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European Journal of Heart Failure 2008 10(6):560-565; doi:10.1016/j.ejheart.2008.04.009
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© 2008 European Society of Cardiology

Prognostic value of cardiopulmonary exercise testing in children with heart failure secondary to idiopathic dilated cardiomyopathy in a non-β-blocker therapy setting

Guilherme Veiga Guimarães*, Veridiana Moraes d'Avila, Paulo Roberto Camargo, Luiz Felipe Pinho Moreira, Jose Ramon Lanz Luces and Edimar Alcides Bocchi

InCor - Instituto do Coração - HC/FMUSP São Paulo, Brazil

* Corresponding author. InCor - Rua Dr. Baeta Neves, 98 - 05444-050, São Paulo, Brazil. Tel.: +55 11 3069 5419; fax: +55 11 3069–5502. E-mail address: gvguima{at}usp.br


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Peak oxygen consumption and resting left ventricular ejection fraction (LVEF) are independent predictors of survival in adult heart failure (HF) patients. Aim: To evaluate these factors in children.

Methods: We prospectively studied 31 children with NYHA class I to III HF (mean LVEF 26±10%; mean age 8.6±1.9 years). All had dilated cardiomyopathy and were awaiting heart transplantation. A cardiopulmonary treadmill exercise test was performed and LVEF determined by radionuclide ventriculography.

Results: During a median follow-up of 1282 days, 20 children reached at least one end-point (death or heart transplantation). Clinical data from the 11 children without events and the 20 children with events are as follows: NYHA class 1±0 vs. 2±0.9 (p<0.01); SBP 118± vs. 102±16 (p=0.01); DBP 70± vs. 61±10 (p=0.02); heart rate 165± vs. 148±22 (NS); double-product 19±4 vs. 15±4 (p=0.01); end-tidal carbon dioxide tension (PetCO2) 35±5 vs. 30±6 (NS); oxygen consumption (VO2) 22±5.4 vs. 18.3±5.7 (NS); exercise time 19±4 vs. 13±6 (p<0.003), and LVEF 31±8 vs. 22±10 (p=0.02). These variables all correlated with prognosis on univariate analysis. In multivariate analysis, only decreasing exercise time and LVEF were predictive of events during follow-up (p<0.001 and 0.04).

Conclusion: These findings suggest that reduction in LVEF and exercise tolerance in children with heart failure is predictive of functional status.

Key Words: Heart failure • Exercise • Oxygen consumption • Children

Received January 30, 2008; Accepted April 15, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Exercise intolerance in adult heart failure (HF) patients correlates with prognosis [1,2]. Cardiopulmonary exercise testing (CPX) is frequently used to evaluate several physiologic variables that influence respiratory, cardiac, and metabolic responses to progressive exercise [3]. However, a poor correlation exists between central haemodynamic abnormalities and reduction in exercise tolerance [4]. Peak oxygen consumption (peak VO2) is widely used to aid in the optimal timing of orthotopic heart transplantation (OHT) in adults with heart failure [5]. A peak VO2 of <14 mL/kg/min has been identified as an independent predictor of 1-year mortality in adults with HF, and thus a VO2>14 mL/kg/min is used to identify patients in whom OHT can be safely deferred [2,6].

Although CPX is widely used in adults, there are no specific practice guidelines for the use of CPX in paediatric cardiology, and no up-to-date information about current CPX practice in paediatric patients. Data obtained from an analysis of exercise testing in adults cannot be applied to children because of the developmental changes in cardiopulmonary physiology that occur in children and differences in disease entities and pathophysiology between paediatric and adult patients [7]. Understanding current practice patterns of paediatric CPX may be helpful for the development of clinical guidelines in the future. We have previously shown that exercise characteristics in children with HF are abnormal when compared to healthy controls [8]. It has recently been reported that peak VO2 is not a useful criterion for determining OHT listing in children; however, the report was from a study which included patients with a mean age of nearly 16 years who were therefore almost adults, and with multiple aetiologies. [9].

