Cardiopulmonary exercise testing (CPX) has emerged as an essential tool for risk stratification and clinical decision making for patients with congenital heart disease (9). Among various CPX parameters, peak oxygen consumption (peak V˙O2) and HR reserve (HRR), both are maximal exercise parameters, have been demonstrated as valuable prognostic indices for adults with congenital heart disease (9–11,14,15). However, in patients who received Fontan procedure, both peak V˙O2 and HRR were often decreased (11,17), and the prognostic usefulness were considerably reduced as compared with other forms of congenital heart disease (15). The Fontan operation, which requires rerouting of superior and inferior vena cava flow directly to the pulmonary arteries without an intervening pumping ventricle, is the anticipated final surgical intervention in patients with single-ventricle anatomy. One possible explanation is that these maximal exercise parameters depend on maximal effort during exercise test, which is often difficult to achieve for Fontan patients (18,23).
Several submaximal exercise parameters have been introduced to evaluate the cardiopulmonary functional reserve, including the relation among minute ventilation (V˙E) and carbon dioxide production (V˙CO2) (V˙E/V˙CO2 slope) (5) as well as the efficiency of oxygen uptake (oxygen uptake efficiency slope (OUES)) (2). Such data in patients with Fontan circulation are still limited (3,4,11,13), and the prognostic value of these parameters remains largely unknown. We hypothesized that, because of the potential limitation of maximal exercise indices, the submaximal exercise parameters would be better predictors of subsequent adverse cardiac events in Fontan patients.
Between September 2009 and March 2012, we prospectively recruited 52 consecutive patients who had received Fontan completion for more than 12 months. None exhibited musculoskeletal impairment or psychiatric conditions precluding or influencing the CPX. Relevant clinical data were collected from medical records and clinical interviews. All study participants and their parents provided written informed consent, and the institutional review committee of the National Taiwan University Hospital approved the study protocol. This study conformed to the principles of the Helsinki Declaration.
Cardiopulmonary Exercise Test
The symptom-limited exercise test was performed on a cycle ergometer (Corival; Lode BV, Zernikepark 16, Groningen, the Netherlands) in an upright position using a rampwise increase of load, with 5, 10, and 15 W·min−1 depending on the expected individual physical capacity estimated by the investigator. The aim was to reach a testing time of about 8 to 12 min. Oxygen consumption (V˙O2), V˙CO2, and V˙E were measured using a breath-by-breath automatic gas analyzer (MetaMax 3B system; CORTEX Biophysik GmbH, Leipzig, Germany), and peak RER, defined as the ratio of V˙CO2 to V˙O2, was recorded. Patients with a resting arterial oxygen saturation <95% in room air were considered to have cyanosis. The peak exercise RPE was measured using the Borg scale (6–20) of perceived exertion. The achievement of maximal exercise effort can be assumed when peak RER ≥1.10, and the RPE is at least 15 on the Borg scale (19).
Maximal and Submaximal CPX Parameters
Two parameters of maximal exercise testing, peak V˙O2 and HRR, were evaluated. The technical details of measuring peak V˙O2 have been published previously (9). Peak V˙O2 was then expressed as the percentage of predicted value. Predicted values were calculated for patients age 17 yr and older using the regression equations proposed by Jones (16). For participants between the ages of 6 and 17 yr, predicted values were calculated according to Cooper and Weiler-Ravell (7). The HRR was calculated as the difference between peak and resting HR (10).
Regarding submaximal exercise parameters, the V˙E/V˙CO2 slope and the OUES were calculated. The V˙E/V˙CO2 slope represents the relation between ventilation and carbon dioxide production. This parameter was obtained by performing linear regression analysis of the data acquired throughout the period of the exercise (12). The relation between oxygen consumption to ventilation was evaluated according to the OUES, which was calculated by performing a linear regression of V˙O2 on the common logarithm of V˙E, by using the following equation: V˙O2 = a log(V˙E) + b. The slope “a” represents the rate of increase in V˙O2 in response to an increase in V˙E and is called the OUES (2). The OUES was then expressed as the percentage of predicted values, which were based on age, sex, and body size (26).
