Giulia Balbi

Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways

BACKGROUND Angiotensin II (Ang II) is a powerful proinflammatory cytokine and growth factor that activates NF-kappaB, as well as NAD(P)H oxidase, and thus is a key factor for the induction and progression of cardiovascular diseases. Our previous studies have shown high Ang II and high blood pressure-driven proatherogenic remodelling in an animal model. To further explore Ang II in proatherogenic vascular remodelling independent of blood pressure, we used Bartters/Gitelmans syndrome (BS/GS) patients given their elevated plasma Ang II, yet normo/hypotension, because extensive mechanistic studies in these patients suggest they are a good model to explore Ang II-mediated signalling. METHODS The study evaluated BS/GS patients for nitric oxide-dependent (FMD) and -independent vasodilation and intima-media thickness (IMT) of the carotid arteries compared with healthy subjects and essential hypertensive patients. RESULTS The results showed the absence of IMT growth in BS/GS patients as cumulative mean-IMT and mean maximum-IMT levels in BS/GS did not differ from normotensives: 0.58 +/- 0.09 mm versus 0.60 +/- 0.09 and 0.67 +/- 0.09 versus 0.70 +/- 0.13 respectively, P = ns, but were significantly lower compared with hypertensive patients: 0.69 +/- 0.13, P < 0.046 and 0.85 +/- 0.19, P < 0.018, respectively. FMD was increased in BS/GS versus hypertensives or normotensive controls (10.8 +/- 2.7% versus 6.5 +/- 2.3 and 8.7 +/- 1.9, P < 0.002 respectively) while endothelium-independent dilation did not differ (10.2 +/- 3.6% versus 7.2 +/- 1.9 and 8.2 +/- 3.3, P = ns) between groups. CONCLUSIONS Our study in BS/GS provides to our knowledge the first clinical data that point to a direct proatherogenic role for Ang II. However, because the data are derived from findings in BS/GS and therefore are indirect, further studies in this and other models using more direct approaches should be pursued to demonstrate a direct proatherogenic effect of Ang II as well as further studies on Ang II type 2 receptor (AT2R) signalling that the spectrum of findings of this and other studies indicate as involved in the lack of vascular remodelling.

Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: A two-year prospective observational study

OBJECTIVE To evaluate the progression of subclinical atherosclerosis in Psoriatic Arthritis (PsA) patients treated with anti-tumor necrosis factor (TNF)-α agents. METHODS Thirty-two PsA patients classified according to the CASPAR criteria and attending the Rheumatology Unit of the University of Padua Medical Center were enrolled in a two-year prospective, observational study. In accordance with the ASAS/EULAR recommendations on the management of these patients, those studied were prescribed biological agents [etanercept (n=21), adalimumab (n=6), infliximab (n=5)]. Plasma lipids, inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), vessel endothelium growth factor (VEGF), osteoprotegerin (OPG), and TNF-α, as well as Disease Activity Score 28 calculated with CRP (DAS 28-CRP) were evaluated at baseline and after two years of treatment. Bilateral carotid B-mode ultrasound measurements [the mean-intima media thickness (mean-IMT), the mean maximum-IMT (M-Max)] of each carotid artery segment (common, bulb, and internal carotid artery) and the post-occlusion flow-mediated dilation (FMD) of the brachial artery were also assessed at baseline and after two years. RESULTS Despite an improvement in the DAS 28-CRP score (P<0.0005) and lower low-density lipoprotein cholesterol (P<0.013) and triglyceride (P<0.036) values, there was a significant progression in both the mean-IMT (P<0.0005) and M-Max (P<0.0005). Moreover, no recovery in FMD (P=ns) was observed after two years of anti TNF-α treatment. Serum TNF-α levels were increased (P=0.003) and OPG values were decreased (P=0.011) at the end of follow- up with respect to baseline values. CONCLUSIONS Despite improvement in clinical status, arterial remodelling was observed in the PsA patients who were treated with anti TNF-α agents for two years.

Impact of hypertension on vascular remodeling in patients with psoriatic arthritis.

