Background
Cardiopulmonary exercise testing (CPET) has been classically performed on a cycle-ergometer or motorised treadmill using a rapid ramped incremental protocol to the limit of tolerance [
1]. Since most activities of daily living are performed in a non-incremental fashion and at submaximal level of exertion, the 6-Minute Walk Test (6MWT) may be more representative of daily-life activities and may reflect the functional capacity of patients more accurately [
2]. In addition, because most activities of daily living require repetitive submaximal effort, it may be postulated that analysing the cardiopulmonary responses during a transition from rest to submaximal intensity work may provide important information. Therefore, there is a growing interest in submaximal exercise parameters capable of reflecting the functional capacity of patients.
The change of oxygen uptake (VO
2) during constant work exercise (VO
2 on-kinetics) is classically subdivided into three functionally distinct phases [
3,
4]. A rapid first phase characterized by a short time delay of approximately 20 seconds reflects an increase in pulmonary blood flow. After the first phase, O
2 uptake gradually increases in an approximately mono-exponential fashion (phase 2) until a steady state level (VO
2SS) (phase 3) is attained. Phase 2 reflects the ability of the cardiopulmonary system to deliver oxygen and the amount of oxygen that is utilized by skeletal muscles. At the onset of exercise there is a delay in skeletal muscle mitochondrial ATP production due to a limited oxygen supply (oxygen deficit). Until the steady state is attained, anaerobic glycolysis compensates for this short-term oxygen deficit [
5,
6].
VO
2 on-kinetics can be characterized by the time (mean response time: MRT) required for VO
2 to achieve 63% of the VO
2SS in response to physical stress [
7,
8]. MRT is usually calculated in a CPET setting using a constant work rate protocol [
8,
9]. As the work rate during the 6MWT is mostly determined by the patients’ individual effort, MRT has to be calculated differently. In this study, a new MRT index (wMRT) is proposed to quantify VO
2 kinetics at the onset of exercise by correcting MRT for work rate during the first phase of the 6MWT.
It has been demonstrated that patients with chronic pulmonary or cardiac disorders exhibit slower VO
2 on-kinetics [
10,
11] when compared to healthy age-matched controls.
More knowledge of the physiological determinants of O
2 uptake kinetics at the onset of exercise may lead to a better understanding of the pathophysiological mechanisms causing functional impairments in patients. The importance of assessing VO
2 kinetics in the initial phase of low-intensity exercise may be underlined by that fact that peak VO
2 during a maximal exercise test is influenced by conditions other than the underlying disease, the patient’s motivation and the criteria used to terminate the test [
12]. In addition, it has been demonstrated in several chronic diseases that VO
2 on-kinetics have a higher prognostic value than peak VO
2[
13].
No data exist about the clinical utility of this refined method to quantify functional capacity of patients. Therefore, the main purpose of the present study was to analyse VO2 kinetics at the onset of exercise in patients with different pulmonary and cardiovascular diseases using mobile telemetric cardiopulmonary monitoring (MOB). Given the vast pathophysiological heterogeneity of these diseases it may be reasonable to presume that different diseases may have different VO2 kinetics. Secondarily, we investigated the extent to which VO2 kinetics are associated with exercise capacity (VO2SS and 6-Minute Walking Distance, 6MWD). The third aim of the present study was to investigate if VO2 kinetics are associated with morbidity and mortality in these patients.
Discussion
The main purpose of the present study was to analyse VO
2 kinetics during the 6MWT in a relatively large population of patients with different pulmonary and cardiovascular diseases using mobile telemetric cardiopulmonary monitoring (MOB). A new MRT index (wMRT) was developed to quantify VO
2 kinetics by correcting MRT for work rate. The relevance of this new parameterization was further confirmed by the reproducibility of the prior results from Schalcher and colleagues [
9]. wMRT was lower in all patients’ categories compared to healthy controls. Patients with PAH had a significant higher wMRT value compared to the other patients. We found significant associations between wMRT and exercise capacity in all patients. Furthermore, wMRT was found to be a significant prognostic factor in patients with CHF, but not in patients with lung diseases and PAH.
6MWT is easy to administer, well tolerated, and more reflective of activities of daily living than incremental maximal cardiopulmonary exercise testing (CPET) performed on a cycle-ergometer. In addition, because some individuals may not tolerate individualized maximal incremental exercise testing, analysing VO2 kinetics during 6MWT may be a useful alternative to CPET.
There has been controversy about the physiologic responses to the 6MWT in patients and described as both maximal [
24,
25] and submaximal [
26] sustainable exercise. Interestingly, in this study we found that 128 patients (58%) reached criteria for maximal effort according to the ATS guidelines [
1]. Detailed information on factors limiting exercise has been presented in previously published work [
14]. Furthermore, although exercise capacity was clearly diminished, no difference was found between the exercise capacity of the patients with different pulmonary and cardiovascular diseases. Despite the vast pathophysiological heterogeneity of these diseases we found that end-exercise oxygen uptake during the 6MWT was not different between patients groups. On the other hand, we found that the O
2 kinetics at the onset of exercise were clearly different between groups. The results of the present study may, therefore, lead to a better understanding of the pathophysiological mechanisms causing functional impairments in these patients.
