Abnormal neurovascular control during central and peripheral chemoreceptors stimulation in heart failure patients with preserved ejection fraction.

PURPOSE: Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. METHODS: Patients aged 55-80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e' index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. RESULTS: During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. CONCLUSIONS: Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.

Pontos Fortes e Fracos do Exame PET/CT com 18FDG na Avaliação do tratamento Neoadjuvante do Câncer de Esôfago Distal: Discussão de Casos / Strengths and Weaknesses of 18FDG PET/CT in Distal Esophageal Cancer Neoadjuvant Treatment Evaluation: Case Discussion

O Instituto Nacional de Câncer (INCA) reafirma o seu propósito em fortalecer a vigilância do câncer no Brasil, tendo estimado para cada ano trienal, aumento progressivo do número de casos novos para o câncer de esôfago do triênio. Desta maneira, um protocolo de pesquisa, denominado "Quimera", foi direcionado para investigar os benefícios adicionais do tratamento neoadjuvante para os pacientes com câncer de esôfago distal potencialmente ressecável, matriculados nesta instituição. O regime da neoadjuvância no protocolo "Quimera" consistiu inicialmente de dois ciclos de quimioterapia de indução com carboplatina e paclitaxel, seguindo com este mesmo esquema quimioterápico e radioterapia concomitante. A tomografia por emissão de pósitrons integrada à TC de baixa dose (PET/CT) com fluordesoxiglicose marcada com flúor-18 ( 18FDG) desempenhou um papel crucial na triagem dos pacientes com os critérios de inclusão estabelecidos no protocolo "Quimera". O presente trabalho, avalia a resposta metabólica do tumor, baseada no processamento sequencial das imagens durante as etapas do regime neoadjuvante instituído (pré-operatório). Neste contexto, selecionamos dois pacientes do protocolo "Quimera", diagnosticados com carcinoma de células escamosas (CEC) e adenocarcinoma (AdenoCA) moderadamente diferenciados, localizados no esôfago distal, respectivamente. Estes tipos histopatológicos mais prevalentes apresentam hipermetabolismo glicolítico correlacionado à alta taxa de proliferação celular e agressividade. O ponto forte do exame PET/CT com 18FDG demonstrou ser uma ferramenta suplementar, não somente para a exclusão de metástases à distância, como também, para o monitoramento ao longo das etapas da neoadjuvância, e, para a seleção dos pacientes respondedores e não-respondedores metabólicos para a cirurgia curativa, notadamente no diagnóstico de CEC. O ponto fraco a destacar refere-se ao estadiamento nodal (N), pois a avaliação, baseada em PET/CT 18FDG, dos linfonodos regionais para a ressecção em bloco, é dependente da distância entre as cadeias nodais regionais com hipercaptação do radiotraçador e os órgãos situados na vizinhança do longo trato gastroesofágico, como o coração e o estômago, com distribuição glicolítica metabólica fisiológica

The Brazillian National Cancer Institute (INCA) reaffirms its purpose of strengthening cancer surveillance in Brazil, having estimated progressive increase in the number of new cases of esophageal cancer for each triennial year. In this way, a research protocol, called "Quimera", aimed to investigate the additional benefits of preoperative chemoradiotherapy (neoadjuvant treatment) for patients with esophageal cancer considered for curative resection surgery, enrolled in this institution. The neoadjuvant therapy regimen of the "Chimera" protocol initially consisted of induction chemotherapy with carboplatin and paclitaxel, followed by the same chemotherapy scheme and concomitant radiotherapy. The low-dose CT-integrated positron emission tomography (PET/CT) with fluoride-18-labeled fluordeoxyglucose (18FDG) played a major role in screening patients with inclusion criteria for the "Chimera" protocol. The present study evaluates the neoplastic metabolic response based in sequential 18FDG PET/CT imaging during early induction and continued chemoradiotherapy. In this context, we selected two patients included in the "Chimera" protocol, diagnosed with moderately differentiated squamous cell carcinoma (SCC) and adenocarcinoma (AdenoCA) located in the distal esophagus, respectively. These most prevalent histopathological types presented glycolytic hypermetabolism correlated with high cell proliferation and aggressiveness. The strengths of the 18FDG PET/CT scan proved to be not only a supplementary tool for the exclusion of patients with distant metastases, but also, for monitoring throughout the stages of neoadjuvant regimen for the selection of metabolic responders and non-responders, particularly in the case report diagnosed with SCC. The weakness refers to the lymph node staging. The assessment of the regional lymph nodes stations for en bloc resection, based on 18FDG PET/CT, is dependent on the distance between these regional hypermetabolic lymph nodes and the neighboring gastroesophageal organs, as the heart and the stomach, with physiological hypermetabolism distribution

Oscillatory Pattern of Sympathetic Nerve Bursts Is Associated With Baroreflex Function in Heart Failure Patients With Reduced Ejection Fraction.

Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LFMSNA/HFMSNA) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LFMSNA/HFMSNA index: (1) Lower LFMSNA/HFMSNA (lower terciles, n = 46, aged 53 ± 1 y) and (2) Higher LFMSNA/HFMSNA (upper terciles, n = 47, aged 52 ± 2 y). Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LFMSNA/HFMSNA, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LFMSNA/HFMSNA had reduced left ventricular ejection fraction (26 ± 1 vs. 29 ± 1%, P = 0.03), gain (0.15 ± 0.03 vs. 0.30 ± 0.04 a.u./mmHg, P < 0.001) and coupling of sympathetic baroreflex function (0.26 ± 0.03 vs. 0.56 ± 0.04%, P < 0.001) and increased muscle sympathetic nerve activity (48 ± 2 vs. 41 ± 2 bursts/min, P < 0.01) and heart rate (71 ± 2 vs. 61 ± 2 bpm, P < 0.001) compared with HFrEF patients with higher LFMSNA/HFMSNA. Further analysis showed an association between the LFMSNA/HFMSNA with coupling of sympathetic baroreflex function (R = 0.56, P < 0.001) and left ventricular ejection fraction (R = 0.23, P = 0.02). In conclusion, there is a direct association between LFMSNA/HFMSNA and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LFMSNA/HFMSNA.

Effects of inspiratory muscle training combined with aerobic exercise training on neurovascular control in chronic heart failure patients.

AIMS: We tested the hypothesis that the effects of combined inspiratory muscle training and aerobic exercise training (IMT + AET) on muscle sympathetic nerve activity (MSNA) and forearm blood flow in patients with heart failure with reduced ejection fraction are more pronounced than the effects of AET alone. METHODS AND RESULTS: Patients aged 30-70 years, New York Heart Association Functional Class II-III, and left ventricular ejection fraction ≤40% were randomly assigned to four groups: IMT (n = 11), AET (n = 12), IMT + AET (n = 9), and non-training (NT; n = 10). MSNA was recorded using microneurography. Forearm blood flow was measured by venous occlusion plethysmography and inspiratory muscle strength by maximal inspiratory pressure. IMT consisted of 30 min sessions, five times a week, for 4 months. Moderate AET consisted of 60 min sessions, three times a week for 4 months. AET (-10 ± 2 bursts/min, P = 0.03) and IMT + AET (-13 ± 4 bursts/min, P = 0.007) reduced MSNA. These responses in MSNA were not different between AET and IMT + AET groups. IMT (0.22 ± 0.08 mL/min/100 mL, P = 0.03), AET (0.27 ± 0.09 mL/min/100 mL, P = 0.01), and IMT + AET (0.35 ± 0.12 mL/min/100 mL, P = 0.008) increased forearm blood flow. No differences were found between groups. AET (3 ± 1 mL/kg/min, P = 0.006) and IMT + AET (4 ± 1 mL/kg/min, P = 0.001) increased peak oxygen consumption. These responses were similar between these groups. IMT (20 ± 3 cmH2 O, P = 0.005) and IMT + AET (18 ± 3 cmH2 O, P = 0.01) increased maximal inspiratory pressure. No significant changes were observed in the NT group. CONCLUSIONS: IMT + AET causes no additive effects on neurovascular control in patients with heart failure with reduced ejection fraction compared with AET alone. These findings may be, in part, because few patients had inspiratory muscle weakness.

Effect of exercise training on cardiovascular autonomic and muscular function in subclinical Chagas cardiomyopathy: a randomized controlled trial.

PURPOSE: Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy. METHODS: This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized www.random.org/lists/ into two groups: those who underwent exercise training (n = 12) and those who continued their usual activities (n = 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4 months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression. RESULTS: The baroreflex sensitivity for increases (p = 0.002) and decreases (p = 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (p = 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (p = 0.008) and sympathetic activity in the heart (LFnu; p = 0.004) and vessels (p = 0.04) after 4 months. Regarding skeletal muscle, after 4 months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (p = 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (r = 0.86; p = 0.02) and MuRF-1 gene expression (r = 0.64; p = 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (r = -0.72; p = 0.020) and decreases (r = -0.82; p = 0.001) in blood pressure. CONCLUSIONS: ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4 months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression. TRIAL REGISTRATION: ID: NCT02295215. Registered in June 2013.

Pre-frailty status increases the risk of rehospitalization in patients after elective cardiac surgery without complication.

BACKGROUND AND AIM: It has been demonstrated that patients with pre-frailty have more adverse outcomes after cardiac surgery; however, data on prognosis and long-term evolution in patients with pre-frailty after elective cardiac surgery without postoperative complications are still scarce. To evaluate the impact of pre-frailty status on functional survival in patients after elective cardiac surgery without surgical complications. METHODS: This was a retrospective study with 141 patients over 65 years old, with an established diagnosis of myocardial infarction or valve disease. Patients were evaluated by Clinical Frailty Scale (CFS) before surgery, according to the hospital protocol, and allocated into two groups: non-frail (CFS, 1-3) and pre-frail (CFS = 4). Patients with adverse cardiovascular events during surgery or at intensive care unit (ICU), mechanical ventilation more than 24 hours, ICU length of stay more than 48 hours, and in-hospital complications were excluded. For all analyses, the statistical significance was set at 5% (P < .05). RESULTS: There were no differences in demographic, anthropometric, surgical procedure, or baseline data on ICU. Pre-frail patients had more adverse events during the 3-year follow-up period with rehospitalization compared to non-frail (39.4% vs 14.3%, respectively). Rehospitalizations in pre-frail patients were in the first year after cardiac surgery (P < .05), and higher cumulative events in pre-frail have occurred with increased odds ratio (OR) (2.828, 95% confidence interval [CI]: 1.298-6.160; P = .001) and hazard ratio (HR) (3.560, 95% CI: 1.508-84.04; P = .004). The OR and HR for stroke or death were similar between groups when analyzed separately. CONCLUSION: Pre-frail patients have more adverse events after elective cardiac surgery without complications when compared to non-frail patients.