The aim of this study was to determine whether cardiopulmonary exercise testing and resting left ventricular ejection fraction (LVEF) are predictors of survival in children with heart failure who are awaiting OHT and who are not being treated with a β-blocker.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
Thirty-one children with left ventricular systolic dysfunction and HF of more than 6 months' duration, who were being treated with digoxin, angiotensin-converting enzyme inhibitors, and diuretics; in addition to having received general instructions regarding sodium and water restriction, were included. Inclusion criteria were (1) clinically stable HF for at least 3 months; (2) unchanged dosage of medications during the preceding month; (3) LVEF<45% in the 3 months preceding the study as determined by radionuclide ventriculography; (4) a diagnosis of idiopathic dilated cardiomyopathy [10]; (5) CPX stopped for fatigue, dyspnoea, or both; (6) non-participation in organized physical activities; and (7) absence of severe chronic obstructive pulmonary disease or orthopaedic limitations. We excluded children with a previous history of myocarditis, and subjects who were unable to adapt to the CPX evaluation (i.e., those who could not tolerate the nose clip, mouthpiece, or breathing valve necessary for measurements or who cried while walking on a treadmill during their previous visit) or patients younger than 5 years of age. Our institution's Committee on Ethics approved this research, and the parents or custodians provided informed consent.

2.2. Study design
All children with HF who underwent cardiopulmonary exercise testing between August 1996 and May 2000 were considered for inclusion in this study. All patients were receiving outpatient care at InCor's Cardiopediatric Department. Eligible children underwent cardiopulmonary testing one week before the study evaluation to familiarize them with the technique and study protocol. All of the tests were performed in the morning by the same team using standardised procedures.

2.3. Cardiopulmonary exercise testing
A 12-lead resting ECG was performed. Then all children underwent a progressive treadmill exercise test, with continuous ECG (MAX-1, Marquette Electronics, Milwaukee, WI) monitoring, cuff blood pressure, ventilation, and gas exchange during the tests and during the recovery period [11]. All children were encouraged by the physician and their parents to exercise until exhaustion, or the onset of non-tolerated symptoms, or until the respiratory exchange ratio exceeded 1.0, or all of these [8,12]. All patients were studied in a temperature-controlled (21-23 °C) exercise facility, at least 2 h after a light meal. The exercise tests were performed on a programmable treadmill (Q65; Quinton Instrument; Bothell, WA) according to a modified Naughton protocol [13]. Ventilatory and gas exchange data were determined on a breath-by-breath basis with a computerized system (modelCAD/Net 2001; Medical Graphics Corporation; St. Paul, MN). Peak oxygen consumption (peak VO2) was the maximum VO2 value reached during the test [14]. The relationship between ventilation versus carbon dioxide production (VE/VCO2 slope) was calculated as a linear regression, from rest until peak exercise [15].

2.4. Follow-up and documentation of cardiac events
Follow-up ended on 6 June 2006. The children were followed-up for at least 6 years in the hospital's outpatient clinic, and patient's status was obtained from their medical records. Patients who did not attend for their scheduled appointments were followed-up by telephone interview with either the patient's family or primary care physician. The first patient was included on 19 August 1996 and the last patient on 25 May 2000. The last day of follow-up for statistical analysis was 6 June 2006. All patients are included in the analysis and death and heart transplantation were considered as events.

