Non-calcified Coronary Burden Research Articles

Monocyte-to-High-Density Lipoprotein Ratio Is Associated with Systemic Inflammation, Insulin Resistance, and Coronary Subclinical Atherosclerosis in Psoriasis: Results from 2 Observational Cohorts

Systemic inflammation or insulin resistance drive atherosclerosis. However, they are difficult to capture for assessing cardiovascular risk in clinical settings. The monocyte-to-HDL ratio (MHR) is an accessible biomarker that integrates inflammatory and metabolic information and which has been associated with poorer cardiovascular outcomes. Our aim was to evaluate the association of MHR with the presence of subclinical atherosclerosis in patients with psoriasis. The study involved a European and an American cohort including 405 patients with the disease. Subclinical atherosclerosis was assessed by coronary computed tomography angiography. First, MHR correlated with insulin resistance via HOMA-IR, with high sensitivity C-reactive protein and with 18F-FDG uptake in spleen, liver and bone marrow by PET/CT. MHR associated with both the presence of coronary plaques greater than 50% of the artery lumen and non-calcified coronary burden (NCB), beyond traditional cardiovascular risk factors (p<0.05). In an NCB prediction model accounting for cardiovascular risk factors, statins and biologic treatment, MHR added value (AUC base model 0.72 vs AUC base model plus MHR 0.76, p=0.04) within the American cohort. These results suggests that MHR may detect psoriasis patients who have subclinical burden of cardiovascular disease and warrant more aggressive measures to reduce lifetime adverse cardiovascular outcomes.

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 (β= 0.25; P= .03) and low-density granulocytes (β= 0.37; P= .005) but negatively associated with high-density lipoprotein-cholesterol (β=-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 (β= 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.

Abstract 9816: Cholesterol Efflux Capacity Mediates The Relationship Between Neutrophils And Coronary Burden In Psoriasis

Introduction: Psoriasis is a chronic inflammatory disease associated with increased levels of activated neutrophils, lower cholesterol efflux capacity (CEC), and subclinical atherosclerosis. High-density lipoprotein cholesterol efflux is the primary method of cholesterol removal from peripheral tissues and is linked to innate immunity and cardiovascular disease. Preclinical models suggest a strong relationship between CEC, neutrophil frequency and activation, and atherosclerosis, yet this relationship is understudied in clinical models. Hypothesis: (1) Psoriasis patients with high neutrophils have lower CEC and high non-calcified coronary burden (NCB); (2) CEC mediates the relationship between neutrophils and NCB. Methods: Coronary computed tomography angiography was used to quantitate NCB in one-hundred seventy-nine untreated psoriasis patients. Circulating neutrophils were measured via flow cytometry, and mean fluorescence intensity of CD62L and CD11b was determined. CEC was quantified using a cell-based ex-vivo assay measuring the ability of apolipoprotein B depleted plasma to mobilize cholesterol from lipid-loaded macrophages. Results: Patients with high neutrophils had decreased CEC (0.93 (0.15) vs 1.00 (0.17); P =0.03) and higher NCB (1.24 (0.55) vs 1.10 (0.50); P =0.003). The relationship between neutrophils and NCB was mediated by CEC beyond adjustment for Framingham risk score, smoking status, and statin treatment (20%, P =&lt;0.001) ( Figure 1 ). CEC associated with neutrophil activation markers, CD11b and CD62L (β: -0.23 P =0.04, β:0.21, P =0.04). Finally, one year of biologic therapy improved CEC (0.08 (0.17) vs (-0.009 (0.19); P =0.008) and neutrophil counts (-0.45 (-1.36- -0.45) vs -0.14 (-0.60-0.42; P =0.004). Conclusion: Patients with more neutrophils had lower CEC and higher NCB. Further, CEC mediates the relationship between neutrophils and NCB, underscoring the relationship between neutrophils and CEC in atherosclerosis.

