RESUMO
Global population aging is a major challenge to health and socioeconomic policies. The prevalence of diseases progressively increases with aging, with cardiovascular disease being the major cause of mortality among elderly people. The allostatic overload imposed by the accumulation of cardiac senescent cells has been suggested to play a pivotal role in the aging-related deterioration of cardiovascular function. Senescent cells exhibit intrinsic disorders and release a senescence-associated secretory phenotype (SASP). Most of these SASP compounds and damaged molecules are released from senescent cells by extracellular vesicles (EVs). Once secreted, these EVs can be readily incorporated by recipient neighboring cells and elicit cellular damage or otherwise can promote extracellular matrix remodeling. This has been associated with the development of cardiac dysfunction, fibrosis, and vascular calcification, among others. The molecular signature of these EVs is highly variable and might provide important information for the development of aging-related biomarkers. Conversely, EVs released by the stem and progenitor cells can exert a rejuvenating effect, raising the possibility of future anti-aging therapies.
Assuntos
Alostase , Vesículas Extracelulares , Coração , Transporte BiológicoRESUMO
Anthracyclines are chemotherapeutic drugs widely used in the frontline of cancer treatment. The therapeutic mechanisms involve the stabilization of topoisomerase IIα, DNA, and the anthracycline molecule in a ternary complex that is recognized as DNA damage. Redox imbalance is another vital source of oxidative DNA damage. Together, these mechanisms lead to cytotoxic effects in neoplastic cells. However, anthracycline treatment can elicit cardiotoxicity and heart failure despite the therapeutic benefits. Topoisomerase IIß and oxidative damage in cardiac cells have been the most reported pathophysiological mechanisms. Alternatively, cardiac cells can undergo stress-induced senescence when exposed to anthracyclines, a state primarily characterized by cell cycle arrest, organelle dysfunction, and a shift to senescence-associated secretory phenotype (SASP). The SASP can propagate senescence to neighboring cells in an ongoing process that leads to the accumulation of senescent cells, promoting cellular dysfunction and extracellular matrix remodeling. Therefore, the accumulation of senescent cardiac cells is an emerging pathophysiological mechanism associated with anthracycline-induced cardiotoxicity. This paradigm also raises the potential for therapeutic approaches to clear senescent cells in treating anthracycline-induced cardiotoxicity (i,e, senolytic therapies).
Assuntos
Antraciclinas , Cardiotoxicidade , Humanos , Antraciclinas/farmacologia , Senoterapia , Antibióticos Antineoplásicos , Senescência CelularRESUMO
PURPOSE: In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated. METHODS: PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and ß myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed. RESULTS: Pulmonary artery rings of the PAH group showed a lower vasodilatation response to acetylcholine, suggesting endothelial dysfunction. Compound X promoted strong vasodilation in pulmonary artery rings of both control and MCT-induced PAH rats. The untreated hypertensive rats presented remodelling of pulmonary arterioles associated with increased resistance to pulmonary flow; increased systolic pressure, hypertrophy and fibrosis of the RV; prolongation of the QT and Tpeak-Tend intervals (evaluated during electrocardiogram); increased lung and liver weights; and autonomic imbalance with predominance of sympathetic activity. On the other hand, treatment with compound X reduced pulmonary vascular remodelling, pulmonary flow resistance and RV hypertrophy and afterload. CONCLUSION: The use of a selective and potent opener to activate the BKCa channels promoted improvement of haemodynamic parameters and consequent prevention of RV maladaptive remodelling in rats with MCT-induced PAH.
Assuntos
Agonistas dos Canais de Cálcio , Canais de Potássio Ativados por Cálcio de Condutância Alta , Hipertensão Arterial Pulmonar , Quinolinas/farmacologia , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Agonistas dos Canais de Cálcio/metabolismo , Agonistas dos Canais de Cálcio/farmacocinética , Modelos Animais de Doenças , Canais de Potássio Ativados por Cálcio de Condutância Alta/agonistas , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Ratos , Ratos Wistar , Resultado do Tratamento , Remodelação Vascular/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacosRESUMO
Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.
