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Trastuzumab is a monoclonal antibody used in oncotherapy for HER2-positive tumors. However, as an adverse effect, trastuzumab elevates the risk of heart failure, implying the involvement of energy production and mitochondrial processes. Past studies with transcriptome analysis have offered insights on pathways related to trastuzumab safety and toxicity but limited study sizes hinder conclusive findings. Therefore, we meta-analyzed mitochondria-related gene expression data in trastuzumab-treated cardiomyocytes. We searched the transcriptome databases for trastuzumab-treated cardiomyocytes in the ArrayExpress, DDBJ Omics Archive, Gene Expression Omnibus, Google Scholar, PubMed, and Web of Science repositories. A subset of 1270 genes related to mitochondrial functions (biogenesis, organization, mitophagy, and autophagy) was selected from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology Resource databases to conduct the present meta-analysis using the Metagen package (Study register at PROSPERO: CRD42021270645). Three datasets met the inclusion criteria and 1243 genes were meta-analyzed. We observed 69 upregulated genes after trastuzumab treatment which were related mainly to autophagy (28 genes) and mitochondrial organization (28 genes). We also found 37 downregulated genes which were related mainly to mitochondrial biogenesis (11 genes) and mitochondrial organization (24 genes). The present meta-analysis indicates that trastuzumab therapy causes an unbalance in mitochondrial functions, which could, in part, help explain the development of heart failure and yields a list of potential molecular targets. These findings contribute to our understanding of the molecular mechanisms underlying the cardiotoxic effects of trastuzumab and may have implications for the development of targeted therapies to mitigate such effects.
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Insuficiencia Cardíaca , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/metabolismo , Cardiotoxicidad/genética , Cardiotoxicidad/metabolismo , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados/efectos adversos , Trastuzumab/efectos adversos , Insuficiencia Cardíaca/metabolismo , Expresión GénicaRESUMEN
Sudden cardiac death (SCD) is an unpredictable and common mode of death in patients with heart failure (HF). Alterations in calcium handling may lead to malignant arrhythmias, resulting in SCD, and variants in calcium signaling-related genes have a significant association with SCD. Therefore, the aim of the present retrospective cohort study was to investigate the association of Ser96Ala [histidine-rich calcium-binding protein (HRC)], Ser49Gly [ß1-adrenergic receptor (ADRB1)], Arg389Gly (ADRB1) and Gly1886Ser [ryanodine receptor 2 (RYR2)] polymorphisms with serious arrhythmic events and overall mortality in patients with HF with reduced left ventricular ejection fraction of non-ischemic etiology. In total, 136 patients with HF underwent physical examination, routine laboratory tests, non-invasive assessment of cardiac function and an invasive electrophysiological study. The primary outcome was the occurrence of serious arrhythmic events, set as either SCD or appropriate implantable cardioverter-defibrillator (ICD) therapy, and the secondary outcome was all-cause death. During a median follow-up of 37 months, arrhythmic events occurred in 26 patients (19%) and 41 patients (30%) died. Patients carrying the Ser allele of the Ser96Ala polymorphism in HRC had worse survival than those with the Ala/Ala genotype (log-rank P=0.043). Despite the difference in survival time, the Ala/Ala genotype was not associated with all-cause death in the regression analysis [unadjusted hazard ratio (HR)=0.17; 95% CI, 0.02-1.21]. Regarding the Ser49Gly and Arg389Gly polymorphisms in ADRB1, homozygosity for the major alleles at both sites (Ser49Ser and Arg389Arg) was associated with a two-fold increased risk of all-cause death compared with the other genotype combinations (unadjusted HR=1.98; 95% CI, 1.02-3.82). However, this association was lost after controlling for clinical covariates. No association was observed for the Gly1886Ser polymorphism in RYR2. Overall, the present findings are concurrent with the hypothesis that the Ser96Ala (HRC), Ser49Gly (ADRB1) and Arg389Gly (ADRB1) polymorphisms may be associated with HF prognosis. In particular, the Ser96Ala polymorphism might aid in risk stratification and patient selection for ICD implantation.
