Circulating Oxidized mtDNA is Associated Broadly with Cardiovascular Disease in a Longitudinal Cohort Study of Psoriasis.

Psoriasis (PSO) is a chronic and systemic inflammatory autoimmune disease associated with atherosclerosis and myocardial infarction. Given that atherosclerosis is both inflammation and immune driven, we sought to expand on known immune and inflammatory biomarkers in a PSO cohort. In this study, we focus on oxidized mtDNA (ox-mtDNA), a product of cells undergoing pyroptosis, including keratinocytes, which was quantified in patients with PSO and individuals without PSO by ELISA. Patients with PSO had significantly higher ox-mtDNA levels than healthy subjects (mean ± SD = 9246 ± 2518 pg/ml for patients with PSO vs 7382 ± 2506 pg/ml for those without; P = .006). Importantly, ox-mtDNA was positively associated with IL-17a (ß = 0.25; P = .03) and low-density granulocytes (ß = 0.37; P = .005) but negatively associated with high-density lipoprotein-cholesterol (ß = -0.29; P = .006). After adjusting for traditional cardiovascular risk factors, we found that ox-mtDNA was associated with noncalcified coronary burden, which was measured by coronary computed tomography angiography (ß = 0.19; P = .003). Biologic-naïve patients with PSO receiving anti-IL-17a therapy had a 14% decrease in ox-mtDNA (mean ± SD: 10540 ± 614 pg/ml at baseline to 9016 ± 477 pg/ml at 1 year; P = .016) and a 10% reduction in noncalcified coronary artery burden (mean ± SD: 1.06 ± 0.45 at baseline, reducing to 0.95 ± 0.35 at 1 year; P = .0037). In summary, levels of ox-mtDNA in PSO are associated with measures of coronary plaque formation, indicating that this biomarker may be an autoimmune-driven early atherosclerotic feature.

Asthmatic patients with high serum amyloid A have proinflammatory HDL: Implications for augmented systemic and airway inflammation.

RATIONALE: Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity. OBJECTIVE: We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory. METHODS: SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice. RESULTS: An SAA level greater than or equal to 108.8 µg/mL was defined as the threshold to identify 11% of an asthmatic cohort (n = 146) as being SAA-high. SAA-high patients with asthma were characterized by increased serum C-reactive protein, IL-6, and TNF-α; older age; and an increased prevalence of obesity and severe asthma. HDL isolated from SAA-high patients with asthma (SAA-high HDL) had an increased content of SAA as compared with HDL from SAA-low patients with asthma and induced the secretion of IL-6, IL-1ß, and TNF-α from human monocytes via a formyl peptide receptor 2/ATP/P2X purinoceptor 7 axis. Intravenous administration to mice of SAA-high HDL, but not normal HDL, induced systemic inflammation and amplified allergen-induced neutrophilic airway inflammation and goblet cell metaplasia. CONCLUSIONS: SAA-high patients with asthma are characterized by systemic inflammation, older age, and an increased prevalence of obesity and severe asthma. HDL from SAA-high patients with asthma is proinflammatory and, when intravenously administered to mice, induces systemic inflammation, and amplifies allergen-induced neutrophilic airway inflammation. This suggests that systemic inflammation induced by SAA-high HDL may augment disease severity in asthma.

