Search

Quadriceps muscle weakness and wasting are common comorbidities in chronic obstructive pulmonary disease (COPD). Micro-RNA expression upregulation may favor muscle mass growth and differentiation. We hypothesized that the profile of muscle-enriched micro-RNAs in cultured myotubes differs between patients with COPD of a wide range of body composition and healthy controls and that expression levels of those micro-RNAs from patients with COPD and controls differ between in vivo and in vitro conditions. Twenty-nine patients with COPD [ n = 15 with muscle wasting and fat-free mass index (FFMI) 15 kg/m2 and n = 14 with normal body composition and FFMI 18 kg/m2] and 10 healthy controls (FFMI 19 kg/m2) were consecutively recruited. Biopsies from the vastus lateralis muscle were obtained in all study subjects. A fragment of each biopsy was used to obtain primary cultures, in which muscle cells were first proliferated to be then differentiated into actual myotubes. In both sets of experiments (in vivo biopsies and in vitro myotubes) the following muscle-enriched micro-RNAs from all the study subjects were analyzed using quantitative real-time PCR amplification: micro-RNA (miR)-1, miR-133a, miR-206, miR-486, miR-29b, miR-27a, and miR-181a. Whereas the expression of miR-1, miR-206, miR-486, and miR-29b was upregulated in the muscle biopsies of patients with COPD compared with those of healthy controls, levels of none of the studied micro-RNAs in the myotubes (primary cultured cells) significantly differed between patients with COPD and the controls. We conclude from these findings that environmental factors (blood flow, muscle metabolism, and inflammation) taking place in vivo (biopsies) in muscles may account for the differences observed in micro-RNA expression between patients with COPD and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting as the profile of micro-RNA expression in myotubes was similar in patients to that observed in the healthy controls. NEW & NOTEWORTHY Environmental factors taking place in vivo (biopsies) in the muscles may explain differences observed in micro-RNA expression between patients with chronic obstructive pulmonary disease (COPD) and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting and cachexia as micro-RNA expression profile in myotubes was similar between patients and controls. This study was supported by Centro de Investigación en Red de Enfermedades Respiratorias, Fondo de Investigación Sanitaria (FIS) 14/00713 [Fondo Europeo de Desarrollo Regional (FEDER)], FIS 18/00075 (FEDER), Grant SAF2014-54371, Sociedad Española de Neumología y Cirugía Torácica (SEPAR) 2016, SEPAR 2018, Fundació Catalana de Pneumologia 2016, and an unrestricted grant from Menarini SA 2018 (Spain). E. Barreiro was a recipient of the European Respiratory Society COPD Research Award 2008.

While the incidence of thrombotic complications in critically ill patients is very high, in patients under non-invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8-22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16-58)] compared to patients that continued with non-invasive support [11% (CI 5-18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2-16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis.

Sarcopenia is a major comorbidity in chronic obstructive pulmonary (COPD). Whether deficient muscle repair mechanisms and regeneration exist in the vastus lateralis (VL) of sarcopenic COPD remains debatable. In the VL of control subjects and severe COPD patients with/without sarcopenia, satellite cells (SCs) were identified (immunofluorescence, specific antibodies, anti-Pax-7, and anti-Myf-5): activated (Pax-7+/Myf-5+), quiescent/regenerative potential (Pax-7+/Myf-5-), and total SCs, nuclear activation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL]), and muscle fiber type (morphometry and slow- and fast-twitch, and hybrid fibers), muscle damage (hematoxylin-eosin staining), muscle regeneration markers (Pax-7, Myf-5, myogenin, and MyoD), and myostatin levels were identified. Compared to controls, in VL of sarcopenic COPD patients, myostatin content, activated SCs, hybrid fiber proportions, TUNEL-positive cells, internal nuclei, and muscle damage significantly increased, while quadriceps muscle strength, numbers of Pax-7+/Myf-5- and slow- and fast-twitch, and hybrid myofiber areas decreased. In the VL of sarcopenic and nonsarcopenic patients, TUNEL-positive cells were greater, whereas muscle regeneration marker expression was lower than in controls. In VL of severe COPD patients regardless of the sarcopenia level, the muscle regeneration process is triggered as identified by SC activation and increased internal nuclei. Nonetheless, a lower regenerative potential along with significant alterations in muscle phenotype and damage, and increased myostatin were prominently seen in sarcopenic COPD.

