Subcutaneous administration of tocilizumab is effective in myointimal hyperplasia remodelling in refractory Takayasu arteritis.

Takayasu arteritis (TA) is a chronic inflammatory disease of unknown origin that involves large and mediumsized arteries, primarily the aorta and its major branches. TA is a therapeutic challenge because corticosteroids and conventional immunosuppressive agents are not always effective or safe. Interleukin 6 (IL-6) has emerged as a key cytokine in the pathogenesis of TA and its serum levels have been shown to well correlate with disease activity. We report a 19 years old female patient with TA refractory to conventional immunosuppressive agents, successfully treated with subcutaneous tocilizumab, a humanized monoclonal antibody against IL-6 receptor, in which ultrasonography (US) was used as imaging tool to follow up the patient. Currently, clinical indices of disease activity, inflammatory markers, carotid intima media thickness (cIMT) as well as carotid pulse wave velocity (cPWV) normalised, while the prednisone dosage has been tapered. Tocilizumab appears to be a good option in refractory TA, with a remarkable steroid-sparing effect. In addition, it seems to have a favourable effect on endothelial function, as it improved cIMT and PWV.

Circulating progenitor cells in rheumatoid arthritis: association with inflammation and oxidative stress.

OBJECTIVES: To evaluate the association between inflammation, oxidative stress, and circulating progenitor cell (CPC) number and redox equilibrium, vascular lesions and accelerated atherosclerosis in rheumatoid arthritis (RA). METHOD: Circulating CD34+ cells were isolated from 33 RA patients and 33 controls. Reactive oxygen species (ROS) levels and mRNA expression of manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase type 1 (GPx-1) antioxidant enzymes, and the gp91phox-containing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase NOX2 were measured in CD34+ cells. C-reactive protein (CRP), fibrinogen, erythrocyte sedimentation rate (ESR), carotid intima-media thickness (cIMT), and arterial stiffness (AS) were also evaluated. We investigated the relationships between inflammatory markers, vascular parameters, cell number, and antioxidant enzymes. RESULTS: CD34+ cell number was lower in RA patients than in controls. In CD34+ cells from RA patients, ROS levels, MnSOD mRNA, and NOX2 mRNA were higher, while mRNA expression of GPx-1 and CAT was significantly lower. The AS, pulse wave velocity (PWV), and augmentation index (AIx) were higher, as was cIMT. CD34+ cell number was inversely correlated with CRP, ROS, PWV, and AIx, and with the CAT/MnSOD and GPx-1/MnSOD ratios. CRP was correlated with MnSOD mRNA, PWV, and AIx but not with CAT and GPx-1 mRNA. CONCLUSIONS: Our data show a link between inflammation, oxidative stress, and the impairment of the antioxidant system of CPCs and their number, and with arterial stiffness in RA subjects. This could suggest a perspective on the accelerated development of vascular damage and atherosclerosis in RA.

Prescriptive behavior of non-vitamin K oral anticoagulants in patients affected by atrial fibrillation in general practice.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and in recent years the pharmacological approach has been strongly implemented; in Italy, the prescription of the non-vitamin K oral anticoagulants (NOAC) was also extended to General Practitioners (GPs) since 2020. The aim of the present study was to investigate the GPs prescribing behaviour of NOACs. An observational study was performed by using the computerized medical record of 14 GPs in Sicily: patients affected by AF were selected and stratified according to the prescribed antithrombotic drugs. Patients were considered inadequately managed if antithrombotic treatment was not adherent to recent ESC guidelines. A total of 467 (2.7 %) patients were affected by AF, 276 (59.1 %) were treated with an oral anticoagulant (OAC) regardless the high stroke risk (OR 1.64; 95 %CI 0.74-3.62; p = 0.226). The NOAC users were 236 patients as follow: Rivaroxaban 33.5 %, Apixaban 33,1 %, Dabigatran 17,4 %, Edoxaban 16.1 %. In 7 patients an inappropriate NOAC treatment was observed. Among Vitamin-K antagonist users, 25.0 % were considered inappropriate. Patients not treated with OAC were 191, of them 81.7 % were at high stroke risk and did not receive any OAC despite the indication to treat. In addition, the probability to be not properly managed significantly increased in older and in patients with atherosclerosis. Conversely, patients with at least one reported cardiology counselling significantly reduced the likelihood to be not properly managed (OR 0.38, 95 %CI 0.25-0.58; p 0.01). Our results suggest the need to optimize the management of real-life AF patients by improving prescribing adherence to ESC guidelines.

