|Year : 2023 | Volume
| Issue : 1 | Page : 40-44
Postexercise oxygen uptake recovery delay among patients with heart failure: A systematic review
Charounipha Soydara1, Corrine Yvonne Jurgens2, Gregory D Lewis3
1 Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston; William F. Connell School of Nursing, Chestnut Hill, MA, USA
2 William F. Connell School of Nursing, Chestnut Hill, MA, USA
3 Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, USA
|Date of Submission||07-Oct-2022|
|Date of Acceptance||28-Dec-2022|
|Date of Web Publication||13-Mar-2023|
Ms. Charounipha Soydara
Massachusetts General Hospital, 55 Fruit Street, Boston 02114, MA
Source of Support: None, Conflict of Interest: None
Background: Peak oxygen uptake (VO2) is often the focal point of cardiopulmonary exercise testing among patients with heart failure (HF). Breath-by-breath VO2 kinetic patterns at exercise onset, during low-level and submaximal exercise, and during recovery may provide incremental insight into HF severity and etiologies of exercise limitation. Objective: The aim of this systematic review was to explore VO2 recovery delay (VO2RD) across the spectrum of left ventricular function. Methods: A systematic review was conducted using several online databases (EMBASE, Cumulative Index to Nursing and Allied Health Literature, PubMed and Web of Science). Steps outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Search terms included VO2RD OR VO2 off kinetics AND HF, peak VO2 AND recovery. All articles were uploaded to Covidence. Results: Four studies met the inclusion criteria. The definition of VO2RD varied across studies. Recovery delay was consistently observed in HF patients compared to controls indicating VO2RD discriminates between those with and without HF. Control groups showed VO2 decline almost immediately after exercise. VO2RD had a significant positive linear relationship to N-terminal prohormone of brain natriuretic and Doppler echo E/e' while demonstrating an inverse relationship with peak cardiac output and survival duration. Conclusions: VO2RD, unlike peak VO2, is relatively cardiospecific. Oxygen recovery kinetics offer insight into disease severity and discrimination of healthy participants from those with HF.
Keywords: Heart failure, peak oxygen uptake, recovery delay, recovery kinetics
|How to cite this article:|
Soydara C, Jurgens CY, Lewis GD. Postexercise oxygen uptake recovery delay among patients with heart failure: A systematic review. Heart Mind 2023;7:40-4
| Introduction|| |
Among a myriad of clinical manifestations of heart failure (HF), the inability to perform exercise is a major source of morbidity that often prompts patients to seek care. Decreased functional capacity is observed in most patients with HF even when optivolemic. The degree of impairment in exercise capacity is similar between individuals with symptomatic HF with preserved or reduced left ventricular ejection fraction (LVEF)., Understanding the mechanistic underpinnings of exercise response patterns may inform targets for intervention.
Cardiopulmonary exercise testing (CPET) is the gold-standard approach to objectively measuring exercise capacity. Peak oxygen uptake (VO2), a noninvasive CPET derivative, is a well-established predictor of outcome used in determining candidacy for interventions such as heart transplantation or mechanical circulatory support., Although peak VO2 is often the focal point of CPET in HF, the availability of breath-by-breath gas exchange patterns at exercise onset, during low-level and submaximal exercise, and during recovery may provide incremental insight into HF severity and etiologies of exercise limitation., Postexercise VO2 recovery delay (VO2RD), a noninvasive gas exchange metric following conclusion of incremental ramp-loaded exercise, is not currently part of guideline statements for CPET interpretation but represents a potentially important emerging physiologic metric in both HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).,,, Most existing literature has examined recovery kinetics in HFrEF.,,, Given the shortfall of available treatments for HFpEF, there is an unmet need to direct efforts into risk stratification and preventative strategies. In this light, the use of postexercise recovery kinetics may be useful in informing treatment strategies for the heterogeneity of HF phenotypes, in line with the goals of precision medicine and individualized care. The aim of this systematic review was to explore VO2RD across the spectrum of left ventricular (LV) function.
