The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat.

BACKGROUND AND AIMS: Melatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease. MATERIALS AND METHODS: Thirty rats were divided into five groups: a control group, an acetic acid-induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression. RESULTS: Melatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked. CONCLUSION: Melatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides.

Cryptogenic stroke in low-risk patients, consider a cardiac shunt at your peril.

Patent foramen ovale (PFO) as a cause of cryptogenic stroke from paradoxical embolisation remains a controversial issue. The optimal care between medical and surgical management of these patients for the attending clinician remains a conundrum. We report a case of cryptogenic stroke in a woman aged 59, with a PFO, concomitant venous thrombosis and cryptogenic stroke. The case highlights the difficulty in diagnosing and managing such patients, particularly as recent evidence challenges the clinical practice of percutaneous closure and pathophysiological rationale.

Eosinophil count predicts mortality following percutaneous coronary intervention.

INTRODUCTION: Several inflammatory markers have been shown to be independent predictors for both the development of clinically significant atherosclerosis and for adverse outcome in patients with symptomatic coronary artery disease (CAD). We investigated the prognostic role of eosinophil count in low to intermediate risk patients with CAD. METHODS: We studied 909 patients admitted for elective or urgent percutaneous coronary intervention (PCI) from April 2002 to December 2004, and measured pre-procedural total and differential white blood cell (WBC) counts. Inter-tertile WBC differences in short (6months) and long term (up to 74months) mortality were analysed after adjusting for differences in baseline characteristics. RESULTS: Over a median period of 54months (inter-quartile range 47-65), a total of 138 deaths (15.2%) occurred, of which 24 were in the first 6months of follow-up. Cox regression analysis showed that high pre-procedural eosinophil count (top tertile) was associated with improved outcome within the first 6months (OR=0.23 [0.06-0.84]; p=0.03) but after this period there was an increased risk of mortality (OR=2.21, [1.26-3.88]; p=0.006). CONCLUSIONS: Eosinophil count is a novel biomarker for risk stratification of CAD patients, which was associated initially with reduced mortality, but after 6months with increased mortality.

Impact of high-dose atorvastatin on endothelial, platelet, and angiogenic indices: effect of ethnicity, cardiovascular disease, and diabetes.

Lipid lowering with statins improves morbidity and mortality, particularly in diabetics, and may have additional nonlipid effects. South Asians (SAs) are at higher risk of cardiovascular disease and diabetes compared with white Europeans (WEs). We hypothesized that abnormal endothelial (marked by von Willebrand factor), angiogenesis (VEGF, angiopoietins 1 and 2) and platelet function (soluble P selectin, soluble CD40L) improve with statin treatment in diabetics in different ethnic groups. Plasma was obtained before and 8 weeks after treatment with atorvastatin (80 mg/day) by SAs and WEs with or without diabetes. Research indices were measured by enzyme-linked-immunosorbent assay (ELISA). Treatment increased angiopoietin-2 (P < .04) in all groups regardless of diabetes or ethnicity. In those free of diabetes, angiopoietin-2 increased 3-fold, whereas in diabetes, it increased 2-fold. We suggest that an additional effect of statins is to increase levels of growth factor angiopoietin-2 in the direction of normality. This effect is weaker in participants with diabetes.

Plasma haemoxygenase-1 in coronary artery disease. A comparison with angiogenin, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor.

It was the aim of this study to determine plasma haemoxygenase-1 (HO-1) across the spectrum of health, angina but normal coronary arteries (NCA), stable coronary artery disease (CAD), and acute coronary syndromes (ACS), and relationships with angiogenin, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1, and vascular endothelial growth factor. Plasma markers were measured (ELISA) in peripheral venous citrated plasma from 50 healthy subjects, 30 with NCA, 70 with stable CAD and 24 with an ACS, and from patient's aortic root, coronary ostium, coronary sinus and femoral artery. Human umbilical vein endothelial cells (HUVECs) were cultured with or without tumour necrosis factor (TNF), and platelets were probed. HO-1 was raised in stable CAD (p<0.05) and increased further in ACS (p<0.01) compared to healthy controls and NCA. HO-1 correlated only with MMP-9, and then only in the healthy controls. There were no major differences from cardiac or peripheral sites. HO-1 was present in HUVECs and 24-hour HUVEC supernatants but release was abolished by TNF. Platelets had no HO-1. In conclusion, HO-1 is raised in stable CAD and ACS and may arise from the endothelium but not the platelet. This may have implications for our understanding of the pathophysiology of CAD and its acute presentation as ACS.

