JACC: Heart Failure
Volume 6, Issue 4, April 2018 DOI: 10.1016/j.jchf.2018.01.007
PDF Article
Clinical Research

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

Cole S. Bailey, Luke T. Wooster, Mary Buswell, Sarvagna Patel, Paul P. Pappagianopoulos, Kristian Bakken, Casey White, Melissa Tanguay, Jasmine B. Blodgett, Aaron L. Baggish, Rajeev Malhotra and Gregory D. Lewis

Author + information

vol. 6 no. 4 329-339
DOI: 
https://doi.org/10.1016/j.jchf.2018.01.007
Published By: 
JACC: Heart Failure
Print ISSN: 
2213-1779
Online ISSN: 
2213-1787
History: 
  • Received December 17, 2017
  • Accepted January 4, 2018
  • Published online March 26, 2018.

Article Versions

Copyright & Usage: 
2018 American College of Cardiology Foundation

Author Information

  1. Cole S. Bailey, BAa,
  2. Luke T. Wooster, BSa,
  3. Mary Buswell, BSa,
  4. Sarvagna Patel, BSa,
  5. Paul P. Pappagianopoulos, MEdb,
  6. Kristian Bakken, NPb,
  7. Casey White, BSb,
  8. Melissa Tanguay, MS, CEPa,
  9. Jasmine B. Blodgett, MS, CEPa,
  10. Aaron L. Baggish, MDa,
  11. Rajeev Malhotra, MDa and
  12. Gregory D. Lewis, MDa,b,∗ (glewis{at}partners.org)
  1. aCardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  2. bPulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  1. ↵∗Address for correspondence:
    Dr. Gregory D. Lewis, Cardiopulmonary Exercise Laboratory, Heart Failure/Cardiac Transplantation, Massachusetts General Hospital, Gray Bigelow 8th Floor, 55 Fruit Street, Boston, Massachusetts 02114.

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.

Key Words

Impaired exercise capacity is a cardinal feature of heart failure (HF). Peak oxygen uptake (VO2) measured during cardiopulmonary exercise testing (CPET) reflects exercise capacity and is used to grade severity of HF (1). Although the prognostic implications of reduced peak VO2 in patients with HF are well known (2,3), other CPET gas exchange variables measured during exercise have emerged that offer insights into multiorgan physiologic reserve capacity and provide additive prognostic value when combined with peak VO2 (4–6).

Gas exchange patterns immediately following exercise provide information about the metabolic consequences of exercise exposure. Abnormally prolonged VO2 recovery to baseline resting values following exercise has been observed in patients with HF compared with healthy subjects (7,8). Prolonged VO2 and heart rate (HR) recovery following exercise both predict adverse outcomes in HF (9,10). However, attempts to fit various linear and exponential equations to VO2 recovery patterns have not translated into simple metrics that are routinely incorporated into clinical CPET interpretation in patients with HF. Furthermore, mechanistic understanding of VO2 recovery patterns in HF remains limited. Finally, studies of VO2 recovery in HF have focused almost exclusively on the HF with reduced ejection fraction (HFrEF) population. We therefore conducted a comprehensive evaluation of VO2 recovery patterns and their relationships to metabolic and hemodynamic responses to exercise in carefully phenotyped patients with HF with preserved ejection fraction (HFpEF) and HFrEF. We then investigated the prognostic significance of VO2 recovery patterns in a distinct patient cohort.

Methods

Patient population

We studied patients referred to Massachusetts General Hospital for CPET between June 2011 and July 2016. This study was approved by the Partners Human Research Committee. Patients with complete recovery gas exchange data during the 3 min after peak exercise were eligible for the study. The initial patient cohort was derived exclusively from consecutive patients who underwent CPET with invasive hemodynamic monitoring and met the following inclusion criteria: for HFpEF, left ventricular ejection fraction (LVEF) ≥0.50 with supine pulmonary artery wedge pressure (PAWP) ≥15 mm Hg and New York Heart Association (NYHA) functional class II to IV; for HFrEF, LVEF <0.45 and NYHA functional class II to IV; and for control subjects, LVEF >0.50, supine mean pulmonary artery pressure <25 mm Hg, supine PAWP <15 mm Hg, and a normal exercise capacity reflected by peak VO2 ≥85% predicted on the basis of age, gender, and height (11). Patients were excluded if they had any of the following conditions: 1) severe valvular heart disease; 2) intracardiac shunting; and 3) symptomatic, flow-limiting coronary artery disease. Those who achieved only submaximal effort during exercise as reflected by a peak respiratory exchange ratio of <1.00 and a peak HR <85% of predicted were also excluded (6).

