Correction: Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism.

[This corrects the article DOI: 10.1371/journal.pone.0166845.].

Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium.

AIMS: There are conflicting reports on the role of reactive oxygen species (ROS) i.e. beneficial vs. harmful, in vascular endothelium. Here, we aim to examine whether duration of exposure to ROS and/or subcellular ROS levels are responsible for the apparently paradoxical effects of oxidants on endothelium. METHODS AND RESULTS: We have recently generated binary (Tet-ON/OFF) conditional transgenic mice (Tet-Nox2:VE-Cad-tTA) that can induce 1.8 ± 0.42-fold increase in NADPH oxidase (NOX)-derived ROS specifically in vascular endothelium upon withdrawal of tetracycline from the drinking water. Animals were divided in two groups: one exposed to high endogenous ROS levels for 8 weeks (short-term) and the other for 20 weeks (long-term). Using endothelial cells (EC) isolated from mouse hearts (MHEC), we demonstrate that both short-term and long-term increase in NOX-ROS induced AMPK-mediated activation of eNOS. Interestingly, although endothelium-dependent nitric oxide (NO)-mediated coronary vasodilation was significantly increased after short-term increase in NOX-ROS, coronary vasodilation was drastically reduced after long-term increase in ROS. We also show that short-term ROS increase induced proliferation in EC and angiogenic sprouting in the aorta. In contrast, long-term increase in cytosolic ROS resulted in nitrotyrosine-mediated inactivation of mitochondrial (mito) antioxidant MnSOD, increase in mito-ROS, loss of mitochondrial membrane potential (Δψm), decreased EC proliferation and angiogenesis. CONCLUSION: The findings suggest that NOX-derived ROS results in increased mito-ROS. Whereas short-term increase in mito-ROS was counteracted by MnSOD, long-term increase in ROS resulted in nitrotyrosine-mediated inactivation of MnSOD, leading to unchecked increase in mito-ROS and loss of Δψm followed by inhibition of endothelial function and proliferation.

Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism.

PURPOSE: Therapeutic strategies that modulate ventricular remodeling can be useful after acute myocardial infarction (MI). In particular, statins may exert effects on molecular pathways involved in collagen metabolism. The aim of this study was to determine whether treatment with atorvastatin for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a rat model of MI. METHODS: Male Wistar rats were used in this study. MI was induced in rats by ligation of the left anterior descending coronary artery (LAD). Animals were randomized into three groups, according to treatment: sham surgery without LAD ligation (sham group, n = 14), LAD ligation followed by 10mg atorvastatin/kg/day for 4 weeks (atorvastatin group, n = 24), or LAD ligation followed by saline solution for 4 weeks (control group, n = 27). After 4 weeks, hemodynamic characteristics were obtained by a pressure-volume catheter. Hearts were removed, and the left ventricles were subjected to histologic analysis of the extents of fibrosis and collagen deposition, as well as the myocyte cross-sectional area. Expression levels of mediators involved in collagen metabolism and inflammation were also assessed. RESULTS: End-diastolic volume, fibrotic content, and myocyte cross-sectional area were significantly reduced in the atorvastatin compared to the control group. Atorvastatin modulated expression levels of proteins related to collagen metabolism, including MMP1, TIMP1, COL I, PCPE, and SPARC, in remote infarct regions. Atorvastatin had anti-inflammatory effects, as indicated by lower expression levels of TLR4, IL-1, and NF-kB p50. CONCLUSION: Treatment with atorvastatin for 4 weeks was able to attenuate ventricular dysfunction, fibrosis, and left ventricular hypertrophy after MI in rats, perhaps in part through effects on collagen metabolism and inflammation. Atorvastatin may be useful for limiting ventricular remodeling after myocardial ischemic events.

Diacerein improves left ventricular remodeling and cardiac function by reducing the inflammatory response after myocardial infarction.