Anger rumination, social support, and cardiac symptoms in patients undergoing angiography.

OBJECTIVES: Socially isolated individuals report more cardiac symptoms, suffer increased cardiovascular morbidity and mortality, and experience higher levels of stress and anxiety than those with more effective support resources. However, the complex interactions of psychosocial factors implicated in the disease process remain to be fully elucidated. We sought to explore these relationships, with the addition of a novel psychosocial variable, anger rumination, which could be associated with increased cardiovascular risk. DESIGN: We examined the association of psychological stress, social support, and anger rumination, with surgical anxiety, self-reported cardiac symptoms, and angiographically documented coronary artery disease, using a correlational ex post facto design. METHODS: One hundred and one patients scheduled for elective coronary angiography completed questionnaires during the week prior to angiography. Disease severity was objectively assessed using the Gensini scoring system. RESULTS: Self-reported cardiac symptom severity was significantly correlated with higher perceived stress, less social support, and higher anger rumination, but none of the psychosocial variables predicted Gensini score. Social support partially mediated the relationship between anger rumination and surgical anxiety. Perceived stress mediated the relationship between anger rumination and cardiac symptoms. CONCLUSIONS: For patients awaiting angiography, stress, and lack of social support are important predictors of self-reported cardiac symptoms, irrespective of actual disease severity. Intervention could focus on reducing perceived stress by encouraging reappraisal and a support seeking, rather than a ruminative, anger coping style.

Preprocedural hemoglobin predicts outcome in peripheral vascular disease patients undergoing percutaneous transluminal angioplasty.

BACKGROUND: Anemia is a risk factor for adverse outcome in patients with symptomatic cardiovascular disease. This study assessed the association of preprocedural hemoglobin with adverse outcome in patients with advanced peripheral vascular disease (PVD) undergoing percutaneous transluminal angioplasty (PTA). METHODS: Consecutive first-time procedures for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA were analyzed in a retrospective cohort study. Cardiovascular risk factors, preprocedural hemoglobin, and angiographic data were recorded. Preprocedural (

Preprocedural neutrophil count predicts outcome in patients with advanced peripheral vascular disease undergoing percutaneous transluminal angioplasty.

BACKGROUND: The neutrophil count has been associated with adverse cardiovascular events after percutaneous coronary intervention. There are limited data on risk stratification of patients with advanced peripheral vascular disease (PVD) using white blood cell (WBC) subtypes. This study assessed the association of total and differential WBC counts with adverse outcome in patients with advanced PVD undergoing percutaneous transluminal angioplasty (PTA). METHODS: In a retrospective cohort study, consecutive de novo procedures were analyzed for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA. Cardiovascular risk factors, baseline total and differential WBC counts, and angiographic data were recorded. Primary outcome was a composite of events of target vessel revascularization (repeat PTA or vascular bypass operation) or lower limb amputation. RESULTS: A total of 101 patients were studied. Their mean age was 76 +/- 10 years, 54% had diabetes mellitus, 68% were hypertensive, and 12% had had previous myocardial infarction. We observed 29 events during a median period of 14 months (interquartile range, 4-26). Cox regression analysis found diabetes mellitus (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.35-16.14; P = .02), Rutherford category 5 (OR, 4.18; 95% CI, 1.06-16.51; P = .04), poor tibial runoff (OR, 4.42; 95% CI, 1.16-16.82; P = .03), and preprocedural neutrophil count in the third tertile (OR, 10.77; 95% CI, 2.19-52.91; P = .003) were independent predictors of outcome. CONCLUSIONS: The results suggest that the preprocedural neutrophil count could be used in global risk factor assessment of patients with advanced PVD who are being considered for PTA. The neutrophil count may reflect the burden of atherosclerosis and tissue damage, and so could identify patients who need more aggressive intervention for advanced PVD.