Chronic inflammation in psoriasis promotes visceral adipose tissue association with lipid-rich necrotic core through atherogenic myeloid score

Abstract Background/Introduction Psoriasis is a chronic inflammatory condition associated with adipose dysfunction and high-risk coronary artery disease features, including non-calcified coronary burden (NCB) and lipid-rich necrotic core (LRNC). Visceral adipose tissue (VAT) is a metabolically-active depot that secretes inflammatory and proatherogenic factors, and is associated with increased NCB. Additionally, an atherogenic myeloid score (AMS) comprised of classical monocytes, low-density granulocytes, and platelets was shown to associate with psoriasis severity and NCB. Purpose To investigate the relationship between VAT and high-risk plaque features and test whether this relationship was potentially mediated by myeloid cells. Methods A cohort of 131 psoriasis patients were included in this study. Atherogenic myeloid score components were calculated using complete blood count data (platelets) and by flow cytometry (monocytes, LDGs). Coronary NCB and LRNC were quantified using QAngio and vascuCAP respectively. VAT was defined as intra-abdominal fat and was quantified using an automated contouring software with abdominal CT scans. Statistical analyses were performed using STATA 12. Results The cohort was middle-aged 50 (42–61) (median (IQR)), and predominantly male (61%). High VAT vs low VAT groups differed significantly in their NCB ((0.910±0.279) vs (1.431±0.517)); p&amp;lt;0.001), (mean ± SD). After adjustment for cardiovascular risk factors, VAT associated with the atherogenic myeloid score (β=0.221, p=0.044), with LRNC (β=0.128, p=0.047), and atherogenic myeloid score associated with LRNC (β=0.161, p=0.003). The relationship of VAT to LRNC was partially mediated by atherogenic myeloid score (25.14%, p=0.029) (Figure 1). Conclusions VAT associated with LRNC, and this relationship was partially mediated by the atherogenic myeloid score. These findings suggest that bioactive VAT may impart risk on coronary artery disease in part through myeloid cells. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung, and Blood Institute Intramural Research Program in Bethesda, Maryland Figure 1. Log-transformed atherogenic myeloid score partially mediates the relationship between VAT and log-transformed LRNC. Adjusted by Framingham Risk Score, PASI score, biologic therapy, statin therapy, type 2 diabetes, hyperlipidemia, and subcutaneous adipose tissue volume. Red arrow: represents indirect effect; Beta: standard regression coefficient.

Bone marrow and splenic metabolic activity by 18F-FDG PET/CT are associated with noncalcified coronary burden and lipid-rich necrotic core in psoriasis

Abstract Background/Introduction Psoriasis is an immune-mediated inflammatory skin condition with an increased risk of myocardial infarction (MI). Elevated bone marrow (BM) and splenic hematopoiesis occurs after MI. In stable patients without chronic inflammation, higher splenic hematopoiesis predicts major adverse cardiovascular events (MACE). Nevertheless, studies in humans investigating these relationships in states of chronic inflammation on coronary artery disease features associated with MACE are limited. Purpose To investigate the relationships between bone marrow and splenic metabolic activity by [18]-fluorodeoxyglucose (FDG) PET/CT and subclinical cardiovascular disease in psoriasis. Methods Healthy participants (N=30) and psoriasis participants (N=210) were age and sex matched. All participants underwent 18FDG PET/CT and CT angiography (Toshiba 320 slice). Coronary artery plaque characteristics were assessed using QAngio CT (Medis, The Netherlands) and lipid rich necrotic core (LRNC) was assessed using vascuCAP (Elucid Bioimaging, Boston, MA). For tissue metabolic activities target-to-background ratio (TBR) was calculated as the ratio of arterial and venous standardized uptake values (SUV). Results The psoriasis cohort was middle aged 49.2 (±SD 11.9) years and predominantly male (64%). Those with psoriasis vs. healthy participants had higher BM (1.58 (IQR 1.35–1.89) vs. 1.23 (IQR 1.14–1.35); p&amp;lt;0.001) and splenic (1.40 (IQR 1.21–1.66) vs.1.17 (IQR 1.11–1.26); p&amp;lt;0.001) metabolic activity. After adjustment for cardiovascular risk factors bone marrow metabolic activity was associated with total burden, non-calcified burden (NCB) and LRNC (β=0.36, β=0.39, β=0.26; all p&amp;lt;0.001) respectively. Similar findings were observed for splenic activity (β=0.33, β=0.36, β=0.36; all p&amp;lt;0.001). In ROC analysis, when comparing area under the curve, BM activity better incrementally predicted non-calcified burden and lipid rich necrotic core compared to splenic activity (Figure). Conclusions BM and splenic metabolic activity are increased in psoriasis. Both are associated with coronary artery disease but there was a slightly stronger association with BM activity compared to splenic activity, These findings warrant further study to understand immune mechanisms underlying these observations. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung and Blood Institute Intramural Research Program in Bethesda, Maryland Figure 1. Median values of NCB and LRNC were used to convert these continuous variables into dichotomous variables such that values ≤ median were designated as 0 and values &amp;gt;median were designated 1. Bone marrow model compared to base model and splenic model added incremental value in predicting NCB (p&amp;lt;0.0001) and LRNC (p=0.0003). Base model: Framingham risk score, lipid treatment, biologic therapy, homeostasis model assessment as an index of insulin resistance (HOMA-IR), low density lipoprotein (LDL).

