Microsomal prostaglandin E synthase-1, which is not coupled to a particular cyclooxygenase isoenzyme, is essential for prostaglandin E(2) biosynthesis in vascular smooth muscle cells.

BACKGROUND: Prostaglandin (PG) E(2) induces expression of matrix metalloproteinases and angiogenic factors, thereby contributing to plaque instability. OBJECTIVE: To study the influence of cyclooxygenase (COX) and PGE synthase (PGES) isoenzyme expression on PGE(2) and PGI(2) biosynthesis in vascular smooth muscle cells (VSMC) in culture. METHODS: Cells were treated with human recombinant IL-1beta over different periods of time. Expression of PGI synthase, and COX and PGES isoenzymes was determined by real-time reverse transcriptase polymerase chain reaction and immunoblotting. Biosynthesis of prostanoids from exogenous or endogenous substrate was analyzed by high-performance liquid chromatography or enzyme-immunoassay after incubation of cells with labeled arachidonic acid or thrombin, respectively. RESULTS: Cytosolic PGES and microsomal PGES (mPGES) -1 and -2 were expressed in VSMC. PGES activity was mainly linked to mPGES-1. IL-1beta induced COX-2 and mPGES-1 with a different time course. VSMC ability to synthesize PGE(2) and PGI(2) fitted mPGES-1 and COX-2 expression, respectively. The ability of VSMC to produce PGI(2) was downregulated by mPGES-1 expression and was restored when mPGES-1 expression was silenced. Results from COX-1 and COX-2 silencing and selective inhibition showed that both COX-1 and COX-2 were involved in the biosynthesis of PGE(2) and their relative contribution depended on the time of incubation with IL-1beta. CONCLUSIONS: mPGES-1 is the main PGES responsible for PGE(2) biosynthesis by VSMC and its induction downregulates VSMC ability to produce PGI(2.) These results support the concept that under inflammatory conditions VSMC could significantly contribute to plaque instability and that mPGES-1 may be a target for therapeutic intervention in patients with cardiovascular risk.

Inflammatory biomarkers of coronary atheromatous plaque vulnerability.

In the last decade, compelling evidence has evolved at both the basic science and clinical level for the implication of inflammation in the pathogenesis of atherosclerosis and its complications. The composition of the atherosclerotic plaque, rather than the degree of stenosis, is now recognized as a pivotal feature in determining plaque vulnerability and hence the risk of acute coronary ischaemic events. Current evidence supports a key role for inflammation in all phases of the atherosclerotic process, from plaque formation through to progression and, ultimately, the thrombotic complications of atherosclerosis. The growing appreciation of the role of inflammation in atherogenesis has focused attention on whether circulating levels of inflammatory biomarkers may help to identify those at risk of future cardiovascular events. In addition, the protective effects of a variety of interventions, such as statins, aspirin, and fibrates, are often associated with the evidence of reduced inflammation, further strengthening the notion that inflammation and the acute complications of atherosclerosis are causally related. The present review describes the pathophysiology of atheromatous plaque vulnerability and discusses the clinical use of inflammatory biomarkers for prognostic stratification of patients with acute coronary syndromes.

Nuevos conceptos sobre la enfermedad renal crónica y sus implicaciones / No disponible

La National Kidney Foundation americana ha definido recientemente criterios que definen un nuevo concepto denominado enfermedad renal crónica. Más o menos discutibles, suponen un importante método de estandarización de rápida aceptación internacional. En este artículo se revisa la nueva definición y estadios, los métodos de diagnóstico y evaluación, sus complicaciones y asociaciones, así como sus factores de progresión a estadios terminales con necesidad de tratamiento sustitutivo. Asimismo se establece el importante nuevo vínculo de la enfermedad renal crónica como factor de riesgo cardiovascular (AU)

The American National Kidney Foundation has recently defined new criteria to define the concept of chronic Kidney disease (CKD). Althougt they are partially under discussion, they have become a very helpful way of standarization and widely internationally accepted. In this article, we review the new definition and stages, the diagnostic and evaluation methods, complications and associations, as well as progression factors to end stage renal disease. It is also underlined the important newly recognized link between chronic kidney disease and cardiovascular risk (AU)

Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression.

