Alain Simon

Increased prevalence of subclinical atherosclerosis in patients with small-vessel vasculitis.

Background and objective: Although changes in smaller vessels is the hallmark of medium-sized and small-vessel vasculitis, it has been suggested that large arteries of such patients may also be affected by the early atherosclerotic process because of coexisting risk factors or systemic inflammation. This study aimed to bring additional arguments supporting this hypothesis. Design, setting and patients: 50 consecutive patients with primary systemic necrotising vasculitis and 100 controls matched for age and sex underwent ultrasonic detection of plaque in three peripheral vessels (carotid and femoral arteries and abdominal aorta). Cardiovascular risk factors and inflammation (C reactive protein (CRP)) were concomitantly measured in all participants, and diagnosis of high-risk status was defined by the presence of known history of cardiovascular disease, type 2 diabetes or 10-year-Framingham Risk Score ⩾20%. Results: Patients had higher frequency of plaque than controls in the carotid arteries (p<0.05), in the aorta (p<0.01) and in the three vessels examined (p<0.001), and adjustment for high-risk status did not confound such difference in the aorta and in the three vessels. In the overall population of patients and controls, vasculitis was associated with a higher frequency of three-vessel plaques (p<0.05), independently of high-risk status and CRP. In patients, the higher frequency of three-vessel plaques was associated with high-risk status (p<0.05) but not with CRP, or disease and treatment characteristics. Conclusions: Small-vessel vasculitis is associated with more frequent subclinical atherosclerosis, especially extended to multiple peripheral vessels, and such association is not entirely explained by cardiovascular risk factors and systemic inflammation.

Atherosclerosis in ANCA-associated vasculitides.

Abstract:  It is currently accepted that atherosclerosis is rather, or also, an inflammatory disease and, indeed, vasculitis is defined by inflammatory infiltrates in blood vessel walls, albeit initially by different predominant cell populations and in arteries of different calibers. As for other chronic systemic inflammatory diseases, premature and accelerated atherosclerosis has emerged during the last 5–10 years as an important facet of vasculitides, independently of the other risk factors of cardiovascular disease and also, apparently, corticosteroids. Chronic systemic inflammation, like persistently active vasculitis, might play a role in early atherosclerosis, through the actions of C‐reactive protein (CRP), some adhesion molecules, and/or cytokines, as well as local inflammation, perhaps through locally secreted TNF‐α and/or upregulation of matrix metalloproteinases and oxidative stress. Endothelial cell dysfunction and increased arterial stiffness have also been found in vasculitis patients. Notably, some vasculitis treatments were able to reverse some of these endothelial cell anomalies. Unlike antineutrophil cytoplasm autoantibodies (ANCA), which were not shown to correlate with a higher risk of atherosclerosis or cardiovascular events, autoantibodies to endothelial cells, heat‐shock proteins, or oxidized‐LDL may also be implicated, although these latter are now thought to protect against atherosclerosis. It is likely that other, as yet unidentified, factors facilitating atherosclerosis may play more important roles in vasculitides. Until their precise identification, it remains important to take into consideration and treat, every time it is necessary and possible, the other well‐known cardiovascular risk factors.

Blood viscosity as a chronic contributing factor of vasodilatation in humans

Since resistance to flow is theoretically determined by arteriolar geometry and blood viscosity, we studied these two factors in 44 normal and 106 hypertensive subjects. Brachial bed vascular resistance was calculated as the ratio between mean pressure and brachial artery flow. Systemic blood viscosity in vitro was determined at 96 per s, while microvessel blood viscosity in vivo was estimated from the haematocrit-viscosity relationship at 240 per s. A resistive radius index was calculated which was only related to the microvessel viscosity: resistance ratio. Compared to normal subjects, hypertensive subjects had higher systemic in vitro blood viscosity (4.75 +/- 0.47 versus 4.50 +/- 0.43 mPa.s; P less than 0.005) and microvessel blood viscosity (2.60 +/- 0.21 versus 2.43 +/- 0.16 mPa.s; P less than 0.001). Hypertensive subjects also had a higher brachial vascular resistance (161 +/- 89 versus 124 +/- 58 mmHg/ml per s; P less than 0.01), but showed a similar resistive radius index (2.47 +/- 0.36 versus 2.57 +/- 0.35) compared to normal subjects. There was a positive correlation between systemic viscosity and brachial artery diameter and a negative correlation between microvessel viscosity and vascular resistance in the normotensive (P less than 0.05 and P less than 0.001, respectively) and hypertensive groups (P less than 0.001 and P less than 0.005, respectively). The resistive radius index was positively related to viscosity in normal and in hypertensive groups (P less than 0.001) but these relationships were significantly different (P less than 0.001), showing that, at the highest viscosities, arterial radius increased less in hypertensive than in normal subjects. Thus, the level of blood viscosity might influence arterial diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma cGMP and Large Artery Remodeling in Asymptomatic Men

