Faculty Bibliography

OBJECTIVE:=0.02). CONCLUSIONS:In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation, which suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.

BACKGROUND:Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS:mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS:Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS:Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

Background/UNASSIGNED:Psoriasis is an inflammatory skin disease associated with atherosclerotic cardiovascular disease (ASCVD) risk factors and vascular disease. The relative impact of psoriasis on vascular disease is the strongest in young patients with psoriasis, yet data are lacking on how sex differences influence cardiovascular risk factors and vascular disease in these patients. Objective/UNASSIGNED:This observational study aimed to identify the burden of cardiovascular risk factors and vascular disease in patients with psoriasis and to explore whether this burden is different between men and women age < 35 years. Methods/UNASSIGNED:Young (age ≥ 20 and < 35 years) hospitalized patients with psoriasis from the United States National Inpatient Sample were compared with those matched patients without psoriasis. Vascular disease was defined as ASCVD and/or venous thromboembolic disease. Multivariable logistic regression was used to determine the associations between psoriasis, sex, ASCVD risk factors, and vascular disease. Results/UNASSIGNED:Overall, patients with psoriasis (n = 18,353) were more often obese (16% vs. 6%); smokers (31% vs. 17%); and diagnosed with diabetes mellitus (10% vs. 6%), hypertension (16% vs. 8%), hyperlipidemia (6% vs. 2%), ASCVD (2.2% vs. 1.6%), and deep vein thrombosis (6% vs. 4%; all p < .001) compared with patients without psoriasis (n = 55,059; matched by age, sex, and race). When stratified by sex, women with psoriasis were more likely to have multiple cardiovascular risk factors and ASCVD (odds ratio: 2.6; 95% confidence interval [2.1-3.1]) compared with men with psoriasis (odds ratio: 1.2; 95% confidence interval [0.9-1.4]; interaction p < .01). The association between psoriasis and ASCVD in women remained unchanged after multivariable adjustment for traditional cardiovascular risk factors. Conclusion/UNASSIGNED:Psoriasis was associated with cardiovascular disease and risk factors in young hospitalized patients, with stronger associations among women than among men.

BACKGROUND:While progress in the prevention of cardiovascular disease (CVD) has been noted over the past several decades, there are still those who develop CVD earlier in life than others. OBJECTIVE:We investigated traditional and lifestyle CVD risk factors in young to middle-aged patients compared to older ones with obstructive coronary artery disease (CAD). METHODS:A retrospective analysis of patients with a new diagnosis of obstructive CAD undergoing coronary intervention was performed. Young to middle-aged patients were defined as those in the youngest quartile (n = 281, mean age 50 ± 6 years, 81% male) compared to the other three older quartiles combined (n = 799, mean age 69 ± 7.5 years, 71% male). Obstructive CAD was determined by angiography. RESULTS:Young to middle-aged patients compared to older ones were more likely to be male (p < 0.01), smokers (21 vs. 9%, p < 0.001), and have a higher body mass index (31 ± 6 vs. 29 ± 6 kg/m2, p < 0.001). Younger patients were less likely to eat fruits, vegetables, and fish and had fewer controlled CVD risk factors (2.7 ± 1.2 vs. 3.0 ± 1.0, p < 0.001). Compared to older patients, higher levels of psychological stress (aOR 1.6, 95% CI 1.1-2.4), financial stress (aOR 1.8, 95% CI 1.3-2.5), and low functional capacity (aOR 3.3, 95% CI 2.4-4.5) were noted in the young to middle-aged population as well. CONCLUSION/CONCLUSIONS:Lifestyle in addition to traditional CVD risk factors should be taken into account when evaluating risk for development of CVD in a younger population.

Background: The mechanisms for increased cardiovascular risk in patients with Psoriasis (PsO) are unknown. Activated platelets adhere to damaged endothelium and secrete pro-inflammatory cytokines thus promoting atherosclerosis. The contribution of platelets to promote endothelial activation in PsO has not been established. Method(s): Patients with active PsO (n = 6, mean age 46 years, 50% male) were compared to age- and sex- matched controls. Result(s): Platelets were present in PsO lesional skin compared to non-lesional skin, and controls (Figure 1A). To investigate the clinical significance, isolated platelets from PsO and matched-controls demonstrated increased platelet adhesion to human aortic endothelial cells (HAECs) in both basal and activated (thrombin stimulated) states (Figure 1B). Platelets isolated from PsO subjects enhanced HAEC expression of pro-inflammatory transcripts IL-1B, IL-8 and COX-2 (Figure 1C) compared to controls. Next generation RNA sequencing of isolated platelets from PsO and controls revealed upregulation of transcripts indicative of platelet - endothelial interactions such as the pro-atherogenic mediators s100A8/A9 (p < 0.05). Conclusion(s): We describe for the first time platelet-endothelial interactions as a potential mechanism of early cardiovascular risk in patients with PsO. These findings have important clinical implications suggesting that targeting platelet specific pathways in PsO may reduce cardiovascular risk. [Figure presented]2019 American College of Cardiology Foundation. All rights reserved

Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10^-7) including upregulation of CASP5 and interleukin ( IL) -1β. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β( Z score 3.7; P=1.02×10^-23) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.

Psoriasis is an inflammatory skin disease associated with increased cardiovascular risk and serves as a reliable model to study inflammatory atherogenesis. Because neutrophils are implicated in atherosclerosis development, this study reports that the interaction among low-density granulocytes, a subset of neutrophils, and platelets is associated with a noncalcified coronary plaque burden assessed by coronary computed tomography angiography. Because early atherosclerotic noncalcified burden can lead to fatal myocardial infarction, the low-density granulocyte-platelet interaction may play a crucial target for clinical intervention.