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The Persistence of SARS-CoV-2 in tissues has been proposed as a driver of prolonged symptoms in long COVID. Pulmonary rehabilitation with exercise training is a well-established intervention for improving symptoms, functional capacity, and inflammation in chronic cardiorespiratory diseases. To investigate whether long COVID is associated with persistent viral or immune-related signals, we analyzed the long RNA profile of circulating extracellular vesicles (EVs) to determine the presence of virus-related transcripts and assess changes in response to exercise training. Fourteen adults with long COVID participated in this single-center pilot clinical trial and completed a 10-week aerobic exercise training program (twenty 1.5 h sessions). Serum-derived EV RNA profiles were analyzed via sequencing at rest (T0) and peak cardiopulmonary exercise testing (T1), before (V2) and after (V24) exercise training. Differentially expressed genes (DEGs) were identified (q < 0.05), and pathway activation analysis was performed. Serum EVs carried diverse RNA species, including protein-coding RNAs, long non-coding RNAs, short non-coding RNAs, and pseudogenes, with no virus-related RNAs detected. No significant DEGs were identified at rest between pre- and post-training, nor in response to acute exercise at pre-training. However, following training, 53 DEGs were found at peak exercise (V24T1) compared to rest (V24T0), including three upregulated genes (ANK3, FTO, FCN1) and 50 downregulated genes (TOP 5: MYL9, NRGN, H2AC6, MAP3K7CL, B2M). These genes were primarily involved in inflammation and metabolism. Pathway analysis revealed significant regulation of 100 pathways at post-training compared to pre training, predominantly inactivated, including pathways involved in inflammation (STAT3 signaling) and metabolism (O-linked glycosylation). Acute exercise and exercise training modulated EV-associated gene expression in long COVID, primarily through transcriptional downregulation. Suppression of inflammation- and immune-related genes post-training highlights potential molecular mechanisms underlying symptom improvement and identifies candidate biomarkers of recovery biology in long COVID. Importantly, while exercise training did not substantially alter EV RNA content at rest, it enhanced the body’s ability to mount a dynamic EV-mediated molecular response during exertion, reflecting improved physiological adaptability. Clinical trial registration number : NCT05398692.

Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?. A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations. HRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p<0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV %pred; lower airway wall area and wall thickness. HRR was positively associated with FEV %pred and negatively associated with airway wall thickness. An optimal HRR ≤10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58-0.66) for identifying FEV <30%pred. HRR≥11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤10 bt/min was associated with (p<0.001): ≥2 exacerbations in the previous year (OR=1.76[1.33-2.34]); CAT≥10 (OR=1.42[1.18-1.71]); mMRC≥2 (OR=1.42[1.19-1.69]); GOLD 4 (OR=1.98[1.44-2.73]) and GOLD D (OR=1.51[1.18-1.95]). HRR≤10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07-3.12], P=0.027). HRR≤10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.

