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BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline. [ABSTRACT FROM AUTHOR]

BackgroundWhereas several interventions can effectively lower lipid levels in people at risk for atherosclerotic cardiovascular disease (ASCVD), cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to cardiovascular event risk. Monocytes and macrophages play central roles in atherosclerosis, but studies have yet to provide a detailed view of macrophage populations involved in increased ASCVD risk.MethodsA novel macrophage foaming analytics tool, AtheroSpectrum, was developed using 2 quantitative indices depicting lipid metabolism and the inflammatory status of macrophages. A machine learning algorithm was developed to analyze gene expression patterns in the peripheral monocyte transcriptome of MESA participants (Multi-Ethnic Study of Atherosclerosis; set 1; n=911). A list of 30 genes was generated and integrated with traditional risk factors to create an ASCVD risk prediction model (30-gene cardiovascular disease risk score [CR-30]), which was subsequently validated in the remaining MESA participants (set 2; n=228); performance of CR-30 was also tested in 2 independent human atherosclerotic tissue transcriptome data sets (GTEx [Genotype-Tissue Expression] and GSE43292).ResultsUsing single-cell transcriptomic profiles (GSE97310, GSE116240, GSE97941, and FR-FCM-Z23S), AtheroSpectrum detected 2 distinct programs in plaque macrophages-homeostatic foaming and inflammatory pathogenic foaming-the latter of which was positively associated with severity of atherosclerosis in multiple studies. A pool of 2209 pathogenic foaming genes was extracted and screened to select a subset of 30 genes correlated with cardiovascular event in MESA set 1. A cardiovascular disease risk score model (CR-30) was then developed by incorporating this gene set with traditional variables sensitive to cardiovascular event in MESA set 1 after cross-validation generalizability analysis. The performance of CR-30 was then tested in MESA set 2 (P=2.60×10-4; area under the receiver operating characteristic curve, 0.742) and 2 independent data sets (GTEx: P=7.32×10-17; area under the receiver operating characteristic curve, 0.664; GSE43292: P=7.04×10-2; area under the receiver operating characteristic curve, 0.633). Model sensitivity tests confirmed the contribution of the 30-gene panel to the prediction model (likelihood ratio test; df=31, P=0.03).ConclusionsOur novel computational program (AtheroSpectrum) identified a specific gene expression profile associated with inflammatory macrophage foam cells. A subset of 30 genes expressed in circulating monocytes jointly contributed to prediction of symptomatic atherosclerotic vascular disease. Incorporating a pathogenic foaming gene set with known risk factors can significantly strengthen the power to predict ASCVD risk. Our programs may facilitate both mechanistic investigations and development of therapeutic and prognostic strategies for ASCVD risk.

BackgroundSmooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.MethodsWe combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease.ResultsGenomic studies coupled with functional assays in cultured human coronary artery SMCs revealed that AHR modulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes," were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout in comparison with wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses.ConclusionsOverall, we conclude that AHR promotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues.

Background: Physical activity and exercise training are associated with a lower risk for coronary events. However, cross-sectional studies in middle-aged and older male athletes revealed increased coronary artery calcification (CAC) and atherosclerotic plaques, which were related to the amount and intensity of lifelong exercise. We examined the longitudinal relationship between exercise training characteristics and coronary atherosclerosis. Methods: Middle-aged and older men from the MARC-1 (Measuring Athlete's Risk of Cardiovascular Events 1) study were invited for follow-up in MARC-2 (Measuring Athlete's Risk of Cardiovascular Events 2) study. The prevalence and severity of CAC and plaques were determined by coronary computed tomography angiography. The volume (metabolic equivalent of task [MET] hours/week) and intensity (moderate [3 to 6 MET hours/week]; vigorous [6 to 9 MET hours/week]; and very vigorous [≥9 MET hours/week]) of exercise training were quantified during follow-up. Linear and logistic regression analyses were performed to determine the association between exercise volume/intensity and markers of coronary atherosclerosis. Results: We included 289 (age, 54 [50 to 60] years [median (Q1 to Q3)]) of the original 318 MARC-1 participants with a follow-up of 6.3±0.5 years (mean±SD). Participants exercised for 41 (25 to 57) MET hours/week during follow-up, of which 0% (0 to 19%) was at moderate intensity, 44% (0 to 84%) was at vigorous intensity, and 34% (0 to 80%) was at very vigorous intensity. Prevalence of CAC and the median CAC score increased from 52% to 71% and 1 (0 to 32) to 31 (0 to 132), respectively. Exercise volume during follow-up was not associated with changes in CAC or plaque. Vigorous intensity exercise (per 10% increase) was associated with a lesser increase in CAC score (β, −0.05 [−0.09 to −0.01]; P =0.02), whereas very vigorous intensity exercise was associated with a greater increase in CAC score (β, 0.05 [0.01 to 0.09] per 10%; P =0.01). Very vigorous exercise was also associated with increased odds of dichotomized plaque progression (adjusted odds ratio [aOR], 1.09 [1.01 to 1.18] per 10%; aOR, 2.04 [0.93 to 4.15] for highest versus lowest very vigorous intensity tertiles, respectively), and specifically with increased calcified plaques (aOR, 1.07 [1.00 to 1.15] per 10%; aOR, 2.09 [1.09 to 4.00] for highest versus lowest tertile, respectively). Conclusions: Exercise intensity but not volume was associated with progression of coronary atherosclerosis during 6-year follow-up. It is intriguing that very vigorous intensity exercise was associated with greater CAC and calcified plaque progression, whereas vigorous intensity exercise was associated with less CAC progression. [ABSTRACT FROM AUTHOR]

BackgroundCD4+ T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules.MethodsWe constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe-/-) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined.ResultsIn human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4+ T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe-/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells on vaccination, which were enriched for interleukin-10-producing Tregs.ConclusionsThese findings show that APOB p18-specific CD4+ T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.

Background: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort., Methods: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors., Results: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD., Conclusions: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline., Competing Interests: None.

