Increased Plaque Burden Research Articles

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons.

α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.

Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice.

BackgroundThe endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation and ligand to both, pro-inflammatory cannabinoid receptor 1 (CB1) and anti-inflammatory CB2. While the role of both receptors in atherogenesis has been studied extensively, the significance of 2-AG for atherogenesis is less well characterized.MethodsThe impact of 2-AG on atherogenesis was studied in two treatment groups of ApoE-/- mice. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184 [5 mg/kg i.p.], which impairs 2-AG degradation and thus causes elevated 2-AG levels, the other group received vehicle for four weeks. Simultaneously, both groups were fed a high-cholesterol diet. The atherosclerotic plaque burden was assessed in frozen sections through the aortic sinus following oil red O staining and infiltrating macrophages were detected by immunofluorescence targeting CD68. In vitro, the effect of 2-AG on B6MCL macrophage migration was assessed by Boyden chamber experiments. Transcription of adhesion molecules and chemokine receptors in macrophages was assessed by qPCR.ResultsAs expected, application of the MAGL-inhibitor JZL184 resulted in a significant increase in 2-AG levels in vascular tissue (98.2 ± 16.1 nmol/g vs. 27.3 ± 4.5 nmol/g; n = 14–16; p < 0.001). ApoE-/- mice with elevated 2-AG levels displayed a significantly increased plaque burden compared to vehicle treated controls (0.44 ± 0.03 vs. 0.31 ± 0.04; n = 14; p = 0.0117). This was accompanied by a significant increase in infiltrating macrophages within the atherosclerotic vessel wall (0.33 ± 0.02 vs. 0.27 ± 0.01; n = 13–14; p = 0.0076). While there was no alteration to the white blood counts of JZL184-treated animals, 2-AG enhanced macrophage migration in vitro by 1.8 ± 0.2 -fold (n = 4–6; p = 0.0393) compared to vehicle, which was completely abolished by co-administration of either CB1- or CB2-receptor-antagonists. qPCR analyses of 2-AG-stimulated macrophages showed an enhanced transcription of the chemokine CCL5 (1.59 ± 0.23 –fold; n = 5–6; p = 0.0589) and its corresponding receptors CCR1 (2.04 ± 0.46 -fold; n = 10–11; p = 0.0472) and CCR5 (2.45 ± 0.62 –fold; n = 5–6; p = 0.0554).ConclusionTaken together, elevated 2-AG levels appear to promote atherogenesis in vivo. Our data suggest that 2-AG promotes macrophage migration, possibly by the CCL5-CCR5/CCR1 axis, and thereby contributes to vascular inflammation. Thus, decreasing vascular 2-AG levels might represent a promising therapeutic strategy in patients suffering from atherosclerosis and coronary heart disease.

Genetic Deletion of IL-19 (Interleukin-19) Exacerbates Atherogenesis in Il19-/-×Ldlr-/- Double Knockout Mice by Dysregulation of mRNA Stability Protein HuR (Human Antigen R).

To test the hypothesis that loss of IL-19 (interleukin-19) exacerbates atherosclerosis. APPROACH AND RESULTS: Il19-/- mice were crossed into Ldlr-/- (low-density lipoprotein receptor knock out) mice. Double knockout (dKO) mice had increased plaque burden in aortic arch and root compared with Ldlr-/- controls after 14 weeks of high-fat diet (HFD). dKO mice injected with 10 ng/g per day rmIL-19 had significantly less plaque compared with controls. qRT-PCR and Western blot analysis revealed dKO mice had increased systemic and intraplaque polarization of T cells and macrophages to proinflammatory Th1 and M1 phenotypes, and also significantly increased TNF (tumor necrosis factor)-α expression in spleen and aortic arch compared with Ldlr-/- controls. Bone marrow transplantation suggests that immune cells participate in IL-19 protection. Bone marrow-derived macrophages and vascular smooth muscle cells isolated from dKO mice had a significantly greater expression of inflammatory cytokine mRNA and protein compared with controls. Spleen and aortic arch from dKO mice had significantly increased expression of the mRNA stability protein HuR (human antigen R). Bone marrow-derived macrophage and vascular smooth muscle cell isolated from dKO mice also had greater HuR abundance. HuR stabilizes proinflammatory transcripts by binding AU-rich elements in the 3' untranslated region. Cytokine and HuR mRNA stability were increased in dKO bone marrow-derived macrophage and vascular smooth muscle cell, which was rescued by addition of IL-19 to these cells. IL-19-induced expression of miR133a, which targets and reduced HuR abundance; miR133a levels were lower in dKO mice compared with controls. These data indicate that IL-19 is an atheroprotective cytokine which decreases the abundance of HuR, leading to reduced inflammatory mRNA stability.

