The minimum important difference (MID) for field walking tests aims to improve interpretation of outcomes, but the volume and heterogeneity of MIDs for these tests is challenging. We aimed to determine the MID for the 6-min walk distance (6MWD), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT) in adults with long-term conditions.

This systematic review included studies that generated a MID using an anchor-based approach in patients with long-term conditions for the 6MWD, ISWT or ESWT field walking tests. Studies were screened and data extracted by independent reviewers. Meta-analyses were performed using RevMan.

42 studies were included in the analyses, involving n=13 949 participants. Of these, 12 studies involving exercise as an intervention were included in the meta-analyses to produce MIDs, presented as mean (95% confidence interval). The MID for the 6MWD was 25 m (24-26 m) for respiratory conditions, 23 m (8-37 m) for cardiac conditions and 37 m (26-49 m) for neurological/musculoskeletal conditions. The MID for the ISWT was 48 m (39-57 m) for respiratory conditions and 70 m (55-85 m) for cardiac conditions. The MID for ESWT in COPD was 159 s (94-224 s). The pooled MID across conditions within exercise interventions was 26 m (22-40 m) for the 6MWD and 53 m (44-62 m) for the ISWT, with reasonable heterogeneity (I2=48% and I2=47%, respectively).

We propose new MIDs for exercise interventions using anchor-based methodology in long‑term conditions for the 6MWD, ISWT and ESWT. These can be used internationally for meta‑analyses where studies have used different field walking tests, to optimise trial sample size calculations, and for clinical service benchmarking.

There is a need for objective, continuous and remote assessment of exercise capacity in patients with pulmonary arterial hypertension (PAH). Using data from the TRACE study, in which 108 adult patients with PAH were continuously monitored with a wrist-worn accelerometer, we evaluated whether actigraphy can facilitate continuous monitoring of exercise capacity. Distributions of step rate, distance and duration of patient's walking bouts were estimated at baseline, Week 16 and Week 24 using 2-week periods of actigraphy data. Twenty-one metrics per walking bout characteristic were described (mean, standard deviation, 19 percentiles [5th-95th]). The relationships between these metrics and the 6-min walk distance (6MWD), Borg dyspnea index (BDI), and the PAH Symptoms and Impact questionnaire (PAH-SYMPACT) Physical Impact domain score were assessed at the three timepoints. Test-retest reliability, and discriminant and known-group validity of each metric were also evaluated. All metrics of step rate and bout distance were significantly correlated with 6MWD (Pearson's correlation coefficients: 0.34-0.67; p < 0.005) and the PAH-SYMPACT Physical Impact domain score (Pearson's correlation coefficients: -0.51 to -0.32; p < 0.05) at all timepoints. Negative correlations were also observed with the BDI and the actigraphy-derived metrics, with the majority reaching significance. Strong test-retest reliability was demonstrated (intra-class correlation coefficient ≥ 0.70). The metrics differentiated well between patients with varying disease severity levels. In conclusion, actigraphy-derived metrics of patients' walking bouts correlate significantly with 6MWD, BDI and physical impacts of PAH, indicating the utility of actigraphy in facilitating continuous monitoring of exercise capacity in adult patients with PAH.

ClinicalTrials.gov: NCT03078907; URL: clinicaltrials.gov.

Intra-articular corticosteroid injection is commonly used for pain relief in ankle osteoarthritis (OA). The effects of corticosteroids (CS) are short-lived, whereas hyaluronic acid (HA) have longer-lasting effects. The objective was to compare the efficacy of dual injections of CS and HA to CS alone. We hypothesized that intra-articular injections of dual agents would be more effective than CS alone.

A single-blind, randomized, controlled trial was designed to investigate this hypothesis. 135 patients with ankle OA were enrolled into an intra-articular CS injection group (CS group, n = 61) or dual HA plus CS injection group (CS + HA group, n = 74). The CS group received 1 mL of corticosteroid and 1 mL of 0.5% bupivacaine and 1 mL of normal saline once, and the CS + HA group received 3 mL of a total of 5 mL mixtures containing 2 mL of HA, or 1 mL of corticosteroid, 0.5% bupivacaine, and normal saline in the first week, followed by 2 mL of HA in the second and third weeks. Clinical evaluations were performed before injection, 6 and 12 weeks after the first injections. The Ankle Osteoarthritis Scale (AOS) was used as the primary outcome measure, and the Visual Analogue Scale (VAS), Short Form Health Survey (SF-36), and complications were used as secondary outcomes.

The mean AOS change from baseline was significantly greater in the CS + HA group than in the CS group at 6 (p ≤ 0.01) and 12 weeks (p ≤ 0.01). The mean VAS change from baseline was significantly greater in the CS group than in the CS + HA group at 6 weeks (p = 0.023), but not at 12 weeks (p = 0.731). The mean SF-36 change from baseline was not significant between the CS and CS + HA groups at 6 (p = 0.416) and 12 weeks (p = 0.215).