Relationship of Soluble Lectin-Like Low-Density Lipoprotein Receptor-1 (sLOX-1) With Inflammation and Coronary Plaque Progression in Psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory condition associated with coronary artery disease risk. Uptake of oxidized low-density lipoprotein by the lectin-like low-density lipoprotein receptor-1 triggers release of the soluble extracellular domain of the receptor (sLOX-1). We sought to characterize the relationship between sLOX-1, inflammation, and coronary plaque progression in psoriasis. METHODS AND RESULTS: A total of 327 patients with psoriasis had serum sLOX-1 levels measured at baseline by an ELISA-based assay. Stratification by high-sensitivity C-reactive protein ≥4.0 mg/L (quartile 4), identified 81 participants who had coronary plaque phenotyping at baseline and were followed longitudinally by coronary computed tomography angiography. Subjects within high-sensitivity C-reactive protein quartile 4 were middle-aged (51.47±12.62 years), predominantly men (54.3%) with moderate psoriasis disease severity (6.60 [interquartile range, 3.30-13.40]). In the study cohort, participants with sLOX-1 above the median displayed increased vulnerable coronary plaque features. At baseline, sLOX-1 was associated with total burden (rho=0.296; P=0.01), noncalcified burden (rho=0.286; P=0.02), fibro-fatty burden (rho=0.346; P=0.004), and necrotic burden (rho=0.394; P=0.002). A strong relationship between sLOX-1, noncalcified burden (ß=0.19; P=0.03), and fibro-fatty burden (ß=0.29; P=0.003) was found in fully adjusted models at baseline and 1- and 4-year follow-up. Finally, coronary plaque features progressed over 1 year regardless of biologic or systemic treatment in subjects with high sLOX-1. CONCLUSIONS: Patients with psoriasis with both high sLOX-1 and high-sensitivity C-reactive protein levels have increased coronary plaque burden associated with atherosclerotic plaque progression independent of biologic and systemic treatment. Thus, sLOX-1 might be considered as a promising marker in coronary artery disease risk estimation beyond traditional risk factors. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01778569.

Longitudinal association of epicardial and thoracic adipose tissues with coronary and cardiac characteristics in psoriasis.

Background: s: Psoriasis is a disease of systemic inflammation associated with increased cardiometabolic risk. Epicardial adipose tissue (EAT) and thoracic adipose tissue (TAT) are contributing factors for atherosclerosis and cardiac dysfunction. We strove to assess the longitudinal impact of the EAT and TAT on coronary and cardiac characteristics in psoriasis. Methods: The study consisted of 301 patients with baseline coronary computed tomography angiography (CTA), of which 139 had four-year follow up scans. EAT and TAT volumes from non-contrast computed tomography scans were quantified by an automated segmentation framework. Coronary plaque characteristics and left ventricular (LV) mass were quantified by CTA. Results: When stratified by baseline EAT and TAT volume quartiles, a stepwise significant increase in cardiometabolic parameters was observed. EAT and TAT volumes associated with fibro-fatty burden (FFB) (TAT: ρ = 0.394, P < 0.001; EAT: ρ = 0.459, P < 0.001) in adjusted models. Only EAT had a significant four-year time-dependent association with FFB in fully adjusted models (ß = 0.307 P = 0.003), whereas only TAT volume associated with myocardial injury in fully adjusted models (TAT: OR = 1.57 95 % CI = (1.00-2.60); EAT: OR = 1.46 95 % CI = (0.91-2.45). Higher quartiles of EAT and TAT had increased LV mass and developed strong correlation (TAT: ρ = 0.370, P < 0.001; EAT: ρ = 0.512, P < 0.001). Conclusions: Our study is the first to explore how both EAT and TAT volumes associate with increased cardiometabolic risk profile in an inflamed psoriasis cohorts and highlight the need for further studies on its use as a potential prognostic tool for high-risk coronary plaques and cardiac dysfunction.

Association of oxidized ApoB and oxidized ApoA-I with high-risk coronary plaque features in cardiovascular disease.

BACKGROUND: Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing. METHODS: In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA. RESULTS: Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; ß = 0.20; P < 0.0001) and fibrofatty burden (FFB; ß = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27-3.88, and OR, 2.80; 95% CI, 1.71-4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (ß = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL. CONCLUSION: Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD. CLINICALTRIALS: gov NCT01621594. FUNDING: National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease.

BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).

Estimated sdLDL-C for predicting high-risk coronary plaque features in psoriasis: a prospective observational study.