Assuntos
Canal de Potássio ERG1/genética , Células-Tronco Pluripotentes Induzidas/fisiologia , Síndrome do QT Longo/genética , Mutação/genética , Miócitos Cardíacos/fisiologia , Transporte Proteico/genética , Potenciais de Ação/genética , Adolescente , Adulto , Membrana Celular/genética , Feminino , Edição de Genes/métodos , Humanos , Leucócitos Mononucleares/fisiologia , Masculino , Fenótipo , Adulto JovemRESUMO
Background: The failure to translate preclinical results to the clinical setting is the rule, not the exception. One reason that is frequently overlooked is whether the animal model reproduces distinctive features of human disease. Another is the reproducibility of the method used to measure treatment effects in preclinical studies. Left ventricular (LV) function improvement is the most common endpoint in preclinical cardiovascular disease studies, while echocardiography is the most frequently used method to evaluate LV function. In this work, we conducted a robust echocardiographic evaluation of LV size and function in dogs chronically infected by Trypanosoma cruzi. Methods and Results: Echocardiography was performed blindly by two distinct observers in mongrel dogs before and between 6 and 9 months post infection. Parameters analyzed included end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and fractional shortening (FS). We observed a significant LVEF and FS reduction in infected animals compared to controls, with no significant variation in volumes. However, the effect of chronic infection in systolic function was quite variable, with EF ranging from 17 to 66%. Using the cut-off value of EF ≤ 40%, established for dilated cardiomyopathy (DCM) in dogs, only 28% of the infected dogs were affected by the chronic infection. Conclusions: The canine model of CCC mimics human disease, reproducing the percentage of individuals that develop heart failure during the chronic infection. It is thus mandatory to establish inclusion criteria in the experimental design of canine preclinical studies to account for the variable effect that chronic infection has on systolic function.
Assuntos
Cardiomiopatia Chagásica/diagnóstico por imagem , Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Cães , Reprodutibilidade dos Testes , Função VentricularRESUMO
BACKGROUND: Transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS) have been described as promising alternatives to treat different pain syndromes. This study evaluated the effects of TMS and tDCS in the treatment of chronic orofacial pain, through a systematic review. METHODS: An electronic search was performed in major databases: MEDLINE, Scopus, Web of Science, Cochrane, Embase, LILACS, BBO, Open Gray and CINAHL. The eligibility criteria comprised randomized clinical trials (RCTs) that applied TMS or tDCS to treat chronic orofacial pain. The variables analyzed were pain, functional limitation, quality of life, tolerance to treatment, somatosensory changes, and adverse effects. The risk of bias was assessed through the Cochrane Collaboration tool, and the certainty of evidence was evaluated through GRADE. The protocol was registered in the PROSPERO database (CRD42018090774). RESULTS: The electronic search resulted in 636 studies. Thereafter, the eligibility criteria were applied and the duplicates removed, resulting in eight RCTs (four TMS and four tDCS). The findings of these studies suggest that rTMS applied to the Motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC) and the secondary somatosensory cortex (S2) provide adequate orofacial pain relief. Two studies reported significant pain improvement with tDCS applied over M1 while the other two failed to demonstrate significant effects compared to placebo. CONCLUSIONS: rTMS, applied to M1, DLPFC or S2, is a promising approach for the treatment of chronic orofacial pain. Moreover, tDCS targeting M1 seems to be also effective in chronic orofacial pain treatment. The included studies used a wide variety of therapeutic protocols. In addition, most of them used small sample sizes, with a high risk of biases in their methodologies, thus producing a low quality of evidence. The results indicate that further research should be carried out with caution and with better-standardized therapeutic protocols.
Assuntos
Dor Crônica/terapia , Dor Facial/terapia , Manejo da Dor , Qualidade de Vida , Estimulação Transcraniana por Corrente Contínua , Estimulação Magnética Transcraniana , Dor Crônica/patologia , Dor Crônica/fisiopatologia , Dor Facial/patologia , Dor Facial/fisiopatologia , HumanosRESUMO
S17 is a clonogenic bone marrow stromal (BMS) cell line derived from mouse that has been extensively used to assess both human and murine hematopoiesis support capacity. However, very little is known about the expression of potassium ion channels and their function in cell survival and migration in these cells. Thus, the present study was designed to characterize potassium ion channels using electrophysiological and molecular biological approaches in S17 BMS cells. The whole-cell configuration of the patch clamp technique has been applied to identify potassium ion currents and reverse transcription polymerase chain reaction (RT-PCR) used to determine their molecular identities. Based on gating kinetics and pharmacological modulation of the macroscopic currents we found the presence of four functional potassium ion channels in S17 BMS cells. These include a current rapidly activated and inactivated, tetraethylammonium-sensitive, (IKV ) in most (50%) cells; a fast activated and rapidly inactivating A-type K + current (IK A -like); a delayed rectifier K + current (IK DR ) and an inward rectifier potassium current (IK IR ), found in, respectively 4.5%, 26% and 24% of these cells. RT-PCR confirmed the presence of mRNA transcripts for the alpha subunit of the corresponding functional ion channels. Additionally, functional assays were performed to investigate the importance of potassium currents in cell survival and migration. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses revealed a reduction in cell viability, while wound healing assays revealed reduced migration potential in cells incubated with different potassium channel blockers. In conclusion, our data suggested that potassium currents might play a role in the maintenance of overall S17 cell ionic homeostasis directly affecting cell survival and migration.
