Ann Thorac Surg 2009;88:1961-1969. doi:10.1016/j.athoracsur.2009.07.079
© 2009 The Society of Thoracic Surgeons
Original Articles: Pediatric Cardiac
How Good Is a Good Fontan? Quality of Life and Exercise Capacity of Fontans Without Arrhythmias
Yves d'Udekem, MD, PhDa,*,
Michael M.H. Cheung, MD, MRCPb,
Stella Setyapranata, BMedScia,
Ajay J. Iyengar, BmedScia,
Patricia Kelly, BSCib,
Naomi Buckland, BSCi, B Engb,
Leeanne E. Grigg, MBBS, FRACPd,
Robert G. Weintraub, MBBS, FRACPb,
Alasdair Vance, MD, PhDc,
Christian P. Brizard, MDa,
Dan J. Penny, MD, PhDb
a Department of Cardiac Surgery, Royal Children's Hospital, Department of Pediatrics of the University of Melbourne, Murdoch Children's Research Institute, and the ANZCHRC, Parkville, Victoria, Australia
b Department of Cardiology, Royal Children's Hospital, Department of Pediatrics of the University of Melbourne, Murdoch Children's Research Institute, and the ANZCHRC, Parkville, Victoria, Australia
c Department of Academic Child Psychiatry Unit, Royal Children's Hospital, Department of Pediatrics of the University of Melbourne, Murdoch Children's Research Institute, and the ANZCHRC, Parkville, Victoria, Australia
d Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia
Accepted for publication July 31, 2009.
* Address correspondence to Dr d'Udekem, Department of Cardiac Surgery, Royal Children's Hospital, Flemington Rd, Parkville, Melbourne, Victoria, 3052, Australia (Email: yves.dudekem{at}rch.org.au).
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Abstract
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Background: Poor long-term outcomes are expected after Fontan surgery, but these perspectives have been tainted by the poorly functioning Fontans suffering from arrhythmias. No predictions of outcome can be quoted to the increasing number of Fontan patients free from arrhythmic complications. The parameters determining improved exercise capacity and quality of life in this subgroup are yet unknown.
Methods: Fontan survivors from our institution and living in Victoria were invited to participate in the study if they were more than 10 years of age, and free of arrhythmias. A mean of 17 ± 4 years after Fontan, 36 patients, 23 with a classical atriopulmonary connection (AP) and 13 with a lateral tunnel (LT) underwent transthoracic echocardiography, cycloergometer exercise study, neurohumoral screening, and assessment of quality of life.
Results: The only factor predicting worse exercise capacity was the type of Fontan performed; patients with LT having better exercise capacity than those with AP (percentage of predicted anaerobic threshold: 88 ± 14% vs 72 ± 14%, p < 0.005; percentage of predicted VO
2max: 62 ± 8% vs 54 ± 7%, p < 0.005). Endothelin-1 levels were elevated in all patients (2.9 pmol/L, 2.5 to 3.7). Responses from the quality of life measures placed our Fontan cohort mainly within the normal population range. None of the preoperative and postoperative variables adversely affected patients' quality of life.
Conclusions: The anaerobic threshold of arrhythmia-free Fontan patients operated with the lateral tunnel technique was relatively preserved. Despite restricted exercise capacity, Fontan patients, provided that they are free of arrhythmias, have a normal quality of life reflected in their reports of psychiatric symptoms and family relationships.