Prediction of coronary plaque progression using biomechanical factors and vascular characteristics based on computed tomography angiography

Objectives: Coronary atherosclerotic plaques progress in a highly individual manner. Accurately predicting plaque progression will promote clinical management of atherosclerosis. The purpose of this study was to investigate the role of local biomechanics factors and vascular characteristics in coronary plaque progression and arterial remodeling.Methods: Computed tomography angiography-based three-dimensional reconstruction of the native right coronary artery was performed in vivo in twelve patients with acute coronary syndrome at baseline and 12-month follow-up. The reconstructed arteries were divided into sequential 3-mm-long segments. Wall shear stress (WSS) and von Mises stress (VMS) were computed in all segments at baseline by applying fluid-structure interaction simulations.Results: In total, 365 segments 3-mm long were analyzed. The decrease in minimal lumen area was independently predicted by low baseline VMS (−0.73 ± 0.13 mm2), increase in plaque burden was independently predicted by small minimal lumen area and low baseline WSS (6.28 ± 0.96%), and decrease in plaque volume was independently predicted by low baseline VMS (−0.99 ± 0.49 mm3). Negative remodeling was more likely to occur in low- (55%) and moderate-VMS (40%) segments, but expansive remodeling was more likely to occur in high-VMS (44%) segments.Conclusions: Local von Mises stress, wall shear stress, minimal lumen area, and plaque burden provide independent and additive prediction in identifying coronary plaque progression and arterial remodeling.

Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow

It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to low SS and are characterized by a proinflammatory, apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high SS are protected from plaque development, but the mechanisms have remained elusive. Autophagy is a protective mechanism that allows recycling of defective organelles and proteins to maintain cellular homeostasis. We aimed to understand the role of endothelial autophagy in the atheroprotective effect of high SS. Atheroprotective high SS stimulated endothelial autophagic flux in human and murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS were characterized by inefficient autophagy as a result of mammalian target of rapamycin (mTOR) activation, AMPKα inhibition, and blockade of the autophagic flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased plaque burden only in the atheroresistant areas exposed to high SS; plaque size was unchanged in atheroprone areas, in which endothelial autophagy flux is already blocked. In cultured cells and in transgenic mice, deficiency in endothelial autophagy was characterized by defects in endothelial alignment with flow direction, a hallmark of endothelial cell health. This effect was associated with an increase in endothelial apoptosis and senescence in high-SS regions. Deficiency in endothelial autophagy also increased TNF-α-induced inflammation under high-SS conditions and decreased expression of the antiinflammatory factor KLF-2. Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence, and inflammation.

Anatomical plaque and vessel characteristics are associated with hemodynamic indices including fractional flow reserve and coronary flow reserve: A prospective exploratory intravascular ultrasound analysis

