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Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II–III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2–4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (−36 mm Hg, 95% CI −43·2 to −28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB −1·8, −2·4 to −1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. MyoKardia.

Abstract Rationale Single-center randomized controlled trials of the Zephyr endobronchial valve (EBV) treatment have demonstrated benefit in severe heterogeneous emphysema. This is the first multicenter study evaluating this treatment approach. Objectives To evaluate the efficacy and safety of Zephyr EBVs in patients with heterogeneous emphysema and absence of collateral ventilation. Methods This was a prospective, multicenter 2:1 randomized controlled trial of EBVs plus standard of care or standard of care alone (SoC). Primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute-walk distance, St. George’s Respiratory Questionnaire score, and modified Medical Research Council score were assessed at 3 and 6 months, and target lobe volume reduction on chest computed tomography at 3 months. Measurements and Main Results Ninety seven subjects were randomized to EBV (n = 65) or SoC (n = 32). At 3 months, 55.4% of EBV and 6.5% of SoC subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: EBV 56.3% versus SoC 3.2% (P < 0.001), with a mean ± SD change in FEV1 at 6 months of 20.7 ± 29.6% and −8.6 ± 13.0%, respectively. A total of 89.8% of EBV subjects had target lobe volume reduction greater than or equal to 350 ml, mean 1.09 ± 0.62 L (P < 0.001). Between-group differences for changes at 6 months were statistically and clinically significant: ΔEBV–SoC for residual volume, −700 ml; 6-minute-walk distance, +78.7 m; St. George’s Respiratory Questionnaire score, −6.5 points; modified Medical Research Council dyspnea score, −0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, −1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of EBV subjects. Conclusions EBV treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance, and quality of life, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT02022683).

Lung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis. We did a single-centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score ≥3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to-treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234. 50 patients (62% male, FEV1 [% predicted] mean 31·7% [SD 10·2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8·77% (IQR 2·27–35·85) versus 2·88% (0–8·51) in the control group (Mann-Whitney p=0·0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax. Unilateral lobar occlusion with endobronchial valves in patients with heterogeneous emphysema and intact interlobar fissures produces significant improvements in lung function. There is a risk of significant complications and further trials are needed that compare valve placement with lung volume reduction surgery. Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

RationaleIn patients with COPD, oxygen (O2)-supplementation via a constant flow oxygen system (CFOS) can result in insufficient oxygen saturation (SpO2 <90%) during exercise. An automatically titrating O2-system (ATOS) has been shown to be beneficial compared with an untitrated CFOS, however, it is unknown if ATOS is superior to CFOS, titrated during exercise as stipulated by guidelines. The aim was to investigate the effects of ATOS compared with titrated CFOS on walking capacity in people with hypoxaemic COPD.MethodsFifty participants completed this prospective randomised controlled, double-blind, crossover trial. Participants performed two endurance shuttle walk tests (ESWTs) with: (1) exercise titrated CFOS (ESWTCFOS) and (2) ATOS targeting an SpO2 of 92% (ESWTATOS). Primary outcome measure was walking time. Secondary measures were SpO2, transcutaneous-PCO2 (TcPCO2), respiratory rate (RR), heart rate (HR) at isotime (end of shortest ESWT) with blood gases and dyspnoea at rest and end exercise.ResultsParticipants (median (IQR): age 66 (59, 70) years, FEV1 28.8 (24.8, 35.1) % predicted, PO2 54.7 (51.0, 57.7) mm Hg, PCO2 44.2 (38.2, 47.8) mm Hg) walked significantly longer with ESWTATOS in comparison to ESWTCFOS (median effect (95% CI) +144.5 (54 to 241.5) s, p<0.001). At isotime, SpO2 was significantly higher (+3 (95% CI 1 to 4) %, p<0.001) with ATOS while TcPCO2, RR and HR were comparable. End exercise, PO2 (+8.85 (95% CI 6.35 to 11.9) mm Hg) and dyspnoea (−0.5 (95% CI −1.0 to −0.5) points) differed significantly in favour of ATOS (each p<0.001) while PCO2 was comparable.ConclusionIn patients with hypoxaemia with severe COPD the use of ATOS leads to significant, clinically relevant improvements in walking endurance time, SpO2, PO2 and dyspnoea with no impact on PCO2.Trial registration number NCT03803384.

Background Few data are available on the long-term effect of pulmonary rehabilitation (PR) and on long PR programs in interstitial lung diseases (ILD). We aimed to evaluate the effects of PR on exercise capacity (6-Minute Walking Distance, 6MWD; Peak Work Rate, W max ), quality of life (St George’s Respiratory Questionnaire, SGRQ), quadriceps force (QF) and objectively measured physical activity in ILD after the 6-month PR-program and after 1 year. Methods 60 patients (64 ± 11 years; 62% males; 23% with IPF) were randomly assigned to receive a 6 month-PR program or usual medical care. Results Exercise capacity, quality of life and muscle force increased significantly after the program as compared to control (mean,95%CI[ll to ul]; 6MWD + 72,[36 to 108] m; W max 19, [8 to 29]%pred; SGRQ − 12,[− 19 to − 6] points; QF 10, [1 to 18] %pred). The gain was sustained after 1 year (6MWD 73,[28 to 118] m; Wmax 23, [10 to 35]%pred; SGRQ − 11,[− 18 to − 4] points; QF 9.5, [1 to 18] %pred). Physical activity did not change. Conclusions PR improves exercise tolerance, health status and muscle force in ILD. The benefits are maintained at 1-year follow-up. The intervention did not change physical activity. Trial registration Clinicaltrials.gov NCT00882817 .