The combination of corticosteroid and HA injection is more effective than corticosteroid alone in relieving pain in ankle OA.

Clinical Research Information Service in South Korea, KCT0008690 // Registration Date (First Posted): July 21th, 2023 ( http://cris.nih.go.kr ).

Postoperative rehabilitation following total knee arthroplasty (TKA) varies worldwide. In Finland, patients receive guidance on safe walking and home exercises from a physiotherapist both before and after TKA. These are performed independently after surgery. However, a sedentary lifestyle is rather common among patients who have undergone TKA, with pain often limiting postoperative walking, training, and activities of daily living.

This randomized controlled trial aimed to investigate the effectiveness of anti-gravity exercise, precisely the AlterG anti-gravity treadmill, on postoperative rehabilitation following TKA and to obtain new knowledge on this form of rehabilitation to better use it in the future.

This randomized controlled trial study divided the patients into two groups: the intervention group and the control group. The follow-up period was 12 months. Research data were collected through questionnaires and functional tests. All patients in both groups responded to the questionnaires and participated in functional tests before surgery as well as 4 and 12 months after surgery. Patients in the intervention group exercised on the AlterG treadmill 10 times after the surgery. All the patients in this study performed the exercises as instructed when they were in the hospital. The primary outcomes were perceived pain, walking ability, and quality of life.

The data collection process began in 2018 and concluded in 2022, intending to obtain valuable information regarding the effect of AlterG training after TKA and determine whether it, along with traditional exercises, could be an effective form of rehabilitation that can be performed at home. We hypothesized that AlterG training would lead to faster rehabilitation, better walking quality, improved quality of life, improved physical activity, and improved overall functioning. The results of this study will be analyzed in 2025 and 2026.

This study provides information on how AlterG training can be used in rehabilitation after TKA, further enhancing the rehabilitation program for patients undergoing TKA in general.

ClinicalTrials.gov NCT03904030; https://clinicaltrials.gov/study/NCT03904030.

DERR1-10.2196/59935.

The minimally important difference (MID) in the 6-min walk test (6MWT) for pulmonary arterial hypertension (PAH) is estimated to be 33 m using distributional and anchor-based methods. Quality of life was used as the anchor. Here, we sought to determine whether the MID is predictive of clinical worsening.

This was a post hoc analysis of the pivotal clinical trial of tadalafil in PAH (n = 405) and its extension phase (n = 161). The 6MWT was determined at the end of the placebo-controlled phase of 16 weeks and dichotomized as < 33 or ≥33 m. Primary outcome was clinical worsening ascertained at 16 weeks and at 68 weeks of follow up. Cox proportional hazard analysis was used to determine the association between 6MWT and clinical worsening.

Mean age for patients in the pivotal trial of tadalafil was 54 years old ( ± 15.5 yrs). There were 317 (78.3 %) female patients and 61 % with idiopathic PAH. 53 % of the patients were on background bosentan therapy. A 6MWT <33 m was associated with an increased risk of clinical worsening at 16 and 68 weeks. These results were unchanged after adjusting for age, sex, background therapy with bosentan, and tadalafil dose. There were no PAH hospitalizations during short-term and long-term follow up in patients achieving a 6MWT ≥33 m CONCLUSIONS: The 6MWT MID of 33 m is predictive of short- and long-term clinical worsening. These results further validate 33 m as a relevant MID for the 6MWT.

Adaptation of the right ventricle is a key determinant of outcomes in pulmonary arterial hypertension (PAH). Despite a compelling rationale to develop targeted therapies for the right ventricle in PAH, no such treatments exist. H2-receptor antagonism is a potential myocardial-focused paradigm in heart failure.

Do H2-receptor antagonists improve outcomes in patients with PAH?

We conducted a 24-week, single-center, 1:1 randomized, double-masked, placebo-controlled trial of the H2-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in 6-minute walk distance (6MWD) at 24 weeks. Secondary end points included B-type natriuretic peptide levels, New York Heart Association functional class, right ventricular parameters measured from echocardiography, health-related quality of life, and escalation in PAH-focused care.

From May 2019 through July 2023, 80 participants were randomized with 79 receiving study drug. No significant difference in the primary outcome of 6MWD at 24 weeks was found, with an increase of 4.7 m seen in the placebo arm vs a decrease of 17.0 m in the famotidine arm (P = .24). Also no differences were found in secondary end points at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct were good overall. Participants with methamphetamine-associated PAH were similar in all aspects to the study participants more broadly.

The results of this trial do not support the routine use of famotidine 20 mg daily as an adjunct therapy for the treatment of PAH. The findings of the Repurposing a Histamine Antagonist to Benefit Patients With Pulmonary Hypertension (REHAB-PH) trial argue against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies.

ClinicalTrials.gov; No.: NCT03554291; URL: www.

gov.

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Pulmonary rehabilitation (PR) guidelines support the efficacy and safety of supervised exercise training in mild-moderate pulmonary arterial hypertension (PAH). However, the exercise training response and safety of PR in PAH lung transplant (LTx) candidates has not been described.

