Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Abstract

Background— Exercise capacity as measured by peak oxygen uptake (V o 2 ) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of V o 2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o 2 extraction (arterio-mixed venous o 2 content difference, [C(a-v)o 2 ]) during exercise significantly contributes to impaired exercise capacity in HFpEF. Methods and Results— We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak V o 2 =13.9±0.5 mL kg −1  min −1 , mean±SEM, and HFrEF, n=56, peak V o 2 =12.1±0.5 mL kg −1  min −1 ) and 24 control subjects (peak V o 2 27.0±1.7 mL kg −1  min −1 ). Peak exercise C(a-v)o 2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P <0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Ca o 2 , or cardiac filling pressures. Peak C(a-v)o 2 and peak heart rate emerged as the leading predictors of peak V o 2 in HFpEF. Impaired peripheral o 2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise ( r =0.49, P =0.0005). Conclusions— In the first study to directly measure C(a-v)o 2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o 2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o 2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.