BACKGROUND: Psoriasis (PSO) is a skin disorder with systemic inflammation and high coronary artery disease risk. A distinct lipid phenotype occurs in psoriasis, which is characterized by high plasma triglycerides (TGs) with typically normal or even low LDL-C. The extent to which cholesterol on LDL subfractions, such as small dense LDL-C (sdLDL-C), are associated with vulnerable coronary plaque characteristics in PSO remains elusive. METHODS: A recently developed equation for estimating sdLDL-C from the standard lipid panel was utilized in a PSO cohort (n = 200) with 4-year follow-up of 75 subjects. Coronary plaque burden was assessed by quantitative coronary computed tomography angiography (CCTA). Multivariate regression analyses were used for establishing associations and prognostic value of estimated sdLDL-C. RESULTS: Estimated sdLDL-C was positively associated with non-calcified burden (NCB) and fibro-fatty burden (FFB), which remained significant after multivariate adjustment for NCB (ß = 0.37; P = 0.050) and LDL-C adjustment for FFB (ß = 0.29; P < 0.0001). Of note, total LDL-C calculated by the Friedewald equation was not able to capture these associations in the study cohort. Moreover, in the regression modelling estimated sdLDL-C was significantly predicting necrotic burden progression over 4 years follow-up (P = 0.015), whereas LDL-C did not. Finally, small LDL particles (S-LDLP) and small HDL particles (S-HDLP), along with large and medium TG-rich lipoproteins (TRLPs) had the most significant positive correlation with estimated sdLDL-C. CONCLUSIONS: Estimated sdLDL-C has a stronger association than LDL-C with high-risk features of coronary atherosclerotic plaques in psoriasis patients. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique identifiers: NCT01778569.

The Relationship between Circulating APOA-1 and Atherosclerosis Initiation and Progression in Psoriasis.

APOA-1 is central to the high-density lipoprotein function of reverse cholesterol transport measured by cholesterol efflux capacity. Psoriasis is a systemic inflammatory disease associated with poor cholesterol efflux capacity and accelerated noncalcified coronary burden (NCB) as measured by coronary computed tomographic angiography. In this study, we characterized the relationship between APOA-1, cholesterol efflux capacity, and progression of NCB over 4 years. Consecutively recruited participants with psoriasis underwent coronary computed tomographic angiography for NCB quantification (Medis QAngio, Leiden, The Netherlands) at baseline (n = 310) and at four years (n = 124). Blood was assessed for cardiometabolic biomarkers. The lowest quartile of APOA-1 was associated with cardiometabolic blood markers (insulin, homeostatic model assessment for insulin resistance, and cholesterol efflux capacity) and higher NCB (P < 0.001). The low APOA-1 quartile had higher NCB at 4 years (ß = -0.36, P = 0.02) in fully adjusted models. Finally, a 10-unit decrease of APOA-1 was associated with a 16% increase in NCB progression over 4 years (OR = 0.83, 95% confidence interval = 0.70-0.99, P = 0.04). In addition to being associated with cardiometabolic disease, low APOA-1 was associated with more NCB over time. These findings show that low APOA-1 is correlated with initiation and progression of coronary artery disease and may have clinical utility in identifying high-risk populations for development of cardiovascular disease.

Comparison of the dietary omega-3 fatty acids impact on murine psoriasis-like skin inflammation and associated lipid dysfunction.

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 E2 and thromboxane B2. 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.

Cholesterol efflux capacity is associated with lipoprotein size and vascular health in mild to moderate psoriasis.

Background and objective: Psoriasis is a systemic inflammatory condition with poor cholesterol transport measured by cholesterol efflux capacity (CEC) that is associated with a heightened risk of cardiovascular disease (CVD). In psoriasis patients, we sought to characterize the lipoprotein profile by size using a novel nuclear magnetic resonance algorithm in patients with low CEC compared to normal CEC. Methods: Lipoprotein profile was assessed using the novel nuclear magnetic resonance LipoProfile-4 deconvolution algorithm. Aortic vascular inflammation (VI) and non-calcified burden (NCB) were characterized via positron emission tomography-computed tomography and coronary computed tomography angiography. To understand the relationship between lipoprotein size and markers of subclinical atherosclerosis, linear regression models controlling for confounders were constructed. Results: Psoriasis patients with low CEC had higher more severe psoriasis (p = 0.04), VI (p = 0.04) and NCB (p = 0.001), concomitant with smaller high-density lipoprotein (HDL) (p < 0.001) and low-density lipoprotein (LDL) particles (p < 0.001). In adjusted models HDL size (ß = -0.19; p = 0.02) and LDL size (ß = -0.31; p < 0.001) associated with VI and NCB. Lastly, HDL size strongly associated with LDL size in fully adjusted models (ß = -0.27; p < 0.001). Conclusion: These findings demonstrate that in psoriasis, low CEC associates with a lipoprotein profile comprised of smaller HDL and LDL particles which correlates with vascular health and may be driving early onset atherogenesis. Further, these results demonstrate a relationship between HDL and LDL size and provide novel insights into the complexities of HDL and LDL as biomarkers of vascular health.

Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity.

Background: Myriad roles for high-density lipoprotein (HDL) beyond atheroprotection include immunologic functions implicated in the severity of coronavirus disease-2019 (COVID-19) in adults. We explored whether there is an association between HDL and COVID-19 severity in youth. Methods: A pediatric cohort (N = 102), who tested positive for COVID-19 across a range of disease manifestations from mild or no symptoms, to acute severe symptoms, to the multisystem inflammatory syndrome of children (MIS-C) was identified. Clinical data were collected from the medical record and reserve plasma aliquots were assessed for lipoproteins by NMR spectroscopy and assayed for HDL functional cholesterol efflux capacity (CEC). Findings were compared by COVID-19 status and symptom severity. Lipoprotein, NMR spectroscopy and CEC data were compared with 30 outpatient COVID negative children. Results: Decreasing HDL cholesterol (HDL-c), apolipoprotein AI (ApoA-I), total, large and small HDL particles and HDL CEC showed a strong and direct linear dose-response relationship with increasing severity of COVID-19 symptoms. Youth with mild or no symptoms closely resembled the uninfected. An atypical lipoprotein that arises in the presence of severe hepatic inflammation, lipoprotein Z (LP-Z), was absent in COVID-19 negative controls but identified more often in youth with the most severe infections and the lowest HDL parameters. The relationship between HDL CEC and symptom severity and ApoA-I remained significant in a multiply adjusted model that also incorporated age, race/ethnicity, the presence of LP-Z and of GlycA, a composite biomarker reflecting multiple acute phase proteins. Conclusion: HDL parameters, especially HDL function, may help identify youth at risk of more severe consequences of COVID-19 and other novel infectious pathogens.

Association of Apremilast With Vascular Inflammation and Cardiometabolic Function in Patients With Psoriasis: The VIP-A Phase 4, Open-label, Nonrandomized Clinical Trial.

Importance: Psoriasis is an inflammatory condition associated with metabolic and cardiovascular disease. Apremilast, a phosphodiesterase 4 inhibitor, is commonly used for psoriasis and can cause weight loss. Objective: To determine the association between apremilast and aortic vascular inflammation as assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), cardiometabolic markers (primary outcomes at week 16), and abdominal fat composition. Design, Setting, and Participants: A single-arm, open-label, interventional, nonrandomized clinical trial in which the imaging and laboratory outcomes were measured by an investigator who was blinded to time was conducted between April 11, 2017, and August 17, 2021, at 7 dermatology sites in the United States. A total of 101 patients with moderate to severe psoriasis were screened, 70 enrolled, 60 completed week 16, and 39 completed week 52. Intervention: Apremilast, 30 mg, twice daily. Main Outcomes and Measures: Aortic vascular inflammation (measured by FDG-PET/CT), 68 cardiometabolic biomarkers, and abdominal fat composition (measured by CT) at week 16 and week 52 compared with baseline. Results: The mean (SD) age of the 70 patients was 47.5 (14.6) years, 54 were male (77.1%), 4 were Black (5.7%), and 58 were White (82.9%). There was no change in aortic vascular inflammation at week 16 (target to background ratio, -0.02; 95% CI, -0.08 to 0.05; P = .61) or week 52 (target to background ratio, -0.07; 95% CI, -0.15 to 0.01; P = .09) compared with baseline. At week 16, potentially beneficial decreases in interleukin 1b, valine, leucine, isoleucine, fetuin A, and branched-chain amino acids were observed. At week 52 compared with baseline, potentially beneficial decreases in ferritin, ß-hydroxybutyrate, acetone, and ketone bodies, with an increase in apolipoprotein A-1, were observed, but there was a reduction in cholesterol efflux. There was an approximately 5% to 6% reduction in subcutaneous and visceral adiposity at week 16 that was maintained at week 52. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that apremilast has a neutral association with aortic vascular inflammation, variable but generally beneficial associations with a subset of cardiometabolic biomarkers, and associations with reductions in visceral and subcutaneous fat, indicating that the drug may have an overall benefit for patients with cardiometabolic disease and psoriasis. Trial Registration: ClinicalTrials.gov Identifier: NCT03082729.

