Sergi Pascual

Respiratory diseases and muscle dysfunction

Many respiratory diseases lead to impaired function of skeletal muscles, influencing quality of life and patient survival. Dysfunction of both respiratory and limb muscles in chronic obstructive pulmonary disease has been studied in depth, and seems to be caused by the complex interaction of general (inflammation, impaired gas exchange, malnutrition, comorbidity, drugs) and local factors (changes in respiratory mechanics and muscle activity, and molecular events). Some of these factors are also present in cystic fibrosis and asthma. In obstructive sleep apnea syndrome, repeated exposure to hypoxia and the absence of reparative rest are believed to be the main causes of muscle dysfunction. Deconditioning appears to be crucial for the functional impairment observed in scoliosis. Finally, cachexia seems to be the main mechanism of muscle dysfunction in advanced lung cancer. A multidimensional therapeutic approach is recommended, including pulmonary rehabilitation, an adequate level of physical activity, ventilatory support and nutritional interventions.

Vastus Lateralis Fiber Shift Is an Independent Predictor of Mortality in Chronic Obstructive Pulmonary Disease

To the Editor: Quadriceps weakness and atrophy is present in approximately 30% of patients with chronic obstructive pulmonary disease (COPD) in secondary care (1, 2). The quadriceps also displays a shift in fiber type so that there are fewer type I (oxidative) fibers and more type II (glycolytic) fibers (3). Pulmonary rehabilitation only partially addresses this fiber shift (4). Muscle mass (5) and strength (6) are both associated with increased mortality, but the prognostic significance of fiber shift is unknown. In a retrospective multicenter analysis of 392 patients from four sites (see Tables E1–E4 in the online supplement), mortality data were collated, as part of audit procedures, on outpatients with stable COPD who had undergone a vastus lateralis biopsy between 1995 and 2013. Data from these subjects have been previously published (e.g., References 2, 4, 5). Fiber proportion, reported as the percentage of type II fibers (type II fiber %), was established by immunohistochemistry. Fiber shift, evaluated as a dichotomous variable, was considered to have occurred when the proportion of type II fibers was greater than 68% (men) or greater than 65% (women) based on normal ranges established from an age-matched healthy population published by Natanek and colleagues (3). Body mass index (BMI), fat-free mass index (FFMI), dominant leg isometric quadriceps maximum voluntary contraction (QMVC and QMVC/BMI), mid-thigh cross-sectional area determined by computed tomography scan (MTCSA), residual volume normalized to total lung capacity (RV/TLC), and percent predicted value for the carbon monoxide transfer factor corrected for hemoglobin (TLCOc), when available, were included in subanalyses. Data were analyzed for the whole dataset and also after splitting the group into those with an FEV1 less than 50% predicted and those with an FEV1 greater than or equal to 50% predicted. Further details on the methodology and statistical analyses are presented in the online supplement. Some of the results of this study have been previously reported in abstract form (7). Patients were followed up for a median of 1,699 days (127–6,601 d); 102 of 392 (26.7%) patients died during follow-up (Table E6). Cohort characteristics are presented in Tables 1 and ​and22 and Tables E1–E5. One hundred fifty-one patients had Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II disease and 241 had GOLD stage III/IV disease. Those who died were older and had a lower FEV1 % predicted, and there was a greater male preponderance (Table E6A). One hundred seventy-seven (45.1%) of the patients had fiber shift. The patients who died had a higher percentage of type II fibers (69.5% [62.2, 76.3%] vs. 66.0% [54.0, 74.2%]; P = 0.002) and a higher proportion of them exhibited fiber shift (58% vs. 41%, P = 0.004). BMI, FFMI, QMVC, MTCSA, and TLCOc were all lower, and RV/TLC higher, in those who died (Table E6B). Table 1. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion Dichotomized into the Occurrence of Fiber Shift Table 2. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II Fiber Proportion as a Continuous Measure In the cohort considered as a whole, both type II fiber % and the presence of fiber shift were univariate predictors of mortality, as were age and FEV1 % predicted (Tables 1 and ​and2).2). In a multivariate analysis including fiber shift as a dichotomous variable, fiber shift was retained, as were age and FEV1 % predicted, Table 1. When age, FEV1 % predicted, and type II fiber % were entered into a multivariate analysis, age and FEV1 % predicted were retained as independent predictors, but the association between fiber type and mortality just missed statistical significance (Table 2). The relationship between FEV1 and fiber proportion is shown in Figure 1A, and survival as a function of fiber shift, adjusted for age and FEV1, is shown in Figure 1B. Additional data regarding other lung function and muscle parameters are presented in Tables E7–E10. FEV1 expressed in liters and TLCOc were also univariate predictors of mortality; however, RV/TLC was not. When including TLCOc in the analysis (n = 209), fiber shift, age, FEV1 % predicted, and TLCOc were all independent predictors of mortality. In other subanalyses, BMI, FFMI, QMVC, QMVC/BMI, and MTCSA were not univariate predictors of mortality. Figure 1. (A) The relationship between type II fiber percentage and FEV1 % predicted (dashed lines demonstrate the 95% confidence interval), and (B) survival curves for those with fiber shift (n = 177) and those without fiber shift (n = 215) after adjusting for ... When limiting the analysis to those with an FEV1 greater than or equal to 50% predicted, age was the only predictor of mortality (hazard ratio [HR], 1.16; 95% CI, 1.07, 1.25; P < 0.0001; Table E11). In a multivariate analysis confined to those with an FEV1 less than 50%, fiber shift was retained as an independent predictor (HR, 1.71; 95% CI, 1.08, 2.71; P = 0.02), as were age (HR, 1.06; 95% CI, 1.03, 1.09; P < 0.0001), and FEV1 % predicted (HR, 0.96; 95% CI, 0.94, 0.99; P = 0.002; Table E12A). In a separate analysis confined to those with an FEV1 less than 50%, type II fiber % was not retained as an independent predictor (HR, 1.014; 95% CI, 0.996, 1.032; P = 0.13), whereas age and FEV1 % predicted were (Table E12B). Fiber shift in the vastus lateralis of patients with COPD was associated with increased mortality, although this association was weaker when lung function and age were included in the analysis. This finding was pronounced in patients with GOLD stage III/IV disease but undetectable in those with GOLD stage I/II disease. The relationship between skeletal muscle atrophy (5) and weakness (6) with mortality has been previously noted in COPD. However, we believe the present analysis is timely because we (3) and others (8) have recently shown that the nature of skeletal muscle involvement in COPD is heterogeneous rather than uniform. No prior study has related quadriceps biopsy appearances to long-term outcome in COPD. Given the known relationship between exercise capacity and survival (9), these data are consistent with our prior studies, which demonstrated a relationship between fiber shift (although not fiber atrophy) and impaired exercise capacity (3) and functional performance (10). Nevertheless, it remains unclear whether fiber shift causes poor exercise tolerance or is a manifestation of exercise intolerance and reduced physical activity, which are both associated with increased mortality in COPD (9, 11). Both concepts can be supported by in vivo models that demonstrate that muscle disuse results in type I to type II fiber shift (12) and that fiber shift toward a type I fiber predominance increases exercise performance (13). Due to the retrospective nature of the current analysis, exercise performance and physical activity data were not available for inclusion in this report, so a causative role for fiber shift in mortality cannot be demonstrated from this study. A prospective study would have been preferable and could also have considered other factors of relevance, including pulmonary rehabilitation over the intervening period. Despite the limitations of the current study, it is doubtful that a prospective study of comparable size and duration will ever be done. Interest in pharmacological management of skeletal muscle dysfunction is growing (14), and addressing fiber shift may eventually become a therapeutic possibility. Further studies to address whether the reversal of fiber shift is of benefit are of value.

Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings

Respiratory and/or limb muscle dysfunction, which are frequently observed in chronic obstructive pulmonary disease (COPD) patients, contribute to their disease prognosis irrespective of the lung function. Muscle dysfunction is caused by the interaction of local and systemic factors. The key deleterious etiologic factors are pulmonary hyperinflation for the respiratory muscles and deconditioning secondary to reduced physical activity for limb muscles. Nonetheless, cigarette smoke, systemic inflammation, nutritional abnormalities, exercise, exacerbations, anabolic insufficiency, drugs and comorbidities also seem to play a relevant role. All these factors modify the phenotype of the muscles, through the induction of several biological phenomena in patients with COPD. While respiratory muscles improve their aerobic phenotype (percentage of oxidative fibers, capillarization, mitochondrial density, enzyme activity in the aerobic pathways, etc.), limb muscles exhibit the opposite phenotype. In addition, both muscle groups show oxidative stress, signs of damage and epigenetic changes. However, fiber atrophy, increased number of inflammatory cells, altered regenerative capacity; signs of apoptosis and autophagy, and an imbalance between protein synthesis and breakdown are rather characteristic features of the limb muscles, mostly in patients with reduced body weight. Despite that significant progress has been achieved in the last decades, full elucidation of the specific roles of the target biological mechanisms involved in COPD muscle dysfunction is still required. Such an achievement will be crucial to adequately tackle with this relevant clinical problem of COPD patients in the near-future.

Utilización de glucosa en los músculos de pacientes con enfermedad pulmonar obstructiva crónica

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<.05). A similar trend was observed with the quadriceps. In COPD patients, uptake in the two respiratory muscles and the quadriceps correlated directly with air trapping (r=0.388, 0.427 and 0.361, respectively, P<.05). CONCLUSIONS There is greater glucose uptake and metabolism in the human diaphragm compared to other muscles when the subject is at rest. Increased glucose metabolism in the respiratory muscles (with a similar trend in their quadriceps) of COPD patients is confirmed quantitatively, and is directly related to the mechanical loads confronted.

Clinical management of chronic obstructive pulmonary disease patients with muscle dysfunction

Muscle dysfunction is frequently observed in chronic obstructive pulmonary disease (COPD) patients, contributing to their exercise limitation and a worsening prognosis. The main factor leading to limb muscle dysfunction is deconditioning, whereas respiratory muscle dysfunction is mostly the result of pulmonary hyperinflation. However, both limb and respiratory muscles are also influenced by other negative factors, including smoking, systemic inflammation, nutritional abnormalities, exacerbations and some drugs. Limb muscle weakness is generally diagnosed through voluntary isometric maneuvers such as handgrip or quadriceps muscle contraction (dynamometry); while respiratory muscle loss of strength is usually recognized through a decrease in maximal static pressures measured at the mouth. Both types of measurements have validated reference values. Respiratory muscle strength can also be evaluated determining esophageal, gastric and transdiaphragmatic maximal pressures although there is a lack of widely accepted reference equations. Non-volitional maneuvers, obtained through electrical or magnetic stimulation, can be employed in patients unable to cooperate. Muscle endurance can also be assessed, generally using repeated submaximal maneuvers until exhaustion, but no validated reference values are available yet. The treatment of muscle dysfunction is multidimensional and includes improvement in lifestyle habits (smoking abstinence, healthy diet and a good level of physical activity, preferably outside), nutritional measures (diet supplements and occasionally, anabolic drugs), and different modalities of general and muscle training.