BACKGROUND Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. CONCLUSIONS Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, .)

Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male Sprague-Dawley rats were exposed to hypoxia (9% O 2 ) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index [right/(left ϩ septum) ventricular weight] were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N -nitro-L-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxiaand MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/ synthetic and less contractile phenotype in PH.

Christou H, Reslan OM, Mam V, Tanbe AF, Vitali SH, Touma M, Arons E, Mitsialis SA, Kourembanas S, Khalil RA. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302: L875-L890, 2012. First published January 27, 2012; doi:10.1152/ajplung.00293.2011.-Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. pulmonary artery; pulmonary circulation; nitric oxide; vascular smooth muscle PULMONARY HYPERTENSION (PH) is a serious disease and a major and expanding public health problem with ϳ1,000 new patients diagnosed every year in the United States (6,20). PH is characterized by increased pulmonary arterial pre...

Results: Acute DVT occurred in 7.3%, and chronic DVT occurred in 9.7% of patients studied (24.0% inpatients, 60.9% female; mean age, 56.3 years [range, 4-91 years, 1.1% aged Ͻ16 years]). History of previous DVT (74.0%) and smoking (38.0%) were the most common risk factors in patients with DVT. Iliac DVT was identified in 9.6% of acute DVT and in 5.7% of chronic DVT. Common femoral DVT was identified in 30.8% of acute DVT and in 22.9% of chronic DVT. CDL was used in 14.3% and thrombectomy in 4.8% of acute iliac/common femoral DVT and was never used with distal DVT. Warfarin anticoagulation with or without heparin/enoxaparin overlap was the most common treatment for acute (58.5%) and chronic (48.6%) iliac/common femoral DVT. In 2008 the referral base of the IU laboratory increased significantly. Acute DVT occurred significantly less often during the 1-year period of 2008 (5.3%) than in the 10-year period 1998 to 2007 (7.6%), but iliac/common femoral DVT as a component of acute DVT did not differ significantly (40.0% in 2008, 41.9% in 1998-2007).Conclusions: Iliac/common femoral DVT affects almost half of patients with acute DVT. Current recommendations of acute thrombus removal for the treatment of iliofemoral DVT is under-utilized, suggesting that perhaps greater education of clinicians and patients regarding invasive therapy for iliofemoral DVT is necessary.

Background Varicose Veins (VarV) is a common disorder of venous dilation and turtuosity with unclear mechanism. Although venous smooth muscle constitutes a significant component of the vein wall, the functional integrity and the ability of various regions of the VarV to constrict is unclear. The objective of this study was to test the hypothesis that the different degrees of venodilation in different regions of VarV reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the post-receptor signaling mechanisms of vasoconstriction. Methods Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control greater saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass graft (CABG). Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and the changes in isometric constriction in response to angiotensin II (AngII, 10−11−10−7 M), phenylephrine (PHE, 10−9−10−4 M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT1R) was measured in vein tissue homogenate using Western blot analysis. Results AngII caused concentration-dependent constriction in control vein (max 35.3±9.6 mg/mg tissue, pED50 8.48±0.34). AngII caused less contraction and was less potent in proximal (max 7.9±2.5, pED50 6.85±0.61), distal (max 5.7±1.2, pED50 6.74±0.68) and varix segments of VarV (max 7.2±2.0, pED50 7.11±0.50), suggesting reduced AT1R-receptor-mediated contractile mechanisms. Western blot analysis revealed similar amount of AT1R in VarV compared to control veins. α-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0±13.9 mg/mg tissue, pED50 5.48±0.12), that was greater in magnitude than that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments, but produced less constriction and was less potent in proximal segments of VarV (max 32.1±6.4 mg/mg tissue, pED50 4.89±0.13) as compared to control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca2+-dependent response, produced significant constriction in control veins, and similar contractile response in proximal, distal and varix segments of VarV, indicating tissue viability and intact Ca2+-dependent contraction mechanisms. Conclusions Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may play a role in the progressive dilation in VarV. Post-receptor Ca2+-dependent contraction mechanisms remain functional in VarV. The maintained α-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.