Abnormalities of the Ventilatory Equivalent for Carbon Dioxide in Patients with Chronic Heart Failure

Introduction. The relation between minute ventilation (VE) and carbon dioxide production (VCO2) can be characterised by the instantaneous ratio of ventilation to carbon dioxide production, the ventilatory equivalent for CO2 (VEqCO2). We hypothesised that the time taken to achieve the lowest VEqCO2 (time to VEqCO2 nadir) may be a prognostic marker in patients with chronic heart failure (CHF). Methods. Patients and healthy controls underwent a symptom-limited, cardiopulmonary exercise test (CPET) on a treadmill to volitional exhaustion. Results. 423 patients with CHF (mean age 63 ± 12 years; 80% males) and 78 healthy controls (62% males; age 61 ± 11 years) were recruited. Time to VEqCO2 nadir was shorter in patients than controls (327 ± 204 s versus 514 ± 187 s; P = 0.0001). Univariable predictors of all-cause mortality included peak oxygen uptake (X 2 = 53.0), VEqCO2 nadir (X 2 = 47.9), and time to VEqCO2 nadir (X 2 = 24.0). In an adjusted Cox multivariable proportional hazards model, peak oxygen uptake (X 2 = 16.7) and VEqCO2 nadir (X 2 = 17.9) were the most significant independent predictors of all-cause mortality. Conclusion. The time to VEqCO2 nadir was shorter in patients with CHF than in normal subjects and was a predictor of subsequent mortality.


Introduction
Cardiopulmonary exercise testing (CPET) is used to stratify risk in patients with cardiorespiratory disease [1]. In patients with chronic heart failure (CHF), the normal linear relation between ventilation (VE) and carbon dioxide production (VCO 2 ) is maintained, but the slope of the relation is greater than normal, so that, for a given volume of carbon dioxide production, the ventilatory response is greater [2][3][4][5][6]. Another way of characterising the relation between minute ventilation and carbon dioxide production is the instantaneous ratio of ventilation to carbon dioxide production, the ventilatory equivalent for CO 2 (VEqCO 2 ). Recently, we have shown that the lowest VEqCO 2 (VEqCO 2 nadir) provides greater prognostic value than other CPET-derived variables in patients with suspected CHF [7]. Other studies have reported that the lowest VEqCO 2 has similar prognostic power to the VE/VCO 2 slope derived from the whole of exercise [8].
During an incremental CPET, as exercise intensity increases, both VCO 2 and VE increase linearly. However, VEqCO 2 falls at the onset of exercise, possibly due to a reduction in dead space ventilation. Beyond the ventilatory compensation point (VCP), lactic acid production causes an increase in ventilation relative to carbon dioxide production, and thus the VEqCO 2 rises. Although patients with CHF have the same pattern of VEqCO 2 during exercise as normal subjects, with more severe heart failure, the increase in VEqCO 2 towards the end of exercise becomes more marked [9]. In the most severely affected patients, VEqCO 2 increases from the start of exercise [9]. We hypothesised that the time taken to reach VEqCO 2 nadir would be shorter in patients with CHF compared to healthy controls and thus may be an important prognostic indicator.

Methods
The Hull and East Riding Ethics Committee approved the study, and all patients provided informed consent. We recruited consecutive patients referred to a community heart failure clinic with symptoms of breathlessness (NYHA functional class II-III) who were found to have left ventricular systolic dysfunction on investigation. Clinical information obtained included past medical history and drug and smoking history. Clinical examination included assessment of body mass index (BMI), heart rate, rhythm, and blood pressure. Patients were excluded if they were unable to exercise because of noncardiac limitations (such as osteoarthritis) or had significant respiratory disease (defined as a predicted FEV 1 < 70%).
Heart failure was defined as the presence of current symptoms of HF, or a history of symptoms controlled by ongoing therapy, and impaired left ventricular systolic function. Left ventricular function was determined from 2D echocardiography which was carried out by one of three trained operators. Left ventricular function was assessed by estimation on a scale of normal, mild, mild-to-moderate, moderate, moderate-to-severe, and severe impairment and was assessed by a second operator blind to the assessment of the first; where there was disagreement on the severity of left ventricular (LV) dysfunction, the echocardiogram was reviewed jointly with the third operator and a consensus reached. Where possible, left ventricular ejection fraction (LVEF) was calculated using the Simpson's formula from measurements of end-diastolic and end-systolic volumes on apical 2D views, following the guidelines of Schiller and colleagues [10], and LVSD was diagnosed if LVEF was ≤45%. When LVEF could not be calculated, LVSD was diagnosed if LVEF ≤45 or there was at least "mild-to-moderate" impairment.
Patients underwent a symptom-limited, maximal CPET on a treadmill using the Bruce protocol modified by the addition of a Stage 0 (2.74 km·h −1 and 0% gradient) at the onset of exercise. Metabolic gas exchange was measured with an Oxycon Delta metabolic cart (VIASYS Healthcare Inc., Philadelphia, PA, USA). Peak oxygen uptake (pVO 2 ) was calculated as the average VO 2 for the final 30 s of exercise. The ventilatory anaerobic threshold (AT) was calculated by the V-slope method [11]. The gradient of the relationship between VE and VCO 2 (VE/VCO 2 slope) was calculated by linear regression analysis using data acquired from the whole test. The VEqCO 2 relation was plotted from start to the finish of exercise. Each consecutive 30-second reading was averaged, and the lowest point was defined as the VEqCO 2 nadir [7]. The time taken to reach the VEqCO 2 nadir was reported in seconds (s). The peak respiratory exchange ratio (pRER) was calculated as the mean VCO 2 /VO 2 ratio for the final 30 s of exercise. For comparative purposes, we also included a healthy control group who had no evidence of cardiac, respiratory, or musculoskeletal limitation. Healthy controls were randomly invited to participate from two local GP practices.