Whether a deficiency in muscle repair and regeneration may exist in the lower limb muscles of COPD patients remains debatable. We hypothesized that the negative regulator myotastin may inhibit muscle regeneration potential in sarcopenic COPD patients. In vastus lateralis (VL) of control subjects and severe COPD patients with and without sarcopenia, satellite cells (SC) were identified (immunofluorescence, anti-Pax7 and anti-myf5): activated (Pax7+ and myf5+), quiescent/regenerative potential (Pax7+ and myf-5-), and total SC, nuclear activation (TUNEL assay), and muscle fiber type (morphometry, hybrid fibers), muscle damage, muscle regeneration markers (Pax7, myf-5, myogenin, and myoD), and myostatin levels were identified. Compared to control subjects and normal body composition COPD, in the VL of sarcopenic COPD patients, myostatin protein levels, activated SC, hybrid fibers, TUNEL-positive cells, internal nuclei, and total abnormal fraction were significantly increased, while quadriceps muscle strength, numbers of Pax7+ and myf-5- and slow- and fast-twitch muscle fiber areas decreased. In VL of sarcopenic and non-sarcopenic COPD patients, TUNEL-positive cell counts were greater, whereas expression of muscle regeneration markers was lower than in controls. Myostatin may have interfered with the process of muscle cell proliferation early on during the regeneration process, thus leading to poor muscle growth and development following injury in COPD patients with sarcopenia. This may be another relevant mechanism of muscle mass loss in COPD. Method: CIBERES, FIS 18/00075 (FEDER), SEPAR 2018, and unrestricted grant from Menarini SA 2018.

Introduction: In Patients with Mental Disorders (MD) the risk of venous thromboembolic disease has increased. There is little information regarding these patients during acute pulmonary embolism (PE). Objectives and Methods: This was a retrospective observational cohort study performed in a tertiary hospital in Spain. All patients with a primary diagnosis of PE between October 2015-September 2017 were included. The objective of the study was to compare the clinical presentation and the treatment of patients diagnosed of PE with and without MD. Results: One hundred fifty-three consecutive patients were included. Thirty-six (23.6%) had MD [depression 8(22%), anxiety 12(33%), schizophrenia 1(4%), bipolar 1(4%); more than one MD 14 (37%)]. Patients with MD were older compared to patients without MD (mean±SD, 75 ±9 vs 69 ±8 years, p=0.008) and mainly women (80% vs 56%, p=0.007). There were no significant differences in risk factors, comorbidities or clinical presentation. High levels of pro-BNP were showed in patients with MD (5499 ± 3120 vs 1764 ± 2692 pg/ml, p=0.01). Although the treatment was more conservative in patients with MD (97% of patients treated with low molecular weight heparin vs. 82% in the other group, p=0.040), hospital stay was longer in the MD group (11.9 ±6 vs 7.7 ±7 days, p=0.025). Among patients treated with psychotropic drugs, only patients in treatment with antipsychotics (n=9, 25%) were found to have a higher mortality at 90 days (p=0.044). Conclusions: Although conservative treatment of pulmonary embolism was predominant in the context of mental disorder, this was associated with a longer hospital stay. Patients on antipsychotic therapy may represent a potential higher risk population

