Baseline participant information including age, gender, anthropometrics (height and weight), co-morbid conditions and concomitant medications will be collected at the initial visit. In addition, various outcome measures will be undertaken at baseline, during and at completion of the 8-week study period. Clinical worsening will also be monitored for a minimum of 2 year period following commencement of the study (see below). All outcome measurements will be performed by a researcher blinded to the participants’ group allocation.
Secondary outcome measures
Cardiopulmonary exercise test is used to determine exercise capacity on a stationary cycle ergometer using previously described methods [
23] before and after the 8-week study period. During the test, the participant will breathe through a mask so that oxygen uptake can be measured, using open circuit spirometry (Metamax, Cortex BXB, Lepzig, Germany) [
24]. The metabolic system will be calibrated for volume and expired concentrations of oxygen and carbon dioxide prior to each test. Blood pressure, SpO
2, HR and heart rhythm will be constantly monitored and the test will be supervised as per the ACSM guidelines [
20]. All participants will commence cycling at 0 W for a 1 min period. The external workload will then be increased using a ramped protocol (5–10 W per minute, depending on disease severity and baseline exercise capacity), such that each test will be 8–12 min duration. At the completion of the test, participants will perform a supervised warm down. Peak minute average values for oxygen uptake (
\( \dot{\mathrm{V}}{\mathrm{O}}_2 \)), carbon dioxide production (
\( \dot{\mathrm{V}}{\mathrm{CO}}_2 \)), ventilation (
\( {\dot{\mathrm{V}}}_{\mathrm{E}} \)) and HR will be determined. In addition, breathing efficiency (
\( {\dot{\mathrm{V}}}_{\mathrm{E}}/\dot{\mathrm{V}}{\mathrm{CO}}_2 \)), end-tidal CO
2 (P
ETCO
2), and anaerobic threshold will be determined using previously described methods [
25]. The same ramped protocol will be used both pre- and post-exercise training.
Health-related QoL will be measured using a disease-specific PH tool, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) [
26,
27] and the 36 item short-form survey (22). Health-related QoL will be assessed at baseline and following the 8-week study period.
Cardiac function will be measured using both cardiac magnetic resonance imaging (CMRI) and echocardiography, with CMRI serving as the principal method. Left and right ventricular end-diastolic volume and end-systolic volume will be measured using CMRI (1.5 T Scanner, MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany) from which stroke volume, ejection fraction, cardiac output and contractile reserve will be derived [
28]. In addition, measures of both right and left ventricular mass will be obtained. These will be measured at rest and during 2 submaximal exercise intensities (at 30% and 60% of their respective peak workload determined from incremental exercise test) using the MRI cycle ergometer. During the CMRI, electrocardiogram (ECG) and SpO
2 will be continuously monitored and the test will be supervised by a medical practitioner. Echocardiographic evaluation will be performed as part of standard clinical protocol on the same day of the 6MWT. This will be assessed both at baseline and following the 8-week study period. Echocardiographic images will be acquired using a 4 MHz matrix array cardiac transducer (Vivid 7, General Electric, Milwaukee, Wisconsin, USA). All images will be attained with the participant in a semi-recumbent position for both the apical and parasternal windows. Right ventricular systolic pressure will be estimated from the tricuspid regurgitation velocity as per standard guidelines [
29]. Right ventricular systolic function will also be examined by assessing the tricuspid annular plane systolic excursion.
Adverse responses or events including syncope, dizziness or marked worsening in oxygen desaturation during exercise will be monitored and recorded for the duration of the 8-week exercise training period. Such adverse events will also be assessed with weekly phone calls and recorded for the participants in the control group during the 8-week study period.
Long term outcomes will be analysed by examining survival and time to clinical worsening during routine follow-up clinic visits for a 2-year period following the participant’s commencement of the study. We will base this measure on the recent PH intervention studies [
30‐
32]. For the purpose of this study clinical worsening will be defined as [
30]:
-
PH-related death or
-
listing for/completed lung transplantation or
-
hospitalization for PH or clinical worsening leading to initiation of new PH-specific treatment or
-
World Health Organisation (WHO) functional classification deterioration and a > 15% decrease in 6MWT from baseline.
Participants will be assessed for clinical worsening every 3–6 months following randomisation during routine clinical visits. A panel of two clinical experts, blinded to group allocation, will independently evaluate each participant for clinical worsening. Decisions will be moderated by a third expert, blinded to group allocation, in the event that the panel members reach a different decision.