Differential Effect of Dietary Supplementation with a Soybean Oil Enriched in Oleic Acid versus Linoleic Acid on Plasma Lipids and Atherosclerosis in LDLR-Deficient Mice.

Both monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) play important roles in lipid metabolism, and diets enriched with either of these two fatty acids are associated with decreased cardiovascular risk. Conventional soybean oil (CSO), a common food ingredient, predominantly contains linoleic acid (LA; C18:2), a n-6 PUFA. Recently, a modified soybean oil (MSO) enriched in oleic acid (C18:1), a n-9 MUFA, has been developed, because of its improved chemical stability to oxidation. However, the effect of the different dietary soybean oils on cardiovascular disease remains unknown. To test whether diets rich in CSO versus MSO would attenuate atherosclerosis development, LDL receptor knock-out (LDLR-KO) mice were fed a Western diet enriched in saturated fatty acids (control), or a Western diet supplemented with 5% (w/w) LA-rich CSO or high-oleic MSO for 12 weeks. Both soybean oils contained a similar amount of linolenic acid (C18:3 n-3). The CSO diet decreased plasma lipid levels and the cholesterol content of VLDL and LDL by approximately 18% (p < 0.05), likely from increased hepatic levels of PUFA, which favorably regulated genes involved in cholesterol metabolism. The MSO diet, but not the CSO diet, suppressed atherosclerotic plaque size compared to the Western control diet (Control Western diet: 6.5 ± 0.9%; CSO diet: 6.4 ± 0.7%; MSO diet: 4.0 ± 0.5%) (p < 0.05), independent of plasma lipid level changes. The MSO diet also decreased the ratio of n-6/n-3 PUFA in the liver (Control Western diet: 4.5 ± 0.2; CSO diet: 6.1 ± 0.2; MSO diet: 2.9 ± 0.2) (p < 0.05), which correlated with favorable hepatic gene expression changes in lipid metabolism and markers of systemic inflammation. In conclusion, supplementation of the Western diet with MSO, but not CSO, reduced atherosclerosis development in LDLR-KO mice independent of changes in plasma lipids.

Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus.

OBJECTIVES: Premature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE. METHODS: Eighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed. RESULTS: Seventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose. CONCLUSION: PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE. TRIAL REGISTRATION NUMBER: NCT02338999.

Association of S100A8/A9 with Lipid-Rich Necrotic Core and Treatment with Biologic Therapy in Patients with Psoriasis: Results from an Observational Cohort Study.

Psoriasis is a systemic inflammatory disease with an increased risk of atherosclerotic events and premature cardiovascular disease. S100A7, A8/A9, and A12 are protein complexes that are produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. Lipid-rich necrotic core (LRNC) is a high-risk coronary plaque feature previously found to be associated with cardiovascular risk factors and psoriasis severity. LRNC can decrease with biologic therapy, but how this occurs remains unknown. We investigated the relationship between S100 proteins, LRNC, and biologic therapy in psoriasis. S100A8/A9 associated with LRNC in fully adjusted models (ß = 0.27, P = 0.009; n = 125 patients with psoriasis with available coronary computed tomography angiography scans; LRNC analyses; and serum S100A7, S100A8, S100A9, S100A12, and S100A8/A9 levels). At 1 year, in patients receiving biologic therapy (36 of 73 patients had 1-year coronary computed tomography angiography scans available), a 79% reduction in S100A8/A9 levels (‒172 [‒291.7 to 26.4] vs. ‒29.9 [‒137.9 to 50.5]; P = 0.04) and a 0.6 mm2 reduction in average LRNC area (0.04 [‒0.48 to 0.77] vs. ‒0.56 [‒1.8 to 0.13]; P = 0.02) were noted. These results highlight the potential role of S100A8/A9 in the development of high-risk coronary plaque in psoriasis.

