Caterina Oriana Aragona

Vitamin D Status in Rheumatoid Arthritis: Inflammation, Arterial Stiffness and Circulating Progenitor Cell Number

Background and Aims Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA. Methods and Results CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen. Conclusions RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA.

Circulating progenitor cells in hypertensive subjects: Effectiveness of a treatment with olmesartan in improving cell number and miR profile in addition to expected pharmacological effects

CD34+ circulating progenitor cells (CD34+CPCs) are a population of multipotent cells which can delay the development of atherosclerosis and cardiovascular disease (CVD) in conditions of increased CV risk. MicroRNAs (miRs) 221 and 222 modulate different genes regulating angiogenesis and inflammation; moreover, miR221/22 have beenshown to participate in differentiation and proliferation of CD34+CPCs, inhibiting cell migration and homing. miR221/222 in CD34+CPCs from hypertensive subjects are also increased and associated with CD34+cell number and reactive oxygen species (ROS). We evaluated CD34+CPC number, intracellular miR221/222 and ROS levels, arterial stiffness (AS)and echocardiography indices at baseline (T0).Then, after a six-month treatment with olmesartan, 20 mg/day (T1), in 57 hypertensive patients with left ventricular hypertrophy (LVH) and with no additional risk factor for CVD, and in 29 healthy controls (baseline),fibrinogen, C-reactive protein (CRP), glucose and lipid profiles were also evaluated.At T1, blood pressure values, CRP and fibrinogen levels, ROS and miR221/222 were significantly decreased (all p <0.001), as were AS indices and LV mass index (p<0.001), while cell number was increased (p<0.001). Olmesartan is effective in reducing miR and ROS levels in CD34+CPCs from hypertensive subjects, as well as in increasing CD34+CPC number, providing multilevel CV protection, in addition to its expected pharmacological effects.

Clinical impact of angiotensin I converting enzyme polymorphisms in subjects with resistant hypertension

Angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism is thought to affect renin–angiotensin system (RAS) activity and development of cardiovascular disease; significant associations between I/D polymorphism and atherosclerosis, stroke, nephropathy, and early mortality were already found. We investigated whether Southern Italy resistant hypertensives presented an association between the presence of I and/or D alleles and early vascular damage, inflammation, and insulin resistance. One-hundred-fifty resistant hypertensives were enrolled, studied, and genotyped; carotid intima-media thickness (cIMT), arterial stiffness (AS), and HOMA indices were also evaluated. D allele was more prevalent, and 74 patients presented DD homozygosis. Sixty-eight patients had metabolic syndrome (MetS), without significant differences between DD and I allele carriers. DD genotype appeared strongly associated with higher HOMA values (p < 0.001), and also with both Augmentation Index (AIx, p = 0.003) and Pulse Wave Velocity (PWV, p = 0.023). A significant association was found between DD genotype and cIMT (p < 0.005), while no association between ACE genotype and the presence of carotid plaques. HOMA was correlated with AS (PWV: p < 0.001; AIx: p < 0.01). DD genotype appeared to be associated with AS and HOMA index, but not with inflammation, independently from blood pressure values and the presence of other MetS factors, confirming D allele as an independent risk marker. Vascular damage may develop and progress independently from other risk factors in resistant hypertensives, likely through the interplay between ACE gene, RAS activity, and insulin resistance.

CD34+ cell count predicts long lasting life in the oldest old

Circulating progenitor cells (CPCs) represent a pool of cells capable of differentiating into mature cells of different organs and systems, promoting tissue maintenance and repair. Among CPCs, CD34+cells (CD34+CPCs) seem to predict outcome in CV disease, also in elderly people. A decline in CD34+CPCs was reported with advancing age. Moreover, aging is associated with a state of chronic inflammation, influencing life expectancy. Our purpose was to investigate a 10-year predictive ability of CD34+CPCs, inflammatory marker levels, classic CV risk factors (CVRFs), and Framingham Risk Score (FRS) in a population of healthy, self-sufficient octogenarians. We found that baseline CD34+CPCs was strongly associated with mortality, showing a significant difference in CD34+CPC numbers between deceased and living patients. Moreover, by dividing our patients into tertiles based on age reached, this difference was more remarkable the higher the age reached. Regressive analyses suggested that the chances of reaching an older age depend on higher CD34+CPCs at baseline and are not significantly affected by inflammatory markers levels, FRS, CVFRs, or HDL-C levels. We found that higher CD34+CPCs predict longer life also in the oldest old, providing additional insights on the predictive role of CD34+CPCs in subjects aged 80 years or more.