Purpose. Healthy patients with unilateral diaphragm paralysis (UDP) are often asymptomatic; those with UDP and comorbidities that increase work of breathing are often dyspneic. We report the effect of obesity on exercise capacity in UDP patients. Methods. All obese and nonobese patients with UDP undergoing cardiopulmonary exercise testing (CPET) during a 32-month period in the exercise laboratory of an academic hospital were compared to a retrospectively identified cohort of obese and nonobese controls without UDP, matched for key features. CPET used a modified Bruce treadmill protocol with breath-to-breath expired gas analysis. O2 uptake, minute ventilation, exercise time, and work rate were recorded at peak exercise. Static pulmonary functions were measured. Kruskal-Wallis, Wilcoxon rank sum, and Fisher’s exact tests were used to compare continuous and categorical variables, respectively. Stratified linear regression was used to quantify the effect of UDP and obesity on CPET variables. Results. Twenty-two UDP patients and 46 controls were studied. The BMI of obese and nonobese patients was 33.0±4.2 and 25.8±2.4 kg/m2, respectively. UDP subjects with obesity, compared to controls with neither condition, showed significantly reduced peak O2 uptake normalized to actual body weight (1.57±0.64 versus 2.01±0.88 L/min), shorter exercise time (5.7±2.0 versus 8.5±2.9 minutes), and lower peak ventilation. This was not observed in UDP alone or obesity alone. Peak work rate trended lower in the combined UDP-obesity group. Conclusion. Neither UDP nor obesity alone significantly reduced exercise capacity. Superimposed UDP and obesity interact to create a ventilatory limitation to exercise, with reduced peak-VO2, exercise time, and work rate.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by pulmonary and systemic inflammation. Inflammatory mediators show relationships with shortness of breath, exercise intolerance and health related quality of life. Pulmonary rehabilitation (PR), a comprehensive education and exercise training programme, is the most effective therapy for COPD and is associated with reduced exacerbation and hospitalization rates and increased survival. Exercise training, the primary physiological intervention within PR, is known to exert a beneficial anti‐inflammatory effect in health and chronic diseases. The question of this review article is whether exercise training can also make such a beneficial anti‐inflammatory effect in COPD. Experimental studies using smoke exposure mice models suggest that the response of the immune system to exercise training is favourably anti‐inflammatory. However, the evidence about the response of most known inflammatory mediators (C‐reactive protein, tumour necrosis factor α, interleukin 6, interleukin 10) to exercise training in COPD patients is inconsistent, making it difficult to conclude whether regular exercise training has an anti‐inflammatory effect in COPD. It is also unclear whether COPD patients with more persistent inflammation are a subgroup that would benefit more from hypothesized immunomodulatory effects of exercise training (i.e., personalized treatment). Nevertheless, it seems that PR combined with maintenance exercise training (i.e., lifestyle change) might be more beneficial in controlling inflammation and slowing disease progress in COPD patients, specifically in those with early stages of disease. What is the topic of this review? The response of immune cells and inflammatory markers to exercise training in cigarette smoke exposure and COPD. What advances does it highlight? Exercise training modifies pulmonary inflammation and slows development or progression of emphysema in smoke‐exposed mice, but evidence is lacking to support immunomodulation by pulmonary rehabilitation in COPD patients.

Thoroughly revised and updated for today's clinicians, Wasserman Whipp's Principles of Exercise Testing and Interpretation, Sixth Edition, provides a comprehensive, practical overview of cardiopulmonary exercise testing (CPET) ideally suited for pulmonologists, cardiologists, anesthesiologists, and others with an interest in clinical exercise testing. Written by authors who are uniquely positioned to convey relevant aspects of research and apply them to clinical contexts, this volume offers in-depth coverage of essential information for conducting CPET, or for utilizing data from this discipline in clinical practice or research.

The optimal management of patients with intermediate-risk pulmonary embolism (PE), who have right heart dysfunction (determined by a combination of imaging and cardiac biomarkers) but a normal blood pressure, is uncertain. These patients suffer from reduced functional capacity and a lower quality of life over the long-term, despite use of anticoagulant therapy. Catheter-directed therapy (CDT) is a promising treatment for acute PE that rapidly removes thrombus and potentially improves cardiac dysfunction. However, CDT has risk and is costly, and it is not known whether it improves long-term cardiorespiratory fitness and/or quality of life compared with anticoagulation alone. We are therefore conducting an open-label, assessor-blinded, multicenter randomized trial, the Pulmonary Embolism: Thrombus Removal with Catheter-Directed Therapy (PE-TRACT) Study, to compare CDT plus anticoagulation (CDT group) with anticoagulation alone (No-CDT group) in 500 patients with intermediate-risk PE. The primary study hypothesis is that CDT will increase the peak oxygen uptake (peak VO2) with cardiopulmonary exercise testing at 3 months and reduce New York Heart Association (NYHA) Class at 12 months compared with No-CDT. These 2 primary efficacy outcomes will be analyzed sequentially using a “gatekeeping” procedure; for NYHA class to be compared, peak oxygen consumption must first be shown to be significantly increased by CDT. Safety and cost-effectiveness will also be assessed. When completed, PE-TRACT will provide important evidence regarding the benefits and risks of CDT to treat intermediate-risk PE compared with anticoagulation alone. clinicaltrials.gov: NCT05591118.

