Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction

Abstract

Background: Exercise capacity as measured by peak oxygen uptake (Vo2) 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 Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) 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 Vo2=13.9±0.5 mL kg(-1) min(-1), mean±SEM, and HFrEF, n=56, peak Vo2=12.1±0.5 mL kg(-1) min(-1)) and 24 control subjects (peak Vo2 27.0±1.7 mL kg(-1) min(-1)). Peak exercise C(a-v)o2 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, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 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)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

Keywords: diastole; exercise; heart failure.

Figure 1

Arterial oxygen content (CaO₂) and mixed venous oxygen content (CvO₂) at peak exercise in patients with heart failure with preserved ejection fraction (HFpEF), HFrEF, and controls. *P<0.05 for comparison of HFpEF with HFrEF and controls.

Figure 2

Percentage increase in VO₂ and each of its components, heart rate (HR), stroke volume (SV) and arterio-mixed venous saturation difference (C(a-v)O₂) from rest to peak exercise, *P<0.05.

Figure 3

Illustration of the convective and diffusive components that interact to determine exercise capacity (VO₂) in heart failure and controls. Mean values for CvO₂ and VO₂ at rest, 30 W, and peak exercise are used to construct Fick principal lines, which indicate convective O₂ delivery and are curvilinear because they directly reflect the hemoglobin dissociation curve. The vertical lines extending from the origin to the VO₂-CvO₂ plot at peak exercise indicate maximum diffusive oxygen delivery as determined by the Fick law, with a steeper relationship indicating better O₂ diffusion. Black arrow indicates the increment in peak VO₂ in heart failure with preserved ejection fraction (HFpEF) if convective O₂ delivery was corrected to that of normal controls. White arrow indicates the increment in peak VO₂ if O₂ diffusion was normalized in HFpEF.

Figure 4

Diastolic blood pressure (BP) at rest and during incremental exercise in 2 subgroups of heart failure with preserved ejection fraction stratified by median mixed venous oxygen con-tent at peak exercise.