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BACKGROUND: Interleukin-6 (IL-6) is an inflammation-related cytokine associated with an elevated risk of cardiovascular events. In a previous study, we demonstrated that increased IL-6 was predictive of sub-clinical atherosclerotic coronary disease in intermediate-risk patients undergoing coronary angiography. In the present study, we investigated whether increased serum IL-6 is predictive of cardiovascular events in high-risk patients. METHODS: In this observational study, consecutive patients referred for elective coronary angiography due to stable chest pain/myocardial ischemia had IL-6 measured immediately before the procedure. Long-term follow-up was performed by phone call or e-mail, and their clinical registries were revised. The primary outcome was a composite of new myocardial infarction, new ischemic stroke, hospitalization due to heart failure, new coronary revascularization, cardiovascular death, and death due to all causes. RESULTS: From 141 patients submitted to coronary angiography and IL-6 analysis, 100 had complete follow-up data for a mean of 5.7 years. The median age was 61.1 years, 44% were men, and 61% had type-2 diabetes. The median overall time-to-event for the primary outcome was 297 weeks (95% confidence interval [CI] 266.95-327.16). A receiver operator characteristic curve defined the best cut-off value of baseline serum IL-6 (0.44 pg/mL) with sensitivity (84.37%) and specificity (38.24%) to define two groups. High (> 0.44 pg/mL) IL-6 levels were predictive of cardiovascular events. (p for interaction = 0.015) (hazard ratio = 2.81; 95% CI 1.38-5.72, p = 0.01). Subgroup analysis did not find interactions between patients with or without diabetes, obesity, or hypertension. CONCLUSION: In conclusion, an interleukin-6 level higher than 0.44 pg/mL, obtained just before elective coronary angiography, was associated with a poorer prognosis after a mean of 5,7-year. A pre-procedure IL-6 below 0.44 pg/mL, on the other hand, has a very good negative predictive value, suggesting a good prognosis, and may be useful to better indicate coronary angiography in high-risk patients. .
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Grape juice consumption may influence the early occurrence of ductal constriction during pregnancy, since the consumption of foods rich in polyphenols can be linked to the premature constriction of the ductus arteriosus. This study aimed to evaluate the effect of purple grape juice consumption during gestation on fetal ductus arteriosus closure, prostaglandin levels, and oxidative stress markers in Wistar rats. We divided 18 pregnant rats into four groups: a control group (C), a single-dose grape juice group (SDGJ), a two-dose grape juice group (TDGJ) of 7 µl/g body weight per day, and an indomethacin group (I). Blood was collected on gestational day (GD) 0, 14, and 20. Prostaglandin levels were measured, and the livers and hearts were removed from the mothers and fetuses for oxidative stress analysis; histology of the fetal ductus arteriosus was performed. Prostaglandin levels (pg/ml) at GD 20 were (C:1462.10 ± 314.61); (SDGJ:987.66 ± 86.25); (TDGJ:1290.00 ± 221.57), and (I:584.75 ± 46.77). Fetal ductus arteriosus closure occurred only in the indomethacin group. Lipid peroxidation evaluated through thiobarbituric acid reactive substances (nmol/mg protein) in maternal livers was lower in the grape juice groups (C: 4.11 ± 0.76 nmol/mg protein), (SDGJ: 2.34 ± 0.36), (TDGJ: 1.52 ± 0.18), and (I: 4.20 ± 0.76). Sulfhydryls (nmol/mg protein) were lower in the TDGJ group (C:763.59 ± 61.38 nmol/mg protein), (SDGJ:978.88 ± 158.81), (TDGJ:385.32 ± 86.78), and (I:727.72 ± 49.12). Also, superoxide dismutase activity (USOD/mg protein) was higher in fetal hearts in this group: (C:5.29 ± 0.33), (SDGJ:4.48 ± 0.47), (TDGJ:7.35 ± 0.43), and (I:6.00 ± 0.18). We conclude that grape juice consumption in pregnancy does not induce ductus arteriosus closure in the fetus and presented potential antioxidant effects.
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Conducto Arterial , Vitis , Animales , Constricción , Femenino , Indometacina/farmacología , Embarazo , Prostaglandinas/farmacología , Ratas , Ratas WistarRESUMEN
PURPOSE: Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and right ventricle (RV) failure. In this context, oxidative stress is an essential element contributing to PAH's pathophysiology. Thus, blueberry (BB), which has a high antioxidant capacity, emerges as a natural therapeutic approach in PAH. This work evaluated the effect of BB extract on redox balance in RV in a PAH's animal model. METHODS: Male Wistar rats (200 ± 20 g) (n = 72) were randomized into eight groups: control (CTR); monocrotaline (MCT); CTR and MCT treated at doses of 50, 100, and 200 mg/kg BB. PAH was induced by administration of MCT (60 mg/kg, intraperitoneal). Rats were treated with BB orally for 5 weeks (2 weeks before monocrotaline and 3 weeks after monocrotaline injection). On day 35, rats were submitted to echocardiography and catheterization, then euthanasia and RV harvesting for biochemical analyses. RESULTS: RV hypertrophy, observed in the MCT groups, was reduced with BB treatment. MCT elevated RV systolic pressure and pressure/time derivatives, while the intervention with BB decreased these parameters. PAH decreased RV output and pulmonary artery outflow acceleration/ejection time ratio, while increased RV diameters, parameters restored by BB treatment. Animals from the MCT group showed elevated lipid peroxidation and NADPH oxidase activity, outcomes attenuated in animals treated with BB, which also led to increased catalase activity. CONCLUSION: Treatment with BB partially mitigated PAH, which could be associated with improvement of RV redox state. Such findings constitute an advance in the investigation of the role of BB extract in chronic progressive cardiovascular diseases that involve the redox balance, such as PAH.