| Methods|| |
A systematic review was conducted following the steps outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A search of the literature was performed in February 2022, using: (1) EMBASE with search strategy and terms ('VO2 recovery delay' OR ['VO2 off kinetics' AND 'heart failure']), (2) Cumulative Index to Nursing and Allied Health Literature with search strategy and terms ['peak VO2 AND recovery' AND 'heart failure or cardiac failure or CHF or chronic heart failure or congestive heart failure'], (3) PubMed with search strategy and terms (([VO2 recovery delay] OR VO2 off kinetics) AND congestive heart failure), and (4) Web of Science with search strategy and terms (([VO2 recovery delay] OR [VO2 off kinetics]) AND [heart failure]). All articles were uploaded to Covidence.
Eligible studies included those focused on HF, age >18 years old, and full-text studies in English. Exclusion criteria included congenital heart disease, valvular disease as etiology of HF, postlung or heart transplant population, and mitochondrial myopathy. Nonpeer-reviewed studies, protocols, abstracts, and commentaries were ineligible. The date of limitation was not applied to searching, and the earliest published study in our result was from 1992.
The initial search produced 54 articles [Figure 1]. Ten duplicate studies were removed. Forty-four studies were eligible for screening. Using inclusion and exclusion criteria, 38 studies were excluded from the study. Those excluded were due to studies of non-HF study populations (n = 11), studies not focused on VO2RD (n = 10), studies not focused on VO2RD as the main variable of interest (n = 14) and abstract only (n = 3). Six met the eligibility criteria for inclusion. Two were excluded after reviewing due to abstract only status and VO2RD was not the variable of interest. The remainder four eligible studies met the criteria for final review and assessed for quality as guided by the John Hopkins Evidence-Based Practice Research Evidence Appraisal Tool.
|Figure 1: PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. PRISMA: Preferred reporting items for systematic reviews and meta-analyses|
Click here to view
| Results|| |
Four studies met the inclusion criteria [Supplementary File]. Sample size ranged from 22 to 526 participants. All participants were >18 years old and <90 years old. All studies included predominantly male participants and all studies included primarily Caucasian individuals with the exception of Kadariya et al.'s study, in which the cohort was 70% Black. HF classification on the basis of LV ejection fraction was not consistent among the studies. Two studies considered LVEF ≤40% HFrEF, one study considered HFrEF with LVEF <45%, and one study considered HFrEF with LVEF <50%. Only one study classified HF with mid-range ejection fraction as LVEF of 40%–49%. All four studies were level III (nonexperimental), three studies rated as “good quality,≵ and one study rated as “low quality or major flaws.≵ The low-quality rating was given due to insufficient sample size in accordance with the John Hopkins Nursing Evidence-Based Practice guide.
Definition of oxygen uptake recovery delay
The definition of VO2RD varied across studies [Table 1]. Here, we highlight the definition extracted from the eligible studies.
Duration of delay
RD was consistently observed in HF patients compared to controls indicating that VO2RD discriminates between those with and without HF. Control groups showed VO2 decline almost immediately after exercise. Bailey et al. showed VO2RD duration was 5 s (interquartile range [IQR] 0–7 s) in controls compared to 25 s (9–39 s) in HFpEF and 28 s (2–52 s) in HFrEF [Figure 2]. Kadariya et al. reported that HFrEF patients had a median RD of 15 s (IQR 10–50 s), whereas a smaller HFpEF cohort tended to have shorter delays of 10 s (IQR 10–18 s). Kemps et al. showed time constants of recovery kinetics were longer in HF cohort (55 ± 19 vs. 35 ± 10 s, P = 0.004). Despite differences in measuring RD, the phenomenon was observed in all HF patients across studies. Wagner et al. measured RD in % of relative VO2 reduction at 60 s and 120 s. Their results showed a mean difference between HF patients and controls of -5.76%, 95% confidence interval [CI] (-7.94%; -3.59%) at 60 s and -3.54%, 95% CI (-5.8%; -1.23%) at 120 s (P < 0.0001, P = 0.003, respectively).
