Background-Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol. Methods and Results-Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II-III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [meanϮSEM]: 240.31Ϯ38.19% versus 152.10Ϯ18.21% versus 73.96Ϯ10.29%, PϽ0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitroprusside response was unchanged by all treatments. Vitamin C and acetylcholine coinfusion data showed that 600 mg/d allopurinol completely abolished the oxidative stress that was sensitive to high-dose vitamin C. Conclusions-For the first time, we have shown that a steep dose-response relationship exists between allopurinol and its effect on endothelial function. We also showed that the mechanism of improvement in endothelial function with allopurinol lies in its ability to reduce vascular oxidative stress and not in urate reduction. The reduction in vascular oxidative stress was profound because high-dose allopurinol totally abolished the oxidative stress that was sensitive to the high-dose vitamin C that was used in this study.

The antiphospholipid syndrome (APS) is defined by the presence of anti-phospholipid antibodies (aPLs) and venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The syndrome can be either primary or secondary to an underlying condition, most commonly systemic lupus erythematosus (SLE). Echocardiographic studies have disclosed heart valve abnormalities in about a third of patients with primary APS. SLE patients with aPLs have a higher prevalence of valvular involvement than those without these antibodies. Valvular lesions associated with aPLs occur as valve masses (nonbacterial vegetations) or thickening. These two morphological alterations can be combined and are thought to reflect the same pathological process. Both can be associated with valve dysfunction, although such association is much more common with the latter alteration. The predominant functional abnormality is regurgitation; stenosis is rare. The mitral valve is mainly affected, followed by the aortic valve. Valvular involvement usually does not cause clinical valvular disease. The presence of aPLs seems to further increase the risk for thromboembolic complications, mainly cerebrovascular, posed by valve lesions. Superadded bacterial endocarditis is rare but may be difficult to distinguish from pseudoinfective endocarditis. The current therapeutic guidelines are those for APS in general. Secondary antithrombotic prevention with long-term, high-intensity oral anticoagulation is advised. The efficacy of aspirin, either alone or in combination, is yet to be assessed. Corticosteroids are not beneficial and may even facilitate valve damage. Immunosuppressive agents should only be used for the treatment of an underlying condition. Current data suggest a role for aPLs in the pathogenesis of valvular lesions. aPLs may promote the formation of valve thrombi. These antibodies may also act by another mechanism, as indicated by the finding of subendothelial deposits of immunoglobulins, including anticardiolipin antibodies, and of colocalized complement components in deformed valves from patients with APS.

In patients with ACS, naturally occurring CD4(+)CD25(+) Treg numbers are reduced and their functional properties compromised. These findings may aid in understanding the mechanisms leading to culprit plaque associated T-cell activation in patients with ACS.

Objective-Naturally occurring CD4ϩ CD25 ϩ regulatory T cells (Tregs) exert suppressive effects on effector CD4 cells and downregulate experimental autoimmune disorders. We investigated the importance and potential role of Tregs in murine atherogenesis. Methods and Results-Tregs were investigated comparatively between aged and young apolipoprotein E-knockout (ApoE-KO) mice and age-matched C57BL/6 littermates. The effect of oxidized LDL (oxLDL) was tested on the functional suppressive properties of Tregs from ApoE-KO and C57BL/6 mice. Tregs, CD4 ϩ CD25 Ϫ cells, and saline were infused into ApoE-KO mice to study their effects on atherogenesis. Treg numbers were reduced in atherosclerotic compared with nonatherosclerotic ApoE-KO mice. The functional suppressive properties of Tregs from ApoE-KO mice were compromised in comparison with those from their C57BL/6 littermates. Thus, oxLDL attenuated the suppressive properties of Tregs from C57BL/6 mice and more so in ApoE-KO mice. Transfer of Tregs from age-matched ApoE-KO mice resulted in significant attenuation of atherosclerosis compared with that after delivery of CD4 ϩ CD25 ϩ/Ϫ T cells or phosphate-buffered saline. Conclusions-CD4ϩ CD25 ϩ Tregs may play a protective role in the progression of atherosclerosis and could be considered a therapeutic tool if results from human studies can solidify observations in murine models.