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Arándanos Azules (Planta) , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Animales , Modelos Animales de Enfermedad , Ventrículos Cardíacos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Masculino , Oxidación-Reducción , Extractos Vegetales/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND: Risk stratification remains clinically challenging in patients with heart failure (HF) of non-ischemic etiology. Galectin-3 is a serum marker of fibrosis that might help in prognostication. OBJECTIVE: To determine the role of galectin-3 as a predictor of major arrhythmic events and overall mortality. METHODS: We conducted a prospective cohort study that enrolled 148 non-ischemic HF patients. All patients underwent a comprehensive baseline clinical and laboratory assessment, including levels of serum galectin-3. The primary outcome was the occurrence of arrhythmic syncope, appropriate implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, or sudden cardiac death. The secondary outcome was all-cause death. For all statistical tests, a two-tailed p-value<0.05 was considered significant. RESULTS: In a median follow-up of 941 days, the primary and secondary outcomes occurred in 26 (17.5%) and 30 (20%) patients, respectively. Serum galectin-3>22.5 ng/mL (highest quartile) did not predict serious arrhythmic events (HR: 1.98, p=0.152). Independent predictors of the primary outcome were left ventricular end-diastolic diameter (LVEDD)>73mm (HR: 3.70, p=0.001), exercise periodic breathing (EPB) on cardiopulmonary exercise testing (HR: 2.67, p=0.01), and non-sustained ventricular tachycardia (NSVT)>8 beats on Holter monitoring (HR: 3.47, p=0.027). Predictors of all-cause death were galectin-3>22.5 ng/mL (HR: 3.69, p=0.001), LVEDD>73mm (HR: 3.35, p=0.003), EPB (HR: 3.06, p=0.006), and NSVT>8 beats (HR: 3.95, p=0.007). The absence of all risk predictors was associated with a 91.1% negative predictive value for the primary outcome and 96.6% for total mortality. CONCLUSIONS: In non-ischemic HF patients, elevated galectin-3 levels did not predict major arrhythmic events but were associated with total mortality. Absence of risk predictors revealed a prevalent subgroup of HF patients with an excellent prognosis.
FUNDAMENTO: A estratificação de risco continua sendo clinicamente desafiadora em pacientes com insuficiência cardíaca (IC) de etiologia não isquêmica. A galectina-3 é um marcador sérico de fibrose que pode ajudar no prognóstico. OBJETIVO: Determinar o papel da galectina-3 como preditora de eventos arrítmicos graves e mortalidade total. MÉTODOS: Este é um estudo de coorte prospectivo que incluiu 148 pacientes com IC não isquêmica. Todos os pacientes foram submetidos a uma avaliação clínica e laboratorial abrangente para coleta de dados de referência, incluindo níveis de galectina-3 sérica. O desfecho primário foi a ocorrência de síncope arrítmica, intervenções apropriadas do cardioversor desfibrilador implantável, taquicardia ventricular sustentada ou morte súbita cardíaca. O desfecho secundário foi a morte por todas as causas. Para todos os testes estatísticos, considerou-se significativo o valor p<0,05 (bicaudal). RESULTADOS: Em seguimento mediano de 941 dias, os desfechos primário e secundário ocorreram em 26 (17,5%) e 30 (20%) pacientes, respectivamente. A galectina-3 sérica>22,5 ng/mL (quartil mais alto) não foi preditora de eventos arrítmicos graves (HR: 1,98; p=0,152). Os preditores independentes do desfecho primário foram diâmetro diastólico final do ventrículo esquerdo (DDFVE)>73 mm (HR: 3,70; p=0,001), ventilação periódica durante o exercício (VPE) no teste de esforço cardiopulmonar (HR: 2,67; p=0,01) e taquicardia ventricular não sustentada (TVNS)>8 batimentos na monitorização por Holter (HR: 3,47; p=0,027). Os preditores de morte por todas as causas foram: galectina-3>22,5 ng/mL (HR: 3,69; p=0,001), DDFVE>73 mm (HR: 3,35; p=0,003), VPE (HR: 3,06; p=0,006) e TVNS>8 batimentos (HR: 3,95; p=0,007). A ausência de todos os preditores de risco foi associada a um valor preditivo negativo de 91,1% para o desfecho primário e 96,6% para a mortalidade total. CONCLUSÕES: Em pacientes com IC não isquêmica, níveis elevados de galectina-3 não foram preditores de eventos arrítmicos graves, mas foram associados à mortalidade total. A ausência de preditores de risco revelou um subgrupo prevalente de pacientes com IC com excelente prognóstico.
