Physical Therapy Korea

Oxygen uptake inefficiency is an important biomarker for accurately detecting or predicting cardiopulmonary function in patients with acute coronary artery disease, even during submaximal exercise [1]. Oxygen uptake inefficiency, which is associated with cardiopulmonary function, is determined by measuring peak oxygen uptake (VO₂ peak), minute ventilation (VE)/carbon dioxide production (VCO₂) slope, heart rate recovery (HRR), ejection fraction (EF), and oxygen uptake efficiency slope (OUES) parameters. Previous studies have reported a high prognostic value of OUES, VO₂ peak, VE/VCO₂ slope, HRR, and EF cardiopulmonary function testing parameters for cardiac-related events in patients with chronic heart failure [2-6]. Among the cardiopulmonary function testing parameters, OUES is an accurate indicator for estimating the level of exercise performance in patients with heart disease who cannot tolerate a maximum exercise stress test [7]. OUES was used as a quantitative measurement that estimates the VO₂ peak in a study involving submaximal evaluation of older patients with coronary artery disease [8]. Conventionally, VO₂ peak is the gold standard measure of cardiopulmonary function exercise capacity [9] and demonstrates the important relationship between the short-term survival rate and poor VO₂ peak (<10 ml/kg/min) [1,4]. It has also been used as an essential indicator of cardiac transplantation in patients with a VO₂ peak >14 ml/kg/min [1-7]. A delayed decrease in HRR reflects a decrease in vagal activity, which is a strong predictor of overall mortality regardless of exercise intensity or myocardial perfusion defects [10]. The VE/VCO₂ slope is a significant predictor of mortality, along with the OUES [11]. EF is a measure of the heart’s movement efficiency; low EF is related to reduced left ventricular EF and exercise capacity and is a sign of heart failure [12].

Nevertheless, there is a dearth of information demonstrating the relationship between OUES data and other important cardiopulmonary function parameters, including VO₂ peak, VE/VCO₂ slope, HRR, and EF for patients with acute ischemic heart disease over the age of 55 years. The American Heart Association found that the incidence of cardiopulmonary disorder in US men and women is to 40% from 40–59 years, to 75% from 60–79 years, and to 86% in those above the age of 80 years [13]. Therefore, the present clinical study aimed to determine the multiple relationships among the cardiopulmonary function variables mentioned above in adults with acute ischemic heart disease. In a clinical setting, this information may provide important insights into the best predictive parameters for estimating cardiopulmonary function in adults with acute ischemic heart disease. This could aid in making clinical decisions regarding stress tests, cardiac rehabilitation and exercise prescriptions, and surgical procedures for acute ischemic heart disease. We hypothesized that there would be meaningful relationships between VO₂ peak, VE/VCO₂ slope, HRR, EF, and OUES measurement variables.

1. Participants and Experimental Procedure

A convenience sample of 110 adult patients with ischemic heart disease (age: 57.4 ± 11.3 y; 95 males, 15 females) was enrolled as inpatient medical record chart at the hospital cardiac rehabilitation center (Table 1). As a cross sectional study, personal information is not collected and recorded, so it is Institutional Review Board (IRB) review exemption and is not subject to review (IRB exempt no. MJH2022-06-022). All patients underwent the necessary medical treatment, including the indicated procedures, such as percutaneous coronary intervention or coronary artery bypass graft (CABG), during the preliminary phases of their inpatient course in cardiac rehabilitation. The inclusion criteria were as follows: (1) diagnosis of ischemic heart disease, (2) participation in cardiopulmonary exercise testing (CPX) at the hospital cardiac rehabilitation center, and (3) evaluation of the cardiac rehabilitation CPX results from November 2018 to April 2020 for 18 months. The exclusion criteria were as follows: (1) severe heart failure, (2) unstable angina, (3) uncontrolled arrhythmia, (4) psychiatric illness (including dementia), (5) other significant non-cardiac-related comorbidities precluding the ability to exercise on the treadmill or lower extremity ergometer, and (6) readmission for subsequent acute myocardial infarction who had previously received the intervention [14].

Table 1 . Demographic and clinical characteristics of the patients (N = 110).

