BACKGROUND: Lung hyperinflation in COPD adversely affects cardiac function and may influence autonomic nervous system activity. The onset of cardiac improvement with dual bronchodilator therapy remains uncertain. METHODS: In this randomised, placebo-controlled, investigator-blinded, mechanistic, single-dose crossover trial with an open-label 2-week extension we assessed tiotropium/olodaterol (T/O) effects on cardiopulmonary function and muscle sympathetic nerve activity (MSNA) in hyperinflated COPD patients. 32 participants received saline (placebo) and T/O (5 microg/5 microg) in a crossover design, followed by 14 days of open-label T/O. The primary end-point was change in left ventricular end-diastolic volume index (LV-EDVi) measured by magnetic resonance imaging (MRI). Secondary assessments included pulmonary function tests, MSNA measurements and advanced lung imaging including (129)Xe-MRI. FINDINGS: Single-dose T/O significantly increased LV-EDVi relative to placebo (3.25 mL.m(-2); 95% CI 0.95 to 5.56), driven partly by a decrease under placebo. Compared with baseline, T/O's acute LV-EDVi gain was minimal, yet it reached significance at 14 days (4.70 mL.m(-2); 95% CI 1.75 to 7.65). Pulmonary parameters, in contrast, showed immediate improvement, with a marked reduction in residual volume (-0.67 L; 95% CI -0.82 to -0.51) after a single dose. MSNA demonstrated a nonsignificant numerical rise post single-dose T/O. No serious adverse events occurred. INTERPRETATION: T/O rapidly improves pulmonary function in hyperinflated COPD patients, but significant cardiac benefits seem to require sustained therapy. These results underscore the importance of continued dual bronchodilator therapy to achieve cardiovascular improvements. The nonsignificant rise in MSNA after a single dose suggests minimal immediate effect on sympathetic activity; further studies are necessary to evaluate long-term autonomic outcomes.