Assuntos
Movimento Celular , Células-Tronco Mesenquimais/metabolismo , Canais de Potássio/metabolismo , Potássio/metabolismo , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular , Ativação do Canal Iônico , Cinética , Potenciais da Membrana , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/genética , Transdução de SinaisRESUMO
Chronic pain is an important public health issue. Moreover, its adequate management is still considered a major clinical problem, mainly due to its incredible complexity and still poorly understood pathophysiology. Recent scientific evidence coming from neuroimaging research, particularly functional magnetic resonance (fMRI) and positron emission tomography (PET) studies, indicates that chronic pain is associated with structural and functional changes in several brain structures that integrate antinociceptive pathways and endogenous modulatory systems. Furthermore, the last two decades have witnessed a huge increase in the number of studies evaluating the clinical effects of noninvasive neuromodulatory methods, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), which have been proved to effectively modulate the cortical excitability, resulting in satisfactory analgesic effects with minimal adverse events. Nevertheless, the precise neuromechanisms whereby such methods provide pain control are still largely unexplored. Recent studies have brought valuable information regarding the recruitment of different modulatory systems and related neurotransmitters, including glutamate, dopamine, and endogenous opioids. However, the specific neurocircuits involved in the analgesia produced by those therapies have not been fully elucidated. This review focuses on the current literature correlating the clinical effects of noninvasive methods of brain stimulation to the changes in the activity of endogenous modulatory systems.
Assuntos
Dor Crônica/diagnóstico por imagem , Dor Crônica/terapia , Tomografia por Emissão de Pósitrons , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Magnética Transcraniana/métodos , Analgésicos Opioides/metabolismo , Dopamina/metabolismo , HumanosRESUMO
ABSTRACT: The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy.
Assuntos
Espironolactona , Clonidina , Tratamento Farmacológico , HipertensãoRESUMO
BACKGROUND: Left ventricular ejection fraction (LVEF) is a major determinant of long-term prognosis after ST-segment elevation myocardial infarction (STEMI). STEMI patients with reduced LVEF have a poor prognosis, despite successful reperfusion and the use of renin-angiotensin-aldosterone inhibitors. HYPOTHESIS: Intracoronary infusion of bone marrow-derived mononuclear cells (BMMC) may improve LVEF in STEMI patients successfully reperfused. METHODS: The main inclusion criteria for this double-blind, randomized, multicenter study were patient age 30 to 80 years, LVEF ≤50%, successful angioplasty of infarct-related artery, and regional dysfunction in the infarct-related area analyzed before cell injection. Cardiac magnetic resonance imaging was used to assess LVEF, left ventricular volumes, and infarct size at 7 to 9 days and 6 months post-myocardial infarction. RESULTS: One hundred and twenty-one patients were included (66 patients in the BMMC group and 55 patients in the placebo group). The primary endpoint, mean LVEF, was similar between both groups at baseline (44.63% ± 10.74% vs 42.23% ± 10.33%; P = 0.21) and at 6 months (44.74% ± 12.95 % vs 43.50 ± 12.43%; P = 0.59). The groups were also similar regarding the difference between baseline and 6 months (0.11% ± 8.5% vs 1.27% ± 8.93%; P = 0.46). Other parameters of left ventricular remodeling, such as systolic and diastolic volumes, as well as infarct size, were also similar between groups. CONCLUSIONS: In this randomized, multicenter, double-blind trial, BMMC intracoronary infusion did not improve left ventricular remodeling or decrease infarct size.
Assuntos
Ventrículos do Coração/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Transplante de Células-Tronco/métodos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologiaRESUMO
Importance: The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective: To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants: We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions: Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures: The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results: The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance: In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration: clinicaltrials.gov Identifier: NCT02298088.