Cardiac Outcomes after CPX
Participants were observed for the occurrence of cardiac mortality and morbidity after completion of CPX. Cardiac mortality included cardiac death or heart transplantation. Cardiac morbidity was defined as cardiac-related hospitalization, including any admission related to medical or surgical management of heart failure, arrhythmia, or complications characteristic of Fontan circulation such as protein-losing enteropathy. During the observation period, no patient was lost to follow-up; therefore, all cardiac events could be recorded.
Data are expressed as percentage, mean ± SD, or median (25th to 75th percentile), as appropriate. Time-dependent receiver operating characteristic (ROC) curves were used to investigate the prognostic value of exercise parameters. Optimal cutoff values were determined from the ROC curves so that the sum of sensitivity and specificity was maximized. Freedom from the occurrence of cardiac outcome was plotted using the Kaplan–Meier method, with comparisons by the log-rank test. Furthermore, prognostic significance of exercise variables and relevant clinical variables was investigated using univariate Cox proportional hazard analyses. The hazard ratio with 95% confidence interval (CI) was provided. Considering the limited number of end points, we chose not to perform multivariate analyses. Instead, bivariate analyses were conducted. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Version 15.0; SPSS Inc., Chicago, IL) and R statistical software, Version 2.11.1 (R Foundation for Statistical Computing, Vienna, Austria). A P value of ≤0.05 was considered statistically significant.
Table 1 summarizes the demographic and medical characteristics of all participants. Most patients (73%) were in New York Heart Association functional class I at the time of CPX. Before CPX, 12 patients (23%) had a history of heart failure or protein-losing enteropathy. Most patients (n = 49, 94%) received total cavopulmonary connection (TCPC) with either extracardiac conduit (n = 25) or lateral tunnel (n = 24). Atrioventricular Fontan was performed in three patients. All but two patients had concurrent cardiac medications, and negative chronotropic agents (β-blockers and amiodarone) were used in 12 cases (23%).
Maximal and Submaximal Exercise Data
Table 2 summarizes the maximal and submaximal CPX data. Peak RER was 1.10 ± 0.09, and maximal exercise effort was achieved in 33 patients (64%). In our study cohort, peak V˙O2 was markedly reduced (23.7 ± 5.4 mL·kg−1·min−1 corresponding to 58.0% ± 11.2% of age- and sex-related predicted values). The percentage of the predicted OUES was only 56.6% ± 14.5% in reference to the norms.
During a median follow-up period of 22.7 months (16.2–26.7 months), only one patient died. Therefore, factors related to cardiac death or heart transplantation would not be investigated. At follow-up, 11 patients (21%) were hospitalized for cardiac-related problems, and all had symptoms and signs suggesting of heart failure: transcatheter intervention for heart failure was performed in five patients (three for pulmonary artery stents, one for device closure of intraatrial baffle leak, and one for balloon dilatation of TCPC conduit stenosis), intravenous inotropic support in two, unexplained syncope in one, supraventricular tachycardia in one, protein-losing enteropathy in one, and atrioventricular valve replacement in one.
Prognostic Values of Maximal and Submaximal Exercise Parameters
Time-dependent ROC curves were used to investigate the prognostic value of exercise parameters in relation to cardiac-related hospitalization. A percentage of the predicted OUES of 45% was identified as the best cutoff value for predicting 2-yr cardiac morbidity (area under the ROC curve = 0.781, P = 0.018; see Supplemental Digital Content, Fig. 1A, http://links.lww.com/MSS/A301, time-dependent ROC curves for the percentage of predicted OUES in predicting 2-yr cardiac-related hospitalization) with a sensitivity of 64% and a specificity of 93%. The area under the ROC curve for the V˙E/V˙CO2 slope was similar to that of the OUES (see Supplemental Digital Content, Fig. 1B, http://links.lww.com/MSS/A301, time-dependent ROC curves for the percentage of V˙E/V˙CO2 slope in predicting 2-yr cardiac-related hospitalization). A V˙E/V˙CO2 slope cutoff ≥37 produced sensitivity and specificity of 91% and 61%, respectively. In contrast, peak V˙O2 and HRR (regardless of the use of negative chronotropic agents or not) were not related to cardiac-related hospitalization. The Kaplan–Meier analysis for 2-yr cardiac-related hospitalization on the basis of OUES and V˙E/V˙CO2 slope cutoff values is shown in Figure 1.