Indices of angiogenesis, platelet activation, and endothelial damage/dysfunction in relation to ethnicity and coronary artery disease: differences in central versus peripheral levels.

BACKGROUND: We hypothesized that indices of angiogenesis (vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and -2), platelet activation (soluble P-selectin)) and endothelial damage/dysfunction (von Willebrand factor (vWf)) would be more deranged in South Asians than in white Europeans when measured within the coronary sinus or coronary artery per se (that is, intracardiac sampling of blood supplying and draining the heart), as compared to measurements from the peripheral venous system. METHODS: To test this hypothesis, we performed a cross-sectional study of 87 subjects undergoing cardiac catheterization, where 43 were South Asian and 44 were white European. RESULTS: South Asian participants were younger (P = 0.01) but had a lower rate of self-reported smoking (P = 0.01). The extent of coronary atherosclerosis, assessed using presence of lesions > 50%, number of vessels diseased and Gensini score, was comparable between the two ethnic groups (all P = NS). When samples were analysed from the coronary circulation or the femoral vein in relation to South Asian and white European ethnicity, there were no significant differences in the levels of VEGF, angiopoietins 1 and 2, soluble P-selectin and vWf levels between the two ethnic groups. CONCLUSION: Indices of angiogenesis, platelet activation, and endothelial damage/dysfunction are comparable in South Asians and their white European counterparts. Our results suggest that their pathophysiological roles may be comparable in South Asians and white Europeans in the context of coronary artery disease.

Platelet activation in coronary artery disease: intracardiac vs peripheral venous levels and the effects of angioplasty.

BACKGROUND: Platelet activation and aggregation play a key role in coronary artery disease, with antiplatelet therapies leading to improved clinical outcomes. Limited data exist as to whether peripheral venous blood measurements of platelet physical indexes (eg, platelet count, volume, and granularity) and soluble markers of platelet activation (eg, P-selectin [sP-sel] and CD40 ligand [CD40L]) reflect the local (intracardiac) coronary environment. Furthermore, how percutaneous coronary interventions (PCIs) affect levels of peripheral/cardiac platelet indexes is unclear. METHODS: Blood samples were sequentially acquired from the coronary os, aortic root, coronary sinus, and the femoral vein, and where relevant, pre-PCI and post-PCI. Eighty-seven patients undergoing coronary angiography were recruited (mean [+/-SD] age, 59.8+/-10.8 years; 54 men [62%]), of whom 36 proceeded to PCI. Platelet physical indexes and plasma sP-sel and CD40L levels were measured (by enzyme-linked immunosorbent assay). RESULTS: At baseline, no intracardiac vs peripheral differences were noted in sP sel levels, while CD40L levels were elevated in the aorta compared to the coronary sinus and femoral venous. The mean platelet count (MPC) was similar at all four sites, but within the coronary sinus blood, mean platelet volume (MPV) was significantly lower and mean platelet granularity (MPG) was higher when compared to arterial levels. Though aortic and femoral levels of sP-sel were raised following PCI, transcardiac gradients of plasma sP-sel levels were unaffected. PCI was associated with lower CD40L, MPC, and MPV levels but with a higher MPG level in all sampling sites. CONCLUSIONS: sP-sel levels measured peripherally reflect the cardiac environment, unlike CD40L, MPC, MPV, and MPG. PCI leads to further platelet activation (raised sP-sel) despite aggressive antiplatelet therapy.

Systemic and intracardiac vascular endothelial growth factor and angiopoietin-1 and -2 levels in coronary artery disease: effects of angioplasty.