A second distinct patient cohort was studied to determine the prognostic value of VO2 recovery patterns. This cohort consisted of consecutive patients who were referred to the Massachusetts General Hospital for NYHA functional class II to IV symptoms, had HFrEF with LVEF <0.45, and underwent noninvasive CPET from June 2011 to October 2014. We focused on patients with HFrEF in the noninvasive CPET cohort because of the well-circumscribed phenotyping provided by documented low LVEF, as opposed to our limited capacity to definitively distinguish HFpEF from other conditions that limit exercise capacity in patients who undergo noninvasive CPET.

Cardiopulmonary exercise testing

Patients in the first cohort underwent placement of a pulmonary arterial catheter via the internal jugular vein and a systemic arterial catheter via the radial artery. First-pass radionuclide ventriculography of both ventricles was performed at rest (OnePass GVI Medical Devices, Twinsburg, Ohio).

Patients then underwent maximal incremental upright cycle ergometry (5 to 25 W/min continuous ramp following a 3-min rest period and a 3-min period of unloaded exercise; MedGraphics, St. Paul, Minnesota). Breath-by-breath data were binned mid 5-of-7 by the metabolic cart for analysis of gas exchange patterns. Simultaneous hemodynamic measurements were obtained with exercise (Witt Biomedical Inc., Melbourne, Florida), as previously described (12,13). Right atrial pressure, mean pulmonary artery pressure, PAWP, and systemic arterial pressures were measured in the upright position, at end-expiration insert, at rest, and at 1-min intervals during exercise. Fick cardiac output (CO) was calculated at 1-min intervals throughout exercise by measuring VO2 and simultaneous radial arterial and mixed venous O2 saturation to determine the oxygen extraction (C[a-v]O2) at each minute of exercise. VO2/work was defined as the slope of the relationship between VO2 and work from 1 min after the initiation of loaded exercise to the end of exercise. Ventilatory efficiency or VE/VCO2 slope was defined as the relationship between expired carbon dioxide per minute and total ventilation per minute from the start of unloaded exercise to maximal exercise. VO2 efficiency slope (OUES) was defined as the relationship between VO2 and the natural log of total ventilation per minute throughout exercise (5). Following maximal exercise, the patients recovered over a 3-min period, pedaling against no resistance for the first minute of recovery and sitting passively for the final 2 min of recovery. Before testing, patients were instructed to keep the mouthpiece in throughout recovery to ensure data completeness.

Derived VO2 recovery kinetics

Based on the lack of any descent in VO2 during the early part of recovery in a subset of individuals, we termed a novel metric, VO2 recovery delay (VO2RD), as simply the time from the end of loaded exercise until the VO2 permanently falls below peak VO2, as illustrated in Figure 1. Peak VO2 was defined as the highest median breath-by-breath O2 consumption over a 30-s interval in the last minute of exercise. Because VO2RD measures the time until a permanent fall in VO2 below peak levels, this metric is also well-suited to patients with HF with periodic breathing during and after exercise (or oscillatory ventilation) (14,15). Recovery VO2 kinetics were also described by T1/2, the time for VO2 to decrease to 50% of peak VO2 adjusted for resting VO2 (7,16–18) and HR recovery at 2 min, as previously described (10).

Figure 1
Figure 1

Defining VO2 Recovery Delay

This illustration contains data from 2 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 the end of 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 (gray area) with a resultant VO2RD value of 0 s. In contrast, the second patient’s VO2 (red line) remained at values at or above those achieved at peak exercise for 55 s after exercise before beginning to decline. VO2 = oxygen uptake; VO2RD = oxygen uptake recovery delay.

Statistical analyses

STATA version 13.0 (StataCorp, College Station, Texas) was used for all analyses. The Wilk-Shapiro test was used to determine the normality of each continuous variable. Continuous measurements are presented as mean ± SD for normally distributed variables and median (interquartile range) for non-normal variables. Categorical data are presented as percentages. Comparisons with continuous variables involving 2 groups were performed using either the Student’s t-test or the Mann-Whitney test, as appropriate. Comparisons with continuous variables involving 3 groups were made using either a 1-way analysis of variance or Kruskal-Wallis test with post hoc testing adjusted for multiple comparisons, as appropriate. Fisher exact test was used for comparisons of categorical data. Pearson or Spearman correlation analysis was performed, as appropriate. Mortality data were obtained from the Social Security Death Index. Kaplan-Meier survival with log rank testing and multivariable Cox regression analysis were used to determine if VO2 recovery patterns and other variables predict transplant-free survival. A p value of <0.05 was considered significant.