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 (β= 0.28; P < 0.001), fibrofatty (β= 0.49; P < 0.001), and lipid-rich necrotic core (β= 0.28; P= 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.

The relationship between systemic inflammation and increased left ventricular mass is partly mediated by noncalcified coronary artery disease burden in psoriasis

ObjectiveIncreased left ventricular (LV) mass is an important precursor to heart failure. Inflammation plays an important role in increasing LV mass. However, the contribution of subclinical coronary artery disease (CAD) to the inflammation-LV mass relationship is unknown. In subjects with psoriasis, a chronic inflammatory skin disease, we evaluated if systemic inflammation assessed by plasma glycoprotein A (GlycA) associated with LV mass measured on coronary CT angiography (CCTA). Additionally, we analyzed whether this relationship was mediated by early CAD assessed as noncalcified coronary burden (NCB). MethodsWe performed an observational longitudinal study of 213 subjects with psoriasis free of known cardiovascular disease, 189 of whom were followed over one year. All participants had GlycA measurements by nuclear magnetic resonance spectroscopy and LV mass and NCB quantified by CCTA. ResultsThe cohort had a mean age of 50.3 (±12.9) years and 59% were male. There was moderate psoriasis severity and low cardiovascular risk. LV mass increased by GlycA tertiles [1st tertile:24.6 g/m2.7(3.8), 2nd tertile:25.5 g/m2.7(3.8), 3rd tertile:27.7 g/m2.7(5.5), p<0.001]. Both GlycA (β=0.24, p = 0.001) and NCB (β=0.50, p<0.001) associated with LV mass in models adjusted for age, sex, hypertension, hypertension therapy, lipid therapy, biologic therapy for psoriasis, waist:hip ratio, psoriasis disease duration and severity. In multivariable-adjusted mediation analyses, NCB accounted for 32% of the GlycA-LV mass relationship. Finally, over one year, change in NCB independently associated with change in LV mass (β=0.25, p = 0.002). ConclusionsBoth systemic inflammation and coronary artery NCB were associated with LV mass beyond cardiovascular risk factors in psoriasis. Furthermore, a substantial proportion of the inflammatory-LV mass relationship was mediated by NCB. These findings underscore the possible contribution of early coronary artery disease to the relationship between systemic inflammation and LV mass.

Identifying Top Predictors of Change in Noncalcified Coronary Burden in Psoriasis by Machine Learning Over 1-Year

Background: Psoriasis is associated with accelerated non-calcified coronary burden (NCB) by coronary computed tomography angiography (CCTA). Machine learning (ML) algorithms have been shown to effectively identify cardiometabolic variables with NCB in cross-sectional analysis. Objective: To use ML methods to characterize important predictors of change in NCB by CCTA in psoriasis over 1-year of observation. Methods: The analysis included 182 consecutive patients with 80 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative, a prospective, observational cohort study at baseline and 1-year using the random forest regression algorithm. NCB was assessed at baseline and 1-year from CCTA. Results: Using ML, we identified variables of high importance in the context of predicting changes in NCB. For the cohort that improved NCB (n = 102), top baseline variables were cholesterol (total and HDL), white blood cell count, psoriasis area severity index score, and diastolic blood pressure. Top predictors of 1-year change were change in visceral adiposity, white blood cell count, total cholesterol, c-reactive protein, and absolute lymphocyte count. For the cohort that worsened NCB (n = 80), the top baseline variables were HDL cholesterol related including apolipoprotein A1, basophil count, and psoriasis area severity index score, and top predictors of 1-year change were change in apoA, apoB, and systolic blood pressure. Conclusion: ML methods ranked predictors of progression and regression of NCB in psoriasis over 1 year providing strong evidence to focus on treating LDL, blood pressure, and obesity; as well as the importance of controlling cutaneous disease in psoriasis.

Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study

Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome. Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis. This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria. Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (β=.31; P<.001) and its individual factors of waist circumference (β=.33; P<.001), triglyceride levels (β=.17; P=.005), blood pressure (β=.18; P=.005), and fasting glucose (β=.17; P=.009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden. Observational nature with limited ability to control for confounders. In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.

Chronic inflammation in psoriasis promotes visceral adiposity associated with noncalcified coronary burden over time.

BACKGROUNDPsoriasis is a chronic inflammatory skin disease associated with increased obesity, noncalcified coronary artery burden (NCB), and incident myocardial infarction. Here, we sought to assess the relationship among inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis.METHODSConsecutive psoriasis patients underwent coronary CT angiography to quantify NCB and abdominal CT to calculate VAT at baseline (n = 237), 1 year (n = 176), and 4 years (n = 50).RESULTSPatients with high levels of high-sensitivity C-reactive protein (hs-CRP) had significantly greater visceral adiposity (17,952.9 ± 849.2 cc3 vs. 13370.7 ± 806.8 cc3, P < 0.001) and noncalcified coronary burden (1.26 ± 0.03 vs. 1.07 ± 0.02 mm2) than those with low levels of hs-CRP. Those with higher levels of VAT had more systemic inflammation (hs-CRP, median [IQR], 2.5 mg/L [1.0–5.3 mg/L] vs. 1.2 mg/L [0.6–2.9 mg/L]), with approximately 50% higher NCB (1.42 ± 0.6 mm2 vs. 0.91 ± 0.2 mm2, P < 0.001). VAT associated with NCB in fully adjusted models (β = 0.47, P < 0.001). At 1-year follow-up, patients who had worsening hs-CRP had an increase in VAT (14,748.7 ± 878.1 cc3 to 15,158.7 ± 881.5 cc3; P = 0.03), whereas those who had improved hs-CRP improved their VAT (16,876.1 ± 915.2 cc3 to 16310.4 ± 889.6 cc3; P = 0.04). At 1 year, there was 10.3% reduction in NCB in those who had decreased VAT (β = 0.26, P < 0.0001), which persisted in a subset of patients at 4 years (β = 0.39, P = 0.003).CONCLUSIONSInflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its effect on early atherogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778569.FUNDINGThis study was supported by the National Heart, Lung, and Blood Institute Intramural Research Program (HL006193-05), the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and Elsevier as well as private donors.

Association Among Noncalcified Coronary Burden, Fractional Flow Reserve, and Myocardial Injury in Psoriasis.

BackgroundMyocardial infarction and premature death have been observed in patients with psoriasis. Although inflammation‐driven accelerated atherosclerosis has been proposed as a mechanism, the relationship between subclinical noncalcified coronary burden (NCB), functional coronary flow impairment, and myocardial injury is unclear.Methods and ResultsIn an ongoing longitudinal cohort study, 202 consecutive patients with psoriasis (168 at 1 year) underwent coronary computed tomography angiography to identify coronary plaque, quantify NCB, and calculate coronary fractional flow reserve by computed tomography. Serum high‐sensitivity troponin‐T (hs‐cTn‐T) was measured using a fifth‐generation assay. Overall, patients were middle‐aged, predominantly male, and low cardiovascular risk. A higher than median NCB associated with a positive hs‐cTn‐T (fully adjusted model [odds ratio (OR), 1.72; 95% CI, 1.10–2.69, P=0.018]) at baseline. Additionally, patients with a higher than median baseline NCB had higher odds of positive hs‐cTn‐T at 1 year in fully adjusted analyses (adjusted OR, 2.36; 95% CI, 1.47–3.79, P<0.001). Higher NCB was associated with a higher frequency of fractional flow reserve by computed tomography ≤0.80 (36.11% versus 25.11%, Pearson χ2=6.84, P=0.009, unadjusted OR, 2.09; 95% CI, 1.36–3.22, P<0.001) and higher frequency of a positive hs‐cTn‐T (54.36% versus 27.54%, Pearson χ2=32.23, P<0.001) in adjusted models (OR, 2.63; 95% CI, 1.56–4.42, P<0.001).ConclusionsNCB was associated with hs‐cTn‐T at baseline as well as at 1 year. Furthermore, patients with high NCB had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a >2‐ fold higher odds of positive hs‐cTn‐T. These findings underscore the importance of early vascular disease in driving myocardial injury, and support conduct of myocardial perfusion studies to better understand these findings.

