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Background: T-cells play a role in pathogenesis of rheumatoid arthritis (RA) and in its cardiovascular (CV) comorbidities [1]. CD3+CD31+CXCR4+T-cells may be involved in damaged endothelium repair [2]. The percentage of these cells in the peripheral blood was reported to be lower in RA than in healthy controls, as an effect of disease activity rather than of traditional CV risk factors [3]. Abatacept (ABA), a T-cell co-stimulation blocker, is approved for the treatment of RA. In addition to its effect on disease activity, it may have a CV protective action [4]. Objectives: To evaluate CD3+CD31+CXCR4+T-cells in a cohort of RA patients in correlation with disease activity, CV parameters, and the potential effect of ABA therapy. Methods: Thirty-one RA patients (median[10th-90thpercentile] age=60[40-70] years, baseline C-reactive protein (CRP)-DAS28=4[3-5.4], body mass index (BMI)=21[17.3-28.6] kg/m2, rheumatoid factor (RF) positive:55%, anti-citrullinated peptide autoantibodies (ACPA) positive:77%) were enrolled. Thirteen patients were evaluated before and after 6 months of ABA therapy. Among them, in 5 patients without known CV risk factors (history of arterial hypertension, diabetes, hypercholesterolemia, previous CV events and smoking), a morphological evaluation of retinal arterioles was performed by adaptive optics, a validated technique quantifying microvascular damage [5]. The response to treatment was evaluated with the EULAR response criteria. Phenotypic analysis of peripheral blood T lymphocytes was made by flow-cytometry. Results: At baseline, no correlation was found between relative CD3+CD31+CXCR4+T-cell number and age, BMI, CRP DAS28, RF and ACPA titer. However, a negative correlation was observed with retinal wall thickness (Figure1). After ABA therapy (n=13), no significant differences were found between good-moderate responders (n=10) and non-responders (n=3), but the two groups seemed to show an opposite trend (T0 vs T6; from 23.8[4-45.4] to 11.9[5-38.7] and from 20.4[15.4-32.3] to 27.4[17.8-41]% of CD3+ cells, respectively). All 5 patients without known CV risk, evaluated also with adaptive optics, had a good EULAR response. A trend for reduction of CD3+CD31+CXCR4+T-cells after ABA therapy was also observed (19[7.9-45.6] vs 12.4[4.6-26.1]% of CD3+), as well as of the retinal wall thickness (14.4[12.9-16.2] vs 14.2[11.7-14.9] μm). A significant reduction of retinal wall cross-sectional area was observed (5123.3[4027.8-6145.5] vs 4852.3[3554.9-5788.2] μm2;p=0.04). Conclusion: In a subgroup of patients without known CV risk factors, CD3+CD31+CXCR4+T-cell number was inversely related to the possible presence of subclinical CV involvement, as evaluated by retinal microvascular damage. This improved after ABA therapy. These findings may suggest a possible value of CD3+CD31+CXCR4+T-cell number in the evaluation of microvascular damage, and a possible beneficial effect of ABA on the microcirculation in RA patients. Reference [1] Dessein PH, J Rheumatol2005. [2] Hur J, Circulation 2007. [3] Rodriguez Carrio J, ARD 2015. [4] Kallikourdis M, Nat Commun 2017. [5] De Ciuceis, J Hypertens2018. Acknowledgement: Bristol-Myers-Squibb Italy provided an unrestricted research grant for the study conduct. Disclosure of Interests: Silvia Piantoni: None declared, Francesca Regola: None declared, Stefano Caletti: None declared, Rajesh Kumar: None declared, Cecilia Nalli: None declared, Chiara Bazzani: None declared, Claudia Rossini: None declared, Carolina De Ciuceis: None declared, Damiano Rizzoni: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Paolo Airo: None declared

Glucagon-like peptide 1-receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 inhibitors (incretin enhancers) have been recently introduced in the treatment of diabetes mellitus. In particular, incretin mimetics seems to have ancillary antioxidant/antinflammatory properties that might be involved in endothelial protection. To investigate the effect of incretin mimetic therapy (liraglutide, exenatide) given to 11 patients with type 2 diabetes mellitus, on circulating endothelial progenitor cells (EPCs) (bone marrow-derived cells possibly participating in neovascularization and endothelial protection and repair) and capillary density. Four diabetic patients were treated with exenatide (5 μg twice daily for 4 weeks and then 10 μg twice daily for 3 weeks) and 7 with liraglutide (0.6 mg per day for 1 week and then 1.2 mg per day for 3 weeks). Peripheral venous blood samples were obtained before treatment (basal) and after 4 week in patients treated with liraglutide, and after 4 and 7 weeks in patients treated with exenatide, since drug titration is usually longer. EPCs were evaluated by flow cytometry as CD34+/KDR+ cells. Capillary density was evaluated by videomicroscopy, before and after venous congestion, in the dorsum of the 4th finger. Patients treated with liraglutide (6 males 1 female, age 54 ± 12 years) showed a decrease in body mass index and blood pressure during treatment, while patients treated with exenatide (3 males 1 female, age 57 ± 6 years) did not show any relevant change. EPCs were significantly increased after treatment with exenatide, but not after treatment with liraglutide. Capillary density was slightly increased only after 4 weeks of treatment with exenatide, however the increase was no longer present at the final evaluation. Treatment with exenatide, but not with liraglutide, was able to increase the number of circulating EPCs, possibly through an antioxidative/antiinflammatory effect.

