European Journal of Preventive Cardiology http://cpr.sagepub.com/

Systemic inflammation and imbalance between endothelial injury and repair in patients with psoriasis are associated with preclinical atherosclerosis Matteo Pirro, Luca Stingeni, Gaetano Vaudo, Massimo R Mannarino, Stefano Ministrini, Marilisa Vonella, Katharina Hansel, Francesco Bagaglia, Abdalkader Alaeddin, Paolo Lisi and Elmo Mannarino European Journal of Preventive Cardiology published online 6 June 2014 DOI: 10.1177/2047487314538858 The online version of this article can be found at: http://cpr.sagepub.com/content/early/2014/06/06/2047487314538858

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EURO PEAN SO CIETY O F CARDIOLOGY ®

Original scientific paper

Systemic inflammation and imbalance between endothelial injury and repair in patients with psoriasis are associated with preclinical atherosclerosis

European Journal of Preventive Cardiology 0(00) 1–9 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314538858 ejpc.sagepub.com

Matteo Pirro1, Luca Stingeni2, Gaetano Vaudo1, Massimo R Mannarino1, Stefano Ministrini1, Marilisa Vonella2, Katharina Hansel2, Francesco Bagaglia1, Abdalkader Alaeddin1, Paolo Lisi2 and Elmo Mannarino1

Abstract Background: Systemic inflammation and imbalance between endothelial injury and repair, the latter referred to as vascular incompetence, are associated with atherosclerosis and cardiovascular risk. Psoriasis, an inflammatory disease of the skin, has been associated with atherosclerosis. We investigated whether, in psoriasis, inflammation and vascular incompetence are associated with carotid intima-media thickness (cIMT) irrespective of metabolic syndrome and other established cardiovascular risk factors. Methods: High sensitivity C-reactive protein (hsCRP), the ratio between endothelial microparticles (EMPs) and progenitors (EPCs), a marker of vascular incompetence, and cIMT were measured in 84 patients with psoriasis and 90 healthy controls, balanced for age, gender and the prevalence of metabolic syndrome. Results: Patients with psoriasis had higher hsCRP, EMP/EPC ratio and cIMT than controls. Patients with both psoriasis and metabolic syndrome had the highest hsCRP levels, psoriasis and metabolic syndrome being associated with a 3.1- and 2.6-fold increased risk of having high hsCRP levels, respectively. Logarithm transformed hsCRP and EMP/EPC ratio were predictors of high cIMT (odds ratio 3.8; 95% confidence interval 1.3–11.4; p ¼ 0.02 and odds ratio 8.7; 95% confidence interval 2.7–27.5; p < 0.001, respectively) regardless of confounders. Patients with high hsCRP and EMP/EPC ratio had higher cIMT than those with none or at least one of risk variable. Conclusions: Patients with psoriasis have an increased burden of cardiovascular risk, including inflammation, vascular incompetence and early atherosclerosis. Increased hsCRP levels, possibly sustained by the inflammatory nature of psoriasis and metabolic syndrome, and vascular incompetence are associated with early carotid atherosclerosis, regardless of metabolic syndrome and other established cardiovascular risk factors.

Keywords Psoriasis, atherosclerosis, inflammation, C-reactive protein, endothelial microparticles, endothelial progenitor cells Received 18 March 2014; accepted 18 May 2014

Introduction Evidence for the involvement of an inflammatory response in atherogenesis has intensified in the last years.1,2 Accordingly, several studies have confirmed an association between markers of inflammation (mainly high sensitivity C-reactive protein (hsCRP)) and the risk of atherosclerosis mediated cardiovascular (CV) events.2,3 Psoriasis, an inflammatory disease of the skin, has been frequently associated with early

1 Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Italy 2 Unit of Clinical, Allergological and Venereological Dermatology, Department of Medicine, University of Perugia, Italy

Corresponding author: Matteo Pirro, Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, University of Perugia, Hospital ‘Santa Maria della Misericordia’, Piazzale Menghini, 1, Perugia 06129, Italy. Email: [email protected]

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atherosclerosis,4–9 although its prospective association with CV risk is still debated.10–11 The inflammatory nature of psoriasis12 and the high prevalence of several components of the metabolic syndrome in patients with psoriasis13 have been claimed to explain the increased burden of atherosclerosis in these patients.12,13 However, the extent to which the link between psoriasis and carotid intima-media thickness (cIMT) reflects the presence of systemic inflammation and metabolic syndrome has not been definitively elucidated. Impaired vascular competence,14,15 the result of an imbalance between mature endothelium injury and repair by stem cell progenitors, has been expressed by an increased ratio between the number of endothelial microparticles (EMPs) and that of endothelial progenitor cells (EPCs).2,14–17 The number of circulating EMPs increased when mature endothelial cells were exposed to different activating and apoptotic stimuli;18 hence, it is believed that EMPs might reflect the burden of endothelial injury.18 Accumulating evidence also suggested that EMPs might have a proatherogenic role and predict the risk of future CV events.19–21 Because the number and function of EPCs have been linked with an improved endothelial function,22 it is not surprising that reduced levels of circulating EPCs predicted an increased risk of future CV events.23 Interestingly, either an increased number of circulating EMPs or reduced EPC levels have been observed in patients with psoriasis.24–26 However, to our knowledge, neither vascular incompetence nor the association between systemic inflammation, vascular incompetence and cIMT have been investigated in a consistent number of psoriasis patients and corrected for the confounding influence of metabolic syndrome and other established CV risk factors. Therefore, the aims of the study were the following: first, to investigate multiple markers of CV risk (i.e. systemic inflammation, vascular incompetence and cIMT) in psoriasis patients not receiving current systemic anti-psoriatic therapy; second, to ascertain whether systemic inflammation and impaired vascular competence are associated with cIMT irrespective of the confounding effect of metabolic syndrome and other CV risk factors.