AIMS: To investigate the association between plasma endothelin levels and rapid coronary artery disease progression, as assessed by quantitative angiography. METHODS AND RESULTS: Changes in diameter were assessed in 224 coronary stenoses of 92 consecutive patients (62 men) with chronic stable angina pectoris who were on a waiting list for routine coronary angioplasty and underwent coronary angiography on two occasions: the first (diagnostic) angiogram was carried out at study entry and the second 5.5+/-3.0 months later, immediately prior to coronary angioplasty. A digital quantitative angiographic analysis system was used to assess differences in stenosis diameter between the first and second angiogram. Plasma immunoreactive endothelin levels were estimated by radioimmunoassay at study entry. Rapid coronary artery disease progression occurred in 29 (31.5%) patients according to pre-established criteria: 12 (41%) had a > or =10% diameter reduction of at least one pre-existing stenosis > or =50%, 10 (34%) had a > or =30% diameter reduction of a pre-existing stenosis <50%, 5 (17%) patients developed a new stenosis and 2 (7%) had progression of a lesion to total occlusion by the second angiogram. Baseline demographic, clinical and angiographic data were similar in patients with and without stenosis progression. Plasma endothelin levels were significantly higher in patients with rapid disease progression than in those without (5.7+/-2.0 pg. ml(-1)vs 3.9+/-1.6 pg. ml(-1), P<0.001). Multiple logistic regression analysis revealed that endothelin was an independent predictor of disease progression (P=0.001). Moreover, endothelin levels above 4.26 pg. ml(-1)(the median of the total endothelin concentrations) were associated with a sixfold increase in the risk of developing rapid stenosis progression. CONCLUSIONS: Plasma endothelin is raised in patients with coronary artery disease progression and may be a marker of risk of rapid stenosis progression. Endothelin may also play a pathogenic role in this process.

C-reactive protein in patients with chronic stable angina: differences in baseline serum concentration between women and men.

AIMS: Serum C-reactive protein has prognostic significance in apparently healthy men and women and in men with coronary artery disease. Little is known regarding the predictive role of C-reactive protein in women with coronary heart disease. We assessed whether differences exist in C-reactive protein levels and their prognostic value in men compared with women. We also assessed whether C-reactive protein concentrations differed in women receiving hormone replacement therapy vs those on no hormone replacement therapy. METHODS AND RESULTS: We prospectively studied 911 consecutive patients (327 women) with typical exertional angina. All patients underwent clinical, biochemical and angiographic characterization at study entry. Serum C-reactive protein was measured using a highly sensitive assay and correlated with clinical events during follow-up (from 1.0 to 3.7 years). C-reactive protein was significantly higher in women than men (3.0 mg. l(-1)[range 1.3-5.8] vs 2.1 mg. l(-1)[range 1.0-4.2], P<0.001), even after multiple regression adjustment for other risk factors. C-reactive protein was also significantly higher in women receiving hormone replacement therapy than in women not using hormone replacement therapy (P=0.001). C-reactive protein was an independent predictor of cardiovascular risk (logistic regression P=0.033) in the whole group but, despite higher C-reactive protein concentration, women had a similar rate of cardiac events compared to men. CONCLUSIONS: Baseline C-reactive protein levels were higher in women than men but the event rate was similar in men and women. Women on hormone replacement therapy had significantly higher C-reactive protein than women not using hormone replacement therapy. In the group as a whole, increased C-reactive protein was associated with a higher cardiovascular risk.

Increased serum neopterin: a marker of coronary artery disease activity in women.

