Plasma levels of active Von Willebrand factor are increased in patients with first ST-segment elevation myocardial infarction: a multicenter and multiethnic study.

AIMS: Von Willebrand factor (VWF), a key player in hemostasis and thrombosis, is released from endothelial cells during inflammation. Upon release, VWF is processed by ADAMTS13 into an inactive conformation. The aim of our study was to investigate whether plasma levels of active VWF, total VWF, ADAMTS13, osteoprotegerin (OPG) and the ratios between VWF and ADAMTS13 are risk factors for first ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: We assessed 1026 patients with confirmed first STEMI and 652 control subjects from China, Italy and Scotland, within six hours after their cardiovascular event. Median plasma levels of total VWF, active VWF, OPG and ratios VWF/ADAMTS13 were increased, while plasma levels of ADAMTS13 were decreased in patients compared to controls. The odds ratio (OR) of STEMI in patients with high plasma levels of active VWF was 2.3 (interquartile range (IQR): 1.8-2.9), total VWF was 1.8 (1.4-2.3), ADAMTS13 was 0.6 (05-0.8), OPG was 1.6 (1.2-2.0) and high VWF/ADAMTS13 ratios was 1.5 (1.2-2.0). The OR for total VWF, active VWF and ratios VWF/ADAMTS13 remained significant after adjustment for established risk factors, medical treatment, C-reactive protein, total VWF, ADAMTS13 and OPG. When we adjusted for levels of active VWF, the significance of the OR for VWF and ratios VWF/ADAMTS13 disappeared while the OR for active VWF remained significant. CONCLUSIONS: We found evidence that plasma levels of active VWF are an independent risk factor for first STEMI in patients from three different ethnic groups. Our findings confirm the presence of VWF abnormalities in patients with STEMI and may be used to develop new therapeutic approaches.

Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps.

BACKGROUND: Increasing evidence implicates both platelets and neutrophils in the formation, stabilization, and growth of peripheral and coronary thrombi. Neutrophil extracellular traps (NETs) play a key role. The early events in the deregulated cross-talk between platelets and neutrophils are poorly characterized. OBJECTIVES: To identify at the molecular level the mechanism through which platelets induce the generation of NETs in sterile conditions. PATIENTS/METHODS: The presence of NETs was determined in 26 thrombi from patients with acute myocardial infarction by immunohistochemistry and immunofluorescence and markers of NETs assessed in the plasma. In vitro NET generation was studied in static and in physiological flow conditions. RESULTS: Coronary thrombi mainly consist of activated platelets, neutrophils, and NETs in close proximity of platelets. Activated platelets commit neutrophils to NET generation. The event abates in the presence of competitive antagonists of the high mobility group box 1 (HMGB1) protein. Hmgb1(-/-) platelets fail to elicit NETs, whereas the HMGB1 alone commits neutrophils to NET generation. Integrity of the HMGB1 receptor, Receptor for Advanced Glycation End products (RAGE), is required for NET formation, as assessed using pharmacologic and genetic tools. Exposure to HMGB1 prevents depletion of mitochondrial potential, induces autophagosome formation, and prolongs neutrophil survival. These metabolic effects are caused by the activation of autophagy. Blockade of the autophagic flux reverts platelet HMGB1-elicited NET generation. CONCLUSIONS: Activated platelets present HMGB1 to neutrophils and commit them to autophagy and NET generation. This chain of events may be responsible for some types of thromboinflammatory lesions and indicates novel paths for molecular intervention.

¿Quién acompaña a los pacientes a la consulta pediátrica? El acompañante de los pacientes pediátricos en Atención Primaria / Who goes with patients to the pediatrician? The accompanying person of pediatric patients in primary care

Introducción: en la actualidad, los cambios socioculturales pueden haber modificado el habitual esquema de la madre como acompañante principal en la consulta pediátrica. Objetivo: análisis descriptivo de la situación actual en la consulta de Pediatría. Material y métodos: Centro de Salud Las Delicias (distrito sanitario de Málaga capital). Muestra de 250 pacientes seleccionados entre los periodos de 1-15 de julio y 15-30 de septiembre de 2011. Resultados: en la mayoría de los casos (54,8%), la madre se sitúa como acompañante principal; apareciendo ambos progenitores en la consulta en el 16,4% de los casos. La figura de los abuelos como acompañantes toma especial relevancia cuando la madre se encuentra laboralmente activa. La mayoría de las consultas realizadas fueron a demanda con cita (82,4%), por sintomatología aguda, con una duración de los síntomas inferior a tres días en la mayor parte de los casos (59,2%). Discusión: la madre se presenta como acompañante principal de los niños en la consulta de Pediatría de Atención Primaria (en la mayoría de los casos). La figura paterna o de los abuelos, estará presente ante factores socioculturales, principalmente el estado laboralmente activo de la madre(AU)