Assuntos
Clopidogrel/uso terapêutico , Fibrinolíticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Ticagrelor/uso terapêutico , Idoso , Clopidogrel/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Ticagrelor/efeitos adversosRESUMO
Heart failure (HF) is associated with morbidity and mortality. Real-time three-dimensional echocardiography (RT3DE) may offer additional prognostic data in patients with HF. The study aimed to evaluate the prognostic value of real-time three-dimensional echocardiography (RT3DE). This is a prospective study that included 89 patients with HF and left ventricular ejection fraction (LVEF) < 0.50 who were followed for 48 months. Left atrium and ventricular volumes and functions were evaluated by RT3DE. TDI and two-dimensional echocardiography parameters were also obtained. The endpoint was a composite of death, heart transplantation and hospitalization for acute decompensated HF. The mean age was 55 ± 11 years, and the LVEF was 0.32 ± 0.10. The composite endpoint occurred in 49 patients (18 deaths, 30 hospitalizations, one heart transplant). Patients with outcomes had greater left atrial volume (40 ± 16 vs. 32 ± 12 mL/m2; p < 0.01) and right ventricle diameter (41 ± 9 vs. 37 ± 8 mm, p = 0.01), worse total emptying fraction of the left atrium (36 ± 13% vs. 41 ± 11%; p = 0.03), LVEF (0.30 ± 0.09 vs. 0.34 ± 0.11; p = 0.02), right ventricle fractional area change (34.8 ± 12.1% vs. 39.2 ± 11.3%; p = 0.04), and greater E/e' ratio (19 ± 9 vs. 16 ± 8; p = 0.04) and systolic pulmonary artery pressure (SPAP) (50 ± 15 vs. 36 ± 11 mmHg; p < 0.01). In multivariate analysis, LVEF (OR 4.6; CI 95% 1.2-17.6; p < 0.01) and SPAP (OR 12.5; CI 95% 1.8-86.9; p < 0.01) were independent predictors of patient outcomes. LVEF and the SPAP were independent predictors of outcomes in patients with HF.
Assuntos
Ecocardiografia Doppler em Cores , Ecocardiografia Tridimensional , Insuficiência Cardíaca Sistólica/diagnóstico por imagem , Hemodinâmica , Adulto , Idoso , Área Sob a Curva , Intervalo Livre de Doença , Feminino , Insuficiência Cardíaca Sistólica/mortalidade , Insuficiência Cardíaca Sistólica/fisiopatologia , Insuficiência Cardíaca Sistólica/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Variações Dependentes do Observador , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
BACKGROUND: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. DISCUSSION: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014.
Assuntos
Anti-Inflamatórios/administração & dosagem , Linfócitos B/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Mediadores da Inflamação/sangue , Inibidores da Agregação Plaquetária/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Terapia Trombolítica , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Anti-Inflamatórios/efeitos adversos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores/sangue , Brasil , Protocolos Clínicos , Clopidogrel , Angiografia Coronária , Quimioterapia Combinada , ELISPOT , Ezetimiba/administração & dosagem , Feminino , Citometria de Fluxo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Metabolômica , Inibidores da Agregação Plaquetária/efeitos adversos , Proteômica , Projetos de Pesquisa , Rosuvastatina Cálcica/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Sinvastatina/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Terapia Trombolítica/efeitos adversos , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
During the course of Chagas disease, infectious forms of Trypanosoma cruzi are occasionally liberated from parasitized heart cells. Studies performed with tissue culture trypomastigotes (TCTs, Dm28c strain) demonstrated that these parasites evoke neutrophil/CXCR2-dependent microvascular leakage by activating innate sentinel cells via toll-like receptor 2 (TLR2). Upon plasma extravasation, proteolytically derived kinins and C5a stimulate immunoprotective Th1 responses via cross-talk between bradykinin B2 receptors (B2Rs) and C5aR. Awareness that TCTs invade cardiovascular cells in vitro via interdependent activation of B2R and endothelin receptors [endothelin A receptor (ETAR)/endothelin B receptor (ETBR)] led us to hypothesize that T. cruzi might reciprocally benefit from the formation of infection-associated edema via activation of kallikrein-kinin system (KKS). Using intravital microscopy, here we first examined the functional interplay between mast cells (MCs) and the KKS by topically exposing the hamster cheek pouch (HCP) tissues to dextran sulfate (DXS), a potent "contact" activator of the KKS. Surprisingly, although DXS was inert for at least 30 min, a subtle MC-driven leakage resulted in factor XII (FXII)-dependent activation of the KKS, which then amplified inflammation via generation of bradykinin (BK). Guided by this mechanistic insight, we next exposed TCTs to "leaky" HCP-forged by low dose histamine application-and found that the proinflammatory phenotype of TCTs was boosted by BK generated via the MC/KKS pathway. Measurements of footpad edema in MC-deficient mice linked TCT-evoked inflammation to MC degranulation (upstream) and FXII-mediated generation of BK (downstream). We then inoculated TCTs intracardiacally in mice and found a striking decrease of parasite DNA (quantitative polymerase chain reaction; 3 d.p.i.) in the heart of MC-deficient mutant mice. Moreover, the intracardiac parasite load was significantly reduced in WT mice pretreated with (i) cromoglycate (MC stabilizer) (ii) infestin-4, a specific inhibitor of FXIIa (iii) HOE-140 (specific antagonist of B2R), and (iv) bosentan, a non-selective antagonist of ETAR/ETBR. Notably, histopathology of heart tissues from mice pretreated with these G protein-coupled receptors blockers revealed that myocarditis and heart fibrosis (30 d.p.i.) was markedly and redundantly attenuated. Collectively, our study suggests that inflammatory edema propagated via activation of the MC/KKS pathway fuels intracardiac parasitism by generating infection-stimulatory peptides (BK and endothelins) in the edematous heart tissues.