OBJECTIVE: To assess whether neopterin concentrations in women with unstable angina differ from those in women with chronic stable angina. DESIGN: Prospective cohort study. SETTING: University hospital in south west London. PATIENTS: 114 consecutive women with angina were studied: 82 had chronic stable angina (typical exertional chest pain, positive exercise ECG testing, and/or abnormal myocardial scintigraphy; symptoms stable for at least three months), and 32 had unstable angina (Braunwald class III). All patients with chronic stable angina (100%) and 18 with unstable angina (56.3%) underwent digital coronary angiography; neopterin concentrations were determined using a commercially available immunoassay. MAIN OUTCOME MEASURES: Major clinical events during one year follow up were readmission with Braunwald's class IIIb unstable angina, non-fatal myocardial infarction, and cardiac death. RESULTS: Major events occurred in 12 women with chronic stable angina (14.6%) and nine women with unstable angina (28.1%). Mean (range) neopterin concentrations were significantly higher in women with unstable angina than in those with chronic stable angina (7.6 (5.1-11.5) nmol/l v 5.9 (4.4-7.5) nmol/l; p = 0.003), even after adjustment for variables which were significantly different on univariate analysis. In women with chronic stable angina, baseline neopterin concentrations were higher in those with cardiac events than in those without events (7.1 (5.9-9.1) nmol/l v 5.7 (3.9-7.3 nmol/l); p = 0.010), even after adjustment for variables with significant differences between both groups on univariate analysis. CONCLUSIONS: On average, women with unstable angina had significantly higher neopterin concentrations than women with chronic stable angina. Women with chronic stable angina with events during follow up had higher neopterin concentrations than those without events. Neopterin concentrations were similar in patients with unstable angina and women with chronic stable angina who developed events. Neopterin concentrations may therefore be a marker of risk in women with coronary artery disease.

Serum neopterin and complex stenosis morphology in patients with unstable angina.

OBJECTIVES: We sought to assess the relation between serum neopterin concentration and complex coronary artery stenosis in patients with unstable angina. BACKGROUND: Monocyte activation is associated with acute atheromatous plaque disruption and acute coronary syndromes. Angiographically demonstrated complex coronary stenosis is often an expression of plaque disruption. Increased serum concentration of neopterin, a pterydine derivative secreted by macrophages after stimulation by interferon-gamma, has been observed in patients with acute coronary syndromes as compared with control subjects and patients with stable angina pectoris. METHODS: We studied 50 patients with unstable angina (32 men) who underwent coronary angiography after hospital admission. All coronary stenoses with > or =30% diameter reduction were assessed and classified as "complex" (irregular or scalloped borders, ulceration or filling defects suggesting thrombi) or "smooth" (absence of complex features). Serum neopterin levels were assessed within 24 h of hospital admission using a commercially available immunoassay (enzyme-linked immunosorbent assay kit, IBL, Hamburg, Germany). RESULTS: Thirty-nine patients were classified in Braunwald class IIIb, four in class IIb and seven in class Ib. The number of complex lesions per patient was 2.6+/-1.8 (mean +/- SD). The mean neopterin concentration was 7.76+/-3.62 nmol/liter. A significant correlation was observed between neopterin serum concentration and the presence of complex coronary stenoses (r = 0.35, p = 0.015). Multiple regression analysis showed that serum neopterin (p < 0.0001) was independently associated with the number of complex lesions. Other variables associated with complex lesions were the number of vessels with > or =75% stenosis (p < 0.0001), plasma creatinine (p = 0.003), triglycerides (p = 0.014) and a history of unstable angina (p = 0.032). CONCLUSIONS: Serum neopterin concentration is associated with the presence of angiographically demonstrated complex lesions in patients with unstable angina and may represent a marker of coronary disease activity.

[Refractory angina treated by spinal cord stimulation. The results of a long-term follow-up]. / Tratamiento de la angina refractaria con electroestimulación medular. Resultados del seguimiento a largo plazo.

INTRODUCTION AND OBJECTIVES: The quality of life in patients with refractory angina has been shown to improve dramatically with spinal cord stimulation because of its beneficial results. The aim of this study was to assess the long-term morbimortality of this technique of spinal cord stimulation in the long term. PATIENTS AND METHODS: 41 patients with refractory angina and treated with spinal cord stimulation were included. Median follow-up was 31.0 [12.0-42.5] months, and total follow-up was 1,236 months. RESULTS: Annual number of admissions per patient year were dramatically reduced after spinal cord stimulation (2.31 vs. 0.28). Patients that died during follow-up had a 3-fold increase rate of admissions than patients that survived (0.37 vs. 0.19). However, patients that died during follow-up also had a lower admission rate after spinal cord stimulation (2.03 vs. 0.37). Overall mortality was 9.7%/year; cardiac mortality was 7.7%/year. Both figures are not different from those of other groups of patients with similar anatomical characteristics of coronary artery disease severity without spinal cord stimulation. Complications of this treatment were minimal (we only observed an early post implantation infection and a battery extrusion, without any complications with electrodes). The outcome was similar in patients with subacute unstable refractory angina or stable angina. CONCLUSIONS: Spinal cord stimulation can be considered a safe and effective alternative treatment of refractory angina. Long-term morbidity is low, and mortality is not higher than the expected in this group of patients.

