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Introduction: Pulmonary edema with low systemic oxygen (O2) levels is a hallmark of acute decompensated heart failure (HF) related to elevated left heart filling pressures. However, less is known about arterial O2 (PaO2) responses during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Hypothesis: We hypothesized that changes in PaO2 in response to exercise are governed by extra-cardiac organ systems rather than the degree of elevation in pulmonary capillary wedge pressure (PCWP). Methods: We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring in 411 patients (age 58±2.9, 61% female, BMI 29.7±0.7, LVEF 66±2.6 %; mean±SEM) with HFpEF defined by ACC/AHA criteria with exclusion of patients with O2-dependent lung disease. Results: Exercise PaO2 was associated with peak VO2 (r=0.22, p<0.001) but average PaO2 increased only modestly from rest to peak exercise (3.1±0.7mmHg) and overt O2 desaturation was uncommon (1.5% of patients had PaO2<55mmHg and O2sat ≤ 88%). Exercise change in PaO2 was not associated with resting PCWP (r=0.05, p=0.27) or exercise PCWP (r<0.01, P=0.7) (Figure). Change in PaO2was correlated with % predicted diffusion capacity of the lungs (DLCO) (r=0.28, p<0.001) despite relatively normal average spirometry values (FVC 93±1, FEV1 89±5, FVC/FEV 96±5, % predicted mean±SEM). Pulmonary artery pressure (PAP) and transpulmonary pressure gradient (TPG) were also associated with change in PaO2 (r=-0.18 (PAP), r=-0.25 (TPG), p<0.001) in multivariable models adjusting for age, sex, and BMI. Conclusions: Pulmonary and pulmonary vascular function, but not left sided filling pressures, relate to changes in PaO2 during incremental exercise in HFpEF. These findings highlight the important role of extra-cardiac organ systems, specifically the lungs, in mediating systemic O2 bioavailability during exercise in HFpEF. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest. Methods and Results: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP≥15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of “PCWP/CO slope” in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2±0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4±1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo2 (P<0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P=0.03) at a median 5.3-year follow-up. Conclusions: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis. [ABSTRACT FROM AUTHOR]