RESUMO
BACKGROUND: The purpose of this study was to evaluate respiratory muscle strength and endurance in the inpatient period in patients who recently experienced myocardial infarction (MI) and investigate the effects of a home-based walking program on respiratory strength and endurance in low-risk patients after MI. METHODS: Patients were randomized into a usual-care group (UCG) entailing regular care (n = 23) and an intervention group (IG) entailing an outpatient home-based walking program (n = 31). Healthy sex- and age-matched participants served as a control group for respiratory endurance variables. Respiratory muscle strength was evaluated through maximal inspiratory pressure (MIP) and endurance during the inpatient period, at 15 days, and at 60 days after MI. Submaximal functional capacity was determined by a 6-minute walk test (6MWT) at hospital discharge and 60 days after MI. RESULTS: Both groups showed impaired inspiratory muscle strength at hospital discharge. When compared with healthy individuals, after MI, patients had worse respiratory muscle endurance pressure (PTHmax = 73.02 ± 8.40 vs 44.47 ± 16.32; P < 0.05) and time (Tlim = 324.1 ± 12.2 vs 58.7 ± 93.3; P < 0.05). Only the IG showed a significant improvement in MIP and PTHmax at 15 days and 60 days after MI (P < 0.05). When comparing groups, the IG achieved higher values for MIP, PTHmax, and Tlim 15 and 60 days after MI (P < 0.01). The 60-day assessment revealed that the 6MWT distance and level of physical activity was significantly higher in the IG compared with the UCG. CONCLUSIONS: Low-risk patients recently experiencing MI demonstrate impaired MIP and respiratory endurance compared with healthy participants. A home-based walking program improved respiratory endurance and functional capacity.
Assuntos
Terapia por Exercício/métodos , Exercício Físico/fisiologia , Infarto do Miocárdio/reabilitação , Resistência Física/fisiologia , Caminhada/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Infarto do Miocárdio/fisiopatologia , Músculos Respiratórios/fisiopatologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Cardiac arrhythmias are one of the main causes of death in ChCP and other dilated cardiomyopathies. Previous studies demonstrated that ventricular arrhythmias are associated with the presence of autoantibodies with beta-adrenergic activity, Ab-ß. OBJECTIVES: The aim of this study was to investigate whether Ab-ß, present in chronic chagasic patients (ChCP), induce cardiac arrhythmias in the pharmacological type-2 long QT syndrome model (LQTS-2). METHODS/RESULTS: The LQTS2 was established by perfusion of Tyrode saline solution with a potassium channel blocker E-4031 (5µM) in isolated rabbit hearts or in rabbit cardiac strips, in order to record ECG or action potential, respectively. Autoantibodies from ChCP activating (Ab-ß) or not (Ab-NR) cardiac beta 1-adrenergic receptors were used. Ab-ß, but not Ab-NR, were able to significantly shorten QT, QTc and increase Tpeak-Tend interval in the LQTS-2. A positive correlation between higher QTc and Tpeak-Tend was found after Ab-ß perfusion in the same model. In addition, in the LQTS-2 model, in almost 75% (11/15) of the hearts perfused with Ab-ß, ventricular and atrio-ventricular electrical disturbances were observed. Atenolol abolished all Ab-ß-induced arrhythmias. Ab-ß, when perfused in a cellular LQTS-2, drastically reduced the action potential duration and evoked early afterdepolarization (EAD's), while Ab-NR did not modulate the AP properties in the LQTS-2. CONCLUSION: The results indicate that Ab-ß were able to induce cardiac arrhythmias and EAD's. This phenomenon can explain, at least in part, the cellular mechanism of Ab-ß-induced arrhythmias. Furthermore, atenolol is effective for the treatment of Ab-ß-induced arrhythmias.
