Exercise Intolerance in HFpEF: Diagnosing and Ranking its Causes Using Personalized O2 Pathway Analysis

Background —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. Methods —We investigated the mechanism of exercise intolerance in each of 134 patients referred for cardiopulmonary exercise testing (CPET): 79 with HFpEF and 55 controls. We performed CPET 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 2 pathway") in each HFpEF patient, identifying the defective steps that impair each one9s exercise capacity (peak V O2 ). We then quantified the functional significance of each O 2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. Results —Peak V O2 )was reduced by 34%±2% (mean±SEM, P 2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O 2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P 2 pathway defect on a patient9s exercise capacity was strongly influenced by comorbid defects. Conclusions —Systematic analysis of the O 2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient9s personal profile of defects. Personalized O 2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O 2 transport favor treating multiple defects at once, as with exercise training.