Introduction: today, cultural changes may have changed the usual pattern of the mother as the accompanying person in the pediatric office. Objetives: descriptive analysis of the current situation in the pediatrics office. Material and methods: Las Delicias Health Center (health district of Malaga). Selected sample of 250 patients between the periods 1-15 July and 15-30 September, 2011. Results: in most cases (54.8%), the mother stands as the main accompanying person, appearing both parents in the consultation in 16.4% of cases. The figure of the grandparents is of special significance when the mother is an active worker. Most consultations were on-demand by appointment (82.4%), for acute symptoms, with symptoms lasting less than 3 days in most cases (59.2%). Discussion: the mother is presented as the main accompanying person in most cases. The father or grandparents will be present in front of social-cultural factors, mainly active employment status of the mother(AU)

El lavado de manos: ¿una recomendación atendida? / No disponible

Objetivos: determinar la incidencia del lavado de manos en los padres, como factor preventivo en la propagación de infecciones respiratorias víricas en niños menores de dos años asignados a una zona básica de salud pediátrica, afectados por síntomas catarrales durante la época otoñal y coincidiendo con la campaña de vacunación antigripal. Material y métodos: sobre un total de 230 niños menores de dos años incluidos en la zona básica de salud pediátrica y atendidos en el Programa de Salud Infantil, 51 consultan durante la campaña de vacunación antigripal (octubre 2011) por presentar síntomas catarrales. Resultados: se incluyeron 51 niños (23 varones y 28 mujeres). Desde el punto de vista clínico, 33 casos se encontraban afebriles, 18 presentaban fiebre, y el 100% de los casos tenía mucosidad. El diagnóstico clínico fue rinofaringitis en 44 casos; bronquitis aguda en cinco casos y bronquiolitis en dos casos; 19 casos no presentaban ningún antecedente familiar; sin embargo, hasta en 32 casos había algún familiar cursando cuadro catarral. En cuanto a la realización del lavado de manos como medida preventiva, en 34 de los casos se afirmó no cumplir con esta medida, llevándose a cabo solo en 17 casos pese a las recomendaciones. Conclusiones: aunque se conoce la importancia del lavado de manos en la prevención de infecciones respiratorias y se incluye entre las recomendaciones ofrecidas en el Programa de Salud Infantil, solo el 33% de la población de nuestro estudio afirmó realizarla. Dicha recomendación puede también incluirse en las consultas a demanda durante la campaña antigripal, para favorecer su cumplimiento(AU)

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Respuesta a la flunarizina en un preescolar con migraña confusional / Flunarizine response in a pre-school child with confusional migraine

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Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging.

OBJECTIVE: Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. METHODS: 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. RESULTS: LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p<0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p<0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. CONCLUSIONS: This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.

Prognostic value of ventricular arrhythmias and heart rate variability in patients with unstable angina.

OBJECTIVES: To assess the prognostic value of ventricular arrhythmias (VA) and heart rate variability (HRV) in patients with unstable angina. DESIGN: Multicentre prospective study. SETTING: 17 cardiological centres in Italy. PATIENTS: 543 consecutive patients with unstable angina and preserved left ventricular function (ejection fraction >or=40%) enrolled in the SPAI (Stratificazione Prognostica dell'Angina Instabile) study. METHODS: Patients underwent 24 h ECG Holter monitoring within 24 h of hospital admission. Tested variables were frequent ventricular extrasystoles (>or=10/h), complex (that is, frequent or repetitive) VA, and bottom quartile values of time-domain and frequency-domain HRV variables. Primary end points were in-hospital and six-month total and cardiac deaths. RESULTS: Eight patients died in hospital (1.5%) and 32 (5.9%, 29 cardiac) during follow up. Both complex VA and frequent extrasystoles were strongly predictive of death in hospital and at follow up, even after adjustment for clinical (age, sex, cardiac risk factors and history of myocardial infarction) and laboratory (troponin I, C reactive protein and transient myocardial ischaemia on Holter monitoring) variables. At univariate analysis bottom quartile values of three HRV variables (standard deviation of RR intervals index, low-frequency amplitude and low to high frequency ratio) were associated with in-hospital death, and bottom quartile values of most HRV variables predicted six-month fatal events. At multivariate Cox survival analysis reduced low-frequency amplitude was consistently found to be independently associated with fatal end points. CONCLUSION: In patients with unstable angina with preserved myocardial function, both VA and HRV are independent predictors of in-hospital and medium-term mortality, suggesting that these factors should be taken into account in the risk stratification of these patients.