BackgroundMatrix metalloproteinases (MMPs) are thought to play a prominent role in atherogenesis and destabilization of plaque. Pericellularly localized membrane-type (MT)-MMPs activate secreted MMPs. We investigated the hypothesis that MT3-MMP is expressed in human atherosclerotic plaques and is regulated by locally produced inflammatory cytokines and oxidized low-density lipoprotein (Ox-LDL).Methods and resultsExpression and cellular localization of MT3-MMP in normal and atherosclerotic human coronary arteries were examined using specific antibodies. Abundant MT3-MMP expression was noted in medial smooth muscle cells (SMCs) of normal arteries. In atherosclerotic arteries, MT3-MMP expression was observed within complex plaques and colocalized with SMCs and macrophages (Mphi). Cultured human monocyte-derived Mphi constitutively expressed MT3-MMP mRNA and proteolytically active protein, as demonstrated by mRNA analyses, immunoblotting, and gelatin zymography, respectively. Ox-LDL, tumor necrosis factor-alpha, or macrophage colony-stimulating factor caused dose- and time-dependent increases in steady-state levels of MT3-MMP mRNA in cultured Mphi. This correlated with a 2- to 4-fold increase in levels of MT3-MMP immunoreactive protein and enzymatic activity in Mphi membranes. Confocal microscopy and flow cytometry confirmed induction and spatial distribution of MT3-MMP protein from intracellular domains to the Mphi plasma membrane by Ox-LDL, tumor necrosis factor-alpha, or macrophage colony-stimulating factor.ConclusionsMT3-MMP is expressed by SMCs and Mphi in human atherosclerotic plaques. Proinflammatory molecules cause a progressive increase in the expression of MT3-MMP in cultured Mphi. Our results suggest a mechanism by which inflammatory molecules could promote Mphi-mediated degradation of extracellular matrix and thereby contribute to plaque destabilization.

Well into the 21st century, we still triage acute myocardial infarction on the basis of the presence or absence of ST-segment elevation, a century-old technology. Meanwhile, we have learned a great deal about the pathophysiology and mechanisms of acute coronary syndromes (ACS) at the clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light on the mechanisms of ACS. This review discusses these advances and their implications for clinical management of the ACS for the future. Plaque rupture has dominated our thinking about ACS pathophysiology for decades. However, current evidence suggests that a sole focus on plaque rupture vastly oversimplifies this complex collection of diseases and obscures other mechanisms that may mandate different management strategies. We propose segmenting coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation. This distinction may have substantial therapeutic implications as direct anti-inflammatory interventions for atherosclerosis emerge. Coronary artery thrombosis caused by plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS resulting from erosion may permit a less invasive approach to management than the current standard of care. We also now recognize ACS that occur without apparent epicardial coronary artery thrombus or stenosis. Such events may arise from spasm, microvascular disease, or other pathways. Emerging management strategies may likewise apply selectively to this category of ACS. We advocate this more mechanistic approach to the categorization of ACS to provide a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner. [ABSTRACT FROM AUTHOR]

Background: Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma.Methods and Results: D374Y-PCSK9 hypercholesterolemic minipigs (n=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately poststent, 19 weeks, and 34 weeks, and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially collected histological sections and coregistered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis, and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ≈3-fold higher downstream of the SMS than both upstream of the SMS and in the control artery (P<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (P<0.002) and multidirectional (P<0.002) shear stress. Thin cap fibroatheroma regions demonstrated significantly lower shear stress that persisted over the duration of the study in comparison with other plaque types (P<0.005).Conclusions: These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of thin cap fibroatheroma. [ABSTRACT FROM AUTHOR]

Background--The association between passive smoking exposure in childhood and adverse cardiovascular health in adulthood is not well understood. Using a 26-year follow-up study, we examined whether childhood exposure to passive smoking was associated with carotid atherosclerotic plaque in young adults. Methods and Results--Participants were from the Cardiovascular Risk in Young Finns Study (n=2448). Information on childhood exposure to parental smoking was collected in 1980 and 1983. Carotid ultrasound data were collected in adulthood in 2001 or 2007. Childhood serum cotinine levels from 1980 were measured from frozen samples in 2014 (n=1578). The proportion of children with nondetectable cotinine levels was highest among households in which neither parent smoked (84%), was decreased in households in which 1 parent smoked (62%), and was lowest among households in which both parents smoked (43%). Regardless of adjustment for potential confounding and mediating variables, the relative risk of developing carotid plaque in adulthood increased among those children with 1 or both parents who smoked (relative risk, 1.7; 95% confidence interval, 1.0-2.8; P=0.04). Although children whose parents exercised good "smoking hygiene" (smoking parents whose children had nondetectable cotinine levels) had increased risk of carotid plaque compared with children with nonsmoking parents (relative risk, 1.6; 95% confidence interval, 0.6-4.0; P=0.34), children of smoking parents with poor smoking hygiene (smoking parents whose children had detectable serum cotinine levels) had substantially increased risk of plaque as adults (relative risk, 4.0; 95% confidence interval, 1.7-9.8; P=0.002). Conclusions--Children of parents who smoke have increased risk of developing carotid atherosclerotic plaque in adulthood. However, parents who exercise good smoking hygiene can lessen their child's risk of developing plaque. [ABSTRACT FROM AUTHOR]

Background--Time-dependent trends in the incidence of cardiovascular disease have been reported in high-income countries. Because atherosclerosis underlies the majority of cardiovascular diseases, we investigated temporal changes in the composition of atherosclerotic plaques removed from patients undergoing carotid endarterectomy. Methods and Resuks--The Athero-Express study is an ongoing, longitudinal, vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy in the province of Utrecht from 2002 to 2011. Histopathologic features of plaques of 1583 patients were analyzed in intervals of 2 years. The analysis included quantification of collagen, calcifications, lipid cores, plaque thrombosis, macrophages, smooth muscle cells, and microvessels. Large atheroma, plaque thrombosis, macrophages, and calcifications were less frequently observed over time, with adjusted odds ratios of 0.72 (95% confidence interval, 0.650-0.789), 0.62 (95% confidence interval, 0.569-0.679), 0.87 (95% confidence interval, 0.800-0.940), and 0.75 (95% confidence interval, 0.692-0.816) per 2-year increase in time, respectively. These changes in plaque characteristics were consistently observed in patient subgroups presenting with stroke, transient ischemic attack, ocular symptoms, and asymptomatic patients. Concomitantly, risk factor management and secondary prevention strategies among vascular patients scheduled for carotid endarterectomy significantly improved over the past decade. Conclusions--In conclusion, over the past decade, atherosclerotic plaques harvested during carotid endarterectomy show a time-dependent change in plaque composition characterized by a decrease in features currently believed to be causal for plaque instability. This appears to go hand in hand with improvements in risk factor management. [ABSTRACT FROM AUTHOR]