Endothelial progenitor cells and rheumatic disease modifying therapy

Rheumatic diseases are associated with accelerated atherosclerosis and with increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the higher prevalence of cardiovascular disease are not completely clarified, but it is likely that a pivotal role is played by vascular inflammation and consequently to altered vascular endothelium homeostasis. Also, high prevalence of traditional risk factors, proatherogenic activation and endothelial dysfunction further contribute to vascular damage. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and protect against atherosclerotic vascular disease. However, abnormalities in number and function of these cells in patients with rheumatic condition have been extensively reported. During the last years, growing interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD has been shown; in addition, pioneering studies show that EPC dysfunction might be improved with pharmacological strategies. However, how to restore EPC function, and whether achieving this aim may be effective in preventing cardiovascular complications in rheumatic disease, remain to be established. In this review we report an overview on the current stand of knowledge on the effect of pharmaceutical and lifestyle intervention in improving EPCs number and function in rheumatic disease.

Subclinical impairment of myocardial and endothelial functionality in very early psoriatic and rheumatoid arthritis patients: Association with vitamin D and inflammation

BACKGROUND AND AIMS Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34 + cells, vitamin D, and with disease activity. METHODS STE was used to assess the myocardial functionality in patients with very early RA (n = 41) and PsA (n = 35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34 + counts were evaluated by flow cytometry and vitamin D levels were quantified by HPLC. Disease activity was assessed by Disease Activity Score-28 (DAS28). RESULTS RA patients exhibited impaired GLS and GCS (both p < 0.001) as compared to HC, GLS being also altered in PsA (p = 0.020 vs. HC). DAS28 was correlated to GLS (r = 0.908, p < 0.001) and GCS (r = 0.868, p < 0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (r = -0.308, p = 0.026) but not in PsA or RA, although decreased levels were observed (both p < 0.001). Vitamin D was an independent predictor of decreased CD34 + levels in PsA and RA. CD34 + counts negatively correlated DAS28, GLS and GCS in RA. CONCLUSIONS Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity.

[OP.8A.09] EFFICACY OF MONOCLONAL ANTIBODIES ANTI-PROPROTEIN CONVERTASE SUBTILISIN-KEXIN TYPE 9 IN IMPROVING LIPID PROFILE AND ARTERIAL STIFFNESS IN PATIENTS AFFECTED BY FAMILIAL HYPERCHOLESTEROLEMIA

Objective: monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9), have emerged as a new class of drugs that effectively lower LDL cholesterol levels. Hypercholesterolemic patients present early signs of vascular inflammation and damage. We investigate whether after six months of treatment with anti-PCSK9 monoclonal antibodies we can find any improvement of pro-atherogenic profile and of arterial stiffness (AS) in patients affected by familial hypercholesterolemia already in treatment with the maximally tolerated statin therapy. Design and method: We enrolled 34 people who had decided to start treatment with anti-PCSK9 drugs; of these, 32 have completed the 6-months observation period. At enrollment and 6 months later we evaluated anthropometrics, laboratory profile, pulse wave velocity (PWV) and carotid intima-media thickness (cIMT). Results: After 6-months of treatment we found a significant decrease of inflammatory markers (Hs-CRP: −46.5%; Fibrinogen: −18.9%), LDL-C and lipoprotein (a) levels (respectively −65.9% and −34.2%). PWV (−9.5%) appeared to be improved; cIMT remained unchanged. PWV reduction appeared to be correlated with fibrinogen and LDL-C reduction. However, reduced PWV appeared to be not dependent on LDL-C and fibrinogen by the multiple regression analysis. Conclusions: After 6 months of treatment with monoclonal antibodies anti-PCSK9 the levels of CRP, Fibrinogen, LDL-C, and Lp (a), as well AS indices, are significantly improved as compared to baseline. We report the important evidence that a treatment with anti-PCSK9 monoclonal antibodies may improve significantly the arterial stiffness in patients affected by familial hypercholesterolemia.

A Strongyloides stercoralis infection presenting as arthritis of sternoclavicular joint.

Strongyloides stercoralis (S. stercoralis) is a parasite, endemic in tropical, subtropical, and also not rarely in temperate regions, that infects up to 100 million people worldwide [1]. Patients m...

