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- Carl Lewis Backer, MD, FACC⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Carl L. Backer, Division of Cardiovascular-Thoracic Surgery, Children's Memorial Hospital, 2300 Children's Plaza, Box 22, Chicago, Illinois 60614.
The current issue of the Journal contains 3 excellent reports that detail different aspects of patients who have undergone the Fontan operation (1–3).
I had the privilege of having dinner with Francis Fontan a year ago this past February. We invited him to our institution to participate in a seminar on the 40-year evolution of the Fontan procedure and in particular the Fontan conversion procedure (4). I am sure that Professor Fontan never in his wildest dreams imagined the kind of attention and in-depth analysis being paid to patients who have undergone the operation that now bears his name. The incredible in-depth analysis of Fontan patients provided in the 3 articles in this issue of the Journal will help congenital heart surgeons and pediatric cardiologists to both manage these patients and possibly alter their management strategies to enhance the quality of the lives of these patients.
In many respects, considering the single ventricle physiology of these patients, they are doing surprisingly well. The Pediatric Heart Network multicenter study of 546 Fontan patients concluded, “Measures of ventricular systolic function and functional health status, although lower on average in the cohort compared with control subjects, were in the majority of subjects within 2 standard deviations of the mean for control subjects” (1). The exercise testing of these patients, also conducted through the Pediatric Heart Network (n = 411), concluded, “In Fontan patients, maximal aerobic capacity is reduced compared with healthy subjects, with better preservation of submaximal performance” (2). Finally, the article from Meadows et al. (3) at Boston Children's Hospital has focused on the effect of fenestration closure. This group concluded that, “Fontan fenestration closure does not significantly improve peak oxygen consumption (VO2). However, ventilatory abnormalities improve considerably” (3). Again, I am sure Professor Fontan would never have imagined this type of in-depth analysis being performed on such a large number of patients. These manuscripts are strengthened by including patients from many institutions. The power of the first 2 studies is in many respects due to inclusion of a large number of patients from all over the country, a very worthwhile outcome of forming groups like the Pediatric Heart Network.
The Pediatric Heart Network has published 2 studies in this issue—the first entitled “Contemporary Outcomes after the Fontan Procedure,” in which they studied 546 post-Fontan patients between 6 and 18 years of age (mean age at enrollment, 11.9 years; mean age at Fontan, 3.4 years). Tricuspid atresia, hypoplastic left heart syndrome, and double inlet left ventricle were the most common diagnoses. Left ventricular (LV) morphology was present in 49%, right ventricular (RV) in 34%, and mixed in 18%. Fontan types included: atriopulmonary connection (13%), intracardiac lateral tunnel (59%), extracardiac lateral tunnel (13%), extracardiac conduit (13%), and other (2%). Complications after the Fontan procedure included: stroke/thrombosis (8%), seizures (3%), and protein-losing enteropathy (4%). Normal sinus rhythm was present in 67% of patients, and 13% of patients used a pacemaker. The Physical and Psychosocial Summary scores of the Child Health Questionnaire Parent Form were within the normal range for over 80% of patients, although the mean values were lower than those of healthy control subjects. Semilunar and atrioventricular (AV) valve regurgitation was found in 49% and 74% of patients, respectively; both were more likely in patients with RV morphology. Exercise performance showed a weak association to ventricular morphology, with better results in the LV subgroup. An interesting and concerning finding was that 72% of children with a Fontan had abnormal diastolic function. The authors recommend further invasive studies to investigate this particular finding. These are tremendous outcome data in a large cross-section of Fontan patients that can in many respects be used as benchmark data. For example, in our Fontan patients we always place a permanent atrial pacing lead, because of the risk of need for future pacing (only 67% of patients in normal sinus rhythm). Another example is the 8% incidence of thrombosis; this encourages lifelong antiplatelet and/or warfarin therapy.