Pre-frailty status increases the risk of rehospitalization in patients after elective cardiac surgery without complication

ABSTRACT: background and aim: It has been demonstrated that patients with pre­frailty have more adverse outcomes after cardiac surgery; however, data on prognosis and long­ term evolution in patients with pre­frailty after elective cardiac surgery without postoperative complications are still scarce. To evaluate the impact of pre­frailty status on functional survival in patients after elective cardiac surgery without surgical complications. METHODS: This was a retrospective study with 141 patients over 65 years old, with an established diagnosis of myocardial infarction or valve disease. Patients were evaluated by Clinical Frailty Scale (CFS) before surgery, according to the hospital protocol, and allocated into two groups: non­frail (CFS, 1­3) and pre­frail (CFS = 4). Patients with adverse cardiovascular events during surgery or at intensive care unit (ICU), mechanical ventilation more than 24 hours, ICU length of stay more than 48 hours, and in­hospital complications were excluded. For all analyses, the statistical significance was set at 5% (P < .05). RESULTS: There were no differences in demographic, anthropometric, surgical procedure, or baseline data on ICU. Pre­frail patients had more adverse events during the 3­year follow­up period with rehospitalization compared to non­frail (39.4% vs 14.3%, respectively). Rehospitalizations in pre­frail patients were in the first year after cardiac surgery (P < .05), and higher cumulative events in pre­frail have occurred with increased odds ratio (OR) (2.828, 95% confidence interval [CI]: 1.298­6.160; P = .001) and hazard ratio (HR) (3.560, 95% CI: 1.508­84.04; P = .004). The OR and HR for stroke or death were similar between groups when analyzed separately. CONCLUSION: Pre­frail patients have more adverse events after elective cardiac surgery without complications when compared to non­frail patients.

Safety and Efficacy of Aerobic Exercise Training Associated to Non-Invasive Ventilation in Patients with Acute Heart Failure / Segurança e Eficácia do Treinamento Aeróbio Combinado à Ventilação Não-Invasiva em Pacientes com Insuficiência Cardíaca Aguda

Abstract Background: Exercise training (ET) improves functional capacity in chronic heart failure (HF). However, ET effects in acute HF are unknown. Objective: To investigate the effects of ET alone or combined with noninvasive ventilation (NIV) compared with standard medical treatment during hospitalization in acute HF patients. Methods: Twenty-nine patients (systolic HF) were randomized into three groups: control (Control - only standard medical treatment); ET with placebo NIV (ET+Sham) and ET+NIV (NIV with 14 and 8 cmH2O of inspiratory and expiratory pressure, respectively). The 6MWT was performed on day 1 and day 10 of hospitalization and the ET was performed on an unloaded cycle ergometer until patients' tolerance limit (20 min or less) for eight consecutive days. For all analyses, statistical significance was set at 5% (p < 0.05). Results: None of the patients in either exercise groups had adverse events or required exercise interruption. The 6MWT distance was greater in ET+NIV (Δ120 ± 72 m) than in ET+Sham (Δ73 ± 26 m) and Control (Δ45 ± 32 m; p < 0.05). Total exercise time was greater (128 ± 10 vs. 92 ± 8 min; p < 0.05) and dyspnea was lower (3 ± 1 vs. 4 ± 1; p < 0.05) in ET+NIV than ET+Sham. The ET+NIV group had a shorter hospital stay (17 ± 10 days) than ET+Sham (23 ± 8 days) and Control (39 ± 15 days) groups (p < 0.05). Total exercise time in ET+Sham and ET+NIV had significant correlation with length of hospital stay (r = -0.75; p = 0.01). Conclusion: Exercise training in acute HF was safe, had no adverse events and, when combined with NIV, improved 6MWT and reduce dyspnea and length of stay.