With univariate Cox proportional hazard analysis, optimal cutoff values for the OUES and V˙E/V˙CO2 slope produced statistically significant hazard ratios (for percentages of the predicted OUES ≤45%: 7.645, 95% CI, 2.317–25.230, P = 0.001; for V˙E/V˙CO2 slope ≥37: 10.777, 95% CI, 1.378–84.259, P = 0.023; Table 3). Other univariate predictors included history of heart failure or protein-losing enteropathy after Fontan completion, as well as resting oxygen saturation (Table 3). Bivariate analyses were performed to investigate whether these CPX parameters added additional prognostic values to relevant clinical data. The association between the percentage of the predicted OUES ≤45% and increased morbidity risk remains, independent of unfavorable cardiac status and resting oxygen saturation (Table 4). By contrast, the addition of the V˙E/V˙CO2 slope did not provide additional value in predicting cardiac morbidity.
Subgroup Analysis for Patients Achieved Maximal Exercise Effort
Of the 33 patients who achieved maximal effort during the test, 7 (21%) had cardiac-related hospitalization at follow-up. ROC curve analysis identified the OUES as the only CPX parameter predicting 2-yr cardiac morbidity (area under the curve = 0.797, P = 0.035). Peak V˙O2 and HRR still did not predict cardiac morbidity even in the patient subgroup who achieved maximal effort during CPX.
Traditionally, peak V˙O2 is the most frequently used CPX parameter to evaluate exercise capacity and is related to cardiac morbidity and mortality in patients with various congenital heart diseases (9,15). However, controversies existed regarding such association in Fontan patients because the prognostic significance of peak V˙O2 may be reduced in the absence of maximal effort (11,15). In our study cohort, more than one-third of patients could not reach their maximal effort. Similar findings have also been reported before (4,18,23). One possible explanation may be skeletal muscle deconditioning (25), which causes the patient to terminate CPX before the limits of cardiovascular function are reached. However, peak V˙O2 was still not related to cardiac morbidity in the patient subgroup that has achieved maximal effort. From a physiological perspective, a crucial factor limiting peak V˙O2 is the ability of the circulatory system to increase cardiac output during exercise. In Fontan circulation, the systemic venous pressure drives blood into the pulmonary vascular bed. The generally reduced values of peak V˙O2 in Fontan patients may be mostly attributed to an intrinsically impaired capacity to increase adequate pulmonary flow during exercise rather than myocardial or vascular dysfunction alone (11). This inherited limitation may prevent peak V˙O2 from being a useful surrogate of cardiopulmonary reserve in Fontan circulation.
Our study results did not indicate prognostic significance of HRR in Fontan patients, which is different from that reported by Diller et al. (11). Compared with the study cohort in the Diller et al. study (11), our study patients were younger at Fontan completion (mean age, 6.0 vs 7.1 yr), younger at CPX (mean age, 15 vs 21 yr), and with a much lower percentage of non–TCPC-type Fontan operations (6% vs 47%). Besides, our patients presented with a more favorable clinical functional status (the percentage of New York Heart Association functional class I: 73% vs 42%), higher HRR (68 vs 63 bpm), and considerably lower rates of mortality (2% vs 7%) and morbidity (21% vs 41%). Collectively, our patients represented a young Fontan cohort with relatively preserved functional performance and were operated on with contemporary surgical method. Therefore, the discrepancy in the prognostic value of HRR between these two studies may imply that HRR is more likely linked to the outcomes in Fontan patients with a deteriorated functional status.
