Increases in circulating matrix metalloproteinase-9 levels following fibrinolysis for acute pulmonary embolism

Introduction: Fibrinolyis is one of the first line therapies in high risk pulmonary embolism (PE) according to current guidelines. Previous studies showed that brinolytic therapy with tPA (tissue plasminogen activator, or alteplase) upregulates the concentrations of matrix metalloproteinases (MMPs) and contributes to hemorrhagic transformation after cardioembolic stroke. However, no previous study has described the circulating MMPs levels following fibrinolysis for acute PE. Materials and Methods: We serially measured the circulating levels of MMPs (MMP-9 and MMP-2) and their endogenous inhibitors, the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in alteplase and in streptokinase-treated patients with acute PE by gelatin zymography and by enzyme-linked immunosorbent assays, respectively. Results: We found that therapy of PE streptokinase or with alteplase is associated increased pro-MMP-9, but not MMP-2, concentrations for up to 24 hours, whereas no significant changes were found in TIMP-1 or TIMP-2 concentrations. This alteration returned to normal 3 to 5 days after thrombolysis. This is the first study reporting on MMPs alterations following fibrinolysis for acute PE. Conclusions: We found transient increases in circulating pro-MMP-9 levels following fibrinolysis for acute PE. Our findings support the hypothesis that increased MMP-9 levels may underlie the risk of intracerebral hemorrhage or other bleeding complication of thrombolysis for acute PE, and the use of MMP inhibitors may decrease such risk. (C) 2010 Elsevier Ltd. All rights reserved.

Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

Matsumoto T, Tostes RC, Webb RC. Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 301: H409-H417, 2011. First published May 6, 2011; doi:10.1152/ajpheart.00084.2011.-Uridine adenosine tetraphosphate (Up(4)A) was reported as a novel endothelium-derived contracting factor. Up(4)A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up(4)A in hypertensive states remain unclear. The present study examined the effects of Up(4)A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCA-salt rats exhibited increased contraction to Up(4)A versus arteries from control uninephrectomized rats in the absence and presence of N(G)-nitro-L-arginine (nitric oxide synthase inhibitor). On the other hand, the Up(4)A-induced contraction in PA was similar between the two groups. Up(4)A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip5I; P2X(1) antagonist) in RA from both groups. Furthermore, 2-thiouridine 5`-triphosphate tetrasodium salt (2-Thio-UTP; P2Y(2) agonist)-, uridine-5`-(gamma-thio)-triphosphate trisodium salt (UTP gamma S; P2Y(2)/P2Y(4) agonist)-, and 5-iodouridine-5`-O-diphosphate trisodium salt (MRS 2693; P2Y(6) agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y(2)-, P2Y(4)-, and P2Y(6) receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up(4)A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up(4)Astimulated ERK activation was increased. These data are the first to indicate that Up(4)A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up(4)A-induced contraction. Up(4)A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension.

PULSATILITY INDEX CHANGE OF BRACHIAL ARTERY SHOWS BETTER REPRODUCIBILITY THAN FLOW-MEDIATED VASODILATION

We aim to evaluate intra- and interobserver reproducibility of brachial artery flow-mediated dilation (FMD) and of pulsatility index change (PI-C) 1 min after a 5-min forearm compression in pregnant women. Flow-mediated dilation and PI-C were assessed in 31 healthy pregnant women in 3 consecutive days, by two observers. A broader range of response to the stimulus was observed for PI-C (-58.99%-86.71%) than FMD (2.38%-27.01%). The intraclass correlation coefficients were higher for PI-C than for FMD (intra = 0.90 vs. 0.69, p = 0.047; inter = 0.94 vs. 0.61, p = 0.007). Therefore, PI-C measurements were more reliable than FMD. However, studies comprising of subjects with cardiovascular risk factors relating FMD and PI-C become necessary to validate this method for the study of endothelial dysfunction. (E-mail: wpmartins@gmail.com) (C) 2010 World Federation for Ultrasound in Medicine & Biology.