ObjectivesTo assess the relationship between anatomical form and physiological function in atherosclerotic coronary arteries. BackgroundAlthough adverse cardiovascular events are predicted by plaque morphology or invasively-derived hemodynamic indices, the link between these important prognostic measures remains unexplored. MethodsPatients with stable angina underwent fractional flow reserve (FFR), coronary flow reserve (CFR), pressure-derived collateral flow index (CFIp), trans-myocardial biomarker sampling and radiofrequency intravascular ultrasound (IVUS) imaging prior to intervention. Physiological ischemia was defined as either FFR≤0.8 or CFR<2.0. ResultsMean FFR was 0.70±0.15 and CFR was 2.1±1.3, with 68/92 lesions having FFR≤0.8 and 61/92 having CFR<2.0. On IVUS, FFR≤0.8 lesions had reduced minimal luminal area (MLA, p=0.03), increased plaque burden (PB, p=0.04) and volume (p=0.01). There was no relationship between FFR and IVUS-defined plaque composition. FFR≤0.8 was observed in 75.3%, 72.4% and 70.4% of lesions with MLA≤4mm2, PB≥70% and thin-cap fibroatheroma, respectively. Multivariate regression demonstrated FFR≤0.8 was independently predicted by MLA (odds ratio (OR) 0.53, 95% CI 0.29–0.97, p=0.04) and PB (OR 1.10, 95% CI 1.01–1.21, p=0.03). There were no identifiable relationships between plaque structure and CFR or CFIp. CFR<2.0 was associated with whole vessel necrotic core increases (p=0.047), fibrofatty tissue reduction (p=0.004) and elevated baseline transmyocardial high-sensitivity C-reactive protein (hsCRP) gradients (p=0.02). ConclusionsMeasures of plaque structure including PB and MLA are independently associated with FFR, but not with CFR or CFIp. Instead, vessels with low CFR have increased lipid accumulation and a higher transmyocardial hsCRP gradient. These results may explain similarities in clinical outcomes between physiologically and anatomically orientated trials.

P1071Unrecognized myocardial scar in areas of increased plaque burden in patients with suspected coronary artery disease. A clinical coronary CTA and CMR imaging study

P1071Unrecognized myocardial scar in areas of increased plaque burden in patients with suspected coronary artery disease. A clinical coronary CTA and CMR imaging study

Abstract 604: Genetic Deletion of Interleukin-19 Exacerbates Atherogenesis and Inflammatory Gene Expression in Ldlr -/- Mice

IL-19 is an anti-inflammatory interleukin and a member of the IL-10 family. Our laboratory has previously shown that IL-19 treatment is able to decrease atherosclerotic plaque burden in Ldlr -/- mice through polarization of T cells and macrophages to their anti-inflammatory phenotypes. We hypothesized that lack of IL-19 would exacerbate atherosclerosis. We observed that the absence of IL-19 results in increased plaque burden in Ldlr -/- x Il19 -/- (DKO) mice when compared to Ldlr -/- controls after 14 weeks of high fat diet (HFD) administration by en face and Oil Red O staining of aorta and aortic root. In a rescue study wherein DKO mice were placed on HFD for 14 weeks and simultaneously injected i.p. with 10ng/g/day of mIL-19 or PBS, DKO mice injected with mIL-19 had significantly less plaque than PBS controls. To test our hypothesis that exacerbated plaque in the DKO was due to an increased pro-inflammatory environment, we performed gene expression analysis from spleen and arch from Ldlr -/- and DKO mice after 14 weeks of HFD, as well as a series of in vitro experiments in isolated Ldlr -/- and DKO VSMCs and BMDMs. qRT-PCR analysis revealed DKO mice have a global and more dramatic local polarization of T cells and macrophages to pro-inflammatory Th1 and M1 phenotypes in the spleen and aortic arch. We stimulated cultured VSMCs and BMDMs with pro-inflammatory stimulus, TNFα, and found that DKO VSMCs express greater levels of TNFα and MCP-1 mRNA compared to Ldlr -/- controls. DKO BMDMs also exhibit increased expression levels of TNFα, as well as IL-1β when compared to Ldlr -/- . Gene expression analysis also demonstrated increased levels of pro-inflammatory mRNA binding protein, human antigen R (HuR) in the DKO spleen and arch. HuR stabilizes pro-inflammatory transcripts by binding ARE elements in the 3’ UTR. Utilizing the RNA synthesis inhibitor actinomycin D in cultured BMDM and VSMC, we observed increased mRNA stability of inflammatory genes in DKO cells when compared to Ldlr -/- by qRT-PCR. These data suggest that IL-19 is an atheroprotective cytokine which dampens inflammatory gene expression by modulation of mRNA stability.