Resumo Fundamento: O exercício físico melhora a capacidade funcional em pacientes com insuficiência cardíaca (IC) crônica. Entretanto, os efeitos do exercício na IC aguda são desconhecidos. Objetivo: Investigar os efeitos do exercício físico isolado ou associado à ventilação não-invasiva (VNI) em comparação ao tratamento convencional em pacientes com IC durante internação. Métodos: Vinte e nove pacientes (IC sistólica) foram randomizados em três grupos: Controle (tratamento clínico convencional); exercício com ventilação placebo (EX+Sham) e EX+VNI (VNI com 14 e 8 cmH2O de pressão inspiratória e expiratória, respectivamente).O TC6M foi realizado no primeiro e no décimo dia de internação e o exercício realizado em cicloergômetro até o limite de tolerância (20 minutos ou menos) por oito dias consecutivos. Para todas as análises, foi considerado p < 0,05 estatisticamente significante. Resultados: Nenhum paciente dos grupos EX+Sham e EX+VNI apresentou complicações ou necessitou interromper o exercício. O grupo EX+VNI apresentou melhor desempenho no TC6M (Δ120 ± 72 m) que os grupos EX+Sham (Δ73 ± 26 m) e Controle (Δ45 ± 32 m; p < 0,05). O tempo total de exercício foi maior (128 ± 10 vs. 92 ± 8 min; p < 0,05) e a dispneia menor (3 ± 1 vs. 4 ± 1; p < 0,05) no EX+VNI em relação ao EX+Sham. O grupo EX+VNI apresentou menor tempo de internação (17 ± 10 dias) comparado ao EX+Sham (23 ± 8 dias) e Controle (39 ± 15 dias; p < 0,05). O tempo total de exercício nos grupos EX+Sham e EX+VNI correlacionou-se com o tempo de internação hospitalar (r = -0,75; p = 0,01). Conclusão: O exercício físico foi seguro em pacientes com IC aguda, não houve complicações hospitalares e, quando associada à VNI, melhorou o desempenho no TC6M, dispneia e o tempo de internação.

Safety and Efficacy of Aerobic Exercise Training Associated to Non-Invasive Ventilation in Patients with Acute Heart Failure.

BACKGROUND: Exercise training (ET) improves functional capacity in chronic heart failure (HF). However, ET effects in acute HF are unknown. OBJECTIVE: To investigate the effects of ET alone or combined with noninvasive ventilation (NIV) compared with standard medical treatment during hospitalization in acute HF patients. METHODS: Twenty-nine patients (systolic HF) were randomized into three groups: control (Control - only standard medical treatment); ET with placebo NIV (ET+Sham) and ET+NIV (NIV with 14 and 8 cmH2O of inspiratory and expiratory pressure, respectively). The 6MWT was performed on day 1 and day 10 of hospitalization and the ET was performed on an unloaded cycle ergometer until patients' tolerance limit (20 min or less) for eight consecutive days. For all analyses, statistical significance was set at 5% (p < 0.05). RESULTS: None of the patients in either exercise groups had adverse events or required exercise interruption. The 6MWT distance was greater in ET+NIV (Δ120 ± 72 m) than in ET+Sham (Δ73 ± 26 m) and Control (Δ45 ± 32 m; p < 0.05). Total exercise time was greater (128 ± 10 vs. 92 ± 8 min; p < 0.05) and dyspnea was lower (3 ± 1 vs. 4 ± 1; p < 0.05) in ET+NIV than ET+Sham. The ET+NIV group had a shorter hospital stay (17 ± 10 days) than ET+Sham (23 ± 8 days) and Control (39 ± 15 days) groups (p < 0.05). Total exercise time in ET+Sham and ET+NIV had significant correlation with length of hospital stay (r = -0.75; p = 0.01). CONCLUSION: Exercise training in acute HF was safe, had no adverse events and, when combined with NIV, improved 6MWT and reduce dyspnea and length of stay.

Pre-Frailty Increases the Risk of Adverse Events in Older Patients Undergoing Cardiovascular Surgery / Pré-Fragilidade Aumenta o Risco de Eventos Adversos em Idosos Submetidos à Cirurgia Cardiovascular

Abstract Background: Frailty is identified as a major predictor of adverse outcomes in older surgical patients. However, the outcomes in pre-frail patients after cardiovascular surgery remain unknown. Objective: To investigate the main outcomes (length of stay, mechanical ventilation time, stroke and in-hospital death) in pre-frail patients in comparison with no-frail patients after cardiovascular surgery. Methods: 221 patients over 65 years old, with established diagnosis of myocardial infarction or valve disease were enrolled. Patients were evaluated by Clinical Frailty Score (CFS) before surgery and allocated into 2 groups: no-frailty (CFS 1~3) vs. pre-frailty (CFS 4) and followed up for main outcomes. For all analysis, the statistical significance was set at 5% (p < 0.05). Results: No differences were found in anthropometric and demographic data between groups (p > 0.05). Pre-frail patients showed a longer mechanical ventilation time (193 ± 37 vs. 29 ± 7 hours; p<0.05) than no-frail patients; similar results were observed for length of stay at the intensive care unit (5 ± 1 vs. 3 ± 1 days; p < 0.05) and total time of hospitalization (12 ± 5 vs. 9 ± 3 days; p < 0.05). In addition, the pre-frail group had a higher number of adverse events (stroke 8.3% vs. 3.9%; in-hospital death 21.5% vs. 7.8%; p < 0.05) with an increased risk for development stroke (OR: 2.139, 95% CI: 0.622-7.351, p = 0.001; HR: 2.763, 95%CI: 1.206-6.331, p = 0.0001) and in-hospital death (OR: 1.809, 95% CI: 1.286-2.546, p = 0.001; HR: 1.830, 95% CI: 1.476-2.269, p = 0.0001). Moreover, higher number of pre-frail patients required homecare services than no-frail patients (46.5% vs. 0%; p < 0.05). Conclusion: Patients with pre-frailty showed longer mechanical ventilation time and hospital stay with an increased risk for cardiovascular events compared with no-frail patients.

