1. Top of page
  2. Abstract
  7. References

The authors evaluated the minute ventilation/carbon dioxide production relation (VE/VCO2 slope) as a complementary measure to peak oxygen consumption (peak VO2) in 76 patients (mean ± SD age = 44.3±10.8 years, 69.7% female) with morbid obesity (mean ± SD body mass index [BMI] = 49.4±7.0 kg/m2), as it is not limited by effort. Nearly one-half (43%) of the patients achieved a peak respiratory exchange ratio <1.10. Mean peak VO2 and VE/VCO2 slope were 17.0±3.7 mL/kg/min and 27.8±4.0, respectively. Peak VO2 correlated with BMI (r=−0.45, P<.0001), while VE/VCO2 slope did not (r=−0.04, P=.73). There was a linear trend for declining mean peak VO2 (P=.001) but not for VE/VCO2 slope (P=.59) with increasing BMI quintiles. The VE/VCO2 slope is an effort-independent measure that is also independent of BMI and may serve as an adjunctive cardiorespiratory variable when evaluating morbidly obese men and women.

Data from the general US population demonstrate that nearly 2 of 3 adults are overweight/ obese (body mass index [BMI] ≥25 kg/m2) and nearly 1 of 3 are obese (BMI ≥30 kg/m2).1 The obesity epidemic has had a major public health impact; conservative estimates attribute 280,000 deaths annually to obesity, second only to tobacco abuse.2–4 In response to an emerging body of scientific evidence, the American Heart Association and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) reclassified obesity as a major modifiable risk factor for coronary heart disease.5,6 Moreover, increased BMI is strongly associated with an elevated risk of cardiovascular disease (CVD), hypertension, dysmetabolic syndrome, type 2 diabetes mellitus, sleep apnea syndrome, hyperlipidemia, osteoarthritis, certain cancers, and death from all causes.7–11

Decreased peak oxygen consumption (peak VO2) is associated with increased cardiovascular and all-cause mortality in patients with and without CVD, including patients with heart failure.12,13 Laukkanen and colleagues14 found that low cardiorespiratory fitness increases an individual's relative risk of death to that associated with tobacco abuse, hypertension, and/or diabetes. Conversely, Blair and colleagues15 reported that for every 1-minute increase in maximal treadmill time, roughly equivalent to a 1 metabolic equivalent (1 metabolic equivalent = 3.5 mL O2/kg/min) improvement in fitness, a corresponding 8% reduction in mortality was noted. Similarly, unfit men of normal weight had death rates nearly 3 times as high as their obese counterparts with moderate to high levels of cardiorespiratory fitness.16

Although the maximal VO2 (VO2max) has been widely used as a marker of exercise capacity and prognosis, many individuals discontinue exercise at a level of fatigue or discomfort far below their physiologic maximum (eg, peak VO2). This effort-dependent variable, expressed as mL/kg/min, is also adversely influenced by excessive body weight. Consequently, other cardiopulmonary variables are increasingly being studied to assess functional limitations in various patient populations. Of these, the relation between minute ventilation and somatic carbon dioxide production, expressed as the VE/VCO2 slope, has been suggested as a marker of the severity of heart failure and appears to predict mortality at least as well as, and independent from, cardiorespiratory fitness.17 While VE/VCO2 values in the 20s are typically reported in healthy normal patients, values in the 30s and 40s are common in patients with mild to moderate and more severe heart failure, respectively.

Obesity is associated with disproportionate increases in the rate-pressure product during physical exertion.18 Excessive cardiac demands, especially in patients with known or occult coronary disease, may precipitate angina pectoris, malignant ventricular arrhythmias, or both. More recent, Salvadori and colleagues19 evaluated the cardiorespiratory fitness of obese patients and found a decreased physical work capacity and reduced cardiac efficiency as compared with normal-weight controls. In addition, obese patients demonstrated a greater rate-pressure product and VO2 for a given submaximal workload and relative chronotropic incompetence as compared with controls.

Despite the negative health impact of obesity and the associated exercise intolerance, few data are available regarding the cardiorespiratory and hemodynamic responses to peak or symptom-limited exercise testing in morbidly obese adults, including peak VO2 and other variables such as the VE/VCO2 slope and their relation to increasing BMI. Moreover, it remains unclear to what extent these patients demonstrate subsidiary evidence that a “true” VO2max has been attained.


  1. Top of page
  2. Abstract
  7. References

Study Population

We prospectively performed cardiopulmonary exercise stress testing (CPX) on morbidly obese patients referred for bariatric surgery. Eligibility criteria for inclusion were: (1) BMI >35 kg/m2 and >40 kg/m2 in those with and without diabetes, respectively; (2) absence of limiting cardiopulmonary disease (Canadian Cardiovascular Society class 4 angina or functional class 4 dyspnea); and (3) ability to perform CPX to exhaustion. Patients with a history of severe lung disease that required chronic oxygen therapy were excluded from participation. Based on these criteria, 76 morbidly obese patients were used in this analysis.