Pulse wave velocity and augmentation index, but not intima-media thickness, are early indicators of vascular damage in hypercholesterolemic children.

BACKGROUND: Arterial stiffness is an important determinant of cardiovascular risk. It is associated with several cardiovascular risk factors, including hypertension, diabetes and cigarette smoking. However, there are conflicting data about the relationship between arterial stiffness and hypercholesterolemia. Furthermore, augmentation index (AIx), a measure of systemic arterial stiffness, has not been previously investigated in hypercholesterolemic (HCh) children. Aim of our study was to evaluate local and systemic arterial stiffness as well as carotid intima-media thickness (IMT) in HCh children and also to investigate the relation between serum cholesterol levels and arterial stiffness. MATERIALS AND METHODS: We determined lipid profile, body mass index, blood pressure, heart rate, carotid IMT and several arterial stiffness parameters, as beta-index, elastic modulus (E(p)), arterial compliance (AC), pulse wave velocity (PWV) and AIx, in 44 untreated HCh children (mean age 10.7 +/- 2.8 years; 18 with familial hypercholesterolemia, FH, and 26 with primary hypercholesterolemia, PHC) and 18 age- and sex-matched controls. HCh children never received any medication, including antihypertensive and lipid lowering drugs. RESULTS: Respect to controls and to PHC, FH had significantly higher (P < 0.001) beta-index (5.22 +/- 1.13 vs. 3.13 +/- 0.74 and 3.60 +/- 1.02), PWV (4.72 +/- 0.72 m s(-1) vs. 3.66 +/- 0.55 m s(-1) and 4.10 +/- 0.67 m s(-1)), AIx (3.55 +/- 3.97% vs. -4.43 +/- 4.09% and 0.61 +/- 2.39%) and E(p) (64.4 +/- 19.6 kPa vs. 36.2 +/- 11.3 kPa and 42.9 +/- 13.1), whereas AC (1.25 +/- 0.48 mm(2) kPa(-1) vs. 1.9 +/- 0.43 mm(2) kPa(-1) and 1.62 +/- 0.43 mm(2) kPa(-1)) was lower (P < 0.001). There was no significant difference in carotid IMT and blood pressure values between the groups. The multiple regression analysis showed a significant association of arterial stiffness values with plasma cholesterol levels (P < 0.0001). CONCLUSION: Our findings show that local and systemic arterial stiffness are increased in asymptomatic, normotensive HCh children, suggesting that HCh plays a key role in arterial mechanical impairment since the paediatric age.

Ischemic heart disease and early diagnosis. Study on the predictive value of 2D strain.