Aspartame Intake Relates to Coronary Plaque Burden and Inflammatory Indices in Human Immunodeficiency Virus.

BackgroundDietary sweeteners may contribute to metabolic dysregulation and cardiovascular disease (CVD), but this has not been assessed in human immunodeficiency virus (HIV).MethodsOne hundred twenty-four HIV-infected and 56 non-HIV-infected participants, without history of known coronary artery disease were included. Dietary intake was assessed using a 4-day food record. Coronary plaque was determined using cardiac computed tomography angiography.ResultsHuman immunodeficiency virus-infected participants had significantly greater intake of dietary sweeteners, including total sugar (P = .03) and added sugar (P = .009); intake of aspartame (artificial sweetener) was greater among aspartame consumers with HIV versus non-HIV consumers (P = .03). Among HIV-infected participants, aspartame intake was significantly associated with coronary plaque (P = .002) and noncalcified plaque (P = .007) segments, as well as markers of inflammation/immune activation (monocyte chemoattractant protein 1 and lipoprotein-associated phospholipase A2), which may contribute to increased atherogenesis. In multivariable regression modeling, aspartame remained an independent predictor of plaque in HIV. In contrast, among non-HIV-infected participants, no sweetener type was shown to relate to plaque characteristics.ConclusionsWe demonstrate increased intake of dietary sweeteners and a potential novel association between aspartame intake, plaque burden, and inflammation in HIV. Our data suggest that aspartame may contribute to CVD risk in HIV. Further studies should address potential mechanisms by which aspartame may contribute to increased plaque burden and cardiovascular benefits of dietary strategies targeting aspartame intake in HIV.

Abstract 13854: Micro-RNA Regulation of Collagen Production by Vascular Smooth Muscle Cells Mediated by La Ribonucleoprotein Domain Family Member 6: Potential Mechanisms Underlying Stable Phenotype of Atherosclerotic Plaque by Insulin-like Growth Factor 1

Collagen is a major constituent of the extracellular matrix in atherosclerotic plaques and supports plaque stability. La ribonucleoprotein domain family member 6 (LARP6) is an RNA binding protein, which assists translation of fibrillar collagen, thereby promoting mature collagen deposition. In Apoe-null mice, insulin-like growth factor 1 (IGF1) promoted stable features of plaques by increasing smooth muscle cell (SMC) numbers and mature collagen fibril deposition without increasing plaque burden. To study mechanisms underlying the IGF1’s plaque stabilizing effects, we exposed human aortic SMCs to proatherogenic oxidized LDL (oxLDL) or IGF1 and determined collagen expression levels. OxLDL downregulated collagen (I) by 36.0±3.2% (P&lt;0.05), along with LARP6 (40.9±10.4 % decrease, P&lt;0.05) and procollagen (I) (49.0±8.9 % decrease, P&lt;0.05), which are consistent with decreased translation of procollagen (I) mRNA. IGF1 abolished oxLDL effects, reversing LARP6 and procollagen (I) protein levels, and thus increased collagen (I) to the levels comparable with native LDL-treated control. As we found previously, the IGF1 upregulation of collagen (I) was mediated by enhanced expression of LARP6, however IGF1 did not alter LARP6 mRNA levels, suggesting translational/post-translational mechanisms. Micro RNA regulates translation of mRNAs; in fact, miR-126, miR-744, and miR-1976 target LARP6 mRNA. In human aortic SMCs, oxLDL upregulated miR-1976 by 40.4±0.5 %, implying miR-mediated suppression of LARP6 translation. Intriguingly, IGF1 abrogated the oxLDL upregulation of miR-1976; moreover, IGF1 decreased miR-126 (by 25.0±1.0 %, P&lt;0.05) and miR-744 (by 24.0±0.4 %, P&lt;0.01), further suggesting that downregulation of miRs mediated IGF1 upregulation of LARP6. To evaluate LARP6 expression in human atherosclerotic plaques, atherosclerotic carotid artery sections were stained for LARP6, and it was detected mainly in SMCs in the medial layer and in the plaque fibrous cap, where collagen fibrils are integral components supporting plaque stability. Our findings suggest a novel mechanism of collagen accumulation by miR-dependent LARP6 expression, and provide a basis for a novel therapeutic approach to enhance plaque stability by targeting miR.