Cardiopulmonary Testing

Patients underwent peak or symptom-limited CPX testing generally using the conventional Bruce20 or modified Bruce treadmill protocols. Heart rate and blood pressure were measured at rest in the supine and standing positions, during each 3-minute exercise stage, and throughout a minimum 6-minute recovery. Test termination criteria included patient request, volitional fatigue, increasing chest (≥2/4) or severe leg pain, and selected electrocardiographic (ECG) abnormalities (≥2-mm ST-segment depression and/or threatening ventricular arrhythmias).

Respiratory variables, heart rate, blood pressure (standard cuff method), and perceived exertion were determined during submaximal and maximal exercise. The ECG was continuously monitored by oscilloscope, with 3-channel recordings (V1, V5, and aVF) made every minute throughout the exercise test and 12-lead ECGs (1 mV/10 mm) recorded at the end of each stage and during maximal exercise. Perception of the intensity of physical effort at submaximal and maximal exercise was obtained using the Borg category (6–20) scale.21

Metabolic data were obtained using Medical Graphics' CPX/D System (Medical Graphics Corporation, St Paul, MN). The system includes a computer assembly for breath-by-breath and online 60-second calculations of VO2 (mL/kg/min), minute ventilation (VE), carbon dioxide production (VCO2), and respiratory exchange ratio (RER; VCO2/VO2). Before each test, the pneumotachometer was referenced according to manufacturer specifications with a 3-L syringe, and the gas analyzers were calibrated with a certified air mixture representing room air (21% O2, balance nitrogen) and certified O2/CO2 concentrations (12% and 5%, respectively). The pneumotach was a bidirectional differential pressure preVent model (MedGraphics). A standard Kraton mouthpiece with saliva trap was employed.

The V-slope method was used to determine the ventilatory-derived anaerobic threshold (V-AT; ie, the break point in linearity when VCO2 was plotted as a function of VO2), expressed as a percentage of the highest observed value for VO2. This method has been reported to be a sensitive, reliable, noninvasive technique for detection of the onset of metabolic acidosis.22,23 We also computed the slopes of the relation between VE and VO2 and between VE and VCO2, as markers of breathing economy and functional limitations, respectively. These data were analyzed via a 15-second average and entered into a spreadsheet in a time-down format. The VE/VCO2 slope was determined by a least squares linear regression equation (y = a + bx; b = slope).

Patients were classified into 2 groups according to the RER values achieved at peak exercise. RER values <1.0 generally signify inadequate effort, poor motivation, or limiting localized fatigue on the part of the patient. On the other hand, it is common to find RER values >1.0 during exhaustive exercise, with values ≥1.10 suggesting that a “true” VO2max has been attained.24,25 Thus, our patients were grouped according to those who achieved RER values <1.10 and ≥1.10.

Statistical Analysis

Baseline characteristics were expressed as mean ± SD or counts with proportions as appropriate. Univariate comparisons were made with Student t test, Fisher exact test, chi-square, and chi-square for trend as appropriate. Pearson correlation was used to evaluate bivariate relationships between continuous variables. A P value <.05 was considered statistically significant.


  1. Top of page
  2. Abstract
  7. References

Table I shows the baseline characteristics of patients from each group, stratified by RER, who met the inclusion criteria. All patients (N=76) completed the exercise test protocol without demonstrating significant ST-segment depression (≥1.0 mm horizontal or downsloping), serious ventricular arrhythmias, abnormal blood pressure responses, or anginal symptoms. Reasons for test termination included volitional fatigue, leg pain, and dyspnea. Forty-three (57%) and 33 (43%) patients achieved an RER ≥1.10 and <1.10, respectively. The latter subset, that is, those failing to demonstrate subsidiary evidence that a “true” VO2max had been achieved, were generally older and had higher BMI values (P=.03 and .04, respectively). For the entire cohort (n=76), mean peak VO2 and VE/VCO2 slope were 17.0±3.7 mL/kg/min and 27.8±4.0, respectively. The V-AT occurred at 76% and 66% of the peak VO2 values for the cohorts who achieved RERs <1.10 and ≥1.10, respectively.

