Ischemic cardiovascular involvement in psoriasis: A systematic review Susanna Mosca, Paola Gargiulo, Nicola Balato, Luisa Di Costanzo, Antonio Parente, Stefania Paolillo, Fabio Ayala, Bruno Trimarco, Filippo Crea, Pasquale Perrone-Filardi  International Journal of Cardiology  Volume 178, Pages 191-199 (January 2015) DOI: 10.1016/j.ijcard.2014.10.092 Copyright © 2014 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 The PRISMA flowchart of studies included in the systematic review. International Journal of Cardiology 2015 178, 191-199DOI: (10.1016/j.ijcard.2014.10.092) Copyright © 2014 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Prevalence of cardiovascular (CV) disease in psoriatic patients. A. Adjusted relative risk of myocardial infarction (MI) in psoriatic patients based on patient age. In psoriatic patients, the highest relative risk (expressed in log scale) having an MI occurred in younger patients, and the relative risk was attenuated in older patients the risk of MI. For the same age decade the risk increases with severity disease increasing. From: Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296(14):1735-41. B. Incidence of CV disease mortality in psoriatic patients compared with unexposed population. The unadjusted overall risk of mortality due to CV disease per 1000person-years was significantly (p=0.002) increased in patients with severe psoriasis patients (8.75, 95% CI 7.18–10.56) compared with unexposed patients (6.19, 95% CI 5.51–6.93). From: Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J 2010;31(8):1000-6. International Journal of Cardiology 2015 178, 191-199DOI: (10.1016/j.ijcard.2014.10.092) Copyright © 2014 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Molecular mechanisms linking systemic inflammation, insulin resistance and atherosclerosis in psoriatic patients. Psoriasis is characterized by chronic systemic inflammatory state secretion, characterized by a strong Th-1 and Th-17 polarization, with increased expression of cytokines (INF-γ, IL-2, TNF α and IL-17), that involves skin, adipose tissue, skeletal muscle, liver and vascular endothelium. These mediators play an important role in the development of psoriatic plaques, stimulating angiogenesis and keratinocyte proliferation, and promote insuline resistance, metabolic abnormalities and endothelial dysfunction (ED), which contribute to the formation and progression of atherosclerotic plaques. At molecular level, pro-inflammatory cytokines activate serine kinases, including JNK and IKKβ, which in turn inhibit IRS-1, leading to a selective impairment of PI-3-kinase-dependent signaling, with subsequent overstimulation of unaffected MAP-kinase-dependent pathway. This pathway-specific insuline receptor plays a key role in the pathogenesis of ED, characterized by decreased production of NO, increased secretion of ET-1 and expression of adhesion molecules on cell surface. At level of adipose tissue and skeletal muscle, metabolic functions of insulin are mediated by PI-3-kinase-dependent signaling pathway by Akt-dependent phosphorylation of downstream effectors that regulate glucose uptake, glycogen synthesis and lipolysis. Chronic exposure to pro-inflammatory cytokines leads to decreased activity of this signaling and consequently to IR. The combined effect of ED and insuline resistance, induced by psoriatic chronic inflammatory state, could be helped to explain the increased rate and severity of atherosclerosis in psoriatic patients. eNOS, endothelial NO synthase; ET-1, endothelin-1; IKKβ, IkB kinase complex β; IR, insulin receptor; IRS-1, Insulin Receptor Substrates-1; JNK, c-Jun N-terminal kinase; MAP, Mitogen-Activated Protein; VCAM-1; PI-3, Phosphoinositide-3; PDK-1; NO, nitric oxide. International Journal of Cardiology 2015 178, 191-199DOI: (10.1016/j.ijcard.2014.10.092) Copyright © 2014 Elsevier Ireland Ltd Terms and Conditions