Exercise Protocol

All participants performed a supine exercise protocol while lying in the bore of the magnet using an magnetic resonance-compatible cycle ergometer (Lode, Groningen, The Netherlands). CMR images were acquired with subjects breathing room air in the resting state and then at an exercise intensity threshold set at 40% of the watts achieved during upright CPET with a cadence of 60–70 revolutions/min. This protocol accounts for interindividual variation in exercise capacity as well as the difference in efficiency between upright (CPET) and supine (CMR) exercise (6), providing accurate assessment of cardiac output compared with the direct Fick method (21). In normal subjects, the protocol was repeated while subjects breathed 12% O₂ (ensuring resting saturations had dropped and plateaued). The total duration of hypoxia was ~35 min.

CMR was performed on a 1.5-T Philips Achieva system (Best, The Netherlands), and a standard clinical protocol for structural, functional, and phase-contrast breath-hold imaging at rest was followed according to published international guidelines (20). Real-time imaging at both rest and exercise were then acquired using a previously validated ungated high-temporal resolution sequence during free breathing (Philips Healthcare Clinical Science, Surrey, UK) (21) using the following parameters: field of view, 305 × 305 mm; repetition time/echo time, 2.5/1.26 ms; flip angle, 50°; acquired voxel size, 2.73 × 2.73 × 10 mm; section thickness, 10 mm with no gap; reconstructed voxel size, 1.19 × 1.19 × 10 mm; number of sections, 14; slice scan order, base to apex; dynamic scan time, 66 s with 50 dynamics per slice; and temporal resolution, 74 ms. Free breathing, real-time main pulmonary artery and aortic phase-contrast images were acquired using the following parameters: field of view, 300 × 300; repetition time/echo time, 11/3.7 ms; flip angle, 20°; acquired voxel size, 3.0 × 3.0 × 10 mm; section thickness, 10 mm; reconstructed voxel size, 1.17 × 1.17 × 10 mm; dynamic scan time, 4.5 s with 100 dynamics; and temporal resolution, 44 ms.

A standard clinical protocol for assessing biventricular function, volumes, mass, and flow was followed according to published international guidelines (20). Real-time imaging data were analyzed using a specially adapted proprietary software (cvi42, Circle Cardiovascular Imaging, Calgary, AB, Canada) and assessed during the expiratory phase of respiration. Volumes were indexed to body surface area calculated using the Mosteller formula. Indexed volumetric data were left ventricular (LV) and RV end-diastolic volumes (LVEDVi and RVEDVi, respectively), LV end-systolic volume and RV end-systolic volume (LVESVi and RVESVi, respectively), LV and RV stroke volumes (LVSVi and RVSVi, respectively), and LV ejection fraction (LVEF) and RVEF. Cardiac index (CI) was derived as follows: [LVSVi × heart rate (HR)]. RV contractile reserve was defined as RVEF with exercise − RVEF at rest (13). Real-time septal curvature measurements were assessed using previously described techniques (29).