does the combination of a renin inhibitor with a statin have potential for improved inhibition of atherosclerosis?

The concept that pharmacological inhibition of the renin–angiotensin–aldosterone system (RAAS) can reduce atherosclerosis is now well established [1]. In addition to the considerable evidence that components of the RAAS stimulate lesion development, targeting different components of the system has been shown to both reduce lesion formation and to increase markers of plaque stability. For example, in atherosclerosis-prone mice, administration of angiotensin II (Ang II) over long periods promotes lesion formation, whereas angiotensinconverting enzyme (ACE) inhibition, angiotensin 1 receptor antagonism [2] or mineralocorticoid receptor antagonism [3] reduces lesion size. An increasing body of evidence suggests that both Ang II-induced stimulation of lesion formation and the antiatherosclerotic effects of treatment (ACE inhibition/AT1 receptor antagonism) are independent of blood pressure; indicating a direct atherosclerotic effect of Ang II on the cells of the vascular wall. However, the exact mechanisms through which blockade of the RAAS alters lesion formation remain unclear.

Connective Tissue Growth Factor Is Associated With a Stable Atherosclerotic Plaque Phenotype and Is Involved in Plaque Stabilization After Stroke

Carotid plaques remodel toward a more stable phenotype after stroke, but not after TIA. Connective tissue growth factor (CTGF) is involved in extracellular matrix production and is expressed in atherosclerotic plaques. We studied the role of CTGF in plaque remodeling after stroke and TIA. Atherosclerotic plaques from carotid endarterectomy of asymptomatic patients (n = 16) and patients who experienced stroke (n = 15) or TIA (n = 33) were analyzed for CTGF levels, markers of plaque stability (collagen, smooth muscle cells, macrophage content, and lipid core), and levels of matrix metalloproteinase (MMP)-8, MMP-9, IL-4, IL-5, and IL-10. CTGF levels were higher in stroke patients compared to TIA patients. Plaques with a high level of CTGF revealed more collagen and smooth muscle cell content, whereas macrophage content and lipid core size were not different. The amount of CTGF was negatively associated with MMP-8 and MMP-9 activity and showed a positive correlation with the anti-inflammatory cytokines IL-4, IL-5, and IL-10. CTGF levels are associated with a more stable plaque phenotype. CTGF is increased in plaques after stroke compared to TIA, suggesting a role for CTGF in plaque stabilization after stroke.

Possible Role of Osteoprotegerin and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand as Markers of Plaque Instability in Coronary Artery Disease

Osteoprotegerin (OPG) produced by cardiovascular system raising the possibility that alterations of OPG serum levels may be associated with coronary artery disease (CAD). Our aim is to assess the possible role of serum OPG and soluble tumor necrosis factor-related apoptosis-inducing ligand (s-TRAIL) in the pathology of CAD and their uses as markers of plaque stability. A total of 80 male participants were categorized into 3 groups: 28 patients with acute myocardial infarction (AMI), 32 established stable CAD, and 20 healthy controls were enrolled in this study. Acute myocardial infarction and CAD groups exhibited significantly higher OPG levels and lower s-TRAIL levels compared to the stable CAD and control participants. These results are aggravated as the number of affected coronary vessels increase in AMI and stable CAD groups. There is an association between raised serum OPG and reduced s-TRAIL in patients with CAD. Elevation of circulating OPG levels may represent a crucial compensatory mechanism to limit further vascular damage.