From a physiological point of view, VEGFs (vascular endothelial growth factors) and their receptors (VEGFR) play a critical role in vascular development angiogenesis, endothelial function, and vascular tone. On the pathological side, VEGF–VEGFR signaling may induce dysregulated angiogenesis, which contributes to the growth and to the spread of tumors, being essential for neoplastic proliferation and invasion. Pharmacological inhibition of VEGF–VEGFR is now a cornerstone in the treatment of many malignancies; however, treatment with VEGF inhibitors is commonly associated with an increase in blood pressure values. This side effect is strictly connected with the mechanism of action of these medications and might represent an index of therapy efficacy. The optimal management of this form of hypertension is, at present, not clear. Calcium channel blockers and renin-angiotensin system inhibitors probably represent the most appropriate classes of hypertensive dugs for the treatment of this condition; however, no conclusive data are presently available.

none 21 no The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography. none De Ciuceis, Carolina; Agabiti Rosei, Claudia; Caletti, Stefano; Trapletti, Valentina; Coschignano, Maria A; Tiberio, Guido A M; Duse, Sarah; Docchio, Franco; Pasinetti, Simone; Zambonardi, Federica; Semeraro, Francesco; Porteri, Enzo; Solaini, Leonardo; Sansoni, Giovanna; Pileri, Paola; Rossini, Claudia; Mittempergher, Francesco; Portolani, Nazario; Ministrini, Silvia; Agabiti-Rosei, Enrico; Rizzoni, Damiano De Ciuceis, Carolina; Agabiti Rosei, Claudia; Caletti, Stefano; Trapletti, Valentina; Coschignano, Maria A; Tiberio, Guido A M; Duse, Sarah; Docchio, Franco; Pasinetti, Simone; Zambonardi, Federica; Semeraro, Francesco; Porteri, Enzo; Solaini, Leonardo; Sansoni, Giovanna; Pileri, Paola; Rossini, Claudia; Mittempergher, Francesco; Portolani, Nazario; Ministrini, Silvia; Agabiti-Rosei, Enrico; Rizzoni, Damiano

Objective It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. Design and methods We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. Results A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. Conclusion In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.

Objective:Immune system (in particular T lymphocytes) is involved in the pathogenesis of arterial hypertension and microvascular remodelling. It has also been recently suggested a crucial role for spleen in the development and onset of hypertension, through a neuroimmune mechanism mediated by a sple

Background: It was proposed that early vascular ageing may be an important mechanism of vascular damage in large conductance arteries. However it is not known whether aging may also affect small resistance artery morphology. Patients and methods: For this reason, we investigated 100 patients with essential hypertension. Secondary forms of hypertension were excluded according to standard clinical evaluations and biochemical or instrumental assessments. In all patients, an evaluation of small resistance arteries morphology was performed by wire micromyography. A small amount of subcutaneous tissue was obtained by local biopsy or during election surgery and subcutaneous small resistance arteries were dissected and mounted on a myograph; the media to lumen ratio (M/L) was then measured. Results: The age range of our population was 22-81 years, with a mean value of 57±12 years; 14% of them were current smokers, 32% had alterations in lipid patterns, none of them had diabetes mellitus, 58 were males and average blood pressure values were 156/95±19/12 mmHg. We found a significant correlation between M/L and age (r=0.30, p=0.002): the statistical significance of the correlation persisted after correction for confounding variables (gender, serum cholesterol, smoking status, serum glucose, systolic or diastolic blood pressure values). A statistically significant inverse correlation was also observed between internal diameter and age (r=−0.20, p=0.046). Conclusion: Our data suggest that age may affect microvascular structure in hypertensive patients. It is also possible that hypertension may anticipate the effects of physiological aging, and this should be explored in a relatively large population of normotensive subjects.