Parameter	Data
Sex (male/female)	95/15
Age (y)	57.4 ± 11.3
BMI (kg/m²)	25.1 ± 3.4
Past history
Hypertension	54 (49)
Diabetes mellitus	27 (25)
Smoking	46 (42)
Alcohol	37 (34)
Acute coronary syndrome
STEMI	53 (48)
NSTEMI	26 (24)
HF	12 (11)
Angina pectoris	37 (34)
Mitral valve prolapse	2 (2)
Major invasive management
PTCA	93 (85)
CABG	2 (2)

The present investigation was a cross sectional study wherein we analyzed patients’ medical records upon referral for cardiac rehabilitation from other departments of the medical center. Cardiac rehabilitation specialists (physical therapists and nurses) interviewed the potential enrollees to determine their suitability for CPX. Statistical power was set at 0.89, with a medium effect size of 0.3, an alpha error probability of 0.05, and a total sample size of 110, using G-power software (ver. 3.1.9.7; Franz Faul, Kiel University, Kiel, Germany) [15].

2. Cardiopulmonary Exercise Test

The CPX is a commonly used measure of cardiopulmonary function and fitness. All patients were required to refrain from strenuous physical activity and consumption of stimulants (coffee, tobacco, and alcohol) that could influence the heart rate for 24 hours before CPX. The test was performed at least two hours after eating a meal. All patients underwent CPX on a programmable treadmill in a room with controlled environmental conditions (21–23°C and 40%–60% relative humidity) between 10 am and 3 pm with a standard 12-lead continuous electrocardiogram monitor. Blood pressure was monitored by auscultation. VE, oxygen uptake, carbon dioxide output, and other cardiopulmonary variables were recorded breath-by-breath using a computerized system (COSMED Omnia 1.6.7; COSMED, Rome, Italy). Resting oxygen consumption and heart rate were computed as the mean of the final 30 seconds of the resting period, whereas peak effort (oxygen consumption) and heart rate were the mean values of the final 30 seconds of effort before exhaustion. Respiratory exchange ratios were recorded as the average of samples obtained during each stage of the protocol (Modified Bruce protocol or bike incline protocol at 5, 10, 15, and 20 W). The submaximal exercise test was implemented at 2.25 km/h with a resting interval of 5–10 to prevent venous pooling during the recovery phase. The reliability and validity of the CPX have been previously established, and the specific standardized procedure has been well documented [16].

3. Oxygen Uptake Efficiency Slope

The OUES was determined by evaluating the cardiopulmonary functional reserve resulting from the single-segment logarithmic relationship between oxygen uptake and VE through incremental exercise, which was presented as a new linear measure of the ventilatory response to exercise. The relationship between oxygen uptake and ventilation volume was stated using the OUES. This index is best described by a single-segment logarithmic curve-appropriate model using the equation VO₂ = a × logVE + b, in which the constant “a” characterizes the rate of increase in VO₂ in response to an increase in logVE. This constant “a” is called OUES. A steeper slope or higher OUES (Figure 1A) indicates a more effective oxygen efficiency capacity from the cardiopulmonary system by the active skeletal muscles, whereas a shallower slope or lower OUES (Figure 1B) indicates the need for ventilation and less effective oxygen uptake efficiency compared to steeper slopes. The reliability and validity of the OUES test have been established previously, and the specific standardized procedure is well documented [17].

Figure 1. Higher and lower oxygen uptake efficiency slope. (A) Steeper slope, higher oxygen uptake efficiency slope; (B) shallower slope, lower oxygen uptake efficiency slope.

4. VO₂ Peak

VO₂ peak was determined by assessing maximal oxygen consumption, termed “VO₂ max,” which is defined as the volume of oxygen consumed by a participant during incremental exercise, and is the gold standard for assessing cardiopulmonary function [18]. However, achieving VO₂ max as defined by standardized criteria, including a plateau in oxygen consumption with incrementally increased work [19] may increase the risk for older adults [20] and the risk of adverse events (e.g., myocardial infarction and cardiac arrhythmia) [21]. A common resolution is to adapt the VO₂ max criteria (plateau in oxygen consumption) and use oxygen consumption level at peak exercise (VO₂ peak) as a measure of cardiopulmonary function [22]. The VO₂ peak (ml/min) was calculated as the mean of the two highest serials achieved VO₂ values in 10 seconds during peak or submaximal exertion. The reliability and validity of the VO₂ peak measurement have been established previously, and the specific standardized procedure is well documented [23].