Pathology of coronary atherosclerosis and thrombosis.

The process of early atherosclerotic plaque progression is characterized by the development of pathologic intimal thickening (PIT) with lipid pool that may transform into the necrotic core to form fibroatheroma, where infiltration of foamy macrophages plays a crucial role. The expansion of the necrotic core is also attributable to intraplaque hemorrhage. Thin-cap fibroatheroma (TCFA) is characterized by a relatively large necrotic core with an overlying thin fibrous cap measuring <65 µm typically containing numerous macrophages, and is considered to be the precursor lesion of plaque rupture which is the most common cause of coronary thrombosis. The second common cause of acute thrombosis is plaque erosion, while calcified nodules is known to be the least frequent cause of coronary thrombosis. Coronary thrombosis can occur without symptoms to form healed lesions, which contributes to an increase in plaque burden and luminal narrowing. The process of plaque progression is generally accompanied by the progression of calcification. An understanding of the histomorphological characteristics of coronary plaques should provide important insights into the pathogenesis, diagnosis, and treatment of atherosclerotic coronary disease for both basic and clinical researchers as well as for clinicians.

Multimodality Intravascular Imaging to Evaluate Sex Differences in Plaque Morphology in Stable CAD

ObjectivesThe aim of this study was to evaluate sex differences in plaque morphology in stable coronary artery disease (CAD) patients using a multimodality intravascular imaging approach. BackgroundDifferences in atherosclerotic burden and plaque morphology between men and women is a focus of treatment and preventative measures. MethodsWe retrospectively analyzed data from 383 patients with stable CAD who were referred for angiography and underwent optical coherence tomography. Among them, 128 also underwent intravascular ultrasound (IVUS)/near infrared spectroscopy. ResultsOf the 383 patients included in the study, 268 were men and 115 were women. Women tended to be older (66 ± 10 years of age vs. 62 ± 11 years of age; p = 0.002) and have more comorbidities including hypertension (97% vs. 90%; p = 0.031), diabetes with insulin use (18% vs. 10%; p = 0.043), obesity (body mass index 30 kg/m2 vs. 28 kg/m2; p = 0.022), and lower estimated glomerular filtration rate (88 ml/min/1.73m2 vs. 98 ml/min/1.73m2; p = 0.001). Optical coherence tomography data demonstrated that there was no sex difference in plaque morphology as characterized by maximum lipid arc, lipid length, lipid volume index, minimum cap thickness, incidence of thin cap fibroatheroma, microvessels, macrophages, and calcification. There was also no difference in maximal lipid core burden index at the 4-mm maximal segment as seen on near infrared spectroscopy. Plaque characteristics by IVUS were similar between men and women except for an increase in plaque burden in men compared to women in the reference segment (44.4 vs. 39.3; p = 0.031). After adjusting for age, body mass index, percutaneous coronary intervention history, and clinical risk factors, sex was not found to be an independent predictor of severe plaque burden by IVUS. ConclusionAmong men and women with stable CAD referred for coronary angiography, there was no difference in plaque characteristics as assessed by multimodality imaging. These findings, which are hypothesis generating, suggest that equally aggressive primary and secondary preventive efforts irrespective of sex must be undertaken.

Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease.

Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased in APP/PS1 mice fed the western diet. This increase in glial responses was associated with increased plaque burden in the hippocampus. Interestingly, given recent studies highlighting the importance of TREM2 in microglia/monocytes in AD susceptibility and progression, B6 and APP/PS1 mice fed the western diet showed significant increases TREM2+ microglia/monocytes. Therefore, an increase in TREM2+ microglia/monocytes may underlie the increased risk from a western diet to age-related neurodegenerative diseases such as Alzheimer’s disease. This study lays the foundation to fully investigate the impact of a western diet on glial responses in aging and Alzheimer’s disease.