All the research on late outcome of patients undergoing Fontan surgery is focused on its limitations. The operation clearly remains palliative and patients are likely to fail in the decades after their Fontan surgery. Early and midterm results have nonetheless improved, and it is difficult to give families reasonable expectations for a "well-functioning" Fontan. So far, best outcomes in terms of exercise capacity and quality of life have been ascertained by the determination of the outcomes of best Fontan candidates [1, 2]. Instead, we wanted to describe the performances of those achieving the best end results regardless of their preoperative status. Many seemingly best candidates may have long-term performances affected by variables other than preoperative ones. In particular, the perception of the late status of the Fontan patient has been tainted by those suffering from late arrhythmias. In the first cohorts of patients undergoing Fontan surgery, supraventricular arrhythmias have occurred in up to half the patients within 15 years [3]. Typically, Fontan patients suffering from recurrent arrhythmias see a decrease in their functional status and necessitate recurrent hospital admissions. We have recently demonstrated that the introduction of more contemporary techniques of Fontan, such as the lateral tunnel and the extracardiac conduit, significantly reduced the late incidence of arrhythmias [4]. After 15 years, only 13% of our patients with a lateral tunnel suffered from arrhythmias and it is likely that patients undergoing extracardiac conduit will even perform better. We decided to investigate the exercise capacity and the quality of life of our arrhythmia-free Fontan patients in order to determine the best possible expectations of a good Fontan.
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Patients and Methods
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The design of the study was approved by the local hospital ethics committee. All patients from Victoria, Australia who had undergone a Fontan operation at the Royal Children's Hospital between 1980 and 1995 were invited to participate in the study. The current status of the patients had been recently updated for our recent follow-up study [4]. Exclusion criteria were recurrent episodes of tachycardia, previous pacemaker implantation, and impaired neurologic status. Thirty-nine out of the 61 potential candidates agreed to participate in the study. On the same day, after obtaining informed consent, the fasted patients underwent blood sample collection, followed by transthoracic echocardiographic examination and cardiopulmonary exercise testing on a cycloergometer. They were also asked to complete questionnaires assessing their quality of life. Three studies had to be discarded, one because the patient presented with upper respiratory tract infection on the day of the study, and two for technical failures resulting in faulty recording of the exercise parameters. Patients' characteristics are displayed in Table 1. The characteristics of the entire Fontan population of Victoria operated during the same time period is given in Table 2.
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Table 2 Characteristics of the Entire Fontan Population of Victoria Operated During the Same Time Interval as Studied Patients
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Details of the procedures have been previously published [4]. None of the patients with an atriopulmonary connection and 5 of those with a lateral tunnel had a fenestration at the time of the Fontan. Twenty-one of the 23 patients with atriopulmonary connections and all those with lateral tunnel described themselves as being in New York Heart Association (NYHA) functional class I.
Neurohumoral Factors
Resting atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cyclic guanosine triphosphate (cGMP), and endothelin-1 were assayed by Endolab in Christchurch, New Zealand. Plasma ANP, BNP, cGMP, and endothelin-1 concentrations were measured with specific radioimmunoassay using ANP antiserum (locally raised R31), BNP antiserum (cat. number RAS9086, Bachem, Torrance, CA), cGMP antiserum (Glasgow 487/III, Royal Infirmary, Glasgow, UK), and endothelin-1 antiserum (cat. number RAS6901; Bachem), respectively.
Transthoracic Echocardiography
Echocardiographic examinations were performed prior to each exercise test using the iE33 echocardiography system (Philips Medical Systems, Best, the Netherlands) and studies were performed according to international guidelines [5]. Biplane ejection fraction was calculated in patients with left ventricular morphology only. Tissue pulse wave Doppler imaging measurements were taken from the atrioventricular annulus of the free wall of the dominant ventricle. All parameters were averaged over three cardiac cycles. Tissue Doppler velocities were converted to z-scores. For patients with a dominant left ventricle, z-scores were calculated using normative values from a study of 325 healthy children for Doppler tissue imaging velocities on the systemic left ventricle [6]. For subjects with a dominant right ventricle, z-scores were calculated using data from a study of patients with congenitally corrected transposition [7].