[PP.10.19] RENAL DENERVATION RAPIDLY RESTORES CIRCULATING PROGENITOR CELLS IN PATIENTS AFFECTED BY RESISTANT HYPERTENSION

Objective: To investigate whether blood pressure (BP) lowering after renal sympathetic denervation (RSD) affects CD34+ cell number in drug-resistant hypertension (R-HTN). Design and method: We enrolled 11 patients with R-HTN, already treated with at least 6 antihypertensive drugs, including a diuretic, at full dosages; patients with office BP of >160 mmHg (>150 mmHg for type 2 diabetes) were considered eligible for the procedure. Adherence to drug treatment was accurately checked by patients general practitioners. Mean age was 61 ± 7.9 years; M:F 8:5. We measured clinic (sphygmomanometer) and ambulatory (Tonoport V GE-Healthcare) BP, and heart rate (HR; electrocardiogram), at baseline and 30 days after RSD procedure (Symplicity; Medtronic). 24 h BP recordings and home BP protocols were consulted in addition to office BP measurements at the hospital before enrollment. Results: At T0: SBP: 179.1 ± 9.3mmHg; DBP: 101.2 ± 5.5 mmHg; HR 79.9 ± 9.4; CD34+ cells: 1.66 ± 0.51. At T1 SBP values were reduced on the average of 40.2 mmHg (138.9 ± 7.3; −22.5%, p < 0.001) DBP of 18 mmHg (83.2 ± 3.2; −17.7%, p < 0.001), and HR of 10.4 bpm (67.3 ± 6.0; −17.7%, p < 0.005), and CD34+cell number increased on an average of 0.34 cells /microL (2.0 ± 0.51; +21.2%, p < 0.001). Conclusions: RSD rapidly restores CD34+cell number in patients affected by true R-HTN; if these results will be confirmed on a larger scale, they could provide new insights about CD34+ cells and pathophysiological aspects of arterial hypertension.

[PP.36.05] EXPRESSION AND CHANGE IN MIRS 145, 221 AND 222 EXPRESSION IN HYPERTENSIVE SUBJECTS TREATED WITH ENALAPRIL, LOSARTAN OR OLMESARTAN

Objective: To evaluate whether the anti-hypertensive drugs enalapril, losartan or olmesartan may have effects on monocyte expression of different microRNAs (miRs 145, 221 and 222) involved in vasculature homeostasis and damage, in essential hypertensives. Design and method: Sixty-four essential hypertensives without organ damage nor additional risk factor for CVD and 42 controls were included; we evaluated blood pressure (SBP/DBP), lipid profile, fasting glucose, C-reactive protein (CRP), fibrinogen, arterial stiffness (AS) indices (pulse way velocity: PWV; augmentation index: AIx) and carotid intima-media thickness (cIMT) at baseline (T0) and after 24-weeks treatment (T1). Subjects with plasma levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dl, triglycerides (TG) >200 mg/dl, body mass index (BMI) >30, alcohol consumption, a personal or familial history of CVD, diabetes mellitus, or thyroid, liver or kidney diseases were excluded. Patients were randomly assigned to receive once a day enalapril 20 mg, losartan 100 mg or olmesartan 20 mg. Comparisons were carried out by Wilcoxon test (T1 vs T0), Kruskall-Wallis (multiple comparisons), and Mann-Whitney (comparisons between paired treatment arms). A two tailed p of 0.05 was considered for significance. Results: T1: we found a significant improvement of both SBP/DBP (SBP: −19.03%, p < 0.001; DBP: −14.41%, p < 0.001), lipid profile (HDL-C: +4.4%, and LDL-C: −6.4%; both p < 0.001), glucose (−2.5%, p < 0.001), BMI (−3.1%, p < 0.001), fibrinogen (−6.2%, p < 0.001), CRP (−9.2%, p < 0.005), AIx (−19.1%, p < 0.001); PWV (−14.4%, p < 0.001), and miR expression (miR221: −29.8%, miR222: −39.7%, miR145: +41.1%; all p < 0.001). We compared the effects on different variables by analyzing separately each arm of treatment: olmesartan appeared the most effective in reducing CRP (−9.48%), and miRs221/222 (−32.9% and −42.4%, respectively); losartan reduced PWV (−37.6%) and improved HDL-C (+7.9%) and miR145 (+51.5%) more than olmesartan and enalapril; enalapril appeared more effective on fibrinogen reduction (−9%); no differences were found as regards BMI, glucose, LDL-C, SBP, DBP, AIx, and cIMT. Conclusions: Enalapril, losartan and olmesartan are effective in improving mechanical and humoral factors associated to AS and atherogenesis; these drugs restored in untreated hypertensives the deregulated connection between miRs221/222 and miR145, thus contributing to slow the progression of vascular damage already shown in the clinical studies.