(1) characterize the clinical characteristics and illness trajectory of adult patients with severe PAH listed for LTx and participating in PR; (2) evaluate the change in exercise capacity, aerobic and resistance training volumes; (3) assess PR safety.

Single-centre retrospective cohort study of PAH LTx candidates listed January 2014-December 2018 attending a supervised, facility-based outpatient program three times per week. Functional capacity was evaluated using 6-min walk distance (6MWD). Aerobic and muscle training volumes were evaluated with paired comparisons.

40 PAH LTx candidates (age 50 ± 12 years, 73% females, mean pulmonary artery pressure 53 ± 16 mmHg) were included. The median listing duration was 91 [IQR 43-232] days. Sixteen patients (40%) had ≥1 admission pre-transplant. Nine patients (56%) were discharged home and resumed outpatient PR. Baseline 6MWD was 330 ± 119 metres (n = 40) with the final 6MWD pre-LTx increasing by 18 metres 95% CI (-18 to 56), p-value = 0.31, n = 25) over a median duration of 225 [IQR 70-311] days. Modest gains were observed in aerobic and resistance training volumes in PR with no adverse safety events.

Despite progressive and severe disease in PAH LTx candidates, patients safely participated in PR and maintained exercise capacity. Given frequent admissions, physiotherapy during hospitalization should focus on preserving functional capacity and facilitating re-integration into outpatient PR post-discharge.

Pulmonary arterial hypertension leads to significant impairment in haemodynamics, right heart function, exercise capacity, quality of life and survival. Current therapies have mechanisms of action involving signalling via one of four pathways: endothelin-1, nitric oxide, prostacyclin and bone morphogenetic protein/activin signalling. Efficacy has generally been greater with therapeutic combinations and with parenteral therapy compared with monotherapy or nonparenteral therapies, and maximal medical therapy is now four-drug therapy. Lung transplantation remains an option for selected patients with an inadequate response to therapies.

Considerable progress has been made in the genomics of pulmonary arterial hypertension (PAH) since the 6th World Symposium on Pulmonary Hypertension, with the identification of rare variants in several novel genes, as well as common variants that confer a modest increase in PAH risk. Gene and variant curation by an expert panel now provides a robust framework for knowing which genes to test and how to interpret variants in clinical practice. We recommend that genetic testing be offered to specific subgroups of symptomatic patients with PAH, and to children with certain types of group 3 pulmonary hypertension (PH). Testing of asymptomatic family members and the use of genetics in reproductive decision-making require the involvement of genetics experts. Large cohorts of PAH patients with biospecimens now exist and extension to non-group 1 PH has begun. However, these cohorts are largely of European origin; greater diversity will be essential to characterise the full extent of genomic variation contributing to PH risk and treatment responses. Other types of omics data are also being incorporated. Furthermore, to advance gene- and pathway-specific care and targeted therapies, gene-specific registries will be essential to support patients and their families and to lay the foundation for genetically informed clinical trials. This will require international outreach and collaboration between patients/families, clinicians and researchers. Ultimately, harmonisation of patient-derived biospecimens, clinical and omic information, and analytic approaches will advance the field.

Functional tests such as the 6-minute walk test (6MWT) are used in many areas of medicine to monitor disease progression and outcomes of treatment. They are particularly helpful in Orthopaedic surgery as the outcomes have been shown to be responsive to recovery over time. The 6MWT is typically performed in a controlled supervised environment which may limit its widespread use (Terwee et al., Rheumatology (Oxford), 2006, 45, 890-902). The primary aim is to investigate if a patient measured 6MWT is comparable to a 6MWT performed under formal testing conditions (Täger et al., Int. J. Cardiol. 2014, 176, 94-98).

A total of 55 patients undergoing elective primary hip or knee replacement were instructed to use a smart watch to record a 6MWT in their home community environment (C-6MWT). These measurements were compared to a formally tested 6MWT (F-6MWT) at 2 separate time periods-6 and 12 weeks post-surgery.

At 6 weeks post operation the Intraclass Correlation Coefficient between a formally tested and a patient self-administered 6MWT was 0.928 (95% CI 0.832-0.970) and at 12 weeks it was 0.831 (0594-0.935).

A patient recorded 6 minute walk test shows high agreement with a formally recorded one under research conditions. This makes this test a suitable way to monitor rehabilitation progression and research outcomes at multiple time periods and in remote situations.

