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

Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS,
Wagner PD, Lewis GD

Circulation. 2017 Oct 9. pii:

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 “O2 pathway”) in each
HFpEF patient, identifying the defective steps that impair each one’s exercise
capacity (peak VO2). We then quantified the functional significance of each O2
pathway defect by calculating the improvement in exercise capacity a patient
could expect from correcting the defect.

Results -Peak VO2 was reduced by 34%±2% (mean±SEM, P<0.001) in HFpEF
compared with controls of comparable age, gender,
and body mass index. The vast majority (97%) of HFpEF patients harbored defects
at multiple steps of the O2 pathway, the identity and magnitude of which varied
widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were
impaired relative to controls by an average of 27±3% and 36±2%, respectively
(P<0.001 for both). Due to interactions between a given patient’s defects, the
predicted benefit of correcting any single one was often minor; on average,
correcting a patient’s cardiac output led to a 7±0.5% predicted improvement in
exercise intolerance, while correcting a patient’s muscle diffusion capacity led
to a 27±1% improvement. At the individual level, the impact of any given O2
pathway defect on a patient’s exercise capacity was strongly influenced by
comorbid defects.

Conclusions -Systematic analysis of the O2 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 patient’s personal
profile of defects. Personalized O2 pathway analysis could identify patients most
likely to benefit from treating a specific defect; however, the system properties
of O2 transport favor treating multiple defects at once, as with exercise