Disano, L

Gea, J

Hopkinson, NS

Maltais, F

Martinez-Llorens, J

Natanek, SA

Pascual, S

Patel, MS

Polkey, MI

Stratakos, G

Terzis, G

Vogiatzis, I

American Journal of Respiratory and Critical Care Medicine

PubMed

Patel, Mehul S

Natanek, Samantha A

Stratakos, Grigorios

Pascual, Sergi

Martinez-Llorens, Juana

Disano, Laura

Terzis, Gerasimos

Hopkinson, Nicholas S

Gea, Joaquim

Vogiatzis, Ioannis

Maltais, Francois

Polkey, Michael I

Spiral - Imperial College Digital Repository

10. Pickkers P, de Keizer N, Dusseljee J, Weerheijm D, van der Hoeven JG,Peek N. Body mass index is associated with hospital mortality incritically ill patients: an observational cohort study. Crit Care Med2013;41:1878–1883.11. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH,Steurer J. Pulmonary rehabilitation following exacerbations ofchronic obstructive pulmonary disease. Cochrane DatabaseSyst Rev 2011;10:CD005305.12. Prieto-Centurion V, Markos MA, Ramey NI, Gussin HA, Nyenhuis SM,Joo MJ, Prasad B, Bracken N, Didomenico R, Godwin PO, et al.Interventions to reduce rehospitalizations after chronic obstructivepulmonary disease exacerbations: a systematic review. Ann AmThorac Soc 2014;11:417–424.13. Hulzebos EHJ, Helders PJM, Favié NJ, De Bie RA, Brutel de la RiviereA, Van Meeteren NL. Preoperative intensive inspiratory muscletraining to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial.JAMA 2006;296:1851–1857.14. Martin AD, Smith BK, Davenport PD, Harman E, Gonzalez-Rothi RJ,Baz M, Layon AJ, Banner MJ, Caruso LJ, Deoghare H, et al.Inspiratory muscle strength training improves weaning outcomein failure to wean patients: a randomized trial. Crit Care 2011;15:R84.Copyright © 2014 by the American Thoracic SocietyVastus Lateralis Fiber Shift Is anIndependent Predictor of Mortality inChronic Obstructive Pulmonary DiseaseTo the Editor:Quadriceps weakness and atrophy is present in approximately30% of patients with chronic obstructive pulmonary disease(COPD) in secondary care (1, 2). The quadriceps also displaysa shift in fiber type so that there are fewer type I (oxidative)fibers and more type II (glycolytic) fibers (3). Pulmonaryrehabilitation only partially addresses this fiber shift (4). Musclemass (5) and strength (6) are both associated with increasedmortality, but the prognostic significance of fiber shift isunknown.In a retrospective multicenter analysis of 392 patients fromfour sites (see Tables E1–E4 in the online supplement), mortalitydata were collated, as part of audit procedures, on outpatientswith stable COPD who had undergone a vastus lateralis biopsybetween 1995 and 2013. Data from these subjects have beenpreviously published (e.g., References 2, 4, 5). Fiber proportion,reported as the percentage of type II fibers (type II fiber %), wasestablished by immunohistochemistry. Fiber shift, evaluated asa dichotomous variable, was considered to have occurred whenthe proportion of type II fibers was greater than 68% (men) orgreater than 65% (women) based on normal ranges establishedfrom an age-matched healthy population published by Natanekand colleagues (3). Body mass index (BMI), fat-free mass index(FFMI), dominant leg isometric quadriceps maximum voluntarycontraction (QMVC and QMVC/BMI), mid-thigh cross-sectionalarea determined by computed tomography scan (MTCSA),residual volume normalized to total lung capacity (RV/TLC),and percent predicted value for the carbon monoxide transferfactor corrected for hemoglobin (TLCOc), when available, wereincluded in subanalyses. Data were analyzed for the whole datasetand also after splitting the group into those with an FEV1 lessthan 50% predicted and those with an FEV1 greater than or equalto 50% predicted. Further details on the methodology andstatistical analyses are presented in the online supplement. Someof the results of this study have been previously reported inabstract 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 1and 2 and Tables E1–E5. One hundred fifty-one patientshad Global Initiative for Chronic Obstructive Lung Disease(GOLD) stage I/II disease and 241 had GOLD stage III/IVdisease. 