Background: There are no direct comparisons of sotatercept to add-on therapies approved for pulmonary arterial hypertension (PAH). Objective: This study aimed to compare the efficacy and safety of add-on sotatercept versus other add-on therapies using a network meta-analysis. Data Sources: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov until April 15, 2023, for randomized trials involving patients with PAH who were treated with add-on sotatercept or other add-on PAH therapies. Data Extraction: Data extraction and risk-of-bias assessments were performed independently and in duplicate using the Cochrane RoB 2.0 tool. We performed a frequentist random-effects network meta-analysis using the restricted maximum-likelihood estimator and assessed the certainty of evidence using the GRADE (grading of recommendations assessment development, and evaluation) approach. Synthesis: Our search found 18 trials (5,777 patients) eligible for analysis. Sotatercept reduces clinical worsening as compared with placebo (relative risk [RR], 0.21; 95% confidence interval [CI] = 0.11-0.41; with high certainty). Sotatercept probably reduces clinical worsening more, compared with add-on endothelin receptor antagonists (RR, 0.28; 95% CI = 0.14-0.55), inhaled prostanoid (RR, 40.21; 95% CI = 0.07-0.67), and prostanoid taken orally (RR, 0.32; 95% CI = 0.16-0.67; all with moderate certainty). Sotatercept probably improves 6-minute-walk distance compared with placebo (mean difference [MD], 36.89 m; 95% CI = 25.26-48.51). Although sotatercept probably improves 6-minute-walk distance more than add-on endothelin receptor antagonists (MD, 18.38 m; 95% CI = 5.92-30.84) and prostanoid taken orally (MD, 25.66 m; 95% CI = 13.71-37.61), it did not exceed the minimal clinically important difference of 33 m (both with moderate certainty). Conclusions: Sotatercept is an effective add-on therapy for PAH, likely superior to many approved add-on PAH therapies in reducing clinical worsening.

Pulmonary hypertension (PH), a syndrome characterized by elevated pulmonary pressures, commonly complicates connective tissue disease (CTD) and is associated with increased morbidity and mortality. The incidence of PH varies widely between CTDs; patients with systemic sclerosis are most likely to develop PH. Several different types of PH can present in CTD, including PH related to left heart disease and respiratory disease. Importantly, CTD patients are at risk for developing pulmonary arterial hypertension, a rare form of PH that is associated with high morbidity and mortality. Future therapies targeting pulmonary vascular remodeling may improve outcomes for patients with this devastating disease.

The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA).

This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA.

A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year.

The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P < 0.001). A 6MWT distance of <350 m was associated with a 2.2-fold higher risk of mortality (HR: 2.15; 95% CI: 1.85-2.50; P < 0.001), with a similar increased risk across National Amyloidosis Centre disease stages (P for interaction = 0.761) and genotypes (P for interaction = 0.172). An absolute (reduction of >35 m) and relative worsening (reduction of >5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P < 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P < 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro-B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P < 0.001).

The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality.

Pulmonary hypertension (PH) is a serious progressive disorder of the modern world, characterized by endothelial dysfunction and impaired vasoreactivity. Patients with PH usually present exercise intolerance from the very early stages and reduced exercise capacity. Exercise training has been shown to have beneficial effects in patients with cardiovascular comorbidities. However, data regarding the effects of combined exercise training programs in patients with PH still remains limited.

To investigate the effects of combined exercise training programs on exercise capacity and quality of life in patients with PH.

Our search included all available randomized controlled trials (RCTs) regarding combined aerobic, resistance and inspiratory training programs in patients with PH in 4 databases (Pubmed, PEDro, Embase, CINAHL) from 2012 to 2022. Five RCTs were included in the final analysis. Functional capacity, assessed by peak VO2 or 6-min walking test (6MWT), as well as quality of life, assessed by the SF-36 questionnaire, were set as the primary outcomes in our study.

Peak VO2 was measured in 4 out of the 5 RCTs while 6MWT was measured in all RCTs. Both indices of functional capacity were significantly increased in patients with PH who underwent combined exercise training compared to the controls in all of the included RCTs (P < 0.05). Quality of life was measured in 4 out of 5 RCTs. Although patients improved their quality of life in each group, however, only 2 RCTs demonstrated further improvement in patients performing combined training compared to controls.

By this systematic review, we have demonstrated that combined aerobic, resistance and inspiratory exercise training is safe and has beneficial effects on aerobic capacity and quality of life in patients with PH. Such exercise training regimen may be part of the therapeutic strategy of the syndrome.

This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension.

SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function.

Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P=0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function.

The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150.

Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg).

The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.

The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.

ClinicalTrials.gov Identifier NCT04797286.

Managing clinical manifestations of cancer/treatment burden on functional status and quality of life remains paramount across the cancer trajectory, particularly for patients with cachexia who display reduced functional capacity. However, clinically relevant criteria for classifying functional impairment at a single point in time or for classifying meaningful functional changes subsequent to disease and/or treatment progression are lacking. This unmet clinical need remains a major obstacle to the development of therapies for cancer cachexia. This review aims to describe current literature-based evidence for clinically meaningful criteria for (1) functional impairment at a single timepoint between cancer patients with or without cachexia and (2) changes in physical function over time across interventional studies conducted in patients with cancer cachexia. The most common functional assessment in cross-sectional and interventional studies was hand grip strength (HGS). We observed suggestive evidence that an HGS deficit between 3 and 6 kg in cancer cachexia may display clinical relevance. In interventional studies, we observed that long-duration multimodal therapies with a focus on skeletal muscle may benefit HGS in patients with considerable weight loss. Future studies should derive cohort-specific clinically relevant criteria to confirm these observations in addition to other functional outcomes and investigate appropriate patient-reported anchors.

