Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with systemic consequences that can cause a muscle loss phenotype (MLP), which is characterized by the loss of muscle mass, muscle strength, or loss of both muscle and fat mass. There are limited data comparing the individual traits of MLP with clinical outcomes in a large unbiased cohort of COPD patients. Our aim was to determine the proportion of patients who met criteria for MLP in an unbiased sample of COPD patients at the population-level. We also determined if specific MLP features were associated with all-cause and COPD-related mortality. METHODS: A retrospective population-based cohort analysis of the UK Biobank was performed. COPD was defined by a FEV1/FVC ratio < 0.7, physician established diagnosis of COPD, or those with a COPD-related hospitalization before baseline assessment. MLP included one or more of the following: 1) Low fat-free mass index (FFMI) on bioelectric impedance analysis (BIA) or 2) Appendicular skeletal muscle index (ASMI) on BIA, 3) Low muscle strength defined by handgrip strength (HGS), or 4) Low muscle and fat mass based on body mass index (BMI). Cox regression was used to determine the association between MLP and all-cause or COPD-related mortality. All models were adjusted for sex, age at assessment, ethnicity, BMI, alcohol use, smoking status, prior cancer diagnosis and FEV1/FVC ratio. RESULTS: There were 55,782 subjects (56% male) with COPD followed for a median of 70.1 months with a mean(± SD) age at assessment of 59 ± 7.5 years, and FEV1% of 79.2 ± 18.5. Most subjects had mild (50.4%) or moderate (42.8%) COPD. Many patients had evidence of a MLP, which was present in 53.4% of COPD patients (34% by ASMI, 26% by HGS). Of the 5,608 deaths in patients diagnosed with COPD, 907 were COPD-related. After multivariate adjustment, COPD subjects with MLP had a 30% higher hazard-ratio for all-cause death and 70% higher hazard-ratio for COPD-related death. CONCLUSIONS: Evidence of MLP is common in a large population-based cohort of COPD and is associated with higher risk for all-cause and COPD-related mortality.

Noninvasive positive pressure in acute exacerbations of chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Noninvasive positive pressure ventilation (NIV) is standard of care for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We review the most current evidence and highlight areas of uncertainty and ongoing research. We highlight key concepts for the clinician caring for patients with AECOPD which require NIV. RECENT FINDINGS: Implementation of NIV in AECOPD is not uniform in spite of the evidence and guidelines. Initiation of NIV should be done early and following protocols. Low-intensity NIV remains the standard of care, although research and guidelines are evaluating higher intensity NIV. Scores to predict NIV failure continue to be refined to allow early identification and interventions. Several areas of uncertainty remain, among them are interventions to improve tolerance, length of support and titration and nutritional support during NIV. SUMMARY: The use of NIV in AECOPD is the standard of care as it has demonstrated benefits in several patient-centered outcomes. Current developments and research is related to the implementation and adjustment of NIV.

Budget impact analysis of a digital monitoring platform for COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive debilitating condition with frequent exacerbations that have a high burden for patients and society. Digital tools may help to reduce the economic burden for patients and payers by improving outcomes. The Propeller platform is a digital self-management tool that facilitates passive monitoring of inhaler medication utilization, potentially assisting the healthcare team to identify patients at risk of a COPD exacerbation who may require further intervention. This study estimated the budget impact of Propeller from commercial payer and Medicare fee-for-service payer perspectives. METHODS: An Excel-based model was used to estimate the budget impact of Propeller for COPD patients in commercial and Medicare population sizes of 5 million members. Data on prevalence, baseline healthcare resource utilization (HCRU), and baseline use of rescue and controller inhaler medications with unit costs (adjusted to 2020 US dollars) were obtained from peer-reviewed literature. Data on reductions in HCRU during Propeller usage were based on direct evidence. Estimates for costs of remote monitoring were obtained from publicly available information. All patients were assumed to have insurance claims related to ongoing remote monitoring. RESULTS: The estimated number of annual eligible COPD patients for commercial and Medicare was 212,200 and 606,600, respectively. Propeller decreased costs by an estimated $2,475 (commercial) and $915 (Medicare) per enrolled patient. The greatest increase in expenditure was for remote monitoring related expenses. After accounting for estimated reductions in hospitalizations, emergency department visits and short-acting beta-agonist use, total net savings were approximately $1.60 and $1.70 per-member per-month for commercial and Medicare payers, respectively. CONCLUSION: Propeller is projected to be cost saving from both the commercial and Medicare payer perspectives.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Endotracheal Tube Obstruction Among Patients Mechanically Ventilated for ARDS Due to COVID-19: A Case Series.