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 thepatients had fiber shift. The patients who died had a higherpercentage 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 themexhibited fiber shift (58% vs. 41%, P = 0.004). BMI, FFMI,QMVC, MTCSA, and TLCOc were all lower, and RV/TLChigher, in those who died (Table E6B).In the cohort considered as a whole, both type II fiber % andthe presence of fiber shift were univariate predictors of mortality,as were age and FEV1 % predicted (Tables 1 and 2). In amultivariate analysis including fiber shift as a dichotomousvariable, fiber shift was retained, as were age and FEV1 %predicted, Table 1. When age, FEV1 % predicted, and type IIfiber % were entered into a multivariate analysis, age andFEV1 % predicted were retained as independent predictors, butthe association between fiber type and mortality just missedstatistical significance (Table 2). The relationship between FEV1and fiber proportion is shown in Figure 1A, and survival as afunction of fiber shift, adjusted for age and FEV1, is shownin Figure 1B. Additional data regarding other lung function andmuscle parameters are presented in Tables E7–E10. FEV1expressed in liters and TLCOc were also univariate predictors ofmortality; however, RV/TLC was not. When including TLCOcin the analysis (n = 209), fiber shift, age, FEV1 % predicted, andTLCOc were all independent predictors of mortality. In othersubanalyses, BMI, FFMI, QMVC, QMVC/BMI, and MTCSAwere not univariate predictors of mortality.When limiting the analysis to those with an FEV1 greaterthan or equal to 50% predicted, age was the only predictor ofmortality (hazard ratio [HR], 1.16; 95% CI, 1.07, 1.25; P ,0.0001; Table E11). In a multivariate analysis confined to thosewith an FEV1 less than 50%, fiber shift was retained as anindependent predictor (HR, 1.71; 95% CI, 1.08, 2.71; P = 0.02), asSupported by the National Institute for Health Research RespiratoryBiomedical Research Unit at the Royal Brompton & Harefield National HealthService Foundation Trust and Imperial College London, who partly fundM.I.P.’s salary. S.A.N. was supported by the Wellcome Trust.Author Contributions: M.S.P. drafted the manuscript. M.S.P., S.A.N., G.S.,S.P., J.M.-L., G.T., J.G., I.V., and F.M. recruited the patients and collectedthe data. All authors contributed to the analysis of data and preparation of thefinal manuscript. M.I.P. conceived the idea and developed it with I.V., J.G.,and F.M. M.I.P. is the primary investigator who takes responsibility for theintegrity of the work as a whole, from inception to published article.This letter has an online supplement, which is accessible from this issue’stable of contents at www.atsjournals.orgCORRESPONDENCE350 American Journal of Respiratory and Critical Care Medicine Volume 190 Number 3 | August 1 2014were 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 than50%, 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 COPDwas associated with increased mortality, although this associationwas weaker when lung function and age were included inthe analysis. This finding was pronounced in patients with GOLDstage III/IV disease but undetectable in those with GOLD stage I/IIdisease. The relationship between skeletal muscle atrophy (5)and weakness (6) with mortality has been previously noted inCOPD. However, we believe the present analysis is timely becausewe (3) and others (8) have recently shown that the nature ofskeletal muscle involvement in COPD is heterogeneous rather thanuniform. No prior study has related quadriceps biopsy appearancesto long-term outcome in COPD.Given the known relationship between exercise capacity andsurvival (9), these data are consistent with our prior studies,which demonstrated a relationship between fiber shift (althoughnot fiber atrophy) and impaired exercise capacity (3) andfunctional performance (10). Nevertheless, it remains unclearwhether fiber shift causes poor exercise tolerance or isa manifestation of exercise intolerance and reduced physicalactivity, which are both associated with increased mortality inCOPD (9, 11). Both concepts can be supported by in vivo modelsthat demonstrate that muscle disuse results in type I to type IIfiber shift (12) and that fiber shift toward a type I fiberpredominance increases