Brachial artery pulsatility index change 1 minute after 5-minute forearm compression - Comparison with flow-mediated dilatation

Objective. Endothelial impairment evaluation by sonographic measurement of flow-mediated dilatation (FMD) has become broadly used. However, this method has 2 main caveats: the dilatation depends on the baseline arterial diameter, and a high precision level is required. Vasodilatation leads to an amplified fall in impedance. We hypothesized that assessment of the pulsatility index change (PI-C) 1 minute after 5-minute forearm compression might evaluate that fall in impedance. The aim of this study was to compare the PI-C with FMD. Methods. Flow-mediated dilatation and the PI-C were assessed in 51 healthy women aged between 35.1 and 67.1 years. We correlated both FMD and the PI-C with age, body mass index, waist circumference, cholesterol level, high-density lipoprotein level, glucose level, systolic and diastolic blood pressure, pulse pressure, brachial artery diameter, simplified Framingham score, intima-media thickness, and carotid stiffness index. Intraclass correlation coefficients between 2 FMD and PI-C measurements were also examined. Results. Only FMD correlated with baseline brachial diameter (r=-0.53). The PI-C had a high correlation with age, body mass index, waist circumference, cholesterol level, systolic blood pressure, pulse pressure, simplified Framingham score, and intima-media thickness. The correlation between FMD and the PI-C was high (r=-0.66). The PI-C had a higher intraclass correlation coefficient (0.991) than FMD (0.836) but not brachial artery diameter (0.989). Conclusions. The PI-C had a large correlation with various markers of cardiovascular risk. Additionally, PI-C measurement does not require offline analysis, extra software, or electrocardiography We think that the PI-C could be considered a marker of endothelial function. However, more studies are required before further conclusions.

First trimester fetal echocardiography

Objective: The aims of this study were to assess the feasibility of performing a complete fetal echocardiographic study during the first trimester of pregnancy, to establish the best week to accomplish a complete evaluation, and to find a relationship between the diameters of the cardiac valves and gestational age. Methods: 46 fetuses with normal nuchal translucency and venous duct Doppler velocimetry were submitted to echocardiographic studies by the transvaginal approach between the 11 + 0 and 14 + 6 weeks of gestation. A complete echocardiographic evaluation was defined as an examination in which the three basic planes, four-chamber, longitudinal and short-axis views, were obtained. Results: The rates of complete echocardiography evaluation were 37, 85 and 100% at 11, 12 and 13-14 weeks, respectively. The longitudinal view was the easiest to obtain and the short-axis view was the most difficult one. The diameter of the cardiac valves was compared with the crown-rump length (CRL) and there was no statistically significant difference between either the diameters of the mitral and tricuspid or the aortic and pulmonary valves. A linear growth curve was constructed to demonstrate the diameter correlations. Conclusions: The study demonstrated the feasibility of a complete fetal echocardiographic evaluation by the transvaginal approach during the first trimester of gestation. The rate of a complete evaluation increased along the period and reached 100% when the CRL was 64 mm or 13 weeks of gestational age. There was a linear correlation between the cardiac valve diameters and the CRL revealing a relationship between the cardiac and fetal development. The absence of a statistically significant difference between the left and right valve dimensions possibly means that there is no predominance of right or left chambers during this period of evaluation. Copyright (C) 2007 S. Karger AG, Basel.

Tuberculosis incidence among contacts of active pulmonary tuberculosis

BACKGROUND: Treatment of latent tuberculosis (TB) infection (LTBI) in Brazil is recommended only in the case of contacts of pulmonary smear-positive TB patients aged <= 15 years with a tuberculin skin test (TST) >= 10 mm and no previous bacille Calmette-Guerin (BCG) vaccination or with a TST >= 15 mm regardless of previous BCG vaccination. OBJECTIVE: To evaluate the 2-year incidence and predictors of TB among contacts who did not meet the Brazilian criteria for LTBI treatment. DESIGN: Retrospective cohort study. Contacts aged between 12 and 15 years and those aged >15 years who did not meet the Brazilian criteria for LTBI treatment were enrolled in the study. RESULTS: TB incidence was 3.2% (22/667), with an estimated TB rate of 1649 per 100000 population. Risk of TB was greater among the 349 contacts with TST >= 5 mm (5.4%) compared to the 318 contacts with TST <5 mm, (0.9%; RR 6.04, 95%CI 1.7-20.6). CONCLUSION: The high incidence of TB among contacts who did not meet the Brazilian criteria for LTBI treatment strongly suggests that these criteria should be reviewed. Furthermore, even among BCG-vaccinated contacts, TST induration >= 5 mm, was the only variable that predicted the development of TB disease within 2 years.

