Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study.

This is the author accepted manuscript. The final version is available from the American Heart Association via http://dx.doi.org/10.1161/ATVBAHA.115.306460OBJECTIVE: To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography computed tomography. APPROACH: In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using (18)F-fluorodeoxyglucose positron emission tomography computed tomography. RESULTS: Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8-8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (β=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (β=0.53; P=0.02) and vascular inflammation (β=0.48; P=0.02). CONCLUSIONS: Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.JMT is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z) and the NIHR Cambridge Biomedical Research Centre. JHFR is part-supported by the HEFCE, the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trus

Cardiac evaluation of hospitalized children with 2019 coronavirus (COVID-19) infection at a single large quaternary center

Background: Cardiac complications of serious SARS-CoV-2 infections, especially Multisystem Inflammatory Syndrome of Children (MIS-C) are well described, however current studies have not considered pediatric patients hospitalized with no cardiac concerns. We established a protocol for cardiac evaluation of all admitted COVID-19 patients three weeks post-discharge, irrespective of cardiac concerns. We assessed cardiovascular outcomes and hypothesized that patients with absent cardiac concerns are at lower risk for cardiac abnormalities. Methods: This was a retrospective study of 160 patients admitted for COVID-19 (excluding MIS-C) between March 2020 and September 2021 with subsequent echocardiogram(s) performed at our center. Patients were divided into 4 subgroups: Group 1 included patients with absent cardiac concerns, admitted to acute care (1a) and intensive care unit (ICU) (1 b). Group 2 included patients with cardiac concerns, admitted to acute care (2a) and ICU (2 b). Groups were compared based on clinical endpoints and echocardiographic measurements, including tissue Doppler imaging (TDI) assessment of diastolic function (z-score of septal Mitral E/TDI E′ and lateral E/TDI E′). Chi-squared, Fisher's exact, and Kruskal-Wallis tests were used. Results: Traditional cardiac abnormalities varied significantly between the groups; with Group 2 b having the most (n = 8, 21%), but still found in Group 1a (n = 2, 3%) and Group 1 b (n = 1, 5%). No patients in Group 1 demonstrated abnormal systolic function, compared to Group 2a (n = 1, 3%) and Group 2 b (n = 3, 9%, p = 0.07). When including TDI assessment of diastolic function, the total incidence of abnormalities found on echocardiogram was increased in all groups. Conclusion: Cardiac abnormalities were found in pediatric patients admitted with COVID-19, even those without apparent cardiovascular concerns. The risk was greatest in ICU-admitted patients with cardiac concerns. The clinical significance of diastolic function assessment in these patients remains unknown. Further studies are needed to assess long-term cardiovascular sequelae of children with COVID-19, irrespective of cardiac concerns

Skin-specific expression of PCSK9 may provide novel link for increased cardiovascular disease risk in psoriasis

Cardiovascular disease (CVD) remains the most common cause of death worldwide and is more prevalent in chronic inflammatory states such as psoriasis. Recently, pro-protein convertase subtilisin/kexin type 9 (PCSK9) has gained attention as a novel therapeutic target in CVD due to its LDL cholesterol lowering capabilities. Therefore, we sought to investigate the relationship between PCSK9 and psoriasis. In patients with psoriasis (n=88), circulating PCSK9 levels are elevated compared to those of healthy volunteers (HV) (n=52) (Psoriasis: 253 ng/mL vs HV: 189 ng/mL, p\u3c0.001) and are positively associated with coronary artery calcium (CAC) scores, beyond traditional cardiovascular risk factors (β =0.38, p\u3c0.004). Similarly, in our mouse model of psoriasis, we observe a 1.7-fold increase (p\u3c0.0001) in circulating PCSK9 compared to that of littermate controls. Moreover, there is a robust relationship between circulating PCSK9 levels and psoriasis skin severity (β =0.92, p\u3c0.001). We also find that although hepatic PCSK9 protein levels are unchanged in the psoriatic mice, low-density lipoprotein receptor (LDLR), the direct target of PCSK9, is significantly decreased at the protein level. Furthermore, we determine that both PCSK9 mRNA and protein levels are elevated in the lesional skin of psoriatic mice compared to those of littermate controls, a finding we confirmed in our psoriatic human skins. Taken together, we postulate that psoriatic lesional skin, specifically the epidermis, is the source for elevated plasma PCSK9, thereby decreasing hepatic LDLR, and suggesting a potential link between psoriasis and cardiovascular disease

Characterization of PCSK9 in the Blood and Skin of Psoriasis

© 2020 The Authors 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 \u3c 0.05 for each comparison) and correlated with PASI (r = 0.43, P \u3c 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 \u3c 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

GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis.

RATIONALE: GlycA, an emerging inflammatory biomarker, predicted cardiovascular events in population-based studies. Psoriasis, an inflammatory disease associated with increased cardiovascular risk, provides a model to study inflammatory biomarkers in cardiovascular disease (CVD). Whether GlycA associates with psoriasis and how it predicts subclinical CVD beyond hsCRP in psoriasis is unknown. OBJECTIVE: To investigate the relationships between GlycA and psoriasis, and between GlycA and subclinical CVD. METHODS AND RESULTS: Psoriasis patients and controls (n=412) participated in a two-stage study. We measured GlycA by NMR spectroscopy. NIH participants underwent 18-FDG PET/CT scans to assess vascular inflammation (VI) and coronary CT angiography to quantify coronary artery disease (CAD) burden. Psoriasis cohorts were young (mean age=47.9), with low cardiovascular risk and moderate skin disease. HsCRP and GlycA were increased in psoriasis compared to controls [GlycA: (PENN: 408.8±75.4 vs. 289.4±60.2, p<0.0001, NIH: 415.8±63.2 vs. 346.2±46, p<0.0001)] and demonstrated a dose-response with psoriasis severity. In stage 2, VI (β=0.36, p<0.001) and CAD (β=0.29, p=0.004) associated with GlycA beyond CV risk factors in psoriasis. In ROC analysis, GlycA added value in predicting VI (p=0.01) and CAD (p<0.01). Finally, initiating anti-TNF therapy (n=16) reduced psoriasis severity (p<0.001), GlycA (463.7±92.5 vs. 370.1±78.5; p<0.001) and VI (1.93±0.36 vs. 1.76±0.19; p<0.001), while GlycA remained associated with VI (β=0.56, p<0.001) post-treatment. CONCLUSIONS: GlycA associated with psoriasis severity and subclinical CVD beyond traditional CV risk and hsCRP. Moreover, psoriasis treatment reduced GlycA and VI. These findings support the potential utility of GlycA in subclinical CVD risk assessment in psoriasis and potentially other inflammatory diseases