exercise performance (13). Due to theretrospective nature of the current analysis, exercise performanceand physical activity data were not available for inclusion in thisreport, so a causative role for fiber shift in mortality cannot bedemonstrated from this study. A prospective study would havebeen preferable and could also have considered other factorsof relevance, including pulmonary rehabilitation over theintervening period. Despite the limitations of the current study,it is doubtful that a prospective study of comparable size andduration will ever be done.Interest in pharmacological management of skeletal muscledysfunction is growing (14), and addressing fiber shift may eventuallybecome a therapeutic possibility. Further studies to address whetherthe reversal of fiber shift is of benefit are of value. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Acknowledgment: The authors thank Gemma Marsh and other membersof the lung function and muscle laboratory departments at the RoyalBrompton & Harefield Hospitals, Annie Dubé for her technical assistancein the Québec cohort, and the Pulmonary Rehabilitation Units atEvangelismos and Sotiria Hospitals in Athens.Mehul S. Patel, M.B.B.S., B.Sc.Royal Brompton & Harefield NHS Foundation TrustLondon, United KingdomSamantha A. Natanek, Ph.D.Imperial College LondonLondon, United KingdomGrigorios Stratakos, M.D.National and Kapodistrian University of AthensAthens, GreeceSergi Pascual, M.D.Juana Martı́nez-Llorens, M.D., Ph.D.CIBERES, ISC IIIBarcelona, SpainTable 2. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II FiberProportion as a Continuous MeasureParameter %/Mean (SD)/Median (IQR) Univariate HR (95% CI) P Value Multivariate HR (95% CI) P ValueAge, yr 65.9 (8) 1.045 (1.018, 1.072) 0.001 1.072 (1.041, 1.103) ,0.0001Male sex, % 73 1.346 (0.805, 2.252) 0.257 — —FEV1 % predicted 41.6 (28.0, 61.0) 0.970 (0.957, 0.982) ,0.0001 0.965 (0.951, 0.979) ,0.0001% Type II fibers 66.6 (56.0, 75.0) 1.024 (1.009, 1.039) 0.002 1.014 (0.998, 1.030) 0.088Definition of abbreviations: CI = confidence interval; HR = hazard ratio; IQR = interquartile range.Table 1. Core Characteristics of the Cohort (n = 392) in Addition to Univariate and Multivariate Analyses Including Type II FiberProportion Dichotomized into the Occurrence of Fiber ShiftParameter %/Mean (SD)/Median (IQR) Univariate HR (95% CI) P Value Multivariate HR (95% CI) P ValueAge, yr 65.9 (8) 1.045 (1.018, 1.072) 0.001 1.070 (1.040, 1.101) ,0.0001Male sex, % 73 1.346 (0.805, 2.252) 0.257 — —FEV1 % predicted 41.6 (28.0, 61.0) 0.970 (0.957, 0.982) ,0.0001 0.965 (0.951, 0.979) ,0.0001Fiber shift present 45 2.073 (1.390, 3.091) 0.001 1.598 (1.056, 2.419) 0.027Definition of abbreviations: CI = confidence interval; HR = hazard ratio; IQR = interquartile range.CORRESPONDENCECorrespondence 351Laura Disano, M.D.Royal Brompton & Harefield NHS Foundation TrustLondon, United KingdomGerasimos Terzis, M.Sc., Ph.D.National and Kapodistrian University of AthensAthens, GreeceNicholas S. Hopkinson, Ph.D.Imperial College LondonLondon, United KingdomJoaquim Gea, M.D., Ph.D.CIBERES, ISC IIIBarcelona, SpainIoannis Vogiatzis, Ph.D.National and Kapodistrian University of AthensAthens, GreeceFrançois Maltais, M.D.Université LavalQuébec, PQ, CanadaMichael I. Polkey, Ph.D.Royal Brompton & Harefield NHS Foundation TrustLondon, United KingdomReferences1. Seymour JM, Spruit MA, Hopkinson NS, Natanek SA, Man WD, JacksonA, Gosker HR, Schols AM, Moxham J, Polkey MI, et al. The prevalenceof quadriceps weakness in COPD and the relationship with diseaseseverity. Eur Respir J 2010;36:81–88.2. Shrikrishna D, Patel M, Tanner RJ, Seymour JM, Connolly BA,Puthucheary ZA, Walsh SL, Bloch SA, Sidhu PS, Hart N, et al.Quadriceps wasting and physical inactivity in patients with COPD.Eur Respir J 2012;40:1115–1122.3. Natanek SA, Gosker HR, Slot IG, Marsh GS, Hopkinson NS, Man WD,Tal-Singer R, Moxham J, Kemp PR, Schols AM, et al. Heterogeneityof quadriceps muscle phenotype in chronic obstructive pulmonarydisease (COPD); implications for stratified medicine? Muscle Nerve2013;48:488–497.4. Vogiatzis I, Simoes DC, Stratakos G, Kourepini E, Terzis G, Manta P,Athanasopoulos D, Roussos C, Wagner