Resumo Fundamentos: A fragilidade é reconhecida como um importante preditor de eventos adversos em pacientes cirúrgicos idosos. Entretanto, os desfechos em pacientes com pré-fragilidade após a cirurgia cardiovascular ainda permanecem desconhecidos. Objetivos: Investigar os principais desfechos (tempo de internação, tempo de ventilação mecânica, incidência de acidente vascular cerebral e óbito intra-hospitalar) após cirurgia cardiovascular em pacientes com pré-fragilidade em comparação a pacientes sem fragilidade. Métodos: 221 pacientes acima de 65 anos de idade, com diagnóstico de infarto do miocárdio ou doença valvar foram recrutados no estudo. Os pacientes foram avaliados pela escala de fragilidade clínica (CFS, Clinical Frailty Score) antes da cirurgia e separados em 2 grupos: sem-fragilidade (CFS 1~3) vs. pré-fragilidade (CFS 4). Para todas as análises, foi considerada diferença significativa quando p < 0,05. Resultados: Não foram observadas diferenças nos dados antropométricos e demográficos entre os grupos. Os pacientes com pré-fragilidade apresentaram maior tempo de ventilação mecânica em comparação a pacientes sem fragilidade (193 ± 37 vs. 29 ± 7 horas; p < 0,05); resultados similares foram observados para tempo de permanência na unidade de terapia intensiva (5 ± 1 vs. 3 ± 1 days; p < 0,05) e tempo total de internação hospitalar (12 ± 5 vs. 9 ± 3 dias; p < 0,05). Além disso, os pacientes com pré-fragilidade apresentaram maior número de eventos adversos (acidente vascular cerebral-AVC 8,3% vs. 3,9%; óbito intra-hospitalar 21,5% vs. 7,8%; p<0,05) com risco aumentado para AVC (OR: 2,139, IC 95%: 0,622-7,351, p = 0,001; HR: 2,763, IC 95%: 1,206-6,331, p = 0,0001) e morte intra-hospitalar (OR: 1,809, IC 95%: 1,286-2,546, p = 0,001; HR: 1,830, IC 95%: 1,476-2,269, p = 0,0001). Além disso, um maior número de pacientes com pré-fragilidade necessitaram de fisioterapia domiciliar que pacientes sem fragilidade (46,5% vs. 0%; p< 0,05). Conclusão: Pacientes com pré-fragilidade apresentaram maior tempo de ventilação mecânica e maior tempo de internação hospitalar, com maior risco de desenvolverem eventos cardiovasculares adversos em comparação a pacientes sem fragilidade.

Pre-Frailty Increases the Risk of Adverse Events in Older Patients Undergoing Cardiovascular Surgery.

BACKGROUND: Frailty is identified as a major predictor of adverse outcomes in older surgical patients. However, the outcomes in pre-frail patients after cardiovascular surgery remain unknown. OBJECTIVE: To investigate the main outcomes (length of stay, mechanical ventilation time, stroke and in-hospital death) in pre-frail patients in comparison with no-frail patients after cardiovascular surgery. METHODS: 221 patients over 65 years old, with established diagnosis of myocardial infarction or valve disease were enrolled. Patients were evaluated by Clinical Frailty Score (CFS) before surgery and allocated into 2 groups: no-frailty (CFS 1~3) vs. pre-frailty (CFS 4) and followed up for main outcomes. For all analysis, the statistical significance was set at 5% (p < 0.05). RESULTS: No differences were found in anthropometric and demographic data between groups (p > 0.05). Pre-frail patients showed a longer mechanical ventilation time (193 ± 37 vs. 29 ± 7 hours; p<0.05) than no-frail patients; similar results were observed for length of stay at the intensive care unit (5 ± 1 vs. 3 ± 1 days; p < 0.05) and total time of hospitalization (12 ± 5 vs. 9 ± 3 days; p < 0.05). In addition, the pre-frail group had a higher number of adverse events (stroke 8.3% vs. 3.9%; in-hospital death 21.5% vs. 7.8%; p < 0.05) with an increased risk for development stroke (OR: 2.139, 95% CI: 0.622-7.351, p = 0.001; HR: 2.763, 95%CI: 1.206-6.331, p = 0.0001) and in-hospital death (OR: 1.809, 95% CI: 1.286-2.546, p = 0.001; HR: 1.830, 95% CI: 1.476-2.269, p = 0.0001). Moreover, higher number of pre-frail patients required homecare services than no-frail patients (46.5% vs. 0%; p < 0.05). CONCLUSION: Patients with pre-frailty showed longer mechanical ventilation time and hospital stay with an increased risk for cardiovascular events compared with no-frail patients.

Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD). METHODS AND RESULTS: Ninety consecutive patients with HF, New York Heart Association functional class II-III, and left ventricular ejection fraction ≤40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39-53] years) and SDB (n=28, 57 [54-61] years). SDB was characterized by apnea-hypopnea index ≥15 events per hour (polysomnography). Peripheral (10% O2 and 90% N2, with CO2 titrated) and central (7% CO2 and 93% O2) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.01 to all comparisons). Similarly, during hypercapnia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.001 to all comparisons). MSNA were higher in response to hypoxia (P=0.024) and tended to be higher to hypercapnia (P=0.066) in the SDB group. CONCLUSIONS: Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response.

Alternatives to Aerobic Exercise Prescription in Patients with Chronic Heart Failure / Alternativas para Prescrição de Exercício Aeróbio a Pacientes com Insuficiência Cardíaca

Background: Exercise is essential for patients with heart failure as it leads to a reduction in morbidity and mortality as well as improved functional capacity and oxygen uptake (v̇O2). However, the need for an experienced physiologist and the cost of the exam may render the cardiopulmonary exercise test (CPET) unfeasible. Thus, the six-minute walk test (6MWT) and step test (ST) may be alternatives for exercise prescription. Objective: The aim was to correlate heart rate (HR) during the 6MWT and ST with HR at the anaerobic threshold (HRAT) and peak HR (HRP) obtained on the CPET. Methods: Eighty-three patients (58 ± 11 years) with heart failure (NYHA class II) were included and all subjects had optimized medication for at least 3 months. Evaluations involved CPET (v̇O2, HRAT, HRP), 6MWT (HR6MWT) and ST (HRST). Results: The participants exhibited severe ventricular dysfunction (ejection fraction: 31 ± 7%) and low peak v̇O2 (15.2 ± 3.1 mL.kg-1.min-1). HRP (113 ± 19 bpm) was higher than HRAT (92 ± 14 bpm; p < 0.05) and HR6MWT (94 ± 13 bpm; p < 0.05). No significant difference was found between HRP and HRST. Moreover, a strong correlation was found between HRAT and HR6MWT (r = 0.81; p < 0.0001), and between HRP and HRST (r = 0.89; p < 0.0001). Conclusion: These findings suggest that, in the absence of CPET, exercise prescription can be performed by use of 6MWT and ST, based on HR6MWT and HRST.

Fundamento: O exercício físico é fundamental para pacientes com insuficiência cardíaca, pois reduz a morbimortalidade e melhora a capacidade funcional e o consumo de oxigênio (v̇O2). Entretanto, a realização do teste de exercício cardiopulmonar (TECP) pode se tornar inviável, devido à necessidade de médico capacitado e ao alto custo deste exame. Assim, o teste de caminhada de 6 minutos (TC6M) e o teste do degrau (TD) emergem como alternativas para a prescrição de exercício. Objetivo: Correlacionar a frequência cardíaca (FC) durante o TC6M e o TD com a FC no limiar aeróbio (FCLA) e a FC no pico do exercício (FCP), obtidas no TECP. Métodos: Foram incluídos 83 pacientes (58 ± 11 anos) com insuficiência cardíaca (NYHA classe II), com medicação otimizada por pelo menos 3 meses. Foram realizados TECP (v̇O2, FCLA e FCP), TC6M (FCTC6M) e TD (FCTD). Resultados: Os pacientes apresentavam disfunção ventricular grave (fração de ejeção: 31 ± 7%) e baixo v̇O2 pico (15,2 ± 3,1 ml.kg-1.min-1). A FCP (113 ± 19 bpm) foi maior que a FCLA (92 ± 14 bpm; p < 0,05) e a FCTC6M (94 ± 13 bpm; p < 0,05). Não houve diferença entre FCP e FCTD. Além disso, observou-se forte correlação entre a FCLA e a FCTC6M (r = 0,81; p < 0,0001) e entre a FCP e a FCTD (r = 0,89; p < 0,0001). Conclusão: Os resultados obtidos sugerem ser viável a prescrição de exercício através do TC6M e do TD, com base na FCTC6M e na FCTD, na ausência do TECP.

Alternatives to Aerobic Exercise Prescription in Patients with Chronic Heart Failure.

