Avalia??o da resposta inflamat?ria cardiovascular em ratos com hipertens?o renovascular (2R1C) infectados pelo Trypanosoma cruzi.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.A Hipertens?o Arterial Sist?mica (HAS), caracterizada pelo aumento de Angiotensina II plasm?tica/tecidual, ? uma das doen?as com maior preval?ncia no mundo moderno. Evidencias apontam para o envolvimento da inflama??o vascular no processo inicial da HAS. A cardiopatia chag?sica ? causada pelo protozo?rio Trypanosoma cruzi, capaz de desencadear uma resposta inflamat?ria progressiva gerando importantes altera??es el?tricas e morfo-funcionais ao cora??o. Nosso objetivo neste estudo foi avaliar a associa??o da HAS e os aspectos inflamat?rios cardiovasculares em animais infectados pela cepa Y do T. cruzi. Ratos Wistars machos foram submetidos ? cirurgia renovascular (modelo Goldblatt ? 2Rins/1CLIP) ou ? cirurgia fict?cia (SHAM) e divididos e agrupados de acordo com a infec??o ou n?o pelo T. cruzi. Foram realizados tr?s experimentos em diferentes momentos da ?infec??o e cirurgia? para avalia??o da HAS e do patol?gico induzido pelo parasito sendo (I) indu??o da HAS + infec??o pelo T.cruzi (ao mesmo tempo), experimento teve dura??o de 1 semana; (II) indu??o da HAS + infec??o com o T. cruzi 3 semanas ap?s a cirurgia e (III) indu??o da HAS + infec??o pelo T.cruzi (ao mesmo tempo) e experimento teve dura??o de 8 semanas. Nesse estudo, avaliou-se par?metros fisiol?gicos e inflamat?rios como pletismografia, Ang II e mediadores inflamat?rios plasm?ticos, parasitemia e achados histopatol?gicos no tecido card?aco. Ap?s a 3? semana de cirurgia os animais apresentaram picos press?ricos havendo concord?ncia com a produ??o de Angio II plasm?tica nas primeiras semanas, mas n?o se observando rela??o direta entre o aumento da press?o arterial e o numero de parasitos circulantes. No entanto, o T. cruzi exerceu papel definidor na alta produ??o de TNF-alfa e da CX3CL1/Fractalkine e, em associa??o com a cirurgia renovascular, observou-se maior eleva??o nesses mediadores inflamat?rios em diferentes etapas do estudo. Por outro lado, o aumento da press?o arterial n?o exerceu interfer?ncia no processo inflamat?rio tecidual nem na invas?o tecidual pelo parasito, mas contribuiu para a manuten??o do n?mero de vasos sangu?neos ap?s 8 semanas de experimento, quando houve diminui??o no grupo de animais normotensos. Com este estudo conclui-se que o tempo de infec??o pelo T. cruzi e o tempo de desenvolvimento da hipertens?o interferem, mutualmente, no perfil inflamat?rio induzido pelo hospedeiro mam?fero. No entanto, acredita-se tamb?m, que esse estudo fosse reproduzido em outro modelo experimental mais suscept?vel ? infec??o pelo T. cruzi, as les?es cardiovasculares seriam mais evidenciadas principalmente numa etapa cr?nica de ambas as doen?as.Systemic arterial hypertension (SAH) is characterized by the increase of plasma/tissue Angiotensin II (Angio II) and presents high prevalence in the world. There are evidences suggesting the involvement of vascular inflammation in the initial phase of SAH. Chagas cardiomyopathy is a disease caused by Trypanosoma cruzi infection that triggers a progressive inflammatory response with prominent fibrosis and, as a consequence, there are important cardiac electrical and functional disturbances and/or hypertrophy in this organ. Our aim in this study was evaluate SAH and the cardiovascular inflammation in Wistar rats infected by Y strain of T. cruzi. Male rats were submitted to renovascular surgery (Goldblat model ? 2Kidneys/1CLIP) or to a fictional surgery (SHAM) and grouped according to infection or not by T. cruzi. It was proposed 3 experiments in different times of infection and surgery to evaluate the SAH and the pathological aspects induzed by the parasite: (I) SAH induction and T.cruzi infection at same time ? experiment occurred in one week; (II) SAH induction + T.cruzi infection after 3 weeks of surgery and (III) SAH induction and T.cruzi infection at same time ? experiment occurred during 8 weeks. For these sets of experiments, there was evaluation of physiological, parasitological, inflammatory and histological parameters in the plasma and/or cardiac tissue. After the 3rd week of the renovascular surgery, animals presented high pressoric levels in accordance with high plasma Angio II on the first weeks. However, there were not observed relation between the increase of SAH and the number of circulating parasites. In our data, T. cruzi exerted an important role in the production of TNF-alpha and CX3CL1/Fractalkine by host cells and we observed high plasma release of these mediators when associated with SAH, in distinct times of this study. On the other hand, SAH does not exerted influence on cardiac inflammatory infiltration neither in the amastigote proliferation, but contributed to the maintenance of the number of blood vessels after 8 weeks of the experiment in comparison with the reduction observed in the control group (without SAH). Together, these data suggest that the time of T.cruzi infection and the time of SAH development interfere, mutually, in the inflammatory profile induced by host mammalian. However, other studies performed in other T.cruzi-susceptible experimental model might develop cardiovascular lesions with high magnificence as well as inflammatory process in heart tissue during chronic stages of both diseases