The importance of scavenging reactive oxygen species in anti‐aging medicine

AbstractIn a pilot study, we had reported on the beneficial effects of Ginkgo biloba (EGb 761) on arteriosclerotic nanoplaque formation and size in cardiovascular high‐risk patients who had undergone an aortocoronary bypass operation. Briefly, nanoplaque formation and size, the ratio oxLDL/LDL, and the highly atherothrombotic lipoprotein(a) concentration were substantially reduced, while superoxide dismutase activity and the blood concentration of the vasodilating substances cAMP and cGMP were upregulated. Since the arteriosclerosis prophylactic and well‐aging promotive impact of Ginkgo extract has been proven in this pilot study, we wanted to confirm these beneficial effects through a second observational clinical trial. The measurable variables formerly used were additionally supplemented by a wide, novel biomarker spectrum, through which the latest parameters and markers of plaque stability and progression, oxidative stress, and inflammation were available. In eleven patients with metabolic syndrome in the initial stage, the reduction of arteriosclerotic nanoplaque formation amounted to 14.3±2.9% (p&lt;0.0077) and of nanoplaque size to 23.4±3.7% (p&lt;0.0004), respectively, after 2‐months of treatment with Ginkgo biloba extract. Additionally, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were upregulated by 19.6±10.0% (p&lt;0.0785) and 11.6±2.3% (p&lt;0.001), respectively, the quotient oxLDL/LDL lowered by 21.0±4.3% (p&lt;0.002), and lipoprotein(a) concentration decreased by 26.3±4.8% (p&lt;0.001) in the patients' blood. The concentration of cAMP and cGMP was augmented by 43.5±12.0% (p&lt;0.001) and 32.9±10.4% (p&lt;0.001), respectively. Surprisingly, we found a lowering of the serum Ca2+ concentration by 5.4±1.6% (p&lt;0.0076) from 2.37±0.03 to 2.24±0.04 mmol/L (p&lt;0.0069). Apart from an additional vasodilatory effect, the lowered extracellular Ca2+ concentration affects nanoplaque formation restrictively, since this is a Ca2+ driven process. Furthermore, we could show a favourable development of the biomarkers 8‐iso‐PGF2α, oxLDL/LDL, SOD, GPx (oxidative stress), hs‐CRP, MPO, TNFα, TGFβ1 (inflammatory status) and MMP‐9 (plaque stability). The markers selected here are suited to provide a comprehensive risk profile for the prevention of arteriosclerosis. Finally, a multiple regression analysis reveals a basis for a mechanistic explanation of nanoplaque reduction under Ginkgo treatment. The arteriosclerosis inhibiting effect is due to an attenuation of the risk factors oxLDL/LDL, Lp(a), and [Ca2+]o as well as to a significant increase in the vasodilator cAMP and cGMP concentration. Thus, Ginkgo with its pleiotropic effects should be assigned a fixed rank among the anti‐aging medical therapeutics as a prophylactic measure, especially in patients with early‐stage metabolic syndrome.

Calcification in atherosclerosis

Coronary calcification has long been known to occur as a part of the atherosclerotic process, although whether it is a marker of plaque stability or instability is still a topic of considerable debate. Coronary calcification is an active process resembling bone formation within the vessel wall and, with the advances in CT technology of the past decade, can be easily quantified and expressed as a coronary artery calcium (CAC) score. The extent of calcium is thought to reflect the total coronary atherosclerotic burden, which has generated interest in using CAC as a marker of risk of cardiovascular events. The current consensus is that large amounts of CAC identify a highly vulnerable patient rather than a vulnerable plaque or vulnerable vessel. Indeed, CAC has incremental prognostic value beyond traditional risk factors in various subsets of the population. Furthermore, whereas the presence of CAC is associated with increased risk, a zero CAC score predicts excellent short-term to mid-term prognosis, even in high-risk patients. The advent of CT angiography has perhaps clouded the importance of CAC as a long-term marker of risk, as opposed to the presence of luminal stenoses that are associated with a more immediate risk of events.

Soluble CD36 in Plasma Is Increased in Patients With Symptomatic Atherosclerotic Carotid Plaques and Is Related to Plaque Instability