Bioresorbable Scaffolds for Atheroregression: Understanding of Transient Scaffolding.

This review focuses on the clinical and biological features of the bioresorbable scaffolds in interventional cardiology highlighting scientific achievements and challenges of the transient scaffolding with Absorb BVS. Special attention is granted to the vascular biology pathways which, involved in the resorption of scaffold, artery remodeling and mechanisms of Glagovian atheroregression setting the stage for subsequent clinical applications. Twenty five years ago Glagov described the phenomenon of limited external elastic membrane enlargement in response to an increase in plaque burden. We believe this threshold becomes the target for development of strategies that reverse atherosclerosis, and particularly transient scaffolding has a potential to be a tool to ultimately conquer atherosclerosis.

Efecto del armazón bioabsorbible liberador de everolimus en la aterosclerosis coronaria

Introduction and objectivesThe Absorb bioresorbable vascular scaffold has been shown to decrease total plaque areas in the treated segment. However, it is unknown whether plaque size is modified in scaffolded segments only or whether the modification extends to other coronary segments. MethodsAbsorb Cohort A is a single-arm, prospective study, with safety and imaging endpoints, in which 30 patients underwent percutaneous coronary intervention with the first generation Absorb bioresorbable vascular scaffold. Noninvasive multislice computed tomography imaging was performed in 18 patients at 18 months and 5 years of follow-up. The present study was an intrapatient comparison of matched segments (normalized by the segment length) of the scaffolded region with nonintervened segments for lumen volume, vessel volume, plaque volume, plaque burden, and percent change in plaque atheroma volume. ResultsAll 18 scaffolded segments could be analyzed. In the nonintervened segments, 1 of 72 segments had a motion artifact and was excluded. Serial comparison showed that the scaffolded segments showed no significant change in the mean plaque burden, total atheroma volume, total lumen volume, or vessel volume between 18 months and 5 years. Conversely, the untreated segments showed a significant increase in plaque burden (2.7 ± 6.5%; P < .01) and normalized plaque volumes (8.0 ± 22.8mm3; P < .01). This resulted in a significant difference in plaque burden between scaffolded and nonintervened segments (P = .03). ConclusionsIn this small series, the Absorb bioresorbable vascular scaffold showed the potential to provide an additional benefit to pharmacological therapy in locally reducing progression of percent plaque burden. These findings need to be confirmed in larger studies.Full English text available from:www.revespcardiol.org/en

Impact of the Everolimus-eluting Bioresorbable Scaffold in Coronary Atherosclerosis

Introduction and objectivesThe Absorb bioresorbable vascular scaffold has been shown to decrease total plaque areas in the treated segment. However, it is unknown whether plaque size is modified in scaffolded segments only or whether the modification extends to other coronary segments. MethodsAbsorb Cohort A is a single-arm, prospective study, with safety and imaging endpoints, in which 30 patients underwent percutaneous coronary intervention with the first generation Absorb bioresorbable vascular scaffold. Noninvasive multislice computed tomography imaging was performed in 18 patients at 18 months and 5 years of follow-up. The present study was an intrapatient comparison of matched segments (normalized by the segment length) of the scaffolded region with nonintervened segments for lumen volume, vessel volume, plaque volume, plaque burden, and percent change in plaque atheroma volume. ResultsAll 18 scaffolded segments could be analyzed. In the nonintervened segments, 1 of 72 segments had a motion artifact and was excluded. Serial comparison showed that the scaffolded segments showed no significant change in the mean plaque burden, total atheroma volume, total lumen volume, or vessel volume between 18 months and 5 years. Conversely, the untreated segments showed a significant increase in plaque burden (2.7 ± 6.5%; P < .01) and normalized plaque volumes (8.0 ± 22.8mm3; P < .01). This resulted in a significant difference in plaque burden between scaffolded and nonintervened segments (P = .03). ConclusionsIn this small series, the Absorb bioresorbable vascular scaffold showed the potential to provide an additional benefit to pharmacological therapy in locally reducing progression of percent plaque burden. These findings need to be confirmed in larger studies.