2.5. Statistical analysis
All data are reported as mean values±standard deviation (SD). The Mann-Whitney test was used to compare variables that did not exhibit a normal distribution. Univariate and multivariate Cox regression analysis were used to assess the ability of variables to predict death or heart transplantation after CPX. The following variables at rest and at maximal exertion were included in the model: heart rate (HR, in bpm); systolic and diastolic blood pressure (SBP and DBP, in mm Hg); double-product (DP, in mm Hg-beats/min); O2 pulse [O2 uptake/heart rate (VO2/HR, in mL/beat)]; pulmonary ventilation (VE, in L/min); oxygen uptake (VO2, in mL/kg/min); carbon dioxide production (VCO2, in mL/min); relationship between minute ventilation and carbon dioxide production (VE/VCO2 slope); physiologic dead space and tidal volume (Vd/Vt); ventilatory equivalent for oxygen uptake and carbon dioxide production (VE/VO2 and VE/VCO2); end-tidal oxygen and carbon dioxide tension (PetO2 and PetCO2, in mm Hg); tidal volume (Vt; mL); and exercise time (ET, in minutes). Variables found to be significant predictors in the univariate analysis were included in the multivariate analysis. The forward stepwise method was used for the multivariate analysis, with entry and removal p values set at 0.05 and 0.10, respectively. The variables that had a significant association with outcome (p<0.05) on multivariate analysis were included in the survival curve analysis. Cutoff point values for predictive variables were generated with receiver operating characteristic (ROC) curves. Survival was estimated by the product-limit Kaplan-Meier method. Differences between survival curves were tested with the log-rank statistic. In the follow-up comparison between non-event and event groups, we considered events to be those that occurred from the initial cardiopulmonary exercise testing until analysis of all patients was completed. Statistical differences with a p value<0.05 were considered significant. All the analyses were performed with SPSS statistical software, version 11.5 (SPSS Inc, Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
No children were lost to follow-up, and the median follow-up duration was 1282 days (25th and 75th percentiles 146 and 2190 days). Eleven children died due to cardiac causes: sudden death (n=5) and progressive heart failure (n=6). Nine children underwent heart transplantation; of these 5 children were hospitalised for haemodynamic support and urgent heart transplantation, and 4 for clinical worsening. In the univariate Cox regression analysis model, NYHA, LVEF, peak HR, SBP, DBP, DP, PetCO2, VO2, and exercise time were significantly associated with prognosis (Table 1). With multivariate Cox regression analysis, however, only exercise time (p<0.001) and LVEF (p=0.04) were independent, additional predictors of cardiac events. ROC analysis showed the best cut-offs for ET (area under the curve 0.81, 95% CI 0.67 to 0.96, optimal threshold: </>15 min, 81% sensitivity/70% specificity, p=0.004) and LVEF (area under the curve 0.74, 95% CI 0.56 to 0.92, optimal threshold</>26%, 72% sensitivity/60% specificity, p=0.02). The Kaplan-Meier analysis for 2190-day follow-up of cardiac events with an exercise time median of <15 min is illustrated in Fig. 1, and LVEF median of <26% is illustrated in Fig. 2.


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  		Table 1 Univariate Cox regression analysis showing variables significantly associated with prognosis

 


Figure 01
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  		Fig. 1 Kaplan-Meier analysis of cardiac events according to exercise times of < and >15 min, in children with heart failure secondary to idiopathic dilated cardiomyopathy.

 


Figure 02
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  		Fig. 2 Kaplan-Meier analysis of cardiac events according to resting left ventricular ejection fractions of < and >26%, in children with heart failure secondary to idiopathic dilated cardiomyopathy.

 
3.1. Event group versus non-event group
The clinical characteristics of the non-event group and event group are presented in Table 2. Significant differences were observed in age, height, BSA, and NYHA class, which were greater in the event group, which also had a lower ejection fraction and SBP and DBP at rest. Data from a maximal cardiopulmonary exercise test are summarized in Table 3. Systolic and diastolic blood pressure, DP, and exercise time were significantly greater in the non-event group.


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  		Table 2 Baseline characteristics in heart failure children

 


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  		Table 3 Maximal cardiopulmonary exercise test data from heart failure children

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Objective assessment of exercise tolerance by non-invasive measurement of aerobic capacity during incremental upright exercise has been suggested as a reliable measure of functional status in HF patients. Maximal exercise is determined by cardiac output response to exercise and maximal oxygen extraction. Peak oxygen uptake (peak VO2) measured during maximal CPX is a powerful predictor of mortality in HF and an important criterion in the selection of candidates for heart transplantation (2,5). We found that exercise tolerance and functional capacity are strongly correlated with cardiac events in children with HF.