Exercise Study
Exercise testing was performed using an upright bicycle ergometer (Lode Corival 400; Lode B.V., Groningen, Nederland). Gas exchange data were collected continuously using Breeze Suite version 6.2 (MedGraphics Corporation, St. Paul, MN). Arterial oxygen saturation was monitored continuously by an infrared sensor (Nellcor NPB 290; Covidien-Nellcor, Boulder, CO) placed on the fingertip. Heart rhythm and heart rate were recorded continuously throughout the test using a 12-lead electrocardiogram (version 2.3; Cambridge Heart Inc, Tewksbury, MA). After a 3 minute warm up period without load, the workload was progressively increased by 5 watts per minute for subjects weighing less than 40 kg, and 10 watts per minute for those weighing more than 40 kg. Patients were uniformly encouraged to reach their anaerobic threshold (AT). Maximal oxygen consumption (VO
2max) values were used to calculate a percentage of predicted VO
2max reached, using the following equations; VO
2max (predicted, male) = 185.72 + 2.23 x (1,824 x Height(m)/100) – 1,934; VO
2max (predicted, female) = 185.72 + 2.23 x (2,065 x Height(m)/100) – 2,484. Anaerobic threshold was determined by the V-slope method. Predicted AT was defined as 60% of the predicted VO
2max.
Quality of Life Questionnaires
Patients aged over 18 years completed the following questionnaires assessing impairing psychiatric symptoms, family functioning, and relationship functioning, respectively: the Short Form-36 Questionnaire [8], the Hopkins Symptoms Checklist [9], the Family Assessment Device [10], and the Spanier Dyadic Adjustment Scale [11]. Those aged below 18 had their parents-guardians answer the above series of questionnaires. These questionnaires were used to investigate the general and mental health and the well-being of the patients, their trend toward depression and anxiety, and their ability to function in a family or a couple relationship (Table 3). Normative data are available for all these questionnaires, which were chosen because they have been used widely and have robust psychometric properties [12].
Statistical Analysis
All perioperative, echocardiographic variables listed in the Appendix and levels of neurohumoral factors were tested for their impact on VO
2max and AT, expressed in mL/kg/minute or in percentage of predicted value, and on the scores achieved in each quality of life questionnaire. Correlations between perioperative variables, echocardiographic parameters, and neurohumoral factor levels were investigated. Continuous data were expressed as mean ± standard deviation or median (interquartile range) while categoric data were expressed as frequency (percentage). Continuous outcomes with binary variables were compared using unpaired t tests. A p value of less than 0.05 was considered statistically significant. Outcomes with continuous variables were analyzed using correlation and linear regression, and a correlation coefficient r greater than 0.5 and correlation of determination R
2 greater than or equal to 0.25 were considered significant. All statistical analyses were performed using Stata version 8.2 (StataCorp, College Station, TX).
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Results
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Exercise Study
Patients with lateral tunnel performed better than those with atriopulmonary connections, especially when considering percentages of predicted values (p < 0.005) (Table 4). Males had a higher exercise capacity than females (mean VO
2max: 23.9 ± 4.8 vs 18.5 ± 3.1 mL/kg/minute, p < 0.0005; mean AT: 19.9 ± 5.4 vs 15.1 ± 3.2 mL/kg/minute; p < 0.005) but this difference disappeared when corrected for predicted values for males and females (mean percentage of predicted VO
2max: 57.5 ± 8.6% vs 56.2 ± 8.4%, p = 0.64; mean percentage of predicted AT: 79.4 ± 16.4% vs 76.6 ± 15.6%; p = 0.6). There were no correlations between exercise capacity and older age at exercise or longer interval time between Fontan surgery and exercise.
There were no differences between the results of patients with a predominant left ventricle (mean percentage of predicted VO
2max: 56.2 ± 8.3%, mean percentage of predicted AT: 77.7 ± 16.4%) and a predominant right ventricle (mean percentage of predicted VO
2max: 53.3 ± 5.4%, mean percentage of predicted AT: 73.6 ± 12.4%) (p > 0.3).
