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Persistent skin inflammation and impaired resolution are the main contributors to psoriasis and associated cardiometabolic complications. Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are known to exert beneficial effects on inflammatory response and lipid function. However, a specific role of omega-3 PUFAs in psoriasis and accompanied pathologies are still a matter of debate. Here, we carried out a direct comparison between EPA and DHA 12 weeks diet intervention treatment of psoriasis-like skin inflammation in the K14-Rac1V12 mouse model. By utilizing sensitive techniques, we targeted EPA- and DHA-derived specialized pro-resolving lipid mediators and identified tightly connected signaling pathways by RNA sequencing. Treatment with experimental diets significantly decreased circulating pro-inflammatory cytokines and bioactive lipid mediators, altered psoriasis macrophage phenotypes and genes of lipid oxidation. The superficial role of these changes was related to DHA treatment and included increased levels of resolvin D5, protectin DX and maresin 2 in the skin. EPA treated mice had less pronounced effects but demonstrated a decreased skin accumulation of prostaglandin E 2 and thromboxane B 2 . These results indicate that modulating psoriasis skin inflammation with the omega-3 PUFAs may have clinical significance and DHA treatment might be considered over EPA in this specific disease., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12 -/+ murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12 -/+ mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters., Background: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques., Methods: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB., Results: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: β = 0.20, p = 0.01) and subclinical CVD (VI: β = 0.31, p < 0.001; NCB: β = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB., Conclusions: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact., (Published by Elsevier Inc.)

Importance: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis., Objective: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time., Design, Setting, and Participants: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year., Exposures: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay., Main Outcomes and Measures: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status., Results: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P < .001), and were associated with Psoriasis Area Severity Index (PASI) score (β = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (β = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (β = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (β = 0.14; 95% CI, 0.028-0.246; P = .02)., Conclusions and Relevance: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

Rationale: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis., Objective: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis., Methods and Results: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index, and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P <0.05 for all) with significant association of oxidized LDL (β=0.10; P=0.020) and oxHDL (β=-0.11; P=0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P=0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P<0.001) and with a concomitant decrease in NCB at 1 year (1.04±0.44 versus 0.95±0.32; P=0.03)., Conclusions: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.

Importance: Inflammation is critical to atherosclerosis. Psoriasis, a chronic inflammatory disease associated with early cardiovascular events and increased aortic vascular inflammation (VI), provides a model to study the process of early atherogenesis. Fludeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT) helps quantify aortic VI, and coronary computed tomography angiography provides coronary artery disease (CAD) assessment through evaluation of total plaque burden (TB) and noncalcified coronary plaque burden (NCB), luminal stenosis, and high-risk plaques (HRP). To our knowledge, association between aortic VI and broad CAD indices has not yet been assessed in a chronic inflammatory disease state. Such a study may provide information regarding the utility of aortic VI in capturing early CAD., Objective: To assess the association between aortic VI and CAD indices, including TB, NCB, luminal stenosis, and HRP prevalence, in psoriasis., Design, Setting, and Participants: In a cross-sectional cohort study at the National Institutes of Health, 215 consecutive patients with psoriasis were recruited from surrounding outpatient dermatology practices. All patients underwent 18F-FDG PET/CT for aortic VI assessment, and 190 of 215 patients underwent coronary computed tomography angiography to characterize CAD. The study was conducted between January 1, 2013, and May 31, 2017. Data were analyzed in March 2018., Exposures: Aortic VI assessed by 18F-FDG PET/CT., Main Outcomes and Measures: Primary outcome: TB and NCB. Secondary outcomes: luminal stenosis and HRP., Results: Among 215 patients with psoriasis (mean [SD] age, 50.4 [12.6] years; 126 men [59%]), patients with increased aortic VI had increased TB (standardized β = 0.48; P < .001), and higher prevalence of luminal stenosis (OR, 3.63; 95% CI, 1.71-7.70; P = .001) and HRP (OR, 3.05; 95% CI, 1.42-6.47; P = .004). The aortic VI and TB association was primarily driven by NCB (β = 0.49; P < .001), whereas the aortic VI and HRP association was driven by low-attenuation plaque (OR, 5.63; 95% CI, 1.96-16.19; P = .001). All associations of aortic VI remained significant after adjustment for cardiovascular risk factors: aortic VI and TB (β = 0.23; P < .001), NCB (β = 0.24; P < .001), luminal stenosis (OR, 3.40; 95% CI, 1.40-8.24; P = .007), and HRP (OR, 2.72; 95% CI, 1.08-6.83; P = .03). No association was found between aortic VI and dense-calcified coronary plaque burden., Conclusions and Relevance: Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.