Our data indicate that low exercise time and low LVEF are powerful, independent predictors of major cardiac events in children with HF. Exercise time of >15 min and an LVEF >26% significantly separated non-events (22%) from events (13%) in our population.

The pathophysiological mechanisms underlying the exercise limitation of adults with heart failure remain unclear. It has long been recognized that there is little direct correlation between measures of resting LVEF and exercise performance. The decrease in cardiac function associated with heart failure provokes a redistribution of blood flow that is mediated by neurohormonal systems (sympathetic nervous system, renin-angiotensin system, and vasopressin) and local mediators (endothelin). These mechanisms make the tissues extract more O2 from the regional blood. This is especially true during physical exercise [16,17] when greater oxygen extraction occurs, therefore, accentuating the arteriovenous oxygen difference. With disease aggravation, blood flow reduction causes tissues to quickly reach their oxygen extraction limit. However, the capacity to exercise can be relatively preserved in some patients with poor left ventricular systolic function, this could be due to: the ability to tolerate elevated pulmonary arterial wedge pressures without developing dyspnoea, the ability to increase pulmonary lymphatic flow that limits pulmonary venous congestion, preservation of appropriate chronotropic response, adequate left ventricular dilatation during exercise, the ability to further activate the already stimulated neurohormonal mechanisms and chronic changes in left ventricular compliance that limit augmentation of filling pressures during exercise [18].

In our study, the survivor and non-survivor groups attained 82% and 76% of the average maximal HR predicted for age, respectively. Attenuation of the heart rate response to exercise has been identified as a possible mechanism of reduced exercise capacity [19]. This has considerable functional importance in patients with HF, because these patients generally lack the ability to increase stroke volume during exercise [20]. With a relatively fixed stroke volume, the heart rate response assumes greater importance in enabling patients to increase cardiac output during exercise [21,22]. Mechanisms involved in the HR response to physical exercise may include tonic sympathetic nervous system alterations and baroreflex dysfunction at the pulmonary or systemic level [23,24]. Down-regulation of β-adrenergic receptors by chronic exposure to high catecholamine levels might be involved in the blunted chronotropic response to maximal exercise [25,26].

This study has several limitations. We deliberately selected children with HF due to idiopathic dilated cardiomyopathy. Our heart failure population consisted of a small sample size followed for a rather short period. Not all children were treated with a β-blocker, because during the study period there was no consensus regarding the use of this agent in this population [27]. In fact, we realize that this study does not have the power to provide a definitive conclusion about the absence of an effect provided by β-blocker therapy in children with HF. However, studies suggest that the improved survival observed with β-blockers may be weaker among patients with severely impaired functional capacity, in whom mortality rates are high irrespective of treatment. In addition, there was no difference in mortality rates in patients receiving a low-to-medium dose compared with patients receiving a high dose of β-blockade [28,29]. Future studies should seek to determine the optimal prognostic interpretation of cardiopulmonary responses while strictly controlling exercise testing procedures and end-point tracking.

The first step in the interpretation of cardiopulmonary exercise test data and the decision-making process is dependent on the children's therapeutics. The second step is stratification according to resting LVEF and exercise tolerance. Children not receiving β-blocker therapy can be correctly designated as high- and low-risk according to resting LVEF and exercise tolerance. However, the role of symptom-limited CPX is restricted, and additional outcome predictors for appropriate disease management are required. Thus, prospective studies with larger numbers of children are now required to determine the importance of using this technique in children with HF.

In conclusion, exercise time and resting left ventricular ejection fraction were predictors of prognosis in children with HF due to idiopathic cardiomyopathy who were not taking β-blockers. These variables should be integrated with other recognized prognostic indexes in risk stratification strategies for children with heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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