Results

Population characteristics

Baseline characteristics for control (n = 22), HFpEF (n = 30), and HFrEF (n = 20) patients are summarized in Table 1. All 3 groups were similar in age. The HFrEF population was predominantly male. As expected, HFpEF patients had a greater body mass index compared with control subjects, and more frequent comorbidities of hypertension, diabetes mellitus, and hyperlipidemia. HFpEF and HFrEF patients exhibited very similar resting hemodynamic values with average resting supine mean pulmonary artery pressure of 26 ± 6 mm Hg and 26 ± 7 mm Hg and PAWP of 20 ± 5 mm Hg and 20 ± 6 mm Hg, respectively. Measurements performed during exercise testing are provided in Table 2. All 3 groups demonstrated peak exercise respiratory exchange ratios consistent with maximal effort, as indicated by an average respiratory exchange ratio in excess of 1.10. HFpEF (13.3 ± 2.8 ml/kg/min) and HFrEF (13.2 ± 2.8 ml/kg/min) patients exhibited similarly reduced peak VO2 levels compared with control subjects (25.6 ± 5.7 ml/kg/min).

View this table:
Table 1

Baseline Characteristics

View this table:
Table 2

Peak Exercise and Hemodynamic Measurements

Post-exercise VO2 recovery kinetics

In control subjects, VO2 consistently declined almost immediately following peak exercise. However, in patients with HF we commonly observed a prolonged VO2RD duration (Figure 1). Post-exercise VO2RD and T1/2 durations are displayed for the 3 groups in Figure 2. Control subjects exhibited minimal VO2RD durations with a median value of 5 s (interquartile range [IQR]: 0 to 7 s) compared with 25 s (IQR: 7 to 43 s) for patients with HF (p < 0.0001). HFpEF and HFrEF patients exhibited similarly prolonged VO2RD (25 s [IQR: 9 to 39 s] vs. IQR: 28 s [IQR: 2 to 52 s]; p = 0.99). T1/2 was also significantly increased in patients with HF compared with control subjects (107 ± 28 s vs. 62 ± 14 s; p < 0.0001) and the T1/2 of HFpEF and HFrEF patients were similar (102 ± 22 s vs. 114 ± 36 s; p = 0.21) (Figure 2). Additionally, HR recovery 2 min post-exercise was attenuated in patients with HF relative to control subjects (Table 2).

Figure 2
Figure 2

VO2 Recovery Kinetics

(A) VO2RD with median (interquartile range) for control subjects and patients with HFpEF and HFrEF. (B) T1/2 with mean ± SD for control subjects and patients with HFpEF and HFrEF. HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; other abbreviation as in Figure 1.

Patients with HF stratified by the median recovery delay

Because HFpEF and HFrEF patients exhibited similar post-exercise VO2RD durations, the 2 HF phenotypes were combined into 1 group and stratified by the median HF VO2RD duration of 25 s. The baseline characteristics of the stratified patients with HF are summarized in Table 3. Baseline characteristics, comorbidities, and medication exposures were similar between the 2 strata. There was no difference in resting PAWP or cardiac index in those with prolonged VO2RD (≥25 s) compared with shorter VO2RD (<25 s). In both the HFpEF and HFrEF cohorts, there was no difference in volitional effort between patients with VO2RD less than and greater than 25 s.

View this table:
Table 3

Baseline Characteristics and Exercise Measurements When Heart Failure Patients Are Stratified by the Median VO2 Recovery Delay