Background--Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture. Methods and Results--We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2+/+Ly-6Chigh inflammatory macrophages, but not CCR2-/- leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-I), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G-CD11b+ monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture. Conclusions--The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model. [ABSTRACT FROM AUTHOR]

Background-Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results-A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, -16.4 to -11.3) and 12.3% (95% confidence interval, -14.9 to -9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, -0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (-11.4%) than in the atorvastatin group (-0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions-Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. [ABSTRACT FROM AUTHOR]

The article presents author's comment on the in vivo analysis of the risk profile related to the individual coronary plaques. It mentions that local endothelial shear stress (ESS) is responsible for the formation and progression of coronary atherosclerotic plaque. It mentions that analysis of the radiofrequency patterns using intravascular ultrasound (IVUS) helps in estimating plaque composition.

The article focuses on a study published in this issue that links RBP4 to macrophage foam cell formation, experimental atherosclerosis, and human cardiovascular disease risk. It is mentioned that a signaling pathway in murine macrophages and macrophage cell lines is triggered by RBP4 that involved phosphorylation and activation of the tyrosine kinase c-Src.

Introduction: Subcutaneous lipoatrophy and central lipohypertrophy are common among HIV-infected (HIV+) persons and may contribute to co-morbid conditions, such as cardiovascular disease (CVD). Hypothesis: We hypothesized that adipose tissue volumes are associated with progression of coronary artery plaque and that these associations differ by HIV serostatus. Methods: We studied 363 men (208 HIV+, 155 HIV-) in the Multicenter AIDS Cohort Study (MACS) who completed both contrast and non-contrast cardiac CT scanning at baseline (2010-13) and follow-up (median 4.6 yrs), and had plaque present at baseline. Regional body fat area at baseline (abdominal visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), thigh SAT (tSAT) was categorized into tertiles for analyses. We measured coronary artery plaque volume from baseline and follow-up coronary CTA and examined relationships between baseline body fat area tertiles with coronary artery plaque progression tertiles by multinomial logistic regression, stratified by HIV serostatus and adjusting for demographic and CVD risk factors. Results: Median age was 53 years, 30% were African American, and median body mass index 26 kg/m2. aSAT area was inversely associated with plaque progression (adjusted odds ratio [aOR]=0.38 (0.18-0.79) for the second tertile compared to first; aOR=0.40 (0.20-0.82) for third tertile compared to first). Moreover, the protective association of the second SAT tertile was significantly stronger among HIV+ than HIV- men (aOR=0.19 (0.07-0.56) for HIV+; aOR=0.71 (0.19- 2.66) for HIV-, interaction p=0.05). There were no significant associations between VAT or tSAT area and progression of coronary plaque. Conclusions: Lower aSAT was associated with greater progression of coronary plaque, particularly among HIV+ persons. These results are consistent with hypotheses suggesting that lipoatrophy contributes to CVD risk in this population. [ABSTRACT FROM AUTHOR]

Introduction: Aerobic exercise capacity measured in metabolic equivalents of task (METs) and amount of exercise are inversely related with cardiovascular (CV) morbidity and mortality and all-cause mortality in men and women. However, recent reports suggest that higher exercise volume may accelerate coronary plaque formation. In a study in athletes using self-reported exercise data converted to METs, athletes in the > 2000 Met-min/week group had a significantly higher prevalence of noncalcified plaque and coronary artery calcium (CAC), a measure of subclinical CV disease. In the CARDIA study, CAC was 1.86-fold higher in white males achieving ≥450 min of exercise/week (3x the recommended guideline of 150 min/week) over 25 years. Higher CAC scores predict higher CV events and mortality. Hypothesis: Higher exercise capacity (METs) is inversely associated with coronary plaque volume at moderate exercise volume. Methods: A total of 270 subjects with stable CAD underwent maximal exercise treadmill testing with calculation of METs. Noncalcified coronary plaque volume and CAC were measured with CT scanning. METs were divided into three groups and the association with plaque volume examined after multivariate adjustment. Results: Higher METs (≥ 10.6) with an average of 150 min/week of exercise were associated with a significantly larger volume of fibrous and total plaque but a lower CAC score after multivariate adjustment. After adjustment, no difference was observed in volume of fatty plaque, the plaque type more likely to rupture and cause an acute coronary syndrome. Conclusion: Higher exercise capacity in CAD subjects was associated with significantly more fibrous and total plaque but a lower CAC score after adjustment in subjects averaging 150 min exercise/week, the current guideline. Since higher CAC predicts CV events, our findings support a benefit of the current physical activity guideline of 150 min/week as opposed to higher amounts of exercise. [ABSTRACT FROM AUTHOR]

Introduction: Racial differences in the prevalence of coronary artery calcification (CAC) are well documented. African Americans (AA) tend to have a lower prevalence of CAC despite greater coronary risk factors and according to some reports higher cardiovascular disease (CVD) morbidity and mortality Hypothesis: We hypothesize despite a lower prevalence of CAC; AA would have similar or higher burden of non-calcified plaque (NCP). Methods: We retrospectively evaluated data from 4280 (3886 whites and 482 AA) consecutive patients, who underwent non-contrast and contrast cardiac computed tomography at our center. We used the 17-segment American Heart Association classification for assessment of coronary arteries. We quantified the amount of plaque in each segment as mild (score of 1), moderate (score of 2), or severe (score of 3) using a previously described method. We calculated total plaque score (TPS) by summation of the amount of plaque of each coronary segment. The non-calcified plaque score (NCPS) and mixed plaque score (MPS) were similarly calculated by summing the plaque scores in each segment separately. The segment involvement score (SIS), ranging from 0 to 17, was calculated as the total number of segments with any plaque; the segment stenosis score (SSS), was obtained by grading the stenosis severity of each segment with plaque, as was previously described in literature. Results: Prevalence of CAC>0 was 77% in whites versus 61% in AA (median Interquartile range]:190[13-780] versus 38[0-275];P<0.001). After adjustment for age, diabetes, BMI, family history of CAD, chest pain, hyperlipidemia, HTN and smoking, there was no significant difference in NCPS (β(Se) = 0.1 (0.4), P=0.731) and MPS (β(Se) = -0.4 (0.8), p=0.590) in AA compared with whites. TPS (β(Se) = -1.6 (0.4), P<0.001), SSS (B(Se)=-1.5(0.5), p<0.001 and Segment involvement score (B(Se)= 0.9 (0.2), P<0.001) were significantly lower in AA compared with whites. Conclusion: Despite the significantly lower prevalence of CAC in AA, the burden of NCP and mixed plaque were similar in AA compared with whites. Further studies would be needed to elucidate whether the higher burden of NCP burden despite a lower prevalence of CAC is responsible for higher CVD mortality in AA. [ABSTRACT FROM AUTHOR]