Background: Psoriasis (PSO) is an immune-mediated inflammatory disease associated with metabolic and cardiovascular comorbidities. It is now known that resolution of inflammation is an active process locally controlled by specialized proresolving mediators (SPMs), named resolvins (Rvs), protectins, and maresins., Objective: It is unknown whether these potent lipid mediators (LMs) are involved in PSO pathophysiology and if the skin and blood have disease-specific SPMs phenotype profiles., Methods: We used liquid chromatography-tandem mass spectrometry-based LM metabololipidomics to obtain skin and peripheral blood LM profiles from PSO compared to healthy subjects. Some LMs were tested in cell culture experiments with corresponding gene expression and protein concentration analyses., Results: The levels of several LM were significantly elevated in lesional PSO skin compared to nonlesional and skin from healthy subjects. Particularly, RvD5, protectins Dx, and aspirin-triggered forms of lipoxin were present only in lesional PSO skin, whereas protectin D1 was present in nonlesional PSO skin. To determine specific roles of SPMs on skin-related inflammatory cytokines, RvD1 and RvD5 were incubated with human keratinocytes. RvD1 and RvD5 reduced the expression levels of interleukin 24 and S100A12, whereas only RvD1 significantly abrogated interleukin-24 production by keratinocytes., Conclusions: These findings suggest that an imbalance between locally produced proresolution and proinflammatory LMs identified in PSO skin and blood compartments might play a role in PSO pathophysiology. Moreover, some of the PSO-related cytokines can be modified by specific SPMs and involved mechanisms support investigation of targeting novel proresolving lipid mediators as a therapy for PSO., (Published by Elsevier Inc.)

Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12-/+/Srb1-/-/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.

Chronic inflammation is a critical component of atherogenesis, however, reliable human translational models aimed at characterizing these mechanisms are lacking. Psoriasis, a chronic inflammatory skin disease associated with increased susceptibility to atherosclerosis, provides a clinical human model that can be utilized to investigate the links between chronic inflammation and atherosclerosis development. We sought to investigate key biological processes in psoriasis skin and human vascular tissue to identify biological components that may promote atherosclerosis in chronic inflammatory conditions. Using a bioinformatics approach of human skin and vascular tissue, we determined IFN-γ and TNF-α are the dominant pro-inflammatory signals linking atherosclerosis and psoriasis. We then stimulated primary aortic endothelial cells and ex-vivo atherosclerotic tissue with IFN-γ and TNF-α and found they synergistically increased monocyte and T-cell chemoattractants, expression of adhesion molecules on the endothelial cell surface, and decreased endothelial barrier integrity in vitro, therefore increasing permeability. Our data provide strong evidence of synergism between IFN-γ and TNF- α in inflammatory atherogenesis and provide rationale for dual cytokine antagonism in future studies.

Importance: Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases., Objective: To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation., Design, Setting, and Participants: In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016., Exposure: Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score., Main Outcomes and Measures: Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography., Results: Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti-tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (β = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (β = 0.79; 95% CI, 0.269-1.311; P = .03)., Conclusions and Relevance: Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.

