Ramón Arroyo-Espliguero

Markers of Inflammation and Rapid Coronary Artery Disease Progression in Patients With Stable Angina Pectoris

Background—Both endothelial cell activation and macrophage activation play a significant role in atherogenesis and atheromatous plaque vulnerability and may determine rapid coronary artery disease (CAD) progression. We sought to assess the association between serum inflammatory markers and rapid CAD progression in patients with chronic stable angina pectoris. Methods and Results—We studied 124 chronic stable angina pectoris patients (84 men; mean age, 61±10 years) who were on a waiting list for coronary angioplasty for a mean time of 4.8±2.4 months. CAD progression was defined as ≥10% diameter reduction of a pre-existing stenosis ≥50%, ≥30% diameter reduction of a stenosis <50%, development of a new stenosis ≥30% in a previously normal segment, or progression of any stenosis to total occlusion. CAD progression occurred in 35 patients (28%). After adjustment with binary logistic regression, neopterin (P<0.001), high-sensitivity C-reactive protein (P=0.017), matrix metalloproteinase-9 (P=0.002), soluble intercellular adhesion molecule 1 (P<0.001), and previous history of unstable angina (P=0.01) were independent predictors of rapid CAD progression. The association between rapid disease progression and inflammatory markers remained significant even when presence of complex lesions was introduced into the multivariate model. Conclusions—Rapid CAD progression in patients with stable angina pectoris is associated with increased C-reactive protein levels and raised concentrations of biochemical markers of endothelial and macrophage activation.

Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes

Objective: To assess the relation between markers of inflammation and the presence of multiple vulnerable plaques in patients with non-ST segment elevation acute coronary syndromes. Design: Prospective cohort study of 55 patients with non-ST segment elevation acute coronary syndromes and angiographically documented coronary disease. Blood samples were obtained at study entry for the assessment of high sensitivity C reactive protein (CRP), neopterin, and neutrophil count. Coronary stenoses were assessed by quantitative computerised angiography and classified as “complex” (irregular borders, ulceration, or filling defects) or “smooth” (absence of complex features). Extent of disease was also assessed by a validated angiographic score. Results: Neutrophil count (r  =  0.36, p  =  0.007), CRP concentration (r  =  0.33, p  =  0.02), and neopterin concentration (r  =  0.45, p < 0.001) correlated with the number of complex stenoses. Patients with multiple (three or more) complex stenoses, but not patients with multiple smooth lesions, had a higher neutrophil count (5.9 (1.4) × 109/l v 4.8 (1.4) × 109/l, p  =  0.02), CRP concentration (log transformed) (1.08 (0.63) v 0.6 (0.6), p  =  0.03), and neopterin concentration (log transformed) (0.94 (0.18) v 0.79 (0.15), p  =  0.002). Multiple regression analysis showed that neopterin concentration (B  =  4.8, 95% confidence interval (CI) 1.9 to 7.7, p  =  0.002) and extent of coronary artery disease (B  =  0.6, 95% CI 0.03 to 1.2, p  =  0.04) were independently associated with the number of complex stenoses. Conclusions: Acute inflammatory markers such as high neutrophil count, CRP concentration, and neopterin concentration correlate with the presence of multiple angiographically complex coronary stenoses. Neopterin concentration was a stronger predictor of multiple complex plaques than were neutrophil count and CRP concentration. These findings suggest that a relation exists between inflammation and pancoronary plaque vulnerability.

CD14 and toll-like receptor 4: a link between infection and acute coronary events?

The CD14 receptor is a pattern recognition molecule in the innate immune response against microorganisms and other exogenous and endogenous stress factors. The most important CD14 signalling co-receptor is toll-like receptor 4 (TLR4), which activates, among others, the nuclear factor κB (NF-κB) inflammatory pathway. Besides its role in innate immunity and host defence, the proinflammatory cytokines expressed upon TLR4/NF-κB pathway activation exert proatherogenic effects. The CD14 C(–260)T promoter and TLR4 Asp299Gly functional polymorphisms have been recently implicated in the development of cardiovascular events, suggesting that the genetically determined inflammatory response against pathogens or their antigens may have a major role in atherogenesis and subsequent acute events. Is the association of these polymorphisms with cardiovascular disease more evidence for the implication of infection, especially by Gram negative bacteria, in the development of acute coronary events? This article reviews the molecular basis, biological functions, and clinical implications of the CD14/TLR4 polymorphisms in the development of cardiovascular events.

Microvascular dysfunction in cardiac syndrome X: the role of inflammation

Between 10% and 30% of patients who undergo diagnostic coronary angiography because of typical symptoms of angina pectoris are found to have “normal” or “near normal” epicardial coronary arteries. Of these patients, those who have predominantly effort-induced chest pain and ST-segment

Neopterin—a forgotten biomarker

In a recent issue of the Journal, Blake and Ridker [(1)][1]summarized findings regarding the prognostic role of C-reactive protein (CRP) and other inflammatory markers in patients with acute coronary syndromes (ACS). We would like to point out that the investigators did not include the role of

Neopterin and Cardiovascular Disease: Growing Evidence for a Role in Patient Risk Stratification

Compelling evidence has emerged in recent years regarding the implications of inflammation in the pathogenesis of atherosclerosis and its complications (1). The growing appreciation of the role of inflammation in atherogenesis, atheromatous plaque growth, and plaque disruption has triggered interest as to whether circulating inflammatory biomarkers may help to identify subjects at risk of future cardiovascular events. Of all currently available biomarkers, high-sensitivity C-reactive protein (hsCRP)1 appears to have the best profile as an independent predictor of increased coronary risk (2). Despite being a nonspecific acute-phase reactant, hsCRP has been shown in large epidemiological and clinical studies to be an independent predictor of cardiovascular events (3), i.e., myocardial infarction, stroke, and death in patients with angina (4) and apparently healthy subjects. Because hsCRP is not a specific marker of vascular inflammation, however, the search for highly sensitive and specific markers of risk continues unabated. Evidence from our group (5)(6)(7)(8) and others (9)(10) in recent years indicates that neopterin, an immune modulator produced by activated macrophages, may be useful for cardiovascular risk stratification in patients with coronary artery disease. In this issue of Clinical Chemistry , Grammer et al. (11 …