Introduction: It has been demonstrated using statistical methods that smaller lipoprotein (a) [Lp(a)] particles are more strongly associated with atherosclerosis. However, the exact relationship between Lp(a) size (defined by the number of kringle IV repeats) and atherogenicity has not been elucidated. Hypothesis: We hypothesized that smaller, but not larger, Lp(a) particles are atherogenic, with a clear size cut-point. Methods: We determined Lp(a) levels and precise isoform size (defined by number of kringle IV repeats) in 340 subjects in the GLOBAL clinical study (NCT01738828). Atherosclerosis was quantitatively phenotyped using cardiovascular computed tomography angiography, analyzed in central core laboratory. We generated cumulative incidence curves (CIC) to assess relationship between isoform size, concentrations and atherosclerosis. Once we determined cut-point for small vs. large Lp(a), we compared levels by Mann-Whitney test; p<0.05 was significant. Results: Mean age was 56.2±0.72; 49% were male. Lp(a)-mass, particle number and Lp(a)-cholesterol were significantly higher in those with atherosclerosis (Table). In 12 patients who had single isoform only, there was sharp stepdown in atherogenicity with >24 kringle IV repeats (Figure; A); median isoform size was 26 vs. 16 in Controls vs. Atherosclerosis (p<0.05) (Figure; B). Small Lp(a) (24 kringle IV repeats or less) levels were significantly higher in Atherosclerosis; large Lp(a) levels were not different (Figure; D). Increasing levels of small, but not large, Lp(a) particles was associated with atherosclerosis (Figure; E, F). Conclusions: We demonstrated for the first time that 24 kringle IV repeats represent a sharp demarcation between small/atherogenic and large, non-atherogenic Lp(a) particles in humans. [ABSTRACT FROM AUTHOR]

Introduction: Endothelial function evaluated by flow-mediated dilation (FMD) is associated with the incidence of coronary artery disease (CAD). However, the association between FMD and severity of CAD remains to be elucidated. Hypothesis: Lower FMD is associated with severe CAD. Methods: A total of 256 consecutive patients who underwent percutaneous coronary intervention (PCI) for stable angina were enrolled. FMD was evaluated in the brachial artery before PCI. Severity of CAD was evaluated by angiogram and optical coherence tomography imaging of culprit lesion and compared between the lower FMD group (<2.0; n=82) and the higher FMD group (≥2.0; n=163). Results: The prevalence of left main trunk (LMT) disease was significantly higher in the lower FMD groupthan the higher FMD group(Figure 1) although the prevalence of multivessel disease was comparable between the groups (66 vs. 72%, P=0.34). The lower FMD was independently associated with higher prevalence of LMT disease (odds ratio: 3.89, 95% confidence interval: 1.12-15.5, P=0.03). The minimal lumen area (MLA) of culprit lesion was significantly smaller in the lower FMD group than the higher FMD group (Figure 1).The general linear model with multiple variables revealed that the MLA was significantly smaller in the lower FMD group than in the higher FMD group (Figure 2). The prevalence of thin-cap fibroatheroma (12 vs. 13%, P=1.00), macrophage (31 vs. 37%, P=0.48), and microchannel (27 vs. 24%, P=0.84) was comparable between the two groups. Conclusions: Patients with lower FMD had higher prevalence of LMT disease and smaller MLA in culprit lesion. FMD may be a useful non-invasive indicator to assess the severity of CAD. [ABSTRACT FROM AUTHOR]

Introduction: Studies have shown that South Asians (SA) (individuals from India, Pakistan, Bangladesh, Nepal, and Sri Lanka) living in the United States (U.S.) have a high rate of Cardiovascular Disease (CVD). Traditional risk factors have not adequately explained this. We aimed to investigate if differences in coronary plaque prevalence and composition could explain the higher rates of CVD seen in SA. Methods: We identified 4,135 Caucasian or SA patients clinically referred to undergo Coronary Artery Calcium (CAC) scoring and Coronary Computed Tomography Angiography (CCTA) at our center. 249 self-identified themselves as SA, and 3,886 as Caucasians. 188 of the SA and 2,755 of the Caucasians were male. The average age among SA was 60.4 + 12.5 years, and Caucasians was 63 + 11.6 years (p<0.0001). The average Body Mass Index (BMI) was 26.5 + 3.9 among South Asians & 27.8 + 5.5 among Caucasians (p<0.0001). CAC was scored using Agatston method. Plaque Severity Score (PSS) (minimal-1; mild-2; moderate-3; severe-4) for non-calcified and mixed plaques were calculated separately for the 17-segment American Heart Association model. Total Plaque Severity Scores (TPS) were obtained by adding the corresponding PSS for these two types of plaque. Multivariate regression analysis was used to analyze differences in calcified, non-calcified & mixed plaque burden between the groups. Results: After multivariable analysis, when compared to Caucasians, South Asians had significantly higher mixed plaque (ß 4.9, SE 1.0, CI 2.9- 6.9, p <0.001). No statistically significant difference was noted in non-calcified plaque and CAC burden (Table 1). There was no difference in prevalence of disease between the races either. Conclusions: Our results add to the concept of ethnic differences in plaque composition, which accounts for higher subclinical atherosclerosis in South Asians and hence, higher rates of CVD. Further studies to investigate plaque progression, vulnerability characteristics and their effect on prognosis among ethnic groups are warranted. [ABSTRACT FROM AUTHOR]