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Desfibriladores Implantables , Galectina 3/sangre , Insuficiencia Cardíaca , Muerte Súbita Cardíaca , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
Resumo Fundamento: A estratificação de risco continua sendo clinicamente desafiadora em pacientes com insuficiência cardíaca (IC) de etiologia não isquêmica. A galectina-3 é um marcador sérico de fibrose que pode ajudar no prognóstico. Objetivo: Determinar o papel da galectina-3 como preditora de eventos arrítmicos graves e mortalidade total. Métodos: Este é um estudo de coorte prospectivo que incluiu 148 pacientes com IC não isquêmica. Todos os pacientes foram submetidos a uma avaliação clínica e laboratorial abrangente para coleta de dados de referência, incluindo níveis de galectina-3 sérica. O desfecho primário foi a ocorrência de síncope arrítmica, intervenções apropriadas do cardioversor desfibrilador implantável, taquicardia ventricular sustentada ou morte súbita cardíaca. O desfecho secundário foi a morte por todas as causas. Para todos os testes estatísticos, considerou-se significativo o valor p<0,05 (bicaudal). Resultados: Em seguimento mediano de 941 dias, os desfechos primário e secundário ocorreram em 26 (17,5%) e 30 (20%) pacientes, respectivamente. A galectina-3 sérica>22,5 ng/mL (quartil mais alto) não foi preditora de eventos arrítmicos graves (HR: 1,98; p=0,152). Os preditores independentes do desfecho primário foram diâmetro diastólico final do ventrículo esquerdo (DDFVE)>73 mm (HR: 3,70; p=0,001), ventilação periódica durante o exercício (VPE) no teste de esforço cardiopulmonar (HR: 2,67; p=0,01) e taquicardia ventricular não sustentada (TVNS)>8 batimentos na monitorização por Holter (HR: 3,47; p=0,027). Os preditores de morte por todas as causas foram: galectina-3>22,5 ng/mL (HR: 3,69; p=0,001), DDFVE>73 mm (HR: 3,35; p=0,003), VPE (HR: 3,06; p=0,006) e TVNS>8 batimentos (HR: 3,95; p=0,007). A ausência de todos os preditores de risco foi associada a um valor preditivo negativo de 91,1% para o desfecho primário e 96,6% para a mortalidade total. Conclusões: Em pacientes com IC não isquêmica, níveis elevados de galectina-3 não foram preditores de eventos arrítmicos graves, mas foram associados à mortalidade total. A ausência de preditores de risco revelou um subgrupo prevalente de pacientes com IC com excelente prognóstico.
Abstract Background: Risk stratification remains clinically challenging in patients with heart failure (HF) of non-ischemic etiology. Galectin-3 is a serum marker of fibrosis that might help in prognostication. Objective: To determine the role of galectin-3 as a predictor of major arrhythmic events and overall mortality. Methods: We conducted a prospective cohort study that enrolled 148 non-ischemic HF patients. All patients underwent a comprehensive baseline clinical and laboratory assessment, including levels of serum galectin-3. The primary outcome was the occurrence of arrhythmic syncope, appropriate implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, or sudden cardiac death. The secondary outcome was all-cause death. For all statistical tests, a two-tailed p-value<0.05 was considered significant. Results: In a median follow-up of 941 days, the primary and secondary outcomes occurred in 26 (17.5%) and 30 (20%) patients, respectively. Serum galectin-3>22.5 ng/mL (highest quartile) did not predict serious arrhythmic events (HR: 1.98, p=0.152). Independent predictors of the primary outcome were left ventricular end-diastolic diameter (LVEDD)>73mm (HR: 3.70, p=0.001), exercise periodic breathing (EPB) on cardiopulmonary exercise testing (HR: 2.67, p=0.01), and non-sustained ventricular tachycardia (NSVT)>8 beats on Holter monitoring (HR: 3.47, p=0.027). Predictors of all-cause death were galectin-3>22.5 ng/mL (HR: 3.69, p=0.001), LVEDD>73mm (HR: 3.35, p=0.003), EPB (HR: 3.06, p=0.006), and NSVT>8 beats (HR: 3.95, p=0.007). The absence of all risk predictors was associated with a 91.1% negative predictive value for the primary outcome and 96.6% for total mortality. Conclusions: In non-ischemic HF patients, elevated galectin-3 levels did not predict major arrhythmic events but were associated with total mortality. Absence of risk predictors revealed a prevalent subgroup of HF patients with an excellent prognosis.