The risk for cardiovascular events is related to the composition and stability of an atherosclerotic plaque driven by inflammation and deposition of lipids. Scavenger receptors are a family of cell surface receptors involved in lipid uptake and inflammation. Recently, we found that soluble CD36 is increased in plasma from patients with diabetes strongly correlated with insulin resistance. We tested whether soluble CD36 is a marker of plaque stability in patients with high-grade internal carotid stenoses (n=62). The patients were classified according to plaque symptomatology and plaque echogenicity on ultrasound examination. When patients were divided into 3 groups according to the latest clinical symptoms from plaques (ie, symptoms within the last 2 months [n=16], symptoms within the last 2 to 6 months [n=15], or asymptomatic [n=31]), the former group had significantly raised plasma levels of soluble CD36 as compared with the other 2 groups. In contrast, we found no differences in plasma levels of C-reactive protein, beta-thromboglobulin, lipid parameters, or HbA1C between these groups. The patients with echolucent carotid plaques (n=20) tended to have higher soluble CD36 levels in plasma compared with those with echogenic/heterogenic plaque (n=39; P=0.087). By immunohistochemistry, CD36 was localized to macrophages-rich area of intima within the atherosclerotic lesion. We propose that sCD36 may be a marker of plaque instability and symptomatic carotid atherosclerosis, possibly at least partly as a result of CD36 release to the circulation from the foam cells within the atherosclerotic lesion.

Poly(ADP-Ribose) Polymerase Inhibition Reduces Atherosclerotic Plaque Size and Promotes Factors of Plaque Stability in Apolipoprotein E–Deficient Mice

Poly(ADP-ribose) polymerase (PARP) was suggested to play a role in endothelial dysfunction that is associated with a number of cardiovascular diseases. We hypothesized that PARP may play an important role in atherogenesis and that its inhibition may attenuate atherosclerotic plaque development in an experimental model of atherosclerosis. Using a mouse (apolipoprotein E [ApoE](-/-)) model of high-fat diet-induced atherosclerosis, we demonstrate an association between cell death and oxidative stress-associated DNA damage and PARP activation within atherosclerotic plaques. PARP inhibition by thieno[2,3-c]isoquinolin-5-one reduced plaque number and size and altered structural composition of plaques in these animals without affecting sera lipid contents. These results were corroborated genetically with the use of ApoE(-/-) mice that are heterozygous for PARP-1. PARP inhibition promoted an increase in collagen content, potentially through an increase in tissue inhibitor of metalloproteinase-2, and transmigration of smooth muscle cells to intima of atherosclerotic plaques as well as a decrease in monocyte chemotactic protein-1 production, all of which are markers of plaque stability. In PARP-1(-/-) macrophages, monocyte chemotactic protein-1 expression was severely inhibited because of a defective nuclear factor-kappaB nuclear translocation in response to lipopolysaccharide. Furthermore, PARP-1 gene deletion not only conferred protection to foam cells against H2O2-induced death but also switched the mode of death from necrosis to apoptosis. Our results suggest that PARP inhibition interferes with plaque development and may promote plaque stability, possibly through a reduction in inflammatory factors and cellular changes related to plaque dynamics. PARP inhibition may prove beneficial for the treatment of atherosclerosis.

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE −/− Mice

Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice. Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.

Th-P15:148 Lipid peroxidation in patients with retinal artery arteriosclerosis

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (−52%) in the aortic root, comparable to atorvastatin (−40%) and the combination of both drugs (−47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (−19%) comparable to atorvastatin (−19%) and the combination (−22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin.

Estrogen/Statin-Kombination: Wirkung auf Marker für die Plaquestabilität

Purpose: At present a particularly important question in the field of hormone replacement therapy (HT) is how women with increased cardiovascular risk as indication for HT can be treated. The most recent intervention studies point to the fact that hormone-induced cardiovascular risks in patients can be avoided with statin treatment. So far there are only few investigations into the combination of statins and HT. The aim of this study was to examine the effect of the individual substances and their combinations on known markers of plaque stability. Material and Methods: As a cell model endothelial cells and muscle cells from the human female coronary artery were applied. Markers of plaque stability were the chemokine MCP-1, the matrixmetalloproteinase MMP-1, and the growth factor VEGF. Fluvastatin and estradiol were tested alone and in equimolar combinations in the concentrations 0.1,1 and 10 μM. Results: Fluvastatin significantly reduced the synthesis of all three markers. Estradiol showed a significant inhibition for pro-MMP 1 and VEGF. Neither significant additive nor antagonistic effects were observed for the combination of both substances. Conclusion: Inhibiting effects of statins on markers of plaque stability remain effective in combination with estradiol, so that women, adjusted to statins, can be treated with HT. This has yet to be proven in further clinical studies.