Background: Most acute coronary syndrome (ACS) patients are caused by rupture of preexisting lipid core plaque (LCP). Furthermore, such LCP may be prone to distal embolization which is associated with poor prognosis after percutaneous coronary intervention (PCI). Recently, near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) has emerged as a novel imaging tool for the prediction of LCP. We aimed to assess the comparison of NIRS-IVUS derived LCP composition and reduction during PCI between patients with ACS and stable angina pectoris (sAP). Methods: We studied 85 patients with ACS (n= 25) and sAP (n= 60) undergoing culprit vessel NIRS-IVUS before and after PCI procedure. The ACS group was subdivided into patients with as ST elevation myocardial infarction (STEMI group; n= 10) or unstable AP / non-ST elevation myocardial infarction group (NSTEMI group; n= 15). The parameters measured by NIRS-IVUS at the culprit lesion were compared among the groups. Results: The baseline maximal lipid core burden index (LCBI) score for each of the 4-mm longitudinal segments in the culprit lesion (maxLCBI4mm) was 640.3 ± 184.1, 579.3 ± 225.9, and 360.0 ± 237.1 in STEMI, NSTEMI, and sAP groups (p < 0.001). Similarly, post-procedural maxLCBI4mm was significantly difference among the groups (233.4 ± 183.9, 284.1 ± 142.5, and 128.7 ± 155.3; p = 0.002, respectively). Notably, STEMI group had significantly greater delta-LCBI (defined as maxLCBI4mm at baseline - maxLCBI4mm after PCI) compared with NSTEMI and sAP groups (406.9 ± 231.0 vs. 295.3 ± 201.9 and 231.3 ± 199.5; p = 0.038, respectively), and no reflow/ slow flow phenomenon during PCI was more frequent in STEMI patients (40.0% vs. 13.3% and 1.7%; p < 0.001, respectively). Conclusions: Culprit lesions with STEMI, NSTEMI and sAP display different plaque characteristics assessed by NIRS-IVUS and difference in peri-procedural risk of complications. [ABSTRACT FROM AUTHOR]

Introduction: Emerging evidence suggests that Matrix Metalloprotease-1 (MMP-1) is involved in the progression of atherosclerosis in humans. MMP1 has been recently documented to activate protease-activated Receptor-1 (PAR1) on endothelium and platelets which contributes to arterial thrombosis and endothelial inflammation. However, the mouse homolog of human MMP1, namely MMP1a has not yet been definitively shown to contribute to progression of atherosclerosis. Hypothesis: Here, we test the hypothesis that genetic deficiency of Mmp1a will affect atherosclerotic plaque development and vessel inflammation in ApoE-/- mouse models. Methods and Results: ApoE-/-/Mmp1a-/- and ApoE/Mmp1a+/+ mice were maintained for 12 weeks on the Western Diet. ApoE-/- mice genetically deficient in Mmp1a had significantly less plaque area in the aortic arch and abdominal aorta as compared to ApoE-/-/Mmp1a+/+ mice. FACs analysis of inflammatory cells isolated from the aortic arch plaques of the Mmp1a -deficient mice revealed significant suppressive effects on levels of macrophages and T cells. Circulating MMP1, but not MMP13, was found to correlate with total coronary artery burden in patients undergoing percutaneous coronary interventions from the recently completed TRIP-PCI study. Conclusion: These data suggest that genetic deficiency of Mmp1a results in decreased atherosclerotic burden and inflammatory infiltrates in the aorta of ApoE-/- mice and that human MMP1 may likewise be involved in the development of human coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: HIV-infected (HIV+) individuals are at increased risk of cardiovascular disease (CVD). CVD risk scores are commonly used to identify patients at high risk for optimal long-term prevention strategies. We evaluated the association of ACC/AHA pooled cohort equation (PCE) risk categories and coronary artery plaque volume progression by HIV serostatus in the Multicenter AIDS Cohort Study (MACS). We also evaluated whether Data collection on adverse events of anti-HIV drugs (D:A:D) risk categories more precisely identified plaque progression in HIV+ men. Methods: We studied men with and without HIV infection enrolled in the MACS CVD study. Cardiac computed tomography angiography was performed to assess coronary artery plaque volume at baseline and follow-up (median 4.6 yrs). Plaque progression was stratified into tertiles. We examined the association between baseline CVD risk score categories among men with a plaque at baseline with coronary artery plaque volume progression by multinomial logistic regression, stratified by HIV serostatus and adjusted for HCV, scanning site, and statin use. Results: We studied 363 men (154 HIV-, 209 HIV+) with median age 53 yrs for HIV- and 49 yrs for HIV+ men. ACC/AHA categorized 97 (63%) HIV- men and 106 (51%) HIV+ men in the high-risk PCE category. The odds of total plaque volume (TPV) and non-calcified plaque volume (NCPV) progression in the highest relative to lowest tertile was 4.8 (95% CI 1.9- 11.8, p<0.001) and 5.2 (2.0-13.4, p<0.001) times greater, respectively, among HIV- men in the PCE high-risk vs. moderate/low-risk category. Among HIV+ men, no association was found for TPV and NCPV progression by PCE categories in high risk vs. moderate/low risk, OR 1.0 (0.5, 2.1) and OR 1.5 (0.7, 3.1) respectively (p-values for interaction by HIV=0.02 and 0.08). Similarly, the D:A:D high-risk category was not associated with the highest tertile of plaque progression among HIV+ men (OR 1.1 (0.5,2.4). Conclusions: PCE categories predict plaque progression better among HIV- men compared to HIV+ men. Improved CVD risk scores are needed to identify high-risk HIV+ men for more aggressive CVD risk prevention strategies. [ABSTRACT FROM AUTHOR]

Introduction: The SMARTool clinical study (Horizon 2020) aims to develop an integrated artery- and patient-specific comprehensive predictive model of plaque progression using serial coronary CT angiography (CTA). Although semi-automated techniques for quantitative assessment of coronary plaques are highly reproducible, only few studies have investigated the use of these techniques to assess plaque progression. Hypothesis: We assessed the hypothesis that baseline clinical parameters are associated with plaque progression using serial coronary CTA. Methods: Patients were prospectively included to undergo serial coronary CTA. Quantitative assessment of all coronary plaques was performed using a dedicated software package (QAngio CT RE, Medis, Leiden, The Netherlands). Plaque progression was defined by an increase in plaque volume above the median. A binomial logistic regression was performed, including the baseline clinical parameters, low-density lipoprotein (LDL) and statin use at follow-up as independent variables and the annual change in plaque volume (also classified according to the tissue components) as dependent variable. Results: In total, 590 coronary segments from 212 patients were quantitatively assessed with a mean interscan period of 6.2 ± 1.4 years. The median annual change in overall plaque volume was 2.33 (interquartile range (IQR) 0.36-6.46) mm3. In multivariable analysis, only hypertension was independently associated with an annual change in overall plaque volume (odds ratio (OR) 1.64, 95% confidence interval (CI) 1.17-2.31; P = 0.004). Although statin use at follow-up was not associated with an annual change in overall plaque volume (OR 1.02, 95% CI 0.71-1.46; P = 0.93), an independent association with dense calcium volume change was found (OR 1.88, 95% CI 1.22-2.89; P = 0.004). Conclusions: Hypertension was the only clinical parameter associated with overall plaque progression, assessed by quantitative CTA analysis. Although statin use did not show any effect on overall plaque progression, its use was associated with a significant increase in dense calcium volume, thereby potentially reducing coronary plaque vulnerability. [ABSTRACT FROM AUTHOR]

Introduction: The capacity of high-density lipoprotein (HDL) to promote cholesterol efflux is associated with coronary artery disease (CAD) risk. While apolipoprotein C-III (apoC-III)-enriched HDL has been reported in CAD patients, little is known about its impact on plaque burden and cholesterol efflux capacity (CEC). Hypothesis: We aimed to examine the association of apoC-III distribution with HDL-mediated CEC and atheroma burden. Methods: 73 CAD patients who underwent intravascular ultrasound imaging were investigated. We measured apoC-III levels in serum (apoC-IIIserum) and apolipoprotein B-depleted serum (apoC-IIIHDL). ApoC-III distribution between HDL and serum (apoC-IIIHDL/serum ratio) was determined, and patients with the ratio >0.5 were defined as HDL dominant. The relationship between percent atheroma volume (PAV) and HDL-mediated CEC mediated by ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), and scavenger receptor B type I (SR-BI) according to levels of apoC-IIIHDL/serum ratio were examined. Results: 63% of the patients showed apoC-III dominant in HDL. A strong positive correlation was observed between apoC-IIIserum and apoC-IIIHDL levels (r=0.82, P<0.001). Patients with apoC-IIIHDL/serum ratio >0.5 demonstrated lower levels of apoC-IIIserum (125.6 vs. 190.7 μg/ml, P<0.001) whereas they showed comparable apoC-IIIHDL levels (80.8 vs. 80.4 μg/ml, P=0.51). ApoC-IIIHDL/serum ratio was correlated inversely with ABCA1-mediated CEC (r=-0.30, P=0.001) and positively with PAV (r=0.39, P<0.001), but not with ABCG1- (P=0.20) and SR-BI-mediated CEC (P=0.31). Multivariate linear regression analyses demonstrated that apolipoprotein A-I (P=0.003) and beta-blocker use (P=0.007) were positively associated with ABCA1-mediated CEC, while apoC-IIIHDL/serum ratio just failed to meet statistical significance (P=0.096). On the other hand, apoC-IIIHDL/serum ratio (P=0.038) and male gender (P<0.001) were positively associated with PAV. Conclusions: The metric of apoC-IIIHDL/serum ratio provides an alternative approach to characterization of apoC-III distribution. The HDL dominant distribution of apoC-III has important implications for both HDL functionality and burden of atherosclerotic plaque. [ABSTRACT FROM AUTHOR]

Introduction: Achilles tendon xanthomas are a marker of high risk for coronary artery disease (CAD) among patients with heterozygous familial hypercholesterolemia. However, the association of Achilles tendon thickening (ATT) with disease severity and plaque vulnerability among CAD patients is unclear. In the present study, we aimed to clarify whether the presence of ATT was associated with disease severity and plaque vulnerability in patients with CAD. Methods: A total of 241 consecutive patients who underwent percutaneous coronary intervention and ATT assessment were analyzed. ATT were defined as the Achilles tendon thickness of 9 mm or more on radiograph. The severity of CAD and plaque vulnerability were assessed by the findings on angiogram and optical coherence tomography, respectively. Results: ATT was found in 44 patients (18.2%). The frequency of multivessel disease (79.6 vs. 58.4%, p=0.009) and left main disease (13.6 vs. 3.1%, p=0.004) was significantly higher in patients with ATT (ATT group) than in patients without ATT (no ATT group). Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (Table). The ATT group had a higher prevalence of microchannel (50.0 vs. 24.7%, p=0.018) and macrophage accumulation (58.3 vs. 33.3%, p=0.028) in culprit plaque than the no ATT group (Figure). Conclusions: The presence of ATT was associated with multivessel coronary disease and left main disease in patients with CAD. The presence of ATT was also associated with vulnerable features, including microchannel and macrophage accumulation in culprit plaques. [ABSTRACT FROM AUTHOR]

Introduction: It remains unclear whether atherosclerotic plaque structure or composition is related to translesional biomechanical stresses in coronary artery disease. Hypothesis: We assessed the hypothesis that there would be a relationship between translesional pressure parameters and plaque characteristics with lipid core. Methods: Fractional flow reserve (FFR), delta (Δ) FFR, and Δpressure were obtained by pressure wire during adenosine induced maximum hyperemic status. Lipid core burden index (LCBI) and maximum LCBI within 2mm (maxLCBI2mm) and tomographic anatomy were evaluated by near-infrared spectroscopy with intravascular ultrasound imaging catheter. Results: A total of 57 patients were enrolled. Among the 57 eligible vessels with 66 target lesions, continuous pullback pressure measurements - necessary to obtain ΔFFR and Δpressure - were available in 45 lesions (36 patients). The minimal lumen area was positively related with FFR while it tended to be inversely related with ΔFFR. Plaque burden and lesion length were inversely related with FFR and positively related with ΔFFR. There was a negative correlation between FFR and maxLCBI2mm (r=-0.264, p=0.049) and a positive correlation between ΔFFR and maxLCBI2mm (r=0.299, p=0.049). ΔFFR of lesions with maxLCBI2mm ≥500 was higher than maxLCBI2mm <500 (0.159±0.085 vs. 0.104±0.075, p=0.036). By receiver-operating characteristic curve analysis, ΔFFR ≥ 0.1 was a predictor for maxLCBI2mm ≥500 (area under curve = 0.707, p=0.027); and lesions with ΔFFR ≥0.1 had higher proportion with maxLCBI2mm ≥500 versus those with ΔFFR <0.1 (odds ratio=5.077, p=0.023). On multivariate analysis, ΔFFR was the only predictor of maxLCBI2mm (β =0.347, p=0.032). Conclusions: In conclusion, ΔFFR across a coronary artery lesion is related to lipid core burden assessed using near-infrared spectroscopy with intravascular ultrasound and might be a meaningful predictor of high-risk plaque which is with high lipid content. [ABSTRACT FROM AUTHOR]