Remote ischemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI): study protocol for a randomized controlled trial

BACKGROUND: ST-elevation myocardial infarction (STEMI) accounts for nearly one third of acute coronary syndromes. Despite improved STEMI patient care, mortality remains high, contributing significantly to the ischemic heart disease burden. This may partly be related to ischemia-reperfusion injury (IRI). Remote ischemic conditioning (RIC), through short cycles of ischemia-reperfusion applied to a limb, has been shown to reduce IRI in various clinical settings. Our primary hypothesis is that RIC will reduce adverse events related to STEMI when applied as adjunctive therapy to primary percutaneous coronary intervention (PCI). METHODS/DESIGN: "Remote ischemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty" (RIC-STEMI) is an ongoing prospective, single-center, open-label, randomized controlled trial to assess whether RIC as an adjunctive therapy during primary PCI in patients presenting with STEMI can improve clinical outcomes. After enrollment, participants are randomized according to a computer-generated randomization schedule, in a ratio of 1:1 to RIC or no intervention, in blocks of four individuals. RIC is begun at least 10 min before the estimated time of the first balloon inflation and its duration is 30 min. Ischemia is induced by three cycles of inflation of a blood pressure cuff placed on the left lower limb to 200 mmHg and then deflation to 0 mmHg for another 5 min. Primary endpoint is a combined endpoint of death from cardiac cause or hospitalization for heart failure (HF) on follow-up (including device implantation: implantable cardioverter defibrillator, cardiac resynchronization and left ventricular assist device). Secondary endpoints are myocardial infarction (MI) size (estimated by the 48 h area under the curve of serum troponin I levels), development of Q-wave MI, left ventricular function (assessed by echocardiography within the first 3 days after admission), contrast-induced nephropathy, in-hospital mortality, all-cause mortality and, finally, major adverse cardiovascular events. Patients will have a minimum follow-up period of 12 months. From 11 March 2013 to 31 December 2014, 324 patients have been enrolled and randomized. We expect to complete enrollment of the 494 patients deemed necessary within 3 years.info:eu-repo/semantics/publishedVersio

Insuficiência cardíaca após síndrome coronária aguda: identificar para melhor tratar!