PurposePathogen transmission during cardio-pulmonary exercise testing (CPET) is caused by carrier aerosols generated during respiration.MethodsTen healthy volunteers (age range: 34 ± 15; 4 females) were recruited to see if the physiological reactions to ramp-incremental CPET on a cycle ergometer were affected using an in-line filter placed between the mouthpiece and the flow sensor. The tests were in random order with or without an in-line bacterial/viral spirometer filter. The work rate aligned, time interpolated 10 s bin data were compared throughout the exercise period.ResultsFrom rest to peak exercise, filter use increased only minute ventilation (V˙E) (ΔV˙E = 1.56 ± 0.70 L/min, P < 0.001) and tidal volume (VT) (ΔVT = 0.10 ± 0.11 L, P = 0.014). Over the entire test, the slope of the residuals for V˙CO2 was positive (0.035 ± 0.041 (ΔL/L), P = 0.027). During a ramp-incremental CPET in healthy subjects, an in-line filter increased V˙E and VT but not metabolic rate.ConclusionIn conclusion, using an in-line filter is feasible, does not affect appreciably the physiological variables, and may mitigate risk of aerosol dispersion during CPET.

Oxygen uptake (V.o2) measured at the mouth, which is equal to the cardiac output (CO) times the arterial–venous oxygen content difference [C(a–v)O2], increases more than 10- to 20-fold in normal subjects during exercise. To achieve this substantial increase in oxygen uptake [V.o2 = CO × C(a–v)O2] both CO and the arterial–venous difference must simultaneously increase. Although this occurs in normal subjects, patients with heart failure cannot achieve significant increases in cardiac output and must rely primarily on changes in the arterial–venous difference to increase V.o2 during exercise. Inadequate oxygen delivery to the tissue during exercise in heart failure results in tissue anaerobiosis, lactic acid accumulation, and reduction in exercise tolerance. H+ is an important regulatory and feedback mechanism to facilitate additional oxygen delivery to the tissue (Bohr effect) and further aerobic production of ATP when tissue anaerobic metabolism increases the production of lactate (anaerobic threshold). This H+ production in the muscle capillary promotes the continued unloading of oxygen (oxyhemoglobin desaturation) while maintaining the muscle capillary Po2 (Fick principle) at a sufficient level to facilitate aerobic metabolism and overcome the diffusion barriers from capillary to mitochondria (“critical capillary Po2,” 15–20 mm Hg). This mechanism is especially important during exercise in heart failure where cardiac output increase is severely constrained. Several compensatory mechanisms facilitate peripheral oxygen delivery during exercise in both normal persons and patients with heart failure.

The relationship of oxygen uptake to ventilation , i.e., oxygen uptake efficiency (OUE) is known to differ between normal subjects and patients with congestive heart failure. However, only the oxygen uptake efficiency slope (OUES, i.e., slope of has previously been reported. To understand the physiology and to improve the usefulness of OUE in assessing cardiovascular function, we analyzed the complete response pattern of OUE during entire incremental exercise tests and ascertained effect of age, body size, gender, fitness, and ergometer type on exercise OUE to generate reference values in normal healthy subjects. We investigated the effect of age, gender, and fitness on OUE using incremental cardiopulmonary exercise in 474 healthy subjects, age 17–78 years, of which 57 were highly fit. The final methods of OUE analysis were: (1) OUE plateau at the highest values (OUEP), (2) OUE at anaerobic threshold (OUE@AT), and (3) OUES using the entire exercise period. The OUEP and OUE@AT were similar, highly reproducible, less variable than the OUES ( p  < 0.0001), and unaffected by the study sites or types of ergometry. The resultant prediction equations from 417 normal subjects for men were OUEP (mL/L) = 42.18 − 0.189 × years + 0.036 × cm and OUES [L/min/log(L/min)] = −0.610 − 0.032 × years + 0.023 × cm + 0.008 × kg. For women, OUEP (mL/L) = 39.16 − 0.189 × years + 0.036 × cm and OUES [L/min/log(L/min)] = −1.178 − 0.032 × years + 0.023 × cm + 0.008 × kg. OUE@AT was similar to OUEP. Extreme fitness has a minimal effect on OUEP. OUEP is advantageous, since it measures maximal oxygen extraction from ventilated air but does not require high intensity exercise. The OUEP is a non-invasive parameter dependent only on age, gender, height, and cardiovascular health.