Given the near immediate decline of VO2 postexercise in healthy patients, VO2RD discriminated healthy participants from those with HF, irrespective of the degree of LV systolic function in all studies. In two studies that compared VO2RD in HFpEF vs. HFrEF, conflicting results were observed. Kadariya et al. found VO2RD to be statistically significantly longer in HFrEF vs. HFpEF (P = 0.006), whereas Bailey et al. observed VO2RD to be similarly prolonged in both HFpEF and HFrEF. Notably, patient selection may have influenced these findings. Bailey et al. required hemodynamic criteria for HFpEF to be met on the day of study, which may have led to the inclusion of patients with more advanced HF, an associated more prolonged VO2 recovery, compared to that of Kadariya et al. Finally, medication exposures are also important to consider as these agents antagonize the sympathetic nervous system and attenuate heart rate response. Bailey et al. stratified HFpEF and HFrEF phenotypes by the median duration of VO2RD of 25 s, along with combing them into one group. The exposure to beta-blockers was similar among VO2RD strata, thus suggesting no significant correlation.
Peak VO2 is recognized to reflect the entirety of the oxygen (O2) pathway including contributions from central cardiac performance and peripheral O2 utilization. Multiple studies have suggested relative “cardiospecificity≵ to VO2RD. For example, Bailey et al. found that above median VO2RD was associated with ~40% lower average peak exercise cardiac output (CO), but no difference in peak exercise peripheral O2 extraction, the other component of peak VO2 in the Fick equation. When modeled as a continuous variable VO2RD was closely inversely correlated with peak CO. In complementary findings, Kadariya et al. found VO2RD to have a significant positive linear relationship to N-terminal prohormone of brain natriuretic and Doppler echo E/e' values (P ≤ 0.01, P = 0.04, respectively). VO2RD significantly predicted LV strain by comparison to existing biomarkers. Those with lower peak VO2 demonstrated prolonged VO2RD in excess of control groups. In another study, the largest R2 was observed for the linear slope VO2 off kinetics, which improved the model (containing sex, age, and peak VO2) in predicting HF severity through correlation with the New York Heart Association functional class. However, it did not provide further contributions to the model in predicting severity beyond the contribution of peak VO2.
Prognostic value of VO2RD was examined in one study. It was found to be a better predictor of cardiac transplant-free survival than T1/2, which is the time VO2 drops by 50% measured during peak exercise until 3 min postrecovery. Bailey et al. reported that VO2RD predicted transplant-free survival after adjusting for minute ventilation/carbon dioxide production (VE/CO2 slope), O2 uptake efficiency slope, HR recovery at 2 min, and VO2% predicted, every 10 s increase in recovery delay offered a 37% greater hazard for cardiac transplant or death.
| Discussion|| |
In this review, investigators consistently found that VO2RD is associated with abnormalities in cardiac structure and function that lead to circulatory delay. VO2RD, unlike peak VO2, is relatively cardiospecific. As an easily-derived noninvasive measure, VO2RD has the ability to distinguish HF disease presence and prognosis. Although the concept of VO2RD is not new, it has not been routinely adopted into CPET interpretation algorithms and its prevalence, ascription, and clinical implication remain insufficiently investigated.