Giant right coronary artery aneurysm presenting as a paracardiac mass

Coronary artery aneurysms, commonly atherosclerotic, are usually asymptomatic and can be diagnosed incidentally during investigation for ischemic heart disease or on autopsy. An asymptomatic giant right coronary artery aneurysm presenting as a paracardiac mass discovered on autopsy is reported here. Even though there was great concern due to its large size, complex atherosclerotic lesions, and potential obstruction of blood flow, it had no direct link to the cause of death. We also review the literature on giant right coronary artery aneurysms exceeding 5 cm in the last 10 years. (C) 2008 Elsevier Inc. All rights reserved.

Influence of pregnancy and smoking on brachial artery flow-mediated dilation values and time until maximum response

To evaluate the effect of pregnancy and smoking on endothelial function using brachial artery flow-mediated dilation (FMD) and to determine the time necessary until the occurrence of maximum brachial artery dilation after stimulus. This study was an observational study evaluating 133 women, who were grouped as follows: non-smoking pregnant women (N = 47), smoking pregnant women (N = 33), non-smoking women (N = 34), and smoking pregnant women (N = 19). The diameter of the brachial artery was measured at baseline and at 30, 60, 90 and 120 s after stimulus. The relative change of brachial artery was determined for each of these four moments. FMD measured at 60 s after stimulus was compared between the groups. The maximum FMD was observed at 60 s after cuff release in all groups. FMD was greater among non-smoking pregnant women compared to smoking pregnant women (11.50 +/- A 5.77 vs. 8.74 +/- A 4.83; p = 0.03) and also between non-smoking non-pregnant women compared to smoking non-pregnant women (10.52 +/- A 4.76 vs. 7.21 +/- A 5.57; p = 0.03). Maximum FMD was observed approximately 60 s after stimulus in all groups regardless of smoking and pregnancy status. The smoking habit seems to lead to endothelial dysfunction both in pregnant and non-pregnant women, as demonstrated by the lower FMD in smokers.

Analysis of placenta vascularization in patients with uterine altered artery Doppler flow velocity exams

Background: One of the frequent questions in obstetric practice is to determine placental vascular changes that may account for abnormal Doppler flow velocity alterations in maternal uterine vessels from women and fetuses without pregnancy pathology. Methods: A retrospective morphometric study was realized using 27 placentas from patients submitted for Doppler flow velocity exam during pregnancy. The placentas were morphologically examined using hematoxylin-eosin staining. Measurements of villi were made with the use of a video camera coupled to a common light microscope and a computer with automatic image analyzing software. Results: Of the 27 placentas, 13 (48%) were of patients showing unaltered Doppler and 14 (52%) showing altered Doppler. The number of stem villi vessels was significantly larger in the placentas of patients with Doppler exam alterations (P = 0.003). This group also presented greater stem villi vessel thickness, although without significant difference. The number of intermediary and terminal villi vessels was greater in the placentas of patients with altered Doppler exams (P < 0.001), and a greater terminal villi area was observed in these cases (P < 0.001). Conclusion: The morphological proof that uterine artery Doppler flow velocity exam alterations are associated with placental vascular alterations demonstrates the importance of this exam during prenatal care, even in the absence of maternal-fetal alterations.

Role of sensory innervation in the rat pulmonary neutrophil recruitment induced by staphylococcal enterotoxins type A and B