Introduction: Identification of high cardiovascular risk subjects is challenging in a wide variety of baseline risks. Carotid plaques predict increased risk in older adults, but there is no data for femoral plaques and younger individuals. Femoral atherosclerosis occurs earlier in life, and we demonstrated that femoral plaque by ultrasound predicts coronary calcium, as surrogate disease marker, beyond cardiovascular risk factors (CVRF). Hypothesis: Femoral plaques will be associated and will be able to discriminate subjects with future cardiovascular events in the 40-60 years age-range. Methods: Carotid and femoral ultrasound studies from participants from the AWHS, without cardiovascular disease (N=1730), were analyzed for predicting major adverse cardiovascular events (MACE) after a median follow-up of 3.5 years. MACE included myocardial infarction, unstable angina with hospitalization, stroke, coronary revascularization, and cardiovascular death. Poisson models were used to calculate rate ratios (RR) and to provide a continuous risk function for area under the curve (AUC) analyses. A base model included age, sex, smoking, diabetes, hypercholesterolemia, and hypertension, compared to models adding carotid and femoral plaques. Results: Age range was 42-60 years (mean 51) and 95% were men. During follow-up, 18 MACE occurred, incidence rate 303 per 100 000 person-years. AUCs were 0.496 (95% CI: 0.363, 0.629), 0.545 (0.411, 0.679), 0.624 (0.513, 0.735), and 0.646 (0.534, 0.758) for the CVRF model, CVRF + carotid, CVRF + femoral, and CVRF + carotid + femoral models respectively. The two later models (their AUCs were not different), discriminated events (AUC > 0.5) and significantly better than the models based on risk factors alone or with carotid plaques (all p < 0.01). Adjusted MACE RR for femoral plaques was 8.29 (p = 0.04). Conclusions: Femoral plaque was able to discriminate participants at risk of future MACE better than risk factors and carotid plaque. [ABSTRACT FROM AUTHOR]

Introduction: The basis of discordance between invasive coronary angiographic (ICA) anatomical stenosis and physiological fractional flow reserve (FFR) remains poorly understood. Hypothesis: We assumed the plaque characteristics have more powerful influence on FFR rather than lesion territory myocardial mass in nonobstructive left anterior descending artery (LAD) lesions. Methods: Coronary CT angiography (cCTA), ICA and FFR underwent within 4 weeks in 104 patients. cCTA-verified plaque characteristics (Area remodeling index (ARI), low attenuation plaque (LAP≤30HU), %Plaque Area (%PA), Vessel Area (VA) at minimum lumen area (MLA)) and lesion territory myocardial absolute mass (Mass) and %mass of LV mass (%Mass) between 51 consecutive ICA-FFR mismatches (ICA-quantitative coronary angiography (QCA) <50%, FFR ≤0.8) and 53 ICA-FFR matches (ICA-QCA <50%, FFR >0.8) were compared. Results and Conclusions: cCTA-verified VA (20.5±0.06 vs. 16.7±0.05 mm2, P=0.0008), ARI (1.38±0.24 vs. 1.05±0.11, P<0.0001), %PA (64.5±12.9 vs. 57.0±8.4 %, P=0.0006), the prevalence of LAP (81.3 vs. 18.1 %, P<0.0001) at MLA, Mass (46.2±18.5 vs. 37.1±14.3 cm3, P=0.0056) and %Mass (35.2±10.4 vs. 30.2±9.4 %, P=0.012) were significantly higher in the ICA-FFR mismatch than the match group. ARI (Odds Ratio 56.6, 95%CI: 9.56-335.75, P<0.0001), %plaque area (OR 56.6, 95%CI: 9.56-335.75, P<0.0001) and presence of LAP (OR 5.84, 95%CI: 1.39-24.60, P=0.016) were independent significant predictors of ICA-FFR mismatch in multivariable logistic regression analysis. Mass (OR 8.91, 95%CI: 0.876-90.66, P=0.065) and %Mass (OR 4.25, 95%CI: 0.981-18.390, P=0.0531) are not significant independent predictors. By receiver operation curve analysis, the areas under the curve for ARI and %PA were 0.921 and 0.682 respectively for the diagnosis of mismatch (best cut off values 1.13 and 65.6% respectively. The sensitivity and specificity ARI >1.13 for predicting ICA-FFR mismatch were 90.2% and 79.2%, respectively. In conclusion, CTA-derived ARI, %PA and LAP have more powerful influence on FFR rather than Mass or %Mass in the absence of anatomically significant stenosis in LAD. [ABSTRACT FROM AUTHOR]