Table I.  Baseline Characteristics Stratified by Peak RER During Cardiopulmonary Exercise Stress Testing
CharacteristicRER <1.10RER ≥1.10P Value
Age, y47.5±10.342.0±10.7.03
Male9 (27.3)14 (32.6).62
Female24 (72.7)29 (67.4).62
 Caucasian29 (87.9)36 (83.7) 
 African American3 (9.1)5 (11.6) 
 Other1 (3.0)2 (4.7) 
Body mass index, kg/m251.3±8.547.8±5.1.04
Weight, kg143.4±29.2136.2±20.2.23
β-Blocker use6 (18.2)7 (16.3).83
Hypertension20 (60.6)18 (41.9).11
Diabetes12 (36.4)13 (30.2).57
Coronary disease4 (12.1)3 (7.0).46
Asthma or COPD10 (30.3)10 (23.3).49
Tobacco abuse3 (9.1)5 (11.6).72
Regular exercise3 (9.1)8 (18.6).24
Values are expressed as mean ± SD or No. (%). Abbreviations: COPD, chronic obstructive pulmonary disease; RER, respiratory exchange ratio.

Baseline and maximal exercise responses, including hemodynamic and cardiopulmonary data, as stratified by RER, are listed in Table II. Those achieving RER values < 1.10 demonstrated lower peak heart rates; however, the percentage of maximum predicted heart rate achieved for both groups was comparable, 86.8%±8.3% vs 89.2%±10.7%, respectively, P=.29. Likewise, the peak rate-pressure product (heart rate x systolic blood pressure) was comparable for both groups, P=.32. Those with peak RER values <1.10 achieved lower peak VE, peak VO2, and VE at peak VO2. The VE/VCO2 slope, however, was similar for those below and above the RER cutpoint of 1.10, 28.6±4.5 and 27.1±3.5, P=.10, respectively. The overall median, interquartile range and outliers for the peak VO2 and VE/VCO2 slope are shown in Figure 1. The VE/VCO2 slope appeared to be influenced by high outliers in those with peak RER values <1.10.

Table II.  Resting Hemodynamic and Peak Cardiopulmonary Stress Testing Data
CharacteristicRER <1.10RER ≥1.10P Value
Resting heart rate, bpm84.2±12.380.1±11.3.13
Systolic BP, mm Hg137.8±18.1131.2±15.3.09
Diastolic BP, mm Hg86.5±11.286.0±10.7.84
Peak heart rate, bpm149.9±16.4159.0±22.2.05
Percent predicted peak heart rate86.8±8.389.2±10.7.29
Peak systolic BP, mm Hg193.3±25.8189.8±24.0.54
Peak diastolic BP, mm Hg84.8±11.280.6±8.5.06
Heart rate × systolic BP product28,948.5±5657.930,288.4±5965.2.32
Rating of perceived exertion16.4±1.316.6±0.9.54
Peak VE, L/min65.0±16.375.2±19.7.02
Peak VO2, mL/kg/min16.0±3.717.8±3.6.04
VO2 at anaerobic threshold, mL/kg/min12.1±3.011.8±1.9.67
VE at peak VO2, L/min63.1±16.172.0±19.2.04
VE/VCO2 slope28.6±4.527.1±3.5.10
Abbreviations: BP, blood pressure; bpm, beats per minute; RER, respiratory exchange ratio; VCO2, carbon dioxide production; VE, minute ventilation; VO2, oxygen consumption.

Figure 1. Boxplots for peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope stratified by respiratory exchange ratio. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers, which are indicated by an open circle. A line across the box indicates the median.

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The overall correlation for peak VO2 and VE/VCO2 slope was r=−0.33 (P=.004). When stratified by RER, however, the correlation for peak VO2 and VE/VCO2 slope was r=−0.35 (P=.05) and r=−0.24 (P=.12) for those in the RER <1.10 and ≥1.10, groups, respectively. Both peak VO2 and VE/VCO2 slope were correlated with the rate pressure product (heart rate systolic blood pressure), r=0.32 (P=.005) and r=0.26 (P=.03), respectively. There was a significant inverse relationship between peak VO2 and BMI, which was not seen with VE/VCO2 slope, as shown in the scatterplots in Figure 2 and Figure 3. The linear relationship between BMI quintile and peak VO2 is shown in Figure 4. In contrast, there was no relation between BMI and the VE/VCO2 slope or peak RER and VE/VCO2 slope (Figure 5). Lastly, no relation was noted between the patient's reported effort, as signified by the rating of perceived exertion (RPE) at peak exercise and the VE/VCO2 slope (Figure 6). However, those few patients (n=3) who reported an RPE of 19 demonstrated a higher mean VE/VCO2 slope when compared with those with lower RPE values.


Figure 2. Scatterplot of peak oxygen consumption (VO2) by body mass index.

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Figure 3. Scatterplot of minute ventilation/carbon dioxide production (VE/VCO2) slope by body mass index.

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Figure 4. Mean peak oxygen consumption (mL/kg/min) and mean minute ventilation/carbon dioxide production (VE/VCO2) slope by body mass index quintile with mean body mass index for each quintile in parentheses.

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Figure 5. Scatterplot of minute ventilation/carbon dioxide production (VE/VCO2) slope as a function of peak respiratory exchange ratio.

