Post-Exercise Oxygen Uptake Recovery Delay: A Novel Index of Impaired Cardiac Reserve Capacity in Heart Failure

Abstract

Objectives: This study sought to characterize the functional and prognostic significance of oxygen uptake (VO₂) kinetics following peak exercise in individuals with heart failure (HF).

Background: It is unknown to what extent patterns of VO₂ recovery following exercise reflect circulatory response during exercise in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).

Methods: We investigated patients (30 HFpEF, 20 HFrEF, and 22 control subjects) who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and a second distinct HF cohort (n = 106) who underwent noninvasive cardiopulmonary exercise testing with assessment of long-term outcomes. Fick cardiac output (CO) and cardiac filling pressures were measured at rest and throughout exercise in the initial cohort. A novel metric, VO₂ recovery delay (VO₂RD), defined as time until post-exercise VO₂ falls permanently below peak VO₂, was measured to characterize VO₂ recovery kinetics.

Results: VO₂RD in patients with HFpEF (median 25 s [interquartile range (IQR): 9 to 39 s]) and HFrEF (28 s [IQR: 2 to 52 s]) was in excess of control subjects (5 s [IQR: 0 to 7 s]; p < 0.0001 and p = 0.003, respectively). VO₂RD was inversely related to cardiac output augmentation during exercise in HFpEF (ρ = -0.70) and HFrEF (ρ = -0.73, both p < 0.001). In the second cohort, VO₂RD predicted transplant-free survival in univariate and multivariable Cox regression analysis (Cox hazard ratios: 1.49 and 1.37 per 10-s increase in VO₂RD, respectively; both p < 0.005).

Conclusions: Post-exercise VO₂RD is an easily recognizable, noninvasively derived pattern that signals impaired cardiac output augmentation during exercise and predicts outcomes in HF. The presence and duration of VO₂RD may complement established exercise measurements for assessment of cardiac reserve capacity.

Keywords: cardiopulmonary exercise testing; exercise hemodynamics; heart failure; recovery kinetics.

Figure 1. Defining VO₂ recovery delay

This illustration contains data from two patients with heart failure who demonstrate distinct patterns of VO₂RD. The gray area illustrates the final portion of incremental ramp exercise. VO₂RD was defined as the duration of time from end exercise until the time when oxygen consumption (VO₂) fell permanently below peak VO₂ (dashed lines). The blue line represents a patient who has an immediate decrement in VO₂ following completion of the exercise period (shaded in gray) with a resultant VO₂RD value of 0 seconds. In contrast, the second patient’s VO₂ (red line) remained at values at or above those achieved at peak exercise for 55 seconds after exercise before beginning to decline.

Figure 2. VO₂ recovery kinetics

A) VO₂RD with median (IQR) for controls and patients with HFpEF and HFrEF. B) T_1/2 with mean ± SD for controls and patients with HFpEF and HFrEF.

Figure 3. Prolonged VO₂ recovery delay is associated with impaired hemodynamic response to exercise

A) Cardiac output augmentation during exercise for the controls, HFpEF, and HFrEF groups is depicted as median with IQR. HFpEF and HFrEF groups are stratified by the median HF VO₂RD (25s). (* indicates p=0.0015 between HFpEF < 25s and HFpEF ≥25s and ** indicates p=0.003 between HFrEF < 25s and HFrEF ≥25s. A scatter plot of cardiac output augmentation during exercise versus VO₂RD for B) HFpEF and C) HFrEF. Spearman rank correlation is included.

Figure 4. Prolonged VO₂ recovery delay is associated with reduced VO₂/work slope

A) Oxygen uptake plotted against workload during progression of an exercise test in a representative patient with HF and a prolonged VO₂RD of 26s. The red area highlights the difference between normal VO₂/work (10 ml/min/watt) and the subject’s reduced VO₂/work of 7.6 ml/min/watt, which represents an O₂ deficit at the tissue. B) A scatter plot of VO₂/work versus VO₂RD for the combined HF group (n=50). Spearman rank correlation is included. The HF patients with prolonged VO₂RD and abnormal VO₂/work (< 8.5 mL/watt) are denoted in red (n=20 of 25 with prolonged VO₂RD)

Figure 5. VO₂ recovery delay is a prognostic indicator in HFrEF

A) Kaplan-Meier transplant-free survival curves for HFrEF patients (n=106) dichotomized by a VO₂RD of 25s. B) Kaplan-Meier VAD/transplant-free survival curves for HFrEF patients (n=106) stratified by VO₂ % predicted and VO₂RD