Introduction: Arterial wall thickness (WT) and plaque burden, indicators of arteriosclerosis and atherosclerosis, respectively, are associated with cardiovascular disease (CVD). We hypothesized that aortic wall area (AWA) and plaque volume measured by cardiovascular magnetic resonance (CMR) predict incident adverse CVD events in a community sample. Methods: Framingham Heart Study Offspring participants without prevalent CVD (n=1532, 64±9 years, 44% men) underwent 1.5T CMR (2002-2006) with ECG-gated axial 2D T2 weighted black-blood acquisitions (5 mm slice thickness) from the aortic arch to the aortoiliac bifurcation. The radial WT of the descending thoracic aorta (pulmonary artery bifurcation level) was measured at 12, 3, 6, and 9 o'clock orientations. AWA at this level was calculated as: [π x (average WT + average lumen radius)2] - [π x (average lumen radius)2]. Aortic plaque protruding ≥1 mm into the lumen beyond the vessel wall was outlined to determine plaque area in 36 axial slices from the aortic arch to the iliac bifurcation. Total plaque volume was calculated by multiplying plaque area x (slice thickness + gap) and summing over all slices. Participants were followed for incident CVD, (myocardial infarction, angina pectoris, ischemic stroke, transient ischemic attack, heart failure, claudication, CVD death). Results: Over a median 10.4 years follow-up, 167 incident CVD events occurred (see Table for cohort characteristics + events). In multivariable-adjusted Cox proportional hazards models, AWA (hazard ratio [HR]: 1.25 per SD Unit; 95% CI 1.07 – 1.45) but not total plaque volume (HR: 1.14 per SD Unit; 95% CI 0.97 – 1.32) significantly predicted incident CVD. Conclusions: In a middle-aged community-dwelling cohort free of CVD, AWA but not plaque volume, predicted incident CVD beyond risk factors. Our findings suggest that arteriosclerosis may play a greater role in CVD morbidity and mortality than atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Evidence suggests that inflammatory mediators are important in the pathogenesis of atherosclerosis and their inhibition not only reduces cardiovascular (CV) events, but also may favorably modify plaque morphology. Psoriasis (PSO) is a chronic inflammatory disease associated with early myocardial infarction and it was recently shown that it is associated with non-calcified plaque. We hypothesized that anti-inflammatory biologic therapy for psoriasis will favorably modify coronary plaque morphology compared to non-biologic treated patients. Methods: Consecutive patients (n=107) stratified by biologic therapy underwent coronary computed tomography angiography (320 detector row, Toshiba) at baseline and one-year. Coronary plaque indices and attenuation-based plaque sub-components were quantified using dedicated software (QAngio, Medis). Reader was blinded to both time of scan and treatment. Results: PSO patients were middle aged and at low CV risk by traditional risk scores with no significant differences in demographics, laboratory values, or coronary indices between the two groups. At one-year (Table 1) , there was a reduction in non-calcified plaque burden in the biologic treated group only (1.12 ± 0.46 mm2 vs. 1.04 ± 0.40 mm2; p<0.001). While there was a significant reduction in necrotic core (NC) in the biologic group, there was progression of NC in the non-biologic group (ΔNC, Biologic: -0.11 mm2 vs. Non-biologic: 0.005 mm2; p=0.02). Additionally, there was an increase in fibrous burden in both groups; however, the difference between change in fibrous burden (FB) in the biologic group was greater (ΔFB, Biologic: 0.02 mm2 vs. Non-biologic: 0.008 mm2; p=0.02). After adjustment for traditional CV risk factors including age, gender, body mass index, and statin use, biologic therapy was associated with reduction in NC (β=0.13, p=0.02). Conclusions: Biologic therapy had significant effects on coronary plaque morphology, with a reduction in overall non-calcified plaque burden driven by increases in fibrous burden and decrease in necrotic core. These findings suggest that biologic therapies may reduce both coronary plaque burden and high-risk features. Larger, randomized studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Introduction: Obstructive sleep apnea (OSA) is a common disorder that is associated with an increased risk of cardiovascular disease. Optical frequency domain imaging (OFDI) is a useful modality for visualizing in-depth microstructure of coronary atherosclerotic plaque due to its high resolution. Hypothesis: In this study, we hypothesized that obstructive sleep apnea might be associated with increased coronary plaque instability. We examined the association of OSA with plaque instability using OFDI in patients undergoing percutaneous coronary intervention (PCI). Methods: We retrospectively analyzed OFDI data for coronary artery plaques from 13 patients with OSA and 27 non-OSA patients treated between October 2015 and December 2017. Plaque morphology was evaluated for 60 lesions, including 19 from patients with OSA and 41 from non-OSA patients. Results: Compared with the non-OSA group, patients with OSA had significantly higher prevalences of thinned cap fibroatheroma (TCFA) (P=0.034) and microchannels (P=0.025); a significantly higher mean lipid index (1392±977 vs. 848±672, P=0.037), macrophage grade (7.5±6.0 vs. 3.7±3.6, P=0.015), and maximum number of microchannels (1.5±1.0 vs. 0.7±0.7, P=0.003); and a significantly lower mean minimum fibrous cap thickness (70.7±29.0 vs. 99.3±55.8 μm, P=0.012). Conclusions: This OFDI analysis suggests that OSA is associated with unstable plaque characteristics in patients with coronary artery disease. More intensive medical management for stabilization of coronary atherosclerotic plaque is required in patients with OSA. [ABSTRACT FROM AUTHOR]

Introduction: The potential involvement of c-reactive protein (CRP), interleukin (IL)-6 and intracellular adhesion molecule (ICAM)-1 in the destabilization, erosion, or rupture of arterial plaque, particularly plaques in the lower extremity arteries is not well-established. Thus, we sought to determine whether circulating levels of CRP, IL-6, and ICAM-1 were associated with the presence, burden, and characteristics of femoral artery plaques. Methods: The San Diego Population Study is a prospective, population-based, multi-ethnic cohort of 1103 men and women averaged age 70 at a follow up exam taking place from 2007-11. At this exam, B-mode ultrasound was used to measure plaque presence, burden, and characteristics, including total plaque area (TPA), mean grey-scale median (GSM), and presence of calcification. Plaques were assessed in the left and right superficial and common femoral arteries. Plaque presence was defined as any plaque in any arterial segment, while plaque burden was total number of plaques summed over all four segments. Circulating CRP, ICAM-1, and IL-6 were also measured at this exam. Associations of CRP, IL-6, and ICAM-1 with plaque presence and burden were assessed using logistic and zero-inflated Poisson regression, respectively. Among those with plaque, linear and logistic regression were used to assess associations of the biomarkers with plaque characteristics. All models adjusted for age, sex, race/ethnicity, BMI, BP, statin use, smoking status, diabetes, peripheral artery disease, and chronic kidney disease. Results: Higher circulating CRP was significantly associated with plaque presence with participants in the highest quartile of CRP having 1.8 times higher odds of having femoral plaque compared to those in the lowest quartile. Participants in the highest quartiles of CRP and IL-6 were significantly more likely to have greater plaque burden compared to those in the lowest quartiles (CRP OR=1.64, 95% CI=1.09-2.44; IL-6 OR=1.65, 95%CI=1.06-2.55). No associations were observed between circulating biomarkers and plaque characteristics, including TPA, GSM, or calcification. Conclusions: Higher levels of circulating CRP and IL-6 are associated with greater plaque burden in the femoral arteries of participants in the SDPS; however, these biomarkers do not appear to be associated with characteristics of femoral artery plaques. These results are consistent with findings in the carotid and coronary arteries. [ABSTRACT FROM AUTHOR]

Background: Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture., Methods and Results: We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture., Conclusions: The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model.