BACKGROUND: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing endotracheal tube (ETT) obstruction that has not been previously described in patients with ARDS due to other causes. The purpose of this report is to describe a case series of patients with COVID-19 and ARDS in which ETT occlusion resulted in significant clinical consequences and to define the pathology of the obstructing material. METHODS: Incidents of ETT occlusion during mechanical ventilation of COVID-19 patients were reported by clinicians and retrospective chart review was conducted. Statistical analysis was performed comparing event rates between COVID-19 and non-COVID 19 patients on mechanical ventilation over the predefined period. Specimens were collected and submitted for pathological examination. FINDINGS: Eleven COVID-19 patients experienced endotracheal tube occlusion over a period of 2 months. Average age was 69 (14.3, range 33-85) years. Mean APACHE III score was 73.6 (17.3). All patients had AKI and cytokine storm. Nine exhibited biomarkers for hypercoagulability. Average days on mechanical ventilation before intervention for ETT occlusion was 14 (5.18) days (range of 9 to 23 days). Five patients were discharged from the ICU, and 4 expired. Average documented airway resistance on admission was 14.2 (3.0) cm H2O/L/sec. Airway resistance before tube exchange was 28.1 (8.0) cm H2O /L/sec. No similar events of endotracheal tube occlusion were identified in non-COVID patients on mechanical ventilation during the same time period. Microscopically, the material consisted of mucin admixed with necrotic cell debris, variable numbers of degenerated inflammatory cells, oral contaminants and red blood cells. INTERPRETATION: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing ETT obstruction due to deposition of a thick, tenacious material within the tube that consists primarily of mucin and cellular debris. Clinicians should be aware of this dangerous but treatable complication.

Muscle loss contributes to higher morbidity and mortality in COPD: An analysis of national trends.

BACKGROUND AND OBJECTIVE: COPD is the third most common cause of death worldwide and fourth most common in the United States. In hospitalized patients with COPD, mortality, morbidity and healthcare resource utilization are high. Skeletal muscle loss is frequent in patients with COPD. However, the impact of muscle loss on adverse outcomes has not been systematically evaluated. We tested the hypothesis that patients hospitalized for COPD exacerbation with, compared to those without, a secondary diagnosis of muscle loss phenotype (all ICD-9 codes associated with muscle loss including cachexia) will have higher mortality and cost of care. METHODS: The NIS database of hospitalized patients in 2011 (1 January-31 December) in the United States was used. The impact of a muscle loss phenotype on in-hospital mortality, LOS and cost of care for each of the 174 808 hospitalizations for COPD exacerbations was analysed. RESULTS: Of the subjects admitted for a COPD exacerbation, 12 977 (7.4%) had a secondary diagnosis of muscle loss phenotype. A diagnosis of muscle loss phenotype was associated with significantly higher in-hospital mortality (14.6% vs 5.7%, P < 0.001), LOS (13.3 + 17.1 vs 5.7 + 7.6, P < 0.001) and median hospital charge per patient ($13 947 vs $6610, P < 0.001). Multivariate regression analysis showed that muscle loss phenotype increased mortality by 111% (95% CI: 2.0-2.2, P < 0.001), LOS by 68.4% (P < 0.001) and the direct cost of care by 83.7% (P < 0.001) compared to those without muscle loss. CONCLUSION: In-hospital mortality, LOS and healthcare costs are higher in patients with COPD exacerbations and a muscle loss phenotype.

Quantitative Computed Tomography Assessment of Pectoralis and Erector Spinae Muscle Area and Disease Severity in Chronic Obstructive Pulmonary Disease Referred for Lung Volume Reduction.