The historical context of persistent elevation of VO2 after cessation of exercise initially was described by Hill et al. as the requirement of repaying O2 debt due to the delay in the achievement of steady-state VO2 requirement of the work in early minutes of exercise kinetic.,, In Bailey et al.'s study, peak exercise CO differed markedly between HF patients with shorter VO2RD (<25 s) and longer VO2RD (≥25 s), 11.4 L/min vs. 7.1 L/min (P < 0.05), respectively. Furthermore, when VO2RD was assessed as a continuous variable, it correlated with exercise-induced change in CO with r ≥ 0.70 and P < -0.001 in HFpEF and HFrEF. Taken together, these findings support the notion that inadequate CO to keep pace with incremental ramp exercise incurs an O2 debt that requires “repayment≵ during recovery. In contrast, VO2RD was not related to peripheral O2 extraction, cardiac filling pressures or pulmonary arterial pressures as these parameters were similar between groups with more and less VO2RD. Taken together, our findings suggest that VO2RD closely reflects the ability to augment CO during exercise, a finding that historically would obligate the use of invasive hemodynamic monitoring to ascertain.
Another potential mechanism of VO2RD is CO2 retention in the muscle due to lactic acid buildup, which promotes excess ventilation that extends immediately following cessation of incremental ramp exercise to eliminate CO2. Kemps et al. compared the kinetics of CO and oxygen consumption during submaximal exercise using the temporal profile of CO as a surrogate for O2 delivery. Their findings suggest that in moderately impaired HF patients O2 recovery kinetics are limited by O2 delivery as opposed to oxygen consumption because the redistribution of blood during exercise varies with HF severity.
Oxygen recovery kinetics offer insight into disease severity and permit discrimination of healthy participants from those with HF in all four studies. Duration of prolongation in HFpEF vs. HFrEF was not consistent in two studies., One demonstrated a statistically significant longer VO2RD in HFrEF vs. HFpEF. The ability to assess VO2RD noninvasively makes it a valuable tool. In addition, it is present in both maximal and submaximal effort testing. Levels of exercise needed for the performance of basic activities of daily living are associated with slow achievement of steady states, and prolonged recovery times in HF patients. Individuals with greater HF severity commonly function at submaximal level of exercise. Gas exchange variables in submaximal range predict prognosis and are independent of the volition on the part of the patient. Recovery kinetics are not routinely assessed, and standardized protocol may vary between institutions. For this reason, mode of assessment differs among studies. Understandably, the novel nature of VO2RD adds to the lack of uniformity; however, this makes it challenging to compare results and findings. Consistency is needed to propel the science forward.
Based on the precision of our method used in Bailey et al.'s study and the close correlation between VO2RD and exercise CO, as well as prediction of outcomes, we recommend the use of mid-5-of-7 breath averaging with breath-by-breath assessment described by Bailey et al. The method used by Kadariya et al. relied on 10-s bins which led to lack of granularity in discerning patterns of recovery as acknowledged by the authors. Similarly, assessing recovery at 60 s and 120 s limits ascertainment of patterns during early recovery. Future study is warranted to understand if assessment of both “early≵ and “late≵ patterns of recovery offer additive insights into HF characterization.
The limitations of this review include potential exclusion of relevant studies published outside of the predefined databases. In addition, non-English studies were not included, possibly excluding relevant work in this area. The lack of standardized protocol for the ascertainment of VO2RD lends to challenges in between-study comparisons. The collective study population in this review was predominantly male with only two studies examining the difference of RD between sexes., Despite several limitations, we can extrapolate from this review that VO2RD closely correlates with cardiac dysfunction yet its role in incrementally predicting outcomes in HF requires further investigation. Future studies are needed to define the critical threshold in which VO2RD may serve as a potent predictor of cardiac function and prognostic marker.
| Future Directions|| |
There is an unmet need to further study various approaches to assessing VO2RD patterns and their relation to prognosis. Whether other cardiac diseases such as coronary artery disease without HF, atrial arrhythmias or valvular disorders lead to abnormal VO2RD even in the absence of overt HF also merits future study.
Ethical statement is not applicable for this article.
Financial support and sponsorship
Support for this work was obtained from the National Institutes of Health R01HL151841 (GDL) and the Jeffrey and Mary Ellen Jay Chair in HF (GDL).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Patel H, Shafazand M, Schaufelberger M, Ekman I. Reasons for seeking acute care in chronic heart failure. Eur J Heart Fail 2007;9:702-8.