Background: It was proposed that early vascular ageing may be an important mechanism of vascular damage in large conductance arteries. However it is not known whether aging may also affect small resistance artery morphology. Patients and Methods: For this reason, we investigated 100 patients with essential hypertension. Secondary forms of hypertension were excluded according to standard clinical evaluations and biochemical or instrumental assessments. In all patients, an evaluation of small resistance arteries morphology was performed by a wire micromyographic approach (Mulvany’s technique). A small amount of subcutaneous tissue was obtained by local biopsy or during election surgery and subcutaneous small resistance arteries were dissected and mounted on a myograph; the media to lumen ratio (M/L) was then measured. Results: The age range of our populaton was 22-81 years, with a mean value of 57±12 years; 14% of them were current smokers, 32% had alterations in lipid patterns, none of them had diabetes mellitus, 58 were males and average blood pressure values were 156/95±19/12 mmHg. We found a significant correlation between M/L and age (r=0.30, p=0.002): the statistical significance of the correlation persisted after correction for counfounding variables (gender, serum cholesterol, smoking status, serum glucose, systolic or diastolic blood pressure values). A statistically significant inverse correlation was also observed between internal diameter and age (r=-0.20, p=0.046), while the correlation beween age and media thickness did not reach statistical significance (r=0.09, p=0.37). Conclusion: Our data suggest that age may affect microvascular structure in hypertensive patients. It is also possible that hypertension may anticipate the effects of physiological aging, and this should be explored in a relatively large population of normotensive subjects.

Objective: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th17 lymphocytes may contribute to the progression of hypertension and microvascular damage while TREG lymphocytes seem to be protective. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. Methods: We have investigated 32 severely obese patients undergoing bariatric surgery, 24 normotensive lean subjects and 11 hypertensive lean subjects undergoing an election surgical intervention. No sign of local or systemic inflammation was present in any subject or patient. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry after 5 hour in vitro activation in order to assess T-effector and T-regulatory (TREG) lymphocytes. Subsets of TREGS were defined as follows: −TREGS recent thymic emigrants (RTE), directly derived from thymus: CD31+; −TREGS naïve: CCR7+CD45RA+; −TREGS central memory (CM): CCR7+CD45RA−; −TREGS effector memory (EM): CCR7−CD45RA−; −TREGS terminal differentiated effector memory (TDEM): CCR7−CD45RA+. Results: The results are summarized in the Table (*p < 0.05, **p < 0.01, ***p < 0.001 vs. lean normotensives; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. lean hypertensives). A marked reduction of several TREG subpopulations was observed in obese patients compared with controls, together with an increased in some T-effector cells. Lean normotensives Lean hypertensives Obese patients TREGs (%) 4.11 ± 1.60 4.64 ± 1.66 2.69 ± 1.81**## TREGs (abs number) 45.4 ± 24.3 45.4 ± 23.8 27.3 ± 21.1**# TREGs naíve (%) 22.1 ± 10.1 18.1 ± 13.1 13.34 ± 12.9** TREGs naíve (abs number) 10.6 ± 7.75 9.71 ± 8.87 3.87 ± 5.28***## TREG CM (%) 32.3 ± 13.8 32.8 ± 17.8 22.7 ± 15.2*# TREGs CM (abs number) 14.7 ± 10.2 14.2 ± 9.08 6.10 ± 8.08***## CD4+ EM (%) 24.4 ± 9.96 26.8 ± 12.5 34.1 ± 13.3** CD161+CD28+ (%) 86.2 ± 28.5 94.9 ± 5.63 97.2 ± 5.39* Conclusion: TREG lymphocytes are clearly reduced in severely obese patients, possibly contributing to the development of marked microvascular alterations previously observed in such a population.

Background: In the development of hypertensive microvascular remodeling, a relevant role may be played by changes in extracellular matrix proteins. Aim of this study was the to evaluate some extracellular matrix components within the tunica media of subcutaneous small arteries in 9 normotensive subjects and 12 essential hypertensive patients, submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region. Patients and Methods: Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media to internal lumen ratio was measured. In addition, fibronectin, laminin, transforming growth factor-beta-1 (TGF-β1) and emilin-1 contents within the tunica media were evaluated by immunofluorescence and relative immunomorphometrical analysis (immunopositivity % of area). The total collagen content and collagen subtypes within the tunica media were evaluated using both Sirius red staining (under polarized light) and immunofluorescence assay. Results: Normotensive controls had less total and type III collagen in respect with hypertensive patients. Fibronectin and TGF-β1 tunica media content was significantly greater in essential hypertensive patients, compared with normotensive controls, while laminin and emilin-1 tunica media content was lesser in essential hypertensive patients, compared with normotensive controls. A significant correlation was observed between fibronectin tunica media content and media to lumen ratio. Conclusions: Our results indicate that, in small resistance arteries of patients with essential hypertension, a relevant fibrosis may be detected; fibronectin and TGF-β1 tunica media content is increased, while laminin and emilin-1 content is decreased; these changes might be involved in the development of small resistance artery remodeling in humans.