Cardiac computed tomography imaging in familial hypercholesterolaemia

The purpose of the present review is to summarize the potential clinical applications of computed tomographic angiography (CTA) in familial hypercholesterolemia so far and recent advances of CTA research in other high-risk patients. Long-term, aggressively statin-treated, asymptomatic familial hypercholesterolemia patients may still have dramatic coronary artery disease (CAD). A clear association between the presence and the extent of nonobstructive CAD and all-cause mortality was found in the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry. Notably, baseline statin therapy was associated with a significantly lower mortality for individuals with atherosclerotic plaque on CTA, but not for individuals with normal coronary arteries. CTA imaging has made clear that an increased plaque burden can be present even among asymptomatic, long-term aggressively statin-treated familial hypercholesterolemia patients. In the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry, nonobstructive CAD predicted all-cause mortality and statin treatment improved the life span of persons with nonobstructive CAD. Clinical trials with CTA are required to develop and test identification of CAD and personalized treatment strategies for familial hypercholesterolemia.

Non-invasive Assessment of Coronary Plaque Morphology

The majority of acute coronary syndromes are a result of atherosclerotic plaque rupture and subsequent occlusive luminal thrombus formation. Identification of rupture prone plaques could provide the means of reducing cardiovascular mortality and morbidity. Vulnerable plaques have distinct morphologic features which might serve as potential targets for imaging. Coronary CT angiography (CTA) is a non-invasive imaging modality which allows the visualization of the coronary artery lumen and wall with a sub-millimeter spatial and sub-second temporal resolution. Several coronary CTA plaque features have been linked to higher cardiovascular event rates, such as spotty calcification, low CT attenuation, positive remodeling, napkin-ring sign, large plaque volume, and increased plaque burden. The combined assessment of total plaque burden and single high-risk plaque features might improve cardiovascular risk stratification, and enable the early identification of vulnerable patients. Magnetic resonance angiography (MRA) with or without the use of contrast agents enables imaging of blood vessels; therefore, MRA might be an alternative to coronary CTA. However, the assessment of coronary vessel wall structure using MRA is currently limited due to breathing artifacts, heart motion artifacts, and lower spatial resolution.

Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer's Disease Model.

Alzheimer’s disease (AD) and prion diseases carry a significant inflammatory component. The astrocytic overexpression of CCAAT/enhancer-binding protein delta (C/EBPD) in prion- and AD-affected brain tissue prompted us to study the role of this transcription factor in murine model systems of these diseases. Ablation of C/EBPD had neither in the AD model (APP/PS1double transgenic mice) nor in the prion model (scrapie-infected C57BL/6 mice) an influence on overt clinical symptoms. Moreover, the absence of C/EBPD did not affect the extent of the disease-related gliosis. However, C/EBPD-deficient APP/PS1 double transgenic mice displayed significantly increased amyloid beta (Abeta) plaque burdens while amyloid precursor protein (APP) expression and expression of genes involved in beta amyloid transport and turnover remained unchanged. Gene expression analysis in mixed glia cultures demonstrated a strong dependency of complement component C3 on the presence of C/EBPD. Accordingly, C3 mRNA levels were significantly lower in brain tissue of C/EBPD-deficient mice. Vice versa, C3 expression in U-373 MG cells increased upon transfection with a C/EBPD expression vector. Taken together, our data indicate that a C/EBPD-deficiency leads to increased Abeta plaque burden in AD model mice. Furthermore, as shown in vivo and in vitro, C/EBPD is an important driver of the expression of acute phase response genes like C3 in the amyloid-affected CNS.

The 5XFAD Mouse Model of Alzheimer's Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden.

We present evidence that 5XFAD Alzheimer's disease model mice develop an age-dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer's disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-β levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide-treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque formation.