BACKGROUND: Vascular growth factors are involved in the pathophysiology of human atherosclerotic vascular disease and plaque destabilization. We hypothesized that in stable patients with coronary artery disease (CAD), plasma levels of vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2 (as indices of angiogenesis) would be no higher in coronary sinus blood when compared to the aortic root, coronary ostium, and peripheral femoral vein. Secondly, we hypothesized that percutaneous coronary intervention (PCI; angioplasty+/-stenting) would increase intracardiac levels of these indices, perhaps by destabilizing coronary plaques. METHODS: Patients undergoing elective diagnostic coronary angiography (n = 70; mean age 58.8+/-11.2 years) of which 37 proceeded to PCI were recruited. Blood samples were obtained from the aortic root, coronary ostium, coronary sinus, and femoral vein. Plasma VEGF, angiopoietin-1 and angiopoietin-2 levels were measured by immunoassays. RESULTS: There were no significant differences in VEGF, angiopoietin-1 and angiopoietin-2 levels when aortic root, coronary ostium, coronary sinus, and femoral vein samples were compared (P = not significant (NS)). In patients undergoing PCI, peripheral angiopoietin-2 levels were increased significantly post PCI (P = 0.01). There was also a difference in intracardiac gradient (that is, aortic root-coronary sinus difference) in angiopoietin-1 (P = 0.02) following PCI. No significant changes in VEGF with PCI were noted. CONCLUSION: There were no differences in indices of angiogenesis when aortic root, coronary ostium, coronary sinus, and femoral vein levels of VEGF and angiopoietins are compared, suggesting that peripheral blood measurements of these indices are comparable to intracardiac levels. Although no immediate effects were observed in soluble VEGF levels, PCI affected intracardiac angiopoietin-1 with a systemic release of angiopoietin-2. Further investigations are necessary to determine the relative systemic and intracardiac effects of the angiopoietins in vascular remodelling post PCI.

Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment?

Atherosclerosis remains the underlying cause of cardiovascular disease and is a dynamic process involving inflammation, haemostasis, endothelial dysfunction, and angiogenesis. Studies of circulating factors from peripheral blood can provide an insight into this pathophysiology but may remain indicative of a more generalized, systemic process. More localized interaction(s) within the heart may be better studied from coronary blood samples. Indeed, an increasing number of prospective studies show good correlation between indices of these processes and clinical outcomes. As local sampling offers a unique way of assessing the local cardiac milieu, this may prove useful in the monitoring of both local/systemic drug therapies and interventional technologies.

Effects of low osmolar contrast (iomeprol) on haemorheology and platelet activation in patients with coronary artery disease.

BACKGROUND: Non-ionic low osmolar contrast agents are widely used during coronary angiography. As these agents cause activation of thrombotic pathways in vitro, this may have potentially significant clinical impact. However, limited evidence exists as to their in vivo effects from selective coronary cannulation. METHODS: We initially performed an in vitro experiment to assess the effect of serial contrast (Iomeprol 300, Bracco) dilution on platelet indices [mean platelet count (MPC), platelet volume (MPV), platelet granularity (MPG)]. The in vivo effect of contrast injection on platelet activation markers [soluble P-selectin (sPsel), soluble CD40 ligand (sCD40L)], MPC, MPV, MPG, haemoglobin and haematocrit was subsequently determined in 35 patients (mean age 58 +/- 11; 22 males) undergoing cardiac catheterisaton. RESULTS: No significant in vitro effect of contrast on MPC or MPV was seen but there was a significant increase in MPG (p = 0.40, 0.10 and 0.01, respectively). In the in vivo study, there was a reduction in mean haemoglobin and haematocrit levels, suggesting an average increase in plasma volume of 6.5 +/- 5.8%. The in vivo effect of Iomeprol was associated with an unadjusted reduction in sPsel concentrations (p = 0.04) and MPV (p < 0.05), with denser platelets (p < 0.05). There was no difference in MPC or sCD40L concentration (both p = NS). After adjustment for the haemodilution effect, no significant reduction in P-sel levels was seen with contrast (p = 0.27), although the adjusted post-contrast change in MPG (p = 0.01), MPC (p = 0.01) and sCD40L (p < 0.05) levels were significant. CONCLUSION: Low osmolar contrast led to a minimal effect on soluble and physical indices of platelets within the coronary artery, primarily due to plasma volume expansion.