Prospective observational cohort study of the association between antiplatelet therapy, bleeding and thrombosis in patients with coronary stents undergoing noncardiac surgery.

BACKGROUND: The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). METHODS: Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. RESULTS: A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93-3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31-3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3-17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69-4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15-13.93), P=0.031. CONCLUSIONS: OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI.

Preservation of vascular endothelial repair in mice with diet-induced obesity.

INTRODUCTION: Preservation of structural integrity of the endothelial monolayer and maintenance of endothelial cell function are of critical importance in preventing arterial thrombosis, restenosis and atherosclerosis. Obesity has been intimately linked with endothelial dysfunction, and reports of reduced abundance and functional impairment of circulating progenitor cells in obesity have led to the suggestion that defective endothelial repair contributes to obesity-related cardiovascular disease. METHODS: C57BL/6 mice were fed a high-fat diet for either 3 or 6 months to induce obesity; metabolic phenotyping was then carried out before femoral artery wire injury was performed. Endothelial regeneration was then quantified. Mononuclear cells and myeloid angiogenic cells were cultured and characterized for pro-angiogenic properties. RESULTS: No impairment of endothelial regeneration following mechanical endothelial injury in diet-induced obese mice when compared with chow-fed controls was observed, despite the induction of an adverse metabolic phenotype characterized by glucose intolerance and insulin resistance. Dietary-obese mice had increased numbers of circulating myeloid angiogenic cells, which retained normal functional properties including intact paracrine angiogenic effects. CONCLUSION: Preserved endothelial regeneration despite metabolic dysregulation in dietary obese mice suggests that compensatory mechanisms mitigate the deleterious influence of insulin resistance on endothelial repair in obesity.

Optimal medical therapy and percutaneous coronary intervention for stable angina: why patients should 'be taking' and 'keep taking' the tablets.

WHAT IS KNOWN AND OBJECTIVE: Cardioprotective drug regimens improve outcomes in patients with stable coronary artery disease. Revascularization is recommended for the persistence of symptoms despite optimal medical therapy (OMT) or in patients likely to derive prognostic benefit. Our objective is to comment on recent evidence that initiation of OMT is suboptimal in patients undergoing percutaneous coronary intervention (PCI) but conversely adherence to medication may be higher in patients treated with PCI. COMMENT: Large randomized controlled trials demonstrate that the risk of death or myocardial infarction is similar in patients treated by OMT alone and those treated with PCI and OMT. Despite the recommendations of international practice guidelines, OMT remains underutilized in recent analyses of patients referred for PCI. Notwithstanding the underutilization of proven therapies, a recent study suggests that adherence to medication is significantly higher in patients treated with PCI than in those treated with OMT alone. We discuss the potential factors that may contribute to underprescription of OMT and predict adherence in patients undergoing PCI. WHAT IS NEW AND CONCLUSION: Contemporary studies continue to demonstrate underutilization of OMT in patients referred for PCI but increased medication adherence in patients treated by PCI. We argue for increased recognition of OMT as the definitive treatment for stable angina, so that we can be sure those patients who require PCI 'are taking' and 'keep taking' the tablets.

Cell-specific insulin resistance: implications for atherosclerosis.

Insulin resistance is increasingly acknowledged as an independent risk factor for cardiovascular disease. Despite this, our understanding of the cellular and molecular mechanisms that might account for this relationship remain incompletely understood. A key challenge has been in distinguishing between a 'whole-body' milieu of inflammation and oxidative stress from the ramifications of cell-specific resistance to insulin. Transgenic models have now begun to explore the cellular influences of insulin resistance on vascular biology, with novel implications for atherosclerosis across a range of cells including endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, macrophages and fibroblasts. Emerging data from these models have also begun to challenge conventional dogma. In particular, the findings across various cell types are disparate with some even implying a protective influence on vascular biology. We now review these data, highlighting recent advances in our understanding of cellular resistance to insulin as well as those areas where there remains a paucity of data.

Effect of fat distribution on endothelial-dependent and endothelial-independent vasodilatation in healthy humans.