Pulsed tissue Doppler imaging detects early myocardial dysfunction in asymptomatic patients with severe mitral regurgitation.

OBJECTIVE: To assess whether tissue Doppler myocardial imaging (TDI) indices can predict postoperative left ventricular function in patients with mitral regurgitation (MR) after surgical correction. METHODS: 84 patients (mean (SD) age 54.3 (10.8) years) with asymptomatic severe MR, an end systolic diameter < 45 mm, and an ejection fraction (EF) > 60% were subdivided in two groups: 43 patients with a postoperative EF reduction < 10% (group 1) and 41 patients with a postoperative EF reduction > or = 10% (group 2).TDI systolic indices of the lateral annulus were analysed preoperatively to assess myocardial systolic wave (Sm) velocity, myocardial precontraction time (PCTm), myocardial contraction time (CTm), and the PCTm:CTm ratio. RESULTS: Postoperative EF decreased significantly (from 67 (5)% to 60 (5.5)%, p = 0.0001). Group 2 had a higher PCTm, CTm, and PCTm:CTm ratio and a lower Sm velocity than group 1 (PCTm 100.4 (19) ms v 82 (21.8) ms, p = 0.004; CTm 222 (3.1) ms v 215 (2.3) ms, p = 0.01; PCTm:CTm 0.45 (0.08) v 0.38 (0.09), p = 0.001; Sm velocity 10.4 (1.1) cm/s v 13 (1.3) cm/s, p = 0.0001). Multivariate regression analysis showed that the combination of PCTm:CTm ratio > or = 40 ms and Sm velocity < or = 10.5 cm/s was the main independent predictor of postoperative EF reduction > or = 10% (sensitivity 78%, specificity 95%). CONCLUSIONS: TDI systolic indices can predict postoperative left ventricular function in patients with asymptomatic MR undergoing surgical correction.

G20210A prothrombin gene polymorphism and coronary ischaemic syndromes: a phenotype-specific meta-analysis of 12 034 subjects.

OBJECTIVE: To investigate the possible link between the G20210A prothrombin gene variant and different forms of ischaemic heart disease. DESIGN: Phenotype-specific meta-analysis of 19 studies published within March 2002, globally including 4944 patients and 7090 controls. Sample size, inclusion criteria, geographical location, clinical presentation, age, cardiovascular risk factors, and angiographic extent of disease were extracted from each study. Analyses were done according to Mantel-Haenszel. RESULTS: Overall, the odds ratio (OR) for unspecified ischaemic heart disease associated with the 20210A allele was 1.21 (95% confidence interval (CI) 0.99 to 1.59, n = 12 034). Similar findings were seen for acute coronary syndromes (unstable angina and myocardial infarction) and for myocardial infarction without age limits (OR 1.24, 95% CI 0.98 to 1.63, n = 10 240; and OR 1.19, 95% CI 0.93 to 1.58, n = 9765). The effects were similar in male and female subjects. In the 1931 subjects < 55 years of age, the OR for myocardial infarction increased to 1.77 (95% CI 1.16 to 3.42) and in the 1359 subjects < 45 years to 2.30 (95% CI 1.27 to 4.59). No significant association was found between the 20210A allele and the presence of angiographically documented coronary disease (OR 1.08, 95% CI 0.70 to 1.64, n = 3444). However, patients with 0/1 vessel disease at angiography showed a greater prevalence of the A allele than those with multivessel disease (relative risk 2.0, 95% CI 1.2 to 3.1, n = 2376). CONCLUSIONS: G20210A prothrombin gene polymorphism may represent a modest but significant risk factor for myocardial infarction at young ages and favour the expression of ischaemic heart disease among individuals who have a limited extent of coronary atherosclerosis at angiography.

Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation.

OBJECTIVE: To identify in humans the temporal patterns of no reflow and their functional implications. METHODS: 24 patients with first acute myocardial infarction and successful coronary recanalisation by recombinant tissue-type plasminogen activator (n = 15) or primary percutaneous transluminal coronary angioplasty (n = 9) were studied by myocardial contrast echocardiography within 24 hours of recanalisation and at one month's follow up. Myocardial contrast echocardiography was performed by intermittent harmonic power Doppler and intravenous Levovist. The regional contrast score index (CSI) was calculated within dysfunctioning myocardium. Videointensity was measured (dB) within risk and control areas and their ratio was calculated. RESULTS: In 8 patients reflow was observed at 24 hours and persisted at one month. Conversely in 16 patients areas of no reflow were detectable at 24 hours. At one month, no reflow was spontaneously reversible in 9 patients (mean (SD) CSI and videointensity ratio improved from 2.5 (0.5) to 1.4 (0.6) and from 0.6 (0.1) to 0.7 (0.1), respectively; p < 0.05) and was sustained in the remaining 7 patients (CSI and videointensity ratio remained unchanged from 2.6 (0.6) to 2.6 (0.5) and from 0.5 (0.2) to 0.5 (0.2), respectively; NS). Left ventricular function improved significantly in patients with reflow and reversible no reflow. Volumes were enlarged only in patients with sustained no reflow. CONCLUSIONS: No reflow detected at 24 hours may be sustained or spontaneously reversible at one month. Such reversibility of the phenomenon is associated with preserved left ventricular volumes and function. Clarification of the mechanisms of delayed reversibility may lead to tailored treatment of no reflow even in the subacute phase of myocardial infarction.

Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies.

Inflammation and genetics are both prominent mechanisms in the pathogenesis of atherosclerosis and arterial thrombosis. Accordingly, a number of population studies have explored the association of ischaemic heart disease with gene polymorphisms of the inflammatory molecules tumour necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta1 and 2, interleukin (IL) 1 and its receptor antagonist (IL 1ra), CD14 (the receptor for lipopolysaccharide), P and E selectins, and platelet endothelial cell adhesion molecule (PECAM) 1. Although they are very preliminary and partly conflicting, the data provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of ischaemic heart disease.

Increased prevalence of the G20210A prothrombin gene variant in acute coronary syndromes without metabolic or acquired risk factors or with limited extent of disease.

AIMS: To investigate the prevalence of the G20210A prothrombin and G1691A factor V gene variants in patients with acute coronary syndrome stratified according to risk factor profile and to extent of coronary disease, in comparison with matched healthy controls. METHODS AND RESULTS: The 20210 prothrombin and the 1691 factor V loci were genotyped in 247 patients < or =65 years of age (190 myocardial infarction and 57 unstable angina as first presentation of disease) and in 247 healthy age- and sex-matched controls. The prevalence of the 1691A factor V allele was similar in cases and controls. The frequency of heterozygotes for the 20210A prothrombin allele was 6.5% among patients and 2.8% among controls (OR 2.4, 95% CI 1.0-5.9), increasing to 8.7% in patients with a family history of myocardial infarction (OR 3.3, 95% CI 1.2-9.1), to 9.9% in patients (n=81) with < or =1 vessel disease (OR 3.8, 95% CI 1.3-10.8), and to 13.0% in patients who were normocholesterolaemic, non-diabetic, normotensive and non-smokers (OR 5.1, 95% CI 1.2-21.4). CONCLUSIONS: These findings suggest that the 20210A prothrombin allele represents an inherited risk factor for acute coronary syndrome among patients who have limited extent of coronary disease at angiography or who lack major metabolic and acquired risk factors.

Relation of the -174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization.