Complex association of apolipoprotein E-containing HDL with coronary artery disease burden in cardiovascular disease.

BackgroundAlthough traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed.MethodsIn a prospective, observational study, 795 individuals had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E-containing HDL-cholesterol (ApoE-HDL-C). Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiography (CCTA) characterization of total burden, noncalcified burden (NCB), and fibrous plaque burden (FB) was performed in a subcohort (n = 300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured.ResultsMost patients had a clinical diagnosis of coronary artery disease (CAD) (n = 80.4% of 795), with mean age of 59 years, a majority being male (57%), and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P < 0.001), with higher CAC as compared with high ApoE-HDL-C. On quantitative CCTA, the high ApoE-HDL-C group had lower NCB (ß = -0.24, P = 0.0001), which tended to be significant in a fully adjusted model (ß = -0.32, P = 0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (ß = 0.31; P = 0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P = 0.0001) in a fully adjusted model.ConclusionApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity.Trial RegistrationClinicalTrials.gov: NCT01621594.FundingThis work was supported by the NHLBI at the NIH Intramural Research Program.

Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.

Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n = 76 psoriasis participants and 76 controls), nonalcoholic fatty liver disease, assessed by the sonographic hepatorenal index, was more prevalent in psoriasis than in controls (61% vs. 45%; P = 0.04). Participants with psoriasis with nonalcoholic fatty liver disease had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than participants with psoriasis without nonalcoholic fatty liver disease (61% vs. 23%; P = 0.006) and controls with nonalcoholic fatty liver disease (61% vs. 32%; P < 0.05). Sonographic hepatorenal index was a determinant of subclinical atherosclerosis in psoriasis (OR = 3.5; P = 0.01). In the United States cohort (n = 162 participants with psoriasis who underwent positron emission tomography and coronary computed tomography angiography), those with high hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake had higher noncalcified (1.3 [0.49 mm2] vs. 1.0 [0.40 mm2]), fibrofatty (0.23 [0.15 mm2] vs. 0.11 [0.087 mm2]), and lipid-rich necrotic core (4.3 [2.3 mm2] vs. 3.0 [1.7 mm2]) coronary burden (all P < 0.001). Hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake associated with noncalcified (ß = 0.28; P < 0.001), fibrofatty (ß = 0.49; P < 0.001), and lipid-rich necrotic core (ß = 0.28; P = 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.

Underperformance of clinical risk scores in identifying imaging-based high cardiovascular risk in psoriasis: results from two observational cohorts.

AIMS: We aimed to evaluate whether traditional risk scores [short-term, 'psoriasis-modified' (multiplied by 1.5) and lifetime] were able to capture high cardiovascular disease (CVD) risk as defined by the presence of atherosclerotic plaques in coronary, femoral, or carotid arteries in psoriasis. METHODS AND RESULTS: We used two prospectives obseravational cohorts. European cohort: femoral and carotid atherosclerotic plaques were evaluated by ultrasound in 73 psoriasis patients. Lifetime CVD risk (LTCVR) was evaluated with QRISK-LT; short-term CVD risk was evaluated with SCORE and psoriasis-modified SCORE. American cohort: 165 patients underwent coronary computed tomography angiography to assess presence of coronary plaques. LTCVR was evaluated with atherosclerotic cardiovascular disease (ASCVD-LT) lifetime; short-term CVD risk was evaluated with ASCVD and psoriasis-modified ASCVD. European cohort: subclinical atherosclerosis was present in 51% of patients. QRISK-LT identified 64% of patients with atherosclerosis missing a high proportion (35%) with atheroma plaque (P < 0.05). The percentage of patients with atherosclerosis identified by QRISK-LT was significantly higher than those detected by SCORE (0%) and modified SCORE (10%). American cohort: subclinical atherosclerosis was present in 54% of patients. ASCVD-LT captured 54% of patients with coronary plaques missing a high proportion (46%) with coronary plaque (P < 0.05). The percentage of patients with atheroma plaques detected with ASCVD and modified ASCVD were only 20% and 45%, respectively. CONCLUSIONS: Application of lifetime, short-term and 'psoriasis-modified' risk scores did not accurately capture psoriasis patients at high CVD risk.