AIM: The present study aims to explore the relationship between inflammatory cytokines, plasma lipids, insulin, blood pressure (BP), total adiposity/markers of fat distribution and endothelial function in healthy people across a wide range of body fatness. METHODS: Seventy-three healthy people (44 women; age range: 24-64 years) with body mass index (BMI) range of 18.6-73.1 kg/m2 were recruited. All participants underwent assessment of conduit artery endothelial-dependent vasodilatation by using flow-mediated vasodilatation (FMD) of the brachial artery and endothelial-independent vasodilatation to sublingual GTN. They had blood taken for measurement of plasma markers of glucose homeostasis (fasting insulin and glucose), systemic inflammation (interleukin-6 (IL-6), C-reactive protein (CRP) and tumour necrosis factor-alpha receptor 2 (TNF-alpha R2)) and lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides). Morphometric assessment (waist circumference, BMI and waist-to-hip ratio (WHR)) and systolic and diastolic arterial pressure were also measured. RESULTS: Markers of total body fat/fat distribution (waist circumference, BMI and WHR), inflammation (IL-6, CRP and TNF-alpha R2), metabolism (fasting insulin, HDL, LDL and triglycerides) and BP (systolic and diastolic) correlated with FMD. Among these measurements, WHR was the only independent predictor of FMD (r2 = 0.30; p = 0.0001). CONCLUSIONS: WHR is an important marker of endothelial dysfunction in healthy people across a wide range of body fatness.

Pathophysiological implications of insulin resistance on vascular endothelial function.

BACKGROUND: Insulin resistance is a key component of the insulin resistance syndrome and is a crucially important metabolic abnormality in Type 2 diabetes. Insulin-resistant individuals are at significantly increased risk of cardiovascular disease, although the underlying mechanisms remain incompletely understood. The endothelium is thought to play a critical role in maintaining vascular homeostasis, a process dependent on the balance between the production of nitric oxide, superoxide and other vasoactive substances. Endothelial dysfunction has been demonstrated in insulin-resistant states in animals and humans and may represent an important early event in the development of atherosclerosis. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signalling pathways common to both insulin action and nitric oxide production. Other potential unifying links include the roles of oxidant stress, endothelin, the renin angiotensin system and the secretion of hormones and cytokines by adipose tissue. Lifestyle measures and drug therapies which improve insulin sensitivity and ameliorate endothelial dysfunction may be important in delaying the progression to overt cardiovascular disease in at risk individuals. METHODS: We conducted a literature search using Medline, restricted to articles published in the English language between 1966 and the present, and reviewed bibliographies of relevant articles. An initial search strategy employing combinations of the MeSH terms: insulin resistance; endothelium, vascular; insulin; nitric oxide or hyperinsulinaemia produced over 300 references. Focused searches using keywords relevant to the molecular aspects of endothelial function and insulin signalling, and lifestyle or pharmacological interventions relevant to insulin resistance or endothelial function, produced over 300 further references. Abstracts of all references were screened before selecting those relevant to this review.

Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans.

It is now well established that obesity is an independent risk factor for the development of coronary artery atherosclerosis. The maintenance of vascular homeostasis is critically dependent on the continued integrity of vascular endothelial cell function. A key early event in the development of atherosclerosis is thought to be endothelial cell dysfunction. A primary feature of endothelial cell dysfunction is the reduced bioavailability of the signalling molecule nitric oxide (NO), which has important anti atherogenic properties. Recent studies have produced persuasive evidence showing the presence of endothelial dysfunction in obese humans NO bioavailability is dependent on the balance between its production by a family of enzymes, the nitric oxide synthases, and its reaction with reactive oxygen species. The endothelial isoform (eNOS) is responsible for a significant amount of the NO produced in the vascular wall. NO production can be modulated in both physiological and pathophysiological settings, by regulation of the activity of eNOS at a transcriptional and post-transcriptional level, by substrate and co-factor provision and through calcium dependent and independent signalling pathways. The present review discusses general mechanisms of reduced NO bioavailability including factors determining production of both NO and reactive oxygen species. We then focus on the potential factors responsible for endothelial dysfunction in obesity and possible therapeutic interventions targetted at these abnormalities.