Aims The use of biologic therapy has increased over the past decade well beyond primary autoimmune diseases. Indeed, a recent trial using an anti-IL-1beta antibody reduced second myocardial infarction (MI) in those who have had MI. Psoriasis is a chronic inflammatory disease often treated with biologics when severe, is associated with increased risk of MI, in part driven by high-risk coronary plaque phenotypes by coronary computed tomography angiography (CCTA). We hypothesized that we would observe a reduction in inflammatory-driven phenotypes of coronary plaque, including non-calcified coronary plaque burden and lipid-rich necrotic core in those treated with biologic therapy after one-year compared with non-biologic therapy. Methods and results In a prospective, observational study, 290 participants were recruited from 1 January 2013 through 31 October 2018 with 215 completing one-year follow-up. Of the 238, 121 consecutive participants who were biologic treatment naïve at baseline were included. A blinded reader (blinded to patient demographics, visit and treatment) quantified total coronary plaque burden and plaque subcomponents (calcified and non-calcified) in the three main coronary vessels >2 mm using dedicated software (QAngio, Medis, Netherlands). Psoriasis patients were middle-aged [mean (standard deviation) age, 50.5 (12.1) years], mostly male (n = 70, 58%) with low cardiovascular risk by Framingham score [median (interquartile range, IQR), 3 (1–6)] and had moderate to severe skin disease at baseline [median (IQR) Psoriasis Area Severity Index, PASI, 8.6 (5.3–14.0)]. Biologic therapy was associated with a 6% reduction in non-calcified plaque burden (P = 0.005) reduction in necrotic core (P = 0.03), with no effect on fibrous burden (P = 0.71). Decrease in non-calcified plaque burden in the biologic treated group was significant compared with slow plaque progression in non-biologic treated (Δ, −0.07 mm2 vs. 0.06 mm2; P = 0.02) and associated with biologic treatment beyond adjustment for traditional cardiovascular risk factors (β = 0.20, P = 0.02). Conclusion In this observational study, we demonstrate that biologic therapy in severe psoriasis was associated with favourable modulation of coronary plaque indices by CCTA. These findings highlight the importance of systemic inflammation in coronary artery disease and support the conduct of larger, randomized trials. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease (CVD) risk is increased in psoriasis, a chronic inflammatory disease that affects 2-3% of the population. Notably, psoriasis is associated with increased aortic vascular inflammation (VI) compared to non-psoriasis. Recently, neutrophils and associated neutrophil extracellular traps (NETs) have gained attention in inflammatory atherogenesis in pre-clinical models. Hypothesis: Neutrophils and NETs proteins would associate with aortic vascular inflammation. Methods: Consecutively recruited psoriasis patients (N=81) and healthy controls (n=36) underwent FDG PET/CT for assessment of VI (global aorta) as target-to-background ratio. Circulating neutrophils were measured via flow cytometry. Circulating NETs and deoxyribose nuclease 1 (DNase 1) levels were measured by ELISA. In vitro experiments were conducted to investigate NET-induced changes in Human Aortic Endothelial Cell (HAoEC) gene expression. Results: Neutrophil frequency was increased in psoriasis (p=0.01) compared to non-psoriasis and associated with aortic vascular inflammation beyond CVD risk factors (β=0.27, p=0.04). Psoriasis was associated with increased circulating NETs (Histone 4-associated NET absorbance p=0.056) and decreased NET clearance (DNase 1 concentration; p<0.0001). Finally, human aortic endothelial cells (HAoECs) co-cultured with psoriasis NETs had upregulated expression of ICAM-1, VCAM-1, and E-Selectin (p<0.05). Conclusions: Aortic vascular inflammation in psoriasis was associated with neutrophil frequency. Psoriasis was associated with poor clearance of elevated circulating NETs and neutrophil NETs activated endothelial cells. These data suggest that psoriasis neutrophils produce NETs which may adhere to and damage the endothelium augmenting aortic vascular inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis (PSO) is a chronic inflammatory disorder associated with increased cardiovascular (CV) risk and lipoprotein dysfunction. Small dense LDL particle number (s-LDLp) is now recognized as an important predictor of CV events. Furthermore, non-calcified coronary plaque burden (NCB) is associated with future CV events and is increased in PSO. Hypothesis: A reduction in psoriasis severity at one year would be associated with a reduction in s-LDLp levels and change in NCB. Methods: Consecutive PSO patients (N = 138) underwent CCTA (Toshiba, 320-dector row) for coronary NCB characterization using QAngio (Medis) at baseline and 1-year. Lipoprotein profiling was done using NMR spectroscopy. Psoriasis severity was assessed using the Psoriasis Area Severity Index (PASI). Results: The cohort was middle aged, predominantly male, low CV risk by FRS, and had moderate-to-severe PSO severity at baseline (Table 1). PSO patients with decreased psoriasis at one-year had a decrease in s-LDLp (537.5 ± 37.5 vs 338.8 ± 34.9, p<0.001) with comparable LDL concentration (LDLc 105.9 ± 4.1 vs 109.4 ± 6.9, p=0.27) at 1-year. NCB (1.22 ± 0.004 vs 1.14 ± 0.004, p <0.001) decreased concurrent with improvement in PASI. In contrast, PSO patients with worsening psoriasis severity at one-year had increased LDLc (103.1 ± 7.1 vs 126.2 ± 13.0, p = 0.01), comparable s-LDLp (487.5 ± 37.5 vs 447.1 ± 40.8, p = 0.11) levels, and a non-significant increase in NCB (1.05 ± 0.05 vs 1.11 ± 0.06, p =0.15). Finally, change in NCB associated with change in s-LDLp in all PSO patients beyond adjustment for CV risk factors (Beta= 0.13, p=0.03). Conclusions: Psoriasis improvement was associated with improvement in s-LDLp and NCB beyond traditional CV risk factors. These findings underscore the need to understand the spectrum of LDL characterization in context of sub-clinical atherosclerosis and demonstrate the potential incremental value NMR profiling may provide to better capture CV risk in chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: The chronic inflammatory skin disease psoriasis affects 2-3% of the population and is associated with increased cardiovascular disease (CVD) risk. Numerous studies have deemed neutrophils as critical mediators of chronic inflammation and atherosclerotic development, however the role of neutrophil subsets, specifically low-density granulocytes (LDGs), and their interactions with platelets in early atherosclerosis is understudied. Hypothesis: We hypothesize LDGs and platelets would be associated with early atherosclerosis assessed as non-calcified coronary plaque by computed coronary tomographic angiography (CCTA) in psoriasis. Methods: Non-calcified coronary plaque burden was measured in eighty-one biologically naïve psoriasis patients and thirty-six healthy controls using CCTA. Flow cytometry was used to quantify circulating normal-density granulocyte (NDG) and LDG frequencies, their colocalization with platelets and Human Aortic Endothelial Cell (HAoEC) apoptosis. RNA sequencing was performed on psoriasis NDGs and LDGs to identify potential genes associated with enhanced cytotoxicity. Results: Elevated LDG, but not elevated NDG frequencies in psoriasis compared to healthy controls (p<0.001, p<0.05), were associated with non-calcified coronary burden (β=0.26, p<0.05). In vitro , LDGs induced HAoEC apoptosis upon cell-cell interactions. RNA sequencing revealed an upregulation of adhesion molecules in LDGs, specifically related to adherence of platelets and the endothelium. In LDGs, increased expression of the platelet-associated gene CD36 (p<0.01) had a robust association with non-calcified coronary burden (β=0.85, p<0.0001). Furthermore, the percentage of platelet-LDG colocalization highly correlated with non-calcified coronary burden (β=0.63, p<0.05). Conclusions: We identify a novel association between LDGs, platelets, and early coronary artery disease, suggesting that the LDG-platelet interaction may play a key role in early onset inflammatory atherogenesis. [ABSTRACT FROM AUTHOR]