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Humanos , Desfibriladores Implantables , Galectina 3/sangre , Insuficiencia Cardíaca , Pronóstico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Muerte Súbita CardíacaRESUMEN
The tissue response to acute myocardial infarction (AMI) is key to avoiding heart complications due to inflammation, mitochondrial dysfunction, and oxidative stress. Antioxidant and anti-inflammatory agents can minimize the effects of AMI. This study investigated the role of 2-methoxy-isobutyl-isonitrile (MIBI)-associated gold nanoparticles (AuNP) on reperfusion injury after ischemia and its effect on cardiac remodeling in an experimental AMI model. Three-month-old Wistar rats were subjected to a temporary blockade of the anterior descending artery for 30â¯min followed by reperfusion after 24â¯h and 7 days by intraventricularly administering 0.4, 1.3, and 3â¯mg/kg AuNP-MIBI. The cardiac toxicity and renal and hepatic function levels were determined, and the infarct and peri-infarct regions were surgically removed for histopathology, analysis of inflammation from oxidative stress, and echocardiography. MIBI-conjugated AuNP promoted changes in oxidative stress and inflammation depending on the concentrations used, suggesting promising applicability for therapeutic purposes.
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The effects of non-nutritive sweeteners (NNS) on the gut microbiota are an area of increasing research interest due to their potential influence on weight gain, insulin resistance, and inflammation. Studies have shown that mice and rats fed saccharin develop weight gain and metabolic alterations, possibly related to changes in gut microbiota. Here, we hypothesized that chronic exposure to a commercial NNS would change the gut microbiota composition in Wistar rats when compared to sucrose exposure. To test this hypothesis, Wistar rats were fed either NNS- or sucrose-supplemented yogurt for 17 weeks alongside standard chow (ad libitum). The gut microbiome was assessed by 16S rDNA deep sequencing. Assembly and quantification were conducted using the Brazilian Microbiome Project pipeline for Ion Torrent data with modifications. Statistical analyses were performed in the R software environment. We found that chronic feeding of a commercial NNS-sweetened yogurt to Wistar rats, within the recommended dose range, did not significantly modify gut microbiota composition in comparison to sucrose-sweetened yogurt. Our findings do not support the hypothesis that moderate exposure to NNS is associated with changes in gut microbiota pattern compared to sucrose, at least in this experimental model.
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The aim of this study was to evaluate the acute effect of aerobic (AER) and eccentric (ECC) exercise on glucose variability, correlating it with circulating markers of inflammation and oxidative stress in healthy subjects. Sixteen healthy subjects (32 ± 12 years old) wore a continuous glucose monitoring system for three days. Participants randomly performed single AER and ECC exercise sessions. Glucose variability was evaluated by glucose variance (VAR), glucose coefficient of variation (CV%) and glucose standard deviation (SD). Blood samples were collected to evaluate inflammatory and oxidative stress markers. When compared with the pre-exercise period of 0-6 h, all the indices of glucose variability presented comparable reductions 12-18 h after both exercises (∆AER: VAR= 151.5, ∆CV% = 0.55 and ∆SD = 3.1 and ECC: ∆VAR = 221.2 , ∆CV% = 3.7 and ∆SD = 6.5). Increased interleukin-6 (IL-6) levels after AER (68.5%) and ECC (30.8%) (P<0.001) were observed, with no differences between sessions (P = 0.459). Uric acid levels were increased after exercise sessions (3% in AER and 4% in ECC, P = 0.001). In conclusion, both AER and ECC exercise sessions reduced glucose variability in healthy individuals. Inflammatory cytokines, such as IL-6, and stress oxidative markers might play a role in underlying mechanisms modulating the glucose variability responses to exercise (clinicalTrials.gov NCT02262208).
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Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain ß-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis.