BACKGROUND: Exercise is essential for patients with heart failure as it leads to a reduction in morbidity and mortality as well as improved functional capacity and oxygen uptake (v̇O2). However, the need for an experienced physiologist and the cost of the exam may render the cardiopulmonary exercise test (CPET) unfeasible. Thus, the six-minute walk test (6MWT) and step test (ST) may be alternatives for exercise prescription. OBJECTIVE: The aim was to correlate heart rate (HR) during the 6MWT and ST with HR at the anaerobic threshold (HRAT) and peak HR (HRP) obtained on the CPET. METHODS: Eighty-three patients (58 ± 11 years) with heart failure (NYHA class II) were included and all subjects had optimized medication for at least 3 months. Evaluations involved CPET (v̇O2, HRAT, HRP), 6MWT (HR6MWT) and ST (HRST). RESULTS: The participants exhibited severe ventricular dysfunction (ejection fraction: 31 ± 7%) and low peak v̇O2 (15.2 ± 3.1 mL.kg-1.min-1). HRP (113 ± 19 bpm) was higher than HRAT (92 ± 14 bpm; p < 0.05) and HR6MWT (94 ± 13 bpm; p < 0.05). No significant difference was found between HRP and HRST. Moreover, a strong correlation was found between HRAT and HR6MWT (r = 0.81; p < 0.0001), and between HRP and HRST (r = 0.89; p < 0.0001). CONCLUSION: These findings suggest that, in the absence of CPET, exercise prescription can be performed by use of 6MWT and ST, based on HR6MWT and HRST.

Increased Muscle Sympathetic Nerve Activity and Impaired Executive Performance Capacity in Obstructive Sleep Apnea.

STUDY OBJECTIVES: To investigate muscle sympathetic nerve activity (MSNA) response and executive performance during mental stress in obstructive sleep apnea (OSA). METHODS: Individuals with no other comorbidities (age = 52 ± 1 y, body mass index = 29 ± 0.4, kg/m2) were divided into two groups: (1) control (n = 15) and (2) untreated OSA (n = 20) defined by polysomnography. Mini-Mental State of Examination (MMSE) and Inteligence quocient (IQ) were assessed. Heart rate (HR), blood pressure (BP), and MSNA (microneurography) were measured at baseline and during 3 min of the Stroop Color Word Test (SCWT). Sustained attention and inhibitory control were assessed by the number of correct answers and errors during SCWT. RESULTS: Control and OSA groups (apnea-hypopnea index, AHI = 8 ± 1 and 47 ± 1 events/h, respectively) were similar in age, MMSE, and IQ. Baseline HR and BP were similar and increased similarly during SCWT in control and OSA groups. In contrast, baseline MSNA was higher in OSA compared to controls. Moreover, MSNA significantly increased in the third minute of SCWT in OSA, but remained unchanged in controls (P < 0.05). The number of correct answers was lower and the number of errors was significantly higher during the second and third minutes of SCWT in the OSA group (P < 0.05). There was a significant correlation (P < 0.01) between the number of errors in the third minute of SCWT with AHI (r = 0.59), arousal index (r = 0.55), and minimum O2 saturation (r = -0.57). CONCLUSIONS: As compared to controls, MSNA is increased in patients with OSA at rest, and further significant MSNA increments and worse executive performance are seen during mental stress. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov, registration number: NCT002289625.

Glioblastoma cells: a heterogeneous and fatal tumor interacting with the parenchyma.

Glioblastomas (GBMs) are considered to be one of the deadliest human cancers, characterized by a high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy, as well as a short patient survival period. Moreover, GBMs are among the most vascularized and invasive cancers in humans. Angiogenesis in GBMs is correlated with the grade of malignancy and is inversely correlated with patient survival. One of the first steps in tumor invasions is migration. GBM cells have the ability to infiltrate and disrupt physical barriers such as basement membranes, extracellular matrix and cell junctions. The invasion process includes the overexpression of several members of a super-family of zinc-based proteinases, the Metzincin, in particular a sub-group, metalloproteinases. Another interesting aspect is that, inside the GBM tissue, there are up to 30% of microglia or macrophages. However, little is known about the immune performance and interactions of the microglia with GBMs. These singular properties of GBMs will be described here. A sub-population of cells with stem-like properties may be the source of tumors since, apparently, GBM stem cells (GSCs) are highly resistant to current cancer treatments. These cancer therapies, while killing the majority of tumor cells, ultimately fail in GBM treatment because they do not eliminate GSCs, which survive to regenerate new tumors. Finally, GBM patient prognostic has shown little improvement in decades. In this context, we will discuss how the membrane-acting toxins called cytolysins can be a potential new tool for GBM treatment.

Aplicabilidade das técnicas de bag squeezing e manobra zeep em pacientes submetidos à ventilação mecânica / Applicability of bag squeezing and zeep maneuvers in mechanically ventilated patients

OBJETIVOS: Avaliar a aplicabilidade das manobras de bag squeezing e zeep em pacientes sob ventilação mecânica invasiva. MÉTODOS: Foram estudados vinte pacientes sob ventilação mecânica invasiva e hemodinamicamente estáveis. Os pacientes foram randomizados e alocados em uma das duas sequências de tratamento (bag squeezing ou manobra zeep). A ordem de aplicação da sequência foi invertida após quatro horas. Foram avaliadas frequência cardíaca, frequência respiratória, saturação periférica de oxigênio e pressão arterial, antes, durante e após a execução de cada técnica. A secreção aspirada foi coletada e mensurada. Os dados foram avaliados utilizando análise estatística pareada para comparação entre os dois grupos e ANOVA para comparar os resultados obtidos em cada grupo nas avaliações. RESULTADOS: Houve um aumento significativo na frequência cardíaca, de 92,6 ± 18,3 bpm para 99,8 ± 18,5 bpm e uma redução significativa na saturação periférica de oxigênio, de 96,9 ± 3,0 por cento para 94,5 ± 4,3 por cento durante a aplicação da técnica bag squeezing, embora os valores tenham se mantido dentro da normalidade. Não houve alterações durante a manobra zeep. Quando comparadas as duas técnicas foi encontrado diferença na saturação periférica de oxigênio durante a aplicação das mesmas. Não houve diferença na quantidade de secreção removida. CONCLUSÃO: Os resultados sugerem que ambas as técnicas são viáveis no tocante a sua aplicação, pois causam poucas alterações hemodinâmicas, e ambas as técnicas são eficazes na remoção de secreção brônquica.