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Figure 6. Boxplot of minute ventilation/carbon dioxide production (VE/VCO2) slope as a function of peak perceived exertion (Borg scale). The box represents the interquartile range, which contains 50% of the values. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers, which are indicated by an asterisk. A line across the box indicates the median. ANOVA indicates analysis of variance.

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  1. Top of page
  2. Abstract
  7. References

Previous reports have suggested that low cardiorespiratory fitness in morbidly obese patients may, as in normal-weight healthy and diseased populations, serve as a prognostic indicator for cardiovascular and all-cause mortality.26–28 Using a portion of the present database, Gallagher and associates26 found significantly reduced aerobic fitness in morbidly obese men and women, comparable to the levels often reported in patients with New York Heart Association class II through IV heart failure due to systolic dysfunction. The reduced aerobic fitness in our morbidly obese patients may be attributed, at least in part, to a low rate of regular exercise participation (11 of 76 [14.5%]), excessive body weight and fat stores, poor patient motivation (ie, inadequate effort), chronotropic impairment, or combinations thereof. These findings are consistent with previous studies that reported a decreased aerobic capacity in morbidly obese patients,29,30 as well as significantly lower peak heart rates and achievement of the ventilatory anaerobic threshold at reduced work rates.30 Although peak VO2, expressed as mL/kg/min, is widely considered the single best index of physical work capacity or cardiorespiratory fitness in normal-weight individuals, it is inversely related to BMI and the degree of adiposity in the morbidly obese. Abundant data are available regarding these parameters in healthy patients and patients with CVD. The average peak VO2 in our morbidly obese population (17.0±3.7 mL/kg/min) was significantly lower than the aerobic capacity typically reported in age-matched healthy men and women. Moreover, this parameter was directly measured and considered valid in only 43 of 76 (57%) patients who achieved an RER ≥1.10. On the other hand, our findings suggest that the decreased peak VO2 in morbidly obese patients is not paralleled by a relative reduction in the V-AT, expressed as a percentage of aerobic capacity.

The VE/VCO2 slope has been reported as a functional and prognostic marker that responds favorably to aerobic training.31 In addition, the VE/VCO2 slope has been proposed as a marker of heart failure severity that appears to predict mortality at least as well as, and independent from, peak VO2.32 Recent investigations have even suggested that indices related to ventilatory inefficiency, specifically the VE/VCO2 slope, has greater prognostic power than peak VO2 in the heart failure population.33–37 Studies have also shown that risk stratification algorithms are enhanced by the application of multivariate models, which include peak VO2, ventilatory abnormalities during exercise, and other clinical and hemodynamic responses.38 Interestingly, Arena and colleagues39 found that in patients with heart failure, the prognostic advantage is not explained by subject effort, but may be partially attributed to the ability of the VE/VCO2 slope to better reflect the cardiopulmonary response to exercise and therefore the prognosis. In our morbidly obese population, the present findings suggest the VE/VCO2 slope has the desirable features of being independent of both effort (as reflected by the peak RER), as shown in Figure 5, and BMI. In patients with inadequate effort during treadmill testing, as reflected by an RER <1.10, the VE/VCO2 slope revealed several outliers, indicating it can further discriminate those with cardiorespiratory dysfunction, regardless of peak VO2. Unlike the relationship found for peak VO2, the VE/VCO2 slope appeared largely unaffected by cardiorespiratory fitness and BMI, as shown in Figure 3 and Figure 4, suggesting that it may provide independent and additive cardiorespiratory information in this escalating patient population.

We recognize several limitations in our study methodology. Exercise testing was conducted to volitional fatigue and suboptimal effort in some patients (eg, 33 of 76 [43%] demonstrated peak RER values <1.10) may be attributed to an associated localized muscle fatigue and somatic discomfort or to a lack of confidence in their physical abilities. The use of the Bruce treadmill protocol may have contributed to the sub-optimal effort and could thus be considered a study limitation as well. Echocardiographic and spirometry data were unavailable for our morbidly obese men and women; hence, we relied solely on their clinical history to confirm the absence of heart failure, pulmonary disease, or both. In addition, we did not document the use of all medications that may have lowered heart rate (eg, calcium channel blockers), nor did we assess the β-blocker dosage. Lastly, we recognize that the small number of men and relative youth of our population limit the generalizability of our findings.


  1. Top of page
  2. Abstract
  7. References

The VE/VCO2 slope is a measure of cardiorespiratory function that is independent of subject effort and BMI. Because many of our morbidly obese patients were unable to achieve an RER ≥1.10 during peak or symptom-limited treadmill testing, the VE/VCO2 slope may serve to better reflect the cardiopulmonary response to exercise, as compared with peak VO2, when assessing functional status in this escalating patient population.


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  2. Abstract
  7. References
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