Despite the growing evidence supporting the use of biventricular cardiac resynchronization therapy (CRT) in patients with chronic heart failure (CHF), the mechanisms whereby acute hemodynamic improvements lead to improved exertional dyspnea are not precisely known. We hypothesized that improved cardiac function and ventilation-perfusion relations following CRT would reduce ventilatory demand, thereby improving dynamic operating lung volumes and enhancing tidal volume expansion during exercise. This, in turn, would be expected to reduce perceived exertional dyspnea and contribute to improved exercise performance. In a randomized, double-blind, crossover study, we compared cardiovascular, metabolic, ventilatory responses (breathing pattern, operating lung volumes, pulmonary gas exchange) and exertional symptoms in seven stable CHF patients who undertook incremental cardiopulmonary cycle exercise test with CRT switched to the "on" (CRT(on)) or "off" (CRT(off)) modality. Following CRT(on), peak oxygen uptake was significantly increased by 15%, and dyspnea ratings were lower for a given work rate (at work rate of 40 W, dyspnea = 1 +/- 0.4 vs. 2.5 +/- 0.9 Borg units, P < 0.05) and ventilation (at ventilation of 31 l/min, dyspnea = 2 +/- 0.7 vs. 3.3 +/- 1.1 Borg units, P < 0.05). CRT(on) was associated with improvements in ventilatory threshold, oxygen pulse, and oxygen uptake/work rate relationships (10.2 +/- 1 vs. 7.9 +/- 1.3 ml.min(-1).W(-1), P < 0.05). CRT(on) reduced the ventilatory requirement during exercise as well as the steepness of ventilation-CO(2) production slope (35 +/- 4 vs. 45 +/- 7, P < 0.05). Changes in end-expiratory lung volume during exercise were less with CRT(on) than with CRT(off) (0.12 vs. 0.37 liter, P < 0.05), and breathing pattern was correspondingly slower and deeper. Biventricular pacing improved all noninvasive indexes of cardiac function and oxygen delivery during exercise. The decreased ventilatory demand, improved dynamic operating lung volumes, and the increased ability to expand tidal volume during exercise are potential factors in the reduction of exertional dyspnea.