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Cardiomegalia/metabolismo , Miocardio/metabolismo , Sistema Renina-Angiotensina/fisiología , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animales , Cardiomegalia/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones Endogámicos BALB C , Miocardio/patología , Fragmentos de Péptidos/metabolismo , Condicionamiento Físico Animal , Receptor de Angiotensina Tipo 1/metabolismo , Natación , Remodelación Ventricular/fisiologíaRESUMEN
INTRODUCTION: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during infection. AGEs and RAGE cause oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate levels of AGEs and its soluble receptor (sRAGE), and to investigate their relationship with food intake and nutritional status, in a university-affiliated hospital in Brazil. METHODS: Case-control study, from June 2017 to June 2018. AGE (carboxymethyl lysine, CML) and sRAGE were measured from blood samples by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. RESULTS: We included in the study 35 tuberculosis (TB) patients and 35 controls. The mean sRAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0 pg/mL; p = 0.046). Among cases that were current smokers, lower sRAGE levels were associated with mortality, evaluated at the end of hospitalization (p = 0.006), and with weight loss (p = 0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases, but there was no correlation between nutritional parameters and CML or sRAGE levels. CONCLUSIONS: TB patients had higher sRAGE levels than controls, although it is not clear that this difference is clinically relevant. Also, sRAGE was associated with weight loss and mortality.
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Antígenos de Neoplasias/sangre , Productos Finales de Glicación Avanzada/sangre , Proteínas Quinasas Activadas por Mitógenos/sangre , Tuberculosis Pulmonar/sangre , Adulto , Brasil/epidemiología , Estudios de Casos y Controles , Ingestión de Alimentos/fisiología , Femenino , Humanos , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Evaluación Nutricional , Estado Nutricional/fisiología , Estrés Oxidativo , Estudios Prospectivos , Tuberculosis Pulmonar/mortalidad , Tuberculosis Pulmonar/fisiopatología , Pérdida de Peso , Adulto JovenRESUMEN
Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.
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Productos Finales de Glicación Avanzada/sangre , Infarto del Miocardio/sangre , Miocardio/metabolismo , Receptor para Productos Finales de Glicación Avanzada/sangre , Animales , Modelos Animales de Enfermedad , Ecocardiografía , Masculino , Infarto del Miocardio/diagnóstico por imagen , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
AIM: To systematically review the literature about the effect of periodontal treatment on oxidative stress (OxS) biomarkers. MATERIAL AND METHODS: Three databases (PubMed, EMBASE, and Scopus) were searched up to February 2018. Clinical trials with a follow-up of at least 6 weeks after mechanical periodontal treatment were included. Due to the high heterogeneity among the units and indices of measurements used in the studies, a meta-analysis was not performed. RESULTS: Overall, 3,199 studies were retrieved, of which 20 were included. Four studies were randomized clinical trials (RCT), and 16 studies were non-RCTs. The most common OxS biomarkers used were 8-hydroxydeoxiguanosine (8-OHdG), total oxidant status (TOS), and total antioxidant status (TAS). After treatment, most of the studies reported a decrease in 8-OHdG concentration in the gingival crevicular fluid (GCF) and saliva. In addition, the salivary concentration of this biomarker was similar to periodontally healthy patients. Periodontal therapy was effective in reducing TOS in GCF, saliva, and serum in most studies. TAS, however, responded inconsistently to the periodontal intervention. CONCLUSION: Periodontal therapy reduces the levels of OxS biomarkers, even to values similar to those found in periodontally healthy individuals. Additional RCTs are warranted, as the information is mainly based on nonrandomized studies.
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Periodontitis Crónica , Biomarcadores , Líquido del Surco Gingival , Humanos , Estrés Oxidativo , Pérdida de la Inserción Periodontal , Índice Periodontal , SalivaRESUMEN
Antioxidant-rich foods may decrease oxidative stress and have a direct impact on atherosclerosis by reducing low-density lipoprotein (LDL) oxidation. Our aim was to assess the impact of a flavonoid-rich diet on oxidative stress, inflammatory response, and lipid profile in patients with coronary artery disease submitted to elective percutaneous coronary intervention (PCI). Thirty-three patients submitted to elective PCI were randomly allocated to follow either a flavonoid rich antioxidant (AOX) diet or a control diet based on National Cholesterol Education Program Adult Treatment Panel III recommendations. Patients were followed for 6 months. Dietary intake was recorded at the start and at the end of the follow-up period, as were oxidative stress markers (ferric reducing ability of plasma and protein sulphydryl) and C-reactive protein (CRP). Patients randomized to follow the AOX diet had a reduction in energy, carbohydrate, and lipid intake, as well as increased flavonoid intake. Compared to the control group, there were no changes in oxidative stress markers or CRP in the patients following the AOX diet, but these patients had a significant decrease in LDL cholesterol levels. In conclusion, the findings of this study suggest that a flavonoid-based antioxidant-rich diet is not associated with reductions in oxidative stress or inflammatory markers 6 months after percutaneous coronary intervention. Nonetheless, patients in the intervention group experienced significant reductions in LDL cholesterol, which may indicate cardiovascular benefits of AOX diets despite of inflammation and oxidative stress markers.