Recent data suggest that hypoxia and its principal molecular signature HIF-1 (hypoxiainducing factor-1) may tune down inflammation by dictating anti-inflammatory programs. We tested the effects of hypoxia and HIF-1a on the homeostasis of naturally occurring regulatory T cells (Treg) and their transcriptional activator Foxp3. Hypoxia induced a timedependent increase in HIF-1a in mouse and human T cells. Hypoxia upregulated the expression of Foxp3 in Jurkat T cells, human and murine mononuclear cells. The effects of hypoxia on Foxp3 expression were HIF-1a-dependent as they were abolished upon transfection with short-interfering RNAs for HIF-1a and promoted by HIF-1a overexpression. Hypoxia increased the potency of Treg, as hypoxic CD4 1 CD25 1 lymphocytes were more effective than normoxic cells in suppressing the proliferation of CD4 1 CD25 À effectors. In vivo expression of HIF-1a achieved by hydrodynamic injection of the respective naked DNA similarly induced an increase in Foxp3 expression and an increase in the number of functionally active Foxp3 1 CD4 1 CD25 1 Treg. Thus, hypoxia dictates an antiinflammatory program by driving expression of HIF-1a that acts to increase the number and suppressive properties of naturally occurring CD4 1 CD25 1 Treg.Key words: Foxp3 Á HIF-1 Á Hypoxia Á Inflammation Á Regulatory T cells IntroductionUnder hypoxia, hypoxia-inducible factor-1 (HIF-1) plays a key role in controlling glycolysis, angiogenesis, erythropoiesis and cell survival [1]. HIF-1 constitutes an oxygen-dependent a-subunit and a constitutively expressed b-subunit that interact through mutual basic helix-loop-helix domains [2]. HIF-1a oxygen-dependent domain undergoes site-specific proline hydroxylation by prolyl hydroxylases, which allows subsequent ubiquitination mediated by the von Hippel-Lindau protein [3][4][5]. In the absence of molecular oxygen, HIF-a hydroxylation is abrogated, leading to its cellular accumulation. HIF subunits heterodimerize, and activate a wide range of target genes by binding to hypoxia response elements.T-lymphocytes that comprise a principal effector component of the cellular immune response are exposed to hypoxia in target microenvironments in which they are assumed to dictate inflammatory programs. Target sites include tumors and healthy organs that confront T cells with gradients of low oxygen tension. Recent literature suggests that blunted HIF-1a expression results in a net proinflammatory program evident by increased production inflammatory cytokines upon TCR engagement [6]. Similar results were obtained upon knocking out HIF-1 selectively in T cells [7]. Additionally, HIF-1a was reported to play an inhibitory role in the regulation of T-cell receptor signal transduction by controlling intracellular calcium balance [8]. Collectively, these observations suggest that HIF-1 drives a Th2 favored response by downregulated Th1 programs [9][10][11]. Naturally occurring CD4 1 CD25 1 regulatory T cells (Treg) comprise a relatively newly characterized population that has evolved to tune do...

Objectives: To determine concentrations of adiponectin and its predictive value on outcome in a cohort of patients with congestive heart failure (CHF). Methods: Serum and clinical data were obtained for outpatients with clinically controlled CHF (n = 175). Serum concentrations of adiponectin, C reactive protein, N-terminal pro-brain natriuretic peptide (NTproBNP), interleukin (IL) -1b, IL-6, IL-8, IL-10, IL-12, tumour necrosis factor a and CD-40 ligand were determined. The association of adiponectin with the clinical severity of CHF was sought as well as the predictive value of this adipokine on mortality, CHF hospitalisations or the occurrence of each of these end points.Results: Concentrations of adiponectin were significantly increased in patients with CHF. Patients with higher New York Heart Association class had significantly higher serum concentrations of adiponectin. Adiponectin serum concentrations were lower in patients with diabetes and CHF as well as in patients with ischaemic cardiomyopathy. Serum adiponectin concentration was positively associated with age and NTproBNP but was negatively correlated with C reactive protein concentrations. Serum adiponectin above the 75th centile was found to be an independent predictor of total mortality, CHF hospitalisations or a composite of these end points over a two-year prospective follow up. Conclusion: Adiponectin is increased in CHF patients and predicts mortality and morbidity.

Patients with unstable angina and no evidence of cardiac necrosis exhibited increased circulating EPCs. Systemic inflammation, in addition to recognised growth factors, could play a role in the peripheral mobilisation of EPCs in patients with anginal syndromes.

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