There is growing evidence that emphysema on thoracic computed tomography (CT) is associated with poor exercise tolerance in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that an excessive ventilatory response to exercise (ventilatory inefficiency) would underlie these abnormalities. In a prospective study, 19 patients (FEV₁ = 82 ± 13%, 12 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1) and 26 controls underwent an incremental exercise test. Ventilatory inefficiency was assessed by the ventilation ([Formula: see text]E)/CO₂ output ([Formula: see text]CO₂) nadir. Pulmonary blood flow (PBF) in a submaximal test was calculated by inert gas rebreathing. Emphysema was quantified as % of attenuation areas below 950 HU. Patients typically presented with centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/total lung ratio = 0.82 ± 0.04). They had lower peak oxygen uptake ([Formula: see text]O₂), higher [Formula: see text]E/[Formula: see text]CO₂ nadir, and greater dyspnea scores than controls (p < 0.05). Lower peak [Formula: see text]O₂ and worse dyspnea were found in patients with higher [Formula: see text]E/[Formula: see text]CO₂ nadirs (≥30). Patients had blunted increases in PBF from rest to iso-[Formula: see text]O₂ exercise (p < 0.05). Higher [Formula: see text]E/[Formula: see text]CO₂ nadir in COPD was associated with emphysema severity (r = 0.63) which, in turn, was related to reduced lung diffusing capacity (r = -0.72) and blunted changes in PBF from rest to exercise (r = -0.69) (p < 0.01). Ventilation "wasted" in emphysematous areas is associated with impaired exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (D_LCO) to a key clinical outcome (poor exercise tolerance) in COPD patients with only modest spirometric abnormalities.

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