The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.

The 6-minute walk test (6MWT) is a commonly used method to assess the exercise capacity of people with many health conditions, including persistent pain. However, it is conventionally performed with in-person supervision in a hospital or clinic, therefore requiring staff resources. It may also be difficult when in-person supervision is unavailable, such as during the COVID-19 pandemic, or when the person is geographically remote. A potential solution to these issues could be to use GPS to measure walking distance.

The primary aim of this study was to assess the validity of a GPS-based smartphone app to measure walking distance as an alternative to the conventional 6MWT in a population with persistent pain. The secondary aim of this study was to estimate the difference between the pain evoked by the 2 test methods.

People with persistent pain (N=36) were recruited to complete a conventional 6MWT on a 30-m shuttle track and a 6MWT assessed by a smartphone app using GPS, performed on outdoor walking circuits. Tests were performed in random order, separated by a 15-minute rest. The 95% limits of agreement were calculated using the Bland-Altman method, with a specified maximum allowable difference of 100 m. Pain was assessed using an 11-point numerical rating scale before and after each walk test.

The mean 6-minute walk distance measured by the GPS-based smartphone app was 13.2 (SD 46; 95% CI -2.7 to 29.1) m higher than that assessed in the conventional manner. The 95% limits of agreement were 103.9 (95% CI 87.4-134.1) m and -77.6 (95% CI -107.7 to -61) m, which exceeded the maximum allowable difference. Pain increased in the conventional walk test by 1.1 (SD 1.0) points, whereas pain increased in the app test by 0.8 (SD 1.4) points.

In individuals with persistent pain, the 2 methods of assessing the 6MWT may not be interchangeable due to limited validity. Potential reasons for the differences between the 2 methods might be attributed to the variation in track layout (shuttle track vs continuous circuit); poor GPS accuracy; deviations from the 30-m shuttle track; human variability in walking speed; and the potential impact of a first test on the second test due to fatigue, pain provocation, or a learning effect. Future research is needed to improve the accuracy of the GPS-based approach. Despite its limitations, the GPS-based 6MWT may still have value as a tool for remote monitoring that could allow individuals with persistent pain to self-administer frequent assessments of their functional capacity in their home environment.

Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation.

The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a double-blind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year.

No short-term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6-min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months.

Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease-modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.

California Institute for Regenerative Medicine (CIRM). Project Number: CLIN2-09444.

AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135.

Health-oriented physical activity should meet two key criteria: safety and an optimal level of exercise. The system of monitoring and rationalization of training (SMART) was designed to meet them. SMART integrates a custom-configured inertial measurement unit (IMU) and a sensor with real-time heart rate measurement (HR) using a proprietary computer application. SMART was used to evaluate the safety and exercise load with 115 study participants: 51 women (44.35%) and 64 men (55.65%) aged 19 to 65 years. The exercise test was the 6MWT test. In 35% of the participants, the mean HR exceeded the recognized safe limit of HR 75% max. Ongoing monitoring of HR allows for optimal exercise and its safety. Step count data were collected from the SMART system. The average step length was calculated by dividing the distance by the number of steps. The aim of the present study was to assess the risk of excessive cardiovascular stress during the 6MWT test using the SMART system.

Rationale: Being overweight or obese is common among patients with chronic obstructive pulmonary disease (COPD), but whether interventions targeted at weight loss improve functional impairments is unknown. Objectives: INSIGHT (Intervention Study in Overweight Patients with COPD) tested whether a pragmatic low-intensity lifestyle intervention would lead to better physical functional status among overweight or obese participants with COPD. Methods: The trial was a 12-month, multicenter, patient-level pragmatic clinical trial. Participants were recruited from April 2017 to August 2019 from 38 sites across the United States and randomized to receive usual care or usual care plus lifestyle intervention. The intervention was a self-directed video program delivering the Diabetes Prevention Program's Group Lifestyle Balance curriculum. Results: The primary outcome was 6-minute-walk test distance at 12 months. Priority secondary outcomes were postwalk modified Borg dyspnea at 12 months and weight at 12 months. Participants (N = 684; mean age, 67.0 ± 8.0 yr [standard deviation]; 41.2% female) on average were obese (body mass index, 33.0 ± 4.6 kg/m2) with moderate COPD (forced expiratory volume in 1 second % predicted, 58.1 ± 15.7%). At 12 months, participants randomized to the intervention arm walked farther (adjusted difference, 42.3 ft [95% confidence interval (CI), 7.9-76.7 ft]; P = 0.02), had less dyspnea at the end of the 6-minute-walk test (adjusted difference, -0.36 [95% CI, -0.63 to -0.09]; P = 0.008), and had greater weight loss (adjusted difference, -1.34 kg [95% CI, -2.33 to -0.34 kg]; P = 0.008) than control participants. The intervention did not improve the odds of achieving clinically meaningful thresholds of walk distance (98.4 ft) or dyspnea (1 unit) but did achieve meaningful thresholds of weight loss (3% and 5%). Conclusions: Among participants with COPD who were overweight or obese, a self-guided low-intensity video-based lifestyle intervention led to modest weight loss but did not lead to clinically important improvements in physical functional status and dyspnea. Clinical trial registered with www.clinicaltrials.gov (NCT02634268).