Impaired Coronary Blood Flow in Patients with Psoriasis: Findings from an Observational Cohort Study

Psoriasis is a chronic inflammatory skin disease associated with high systemic inflammation, elevated coronary artery disease (CAD), and early cardiovascular events (Gelfand et al., 2006; Lerman et al., 2017; Mehta et al., 2010; Sajja et al., 2018). Moreover, recently, asymptomatic patients with psoriasis have been associated with higher lipid-rich noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA) than age- and gender-matched healthy controls (Lerman et al., 2017); however, it is unknown whether patients with psoriasis have impaired coronary blood flow.

Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis.

BackgroundInflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation.MethodsWe utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo.FindingsWe detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001).InterpretationOur results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis.FundingFunding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).

Abstract P121: Multidimensional Allostatic Load Score Directly Associates With Coronary Artery Disease Burden in Psoriasis

Introduction: Psoriasis is a chronic inflammatory skin disease associated with accelerated development of asymptomatic coronary artery disease (CAD) by coronary computed tomography angiography (CCTA). Allostatic load score is a multidimensional measure related to chronic stress which incorporates cardiovascular, metabolic and inflammatory indices. To better understand the physiologic impact of chronic stress in psoriasis, we studied the association between allostatic load score and subclinical CAD. Hypothesis: We hypothesized that allostatic load score would associate with coronary artery disease burden beyond traditional risk factors in an ongoing psoriasis cohort study. Methods: Consecutive psoriasis patients (n=275) underwent CCTA for assessment of coronary artery disease burden (QAngio, Medis). Allostatic load score was determined using established methods (see Table 1 footnote). The association between coronary artery disease burden and allostatic load score was characterized by multivariable regression (STATA 12). Results: Psoriasis patients were middle-aged, predominantly male and white, with low cardiovascular risk by Framingham risk score and moderate-severe psoriasis severity (Table 1) . Allostatic load score associated with total coronary burden (β=0.39; p&lt;0.001) and non-calcified coronary burden (β=0.40; p&lt;0.001) in unadjusted analyses. In multivariable models, allostatic load score was still associated with total coronary burden (β=0.30; p&lt;0.001) and non-calcified coronary burden (β=0.31; p&lt;0.001) independent of race, Framingham risk score and waist-hip ratio. Conclusions: Allostatic load score positively associated with both total and non-calcified coronary artery burden beyond traditional risk factors, suggesting multisystem physiologic dysregulation related to chronic stress may drive subclinical atherosclerosis in psoriasis. Efforts to understand stress effects and its reduction are critical in this population at high-risk for cardiovascular disease.

RELATIONSHIP BETWEEN CHOLESTEROL EFFLUX CAPACITY, APOLIPOPROTEIN A1 AND NONCALCIFIED CORONARY BURDEN IN PSORIASIS

Psoriasis is a systemic inflammatory disease associated with increased cardiovascular risk and impaired cholesterol efflux. Cholesterol efflux capacity (CEC), the ability of HDL to accept cholesterol from macrophages has been shown to be associated with noncalcified coronary burden (NCB) in

Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis

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. To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. 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. 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. 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. 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). 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.

Application of machine learning to determine top predictors of noncalcified coronary burden in psoriasis: An observational cohort study

Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets. In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis. The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models. Using the random forest algorithm, we found that the top 10predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output. We were unable to provide external validation and did not study cardiovascular events. Machine learning methods identified the top predictors of noncalcified coronary burdeninpsoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing thatthese are important targets when treating comorbidities in psoriasis.

AORTIC DISTENSIBILITY BY MAGNETIC RESONANCE IMAGING INVERSELY ASSOCIATES WITH NON-CALCIFIED CORONARY PLAQUE BURDEN BY CORONARY CT ANGIOGRAPHY IN PSORIASIS

Psoriasis, a chronic inflammatory skin disease, contributes to accelerated atherogenesis and increased risk of cardiovascular (CV) events. Aortic distensibility (AD) by magnetic resonance imaging (MRI) and non-calcified coronary burden (NCB) measured by coronary computed tomography angiography (CCTA