cGMP regulates vascular smooth muscle tone and arterial wall response to proliferative signals. We determined plasma cGMP and carotid artery intima-media thickness (IMT) and diameter in 84 asymptomatic men submitted to investigation of their cardiovascular risk profiles. Plasma cGMP was positively associated with IMT (P<0.01) and diameter (P<0.05), independently of coexisting risk factors. These associations were reinforced in the subgroup of subjects with high-sensitivity C-reactive protein level or multiple atherosclerotic plaques. A positive relationship existed between diameter and IMT (P<0.01) and disappeared after cGMP adjustment. This suggests a link between cGMP pathway and arterial wall geometry that is revealed by vascular injury conditions and may participate in early large artery remodeling.

Carotid artery intima–media thickness, heat shock proteins and oxidized LDL autoantibodies in systemic necrotizing vasculitis

In this study we evaluate early atherosclerotic changes and determine whether anti-HSP-60, anti-HSP-65 and anti-oxLDL autoantibodies are elevated in systemic necrotizing vasculitis. Thirty-two patients having systemic necrotizing vasculitis were compared with normal controls and patients with systemic lupus erythematosus (SLE). The antibodies against human HSP-60, HSP-65 and oxLDL were measured by antihuman ELISA kit. All patients underwent non-invasive measurements of carotid artery intima–media thickness (IMT). In a comparison between carotid IMT extent between vasculitis patients and SLE, no significant differences were noted. Levels of anti-HSP-60, anti-HSP-65 IgG and anti-oxLDL autoantibodies were similar among patients compared to controls. IgM anti-HSP-60 antibody levels were significantly lower in patients compared to controls and a similar trend was found regarding IgM anti-HSP-65. As a group, patients having various necrotizing vasculitis have similar extent of early atherosclerotic changes regardless of the vasculitis type, and these levels are similar to those found in SLE.

Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content

Shear forces induce platelet aggregation and stimulate the endothelial production of anti-aggregatory factors. Among them, endothelin-3 (ET-3) has been reported to reduce aggregation and to increase platelet cyclic GMP (cGMP) content. Since hypercholesterolemia modifies both platelet aggregability and endothelial function, we compared in 14 hypercholesterolemic and 15 normocholesterolemic subjects the influences of shear forces (240 and 650 s(-1)) on platelet aggregation and cGMP content, and their modulation by ET-3. Spontaneous maximal aggregation occurred earlier and at a greater extent in hypercholesterolemic than in normocholesterolemic subjects (63+/-2 vs 46+/-6% P < 0.01). Pre-treatment with ET-3 abolished the shear-induced facilitation of maximal aggregation in platelets of normocholesterolemic (from 70+/-2 to 52+2% at 240 s(-1) and from 73+/-1 to 59+/-2S at 650s(-1); P < 0.05) and hypercholesterolemic (from 78+/-3 to 64+/-2 at 240 s(-1) and from 78+/-2 to 66+/-3 at 650 s(-1); P < 0.05) subjects. cGMP content did not significantly differ between normocholesterolemic and hypercholesterolemic subjects (6.1+/-0.5 vs 6.9+/-0.7 pmol/10(9) platelets). It was reduced in platelets submitted to shear forces (P < 0.05). This shear-dependent reduction was suppressed by ET-3 pre-treatment. These results demonstrate that shear forces enhance platelet aggregation and diminish their cGMP content. ET-3 reduces the pro-aggregating effects of shear, suggesting a rise in cGMP content as a dynamic associated mechanism.