Exercise capacity, quantified by peak VO2 and maximal workload, was significantly reduced for patients with VO2RD ≥25 s compared with those with VO2RD <25 s to a similar extent in HFrEF and HFpEF (Table 3). Patients with HF with VO2RD ≥25 s demonstrated relative inability to augment CO during exercise compared with those with VO2RD <25 s (Figure 3A). Furthermore, strong negative correlations between VO2RD and augmentation of CO with exercise existed in both the HFpEF and HFrEF cohorts (Figures 3B and 3C). The evaluation of components of CO augmentation during exercise revealed that both HR and stroke volume augmentation during exercise were inversely related to VO2RD (ρ = −0.29, p = 0.04 and ρ = −0.44, p = 0.002, respectively) in patients with HF. Although we found a close relationship between VO2RD and the augmentation of CO in HF, there was no correlation between VO2RD and the augmentation in C(a-v)O2 during exercise (ρ = 0.09, p = 0.51). Augmentation in skeletal muscle oxygen extraction also did not differ between groups stratified by VO2RD (VO2RD ≤25 s vs. >25 s; 5.94 ± 1.61 ml/dl vs. 6.45 ± 1.74 ml/dl; p = 0.29). Furthermore, there was no correlation between VO2RD and measurements of pulmonary function, including forced expiratory volume in 1 s and oxygen saturation during exercise (ρ = −0.15, p = 0.32 and ρ = 0.17, p = 0.24, respectively). These findings suggest that VO2RD is specific for impairment in CO reserve, rather than impairment in peripheral oxygen extraction patients with HF. VO2RD also did not correlate with 2-min HR recovery (ρ = −0.11, p = 0.48) or 30-s HR recovery (ρ = −0.27, p = 0.10), indicating distinct physiologic information conferred by VO2RD in comparison with HR recovery. An abnormally low VO2 versus work slope is indicative of poor oxygen use and a greater reliance on anaerobic metabolism for a given workload with an increase in O2 deficit (19). We tested the hypothesis that a low VO2 versus work slope during exercise would be associated with prolonged VO2RD because of the need to “repay the O2 deficit” accumulated with exercise during recovery (Figure 4A). VO2/work slope was reduced in HFpEF (8.3 ± 2.0 ml/min/W) and HFrEF (8.7 ± 1.9 ml/min/W) compared with control subjects (10.4 ± 0.8 ml/min/W) in whom this relationship was within normal expected values of 10 ± 1.5 ml/min/W (p = 0.0001 and p = 0.003, respectively) (6,19). There was an inverse relationship between VO2/work slope and VO2RD duration in patients with HF and most patients with HF with VO2RD ≥25 s demonstrated below normal oxygen use per watt of work performed (i.e., <8.5 ml/min/W) (Figure 4B).

Figure 3
Figure 3

Prolonged VO2 Recovery Delay Is Associated With Impaired Hemodynamic Response to Exercise

(A) Cardiac output augmentation during exercise for the control subjects, HFpEF, and HFrEF groups is depicted as median with interquartile range. HFpEF and HFrEF groups are stratified by the median heart failure VO2RD (25 s). *p = 0.0015 between HFpEF <25 s and HFpEF ≥25 s. **p = 0.003 between HFrEF <25 s and HFrEF ≥25 s. A scatter plot of cardiac output augmentation during exercise versus VO2RD for (B) HFpEF and (C) HFrEF. Spearman rank correlation is included. CO = cardiac output; other abbreviations as in Figures 1 and 2.

Figure 4
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 heart failure and a prolonged VO2RD of 26 s. The red area highlights the difference between normal VO2/work (10 ml/min/W) and the subject’s reduced VO2/work of 7.6 ml/min/W, which represents an O2 deficit at the tissue. (B) Scatter plot of VO2/work versus VO2RD for the combined heart failure group (n = 50). Spearman rank correlation is included. The patients with heart failure with prolonged VO2RD and abnormal VO2/work (<8.5 ml/W) are denoted in red (n = 20 of 25 with prolonged VO2RD). Abbreviations as in Figure 1.

Prognostic value of recovery delay in HFrEF

We used a larger patient cohort (n = 106) (Online Table 1) undergoing noninvasive CPET to determine whether VO2RD predicts transplant-free survival in HFrEF. The median follow-up time was 2.5 years and 23 patients died or underwent cardiac transplantation (14 deaths, 9 heart transplants), whereas 17 additional patients underwent placement of a left ventricular assist device (LVAD), which was censored for transplant-free survival analysis. As a continuous variable, VO2RD predicted transplant-free survival in both univariate (Cox hazard ratio: 1.49 per 10-s increase in recovery delay; 95% confidence interval [CI]: 1.25 to 1.78; p < 0.001) and multivariable Cox regression analysis adjusting for VE/VCO2 slope, OUES, HR recovery at 2 min, and Wasserman VO2 % predicted (Cox hazard ratio: 1.37 per 10-s increase in recovery delay; 95% CI: 1.10 to 1.71; p = 0.005) (Table 4). As a dichotomous variable, VO2RD ≥25 s was associated with worse transplant-free survival with a Cox hazard ratio of 4.9 (95% CI: 1.4 to 16.4; p = 0.01). Kaplan-Meier curves stratified by VO2RD are shown in Figure 5A, with those patients with HF having a prolonged VO2RD exhibiting poorer outcomes (log rank p = 0.0048) with 20 out of 23 events observed in the prolonged VO2RD group. Baseline and exercise characteristics of these patients with HF stratified by VO2RD of 25 s are shown in Online Table 1. Furthermore, VO2RD was a better predictor of cardiac transplant-free survival than T1/2 in multivariable analysis (Cox hazard ratio: 1.32 per 10-s increase in VO2RD; 95% CI: 1.05 to 1.66; p = 0.018; and Cox hazard ratio: 1.16 per 20-s increase in T1/2; 95% CI: 0.93 to 1.40; p = 0.12).