BACKGROUND: The inflammatory response has been implicated in the pathogenesis of left ventricular (LV) remodeling after myocardial infarction (MI). An anthraquinone compound with anti-inflammatory properties, diacerein inhibits the synthesis and activity of pro-inflammatory cytokines, such as tumor necrosis factor and interleukins 1 and 6. The purpose of this study was to investigate the effects of diacerein on ventricular remodeling in vivo. METHODS AND RESULTS: Ligation of the left anterior descending artery was used to induce MI in an experimental rat model. Rats were divided into two groups: a control group that received saline solution (n = 16) and a group that received diacerein (80 mg/kg) daily (n = 10). After 4 weeks, the LV volume, cellular signaling, caspase 3 activity, and nuclear factor kappa B (NF-κB) transcription were compared between the two groups. After 4 weeks, end-diastolic and end-systolic LV volumes were reduced in the treatment group compared to the control group (p < .01 and p < .01, respectively). Compared to control rats, diacerein-treated rats exhibited less fibrosis in the LV (14.65%± 7.27% vs. 22.57%± 8.94%; p < .01), lower levels of caspase-3 activity, and lower levels of NF-κB p65 transcription. CONCLUSIONS: Treatment with diacerein once a day for 4 weeks after MI improved ventricular remodeling by promoting lower end-systolic and end-diastolic LV volumes. Diacerein also reduced fibrosis in the LV. These effects might be associated with partial blockage of the NF-κB pathway.

Development of cardioplegic solution without potassium: experimental study in rat / Desenvolvimento de solução cardioplégica sem potássio: estudo experimental em ratos

INTRODUCTION: Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. OBJECTIVE: To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM) uses low doses of sodium channel blocker (lidocaine), potassium channel opener (cromakalin), and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime). METHODS: Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK), Braile (G/A), and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. RESULTS: The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05). The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01). The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01). All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. CONCLUSION: Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.

INTRODUÇÃO: Preservação do miocárdio durante cirurgias cardíacas abertas e de colheita para transplante são de grande importância. O coração ao final do processo tem de retomar as suas funções, logo que possível. Todas as soluções cardioplégicas são baseadas em potássio, para indução de parada cardioplégica. OBJETIVO: Comparar a uma solução cardioplégica sem adição de potássio à sua fórmula com duas outras soluções cardioplégicas disponíveis comercialmente. A avaliação comparativa foi baseada na citotoxicidade, preservação miocárdica (adenosina trifosfato, ATP) e atividade da caspase 3. A solução testada (LIRM) utiliza baixas doses de bloqueador de canal de sódio (lidocaína), abridor do canal de potássio (cromacalina) e inibidor da ponte actina/miosina (2,3-butanodiona monoxima). MÉTODOS: Ratos Wistar foram submetidos à toracotomia sob ventilação mecânica e três soluções diferentes foram utilizadas para perfusão in situ para a indução de parada cardioplégica: soluções Custodiol (HTK) Braile (G/A) e LIRM. Após parada cardíaca, os corações foram retirados e mantidos em câmara fria por 4 horas. Após esse período, o coração foi avaliado com microscopia de luz ótica, o conteúdo de ATP miocárdico e atividade da caspase 3. Todas as três soluções foram avaliadas quanto à citotoxicidade direta com células L929 e WEHI-164. RESULTADOS: A quantidade de ATP foi maior no grupo Custodiol em comparação às com outras duas soluções (P<0,05). A atividade de caspase foi menor no grupo HTK quando comparado às soluções LIRM e G/A (P<0,01). A solução LIRM demonstrou menor atividade da caspase em comparação à solução Braile (P<0,01). Todas as soluções não mostraram qualquer efeito de citotoxicidade após 24 horas de exposição das células às soluções cardioplégicas. CONCLUSÃO: Soluções cardioplégicas sem potássio são uma perspectiva e a adição de aminoácido pode ser uma estratégia interessante. Mais avaliações são necessárias para o desenvolvimento ideal da solução cardioplégica.

Development of cardioplegic solution without potassium: experimental study in rat.

INTRODUCTION: Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. OBJECTIVE: To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM) uses low doses of sodium channel blocker (lidocaine), potassium channel opener (cromakalin), and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime). METHODS: Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK), Braile (G/A), and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. RESULTS: The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05). The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01). The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01). All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. CONCLUSION: Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.

Use of modified ultrafiltration in adults undergoing coronary artery bypass grafting is associated with inflammatory modulation and less postoperative blood loss: a randomized and controlled study.