Introduction: In individuals without chronic inflammatory conditions, chronic stress independently associates with cardiovascular disease (CVD) in part via a mechanism that involves heightened activity of the amygdala. Psoriasis (PSO), a chronic inflammatory condition, with increased prevalence of stress and subclinical CVD, provides a useful human model to study the effects of perceived psychological stress on CVD. We aimed to study whether there was a relationship between resting amygdala activity (AmygA) and high risk coronary plaque in PSO. Methods: Consecutive PSO patients (N=105) underwent FDG PET/CT scans (60 minutes post-FDG injection) to quantify perceived stress as measured by AmygA target-to-background ratio. Presence of high risk plaque was determined by plaque characterization via CCTA. HRP identification was defined as either positive remodeling (index ≥ 1.1) and/or low attenuation (< 30 HU). The cohort was stratified by mean AmygA values and subsequently statistically analyzed via multivariable logistic regression (STATA 12). Results: The cohort was middle-aged, predominantly male, low CV risk by Framingham risk score and mild-moderate psoriasis severity (Table 1). Unadjusted logistic regression illustrated significant increase in odds of HRP prevalence for patients with higher AmygA (Odds ratio [Confidence Interval]: 3.33 [1.41-7.84]) which remained significant independent of cardiovascular risk factors, statin use, and PSO therapy (2.65 [1.01-6.91]). Conclusion: Perceived stress assessed by AmygA was associated with increased prevalence of HRP in PSO beyond adjustment for cardiovascular risk factors. As such, neurobiological mechanisms related to chronic psychosocial stress, may play a role in inflammatory atherogenesis. [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]