BackgroundThe Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients’ experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation.ObjectiveTo test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries.MethodsWe used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID.ResultsWe included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score.ConclusionsThe D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.

Background Although previous studies suggested that bariatric surgery is the most effective and sustainable treatment method for morbid obesity in long term, but without changing in lifestyle, maintaining optimal weight loss is almost impossible. Methods Sixty morbid obese patients (BMI ≥ 35) were evaluated before and after 12 weeks of bariatric surgery in order to compare the impact of two different exercise programs on body composition and functional capacity outcomes. Participants were divided into three groups: aerobic (A), aerobic-strength (AS), and control (C) group. Aerobic capacity was assessed with 12-min walk-run test (12MWRT). One-repetition maximum (1RM) test was performed to evaluation upper limb muscle strength. Lower extremity functional capacity was assessed by sit-to-stand test. Results Weight, percent body fat (PBF), and fat mass (FM) reduced greater in the trial groups in comparison to the C group ( P  < 0.05). In the AS group, the reduction of fat-free mass (FFM) was significantly lower than that in the other groups. Mean changes in 12MWRT increased significantly in the intervention groups. The mean change in the sit-to-stand scores was not statistically significant between the three groups. Comparing the intervention groups showed that mean changes in 1RM variables increased in AS group ( P  = 0.03). Conclusions The data suggests a positive effect of exercise on weight and PBF decrease after surgery, and it leads to significant improvement on aerobic capacity. Moreover, doing resisted exercise caused greater preserving of lean mass.

The improving ATTENDance (iATTEND) to cardiac rehabilitation (CR) trial tested the hypotheses that hybrid CR (HYCR) (combination of virtual and in-facility CR sessions) would result in greater attendance compared with traditional, facility-based only CR (FBCR) and yield equivalent improvements in exercise capacity and health status. Patients were randomized to HYCR (n = 142) or FBCR (n = 140), stratified by gender and race. Attendance was assessed as number of CR sessions completed within 6 months (primary end point) and the percentage of patients completing 36 CR sessions. Other end points (tested for equivalency) included exercise capacity and self-reported health status. HYCR patients completed 1 to 12 sessions in-facility, with the balance completed virtually using synchronized, 2-way audiovisual technology. Neither total number of CR sessions completed within 6 months (29 ± 12 vs 28 ± 12 visits, adjusted p = 0.94) nor percentage of patients completing 36 sessions (59 ± 4% vs 51 ± 4%, adjusted p = 0.32) were significantly different between HYCR and FBCR, respectively. The between-group changes for exercise capacity (peak oxygen uptake, 6-minute walk distance) and health status were equivalent. Regarding safety, no sessions required physician involvement, there was 1 major adverse event after a virtual session, and no falls required medical attention. In conclusion, although we rejected our primary hypothesis that attendance would be greater with HYCR versus FBCR, we showed that FBCR and HYCR resulted in similar patient attendance patterns and equivalent improvements in exercise capacity and health status. HYCR which incorporates virtually supervised exercise should be considered an acceptable alternative to FBCR. NCT Identifier: 03646760; The Improving ATTENDance to Cardiac Rehabilitation Trial – Full-Text View - ClinicalTrials. gov; https://classic.clinicaltrials.gov/ct2/show/NCT03646760

High-intensity interval training (HIT) has been proposed as a time-efficient alternative to traditional cardiorespiratory exercise training, but is very fatiguing. In this study, we investigated the effects of a reduced-exertion HIT (REHIT) exercise intervention on insulin sensitivity and aerobic capacity. Twenty-nine healthy but sedentary young men and women were randomly assigned to the REHIT intervention (men, n  = 7; women, n  = 8) or a control group (men, n  = 6; women, n  = 8). Subjects assigned to the control groups maintained their normal sedentary lifestyle, whilst subjects in the training groups completed three exercise sessions per week for 6 weeks. The 10-min exercise sessions consisted of low-intensity cycling (60 W) and one (first session) or two (all other sessions) brief ‘all-out’ sprints (10 s in week 1, 15 s in weeks 2–3 and 20 s in the final 3 weeks). Aerobic capacity ( ) and the glucose and insulin response to a 75-g glucose load (OGTT) were determined before and 3 days after the exercise program. Despite relatively low ratings of perceived exertion (RPE 13 ± 1), insulin sensitivity significantly increased by 28% in the male training group following the REHIT intervention ( P  < 0.05). increased in the male training (+15%) and female training (+12%) groups ( P  < 0.01). In conclusion we show that a novel, feasible exercise intervention can improve metabolic health and aerobic capacity. REHIT may offer a genuinely time-efficient alternative to HIT and conventional cardiorespiratory exercise training for improving risk factors of T2D.