INTRODUCTION: Two-dimensional strain echocardiography (2D-SE) quantifies left ventricular global longitudinal strain (GLS) and global circumferential strain (GCS). Our aim was to test 2D-SE during dipyridamole stress echocardiography (Dipy-Stress) in patients with non-diagnostic result, checking by way of coronary CT angiography (CCTA) the possible presence of coronary artery disease (CAD). METHODS: Over twenty-four months 65 consecutive patients with non-diagnostic Dipy-Stress were studied by 2D-SE and by CCTA. GCS and GLS at rest and after stress were compared according to data derived from CCTA. CAD was graded as significant (stenosis ≥50%), mild (stenosis between 15 and 50%) or absent (stenosis <15%). CCTA was defined as "positive" in presence of mild CAD and "negative" in absence of stenoses. Furthermore, Δ strain was defined as follows: [(stressS-restS)/restS]×100. RESULTS: GCS at rest and after stress was similar in CCTA-positive (26±5% and 27±5% respectively) and CCTA-negative groups (27±3% and 28±3% respectively). GLS at rest was significantly reduced (P<0.0001) in CCTA-positive (23±3%) compared to CCTA-negative group (25±2%). GLS after stress was lower (P<0.0001) in CCTA-positive group (20±3%) than CCTA-negative one (26±2%). A significant reduction (P<0.0001) of GLS at rest versus after stress was found in positive-CCTA group. ΔGLS showed a significant decrease (P<0.0001) in CCTA-positive (-10±8%) compared to CCTA-negative (4.4±5.8%) group. ROC analysis of ΔGLS showed high accuracy (area under the ROC curve 0.916, 95% CI: 0.820-0.970) in distinguishing positive and negative CCTA groups. CONCLUSIONS: 2D-SE during Dipy-Stress allows, in case of non-diagnostic test, identification of mild-CAD with high sensitivity and specificity.

Erythrocyte passive potassium flux is increased in patients with ischemic coronary disease (ICD) and in subjects with family history of ICD.

BACKGROUND: It has been proposed that ischemic coronary disease (ICD) associated potassium loss could be due to modifications of potassium permeability. We investigated whether a positive family history of ICD can influence this parameter. We have compared potassium permeability in erythrocytes from ICD patients and from positive family history subjects (FICD) with control subjects. METHODS: All patients and subjects were carefully selected for the absence of hypertension and dysmetabolic pathologies. ICD group: 24 patients (19 males, 5 females; ages 43 to 69) all affected by ischemic coronary disease, under no drug treatment; FICD group: 18 subjects (all males, ages 27 to 42) with a verified positive ICD family history, without hypertensive family history and cardiovascular pathology; control group: 16 subjects (11 males, 5 females; ages 28 to 48) without positive family history of ICD. Passive potassium efflux (PPE) was spectrophotometrically measured in K-free medium containing ouabain and bumetanide. The kinetic constant was calculated by dividing PPE by the erythrocyte potassium concentration. RESULTS: No statistically significant differences were noted between the intracellular potassium content of the three groups. However, (1) the passive potassium permeability of the ICD group was significantly higher (kK=0.055 +/- 0.021 h(-1), n=24) than that of the control group (kK=0.023 +/- 0.008 h(-1), n= 16; p<0.00001), (2) the FICD group was higher (kK=0.036 +/- 0.012 h(-1), n=18) than the control group (p<0.001), and (3) the ICD group was higher than the FICD group (p<0.001). CONCLUSIONS: Our results suggest an inheritability of ICD, paralleling the familial aggregation of the pathology. Erythrocyte potassium permeability could represent an early marker of ischemic coronary disease and be used as a prophylactic tool.

Effects of picotamide on release of endothelin-1, thromboxane and prostacycline after treadmill stress in patients with peripheral artery disease.

To assess the effects of picotamide, an antithromboxane receptor and antithromboxane synthase drug, on vascular function and endothelin-1 release, 20 patients with peripheral arterial disease, without hypertension or diabetes mellitus, receiving placebo and picotamide (900 mg/day) were studied. The modifications of vascular parameters were evaluated by arterial distensibility index and postischemic hyperemia test (postischemic perfusion index and recovery time). Endothelin-1, prostacycline, and thromboxane B2 were determined under resting conditions and after treadmill test. Picotamide treatment caused a decrease of resting thromboxane B2 and endothelin-1 concentrations, produced an improvement of the vascular function as seen by the increase of vascular parameters reported, and attenuated the ischemic treadmill-induced increase of thromboxane B2, but not of endothelin-1. These data confirm that the picotamide improved vascular flow by the reduction of thromboxane-mediated effects, reduced resting endothelin-1 levels, but did not attenuate endothelin-1 concentrations induced by the treadmill stress.