Respiratory muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Chronic contractile activity induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in animals (animals and humans). We hypothesized that the respiratory muscle dysfunction associated with COPD may upregulate ER stress and UPR expression in diaphragm of stable patients with different degrees of airway obstruction and normal body composition. In diaphragm muscle specimens of patients with mild and moderate-to-severe COPD with preserved body composition and non-COPD controls (thoracotomy because of lung localized neoplasms), expression of protein misfolding (ER stress) and UPR markers, proteolysis and apoptosis (qRT-PCR and immunoblotting), and protein aggregates (lipofuscin, histology) were quantified. All patients and non-COPD controls were also clinically evaluated: lung and muscle functions and exercise capacity. Compared with non-COPD controls, patients exhibited mild and moderate-to-severe airflow limitation and diffusion capacity and impaired exercise tolerance and diaphragm strength. Moreover, compared with the controls, in the diaphragm of the COPD patients, slow-twitch fiber proportions increased, gene expression but not protein levels of protein disulfide isomerase family A member 3 and phosphatidylinositol 3-kinase catalytic subunit type 3 were upregulated, and no significant differences were found in markers of UPR transmembrane receptor pathways (activating transcription factor-6, inositol-requiring enzyme-1α, and protein kinase-like ER kinase), lipofuscin aggregates, proteolysis, or apoptosis. In stable COPD patients with a wide range of disease severity, reduced diaphragm force of contraction, and normal body composition, ER stress and UPR signaling were not induced in the main respiratory muscle. These findings imply that ER stress and UPR are probably not involved in the documented diaphragm muscle dysfunction (reduced strength) observed in all the study patients, even in those with severe airflow limitation. Hence, in stable COPD patients with normal body composition, therapeutic strategies targeted to treat diaphragm muscle dysfunction should not include UPR modulators, even in those with a more advanced disease. NEW & NOTEWORTHY In stable chronic obstructive pulmonary disease patients with a wide range of disease severity, diaphragm muscle weakness, and normal body composition, endoplasmic reticulum stress and unfolded protein response (UPR) signaling were not induced in the main respiratory muscle. These findings imply that endoplasmic reticulum stress and UPR are not involved in the documented diaphragm muscle dysfunction observed in the study patients, even in those with severe airflow limitation. In stable chronic obstructive pulmonary disease patients with normal body composition, therapeutic strategies should not include UPR modulators.

Background Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. Objective The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. Patients and methods A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation–Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. Results BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6–69) for RSS score of 4 to 92.2 (95% CI: 90.1–94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=−0.757, r=0.701, and r=0.615, respectively; P, Video abstract

To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in 18F-FDG-PET scan. A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, 18F-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups ( 200 mg/dl). Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p 200 mg/dl had significantly lower SUVmax. If BGL is lower than 200 mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.

Introduccion La disfuncion muscular es una de las manifestaciones sistemicas mas estudiadas en la EPOC. Las alteraciones metabolicas musculares son dificiles de estudiar in vivo, debido a la falta de tecnicas no invasivas. El objetivo fue evaluar sincronicamente la actividad metabolica de diferentes grupos musculares en pacientes con EPOC. Metodos Se incluyeron 39 pacientes y 21 controles (funcion pulmonar normal), candidatos a realizacion de tomografia axial computarizada y por emision de positrones para estadificacion de lesion pulmonar localizada. Tras infusion de 18-fluor-deoxi-glucosa, se captaron imagenes de 2 musculos respiratorios (porciones costal y crural del diafragma, y recto abdominal) y 2 musculos perifericos (cuadriceps y biceps braquial), utilizando como indice de metabolismo glucidico el standard uptake value. Resultados Este indice fue superior en ambas porciones del diafragma comparado con el resto de los musculos en todos los sujetos. Ademas, el diafragma crural y el recto del abdomen mostraban mayor actividad en los pacientes con EPOC que en los controles (1,8 ± 0,7 vs. 1,4 ± 0,8; y 0,78 ± 0,2 vs. 0,58 ± 0,1; respectivamente; p < 0,05). El cuadriceps mostraba una tendencia similar. En los pacientes con EPOC los niveles de captacion de ambos musculos respiratorios y del cuadriceps se correlacionaron directamente con el atrapamiento aereo (r = 0,388; 0,427 y 0,361, respectivamente; p < 0,05). Conclusiones Existe mayor nivel de captacion-utilizacion de glucosa en el diafragma humano respecto de otros musculos en respiracion tranquila. Se confirma cuantitativamente que los pacientes con EPOC tienen incrementado el metabolismo glucidico de sus musculos respiratorios (con tendencia similar para el cuadriceps), en relacion directa con las cargas mecanicas que afrontan.