INTRODUCTION: The development of heart failure (HF) following acute coronary syndromes (ACS) significantly worsens short- and long-term prognosis. The present study aimed to identify clinical characteristics, detectable at admission for ACS, that could predict HF development during hospitalization, and to evaluate its impact on in-hospital mortality. METHODS: This was a retrospective cohort study that included 601 patients consecutively admitted with ACS. Demographic, clinical and laboratory data at admission were collected and HF was defined as maximum Killip class II or III. Logistic regression analysis was performed to identify independent predictors of HF and, additionally, in-hospital death. RESULTS: 29.3% of the population developed HF, mostly older patients (69.52+/-11.9 years vs. 61.81+/-12.4 years, p<0.0001), women, hypertensive, diabetic and non-smokers. On admission, this subgroup of patients presented with higher heart rate and glycemia, and lower glomerular filtration rate (eGFR) and hemoglobin. The percentage of patients with left ventricular systolic dysfunction (LVSD) was significantly higher in the group of patients with HF (74.4% versus 48.7%, p<0.0001); however, no significant differences were found in the type of ACS or its location. In the present study, we found that patients with HF were stratified less invasively (less likely to undergo cardiac catheterization or percutaneous coronary intervention). The development of HF was associated with longer hospitalization and higher in-hospital mortality (7.4% versus 2.1%, p=0.004) on univariate analysis, but not on multivariate analysis. On multivariate analysis, only age (OR=1.04; 95% CI 1.02-1.06), diabetes mellitus (OR=1.77; 95% CI 1.05-2.96), glycemia (OR=1.05; 95% CI 1.01-1.08), eGFR <60 ml/min/1.73m2 (OR=2.90, 95% CI 1.73- 4.84), heart rate (OR=1.03, 95% CI 1.02-1.04) and LVSD (OR=2.48, 95% CI 1.59-3.85) were independent predictors of HF. CONCLUSIONS: HF is a frequent complication in ACS and is associated with higher in-hospital mortality. Identifying risk of HF development on admission, through easily acquired clinical characteristics (older age, diabetes and/or elevated glycemia, renal failure and higher heart rate), will certainly influence immediate therapeutic choices and permit an individualized approach to each patient

Admission glycemia: a predictor of death after acute coronary syndrome in non-diabetic patients?

BACKGROUND: Previous studies have demonstrated that acute phase hyperglycemia is associated with increased in-hospital mortality in diabetic patients admitted with acute coronary syndrome (ACS), but this has not been clearly demonstrated in non-diabetic patients. The present study was designed to determine whether admission hyperglycemia (AG) is an independent predictor of in-hospital and six-month mortality after ACS in non-diabetic patients. METHODS: This was a retrospective cohort study of 426 non-diabetic patients consecutively admitted with ACS. The patients were stratified into quartile groups according to AG, which was also analyzed as a continuous variable. Vital status was obtained at six-month follow-up in 96.8% of the patients surviving hospitalization. Logistic regression analysis was used to identify independent predictors of in-hospital and six-month death. RESULTS: Of the 426 patients included in the study (age 62.6 years+/-13.1, 77% male), 22 (5.4%) patients died during hospitalization and 20 (5.2% of the patients surviving hospitalization) within six months of ACS. Mean AG was 134.89 mg/dl+/-51.95. The higher the AG, the more probable was presentation with ST-segment elevation ACS (STEMI), anterior STEMI, higher heart rate, Killip class higher than one (KK >1), higher serum creatinine and greater risk of in-hospital and six-month death. In multivariate analysis, only age (OR=1.10; 95% CI 1.04-1.17), STEMI (OR=3.02; 95% CI 1.07-8.50), AG (OR=1.073; 95% CI 1.004-1.146), serum creatinine (OR=1.10; 95% CI 1.009-1.204) and KK >1 on admission (OR=4.65; 95% CI 1.59-13.52) were independently associated with in-hospital death. Age (OR=1.07; 95% CI 1.03-1.12), serum creatinine (OR=1.09; 95% CI 1.01-1.18) and in-hospital development of heart failure (OR=2.34; 95% CI 1.07-5.10) were independently associated with higher risk of death within six months of ACS. CONCLUSIONS: AG is an independent predictive factor of in-hospital death after ACS in non-diabetic patients. Although it did not show an independent association with higher risk of six-month death, AG appears to contribute to it, since the risk is greater the higher the AG. Its predictive value may have been blunted by the insufficient power of the sample and/or by the time interval between acquisition of AG and the evaluated endpoint

Proton pump inhibitors in patients treated with aspirin and clopidogrel after acute coronary syndrome