[Transmembrane sodium transport systems in various forms of hyperlipoproteinemia]. / Sistemi di trasporto transmembrana del Na+ in forme diverse di iperlipoproteinemia.

The possible interrelationships between the erythrocytic transport systems of Na+ (Na+/K+ pump, Na+/K+ cotransport, Na+/Li+ countertransport, Na+ passive permeability) and the plasmatic lipids (cholesterol, triglycerides, HDL, LDL, apoprotein A1, apoprotein B) were studied in 42 normotensive subjects with different forms of hyperlipoproteinaemia and with a negative familiarity for arterial hypertension. In subjects with hypercholesterolaemia (hyperlipoproteinaemia II A and II B) an elevated activity of the Na+/K+ pump was noticed, while in subjects with hypertriglyceridaemia (type IV) an increase in Na+ passive permeability and Na+/Li+ countertransport with a lower level of intraerythrocytic Na+ was shown. A negative correlation was observed between the total efflux of Na+ and Na+/K+ pump and the levels of cholesterol (r = -0.43, p < 0.04 and r = -0.41, p < 0.05) and the apoprotein B/A ratio (r = 0.42, p < 0.05 and r = -0.50, p < 0.01). A negative correlation was also noticed between the Na+/K+ pump and the levels of apoprotein B (r = -0.41, p < 0.05). The Na+/K+ cotransport appeared inversely correlated with the levels of HDL cholesterol (r = -0.42, p < 0.05), while the Na+ passive permeability was negatively correlated with the levels of LDL (r = -0.43, p < 0.04) and positively correlated with the plasmatic triglycerides (r = +0.54, p < 0.01). Such data show that the plasmatic lipids can influence the systems of transmembrane ionic transport of Na+ and play an important role also this way, in cardiovascular pathology.

[Effects of adrenergic stimulation on transmembrane transport of Na+ in patients with essential hypertension]. / Effetti della stimolazione adrenergica sui sistemi di trasporto transmembrana del Na+ in pazienti con ipertensione essenziale.

BACKGROUND: It has been studied whether an adrenergic stimulation induced by the cold pressor test (CPT) could influence the behaviour of the transmembrane transport systems of sodium in hypertensive subjects compared to a normotensive control population. MATERIALS AND METHODS: Twenty-two hypertensive subjects (average age 43.2 +/- 5.7 years), with normal weight, without signs of cardiovascular and metabolic diseases, underwent the cold pressor test. The dynamic behaviour of sodium erythrocytic transport systems and plasmatic norepinephrine was evaluated basally, at the third minute during the cold pressor test and 20 minutes after the end of the test. The same test was carried out in a control population made up of 20 normotensive subjects (average age 41.9 +/- 4.8 years), selected on the basis of the absence of any cardiovascular or metabolic pathology and without family history of arterial hypertension. RESULTS: The cold pressor test did not cause significant changes in the sodium transmembrane transport systems in normotensive subjects, while in the hypertensive subjects a significant reduction was observed, during the test, in the total efflux of sodium and in the sodium/potassium pump, respectively from 2636 +/- 296 mumol/l/red blood cells/hr to 2032 +/- 178 mumol/l/red blood cells/hr (p < 0.0001) and from 2156 +/- 149 mumol/l/red blood cells/hr to 1610 +/- 101 mumol/l/red blood cells/hr (p < 0.0001); the intraerythrocytic sodium increased from 6.5 +/- 1.0 mmol/l/cells to 7.2 +/- 1.1 mmol/l/cells (p < 0.04) and the passive permeability decreased from 0.039 +/- 0.004 hr-1 to 0.018 +/- 0.006 hr-1 (p < 0.0001). During cold pressor test the increase in the plasma norepinephrine levels was correlated to the reduction in the total efflux of sodium (r = -0.60; p < 0.003) and in the sodium/potassium pump (r = -0.59; p < 0.003) only in hypertensive subjects. CONCLUSIONS: Our data show that an adrenergic stimulation, induced by the cold pressor test, is able to significantly influence the behaviour of transmembrane fluxes of sodium in hypertensive subjects, and it causes an inhibitory effect on the sodium/potassium pump and an increase in the intraerythrocytic sodium. Such data show the existence in hypertensive subjects of an interrelationship between adrenergic activity and sodium transport systems that could cooperate in causing and/or in maintaining the hypertensive syndrome.