Nayor M, Houstis NE, Namasivayam M, Rouvina J, Hardin C, Shah RV, et al.
Impaired exercise tolerance in heart failure with preserved ejection fraction: Quantification of multiorgan system reserve capacity. JACC Heart Fail 2020;8:605-17.
Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 focused update: Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2016;133:e694-711.
Nayor M, Xanthakis V, Tanguay M, Blodgett JB, Shah RV, Schoenike M, et al.
Clinical and hemodynamic associations and prognostic implications of ventilatory efficiency in patients with preserved left ventricular systolic function. Circ Heart Fail 2020;13:e006729.
Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr., Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778-86.
Malhotra R, Bakken K, D'Elia E, Lewis GD. Cardiopulmonary exercise testing in heart failure. JACC Heart Fail 2016;4:607-16.
Bailey CS, Wooster LT, Buswell M, Patel S, Pappagianopoulos PP, Bakken K, et al.
Post-exercise oxygen uptake recovery delay: A novel index of impaired cardiac reserve capacity in heart failure. JACC Heart Fail 2018;6:329-39.
de Groote P, Millaire A, Decoulx E, Nugue O, Guimier P, Ducloux G. 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 1996;28:168-75.
Fortin M, Turgeon PY, Nadreau É, Grégoire P, Maltais LG, Sénéchal M, et al.
Prognostic value of oxygen kinetics during recovery from cardiopulmonary exercise testing in patients with chronic heart failure. Can J Cardiol 2015;31:1259-65.
Scrutinio D, Passantino A, Lagioia R, Napoli F, Ricci A, Rizzon P. 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 1998;64:117-24.
Nanas S, Nanas J, Kassiotis C, Nikolaou C, Tsagalou E, Sakellariou D, et al.
Early recovery of oxygen kinetics after submaximal exercise test predicts functional capacity in patients with chronic heart failure. Eur J Heart Fail 2001;3:685-92.
Sietsema KE, Ben-Dov I, Zhang YY, Sullivan C, Wasserman K. Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heart failure. Chest 1994;105:1693-700.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009;339:b2535.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al
. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
Kadariya D, Canada JM, Del Buono MG, van Wezenbeek J, Tchoukina I, Arena R, et al.
Peak oxygen uptake recovery delay after maximal exercise in patients with heart failure. J Cardiopulm Rehabil Prev 2020;40:434-7.
Newhouse RP, Dearholt S, Poe S, Pugh LC, White KM. Johns Hopkins Nursing Evidence-Based Practice Model and Guidelines. Indianapolis, IN: Sigma Theta Tau International Honor Society of Nursing; 2007.
Kemps HM, Schep G, Zonderland ML, Thijssen EJ, De Vries WR, Wessels B, et al.
Are oxygen uptake kinetics in chronic heart failure limited by oxygen delivery or oxygen utilization? Int J Cardiol 2010;142:138-44.
Wagner J, Niemeyer M, Infanger D, Pfister O, Myers J, Schmidt-Trucksäss A, et al.
Comparison of V̇O (2)-kinetic parameters for the management of heart failure. Front Physiol 2021;12:775601.
Hill AV, Long CN, Lupton H. Muscular Exercise, Lactic Acid and the Supply and Utilisation of Oxygen – Parts VII–VIII. Proceedings of the Royal Society of London. Vol. 97. Series B, Containing Papers of a Biological Character; 1924. p. 155-76.
Cohen-Solal A, Laperche T, Morvan D, Geneves M, Caviezel B, Gourgon R. 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 1995;91:2924-32.
Marsh GD, Paterson DH, Potwarka JJ, Thompson RT. Transient changes in muscle high-energy phosphates during moderate exercise. J Appl Physiol (1985) 1993;75:648-56.
[Figure 1], [Figure 2]