The objective of this study was to evaluate the effects of cardiorespiratory rehabilitation (CR) and transcranial photobiomodulation (tPBM) on exercise tolerance (ET), heart rate variability (HRV), and peripheral muscle activity in individuals with spasticity. Fifteen participants with spasticity were randomly assigned to two groups: the tPBM group (tPBMG) consisted of eight volunteers who underwent tPBM (on mode) and CR, while the control group (CG) consisted of seven volunteers who underwent simulated tPBM (off mode) and CR. The CR program included 12 weeks of treatment, twice a week for one hour, involving aerobic exercises and lower limb strengthening. For tPBM, a cluster with three lasers (λ = 680 nm, 808 nm), with a power of 100 mW/laser and energy of 36 J, applied to the F7, F8, and Fpz points. The following parameters were evaluated after 8 and 12 weeks: ET, HRV, and surface electromyography (EMG) of the rectus femoris muscle during orthostasis (ORT), isometric squatting (ISOM), and isotonic squatting (ISOT). Both groups showed a 40% increase in ET for the CG and a 30% increase for the tPBMG. The CG had more pronounced parasympathetic modulation alterations during post-exercise effort and recovery compared to the tPBMG. The EMG results showed that the tPBMG exhibited progressive improvement in muscle activity during ISOM and ISOT, as well as a decrease in the interlimb difference. In conclusion, both CR and tPBMG demonstrated improvements in ET. However, tPBMG specifically showed promising effects on HRV modulation and peripheral muscle electrical activity, providing additional benefits compared to CR alone.

Remote exercise tests for patients with pulmonary hypertension (PH) would improve the telemedicine strategies in this disease. The PHRET study assessed the validity and feasibility of four remote exercise tests performed by PH patients at home. Participants undergoing diagnostic assessment for PH were included. At baseline, patients completed a 6MWT followed by a range of study tests including a Timed Up and Go (TUG) test, a Sit-to-Stand (STS), a Step Test (ST), and a tele-6MWT (T6MWT) performed outside using a GPS-enabled smartphone. Patients performed these tests at home following discharge and at first follow-up. Analysis focused on comparing the results of study tests to the standard 6MWT. The discontinuation rate was 15%. Ninety-seven percent of patients were able to complete a TUG, 92% a STS, 73% a ST, and 49% a T6MWT. At baseline, correlation between the standard 6MWT and study tests, respectively, was T6MWT 0.93, ST 0.78, STS 0.71, and TUG -0.76 (p < 0.001). Direction of change in the study test agreed with the standard 6MWT in 68% of the follow-up ST, 68% of the STS, 71% of the TUG, and 79% of the T6MWT. Patients were able to complete the tests at home, there were no adverse incidents and ≥92% of patients were happy to continue performing home tests. Remote exercise testing is feasible. The T6MWT was a valid remote measure of exercise capacity, but could only be performed by a limited number of patients. The high discontinuation rate may impact the utility of remote tests.

Because the 6-minute walking test (6MWT) is a self-paced submaximal test, the 6-minute walking distance (6MWD) is substantially influenced by individual effort level and physical condition, which is difficult to quantify. We aimed to explore the optimal indicator reflecting the perceived effort level during 6MWT. We prospectively enrolled 76 patients with pulmonary arterial hypertension and 152 healthy participants; they performed 2 6MWTs at 2 different speeds: (1) at leisurely speed, as performed in daily life without extra effort (leisure 6MWT) and (2) an increased walking speed, walking as the guideline indicated (standard 6MWT). The factors associated with 6MWD during standard 6MWT were investigated using a multiple linear regression analysis. The heart rate (HR) and Borg score increased and oxygen saturation (SpO2) decreased after walking in 2 6MWTs in both groups (all p <0.001). The ratio of difference in HR before and after each test (ΔHR) to HR before walking (HRat rest) and the difference in SpO2 (ΔSpO2) and Borg (ΔBorg) before and after each test were all significantly higher in both groups after standard 6MWT than after leisure 6MWT (all p <0.001). Multiple linear regression analysis revealed that ΔHR/HRat rest was an independent predictor of 6MWD during standard 6MWT in both groups (both p <0.001, adjusted R2 = 0.737 and 0.49, respectively). 6MWD and ΔHR/HRat rest were significantly lower in patients than in healthy participants (both p <0.001) and in patients with cardiac functional class III than in patients with class I/II (both p <0.001). In conclusion, ΔHR/HRat rest is a good reflector of combined physical and effort factors. HR response should be incorporated into 6MWD to better assess a participant's exercise capacity.