Rat airways exposure to Staphylococcal enterotoxin A (SEA) and B (SEB) induces marked neutrophil influx. Since sensory neuropeptides play important roles in cell infiltration, in this study we have investigated its contribution in triggering SEA- and SEB-induced pulmonary neutrophil infiltration. Male Wistar rats were exposed intratracheally with SEA (3 ng/trachea) or SEB (250 ng/trachea). Animals received different in vivo pretreatments, after which the neutrophil counts and levels of substance P and IL-1 in bronchoalveolar lavage fluid were evaluated. Alveolar macrophages and peritoneal mast cells were incubated with SEA and SEB to determine the IL-1 and TNF-alpha levels. Capsaicin pretreatment significantly reduced SEA- and SEB-induced neutrophil influx in bronchoalveolar lavage fluid, but this treatment was more effective to reduce SEA responses. Treatments with SR140333 (tachykinin NK(1) receptor antagonist) and SR48968 (tachykinin NK(2) receptor antagonist) decreased SEA-induced neutrophil influx, whereas SEB-induced responses were inhibited by SR140333 only. Cyproheptadine (histamine/5-hydroxytriptamine receptor antagonist) and MD 7222 (5-HT(3) receptor antagonist) reduced SEA- and SEB-induced neutrophil influx. The substance P and IL-1 levels in bronchoalveolar lavage fluid of SEA-exposed rats were significantly hi.-her than SEB. In addition, SEA (but not SEB) significantly released mast cell TNF-alpha. Increased production of TNF-alpha and IL-1 in alveolar macrophages was observed in response to SEA and SEB. In conclusion, sensory neuropeptides contribute significantly to SEA- and SEB-induced pulmonary neutrophil recruitment, but SEA requires in a higher extent the airways sensory innervation, and participation of mast cells and alveolar macrophage products. (C) 2009 Elsevier B.V. All rights reserved.

Hemodynamic effects of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary embolism

While endogenous nitric oxide (NO) may be relevant to the beneficial hemodynamic effects produced by sildenafil during acute pulmonary embolism (APE), huge amounts of inducible NO synthase (iNOS)derived NO may contribute to lung injury. We hypothesized that iNOS inhibition with S-methylisothiourea could attenuate APE-induced increases in oxidative stress and pulmonary hypertension and, therefore, could improve the beneficial hemodynamic and antioxidant effects produced by sildenafil during APE. Hemodynamic evaluations were performed in non-embolized dogs treated with saline (n = 4), S-methylisothiourea (0.01 mg/kg followed by 0.5 mg/kg/h, n = 4), sildenafil (0.3 mg/kg, n = 4), or S-methylisothiourea followed by sildenafil (n = 4), and in dogs that received the same drugs and were embolized with silicon microspheres (n = 8 for each group). Plasma nitrite/nitrate (NOx) and thiobarbituric acid reactive substances (TBARS) concentrations were determined by Griess and a fluorometric assay, respectively. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 25 +/- 1.7 mm Hg and by 941 +/- 34 dyn s cm(-5) m(-2), respectively. S-methylisothiourea neither attenuated APE-induced pulmonary hypertension, nor enhanced the beneficial hemodynamic effects produced by sildenafil after APE (>50% reduction in pulmonary vascular resistance). While sildenafil produced no change in plasma NOx concentrations, S-methylisothiourea alone or combined with sildenafil blunted APE-induced increases in NOx concentrations. Both drugs, either alone or combined, produced antioxidant effects. In conclusion, although iNOS-derived NO may play a key role in APE-induced oxidative stress, our results suggest that the iNOS inhibitor S-methylisothiourea neither attenuates APE-induced pulmonary hypertension, nor enhances the beneficial hemodynamic effects produced by sildenafil. (C) 2010 Elsevier Inc. All rights reserved.

Histological analysis of cobalt-chromium stents with and without Camouflage (R) polymer coating: experimental porcine carotid artery model

This study evaluated the arterial response to cobalt-chromium stents with and without polymer coating (Camouflage (R), Hemoteq AG, Wuerselen, Germany) implanted in pigs. Cobalt-chromium balloon-expandable stents (4 x 16 mm) were implanted in the common carotid arteries of nine pigs. Histological analysis of endothelialization, inflammation and injury was performed one month later. All stents were successfully deployed, and all but one animal survived the 30 study days. All arteries were patent. Endothelialization was nearly complete in most sections of all carotid stents in both groups. There were mild inflammatory infiltrate and mild-to-moderate injury, which were associated with the stent shafts and not significantly different between groups. Our findings suggest that, in porcine carotid arteries, the histological response to balloon-expandable cobalt-chromium stents coated with polymer (Camouflage (R), Hemoteq AG) is similar to the response to non-coated cobalt-chromium stents.

Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene

This study was undertaken to test whether the structural remodelling of pulmonary parenchyma can be sequentially altered in a model and method that demonstrate the progression of the disease and result in remodelling within the lungs that is typical of idiopathic pulmonary fibrosis. Three groups of mice were studied: (i) animals that received 3-5-di-tert-butyl-4-hydroxytoluene (BHT) and were killed after 2 weeks (early BHT = 9); (ii) animals that received BHT and were killed after 4 weeks (late BHT = 11); (iii) animals that received corn oil solution (control = 10). The mice were placed in a ventilated Plexiglas chamber with a mixture of pure humidified oxygen and compressed air. Lung histological sections underwent haematoxylin-eosin, immunohistochemistry (epithelial, endothelial and immune cells) and specific staining (collagen/elastic fibres) methods for morphometric analysis. When compared with the control group, early BHT and late BHT groups showed significant decrease of type II pneumocytes, lower vascular density in both and higher endothelial activity. CD4 was increased in late BHT compared with early and control groups, while CD8, macrophage and neutrophil cells were more prominent only in early BHT. The collagenous fibre density were significantly higher only in late BHT, whereas elastic fibre content in late BHT was lower than that in control group. We conclude that the BHT experimental model is pathologically very similar to human usual interstitial pneumonia. This feature is important in the identification of animal models of idiopathic pulmonary fibrosis that can accurately reflect the pathogenesis and progression of the human disease.

Pulmonary Maturation in Canine Foetuses From Early Pregnancy to Parturition

Development of the foetal respiratory system includes both pulmonary growth and maturation. In human medicine, a higher incidence of respiratory distress is reported in newborn males. This study aimed to identify different phases of canine foetal lung maturation throughout pregnancy, to determine the stage of pregnancy in which surfactant production begins and to compare pulmonary development of male and female foetuses. Pregnant bitches (34) were subjected to elective ovariohysterectomy and allocated into four groups, according to the stage of pregnancy: 30-40 days of pregnancy (n = 10), 41-50 days (n = 10), 51-60 days (n = 10) and bitches in the first stage of parturition (n = 4). Foetal lungs were histologically processed and evaluated by optical microscopy. The pseudoglandular phase was identified between the 35th day and 46th day of gestation; the onset of canalicular and saccular periods was observed, respectively, from the 48th day and 60th day of pregnancy. Lungs from foetuses at term were in the saccular phase; thus, the development into the alveolar period occurs in the neonatal period. The histological analyses revealed that respiratory tract development is centrifugal, from upper to lower airways. Therefore, it is possible to identify distinct development periods in different portions of the same organ. In conclusion, the saccular phase of lung development begins around 57 and 60 days of pregnancy, the period in which surfactant production is believed to occur. Male and female foetuses present similar pulmonary development from early pregnancy until parturition.

Functional polymorphisms in the promoter of the matrix metalloproteinase-9 (MMP-9) gene are not linked with significant plasma MMP-9 variations in healthy subjects

Background: Matrix metalloproteinase-9 (MMP-9) is involved in the degradation of the extracellular matrix during physiological and pathological processes. Two functional polymorphisms [C(-1562)T and microsatellite (CA)(13-25)] in the promoter region of the MMP-9 gene have been associated with several diseases. The aim of this study was to examine whether these MMP-9 polymorphisms and haplotypes are linked with plasma MMP-9 variations in healthy subjects. Methods: We studied 177 healthy male white volunteers (age range 20-55 years) who were non-smokers and not taking any medication. Genomic DNA was extracted from whole blood and genotypes for the C(-1562)T and the microsatellite (CA)(n) polymorphisms were determined. MMP-9 levels were measured in plasma samples by gelatin zymography. Results: The frequency of the alleles C and T for the C(-1562)T polymorphism were 90% and 10%, respectively. The frequency of the alleles with less than 21 CA repeats Q and with 21 repeats or higher (H) were 47% and 53%, respectively. We found no differences in plasma MMP-9 levels among the genotype groups or among different haplotypes (all p > 0.05). Conclusions: These findings suggest that functional polymorphisms in the promoter of the MMP-9 gene are not linked with significant plasma MMP-9 variations in healthy subjects.