C-reactive protein predicts functional status and correlates with left ventricular ejection fraction in patients with chronic stable angina

UNLABELLED C-reactive protein (CRP) is a marker for cardiovascular risk but may also participate in the pathogenesis of atherosclerosis and myocardial injury. We sought to investigate the relationship among CRP, left ventricular ejection fraction (LVEF) and symptoms of congestive heart failure (CHF) in patients with chronic stable angina (CSA) pectoris. METHODS We studied 841 patients (63+/-10 years, 72% men) with CSA undergoing coronary angiography. Symptoms of CHF were assessed using the New York Heart Association (NYHA) functional classification. CRP measurements were performed using a high sensitivity (hs-) immunoassay at the time of diagnostic coronary angiography. RESULTS Baseline serum hs-CRP levels showed a significant correlation with LVEF (r=-0.11; P=0.004), and prevalence of moderate-to-severe CHF correlated with serum hs-CRP quartiles (P(trend)<0.0001). After adjustment, age (P=0.004), female gender (P=0.03), body mass index (P<0.0001) and hs-CRP (OR 2.2 [1.3-3.6] CI 95%; P=0.002) were independent predictors of NYHA functional classes III-IV irrespective of LVEF and angiographic severity of CAD. A CRP value of 3.2mg/L had a sensitivity of 72%, a specificity of 75%, and a negative predictive value of 96% for detecting an impaired functional class. INTERPRETATION Hs-CRP serum concentrations showed an inverse correlation with LVEF and were an independent predictor of NYHA functional class in patients with CSA.

Enfermedad cardiovascular aterosclerótica: la utilidad de la proteína C reactiva en la identificación de la placa «vulnerable» y del paciente «vulnerable»

Rev Esp Cardiol 2004;57(5):375-8 375 A pesar de los avances en investigacion cardiovascular, tanto clinica como basica, la enfermedad arterial coronaria sigue siendo una de las principales causas de muerte y discapacidad en el mundo occidental. La inflamacion de la pared arterial se ha consolidado como un mecanismo etiopatogenico implicado en la iniciacion, el desarrollo y la inestabilizacion del proceso aterogenico. De hecho, la aterosclerosis es considerada actualmente una enfermedad inflamatoria. Entre los marcadores biologicos de este proceso inflamatorio (proteina serica A del amiloide, fibrinogeno, recuento leucocitario, neopterina, moleculas de adhesion endotelial, citocinas, etc.), la proteina C reactiva (PCR) es el que mayor esfuerzo investigador ha concentrado en los ultimos anos. La evidencia acumulada hasta el momento actual sugiere que la PCR de alta sensibilidad representa un predictor de riesgo cardiovascular, tanto en pacientes con enfermedad coronaria como en sujetos aparentemente sanos. De hecho, recientemente se ha sugerido que la PCR es un predictor de riesgo mas potente que los valores de colesterol unido a lipoproteinas de baja densidad (cLDL) y anade valor pronostico al de la escala convencional de Framingham1. Diversos tratamientos farmacologicos que han demostrado reducir la morbimortalidad en pacientes con enfermedad cardiovascular y en individuos aparentemente sanos, como la aspirina, los inhibidores de la 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) reductasa, los inhibidores de la enzima de conversion de la angiotensina (IECA), las tienopiridinas y los agonistas del receptor activado ED I TO R I A L E S

Neopterin — Marker of coronary artery disease activity or extension in patients with chronic stable angina?

Abstract We read with great interest the recent article by Alber et al., who assessed the relationship between the extent of coronary artery disease (CAD) and neopterin/CD4+CD28− lymphocytes in patients with chronic stable angina pectoris. The results of Alber et al. – in a small group of patients – contradict previous findings by our group in larger and well characterized groups of patients. Unfortunately, however, Alber et al. seem not to have been aware of our studies, as they are not cited or discussed in the context of their recent findings reported in the Journal. We have previously shown that increased neopterin levels, a marker of macrophage activation, predict adverse cardiovascular events during one year follow-up in patients with chronic stable angina. Our data indicate that patients in the highest neopterin tertile of neopterin concentration had a three fold increase in the risk of developing adverse cardiovascular events compared to those in the lowest tertile, a finding that was independent of the severity of CAD in these patients. In addition, other studies from our group have shown a correlation between neopterin levels and the presence of multiple complex (vulnerable) plaques in patients with unstable angina. We also showed that increased neopterin is a predictor of both worse outcome in hypertensive patients with non obstructive CAD and rapid CAD progression in patients with CAD undergoing revascularization.

Role of Neopterin in Cardiovascular Medicine

Rev Esp Cardiol. 2009;62(11):1332-44 1341 a better understanding of the kinetics of said markers could lead to improvements in their use in cardiovascular diseases. Considering the diversity of the diurnal variations in the intrinsic properties of the cardiovascular system, these should be kept in mind during the design of in vivo experimental studies. Such temporal decisions will undoubtedly reduce the discrepancies between the studies carried out in different laboratories, as well as between animal and human subjects. The majority of these clinical studies are carried out during daytime hours, when the subject is awake. As such, the information available reinforces our opinion when suitably validating the biomarkers and the need to demonstrate their reliability, stability, and lack of variability and standardise the methodology of their measurement.