The study aimed to examine the effects of inspiratory muscle training (IMT) in patients with pulmonary hypertension (PH). A total of 24 patients with PH were included in the randomized controlled evaluator-blind study. IMT was performed at 40% to 60% of the maximal inspiratory pressure for 30 min/d, 7 d/wk (1 day supervised) for 8 weeks. Respiratory muscle strength, dyspnea, diaphragm thickness (DT), pulmonary functions, 24-hour ambulatory blood pressure (BP), arterial stiffness, exercise capacity, upper extremity functional exercise capacity, physical activity levels, fatigue, anxiety-depression levels, activities of daily living (ADL), and quality of life were evaluated. A total of 24 patients (treatment = 12, control = 12) completed the 8-week follow-up. There was no significant difference between the patient groups in terms of demographic and clinical characteristics (p >0.05). Considering the change between the groups in the treatment and control groups, brachial and central BP, dyspnea, respiratory muscle strength, DT in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and quality of life improved in favor of the IMT group (p <0.05). In conclusion, IMT has improved brachial and central BP, dyspnea, respiratory muscle strength, DT in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and quality of life compared with the control group. IMT is an effective method in cardiopulmonary rehabilitation for patients with PH.

Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives".

Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements.

254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening.

This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.

Little is known about long-term quality of life (QOL) and functional status after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). We investigated QOL and functional status late after PEA. All patients who underwent PEA for CTEPH 1993-2020 at one Swedish center were included. Baseline characteristics and data from right heart catheterization, 6-min walk test, and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) were obtained from patient charts and national registers. The RAND 36-Item Health Survey was sent by post, and Karnofsky Performance Status (KPS) was evaluated by telephone. A total of 110 patients were included. The survey was completed by 49/66 (74%) patients who were alive in 2020. In all domains except for bodily pain, QOL was slightly lower than that of an age-matched reference population. The KPS score was obtained from 42/49 (86%) patients; of these, 31 patients (74%) had a KPS score of ≥80% (able to carry on normal activity). All 42 patients were able to live at home and care for personal needs. The median postoperative CAMPHOR scores were: 4 for symptoms, 4 for activity, and 2.5 for QOL. We observed that QOL after PEA approached the expected QOL in a reference population and that CAMPHOR scores were comparable to those of a large UK cohort after PEA. Functional status improved when assessed late after PEA. Three-quarters of the study population were able to conduct normal activities at late follow-up. Our findings suggest that many patients enjoy satisfactory QOL and high functional status late after PEA.

Background  Pulmonary arterial hypertension (PAH) is a rare disease of cardiopulmonary circulation characterized by elevated pressure in the pulmonary artery. The right-heart catheter is the gold standard for diagnosis, but there is interest in identifying additional prognostic indicators. The aim of this study was to examine the importance of the rate of pressure change of the pulmonary artery (dP/dt mean PA) in patients with PAH. Methods  We retrospectively analyzed data from 142 patients with PAH (exclusively clinical group 1) and examined the statistical correlation of dP/dt mean PA with vascular, right ventricular, and clinical parameters. Data was collected mostly from the right heart catheterization and the transthoracal echocardiography at presentation. Results  dP/dt mean PA showed a significant correlation with systolic pressure of the pulmonary artery ( n = 142, R ²  = 56%, p  < 0.001), pulmonary vascular resistance ( n  = 142, R ²  = 51%, p  < 0.001), the rate of pressure change in the right ventricle ( n  = 142, R ²  = 53%, p  < 0.001), and the right ventricular fractional area change ( n  = 110, R ²  = 51%, p  < 0.001). Receiver operating characteristic curve analysis showed that dP/dt mean PA had the highest prognostic value in predicting increase in the 6-minute walk test and decrease in the N-terminal-probrain natriuretic peptide after the initiation of PAH therapy, with an area under the curve of 0.73. Conclusion  Our findings suggest that dP/dt mean PA may be a useful prognostic indicator in the treatment of patients with PAH, and further research is warranted to validate this parameter.

Individuals with pulmonary hypertension (PH) have reduced exercise capacity and quality of life. Despite initial concerns that exercise training may worsen symptoms in this group, several studies have reported improvements in functional capacity and well-being following exercise-based rehabilitation.

To evaluate the benefits and harms of exercise-based rehabilitation for people with PH compared with usual care or no exercise-based rehabilitation.

We used standard, extensive Cochrane search methods. The latest search date was 28 June 2022.

We included randomised controlled trials (RCTs) in people with PH comparing supervised exercise-based rehabilitation programmes with usual care or no exercise-based rehabilitation.

We used standard Cochrane methods. Our primary outcomes were 1. exercise capacity, 2. serious adverse events during the intervention period and 3. health-related quality of life (HRQoL). Our secondary outcomes were 4. cardiopulmonary haemodynamics, 5. Functional Class, 6. clinical worsening during follow-up, 7. mortality and 8. changes in B-type natriuretic peptide. We used GRADE to assess certainty of evidence.