Figure 5
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 25 s. (B) Kaplan-Meier VAD/transplant-free survival curves for HFrEF patients (n = 106) stratified by peak VO2 percent predicted and VO2RD. VAD = ventricular assist device; other abbreviations as in Figures 1 and 2.

View this table:
Table 4

VO2 Recovery Delay Predicts Cardiovascular Transplant-Free Survival in HFrEF Cohort 2 (n = 106) Independently of Other Prognostic CPET Variables

A multioutcome sensitivity analysis demonstrated that VO2RD consistently predicted a range of clinical outcomes in both univariate and multivariable analyses (Online Table 2). When assessing transplant/LVAD-free survival, a VO2RD ≥25 s had a Cox hazard ratio of 4.0 (95% CI: 1.7 to 9.4; p = 0.002) in univariate analysis and was a significant predictor independent of peak VO2 percent predicted, VE/VCO2 slope, OUES, and HR recovery at 2 min in multivariable analysis (Cox hazard ratio: 3.1; p = 0.02). In HFrEF patients, there is a close relationship between degree of impairment in percent predicted peak VO2 (as determined by the Wasserman equation [6]) and prognosis (20). Among those patients with HF with a relatively preserved peak VO2 percent predicted ≥55% (n = 51), those with a prolonged VO2RD ≥25 s (n = 28) exhibited a trend toward worse transplant/LVAD-free survival compared with those with a shorter VO2RD (log rank p = 0.067) (Figure 5B). Furthermore, among those with reduced peak VO2 percent predicted <55% (n = 55), those with a prolonged VO2RD (n = 39) exhibited worse transplant/LVAD-free survival compared with those with a shorter VO2RD (log rank p = 0.028) (Figure 5B). Finally, the presence of peak VO2 percent predicted of <55% and prolonged VO2RD conferred significantly increased risk compared with the absence of both findings (log rank p < 0.0001) (Figure 5B).

Discussion

In this study, we defined a novel, easily discernible pattern of sustained VO2 elevation following exercise in patients with HF, which we term VO2RD. We found that the duration of VO2RD was directly related to the degree of impaired CO augmentation in response to exercise in HFpEF and HFrEF. In addition, VO2RD was prolonged in patients with HF with lower than normal oxygen use per watt of work performed, suggesting that a prolonged VO2RD reflects an increased need to repay oxygen deficit that accumulates during exercise when CO augmentation lags behind the metabolic demands imposed by exercise. VO2RD also predicted transplant/LVAD-free survival, independently of peak VO2 percent predicted. Taken together, our findings indicate that VO2RD is a simple noninvasive measure of the metabolic consequences of exercise exposure in patients with HF that provides additional prognostic value beyond peak VO2.

The utility of performing precise quantification of exercise responses with CPET in patients with HF and other cardiorespiratory conditions is firmly supported by an expanding evidence basis. Multiple recent scientific statements have advocated for increased routine use of CPET in clinical practice in addition to Centers for Medicare- and Medicaid-mandated use of CPET in patient selection for advanced HF interventions (21). Recommended standardized CPET reports within these scientific statements contain numerous gas exchange CPET variables, but not a single recovery gas exchange measurement. This study addresses several limitations of studies done to date characterizing VO2 recovery patterns (10,16,17,22). First, divergent methods have been used to fit exponential equations to recovery patterns, but the multicomponent nature of the recovery patterns often observed in HF (i.e., a recovery overshoot or plateau period followed by an exponential decline) (Figure 1) indicates that a single equation will not suffice to describe VO2 recovery in patients with HF. Second, most studies of recovery VO2 kinetics have not included comprehensive hemodynamic measurements during exercise to provide mechanistic insights into prolonged VO2 recovery. Finally, assessment of VO2 recovery patterns has been confined to patients with known HFrEF despite the fact that there is an unmet need to define metrics that accurately reflect impaired cardiac reserve in patients with HFpEF.