OBJECTIVES: Modified ultrafiltration (MUF) has been shown to decrease the postcardiac surgery inflammatory response and to improve respiratory function and cardiac performance in pediatric patients; however, this approach has not been well established in adults. The present study hypothesized that MUF could decrease the postsurgical inflammatory response, leading to improved respiratory and cardiac function in adults undergoing coronary artery bypass grafting. METHODS: Sixty patients undergoing coronary artery bypass grafting were randomized to the MUF or control group (n = 30 each). MUF was performed for 15 minutes at the end of bypass. The following data were recorded at the beginning of anesthesia, end of bypass, end of experimental treatment, and 24 and 48 hours after surgery: alveolar-arterial oxygen gradient, red blood cell units transfused, chest tube drainage, hemodynamic parameters, and cytokine levels (interleukin-6, P-selectin, intercellular adhesion molecule, and soluble tumor necrosis factor receptor). RESULTS: The MUF group displayed less chest tube drainage than the control group after 48 hours (598 ± 123 mL vs 848.0 ± 455 mL; P = .04) and less red blood cell transfusions (0.6 ± 0.6 units/patient vs 1.6 ± 1.1 units/patient; P = .03). Hematocrit level was higher in the MUF group than in the control group at the end of bypass (37.8% ± 1.1% vs 34.1% ± 1.1%; P < .05), but the levels were comparable at 48 hours. Similar values for interleukin-6 and P-selectin were observed at all stages. Plasma levels of intercellular adhesion molecule were higher in the MUF group than in the control group, particularly in the first sampling after experimental treatment (P = .01). Plasma levels of soluble tumor necrosis factor receptor were higher in the MUF group than in the control group at 48 hours. Hemodynamic and oxygen transport parameters were similar in both groups throughout the observation period. There were no differences in other clinical outcomes. CONCLUSIONS: Use of MUF was associated with increased inflammatory response, reduced blood loss, and less blood transfusions in adults undergoing coronary artery bypass grafting.

The effects of modified ultrafiltration on pulmonary function and transfusion requirements in patients underwent coronary artery bypass graft surgery.

OBJECTIVE: The inflammatory response after cardiac surgery increases vascular permeability leading to higher mortality and morbidity in the post operative time. The modified ultrafiltration (MUF) had shown benefits on respiratory, and hemodynamic in pediatric patients. This approach in adults is not well established yet. We hypothesize that modified ultrafiltration may improve respiratory, hemodynamic and coagulation function in adults after cardiac surgeries. METHODS: A prospective randomized study was carried out with 37 patients who underwent coronary artery bypass graft surgery (CABG) were randomized either to MUF (n=20) at the end of bypass or to control (no MUF) (n=17). The anesthesia and ICU team were blinded for the group selection. The MUF were carried out for 15 minutes after the end of bypass. The patients data were taken at beginning of anesthesia, ending of bypass, ending MUF, 24 hours, and 48 hours after surgery. For clinical outcome the pulmonary, hemodynamic and coagulation function were evaluated. RESULTS: We observed lower drain loss in the MUF group compared to control group after 48 hours (598 +/- 123 ml vs. 848 +/- 455 ml; P=0.04) and required less red blood cells units transfusion compared to control group (0.6 +/- 0.6 units/patient vs.1.6 +/- 1.1 units/patient; P=0.03). The MUF group showed lower airway resistance (9.3 +/- 0.4 cmH2O.L-1s-1 vs. 12.1 +/- 0.8 cmH2O.L-1s-1; P=0.04). There were no deaths in both groups. CONCLUSION: The MUF reduces post operatory bleeding and red blood cells units transfusion, but with no differences on clinical outcome were observed. The routinely MUF employment was not associated with hemodynamic instability.

Efeitos da ultrafiltração modificada na função pulmonar e necessidade de hemotransfusão em pacientes submetidos à revascularização do miocárdio / The effects of modified ultrafiltration on pulmonary function and transfusion requirements in patients underwent coronary artery bypass graft surgery