Aim Right ventricular (RV) pump function is of essential clinical and prognostic importance in a variety of heart and lung diseases. While the evaluation of RV performance at rest has been implemented in the clinical setting, it is unknown whether this assessment during exercise may provide additional benefit. With this aim, we evaluated the exercise-induced pulmonary arterial systolic pressure (PASP) increase during exercise in patients with severe chronic obstructive pulmonary disease (COPD) as an expression of RV contractile reserve. Method Cardiopulmonary exercise testing (CPET) with synchronic echocardiography was performed in 81 patients. Patients were classified into two groups according to an exercise-induced PASP increase above 30mmHg (High PSAP) or below 30mmHg (Low PSAP) during maximal exercise. Patients were then followed for three years. Results Sixteen patients (20%) had low PSAP and 65 (80%) showed high PSAP. These were not significant clinical and functional differences. Low PSAP was associated with a significantly lower peak VO2 (mean (SD), 35 (2) % predicted) compared to high PSAP response (peak VO2 45 (3) % predicted), p=0.045. Factors associated with mortality were age and exercise-induced PASP. Seventeen patients died during the three years of follow-up (7 (39%) in the low PSAP group and only 10 (1%) in the high PSAP group, p=0.041). Conclusion Cardiopulmonary exercise testing with a synchronic echocardiography may be a useful tool for the assessment of RV contractile reserve in severe COPD patients. Exercise-induced PSAP emerges as a possible prognostic factor in these patients.

Introduction Muscle dysfunction is one of the most extensively studied manifestations of COPD. Metabolic changes in muscle are difficult to study in vivo, due to the lack of non-invasive techniques. Our aim was to evaluate metabolic activity simultaneously in various muscle groups in COPD patients. Methods Thirty-nine COPD patients and 21 controls with normal lung function, due to undergo computed axial and positron emission tomography for staging of localized lung lesions were included. After administration of 18-fluordeoxyglucose, images of 2 respiratory muscles (costal and crural diaphragm, and rectus abdominus) and 2 peripheral muscles (brachial biceps and quadriceps) were obtained, using the standard uptake value as the glucose metabolism index. Results Standard uptake value was higher in both portions of the diaphragm than in the other muscles of all subjects. Moreover, the crural diaphragm and rectus abdominus showed greater activity in COPD patients than in the controls (1.8±0.7 vs 1.4±0.8; and 0.78±0.2 vs 0.58±0.1; respectively, P

Impaired muscle strength and mass (sarcopenia) are common in patients with respiratory cachexia, namely chronic obstructive pulmonary disease (COPD) and in lung cancer (LC)-cachexia. Misfolded/unfolded proteins in endoplasmic reticulum (ER) induce the compensatory unfolded protein response (UPR). Expression of ER stress and UPR markers may be differentially upregulated in vastus lateralis (VL) of patients with respiratory sarcopenia associated with either a chronic condition (COPD) or subacute (LC)-cachexia. In VL specimens from 40 COPD patients (n = 21, sarcopenic, fat-free mass index [FFMI] 16 kg/m2 and n = 19, nonsarcopenic, FFMI 18 kg/m2 ), 13 patients with LC-cachexia (FFMI 17 kg/m2 ), and 19 healthy controls (FFMI 19 kg/m 2 ), expression markers of ER stress, UPR (protein kinase-like ER kinase [PERK], activating transcription factor [ATF] 6, and inositol-requiring enzyme [IRE] 1-α), oxidative stress, autophagy, proteolysis, and apoptosis (reverse transcription polymerase chain reaction and immunoblotting), and fiber atrophy (histology) were assessed. Atrophy and muscle wasting and weakness were seen in both groups of sarcopenic patients. Compared to healthy controls, in muscles of LC-cachexia patients, expression of ER stress markers and UPR (three arms) was significantly upregulated, while in sarcopenic COPD, expression of a few ER stress markers and IRE1-α arm was upregulated. ER stress and an exaggerated UPR were observed in the VL muscle of patients with respiratory sarcopenia. The three branches of UPR were similarly upregulated in muscles of cancer cachectic patients, whereas in sarcopenic COPD patients, only IRE1 was upregulated. The differential profile of muscle UPR in chronic and subacute respiratory conditions offers a niche for the design of specific novel therapeutic approaches.