5. VE/VCO₂ Slope

The VE/VCO₂ slope was determined by measuring the minute ventilation/carbon dioxide production, representing ventilatory efficiency. Breath-by-breath gas exchange data were averaged using a 15-second sampling interval, and the VE/VCO₂ slope was determined using the metabolic cart’s Omnia 1.6.7 software (Quark CPET; COSMED, Rome, Italy) by generating a graph of ventilation and VCO₂ and fitting a linear regression equation to the relationship. The reliability and validity of the VE/VCO₂ slope have been established previously, and the specific standardized procedure is well documented [24].

6. Heart Rate Recovery

HRR was defined as the decrease in heart rate from peak exercise exertion to one minute after exercise cessation. HRR was automatically recorded from the exercise phase to the 60-second post-recovery phase using the software.

7. Echocardiography

Heart thickness and blood flow were determined based on standardized EF measurements, which were consistently assessed by a licensed cardiologist. The patient was comfortably seated. Six different portable ultrasound machines were used; data were uploaded to the electronic medical record (EMR) system and made available for use in this study. All the data were measured by the same physician. Standard M-mode and 2-dimensional echocardiography, as well as Doppler blood flow measurements, were performed in accordance with the American Society of Echocardiography guidelines [24]. The left ventricular EF was calculated from 2-dimensional apical images using Simpson’s method [25].

The reliability and validity of the EF have been established previously, and the specific standardized procedure is well documented [26].

8. Statistical Analysis

Statistical tests were expressed as means ± standard deviations. Pearson or Spearman correlation coefficients were used to determine the multidirectional relationships between the OUES and VO₂ peak, VE/VCO₂ slope, HRR, and EF variables measured during submaximal CPX. SPSS software (ver. 23.0; SPSS Inc., Chicago, IL, USA) was used to compute correlations at p < 0.05.

Table 2 presents the mean ± standard deviation, standard error and 95% confidence interval of OUES, VO₂ peak, VE/VCO₂ slope, HRR, and EF in the analysis, respectively.

Table 2 . OUES and other indicators.

Parameter	Mean ± SD	SE	95% CI
OUES	1,877.2 ± 630.1	60.1	1,994.9–1,759.4
VO2 peak	1,506.6 ± 457.2	43.6	1,592.0–1,421.1
VE/VCO2 slope	33.7 ± 9.0	0.86	35.4–32.0
HRR	21.3 ± 10.8	1.0	23.3–19.3
EF	48.0 ± 11.5	1.1	50.2–45.9

Correlation between OUES and VO₂ peak, VE/VCO₂ slope, HRR, and EF showed a strong positive (r = 0.832, p < 0.001) (Figure 2), moderately negative (r = –0.544, p < 0.001) (Figure 3), moderately positive (r = 0.344, p < 0.001) (Figure 4), and no significant correlation (r = 0.181, p = 0.065) (Figure 5), respectively.

Figure 2. VO2 peak and OUES correlation. VO2 peak, peak oxygen uptake; OUES, oxygen uptake efficiency slope.

Figure 3. VE/VCO2 slope and OUES correlation. VE/VCO2, minute ventilation/carbon dioxide production; OUES, oxygen uptake efficiency slope.

Figure 4. HRR and OUES correlation. HRR, heart rate recovery; OUES, oxygen uptake efficiency slope.

Figure 5. EF and OUES correlation. EF, ejection fraction; OUES, oxygen uptake efficiency slope.

The present study established a relationship between OUES data and other important cardiopulmonary function testing parameters, including VO₂ peak, VE/VCO₂ slope, HRR, and EF, in older patients with acute ischemic heart disease. As anticipated, the OUES measurement data were correlated with VO₂ peak, VE/VCO₂ slope, and HRR, but not EF. Most importantly, this correlation information provides important clinical insights into the utility of a different yet accurate alternative cardiopulmonary testing procedure to assess cardiopulmonary function in older adults with acute ischemic heart disease who are unable to tolerate certain testing protocols owing to their medical condition.