The OUES, a submaximal exercise parameter on CPX that is seldom systemically measured in Fontan patients, was a sensitive predictor for cardiac morbidity in our patients. Many studies have indicated the prognostic value of the OUES in adults with heart failure (8,21). Although a few reports have shown that Fontan patients attained lower values of the OUES (3,4), our study is the first to demonstrate the prognostic significance of this submaximal exercise parameter in patients with Fontan circulation. Furthermore, OUES could provide additional prognostic information beyond relevant clinical data (unfavorable cardiac status and resting oxygen saturation). Unlike peak V˙O2, which only measures the amount of oxygen extracted from the lungs at the point of peak exercise, the OUES incorporates cardiovascular and peripheral factors that determine oxygen uptake as well as pulmonary factors that influence the ventilatory response to increased metabolic acidosis during incremental exercise (1). The lower OUES values in Fontan patients could be explained by both a slow increment of V˙O2 at the onset of exercise (20) and accelerated low-efficiency ventilation during exercise (22). These patients usually had a significant ventilation–perfusion mismatch, resulting in an increased physiological dead space to tidal volume ratio (24). In addition, hypoxemia resulting from either TCPC fenestration or small collateral vessels from systemic veins draining to the atrium triggered increased ventilation (22). Therefore, the prognostic significance of the OUES may provide insights into the potential mechanisms leading to chronic complications related to Fontan circulation, including the circulatory factor (impaired augmentation of cardiac output), the pulmonary factor (increased pulmonary dead space ventilation and excessive hyperventilation), and the peripheral factor (aggravated metabolic acidosis) (3).
We also identified the other submaximal exercise parameter, the V˙E/V˙CO2 slope, as a univariate predictor of cardiac-related hospitalization in Fontan patients. The V˙E/V˙CO2 slope reflects a ventilation–perfusion mismatch and derangement of peripheral and central chemoreceptors (6). Therefore, the prognostic significance of the elevated V˙E/V˙CO2 slope may suggest the importance of both ventilation and pulmonary circulation abnormalities in relation to metabolic demand in Fontan circuit dysfunction. Table 5 summarizes the CPX data and their relations with morbidity and mortality from published literatures and our present study. For convenience of clinical application, we identified a cutoff value of 37 for the V˙E/V˙CO2 slope and a cutoff value of 45% for the percentage of the predicted OUES, as optimal prognosticators for 2-yr cardiac morbidity in Fontan patients. These threshold values may help identify high-risk patients and provide appropriate medical or surgical interventions to prevent cardiac-related hospitalization.
The patients enrolled in this study were relatively young, well functioning, and from a single tertiary medical center. Besides, nearly all of our patients received TCPC-type Fontan operation. Therefore, these patients may not represent exactly the overall Fontan population. Furthermore, the number of end points forming the basis of this study is relatively small. Studies with a longer period of observation, and thus, a higher number of cardiac events, are required to validate the findings of this study. On the basis of the results of subgroup analysis, achieving maximal effort may not be the reason for limiting the prognostic value of peak exercise parameters. However, determining the exact explanation for the prognostic difference between maximal and submaximal data from our study remains difficult.
In conclusion, submaximal exercise parameters are prognostically superior to maximal exercise data in assessing short-term cardiac morbidity in Fontan patients. The percentage of the predicted OUES ≤45% and the V˙E/V˙CO2 slope ≥37 are optimal threshold values when applying CPX data in stratifying the risk of cardiac-related hospitalization. Although a history of unfavorable cardiac status and oxygen saturation at rest are strong prognosticators of morbidity, OUES can still provide additional prognostic value beyond baseline clinical information in patients with Fontan circulation.
The authors would like to thank Ms. Meng-Ju Lin, Ms. Hui-Lin Chen, and Ms. Chiu-Yi Hsu for their efforts in administering CPX. The authors also acknowledge the statistical assistance provided by Dr. Chin-Hao Chang and Ms. Heng-Hsiu Liu of the National Translational Medicine and Clinical Trial Resource Center and the Department of Medical Research at National Taiwan University Hospital. This work was supported by the Cardiac Children’s Foundation, Taiwan. All authors declared that there is no conflict of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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CARDIOPULMONARY EXERCISE TEST; FONTAN OPERATION; OXYGEN UPTAKE EFFICIENCY SLOPE; PROGNOSIS; V˙E/V˙CO2 SLOPE
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