Patients with advanced chronic obstructive pulmonary disease (COPD) develop skeletal muscle loss (sarcopenia) that is associated with adverse clinical outcomes including mortality. We evaluated if thoracic muscle area is associated with clinical outcomes in patients with severe COPD. We analyzed consecutive patients with severe COPD undergoing evaluation for lung volume reduction from 2015 to 2019 (n = 117) compared to current and former smoking controls undergoing lung cancer screening with normal lung function (n = 41). Quantitative assessments of pectoralis muscle (PM) and erector spinae muscle (ESM) cross sectional area (CSA) were related to clinical outcomes including composite endpoints. Our results showed a reduction in PM CSA but not ESM CSA was associated with the severity of GOLD stage of COPD. Current smokers demonstrated reduced PM CSA which was similar to that in COPD patients who were GOLD stages 3 and 4. PM CSA was associated positively with FEV1, FEV1% predicted, FVC, DLCO, and FEV1/FVC ratio, and was associated negatively with the degree of radiologic emphysema. ESM correlated positively with DLCO, RV/TLC (a marker of hyperinflation), and correlated negatively with radiologic severity of emphysema. Kaplan-Meier analysis showed that reductions in PM but not ESM CSA was associated with the composite end point of mortality, need for lung volume reduction, or lung transplant. In conclusion, in well-characterized patients with severe COPD referred for lung volume reduction, PM CSA correlated with severity of lung disease, mortality, and need for advanced therapies. In addition to predicting clinical outcomes, targeting sarcopenia is a potential therapeutic approach in patients with severe COPD.

Duration of noninvasive ventilation is not a predictor of clinical outcomes in patients with acute exacerbation of COPD and respiratory failure.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity. Noninvasive ventilation (NIV) is proven to be effective in the majority of patients with acute exacerbation COPD (AECOPD) complicated with respiratory failure. NIV could be lifesaving but also can delay mechanical ventilation if its efficacy is not assessed in a timely manner. In this study, we analyzed potential predictors of NIV failure in AECOPD in a tertiary medical intensive care unit (MICU). In particular, we wondered whether duration of NIV among those who eventually failed was associated with poor outcomes. METHODS: A retrospective review of consecutive patients with a primary diagnosis of AECOPD requiring NIV admitted to the MICU was conducted for the period between 2012 and 2017. Baseline data included demographics, APACHE III score, albumin level, blood lactate, and blood gas elements. Additional chart review was performed to collect NIV setting parameters on presentation to the MICU. Clinical outcome variables collected included outcome and duration of NIV, duration of invasive mechanical ventilation, MICU length of stay, hospital length of stay, and in-hospital mortality. Multivariate regression analysis was performed to determine independent variables associated with clinical outcomes. RESULTS: There were 370 patients who met the inclusion criteria; 53.2% were male. Mean age was 64.7 ± 11.2 years old. Mean baseline FEV1 was 34 ±17% of predicted. Patients had mean pH of 7.20 ± 0.54 and PaCO2 of 70.3 ± 28.7 on presentation; 323 patients (87.3%) were successfully weaned off NIV; 47 patients (12.7%) failed NIV and required invasive mechanical ventilation. APACHE III score was higher among patients who failed NIV (68.3±18.9 versus 48.8± 15.2, P < 0.001). In the subset of 47 patients who failed NIV requiring intubation, duration of NIV was 25.0 ± 58.8 h. Multivariate regression analysis yielded a model consisting of APACHE III score and body mass index as predictive variables for NIV failure (C-statistic = 0.809). Duration of NIV was not associated with worse clinical outcomes among patients who failed NIV. CONCLUSIONS: NIV is successful in preventing invasive mechanical ventilation in majority of patients with acute respiratory failure due to COPD. Patients with worse clinical status at presentation are more likely to fail NIV and require mechanical ventilation. In the subgroup of patients who failed NIV, duration of NIV prior to intubation was not associated with poor clinical outcomes.

Utilization of Thoracic Ultrasound for Confirmation of Central Venous Catheter Placement and Exclusion of Pneumothorax: A Novel Technique in Real-Time Application.