We included eight new studies in the current review, which now includes 14 RCTs. We extracted data from 11 studies. The studies had low- to moderate-certainty evidence with evidence downgraded due to inconsistencies in the data and performance bias. The total number of participants in meta-analyses comparing exercise-based rehabilitation to control groups was 462. The mean age of the participants in the 14 RCTs ranged from 35 to 68 years. Most participants were women and classified as Group I pulmonary arterial hypertension (PAH). Study durations ranged from 3 to 25 weeks. Exercise-based programmes included both inpatient- and outpatient-based rehabilitation that incorporated both upper and lower limb exercise. The mean six-minute walk distance following exercise-based rehabilitation was 48.52 metres higher than control (95% confidence interval (CI) 33.42 to 63.62; I² = 72%; 11 studies, 418 participants; low-certainty evidence), the mean peak oxygen uptake was 2.07 mL/kg/min higher than control (95% CI 1.57 to 2.57; I² = 67%; 7 studies, 314 participants; low-certainty evidence) and the mean peak power was 9.69 W higher than control (95% CI 5.52 to 13.85; I² = 71%; 5 studies, 226 participants; low-certainty evidence). Three studies reported five serious adverse events; however, exercise-based rehabilitation was not associated with an increased risk of serious adverse event (risk difference 0, 95% CI -0.03 to 0.03; I² = 0%; 11 studies, 439 participants; moderate-certainty evidence). The mean change in HRQoL for the 36-item Short Form (SF-36) Physical Component Score was 3.98 points higher (95% CI 1.89 to 6.07; I² = 38%; 5 studies, 187 participants; moderate-certainty evidence) and for the SF-36 Mental Component Score was 3.60 points higher (95% CI 1.21 to 5.98 points; I² = 0%; 5 RCTs, 186 participants; moderate-certainty evidence). There were similar effects in the subgroup analyses for participants with Group 1 PH versus studies of groups with mixed PH. Two studies reported mean reduction in mean pulmonary arterial pressure following exercise-based rehabilitation (mean reduction: 9.29 mmHg, 95% CI -12.96 to -5.61; I² = 0%; 2 studies, 133 participants; low-certainty evidence).

In people with PH, supervised exercise-based rehabilitation may result in a large increase in exercise capacity. Changes in exercise capacity remain heterogeneous and cannot be explained by subgroup analysis. It is likely that exercise-based rehabilitation increases HRQoL and is probably not associated with an increased risk of a serious adverse events. Exercise training may result in a large reduction in mean pulmonary arterial pressure. Overall, we assessed the certainty of the evidence to be low for exercise capacity and mean pulmonary arterial pressure, and moderate for HRQoL and adverse events. Future RCTs are needed to inform the application of exercise-based rehabilitation across the spectrum of people with PH, including those with chronic thromboembolic PH, PH with left-sided heart disease and those with more severe disease.

Patients with pulmonary hypertension (PH) may have impaired exercise capacity and quality of life; this may possibly be due to the early onset of dyspnoea associated with respiratory muscle weakness. Respiratory muscle training could improve the condition of these patients, so this study aimed to determine, through a systematic review and meta-analysis, the effectiveness of respiratory muscle training in adult patients with PH.

Medline, Embase, CENTRAL, clinical trial registries databases, and grey literature and reference lists of reviews related to the objective were searched up to March 2022. Controlled clinical trials comparing the effectiveness of respiratory muscle training with sham or no intervention in adults with PH were included. Records were independently screened by two authors. The primary outcomes were maximal and functional exercise capacity, quality of life, and dyspnoea. The secondary outcomes were respiratory muscle strength, physical activity, lung function, and adverse events. Two authors independently extracted data and the study quality was assessed using the Cochrane risk-of-bias tool 2 (RoB 2). The certainty of the evidence was assessed according to the GRADE approach.

A total of 5,524 records were screened, and seven randomised clinical trials (RCTs) (257 participants) were included. It was uncertain whether inspiratory muscle training (IMT), compared with sham IMT or no intervention, increased the distance walked in the 6-minute walk test (6MWT) (MD, 39 m; 95% CI, 20.72-57.39; I²=27%; four RCTs; very low certainty of evidence) and slightly decreased the perceived sensation of dyspnoea (MD, 0.5 points on the mMRC scale; 95% CI, -0.87 to -0.13; I²=0%; two RCTs; very low certainty of evidence). In addition, it was uncertain whether IMT had no effect on the emotional (SMD, -0.34; 95% CI, -1.06 to 0.38; I²=64%; three RCTs; very low certainty of evidence) and physical (SMD, 0.06; 95% CI, -0.41 to 0.52; I²=16%; three RCTs; very low certainty of evidence) component of quality of life.

It is uncertain whether IMT increases functional exercise capacity and slightly decreases the sensation of dyspnoea. In addition, it is uncertain whether IMT does not affect the quality of life. More RCTs and with a better methodological design are needed to increase the certainty of the evidence and determine the real effect of this intervention.