Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O 2 Pathway Analysis

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. We investigated the mechanism of exercise intolerance in 134 patients referred for cardiopulmonary exercise testing: 79 with HFpEF and 55 controls. We performed cardiopulmonary exercise testing with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the O pathway) in each patient with HFpEF, identifying the defective steps that impair each one's exercise capacity (peak Vo ). We then quantified the functional significance of each O pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. Peak Vo was reduced by 34±2% (mean±SEM,