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MicroRNAs are associated with myocardial damage and heart failure (HF). The present study investigated whether the plasma levels of microRNA (miR)21, 126 and 4235p alter according to the (de)compensated state of patients with HF and are associated with allcause mortality. In 48 patients with HF admitted to the emergency room for an episode of acute decompensation, blood samples were collected to measure miR and Btype natriuretic peptide levels within 24 h of hospital admission, at the time of hospital discharge, and a number of weeks postdischarge (chronic stable compensated state). Levels of miR21, miR126 and miR4235p increased between admission and discharge, and decreased following clinical compensation. During followup (up to 48 months), 38 patients (79%) were rehospitalized at least once and 21 patients (44%) succumbed. Patients who had increased levels of miR21 and miR126 at the time of clinical compensation exhibited better 24month survival and remained rehospitalizationfree for a longer period compared with those with low levels. Additionally, patients whose levels of miR4235p increased between admission and clinical compensation experienced fewer hospital readmissions in the 24 months following the time of clinical compensation compared with those who had decreased levels. It was concluded that the plasma levels of miR21, miR126 and miR4235p altered during clinical improvement and were associated with the prognosis of acute decompensated HF.
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Insuficiencia Cardíaca/diagnóstico , MicroARNs/sangre , Enfermedad Aguda , Anciano , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/mortalidad , Hospitalización , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , PronósticoRESUMEN
Diacerein seems to improve metabolic control and reduce inflammatory marker levels in individuals with type 2 diabetes mellitus (Type 2 DM), but for participants with chronic kidney disease (CKD) its effect is unknown. This study aimed to evaluate the effect of diacerein vs. placebo on urinary albumin/creatinine ratio (ACR), glomerular filtration rate (GFR), and inflammatory cytokines in type 2 DM participants with CKD. Blood pressure (BP) and metabolic control were secondary outcomes. This randomized, placebo-controlled, parallel trial of adjuvant treatment of type 2 DM with diacerein enrolled seventy-two participants with CKD, aged 30-80 years, with glycated hemoglobin levels from 53-97 mmol/mol (7.0-11.0%), receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic agents. Participants randomized to diacerein or placebo were followed-up up to 90 days. Both groups had a marked reduction in ACR, but there was no effect on glomerular filtration rate. While the diacerein group had reduced TNF-α levels at the 75th percentile with a borderline significance (P = 0.05), there were no changes in the IL levels at the 75th percentile. Diacerein prevented the increase in blood glucose to the level observed in the placebo group (P = 0.04), improving metabolic control by 74%, reducing 24-hour diastolic BP, nighttime systolic and diastolic BP compared to the placebo group. In conclusion, among patients with type 2 DM and CKD, diacerein does not have an effect on ACR or GFR, but slows metabolic control deterioration and is associated with lower nighttime systolic and diastolic blood pressure. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clinicos; ReBeC) U1111-1156-0255.
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Antraquinonas/farmacología , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Mediadores de Inflamación/metabolismo , Fallo Renal Crónico/metabolismo , Riñón/efectos de los fármacos , Anciano , Femenino , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , PlacebosRESUMEN
BACKGROUND: Interleukin-6 (IL-6) plays a central role in atherosclerosis and inflammation. It may improve risk prediction in patients at intermediate cardiovascular risk. OBJECTIVE: To analyze the impact of serum IL-6 in predicting early angiographic coronary artery disease in patients at intermediate cardiovascular risk with chest pain. METHODS: In a cross-sectional study, patients referred for coronary angiography due to suspected coronary artery disease (CAD) were included. Coronary artery disease was defined as the presence of at least 30% stenosis in one or more coronary artery. Severity of CAD was classified by the anatomic burden score. Performance of serum IL-6 assay was compared with ACC/AHA atherosclerotic cardiovascular disease (ASCVD) risk score and hs-CRP through receiver operating characteristic (ROC) curves. RESULTS: We have included 48 patients with a mean 10-year ASCVD risk of 10.0 ± 6.8%. The prevalence of CAD was 72.9%. The presence of CAD was associated with higher mean levels of IL-6 (p = 0.025). Patients with CAD had significantly more overweight than subjects without CAD. In 27% of patients, IL-6 was >1.0 pg/mL and 100% of these patients had CAD, while only 64% in those with IL-6 <1.0 pg/mL, corresponding to a positive predictive value of 100% (p = 0.015). The area under the receiver operating characteristic (ROC) curve of IL-6, hs-CRP and ASCVD were respectively 0.72, 0.60 and 0.54. Intermediate risk patients with IL-6 >1.0 pg/mL were further reclassified into ASCVD high risk due to the presence of coronary lesions. CONCLUSION: In intermediate risk patients referred for coronary angiography, a serum IL-6 level above 1 pg/mL is predictive of significant CAD. IL-6 determination may be useful to reclassify ASCVD intermediate risk patients into higher risk categories.