INTRODUCTION: Clopidogrel is an antiplatelet agent converted to its active metabolite by cytochrome P-450 isoenzymes. Numerous drugs are known to inhibit P-450 isoenzymes, including proton pump inhibitors (PPIs), which are often associated with aspirin and clopidogrel to prevent adverse gastrointestinal effects. In vitro studies first showed that PPIs reduced the antiplatelet effect of clopidogrel, while recent clinical studies have raised concerns that the addition of a PPI to clopidogrel in acute coronary syndrome (ACS) patients could actually increase the risk of recurrent cardiovascular events. OBJECTIVE: The aim of this study was to evaluate whether the prescription of a PPI conferred a worse prognosis in patients discharged with aspirin and clopidogrel treatment after ACS. METHODS: A total of 876 patients admitted with ACS and discharged with aspirin and clopidogrel, with a planned duration of at least six months, from January 2004 to March 2008, were reviewed. Patients were classified in two groups according to whether or not a PPI was prescribed at discharge. The PPIs considered were those mainly metabolized by cytochrome P-450 2C19. We excluded patients with insufficient information available on either prescription or clinical records that could allow clearly confirm or exclude exposure to a PPI. Primary end points were six-month all-cause mortality and the composite of death, myocardial infarction and unstable angina at six months. RESULTS: Of the 802 patients considered for further analysis, 274 (34.2%) individuals were medicated with a PPI in addition to dual antiplatelet therapy. Patients taking PPIs were older, more often had renal insufficiency and less often had a history of coronary revascularization and smoking. They more often presented with Killip class >I and lower hemoglobin concentration on admission. There were no significant differences between the two groups in terms of medical treatment (during hospital stay and at discharge) or invasive procedures. By multivariate analysis, independent and positive predictors of PPI prescription were older age and lower hemoglobin concentration on admission. Patients taking PPIs had a slightly higher prevalence of six-month mortality (6.5% vs. 3.9%) and of the composite end point (12.9% vs. 9.2%), although without statistical significance. By multivariate analysis including potential confounding variables, the prescription of a PPI on top of aspirin and clopidogrel was still n ot associated with a worse prognosis. CONCLUSIONS: In the present study, PPI precription in addition to aspirin and clopidogrel after ACS was not associated with a worse six-month prognosis

Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology

Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma–induced retinal dysfunction by operating at the level of tumor-associated microglial activation

Frequency and Pattern of Heteroplasmy in the Complete Human Mitochondrial Genome

Determining the levels of human mitochondrial heteroplasmy is of utmost importance in several fields. In spite of this, there are currently few published works that have focused on this issue. In order to increase the knowledge of mitochondrial DNA (mtDNA) heteroplasmy, the main goal of this work is to investigate the frequency and the mutational spectrum of heteroplasmy in the human mtDNA genome. To address this, a set of nine primer pairs designed to avoid co-amplification of nuclear DNA (nDNA) sequences of mitochondrial origin (NUMTs) was used to amplify the mitochondrial genome in 101 individuals. The analysed individuals represent a collection with a balanced representation of genders and mtDNA haplogroup distribution, similar to that of a Western European population. The results show that the frequency of heteroplasmic individuals exceeds 61%. The frequency of point heteroplasmy is 28.7%, with a widespread distribution across the entire mtDNA. In addition, an excess of transitions in heteroplasmy were detected, suggesting that genetic drift and/or selection may be acting to reduce its frequency at population level. In fact, heteroplasmy at highly stable positions might have a greater impact on the viability of mitochondria, suggesting that purifying selection must be operating to prevent their fixation within individuals. This study analyses the frequency of heteroplasmy in a healthy population, carrying out an evolutionary analysis of the detected changes and providing a new perspective with important consequences in medical, evolutionary and forensic fields

Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling

Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model. GlcA-Lips encapsulating sildenafil (GlcA-sildenafil-Lips) had a size of 90 nm and a pH-sensitive drug release pattern. Immunostaining assay indicated the overexpression of GLUT-1 in PA smooth muscle cells. Cellular uptake studies showed a 1-fold increase of GlcA-Lips uptake by PA smooth muscle cells and pharmacokinetics and biodistribution experiments indicated longer blood circulation time of GlcA-Lips and increased ability to target PAs by 1-fold after 8 hours administration. Two-week treatment indicated GlcA-sildenafil-Lips significantly inhibited the remodeling of PAs, with a 32% reduction in the PA pressure, a 41% decrease in the medial thickening, and a 44% reduction of the right ventricle cardiomyocyte hypertrophy, and improved survival rate. Immunohistochemical analysis showed enhanced expression of caspase-3, after administration of GlcA-sildenafil-Lips, and reduced expression of P-ERK1/2 (phosphorylated ERK1/2) and HK-2 (hexokinase-2), and increased level of eNOS (endothelial nitric oxide synthase) and cyclic GMP (cGMP). In conclusion, targeted delivery of sildenafil to PA smooth muscle cells with GlcA-Lips could effectively inhibit the remodeling of PAs in the monocrotaline-induced PA hypertension