Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial.

AIM: To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. METHODS: This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. RESULTS: Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. CONCLUSIONS: Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids.

Inflammation and plaque vulnerability.

Atherosclerosis is a maladaptive, nonresolving chronic inflammatory disease that occurs at sites of blood flow disturbance. The disease usually remains silent until a breakdown of integrity at the arterial surface triggers the formation of a thrombus. By occluding the lumen, the thrombus or emboli detaching from it elicits ischaemic symptoms that may be life-threatening. Two types of surface damage can cause atherothrombosis: plaque rupture and endothelial erosion. Plaque rupture is thought to be caused by loss of mechanical stability, often due to reduced tensile strength of the collagen cap surrounding the plaque. Therefore, plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap. Endothelial erosion, on the other hand, may occur after injurious insults to the endothelium instigated by metabolic disturbance or immune insults. This review discusses the molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis.

Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development.

BACKGROUND: A growing health problem, venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), requires refined diagnostic and therapeutic approaches. Neutrophils contribute to thrombus initiation and development in experimental DVT. Recent animal studies recognized neutrophil extracellular traps (NETs) as an important scaffold supporting thrombus stability. However, the hypothesis that human venous thrombi involve NETs has not undergone rigorous testing. OBJECTIVE: To explore the cellular composition and the presence of NETs within human venous thrombi at different stages of development. PATIENTS AND METHODS: We examined 16 thrombi obtained from 11 patients during surgery or at autopsy using histomorphological, immunohistochemical and immunofluorescence analyses. RESULTS: We classified thrombus regions as unorganized, organizing and organized according to their morphological characteristics. We then evaluated them, focusing on neutrophil and platelet deposition as well as micro-vascularization of the thrombus body. We observed evidence of NET accumulation, including the presence of citrullinated histone H3 (H3Cit)-positive cells. NETs, defined as extracellular diffuse H3Cit areas associated with myeloperoxidase and DNA, localized predominantly during the phase of organization in human venous thrombi. CONCLUSIONS: NETs are present in organizing thrombi in patients with VTE. They are associated with thrombus maturation in humans. Dissolution of NETs might thus facilitate thrombolysis. This finding provides new insights into the clinical development and pathology of thrombosis and provides new perspectives for therapeutic advances.

Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo.

Macrophages contribute pivotally to cardiovascular diseases (CVD), notably to atherosclerosis. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Proteolytic enzymes serve as key effectors of many macrophage contributions to CVD. Therefore, intravital imaging of protease activity could aid evaluation of the progress and outcome of atherosclerosis, aortic aneurysm formation, or rejection of cardiac allografts. Among the large families of proteases, matrix metalloproteinases (MMPs) and cysteinyl cathepsins have garnered the most interest because of their participation in extracellular matrix remodelling. These considerations have spurred the development of dedicated imaging agents for protease activity detection. Activatable fluorescent probes, radiolabelled inhibitors, and nanoparticles are currently under exploration for this purpose. While some agents and technologies may soon see clinical use, others will require further refinement. Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care.

The molecular mechanisms of the thrombotic complications of atherosclerosis.

Our evolving knowledge of the cellular and molecular mechanisms underlying atherosclerosis has helped uncover the underlying causes behind thrombotic complications of this disease. Most fatal coronary thrombosis result from fibrous cap rupture or superficial erosion. Recent research has established a role for matrix metalloproteinases in the regulation of aspects of plaque structure related to propensity to disrupt and provoke thrombosis. Inflammatory pathways impinge on proteinase activity and aspects of oxidative stress that may favour plaque disruption. Novel molecular imaging strategies may permit visualization of proteinase activity in vivo, providing a new functional window on pathophysiology.

Vascular endothelium and atherosclerosis.

Atherosclerosis depends critically on altered behavior of the intrinsic cells of the artery wall, the endothelial cells and smooth muscle cells, and inflammatory leukocytes that join them in the arterial intima during the atherogenic process. The homeostatic properties of the normal endothelium contribute importantly to maintenance of aspects of arterial health including the appropriate regulation of blood flow, a basal anti-inflammatory state, promotion of fibrinolysis while opposing blood coagulation, and control of the balance of cellular proliferation and death. Alterations in these endothelial homeostatic mechanisms contribute critically to atherogenesis, the progression of this disease, and ist complications. Recent advances have highlighted novel molecular mechanisms that regulate the atheroprotective functions of normal endothelial cells that go awry during atherogenesis. Therapeutic strategies that alter the course of atherosclerosis may act by combating endothelial dysfunction.

Metformin and vascular protection: a cardiologist's view.