Our study is the first to investigate the easily recognizable and measurable pattern of a delay in VO2 recovery following exercise. VO2RD is minimal (i.e., usually ≤5 s) in control subjects, even from a referral cohort of patients undergoing evaluation of dyspnea on exertion who proved to have normal physiologic responses during exercise. In contrast, VO2RD ≥25 s was observed in half of the patients with HF in our initial cohort and more than half in our second cohort.

Although VO2RD is a novel parameter that does not lend itself to comparison with previous studies, the mean T1/2 of patients with HF in our study of 107 ± 28 s was intermediate between that reported by Nanas et al. (16) (90 ± 24 s) and Scrutinio et al. (22) (152 ± 54 s) in HFrEF populations. Notably, the patients studied by Nanas et al. (16) included individuals with NYHA functional class I and average peak VO2 was higher than in our study population (16.7 ml/kg/min vs. 13.3 ml/kg/min), hence it is to be expected that recovery kinetics were more rapid in the Nanas study compared with this study.

Our findings relating VO2RD to impaired exercise CO augmentation and poor prognosis are also consistent with those of other investigators who have linked measures of impaired VO2 recovery kinetics to functional capacity and prognosis in patients with dilated cardiomyopathy (17) and HFrEF (7,23–25). For example, Tanabe et al. (18) described a strong correlation between T1/2 and cardiac index at peak exercise in HFrEF. Our findings extend those of Tanabe by introducing a measurement that correlates with exercise cardiac indices that are independent of resting hemodynamic state (i.e., exercise change in CO). Furthermore, we characterized VO2RD in HFpEF patients in whom surrogate markers for impaired CO response to exercise are desirable in light of the numerous contributing factors to exercise intolerance among patients with HFpEF. We found that VO2RD was closely related to CO augmentation in HFrEF and HFpEF and it was more closely linked to inability to augment stroke volume than HR. Therefore, HR augmentation and recovery patterns alone do not sufficiently capture the information provided by VO2RD.

The close correlations observed between impaired augmentation in CO and prolonged VO2RD, along with the observed low VO2/work slope in patients with prolonged VO2RD, support the hypothesis that VO2RD reflects the need to repay oxygen deficit that accumulates during exercise when CO augmentation lags behind metabolic demands imposed by exercise. The VO2/work slope below 8.5 ml/min/W observed in patients with prolonged VO2RD is indicative of a requisite shift toward anaerobic metabolism for a greater proportion of work performed during exercise, with progressive development of oxygen deficit.

Although impairment in peak VO2 is an established potent predictor of outcomes in HF, our study shows that VO2RD is an additional, independent predictor of cardiac transplant–free survival that offers prognostic value beyond peak VO2 and other prognostic CPET variables. We compared the prognostic strength of recovery delay against that of T1/2 and found that recovery delay outperformed T1/2 as a predictor of transplant-free survival. Additionally, after adjustment for VE/VCO2 slope, OUES, HR recovery at 2 min, and peak VO2 percent predicted every 10-s increase in recovery delay conferred a 37% greater hazard for cardiac transplantation or death.

Study limitations

First, CPET measurements are among the many variables used to select individuals for advanced HF interventions, making it possible that abnormal CPET findings contributed to the development of the transplant or LVAD endpoints. However, VO2RD data were not available in any of the patients at the time of transplantation or LVAD and the transplanted patients included in this study were uniformly United Network for Organ Sharing Status 1B or 1A, whereas patients undergoing LVAD implantation were uniformly INTERMACs Patient Profile 4 or less, indicating use of both interventions more as “rescue therapy” to avert mortality rather than purely elective interventions. Our patient cohort sizes were limited because the collection of 3 min of recovery gas exchange data was not routinely performed in our laboratory before May 2013, when a dedicated recovery protocol was created. The ease of measurement of VO2RD lends itself to confirmatory studies of its prognostic significance in larger HF studies. Additional studies are also warranted in other disease states to further understand the specificity of VO2RD for a circulatory insufficiency in comparison with other sources of exercise intolerance in conditions other than HF.

The control population was limited in size (n = 22) because of the infrequency with which subjects without significant cardiopulmonary disease are referred for CPET with invasive hemodynamic monitoring. Furthermore, the control population cannot be considered as completely normal given that its constituents underwent CPET for the evaluation of dyspnea. “Normal control subjects” were normal based on their exercise capacity, ejection fractions, and hemodynamic measurements at rest and during exercise, but did harbor some cardiovascular disease, such as hypertension. Use of these control patients, however, does tend to underestimate the differences between patients with HF and completely healthy control subjects.