AIM: To evaluate the safety and utility of ultrasonography as a tool to confirm central venous catheter (CVC) position and to exclude insertion-related pneumothorax in place of chest radiography (CXR) in a tertiary medical intensive care unit (ICU). METHODS: We randomized 60 consecutive medical ICU patients to conventional or ultrasound groups for CVC placement. Both groups had CVCs inserted under ultrasound guidance. The intervention group underwent real-time transthoracic echocardiography to assist in catheter positioning and chest ultrasonography for exclusion of pneumothorax. Our primary end point was reduction in CXR use. The secondary end point was time elapsed from the end of procedure to the availability of CVC for use. χ2 test was used to compare the 2 groups for the primary end point. T test was used to compare the 2 groups for the secondary end point. RESULTS: Thirty patients were randomized to the conventional group and 30 were randomized to the ultrasound group. One patient was excluded in the control group since the procedure needed to be aborted. Patient characteristics were well matched for age, body mass index, and acute physiologic assessment and chronic health evaluation (APACHE III) scores. There was a 56.7% ( P < .0001) reduction in CXR use in the ultrasound arm. Mean time to use was 53.6 minutes in the control group and 25 minutes in the ultrasound arm ( P = .0015). Mean time required to complete the procedure was 27.7 minutes in the control group and 24.1 minutes in the ultrasound group ( P = .2053). No pneumothorax was detected in either arm. CONCLUSION: Ultrasound-guided CVC placement and positioning with a minor modification in technique reduced the use of bedside CXR and reduced the time to use of the CVC.

Supplemental oxygen in patients with stable chronic obstructive pulmonary disease: evidence from Nocturnal Oxygen Treatment Trial to Long-term Oxygen Treatment Trial.

PURPOSE OF REVIEW: Oxygen therapy was the first treatment shown to prolong life in patients with chronic obstructive pulmonary disease (COPD) and has been joined by lung volume reduction surgery in selected patients with emphysema, smoking cessation, and potentially noninvasive ventilation in chronic hypercapneic respiratory failure. Although there is consensus around the survival-enhancing effect of supplemental oxygen (SupplO2) for patients with chronic severe hypoxemia at rest, the impact of SupplO2 for COPD patients with moderate hypoxemia and exertional desaturation had been less clear. RECENT FINDINGS: The recently published Long-term Oxygen Treatment Trial (LOTT) showed no benefit of SupplO2 for the composite outcome of survival and all-cause hospitalizations, or for component outcomes, severe COPD exacerbations, or quality of life in COPD patients with moderate resting hypoxemia or room air normoxemia with exercise desaturation. SUMMARY: Results of the LOTT challenge the practice of prescribing SupplO2 for patients with COPD and moderate resting hypoxemia or isolated exertional desaturation. In the context that LOTT may not have recruited patients for whom SupplO2 conferred subjective benefit, there may be a role for short-term trials of SupplO2 with assessment of subjective benefit in such patients.

Intralobar Pulmonary Sequestration Presenting as Chronic Non-productive Cough.

We report a case of a 60-year-old female who was known to have intralobar pulmonary sequestration and her only symptom was chronic cough. She had no history of infections and surgical resection led to complete resolution of her chronic cough.

A Taxonomy for Noninvasive Modes Provided by Portable Ventilators.

The purpose of this article is to identify (by brand name) and then classify the modes available on contemporary portable ventilators used for noninvasive ventilation in the United States. We propose a formal taxonomy that identifies the modes by their control variable, breath sequence, and targeting scheme, therefore describing what the mode does. Use of this taxonomy should be helpful in finding modes with comparable functionality that cater to the specific goal of mechanical ventilation and effective ventilatory strategies for each disease state.