The predicted global epidemic of type 2 diabetes highlights the importance of identifying the most effective ways to reduce the risk of long-term diabetic complications. Although hyperglycaemia is undoubtedly a risk factor for microvascular complications, intensive glycaemic management has delivered only modest improvements in macrovascular endpoints thus far. A multidisciplinary approach addressing the components of the dysmetabolic syndrome, including insulin resistance, dyslipidaemia, hypertension, obesity and impaired fibrinolysis, will be required to protect the cardiovascular system more effectively. The potential vascular protective effects of metformin, demonstrated by the UK Prospective Diabetes Study, may complement other strategies within such a framework.

Deficiency of the cysteine protease cathepsin S impairs microvessel growth.

During angiogenesis, microvascular endothelial cells (ECs) secrete proteinases that permit penetration of the vascular basement membrane as well as the interstitial extracellular matrix. This study tested the hypothesis that cathepsin S (Cat S) contributes to angiogenesis. Treatment of cultured ECs with inflammatory cytokines or angiogenic factors stimulated the expression of Cat S, whereas inhibition of Cat S activity reduced microtubule formation by impairing cell invasion. ECs from Cat S-deficient mice showed reduced collagenolytic activity and impaired invasion of collagens type I and IV. Cat S-deficient mice displayed defective microvessel development during wound repair. This abnormal angiogenesis occurred despite normal vascular endothelial growth factor and basic fibroblast growth factor levels, implying an essential role for extracellular matrix degradation by Cat S during microvessel formation. These results demonstrate a novel function of endothelium-derived Cat S in angiogenesis.

Potential infectious etiologies of atherosclerosis: a multifactorial perspective.

Coronary heart disease (CHD) contributes substantially to illness and death worldwide. Experimental studies demonstrate that infection can stimulate atherogenic processes. This review presents a spectrum of data regarding the link between CHD and infection. In addition, the need for improved diagnostic tools, the significance of multiple pathogens, and potential intervention strategies are discussed.

CD40 signaling and plaque instability.

Today, multiple lines of evidence support the view of atherosclerosis as a chronic inflammatory disease and implicate components of the immune system in atherogenesis. Recent work has documented overexpression of the potent immune mediator CD40 and its counterpart CD40 ligand (CD40L) in experimental and human atherosclerotic lesions. Notably, interruption of CD40/CD40L interactions not only diminished the formation and progression of mouse atheroma, but also fostered changes in lesion biology and structure, which are associated in humans with "plaque stabilization." In accordance with the hypothesis that CD40 signaling promotes plaque instability, in vitro studies demonstrated that ligation of CD40 on atheroma-associated cell types, namely endothelial cells, smooth muscle cells, and macrophages, mediates functions considered crucial to the process of atherogenesis, such as the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, and procoagulants. The combination of the broad gamut of proatherogenic biological responses triggered by ligation of CD40 on endothelial cells, smooth muscle cells, and macrophages in vitro and the results of in vivo studies of interruption of CD40 signaling suggests a central role for this receptor/ligand dyad during atherogenesis, proposing CD40/CD40L interactions as a novel potential therapeutic target for this prevalent human disease.

Soluble CD40L and cardiovascular risk in women.

BACKGROUND: The immune-signaling dyad CD40/CD40L promotes atherogenesis, and patients with unstable angina have elevated plasma levels of soluble CD40L (sCD40L) and membrane-bound CD40L. It is unknown, however, whether elevations of circulating sCD40L precede the onset of acute cardiovascular symptoms. METHODS AND RESULTS: In a prospective, nested case-control evaluation of healthy middle-aged women, mean concentrations of sCD40L at baseline were significantly higher among 130 participants who subsequently developed myocardial infarction, stroke, or cardiovascular death (cases), compared with 130 age- and smoking-matched women who remained free of cardiovascular disease (controls) during a 4-year follow-up (2.86 ng/mL for cases versus 2.09 ng/mL for controls; P=0.02). Women with concentrations above the 95th percentile of the control distribution (>3.71 ng/mL) had a significantly increased relative risk (RR) of developing future cardiovascular events (RR, 3.3; 95% CI, 1.2 to 8.6; P=0.01) that remained after adjustment for usual cardiovascular risk factors (multivariate RR, 2.8; 95% CI, 0.9 to 8.0; P=0.05). CONCLUSIONS: High plasma concentrations of sCD40L may be associated with increased vascular risk in apparently healthy women.

Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves.

BACKGROUND: The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain. METHODS AND RESULTS: To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to alpha-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1beta, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not alpha-actin or desmin, cells in myxomatous valves contained both vimentin and alpha-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1beta, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves. CONCLUSIONS: Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.