Assuntos
Arritmias Cardíacas/sangue , Arritmias Cardíacas/fisiopatologia , Autoanticorpos/sangue , Cardiomiopatia Chagásica/sangue , Síndrome do QT Longo/fisiopatologia , Receptores Adrenérgicos beta 1/sangue , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Arritmias Cardíacas/etiologia , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Síndrome do QT Longo/induzido quimicamente , Estudos Longitudinais , Masculino , Coelhos , Estudos RetrospectivosRESUMO
BACKGROUND: Eisenmenger syndrome (ES) precipitates the extreme manifestation of pulmonary hypertension, which leads to severe functional limitation and poor quality of life. The propose of the current study was: 1) examined the acute effects of 40% oxygen supplementation during the 6-minute walk test (6MWT); and 2) evaluate the relation between exercise capacity and clinical cardiac parameters in patients with ES. METHODS: Thirty subjects were prospectively included; all were submitted to a 6MWT with compressed air and with 40% of oxygen. Heart rate recovery at the first minute (HRR1) and perceived effort Borg scale for dyspnea and lower limb fatigue were recorded in both tests scenarios. RESULTS: The 6MWT distance was modestly, negatively associated with pulmonary vascular resistance (PVR) [r=0.46, p=0.02]. Patients improved 6MWT distance (p<0.001) and exhibited a faster HRR1 (p<0.001) with 40% supplemental oxygen compared to compressed air. With 40% supplemental oxygen, subjects revealed lower dyspnea and lower limb fatigue compared to 6MWT without oxygen supplementation (p<0.001). The amount of change in the 6MWT distance from air to oxygen was moderate, positively associated with tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) [r=0.50, p=0.03; r=0.64, p<0.001, respectively]. CONCLUSION: Acute 40% oxygen supplementation in patients with Eisenmenger syndrome led to an improvement in 6MWT distance, faster HRR1 and lower dyspnea and lower limb fatigue perception. Moreover, functional capacity was positively associated with right ventricular parameters.
Assuntos
Complexo de Eisenmenger/terapia , Tolerância ao Exercício/fisiologia , Frequência Cardíaca/fisiologia , Oxigenoterapia/métodos , Recuperação de Função Fisiológica/fisiologia , Resistência Vascular/fisiologia , Função Ventricular Direita/fisiologia , Adulto , Ecocardiografia , Complexo de Eisenmenger/fisiopatologia , Teste de Esforço , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months...
Assuntos
Espectroscopia de Ressonância Magnética , Infarto do Miocárdio , Linfócitos B , Metabolômica , ProteômicaRESUMO
Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively.
RESUMO
BACKGROUND: Marfan syndrome patients present important cardiac structural changes, ventricular dysfunction, and electrocardiographic changes. An abnormal heart rate response during or after exercise is an independent predictor of mortality and autonomic dysfunction. The aim of the present study was to compare heart rate recovery and chronotropic response obtained by cardiac reserve in patients with Marfan syndrome subjected to submaximal exercise. METHODS: A total of 12 patients on ß-blocker therapy and 13 off ß-blocker therapy were compared with 12 healthy controls. They were subjected to submaximal exercise with lactate measurements. The heart rate recovery was obtained in the first minute of recovery and corrected for cardiac reserve and peak lactate concentration. RESULTS: Peak heart rate (141±16 versus 155±17 versus 174±8 bpm; p=0.001), heart rate reserve (58.7±9.4 versus 67.6±14.3 versus 82.6±4.8 bpm; p=0.001), heart rate recovery (22±6 versus 22±8 versus 34±9 bpm; p=0.001), and heart rate recovery/lactate (3±1 versus 3±1 versus 5±1 bpm/mmol/L; p=0.003) were different between Marfan groups and controls, respectively. All the patients with Marfan syndrome had heart rate recovery values below the mean observed in the control group. The absolute values of heart rate recovery were strongly correlated with the heart rate reserve (r=0.76; p=0.001). CONCLUSION: Marfan syndrome patients have reduced heart rate recovery and chronotropic deficit after submaximal exercise, and the chronotropic deficit is a strong determinant of heart rate recovery. These changes are suggestive of autonomic dysfunction.