Materials and methods

impairment, liver failure or clinical/laboratory evidence of concomitant inflammatory disease. Ninety age- and gender-balanced healthy controls (CTRs) were recruited among those attending the Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases (Perugia, Italy) for CV risk assessment. The study was approved by the local Ethics Committee and all participants gave their informed consent.

Clinical assessment and cIMT All the determinations were made at the medical centre at 08.00 hours, with a room temperature between 21 C and 23 C, after a 13-h overnight fast. Height and weight were measured to the nearest 0.1 cm and 0.1 kg respectively. Body mass index (BMI) was calculated as weight in kilograms divided by height squared in metres; waist circumference was also measured. All participants underwent a complete assessment of traditional CV risk factors. The Psoriasis Area Severity Index (PASI), an index used to express the severity of psoriasis, was calculated. Total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and glucose were determined by enzymatic colorimetric method (Autoanalyzer KONE-PRO; DASIT SpA, Cornaredo, Milan, Italy); low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation. Plasma CRP levels were measured using the hsCRP Assay (Siemens Dade Behring, Siemens SpA, Milan, Italy) by nephelometry (BN100; Siemens Dade Behring, Siemens SpA, Milan, Italy). The presence of metabolic syndrome was defined according to the Joint Scientific Statement.27 cIMT was evaluated with an ultrasound device (Technos MP, ESAOTE, Genoa, Italy) equipped with a 5- to 10-MHz linear array probe. The near and far walls of the left and right common carotid, the bifurcation and the internal carotid arteries were visualized and recorded. Recorded cIMT measurements were performed by the same observer using dedicated software (Artery Measurement System – AMS II v1.1364). Each cIMT measurement was performed in at least three different frames, and the mean cIMT of the whole carotid tree was calculated. The intra-sonographer intraclass correlation coefficients for duplicate cIMT scans was 0.96, and the inter-sonographer intraclass correlation coefficients for the cIMT measurement was 0.86.

Study subjects Eighty-four patients with chronic plaque psoriasis were recruited from the Unit of Clinical, Allergological and Venereological Dermatology (Perugia, Italy). Patients with clinical or radiological evidence of psoriatic arthritis were excluded. Patients with any one of the following were excluded: history of CV disease, diabetes, renal

Statistical analysis SPSS statistical package, release 17.0 (SPSS Inc., Chicago, IL) was used for statistical analyses. Values are expressed as the mean  SD or as the median and 25th–75th percentiles. The ratio of EMPs to EPCs, hereafter referred to as Ratio, was calculated.

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Logarithm (Lg) transformation was performed when appropriate. Independent sample t test was used for two-group comparisons and ANOVA with post-hoc Bonferroni correction was used to compare the study variables between three or more groups. Specifically, patients were grouped according to the presence or not of either psoriasis or metabolic syndrome into four groups (psoriasis-metabolic syndrome (PS-MS) Groups: PS–MS–, PS–MSþ, PSþMS–, PSþMSþ). An additional grouping procedure was performed by definition of specific cut-off points for the risk variables hsCRP and Ratio: high hsCRP was defined by a plasma level above 3 mg/l,28 whereas high Ratio was defined by an absolute level above 2.6 n/ml (median Ratio in the study participants). Hence, participants were separated into three groups (CRP-Ratio Groups) depending on whether they had no or one or two risk variables. The 2 test was used to compare proportions across groups. Correlation analyses were performed using the Pearson’s and Spearman’s coefficients of correlation. Stepwise linear regression analysis was used to estimate prediction of either Lg transformed hsCRP level (LgCRP) or LgRatio, by adjusting for these confounders: age, gender, smoking status, LDL cholesterol,

metabolic syndrome, psoriasis; LgCRP and LgRatio were also added as independent variables in the regression analysis performed to predict cIMT levels. Standardized coefficients were calculated as a measure for the relative predictive value. Participants with a cIMT above or equal to 1.15 mm (median cIMT in the study participants) were defined as having high cIMT. Logistic regression analysis was performed by including cIMT as a categorical dependent variable (high versus low cIMT). Patients with PASI > 18 (median PASI value in psoriasis patients) were defined as having high PASI and patients with PASI  18 as having low PASI. Statistical significance was assumed if a null hypothesis could be rejected at p ¼ 0.05.

Results The characteristics of 174 participants with or without psoriasis are summarized in Table 1. Patients with psoriasis and CTRs were balanced in terms of age, gender, smoking status, BMI and presence of the metabolic syndrome. Psoriasis patients had significantly lower LDL cholesterol and higher diastolic blood pressure.

Table 1. Clinical and biochemical characteristics of patients with psoriasis and healthy controls.

Age, years Gender, % female Smokers, % PASI Disease duration, days Body mass index, kg/m2 Waist circumference, cm Office systolic BP, mmHg Office diastolic BP, mmHg Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glucose, mg/dl Metabolic syndrome, % Last systemic treatment, n None Acitretin Anti-TNF Cyclosporine Methotrexate

Psoriasis (N ¼ 84)

Controls (N ¼ 90)

p

53  14 64 40 18.6  10.0 162  128 27.4  4.9 98  19 126  10 82  7 203  39 133  40 49  13 107 (77–175) 93  13 44

53  9 69 33 – – 27.3  2.8 95  7 128  9 79  5 223  37 151  35 47  13 116 (85–151) 93  13 42

0.82 0.53 0.30 – – 0.86 0.07 0.11 0.01