OBJECTIVES: To evaluate the applicability of the bag squeezing and zeep maneuvers in mechanically ventilated patients. METHODS: Twenty stable mechanically ventilated patients were studied. All patients were randomly allocated to either bag squeezing techinique followed by zeep maneuver, or the reversed sequence. Each group crossed to the other sequence four hours later. Heart rate, respiratory rate, peripheral oxygen saturation and blood pressure were measured before, during and after each technique use. The suctioned secretions were collected and measured. The data were analyzed by pairwise statistical analysis for inter-group comparisons, and ANOVA for each group results analysis. RESULTS: The heart rate was significantly increased, from 92.6 ± 18.3 bpm to 99.8 ± 18.5 bpm and the peripheral oxygen saturation significantly decreased from 96.9 ± 3.0 percent to 94.5 ± 4.3 percent during the bag squeezing maneuver, although the values remained within the normal range. No significant changes were seen for the zeep maneuver. Peripheral oxygen saturation during the maneuvers was found to change when the techniques were compared. No differences were found for the suctionedsecretions amounts. CONCLUSION: The results suggest that both techniques are feasible as they cause few hemodynamic changes, and both are effective for bronchial secretions removal.

Applicability of bag squeezing and zeep maneuvers in mechanically ventilated patients. / Aplicabilidade das técnicas de bag squeezing e manobra zeep em pacientes submetidos à ventilação mecânica.

OBJECTIVES: To evaluate the applicability of the bag squeezing and zeep maneuvers in mechanically ventilated patients. METHODS: Twenty stable mechanically ventilated patients were studied. All patients were randomly allocated to either bag squeezing techinique followed by zeep maneuver, or the reversed sequence. Each group crossed to the other sequence four hours later. Heart rate, respiratory rate, peripheral oxygen saturation and blood pressure were measured before, during and after each technique use. The suctioned secretions were collected and measured. The data were analyzed by pairwise statistical analysis for inter-group comparisons, and ANOVA for each group results analysis. RESULTS: The heart rate was significantly increased, from 92.6 ± 18.3 bpm to 99.8 ± 18.5 bpm and the peripheral oxygen saturation significantly decreased from 96.9 ± 3.0% to 94.5 ± 4.3% during the bag squeezing maneuver, although the values remained within the normal range. No significant changes were seen for the zeep maneuver. Peripheral oxygen saturation during the maneuvers was found to change when the techniques were compared. No differences were found for the suctionedsecretions amounts. CONCLUSION: The results suggest that both techniques are feasible as they cause few hemodynamic changes, and both are effective for bronchial secretions removal.

Antifungal Pisum sativum defensin 1 interacts with Neurospora crassa cyclin F related to the cell cycle.

Plant defensins, components of the plant innate immune system, are cationic cysteine-rich antifungal peptides. Evidence from the literature [Thevissen, K., et al. (2003) Peptides 24, 1705-1712] has demonstrated that patches of fungi membrane containing mannosyldiinositolphosphorylceramide and glucosylceramides are selective binding sites for the plant defensins isolated from Dahlia merckii and Raphanus sativus, respectively. Whether plant defensins interact directly or indirectly with fungus intracellular targets is unknown. To identify physical protein-protein interactions, a GAL4-based yeast two-hybrid system was performed using the antifungal plant peptide Pisum sativum defensin 1 (Psd1) as the bait. Target proteins were screened within a Neurospora crassa cDNA library. Nine out of 11 two-hybrid candidates were nuclear proteins. One clone, detected with high frequency per screening, presented sequence similarity to a cyclin-like protein, with F-box and WD-repeat domains, related to the cell cycle control. GST pull-down assay corroborated in vitro this two-hybrid interaction. Fluorescence microscopy analysis of FITC-conjugated Psd1 and DAPI-stained fungal nuclei showed in vivo the colocalization of the plant peptide Psd1 and the nucleus. Analysis of the DNA content of N. crassa conidia using flow cytometry suggested that Psd1 directed cell cycle impairment and caused conidia to undergo endoreduplication. The developing retina of neonatal rats was used as a model to observe the interkinetic nuclear migration during proliferation of an organized tissue from the S toward the M phase of the cell cycle in the presence of Psd1. The results demonstrated that the plant defensin Psd1 regulates interkinetic nuclear migration in retinal neuroblasts.