Perspectives

COMPETENCY IN MEDICAL KNOWLEDGE: Presence of a prolonged VO2RD after exercise reflects circulatory insufficiency in both HFrEF and HFpEF, correlating strongly with otherwise invasively determined measures of hemodynamic response to exercise. VO2RD further proves to be a strong prognostic marker for HFrEF that is independent of other commonly used CPET variables for HF prognostication, including peak VO2, ventilatory efficiency, and OUES. These findings suggest VO2RD complements exercise gas exchange measurements for assessment of cardiac reserve capacity during noninvasive exercise testing. Furthermore, no recovery gas exchange measures are routinely included in CPET report templates endorsed by recent societal scientific statements. These findings add to the growing evidence base supporting clinical use of CPET in patients with HF and emphasizes the importance of extending gas exchange measurements into the recovery period.

TRANSLATIONAL OUTLOOK: There has been significant recent growth in the recognition of gas exchange patterns during and immediately after exercise that predict prognosis and offer insight into mechanisms of exercise intolerance in heart failure. VO2RD is a novel metric to easily identify circulatory insufficiency and delayed O2 kinetics during exercise. Future studies will focus on whether VO2RD performs similarly well in predicting outcomes in earlier stages of cardiovascular disease. In addition, it is not known whether conditions beyond HF that impair exercise capacity will be associated with similar VO2RD.

Appendix

Online Tables 1 and 2 [S2213177918300490_mmc1.docx]

Footnotes

  • Support was obtained from the National Institutes of Health (5R01HL131029 to Dr. Lewis) (K08HL111210 to Dr. Malhotral), the American Heart Association (15GPSGC24800006 to Dr. Lewis), and the Hassenfeld Clinical Scholars Program (Mr. Bailey, Mr. Wooster, Dr. Malhotra, and Dr. Lewis). Dr. Malhotra is a consultant for MyoKardia and Third Pole; and received grant support from the National Heart, Lung, and Blood Institute. Dr. Lewis has received contractual funding support for cardiopulmonary exercise testing core laboratory services from the NHLBI, Abbott Vascular, Ironwood, and Stealth Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Mr. Bailey and Wooster contributed equally to this paper and are joint first authors. Drs. Malhotra and Lewis contributed equally to this paper and are joint senior authors.

Abbreviations and Acronyms
CI
confidence interval
CO
cardiac output
CPET
cardiopulmonary exercise testing
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HR
heart rate
LVAD
left ventricular assist device
LVEF
left ventricular ejection fraction
NYHA
New York Heart Association
OUES
oxygen uptake efficiency slope
PAWP
pulmonary arterial wedge pressure
VO2
oxygen uptake
VO2RD
VO2 recovery delay
  • Received December 17, 2017.
  • Accepted January 4, 2018.

