Selective Cyclooxygenase-2 Inhibition Protects Against Myocardial Damage in Experimental Acute Ischemia

BACKGROUND: Acute myocardial infarction is associated with tissue inflammation. Early coronary reperfusion clearly improves the outcome but may help propagate the inflammatory response and enhance tissue damage. Cyclooxygenase-2 is an enzyme that catalyzes the initial step in the formation of inflammatory prostaglandins from arachidonic acid. Cyclooxygenase-2 levels are increased when ischemic cardiac events occur. The overall function of COX-2 in the inflammatory process generated by myocardial ischemic damage has not yet been elucidated. GOAL: The objective of this study was to determine whether a selective cyclooxygenase-2 inhibitor (rofecoxib) could alter the evolution of acute myocardial infarction after reperfusion. METHODS AND RESULTS: This study was performed with 48 mongrel dogs divided into two groups: controls and those treated with the drug. All animals were prepared for left anterior descending coronary artery occlusion. The dogs then underwent 180 minutes of coronary occlusion, followed by 30 minutes of reperfusion. Blood samples were collected from the venous sinus immediately before coronary occlusion and after 30 minutes of reperfusion for measurements of CPK-MB, CPK-MBm and troponin I. During the experiment we observed the mean blood pressure, heart rate and coronary flow. The coronary flow and heart rate did not change, but in the control group, there was blood pressure instability, in addition to maximal levels of CPK-MB post-infarction. The same results were observed for CPK-MBm and troponin I. CONCLUSION: In a canine model of myocardial ischemia-reperfusion, selective inhibition of Cyclooxygenase-2 with rofecoxib was not associated with early detrimental effects on the hemodynamic profile or the gross extent of infarction; in fact, it may be beneficial by limiting cell necrosis

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H2O2 release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H2O2 resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca2+-induced permeability transition and reduced H2O2 release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a nonpharmacological tool for heart failure therapy.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Sao Paulo - SP (FAPESP) [2009/18546-4, 2010/00028-4, 2012/05765-2]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Sao Paulo SP (FAPESP)Conselho Nacional de Pesquisa e Desenvolvimento - Brasil (CNPq) [479407/2010-0]Conselho Nacional de Pesquisa e Desenvolvimento Brasil (CNPq)Instituto Nacional de Ciencia e TecnologiaInstituto Nacional de Ciencia e TecnologiaNucleo de Apoio a Pesquisa de Processos Redox em BiomedicinaNucleo de Apoio a Pesquisa de Processos Redox em BiomedicinaFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/12349-2

Value of adenosine infusion for infarct size determination using real-time myocardial contrast echocardiography

BACKGROUND: Myocardial contrast echocardiography has been used for determination of infarct size (IS) in experimental models. However, with intermittent harmonic imaging, IS seems to be underestimated immediately after reperfusion due to areas with preserved, yet dysfunctional, microvasculature. The use of exogenous vasodilators showed to be useful to unmask these infarcted areas with depressed coronary flow reserve. This study was undertaken to assess the value of adenosine for IS determination in an open-chest canine model of coronary occlusion and reperfusion, using real-time myocardial contrast echocardiography (RTMCE). METHODS: Nine dogs underwent 180 minutes of coronary occlusion followed by reperfusion. PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) was used as contrast agent. IS was determined by RTMCE before and during adenosine infusion at a rate of 140 mcg·Kg(-1)·min(-1). Post-mortem necrotic area was determined by triphenyl-tetrazolium chloride (TTC) staining. RESULTS: IS determined by RTMCE was 1.98 ± 1.30 cm(2 )and increased to 2.58 ± 1.53 cm(2 )during adenosine infusion (p = 0.004), with good correlation between measurements (r = 0.91; p < 0.01). The necrotic area determined by TTC was 2.29 ± 1.36 cm(2 )and showed no significant difference with IS determined by RTMCE before or during hyperemia. A slight better correlation between RTMCE and TTC measurements was observed during adenosine (r = 0.99; p < 0.001) then before it (r = 0.92; p = 0.0013). CONCLUSION: RTMCE can accurately determine IS in immediate period after acute myocardial infarction. Adenosine infusion results in a slight better detection of actual size of myocardial damage

Sex work stigma and non-disclosure to health care providers: data from a large RDS study among FSW in Brazil

Abstract Background Stigma in health services may be detrimental to health seeking attitudes and practices. This study investigates non-disclosure of sex work to health care providers among female sex workers (FSW) in Brazil and its association with the utilization of health care services. Methods This study used cross-sectional respondent-driven sampling, carried out in 12 Brazilian cities to identify HIV risk behaviors among FSW. We first assessed statistical associations of sociodemographic, human right violations, health service access and utilization, and discrimination variables with non-disclosure of FSW status to health care providers as outcome. Secondly, we investigated the association of non-disclosure of FSW status with selected preventive health care outcomes: HIV testing, PAP smear exam, and post-exposure prophylaxis (PEP). Adjusted odds ratio with 95% confidence intervals were calculated by multivariable logistic regressions. Results Among 4245 recruited FSW, a high percentage received free condoms (82%) but only 24.4% were counseled on STI. Most FSW used non-specialized public healthcare routinely (62.6%), but only 51.5% had a Pap smear exam in the last two years and less than 40% were tested for HIV in the last 12 months. Among FSW who engaged in risky behavior (49.6%), only 8.3% used PEP. Regarding human rights violations, approximately 15% were required to give part of their earnings to owners of workplace establishments, 38% started sex work under 18 years old and 6% were required to periodically present their HIV test results. 21.3% reported having faced discrimination in health services, and 24.3% always disclosed their FSW status. Multivariable logistic models indicated significant associations of non-disclosure on the four healthcare outcomes, with lower odds of using preventive health services among women who did not disclose their sex work status, even after controlling for age, educational level, NGO affiliation, and type of health care routinely used. Conclusions Our results indicate that sex work stigmatization within health services may be one of the main barriers to STI control and HIV response among FSW. It is essential to combat stigmatization and discrimination against FSW in health services to guarantee the appropriate uptake of preventive services available in the public health system in Brazil

Cholinergic Stimulation Improves Oxidative Stress and Inflammation in Experimental Myocardial Infarction

Abstract We previously reported that cholinergic stimulation with pyridostigmine (PY) induces anti-inflammatory cell recruitment soon after myocardial infarction (MI). In this study, we evaluated the anti-inflammatory effects of PY during the proliferative phase of cardiac repair by analyzing the infiltration of macrophages, Treg lymphocytes, oxidative stress and inflammatory cytokines. Wistar rats underwent control sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated (untreated infarcted group, I) or to receive PY (30 mg·kg(−1)·day(−1)) in the supplied water (infarcted treated group, I + PY). Blood pressure and heart rate variability were registered at day 5 post-MI. The animals were euthanized 7 days after thoracotomy, when the hearts were removed and processed for immunohistochemistry (CD68, CD206, FOXP3), cytokines (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, lipidic and protein peroxidation). PY treatment increased parasympathetic modulation, M2 macrophages and the anti-oxidant enzyme activity but reduced protein oxidation (carbonyls) and the concentration of IL-1β, IL-6, TNF-α and IL-10. Cholinergic stimulation induces parasympathetic neuro-immune modulation and anti-inflammatory cell enrollment as well as prevents oxidative stress and cytokine production after MI