Interleukin (IL)-6 plasma levels are predictive of major cardiovascular events. The -174 G/C promoter polymorphism of the IL-6 gene affects basal levels in vivo and transcription rates in vitro, but its association with IL-6 acute phase levels among patients with coronary artery disease has not been investigated. In 111 patients with multivessel coronary artery disease undergoing elective coronary artery bypass graft surgery, we prospectively assessed genotype at position -174 and serial blood levels of IL-6 and other inflammatory indexes. Clinical and surgical characteristics did not differ among genotypic groups. IL-6 levels--measured daily up to 72 hours before surgery, after surgery, and at discharge--showed a mean 17-fold increase, peaking at 24 hours (p <0.0001). IL-6 levels (but not fibrinogen, white-blood cell count, and C-reactive protein values) differed significantly according to the -174 genotype (p = 0.042 for difference between areas under the curve), the 62 GG homozygotes exhibiting higher concentrations than the 49 carriers of the C allele (widest difference at 48 hours, p = 0.015 in multivariate analysis). GG homozygosity was associated with longer stays in the intensive care unit (2.5 +/- 3.4 vs 1.4 +/- 0.9 days, p = 0.02) and in the hospital (6.7 +/- 4.0 vs 5.3 +/- 1.4 days, p = 0.02) than C carriership. Rates of postoperative death, myocardial infarction, and stroke were 8% in GG homozygotes and 2% in C-carriers (p = 0.16). The IL-6-174 GG genotype is associated with higher acute phase levels of IL-6 and with longer stays in the hospital and in the intensive care unit than C allele carriership after surgical coronary revascularization.

Platelet aggregability in cardiac syndrome X.

AIMS: To assess platelet aggregability at rest and in response to exercise in patients with cardiac syndrome X (anginal chest pain, ST-segment depression on exercise, angiographically normal coronary arteries). METHODS AND RESULTS: We performed a symptom/sign-limited exercise test in 31 patients with syndrome X, 25 patients with coronary artery disease and 29 healthy subjects. Platelet aggregability was measured in flowing whole blood at baseline, at peak exercise, and after 30 and 120 min, as the time to occlude a collagen/adenosine diphosphate coated ring (aggregation time). Resting aggregation time was shorter in syndrome X patients (83.2+/-12 s), compared to patients with coronary disease (94.0+/-18 s, P<0.01) and to healthy subjects (96.4+/-21 s, P<0.01). With exercise, aggregation time did not change in healthy controls, decreased in patients with coronary disease (-13.8 s at peak; 95% CI, -10.2, -17.3 s;P<0.001), but increased in syndrome X (+17.4 s 30 min after exercise; 95% CI, +10.4, +24.4 s;P<0.0001). The intravenous administration of an adenosine antagonist (theophylline) prevented the exercise-induced prolongation of aggregation time in syndrome X patients (n=11), but had no effect in healthy controls (n=11). CONCLUSION: Platelet aggregability at rest was increased in syndrome X patients, compared to patients with coronary artery disease and healthy subjects. In contrast to patients with coronary disease, however, platelet aggregability was reduced by exercise. This response was prevented by theophylline, strongly suggesting the involvement of adenosine.

Coronary artero-venous gradient of endogenous urokinase.

Experimental data indicate that urokinase-type plasminogen activator (u-PA) contributes significantly to endogenous fibrinolysis and vascular remodeling in proportion to its local concentrations. In humans, however, it is not known whether u-PA levels vary at different sites and across specific vascular beds. We investigated possible regional and artero-venous differences in plasma u-PA concentrations in 15 patients undergoing cardiac catheterization. Three pairs of simultaneous samples were taken from: (1) the ascending aorta and coronary sinus; (2) left ventricle and right atrium; (3) femoral artery and femoral vein. Single-chain urokinase-type plasminogen activator (scu-PA) was measured by bioimmunoassay, and total u-PA antigen (including scu-Pa and two-chain urokinase-type plasminogen activator complexed with inhibitors (tcu-PA)) by enzyme-linked immunosorbent assay. Scu-PA represented, on average, 51+/-15% of total u-PA concentrations. Scu-PA and total u-PA levels were correlated (r=.72, P<.0001) and did not differ significantly among the arterial or venous locations. There was a small but consistent increase in mean (+/-standard deviation (S.D.)) scu-PA concentrations from all arterial to all venous samples (1.5+/-0.6 vs. 1.6+/-0.5 ng/ml, P=.038) and from ascending aorta to coronary sinus (1.6+/-0.5 vs. 1.7+/-0.6 ng/ml, P=.046). Similarly, total u-PA levels increased from femoral artery to femoral vein (2.9+/-0.7 vs. 3.0+/-0.8 ng/ml, P<.001). In contrast, across the lungs, no significant concentration-gradient was seen in either scu-PA or total u-PA. The changes in total u-PA roughly followed those of scu-PA. These data identify an artero-venous gradient in human plasma u-PA across the coronary and peripheral beds, but not across the lungs, suggesting differences in u-PA kinetics according to vascular location.