INTRODUÇÃO: A cirurgia cardíaca com circulação extracorpórea aumenta a permeabilidade vascular, com incremento da morbidade e da mortalidade pós-operatória. A ultrafiltração modificada na população pediátrica demonstrou melhora da função pulmonar e hemodinâmica, contudo benefício semelhante não está bem estabelecido em adultos. Nós temos a hipótese que a ultrafiltração modificada pode melhorar a função pulmonar, hemodinâmica e a coagulação no pós-operatório em pacientes adultos. MÉTODOS: Estudo prospectivo e cego para a equipe anestésica e da terapia intensiva em pacientes eletivos submetidos à revascularização do miocárdio. Todos os pacientes foram monitorados quanto à função hemodinâmica, pulmonar e hematológica no intraoperatório e até 48 horas de pós-operatório. Os pacientes foram divididos em dois grupos: um submetido à ultrafiltração modificada por 15 minutos após a saída de circulação extracorpórea e um grupo sem ser submetido à ultrafiltração. Os dados foram estudados com análise de variância com dois fatores para medidas repetidas. RESULTADOS: O grupo ultrafiltração modificada apresentou menor sangramento pós-operatório ao final de 48 horas (598 ± 123 ml vs. 848 ± 455 ml; P = 0,04) e menor necessidade de transfusão de unidades de hemácias (0,6 ± 0,6 unidades/ paciente vs. 1,6 ± 1,1 unidades/paciente; P =0,03). O grupo ultrafiltração apresentou menor resistência de vias aéreas quando comparado ao controle (9,3 ± 0,4 vs. 12,1 ± 0,8 cmH2O. L-1s-1; P =0,04) e menor complacência quando comparado ao controle (47,3 ± 2,0 mLcmH2O vs. 53,1 ± 3,1 mLcmH2O; P=0,04). CONCLUSÃO: O uso ultrafiltração modificada diminuiu o sangramento pós-operatório e a necessidade de transfusão, contudo sem diferenças no resultado clínico final. O uso da ultrafiltração modificada não foi associado com instabilidade hemodinâmica.

OBJECTIVE: The inflammatory response after cardiac surgery increases vascular permeability leading to higher mortality and morbidity in the post operative time. The modified ultrafiltration (MUF) had shown benefits on respiratory, and hemodynamic in pediatric patients. This approach in adults is not well established yet. We hypothesize that modified ultrafiltration may improve respiratory, hemodynamic and coagulation function in adults after cardiac surgeries. METHODS: A prospective randomized study was carried out with 37 patients who underwent coronary artery bypass graft surgery (CABG) were randomized either to MUF (n=20) at the end of bypass or to control (no MUF) (n=17). The anesthesia and ICU team were blinded for the group selection. The MUF were carried out for 15 minutes after the end of bypass. The patients data were taken at beginning of anesthesia, ending of bypass, ending MUF, 24 hours, and 48 hours after surgery. For clinical outcome the pulmonary, hemodynamic and coagulation function were evaluated. RESULTS: We observed lower drain loss in the MUF group compared to control group after 48 hours (598 ± 123 ml vs. 848 ± 455 ml; P=0.04) and required less red blood cells units transfusion compared to control group (0.6 ± 0.6 units/patient vs.1.6 ± 1.1 units/patient; P=0.03). The MUF group showed lower airway resistance (9.3 ± 0.4 cmH2O.L-1s-1 vs. 12.1 ± 0.8 cmH2O.L-1s-1; P=0.04). There were no deaths in both groups. CONCLUSION: The MUF reduces post operatory bleeding and red blood cells units transfusion, but with no differences on clinical outcome were observed. The routinely MUF employment was not associated with hemodynamic instability.

Prevalence of HIV-1 subtypes in Brazilian children with perinatally acquired infection.

HIV-1 infection has increased among women in recent years. The HIV-1 env gene (structural gene) has the greatest variation in all the HIV gene regions. In this study, 58 samples from infants infected with HIV-1 via perinatal transmission were analyzed. All the 58 samples were submitted to Nested-polymerase chain reaction of the env gene region for posterior viral genotyping using EN 70 and EN 85 (first polymerase chain reaction) and EN 80 and EN 95 (second polymerase chain reaction) primers, with the product of the 682 base pair amplification. After Nested-polymerase chain reaction for genotyping, purification of the product, and direct sequencing in a MegaBace 1000 automatic sequencer, 56 genotypes were found in the 58 HIV-1-positive children of the study, where 47 (83.93%) were HIV-1 subtype B infected and 9 (16.07%) were HIV-1 subtype F1 infected. The results demonstrate the predominance of subtype B followed by subtype F in Southeast Brazil.