BACKGROUND: Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects. METHODS: A PV distensibility coefficient α (%/mm~Hg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption. RESULTS: The α coefficient decreased from 1.35 ± 0.58%/mm~Hg in control subjects and 1.1 ± 0.48%/mm~Hg in patients with passive HFpEF to 0.62 ± 0.32%/mm~Hg in exercise PH, 0.54 ± 0.27%/mm~Hg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed. CONCLUSIONS: PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity.