Abstract
BACKGROUND: The primary cause of dyspnea on exertion in heart failure with preserved ejection fraction (HFpEF) is presumed to be the marked rise in pulmonary capillary wedge pressure during exercise; however, this hypothesis has never been tested directly. Therefore, we evaluated invasive exercise hemodynamics and dyspnea on exertion in patients with HFpEF before and after acute nitroglycerin (NTG) treatment to lower pulmonary capillary wedge pressure. RESEARCH QUESTION: Does reducing pulmonary capillary wedge pressure during exercise with NTG improve dyspnea on exertion in HFpEF? STUDY DESIGN AND METHODS: Thirty patients with HFpEF performed two invasive 6-min constant-load cycling tests (20 W): one with placebo (PLC) and one with NTG. Ratings of perceived breathlessness (0-10 scale), pulmonary capillary wedge pressure (right side of heart catheter), and arterial blood gases (radial artery catheter) were measured. Measurements of V˙/Q˙ matching, including alveolar dead space (Vd(alv); Enghoff modification of the Bohr equation) and the alveolar-arterial Po(2) difference (A-aDO(2); alveolar gas equation), were also derived. The ventilation (V˙e)/CO(2) elimination (V˙co(2)) slope was also calculated as the slope of the V˙e and V˙co(2) relationship, which reflects ventilatory efficiency. RESULTS: Ratings of perceived breathlessness increased (PLC: 3.43 ± 1.94 vs NTG: 4.03 ± 2.18; P = .009) despite a clear decrease in pulmonary capillary wedge pressure at 20 W (PLC: 19.7 ± 8.2 vs NTG: 15.9 ± 7.4 mm Hg; P < .001). Moreover, Vd(alv) (PLC: 0.28 ± 0.07 vs NTG: 0.31 ± 0.08 L/breath; P = .01), A-aDO(2) (PLC: 19.6 ± 6.7 vs NTG: 21.1 ± 6.7; P = .04), and V˙e/V˙co(2) slope (PLC: 37.6 ± 5.7 vs NTG: 40.2 ± 6.5; P < .001) all increased at 20 W after a decrease in pulmonary capillary wedge pressure. INTERPRETATION: These findings have important clinical implications and indicate that lowering pulmonary capillary wedge pressure does not decrease dyspnea on exertion in patients with HFpEF; rather, lowering pulmonary capillary wedge pressure exacerbates dyspnea on exertion, increases V˙/Q˙ mismatch, and worsens ventilatory efficiency during exercise in these patients. This study provides compelling evidence that high pulmonary capillary wedge pressure is likely a secondary phenomenon rather than a primary cause of dyspnea on exertion in patients with HFpEF, and a new therapeutic paradigm is needed to improve symptoms of dyspnea on exertion in these patients.