Circulating progenitor cells in hypertensive patients with different degrees of cardiovascular involvement.

We investigated whether different degrees of hypertension-related cardiovascular involvement are associated with changes in circulating proangiogenic hematopoietic cell (PHC) numbers and/or phenotypes and/or in the PHC redox system in hypertensive individuals with isolated arterial stiffening (AS) hypertensives or with both carotid intima-media thickening and left ventricular hypertrophy (LVH) hypertensives. We also evaluated microRNA (miRs) 221 and 222 (miRs221/222) expression in CD34+ cells, the relationship between these miRs and cell number and reactive oxygen species (ROS) levels, and the expression of manganese superoxide dismutase (MnSOD), catalase (CAT) glutathione peroxidase type-1 (GPx-1) and gp91phox-containing nicotinamide-adenine-dinucleotide-phosphate-oxidase (NOX2). Proangiogenic hematopoietic cells (PHCs) from hypertensive patients and controls were isolated by flow cytometry. PHCs were higher in hypertensives than in controls but were lower in LVH than in AS hypertensives. In CD34+ cells from AS hypertensives, NOX2, MnSOD, CAT and GPx-1 were overexpressed; ROS, miRs and NOX2 were also increased and were associated with cell number. In LVH, we found an imbalance in the cell redox system; MnSOD showed the highest values, whereas CAT and GPx-1 were lower than in AS hypertensives. Intracellular ROS, miRs and NOX2 were higher and inversely associated with cell number. In AS hypertensives, the redox balance may sustain the increase in PHCs; by contrast, in hypertensives with more advanced lesions, redox imbalance may result in increased oxidative stress and cell reduction.

Biglycan expression in current cigarette smokers: a possible link between active smoking and atherogenesis.

OBJECTIVE: Cigarette smokers present early signs of vascular damage and systemic inflammation. Biglycan (BGN), an ubiquitous component of extracellular matrix orchestrating several physiological functions, has recently been indicated as a major source of low-density lipoprotein retention in the normal arterial intima-media layer. We evaluated whether BGN-mRNA expression was enhanced in peripheral monocytes of smokers with no additional cardiovascular risk factors (CVRFs), and if it was associated with altered carotid arterial stiffness (AS) or intima media thickness (cIMT). We also evaluated plasma markers of systemic and vascular inflammation, and correlation with BGN-mRNA. METHODS: Two-hundred-fifty-one young smokers were enrolled, with no additional CVRFs, and 60 controls. Plasma lipids, fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), AS and cIMT were assessed. A smoke exposure index (SEIx) was calculated. RESULTS: Fibrinogen, CRP, AS indices, cIMT, and BGN-mRNA were higher in smokers compared to controls; HDL-C levels were lower, no difference was detected in IL-6 levels. After stratification of smokers in quartiles based on SEIx values, smokers in the highest quartiles presented highest fibrinogen, CRP, AS, cIMT, BGN, and also IL-6 values, and lowest HDL-C. CONCLUSION: BGN-mRNA was enhanced in young smokers, compared to controls, and appears associated to a proatherogenic profile, characterized by increased fibrinogen, CRP, and IL-6, lower HDL-C, altered AS and cIMT values, particularly in those with higher SEIx: the more cigarettes smoked over years, the more marked the alterations. Although we cannot state whether BGN have a direct causal role in inducing, maintaining and developing vascular damage, including intima-media wall thickening and arterial stiffening, our data could suggest that it may represent a link between proatherogenic status induced by cigarette smoking, and the development and progression of vascular damage.