Correlation analysis showed a strong relationship between the OUES and VO₂ peak (r = 0.832, p < 0.001). Previous correlation studies [1,27] in healthy young adults reported moderate correlations between submaximal OUES and age (r = 0.557–0.584) [26]. Another cardiopulmonary correlation study showed a moderate correlation (r = –0.58) between the OUES and peak VE/VO₂ in 398 patients with systolic heart failure. The strong correlation between submaximal OUES and VO₂ peak is also in line with the results of a study that reported a very strong correlation between submaximal OUES and VO₂ max (r = 0.95) [1]. This is consistent with our finding that the OUES is derived from the logarithmic relationship between oxygen uptake and VE during incremental exercise. VO₂ max is considered the gold standard for the stratification of patients with heart failure; however, its use is limited by the patient’s condition, motivation, skeletal muscle structure, pulmonary function, and hemoglobin level. Thus, some patients do not achieve their anaerobic threshold during exercise, and the VO₂ peak or VO₂ max cannot be accurately assessed. To overcome these limitations, submaximal metabolic parameters have been proposed as surrogates for estimating the OUES.

Correlation analysis showed a moderately significant relationship between OUES and the VE/VCO₂ slope (r = –0.544, p < 0.001) and HRR and OUES (r = 0.344, p < 0.001). This finding was in line with that of a previous correlational study [28], which reported a strong correlation between VE/VCO₂ and OUES in 341 patients with heart failure (r = –0.65 to –0.61, p < 0.001) [28]. Another study demonstrated a moderate correlation between HRR and peak VO₂/kg in 58 patients with idiopathic pulmonary arterial hypertension (r = 0.569, p < 0.001) [29]. OUES is a novel index derived from the logarithmic relationship between oxygen uptake and VE during incremental exercise and best represents the development of metabolic acidosis, physiological dead space, and arterial CO² partial pressure [1]. Our correlational data corroborate that the OUES reflects a single physical index for cardiovascular and peripheral factors accounting for oxygen uptake and HRR, which influence the ventilatory response to exercise. Furthermore, the OUES had a strong prognostic value in identifying patients with acute ischemic heart disease who presented with a greater increase in ventilation per unit increase in VO₂ due to various metabolic, reflex, and gas exchange abnormalities [30-33]. Correlational data among the OUES, VO₂ peak, VE/VCO₂ slope, and HRR parameters may provide a specific pattern of ventilatory response to exercise having automatically “controlled” for abnormalities present during exercise because the OUES filters out or adjusts outliers to account for measurement errors that may occur during evaluation. It is important to determine exercise intensity using VO₂ peak value without controlling for outliers, as this may lead to an inappropriate exercise intensity. If the exercise is too intense, the patient may be unable to tolerate it.

In another correlation study [34] examining the relationship between VO₂ peak and EF before and after surgery, there was no correlation between EF and VO₂ peak before (r = 0.123, p = 0.6) and after (r = 0.27, p = 0.2) cardiac surgery in 6 months follow-up. A weak correlation was observed between the changes in VO₂ peak and EF from the preoperative period to the postoperative period (r = 0.48, p = 0.048). This is because the factors that affect the patient’s aerobic capacity are not only the EF, but also the change of heart rate through the autonomic nervous system and the aerobic capacity of various muscles activated during exercise.

The present study has some limitations that should be considered in future studies. This study was retrospective in nature, and we only evaluated exercise variables and did not include data obtained from echocardiography, which can provide prognostic information. In addition, there was a lack of follow-up evaluation, which can provide important correlations regarding therapeutic effects in patients with acute ischemic heart disease.

The present correlational study demonstrated that OUES was highly correlated with VO₂ peak, VE/VCO₂ slope, and HRR parameters but not with EF. These findings provide the important clinical insight that OUES can be used as an accurate alternative indicator to measure cardiopulmonary function in patients with acute ischemic heart disease during submaximal exercise to design cardiopulmonary rehabilitation programs more effectively.

None.

None to declare.

No potential conflict of interest relevant to this article was reported.

Conceptualization: JJL, JHY. Data curation: JJL. Formal analysis: JJL, CP. Investigation: JJL. Methodology: CP. Project administration: JHY. Resources: JHY. Supervision: JHY. Validation: CP. Visualization: JJL, CP. Writing - original draft: JJL, CP, JHY. Writing - review & editing: CP, JHY.