Echocardiography
At the time of the study, only one patient with a lateral tunnel had a small patent fenestration. The comparative results of the measured echocardiographic parameters in patients operated with the two different techniques are displayed in Table 5. The Tei index was increased equally in patients operated with both techniques. On tissue Doppler imaging, the diastolic function of the patients operated on with an atriopulmonary connection seemed more impaired than that of patients with lateral tunnels. This difference did not seem to be related to the older age of the patients with an atriopulmonary connection as there was no correlation between age and z-score values of the tissue Doppler E wave velocities. All echocardiographic parameters were compared in patients who had a predominant left or biventricular morphology and those who had a predominantly right morphology. Assessment of diastolic function by conventional Doppler techniques did not show any significant difference in values for the two groups. Differences in diastolic function could only be noted on parameters collected by tissue Doppler imaging. The E wave, A wave, and S wave velocity z-scores for the predominantly left and right ventricles, respectively, were –2.49 ± 1.44 and 0.35 ± 5.24 (p < 0.0005), –0.61 ± 1.31 and 0.80 ± 0.80 (p < 0.05), and –1.95 ± 0.69 and –0.05 ± 0.74 (p < 0.0001). None of the echocardiographic parameters correlated with the results of exercise capacity.
Neurohumoral Factors
Levels of ANP, BNP, cyclic GMP, and endothelin-1 in the patients operated with the two different techniques are given in Table 6. There were no correlations between the level of these humoral factors and exercise capacity indices, or echocardiographic parameters. Similarly, no relationship could be found between levels of these neurohumoral factors and morphologic or perioperative variables.
Quality of Life
The scores in the various health domains assessed are detailed in Table 7. The SF-36 scores were normal in both groups as were the scores for the Hopkins Symptoms Checklist and the Family Assessment Device, except for expected abnormalities known to be associated with clinical patient groups. The Spanier Dyadic Adjustment Scale scores, evaluating the marital or de facto relationships, were within normal limits. However, due to their younger age, only 4 of the 13 patients with lateral tunnels were in such a relationship at the time of the study and it is likely that the comparison between the two groups is not valid at this stage. No correlation could be found between the scores of quality of life of the patients and their exercise capacity, perioperative variables, echocardiographic parameters, or level of neurohumoral factors.
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Comment
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Fontan patients are often perceived to be debilitated, with poor exercise capacity and limited quality of life. This in-depth study of a subgroup of Fontan patients, who were free from arrhythmias at last follow-up, shed new light on the performances achievable by Fontan patients.
Exercise Capacity
In the second decade after their Fontan surgery, maximal performance of our arrhythmia-free patients was in the expected range of 50% to 60% of predicted values. However, the anaerobic threshold of those who had undergone a lateral tunnel was relatively preserved, reaching almost 90% of the predicted value, probably reflecting the fact that these patients may hope for an exercise capacity approaching normal levels, up to submaximal levels of exercise. The finding that patients operated with a lateral tunnel achieved better exercise capacity than those who had undergone an atriopulmonary connection is in contrast with previous studies, and may be due to the longer interval time between the Fontan operation and the exercise test in our patients [13–15]. Rosenthal and colleagues [15] had previously demonstrated that patients with a lateral tunnel had higher pulmonary blood flow and larger stroke volumes during exercise than patients with atriopulmonary connections, but this difference in cardiac output did not result in an increased maximal oxygen consumption in their patients studied less than 10 years after Fontan. Our patients were exercised 16 years after their Fontan, and it is likely that the hemodynamic differences between the two techniques resulting in no clinical differences in the Rosenthal study became apparent in our study because our patients were exercised later.
Previous studies were unable to demonstrate that any subgroup of Fontan patients could have a relatively preserved anaerobic threshold, and we attribute this difference to our selection criteria of well-functioning Fontan patients [16–18]. The maximal exercise performance of these Fontan patients with relatively preserved anaerobic thresholds was still poor compared with what one would have expected from patients with biventricular circulation having similar anaerobic thresholds. It seems that cardiopulmonary performances of Fontan patients may increase progressively up to a certain level, after which the Fontan circuitry becomes too restrictive to allow any further increase in cardiac output. The stroke volume of Fontan patients is known to be relatively normal up to anaerobic threshold, after which it decreases as the patient undertakes higher workloads [16, 19, 20]. It is noteworthy that only one of our patients had a patent fenestration at the time of the exercise. Patients with patent fenestrations have a higher cardiac output than those with no right to left shunting, and it is possible that they could overcome the high resistance of their Fontan circulation by increasing shunting at maximal exercise [21].