PD, Zakynthinos S. Effect ofpulmonary rehabilitation on muscle remodelling in cachectic patientswith COPD. Eur Respir J 2010;36:301–310.5. Marquis K, Debigaré R, Lacasse Y, LeBlanc P, Jobin J, Carrier G, MaltaisF. Midthigh muscle cross-sectional area is a better predictor ofmortality than body mass index in patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med 2002;166:809–813.6. Swallow EB, Reyes D, Hopkinson NS, Man WD, Porcher R, Cetti EJ,Moore AJ, Moxham J, Polkey MI. Quadriceps strength predictsmortality in patients with moderate to severe chronic obstructivepulmonary disease. Thorax 2007;62:115–120.7. Patel MS, Natanek SA, Shrikrisha D, Gea J, Terzis J, Hopkinson NS,Vogiatzis I, Maltais F, Polkey MI. Vastus lateralis fiber shift is predictive ofmortality in COPD [abstract]. Am J Respir Crit Care Med 2014;189:A3646.8. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP,Bruijnzeel PL, Rutten EP, Op ’t Roodt J, Wouters EF, Franssen FM.Clusters of comorbidities based on validated objective measurementsand systemic inflammation in patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med 2013;187:728–735.9. OgaT,NishimuraK,TsukinoM,SatoS,HajiroT.Analysisofthefactorsrelatedtomortality in chronic obstructive pulmonary disease: role of exercisecapacityandhealthstatus.AmJRespirCritCareMed2003;167:544–549.10. Patel MS, Mohan D, Andersson YM, Baz M, Kon SS, Canavan JL, JacksonSG, Clark AL, Hopkinson NS, Natanek SA, et al. Phenotypic characteristicsassociated with reduced short physical performance battery score inchronic obstructive pulmonary disease. Chest 2014;145:1016–1024.11. Waschki B, Kirsten A, Holz O, Müller KC, Meyer T, Watz H, Magnussen H.Physical activity is the strongest predictor of all-cause mortality in patientswith COPD: a prospective cohort study. Chest 2011;140:331–342.12. Guillot C, Steinberg JG, Delliaux S, Kipson N, Jammes Y, Badier M.Physiological, histological and biochemical properties of rat skeletalmuscles in response to hindlimb suspension. J ElectromyogrKinesiol 2008;18:276–283.13. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-OcampoCR, Ham J, Kang H, Evans RM. Regulation of muscle fiber type andrunning endurance by PPARdelta. PLoS Biol 2004;2:e294.14. Steiner MC, Roubenoff R, Tal-Singer R, Polkey MI. Prospects for thedevelopment of effective pharmacotherapy targeted at the skeletalmuscles in chronic obstructive pulmonary disease: a translationalreview. Thorax 2012;67:1102–1109.Published 2014 by the American Thoracic SocietySpirometry in the Occupational SettingTo the Editor:We read with great interest the recent American Thoracic Society(ATS) recommendations for performance of spirometry in theworkplace (1). The first question addressed in the guideline, andabout which a recommendation is made, concerns the importanceof technologist training as a key component for obtaining goodA B1008060402000 50 100r=–0.44, p<0.0001FEV1 % predicted% Type II fibers1.00.80.60.40.20.00 1000 2000 3000 4000 5000p = 0.027Survival time (days)SurvivalNo fiber shiftFiber shiftFigure 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 age and FEV1 % predicted as covariates.CORRESPONDENCE352 American Journal of Respiratory and Critical Care Medicine Volume 190 Number 3 | August 1 2014

Vastus lateralis fiber shift is an independent predictor of mortality in chronic obstructive pulmonary disease

Patel, Mehul

Natanek, Samantha

Martínez-Llorens, Juana

Hopkinson, Nicholas

Maltais, François

Polkey, Michael

Northumbria Research Link

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

Northumbria University Research Portal

Mehul S. Patel

Samantha A. Natanek

Grigorios Stratakos

Sergi Pascual

Juana Martínez-Llorens

Laura Disano

Gerasimos Terzis

Nicholas S. Hopkinson

Joaquim Gea

Ioannis Vogiatzis

François Maltais

Michael I. Polkey

Crossref

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

http://spiral.imperial.ac.uk/bitstream/10044/1/15653/2/American%20Journal%20of%20Respiratory%20and%20Critical%20Care%20Medicine_190_3_2014.pdf

Vastus lateralis fiber shift is an independent predictor of mortality in chronic obstructive pulmonary disease

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