We studied the impact of hypertension along with traditional and new cardiovascular risk factors on the structural and functional properties of arteries in psoriatic arthritis (PsA) patients. We examined 42 PsA subjects (aged 51±9 years) stratified according to hypertensive status (19 normotensive, PsA-NT and 23 hypertensives, PsA-HT). Thirty-eight normotensive subjects (C-NT) and 23 hypertensives (C-HT) comparable by age and sex served as controls. Mean carotid intima-media thickness (mean-IMT) and mean of the maximum IMT (M-Max) were evaluated by ultrasound in carotid artery segment bilaterally. Post-occlusion flow-mediated dilation (FMD) of the brachial artery was evaluated by ultrasonography. These parameters were correlated with risk factors, markers of inflammation and disease activity. Values of mean-IMT were higher in both groups of PsA patients compared with C-NT (0.68 mm in PsA-NT and 0.75 mm in PsA-HT versus 0.61 mm in C-NT). PsA-HT displayed higher M-Max (0.95 mm) versus both C-HT (0.71 mm) and PsA-NT (0.79 mm). FMD was impaired in PsA subjects compared with C-NT (5.7% in PsA-NT and 6.0% PsA-HT versus 9.3% in C-NT), whereas there was no difference among PsA-HT, PsA-NT, and C-HT groups. Values of carotid IMT were directly related to tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), blood pressure and lipid profile levels. FMD showed an inverse relationship with TNF-α and blood pressure, but no correlation with lipids. In conclusion, PsA per se implies a pro-atherogenic remodeling, which is enhanced by the hypertensive status. TNF-α and OPG may have an independent role in the development of such vascular damage.

SUBCLINICAL ATHEROSCLEROSIS IN PATIENTS WITH PSORIATIC ARTHRITIS: THE IMPACT OF CLASSICAL AND NEW CARDIOVASCULAR RISK FACTORS: PP.10.391

Objective: Increased cardiovascular morbidity and mortality have been observed in several immune mediated rheumatic diseases, including psoriatic arthritis (PsA). We evaluated subclinical atherosclerosis in PsA patients according with hypertensive status by studying non invasively structural and functional properties of arteries. Design and Method: We studied 41 consecutive patients with PsA (of whom, 23 hypertensives) attending hospital outpatient clinics. 40 normotensives healthy subjects (NC) and 19 hypertensives (HT-C) served as controls. We evaluated by B-mode ultrasound the carotid intima media thickness (IMT). Measurements were expressed as mean-IMT (cumulative mean of mean IMT measured in each carotid segment, common, bulb, and internal carotid artery, bilaterally) and as M-MAX (cumulative mean of maximum IMT). Endothelial function was evaluated by post-occlusion flow mediated dilation (FMD) of the brachial artery using high-sensitivity brachial ultrasonography. NO-independent vasodilation was evaluated by the response to sublingual glyceril trinitrate (GTN). Results: PsA had a higher mean-IMT compared to NC. Hypertensive PsA displayed higher M-MAX versus both HT-C (p = 0.007) and normotensive PsA (p = 0.026). FMD was significantly lower in PsA than in NC (8.9%), whereas there was no difference between hypertensive PsA (6.1%), normotensive PsA (5.7%), and HT-C (6.3%). GTN response was similar in all groups. The TNFα level was much higher in PsA patients than in the other groups. In the entire cohort, the IMT parameters were significantly related to TNFα as well as classical risk factors, including blood pressure and lipid profile, whereas FMD was inversely related to TNFα levels and blood pressure but not lipid parameters. Conclusions: Subclinical atherosclerosis is enhanced in PsA compared to NC. In PsA, the hypertensive status proved to exert an additional effect on M-MAX, a parameter of advanced pro-atherogenic remodelling. FMD was reduced in PsA irrespective of hypertensives status. Thus, PsA per se implies a pro-atherogenic remodelling which is enhanced by the hypertensive status. In addition, TNFα seems to play a role in the hampering the functional properties of vascular wall probably through endothelial dysfunction. Figure 1. No caption available.