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BACKGROUND: The intestinal dysbiosis is common in chronic liver disease and can induce to inflammatory responses and mediate the collagen deposition in the liver. AIM: To evaluate the probiotic Lactobacillus rhamnosus GG (LGG) for the treatment of liver fibrosis in a model of chronic cholestatic liver disease in rats. METHODS: Male adult Wistar rats (n = 29) were submitted to common bile duct ligation (BDL groups) or manipulation of common bile duct without ligation (Ctrl groups).Two weeks after surgery, each group was randomly divided to receive 1 ml of PBS (Ctrl and BDL) or PBS containing 2.5 x 107 CFU of LGG (Ctrl-P and BDL-P) through gavages for 14 days. Euthanasia occurred 33 days after surgery when samples of blood and liver tissue were collected. RESULTS: The hepatic gene expression of Tlr4, Tnfα, IL-6, Tgfß, and metalloproteinase-2 and -9 were higher in the BDL groups in comparison to Ctrl. The ductular reaction evaluated by immunocontent of cytokeratin-7 (CK7) and the content of collagen were increased in BDL groups. Also, there was an imbalance in the antioxidant defenses (superoxide dismutase and catalase) and an increase in the oxidative stress marker sulfhydryl in BDL groups. The treatment with LGG significantly reduced gene expression of IL-6, collagen deposition, and ductular reaction in hepatic tissue of animals from BDL-P groups. CONCLUSION: The treatment with the probiotic LGG was able to reduce liver fibrosis, ductular reaction, and hepatic gene expression of IL-6 in a model of cholestatic liver disease in rats.
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Lacticaseibacillus rhamnosus , Cirrosis Hepática/prevención & control , Hepatopatías/complicaciones , Probióticos/uso terapéutico , Animales , Enfermedad Crónica , Expresión Génica , Hígado/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Hepatopatías/genética , Hepatopatías/patología , Masculino , Ratas , Ratas WistarRESUMEN
PURPOSE: Risk stratification of serious arrhythmic events in patients with nonischemic heart failure (HF), beyond estimates of left ventricular ejection fraction (LVEF), remains an important clinical challenge. This study aims to determine the clinical value of different noninvasive and invasive tests as predictors of serious arrhythmic events in patients with nonischemic HF. METHODS: A prospective observational study was conducted including 106 nonischemic HF patients who underwent a comprehensive clinical and laboratory evaluation including two-dimensional echocardiography, 24-h Holter monitoring, cardiopulmonary exercise testing (CPX), and an invasive electrophysiological study. The study's primary end-point was either syncope, appropriate therapy by implantable cardioverter-defibrillators, or sudden cardiac death. RESULTS: During a mean follow-up of 704 ± 320 days, the primary end-point occurred in 15 patients (14.2%). In multivariable analysis, LV end-diastolic diameter >73 mm (hazard ratio [HR] 3.7; p = 0.016), exercise periodic breathing (EPB) on CPX (HR 2.88; p = 0.045), and non-sustained ventricular tachycardia (NSVT) ≥10 beats (HR 8.2; p < 0.01) remained independently associated with serious arrhythmic events. The positive predictive value of the presence of two of these predictors ranged from 44 to 100%. The absence of all three factors (n = 65, 61% of the sample) identified a subset of patients with low risk of future arrhythmic events, with a negative predictive value of 96.9%. CONCLUSIONS: In this cohort study of nonischemic HF patients, LV dimension, EPB, and NSVT ≥10 beats were independent predictors of serious arrhythmic events. The presence or absence of these characteristics identified sub-groups of high and low risk of serious arrhythmic events, respectively.