References

  1. ↵
    1. Balady G.J.,
    2. Arena R.,
    3. Sietsema K.,
    4. et al.
    (2010) Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 122:191–25.
  2. ↵
    1. O'Neill J.O.,
    2. Young J.B.,
    3. Pothier C.E.,
    4. Lauer M.S.
    (2005) Peak oxygen consumption as a predictor of death in patients with heart failure receiving beta-blockers. Circulation 111:2313–2318.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Mancini D.M.,
    2. Eisen H.,
    3. Kussmaul W.,
    4. Mull R.,
    5. Edmunds L.H. Jr..,
    6. Wilson J.R.
    (1991) Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 83:778–786.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Guazzi M.,
    2. Dickstein K.,
    3. Vicenzi M.,
    4. Arena R.
    (2009) Six-minute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circ Heart Fail 2:549–555.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Malhotra R.,
    2. Bakken K.,
    3. D'Elia E.,
    4. Lewis G.D.
    (2016) Cardiopulmonary exercise testing in heart failure. J Am Coll Cardiol HF 4:607–616.
    OpenUrl
  6. ↵
    1. Hansen J.E.,
    2. Sue D.Y.,
    3. Wasserman K.
    (1984) Predicted values for clinical exercise testing. Am Rev Respir Dis 129:S49–S55.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Cohen-Solal A.,
    2. Laperche T.,
    3. Morvan D.,
    4. Geneves M.,
    5. Caviezel B.,
    6. Gourgon R.
    (1995) Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy. Circulation 91:2924–2932.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Nanas S.,
    2. Nanas J.,
    3. Kassiotis C.,
    4. et al.
    (2001) Early recovery of oxygen kinetics after submaximal exercise test predicts functional capacity in patients with chronic heart failure. Eur J Heart Fail 3:685–692.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Arena R.,
    2. Guazzi M.,
    3. Myers J.,
    4. Peberdy M.A.
    (2006) Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 151:851.
    OpenUrl
  10. ↵
    1. Fortin M.,
    2. Turgeon P.Y.,
    3. Nadreau E.,
    4. et al.
    (2015) Prognostic value of oxygen kinetics during recovery from cardiopulmonary exercise testing in patients with chronic heart failure. Can J Cardiol 31:1259–1265.
    OpenUrl
  11. ↵
    1. Jones N.L.,
    2. Makrides L.,
    3. Hitchcock C.,
    4. Chypchar T.,
    5. McCartney N.
    (1985) Normal standards for an incremental progressive cycle ergometer test. Am Rev Respir Dis 131:700–708.
    OpenUrlPubMed
  12. ↵
    1. Murphy R.M.,
    2. Shah R.V.,
    3. Malhotra R.,
    4. et al.
    (2011) Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation 124:1442–1451.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Dhakal B.P.,
    2. Malhotra R.,
    3. Murphy R.M.,
    4. et al.
    (2015) Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 8:286–294.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Guazzi M.,
    2. Myers J.,
    3. Peberdy M.A.,
    4. Bensimhon D.,
    5. Chase P.,
    6. Arena R.
    (2008) Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights. Eur Heart J 29:2751–2759.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Arena R.,
    2. Myers J.,
    3. Abella J.,
    4. et al.
    (2008) Prognostic value of timing and duration characteristics of exercise oscillatory ventilation in patients with heart failure. J Heart Lung Transplant 27:341–347.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Nanas S.,
    2. Nanas J.,
    3. Kassiotis C.,
    4. et al.
    (1999) Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation 100:503–508.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. de Groote P.,
    2. Millaire A.,
    3. Decoulx E.,
    4. Nugue O.,
    5. Guimier P.
    (1996) Ducloux. Kinetics of oxygen consumption during and after exercise in patients with dilated cardiomyopathy. New markers of exercise intolerance with clinical implications. J Am Coll Cardiol 28:168–175.
    OpenUrlFREE Full Text
  18. ↵
    1. Tanabe Y.,
    2. Takahashi M.,
    3. Hosaka Y.,
    4. Ito M.,
    5. Ito E.,
    6. Suzuki K.
    (2000) Prolonged recovery of cardiac output after maximal exercise in patients with chronic heart failure. J Am Coll Cardiol 35:1228–1236.
    OpenUrlFREE Full Text
  19. ↵
    1. Tanabe Y.,
    2. Nakagawa I.,
    3. Ito E.,
    4. Suzuki K.
    (2002) Hemodynamic basis of the reduced oxygen uptake relative to work rate during incremental exercise in patients with chronic heart failure. Int J Cardiol 83:57–62.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Arena R.,
    2. Myers J.,
    3. Abella J.,
    4. et al.
    (2009) Determining the preferred percent-predicted equation for peak oxygen consumption in patients with heart failure. Circ Heart Fail 2:113–120.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Guazzi M.,
    2. Arena R.,
    3. Halle M.,
    4. Piepoli M.F.,
    5. Myers J.,
    6. Lavie C.J.
    (2016) 2016 Focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 133:e694–e711.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Scrutinio D.,
    2. Passantino A.,
    3. Lagioia R.,
    4. Napoli F.,
    5. Ricci A.,
    6. Rizzon P.
    (1998) Percent achieved of predicted peak exercise oxygen uptake and kinetics of recovery of oxygen uptake after exercise for risk stratification in chronic heart failure. Int J Cardiol 64:117–124.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Hayashida W.,
    2. Kumada T.,
    3. Kohno F.,
    4. et al.
    (1993) Post-exercise oxygen uptake kinetics in patients with left ventricular dysfunction. Int J Cardiol 38:63–72.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Sietsema K.E.,
    2. Ben-Dov I.,
    3. Zhang Y.Y.,
    4. Sullivan C.,
    5. Wasserman K.
    (1994) Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heart failure. Chest 105:1693–1700.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Kriatselis C.D.,
    2. Nedios S.,
    3. Kelle S.,
    4. Helbig S.,
    5. Gottwik M.,
    6. von Bary C.
    (2012) Oxygen kinetics and heart rate response during early recovery from exercise in patients with heart failure. Cardiol Res Pract 2012:512857.
    OpenUrlPubMed
View Abstract
Back to top

Toolbox

Print PDF
Email
Citation

Metrics

Advertisement

Article Outline

Figures in Article

Figures

  • Figure1
  • Figure 1
  • Figure 2
  • Figure 3
  • Figure 4
  • Figure 5

Supplementary Materials

Similar Articles

Advertisement