The oxygen uptake at the onset of exercise is the product of cardiac output (CO) and the arterial-venous oxygen difference. The relative contribution of Q determinants (i.e., heart rate (HR) and stroke volume (SV)) to oxygen uptake is essential in reducing the O2 deficit and corresponding metabolic demand during exercise. The increase in cardiac output at the onset of exercise predominantly depends on the increase in SV and due to an increase in heart rate.
The delay in O
2 kinetics at the onset of exercise (wMRT) was largest in patients with PAH. A significant difference in wMRT was found between patients with PAH and the rest of the patients. As patients with PAH exhibit impairment in the distensibility and vasodilatory capacity and reduction in the size of the pulmonary vascular bed, the capacity for SV to augment CO is limited [
27‐
30]. In addition, exercise stresses the pulmonary circulation even more causing an abnormal increase in pulmonary artery pressure (PAP) during exercise (exercise-induced pulmonary hypertension) [
31‐
33]. As exercise even further increases PAP during the 6MWT in PAH, this could explain the significant difference in wMRT found between patients with CHF and PAH in the current study.
In patients with pulmonary diseases the delay in O
2 kinetics at the onset of exercise was associated with both 6MWD and VO
2SS. Although reduction in exercise capacity in patients with COPD is predominantly related to the combination of increased ventilatory requirements (mainly secondary to increased ventilation/perfusion mismatching) and acute derangements in dynamic ventilatory mechanics, the role of diminished stroke volume on exercise capacity may be underlined by the results of the present study. Borghi-Silva and colleagues [
10] have recently demonstrated, that VO
2 on-kinetics were associated with disease severity in patients with COPD. Hyperinflation may play an important role regarding heart size and heart dysfunction in patients with COPD. Watz and colleagues [
11] found that patients with COPD have an impaired left ventricular diastolic filling and an impaired global right ventricular function and that impaired left ventricular diastolic filling was independently associated with a reduced exercise tolerance. These results may eventually aid in the development of therapeutic approaches to improve the exercise capacity in patients with COPD.
The delay in O
2 kinetics at the onset of exercise in patients with heart failure was associated with 6MWD too. In patients with heart failure, delayed O
2 on-kinetics may primarily be reduced due to systolic and/ or diastolic left ventricular dysfunction [
34,
35]. Controversially, other researchers found that impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure [
36,
37].
Besides the changes in SV, a reduced arterial-venous oxygen difference may also play a significant role in the oxygen uptake at the onset of exercise. The latter is dependent on systemic blood flow, the amount of oxygen extraction possible from the systemic capillary blood, and the degree of arterial hypoxemia. Studies evaluating the physiological determinants of O
2 uptake kinetics showed that abnormal oxidative metabolism at the skeletal muscle level may also contribute to delayed oxygen-uptake kinetics and to the decreased exercise capacity in patients with several chronic diseases [
35,
38].
Meyers and colleagues investigated if exercise capacity is predictor of mortality in a total of 6213 healthy subjects and those with cardiovascular disease. In both groups, the peak exercise capacity achieved was a stronger predictor of an increased risk of death than other established risk factors for cardiovascular disease such as hypertension, smoking, and diabetes [
39].
In terms of prognosis, our results are in line with the previous findings showing that high MRT values are associated with a bad prognosis in CHF patients [
9]. On the other hand, wMRT was not associated with a bad prognosis for patients with lung disease or PAH.
Limiting factors of our study include the fact that MRT could not be calculated in all patients. In about 17% of cases the curve fit failed. Some of these patients were not able to perform the 6MWT with a constant walking speed or without interruptions. This fact may be the reason for the marked variability in VO
2 in 16 patients in whom curve fitting failed. Those patients whose VO
2 did not reach a plateau probably increased their walking speed during the 6MWT thus also increasing work rate. In addition they may have been exercising above their anaerobic threshold which permits an upward shift in VO
2 and an increased demand on central oxygen transport mediated by increased peripheral metabolism. In the current study only 5 of 204 patients (2.2%) reached the level of RER ≥1.10 suggesting that only a few patients reached an anaerobic threshold. In addition, the RER maximal-exercise RER ≥1.10 is commonly used as a criterion to determine whether a “true” VO
2max has been attained during maximal-effort exercise testing. It should however be stressed, that the use of RER ≥1.10 as a criterion for a valid or “true” VO
2max in patients with pulmonary diseases has been challenged. Peak exercise performance despite low RER is often seen in patients with a pulmonary limitation to exercise [
40].
We did not match age and gender between cases and controls because the purpose of the present study was not to demonstrate exercise intolerance in patients. The current study was in essence “observational”. For this purpose, a cross-sectional design was chosen, using only one single transition per participant. It should be stressed that this may have jeopardized the accuracy and precision of our data.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LK: has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. SC: has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. FB: has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. JW: has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. AG: has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. AA: has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. MT: has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. MB: has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. All authors read and approved the final manuscript.