Negative stress echocardiographic responses in normotensive and hypertensive patients with angina pectoris, positive exercise stress testing, and normal coronary arteriograms.

OBJECTIVES: To systematically compare the results of dobutamine stress echocardiography in matched groups of hypertensive and normotensive patients with anginal chest pain and normal coronary arteriograms (CPNA). SETTING: University hospital. SUBJECTS: 33 patients with exertional anginal chest pain, a positive exercise stress ECG, and a completely normal coronary arteriogram; 17 had a history of systemic hypertension (14 women; mean (SD) age 57 (6) years), and 16 had no hypertensive history (12 women; age 54 (9) years). METHODS: Ambulatory ECG monitoring, dobutamine stress echocardiography, and thallium-201 single photon emission computed tomography (SPECT) were performed in all subjects. RESULTS: All patients had normal left ventricular systolic function at rest and none fulfilled the criteria for ventricular hypertrophy. Eight normotensive patients and 10 hypertensive patients had perfusion abnormalities on thallium SPECT (p = 0.61). Dobutamine infusion reproduced anginal pain in seven normotensive and seven hypertensive patients (p = 0.88). ST segment depression was also recorded in eight normotensive patients and seven hypertensive patients (p = 0. 61). No patient in either group developed regional wall motion abnormalities during dobutamine stress echocardiography. CONCLUSIONS: Neither hypertensive nor normotensive CPNA patients developed regional wall motion abnormalities during dobutamine stress echocardiography, despite the high prevalence of scintigraphic perfusion defects in both groups and the presence of chest pain and ST segment depression. Thus myocardial ischaemia was not present in either group, or else dobutamine stress echocardiography is insensitive to ischaemia caused by microvascular dysfunction.

[Ischemic cardiopathy: inflammation markers and the cardiovascular risk]. / Cardiopatía isquémica: marcadores de inflamación y riesgo cardiovascular.

In recent years it has been established that inflammation is a key mechanism in the pathogenesis of atherosclerosis and in coronary artery disease progression. Inflammation is a host response to a wide variety of tissue injuries. A persistent or continually repeated insult will lead to chronic inflammation which may result in tissue destruction and/or loss of normal organ function. Atherosclerosis and other pathologies involving inflammation are associated with increased levels of cytokines, which in turn raise acute-phase proteins levels in blood (acute inflammation markers, i.e. fibrinogen and C-reactive protein). It has been shown recently that concentrations of these proteins are higher in individuals at increased risk of developing cardiac events in the years to come. This is true both in apparently healthy men and women and in ischaemic heart disease patients. CRP is currently the inflammatory marker which appears to have captured the investigators' attention around the globe. In this report we review the current data on the relationship between atherosclerosis and inflammation, with special attention to cytokines and acute phase reactants. The use of acute phase reactants as prognostic risk markers in ischaemic heart disease is also discussed.

Platelet deposition on eroded vessel walls at a stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in the primary and secondary prevention of cardiovascular diseases. However, regression studies with lipid-lowering drugs have not shown significant lesion reduction associated with the improvement in clinical events. Therefore, our objective has been to study whether treatment with a lipid-lowering drug of this family, atorvastatin, could reduce platelet deposition on the damaged vessel wall at different shear stress conditions, simultaneously with retardation of the development of atherosclerotic lesions. Using cholesterol-fed swine as the model, we found that atorvastatin significantly diminished platelet deposition on the mildly damaged vessel wall at high shear rates (50%, P<0.01), but it did not have any effect in preventing platelet deposition triggered by a severely injured vessel wall. Development of coronary lesions was also reduced by treatment. These findings suggest that atorvastatin may prevent platelet attachment to eroded vessels and hence, contribute to reducing the thrombotic risk associated with the erosions of the luminal surface and the platelet-dependent progression of atherosclerotic plaques.