It is disputed whether age at exercise and interval time since Fontan surgery may alter exercise performance [15, 22, 23]. Because the lateral tunnel technique was adopted later in our center, patients operated with this technique were younger and had a shorter interval since Fontan than those who underwent the classical atriopulmonary connection. In our patients, these two variables did not seem to influence anaerobic threshold or VO
2max, but one cannot exclude that with larger numbers of patients a difference would appear. Similarly to previous reports of Fontan patients, there were no differences between the exercise capacity of our arrhythmia-free Fontan patients with a right or a left dominant ventricle, but again this finding may be limited by the number of patients investigated [13, 24].
Ventricular Function
Fontan patients are known to have an impaired diastolic function but it is still unclear to what extent this dysfunction correlates with reduced exercise capacity [25, 26]. Despite the fact that our patients had a wide range of ventricular systolic and diastolic dysfunction, and even without the confounding factor of arrhythmias, we could not identify any relation between myocardial function and exercise capacity. It has been suggested that impairment of ventricular function has to be severe before impacting on the exercise capacity and our study would tend to suggest that differences in myocardial contractility and diastolic function might not be responsible for any noticeable variation in exercise capacity in well-functioning Fontans [19].
Neurohumoral Factors
The atrial and brain natriuretic peptides were elevated in patients with atriopulmonary connections and remained within the normal range in patients with lateral tunnel. This finding confirms the probable secretion of these peptides by the atrium in response to its stretching under an increased pressure load [27]. It has been postulated that elevated levels of BNP may correlate with severity of heart failure in Fontan patients [28]. Our findings would suggest that these elevated levels probably arise from the stretched dilated atria rather than the ventricles. It is therefore likely that in patients with atriopulmonary connections their use will be of limited value to monitor heart failure, while their prognostic value in patients with lateral tunnel or extracardiac conduits could still be investigated.
Endothelin-1 was uniformly elevated in our Fontan patients. This interesting finding would suggest that chronically elevated levels of circulating endothelin-1 might contribute to pulmonary endothelial dysfunction and the rise of the systemic and pulmonary vascular resistances observed during the long-term follow-up of Fontan patients. In this series of well-functioning Fontan patients, endothelin levels did not correlate with exercise capacity and it therefore seems unlikely that these levels would be predictive of a worse outcome [27, 29].
Quality of Life
The normal perception of their quality of life demonstrated in our arrhythmia-free Fontan patients is in striking contrast to most studies [30–32]. Only Saliba and colleagues [30] were able to show normal results in the French population. Most of the studies examining quality of life of Fontan patients were limited to groups of patients followed in clinics of one or several institutions, which may reflect some degree of patient selection. Our patient population is a longitudinal cohort of patients. Interestingly, it demonstrates that, provided that operated Fontan patients are free of arrhythmias, they can hope for a fulfilling life even though their exercise capacity is limited. As practitioners, this unique finding comes as a great relief. Even though the Fontan operation is still to be considered a palliative procedure, giving some positive perspectives for the second decade after the operation may provide much needed hope for families. In a previous report, 87% of our patients operated with the lateral tunnel were free of tachyarrhythmias 15 years after Fontan, and we can hope that a large number of future patients will fit in this category [4].
Limitations of the Study
Because the patients studied were operated with older versions of the Fontan procedures it is uncertain that the observations reported will be relevant to the population of Fontan operated today. Some of the recorded parameters may have significantly impacted outcomes if a larger population had been studied, in particular age at surgery, interval time between Fontan and exercise study, offloading of the systemic ventricle by staging procedures, and diastolic dysfunction.
In conclusion, the exercise capacity of arrhythmia-free Fontan patients operated with the lateral tunnel technique is near normal up to the anaerobic threshold. Despite restricted exercise capacity, Fontan patients, provided that they are free of arrhythmias, have a normal perception of their well-being and interact normally within their families.
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Appendix
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Acknowledgments
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We are indebted to Melissa Newton, BSCi, who helped us by accumulating the echo data of these patients.
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References
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Abstract
Introduction