Statistical Analysis.
We used SPSS (version 17.0) for statistical analysis. Continuous variables are presented as mean ± SD, and categorical data are presented as percentages. Continuous variables were assessed for normality by the Kolmogorov-Smirnov test. An arbitrary level of 5% statistical significance was used throughout (two tailed). An independent t-test was used to measure differences between CHF patients and healthy controls. All survivors were followed for a minimum of 12 months, and we therefore give the probability of 12-month survival. Receiver operator characteristic (ROC) curves were used to identify the value of the strongest predictor variables of survival to 12 months. We reported the area under the curve (AUC) with 95% confidence intervals (CI), sensitivity, specificity, and optimal cut-points in our ROC analysis. To define the optimal cutpoint, we used the point closest to the upper left corner of the ROC curve, often known as the (0, 1) criterion.
All baseline variables (Table 1) were entered as potential univariable predictors of mortality using Cox analysis, and we adjusted for age, sex, BMI, aetiology of heart failure, and severity of LV dysfunction (none, trivial, mild, mildto-moderate, moderate, moderate-to-severe, severe). Model building was based on backward elimination (P value for entry was <0.05; P value for removal >0.1). A multivariable Cox proportional hazards model using the backward likelihood ratio method was used to identify independent predictors of all-cause mortality from all significant candidate predictor variables. The outcome measure was all-cause mortality. Kaplan-Meier survival curves were plotted for the strongest candidate predictors; data were dichotomised by optimal cut-points.

Discussion
We have shown that the time to VEqCO 2 nadir is significantly lower in patients with CHF compared to controls. To our knowledge, no previous study has evaluated the prognostic value of time to VEqCO 2 nadir. Sun and colleagues [12] showed that the lowest VEqCO 2 (VEqCO 2 nadir) was the most stable marker of ventilatory inefficiency in healthy controls. During maximal exercise testing, the VEqCO 2 nadir was achieved at around the ventilatory anaerobic threshold and occurred during "moderate" exercise intensity. Both VE and VCO 2 are linearly related up to the ventilatory compensation point (VCP). Beyond this point (during heavy to maximal exertion), an increase in VE relative to VCO 2 is dependent upon the fall in pH and PaCO 2 [12]. The exaggerated ventilatory response of patients with CHF is seen at the outset of exercise; that is, the VE/VCO 2 slope is abnormal from the moment exercise starts. A wide variety of factors has been proposed as the reason for the increase in VE/VCO 2 slope including an increased dead space and resultant "wasted" ventilation [13][14][15], early metabolic acidosis [16], and overactivation of chemoreceptors and ergoreceptors [17,18]. The fall in the VEqCO 2 at the onset of exercise is at least in part due to the reduction in fixed anatomical dead space ventilation as a proportion of total ventilation at the onset of exercise, but the increase after the plateau phase is due to a non-CO 2 stimulus to ventilation, wheather lactate production or an alternative stimulus to ventilation, such as the ergoreflex [9,19]. The shorter time to VEqCO 2 nadir reflects the earlier onset (and more important influence of) the non-CO 2 stimulus to ventilation in patients with CHF. We found a strong relation between the time to VEqCO 2 nadir and mortality. The time to VEqCO 2 nadir was an important univariable predictor of all-cause mortality although it was outperformed by peak oxygen uptake and VEqCO 2 nadir in a multivariable survival model. We have previously shown that peak oxygen uptake [20] and VEqCO 2 nadir [7] are independent predictors of all-cause mortality in patients with CHF. Other investigators have also reported similar findings [8,21].
A limitation of our study is that we do not have test-retest CPET data for individual patients/controls; therefore, we cannot determine the reproducibility of the time to VEqCO 2 nadir in either healthy or diseased populations.
Cardiopulmonary exercise testing provides two broad types of prognostic variable: a measure of exercise capacity, such as peak VO 2 , reflecting the complex relation between pump, ventilator, and muscle extraction; and a measure of the ventilatory response to exercise, such as the VE/Vco 2 slope or time to VEqCO 2 nadir, reflecting the abnormal stimulus to ventilation in CHF. The time to VEqCO 2 nadir following maximal CPET was shorter in patients with CHF than in normal subjects and is a predictor of subsequent mortality.

Clinical Messages
(i) Cardiopulmonary exercise testing is becoming increasingly important for prescribing appropriate exercise training volumes in patients with cardiovascular disease including CHF.
(ii) The ventilatory response to exercise is abnormal in patients with CHF compared to age-matched controls.
(iii) Metabolic responses to exercise are important predictors of risk and should be monitored prior to and following a program of rehabilitation in patients with CHF.

Conflict of interests
The authors declare that there is no conflict of interests.