Abstract 197: Active (1,25 OH), but not Inactive (25-OH) Vitamin D levels are inversely associated with aortic Vascular Inflammation, Non-calcified Coronary Plaque Burden and Visceral Adiposity in Psoriasis

Introduction: Psoriasis (PSO), a chronic inflammatory disease associated with increased Cardiovascular (CV) risk provides an ideal model to study the role of vitamin D, a known anti-inflammatory molecule in PSO associated CV disease. Vitamin D exists as inactive 25-hydroxyvitamin D (25(OH)D) in the bloodstream which is converted to active 1,25-dihydroxyvitaminD (1,25(OH)2D) in target tissues. Cohort studies reporting CV disease among individuals with low vitamin D are inconsistent and solely measure 25(OH)D. While serum 25(OH)D is routinely measured , we propose that measurement of 1,25(OH)2D may perform better than 25(OH)D as a surrogate for CV disease. Methods: Consecutive PSO patients (N=122) and healthy controls (N=35) underwent FDG PET/CT and CCTA scans to measure vascular inflammation/ abdominal adiposity volume and coronary plaque burden respectively. Blood levels of both 1,25(OH)2D and 25(OH)D were measured by chemiluminescence (LIASON XL DIaSorin, Stillwater, MN). Results: PSO patients were middle-aged, mostly male, had moderate PSO severity and were at low CV risk by 10-year Framingham risk. PSO patients had lower serum 1,25(OH)2D compared to healthy controls (mean±SEM: 52.4±1.4 pg/ml versus 57.5±2.0, p&lt;0.037) but 25(OH)D was not significantly different (28.7±1.3 versus 27.3±2.2, p=0.30). 1,25(OH)2D, but not 25(OH)D was negatively associated with PASI score beyond adjustment for CV risk factors and systemic/ biological therapy (B=-0.20, p=0.043 vs. B=0.12, p=0.25). Furthermore, serum 1,25(OH)2D but not 25(OH)D was inversely associated with non-calcified coronary burden (B=-0.16, p&lt;0.001 versus B=0.01, p=0.84), vascular inflammation (B=-0.24, p=0.007 versus B=-0.13, p=0.16) and visceral adiposity (B=-0.43, p=0.026 versus B=-0.26, p=0.13) independent of traditional risk factors and statin/PSO therapy. Conclusion: Our data support that active 1,25(OH)2D may more accurately capture cardiometabolic disturbance compared to inactive 25(OH)D in humans.

Abstract 549: Improvement in Large Density HDL Particle Number by NMR is Associated with Reduction in Coronary Soft Plaque Burden by Coronary Computed Tomography Angiography in Psoriasis

Background: Patients with psoriasis (PSO), a chronic inflammatory disease associated with dysfunctional lipoprotein profile and accelerated risk of MI, have increased burden of subclinical atherogenesis by coronary computed tomography angiography (CCTA). Large HDL particle (l-HDLp) number by NMR has been shown to associate negatively with cardiovascular (CV) events independent of traditional lipoprotein levels. We hypothesize that increase in l-HDLp would inversely associate with soft plaque volume (PV) as well as non-calcified coronary burden (NCB). Methods: Consecutive treatment naïve PSO patients (n= 92 arteries) underwent CCTA (320 detector row, Toshiba) at baseline and one-year. Soft plaque volume and non-calcified burden were assessed using a semi-automated software (QAngio, Medis). Lipoprotein profiling and cholesterol efflux capacity was done by NMR. Results: Patients were middle aged and at low CV risk by traditional risk scores (Table 1). With improvement of PSO severity at one year and no change in traditional CV risks, l-HDLp increased (5.8 ± 0.4 vs. 6.3 ± 0.5, p=0.007) concurrently with cholesterol efflux capacity (0.95 ± 0.02 vs 1.01 ± 0.02, p=0.003). PV reduced at one-year (3.7 ± 1.2 vs. 2.9 ± 1.1 mm 3 , p=0.01), as well as NCB (1.20 ± 0.06 vs. 1.07 ± 0.06 mm 2 , p&lt;0.001). Coronary burden was inversely associated with l-HDLp beyond traditional CV risk factors (β = -0.47, p&lt;0.001). Conclusions: Increase in l-HDLp was inversely associated with coronary plaque burden possibly through improvement in HDL function via cholesterol efflux capacity, suggesting a role for NMR lipoprotein profiling in assessment of CVD in chronic inflammatory states.