Nocturnal Hypoxemia Is Associated with Sarcopenia in COPD Patients.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Our previous studies have identified that nocturnal hypoxemia causes skeletal muscle loss (i.e. sarcopenia) in in vitro models of COPD. RATIONALE: We aimed to extend our preclinical mechanistic findings by analyzing a large sleep registry to determine whether nocturnal hypoxemia is associated with sarcopenia in COPD patients. METHODS: Sleep studies from COPD patients (n=479) and control subjects without COPD (n=275) were analyzed. Patients with obstructive sleep apnea (OSA), as defined by apnea hypopnea index >5, were excluded. Pectoralis muscle cross sectional area (PMcsa) was quantified using CT scans performed within one year of the sleep study. We defined sarcopenia as less than the lowest 20% residuals for PMcsa of controls, which was adjusted for age, BMI, and stratified by sex. Youden's optimal cutpoint criteria was used to predict sarcopenia based on mean oxygen saturation (mean SaO2) during sleep. Additional measures of nocturnal hypoxemia were analyzed. Pectoralis muscle index (PMI) was defined as PMcsa normalized to BMI. RESULTS: On average, COPD males had 16.6% lower PMI than control males (1.41+0.44 vs 1.69+0.56 cm2/BMI, p<0.001), while COPD females had 9.4% lower PMI than control females (0.96+0.27 vs 1.06+0.33 cm2/BMI, p<0.001). COPD males with nocturnal hypoxemia had a 9.5% decrease in PMI versus COPD with normal O2 (1.33+0.39 vs 1.47+0.46 cm2/BMI, p<0.05), and 23.6% decrease compared to controls (1.33+0.39 vs 1.74+0.56 cm2/BMI, p<0.001). COPD females with nocturnal hypoxemia had a 11.2% decrease versus COPD with normal O2 (0.87+0.26 vs 0.98+0.28 cm2/BMI, p<0.05), and 17.9% decrease compared to controls (0.87+0.26 vs 1.06+0.33 cm2/BMI, p<0.001). These findings were largely replicated using multiple measures of nocturnal hypoxemia. CONCLUSIONS: We defined sarcopenia in the pectoralis muscle using residuals that take into account age, BMI, and sex. We found that COPD patients have lower PMI than non-COPD patients, and that nocturnal hypoxemia was associated with an additional decrease in the PMI of COPD patients. Additional prospective analyses are needed to determine a protective threshold of oxygen saturation to prevent or reverse sarcopenia due to nocturnal hypoxemia in COPD.

ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Bench Assessment of Work of Breathing During a Spontaneous Breathing Trial on Zero Pressure Support and Zero PEEP Compared to T-Piece.

BACKGROUND: Analysis of observational data suggests that both a T-piece and zero pressure support ventilation (PSV) and zero PEEP impose work of breathing (WOB) during a spontaneous breathing trial (SBT) similar to what a patient experiences after extubation. The aim of our study was to compare the WOB imposed by the T-piece with zero PSV and zero PEEP. We also compared the difference in WOB when using zero PSV and zero PEEP on 3 different ventilators. METHODS: This study was conducted by using a breathing simulator that simulated 3 lung models (ie, normal, moderate ARDS, and COPD). Three ventilators were used and set to zero PSV and zero PEEP. The outcome variable was WOB expressed as mJ/L of tidal volume. RESULTS: An analysis of variance showed that WOB was statistically different between the T-piece and zero PSV and zero PEEP on all the ventilators (Servo-i, Servo-u, and Carescape R860). The absolute difference was lowest for the Carescape R860, which increased WOB by 5-6%, whereas the highest for Servo-u, which reduced the WOB by 15-21%. CONCLUSIONS: Work may be imposed or reduced during spontaneous breathing on zero PSV and zero PEEP when compared to T-piece. The unpredictable nature of how zero PSV and zero PEEP behaves on different ventilators makes it an imprecise SBT modality in the context of assessing extubation readiness.

Bedside Assessment of Lung Recruitability: Making Sense of the Recruitment-to-Inflation Ratio.

Determination of optimum PEEP levels remains an elusive goal. One factor is the recruitability of the lung, yet this is another difficult determination. Recently, a simple bedside technique, called the recruitment-to-inflation ratio, has been described and validated by comparison to the dual pressure-volume curve method. We describe the prior research and concepts of lung mechanics leading up to this metric and develop some background mathematics that help clinicians understand its meaning.

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. METHODS: To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome-wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non-Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity-associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. RESULTS: Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non-coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (ß = 0.151, SE = 0.021, P = 1.40 × 10-12 for UK Biobank |ß= 0.220, SE = 0.041, P = 9.99 × 10-8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (ß = 0.129, SE = 0.024, P = 4.64 × 10-8 for UK Biobank |ß = 0.203, SE = 0.045, P = 6.38 × 10-6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence-associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. CONCLUSIONS: Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.