A particularly interesting set of findings relate to patient age at the time of the Fontan procedure. The authors divided patients into 4 groups on the basis of age at Fontan (<2, 2 to <3, 3 to <4, and ≥4 years) to compare outcome measures. Between 70% and 74% of patients who underwent Fontan at <3 years of age remained in normal sinus rhythm, versus only 59% to 62% who underwent Fontan at ≥3 years of age (p = 0.01 adjusted for age at enrollment). Only 13% to 16% of patients who underwent Fontan at <3 years of age had moderate to severe AV valve regurgitation, versus 23% to 26% who underwent Fontan at ≥3 years of age (p = 0.01). The authors suggest that these findings are due to prolonged volume overloading in the patients who were older at Fontan; these findings support current trends toward primary Fontan at an early age. Median B-type natriuretic peptide (BNP) measurement was 13 pg/ml (range <4 to 652 pg/ml). Higher median BNP values were found in patients with an atriopulmonary Fontan (18 pg/ml) versus those with an extracardiac Fontan (13 pg/ml) or lateral tunnel (10 pg/ml). This is consistent with our data showing that conversion from atriopulmonary Fontan to extracardiac Fontan improves exercise performance (5).
Also of interest are the outcome results related to patients who underwent a Stage II procedure (superior cavopulmonary connection) versus those who did not. Despite the common assumption that Stage II surgery improves outcomes and is beneficial to patients through reducing volume load, Stage II procedure was not associated with improvement in ventricular function or exercise performance. Age-adjusted mean log BNP was significantly lower for patients with LV morphology who underwent Stage II surgery versus those who did not; however, there was no significant difference in patients with RV or mixed morphology who underwent Stage II. Additionally, Stage II surgery was associated with a lower psychosocial summary score on the Child Health Questionnaire. On the basis of these surprising results, the authors recommend a clinical trial to determine the value of Stage II procedures. I personally doubt that many surgeons will be interested in such a trial. Stage II procedures have in my opinion definitely decreased overall mortality (and morbidity) of single ventricle patients. Further examination of this data may reveal confounding variables that explain the apparent contradictory data.
This may relate to the primary limitation of this study, which is that it is only able to look at characteristics of survivors; thus any differences that may have been present in patients who died within the first few years after Fontan are still unknown. Furthermore, marked deterioration of the Fontan patient's clinical status may not occur until later in life. Hopefully the Pediatric Heart Network will be able to continue follow-up on these patients into their adult life, and it will continue to add to our collective knowledge about clinical outcomes in the Fontan patient.
In the second Pediatric Heart Network study, Paridon et al. (2) evaluated exercise performance in children after the Fontan operation as part of a multicenter cross-sectional study funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Exercise capacity is “an important component of a child's quality of life and functional status,” and until now there have been limited study data on younger Fontan patients. As such the authors sought to define exercise capacity in this large study population. Of 644 eligible patients, 411 subjects (mean age, 12.4 years) were enrolled in the prospective study and underwent ramp cycle ergometry testing with expired gas analysis. Results were analyzed for the study population as a whole and also by division into submaximal (n = 235) and maximal effort (n = 166) groups. In regard to exercise performance, peak VO2 was decreased compared with expected values for age and gender (65% of predicted), and only 28% of patients had a peak VO2 within normal range. However, VO2 at ventilatory anaerobic threshold (VAT) was higher at 78% of predicted. The authors note that their finding of better preservation of VO2 at VAT as compared with peak VO2 indicates that “Fontan subjects can tolerate a higher level of submaximal activity than might be anticipated from measurement of peak VO2” (2). Slow but steady wins the race! In terms of pulmonary performance, the forced vital capacity, forced expiratory volume at 1 s, and forced expiratory volume at 1 s/forced vital capacity values were decreased, independent of effort group. In 34% of patients, breathing reserve was below 15% (lower limit of normal). The authors note that the patients' low breathing reserves, although possibly an effect of inadequate effort in some subjects, indicate some limitation of pulmonary function. This may be related to prior thoracotomies and sternotomies.
An analysis of the maximal effort group to determine the relative contributions of heart rate, O2 saturation, and O2 pulse showed that, “maximum % predicted oxygen pulse, as a surrogate of stroke volume, accounts for 73% of the variation in % predicted peak VO2, 26% of the variation in % predicted maximum work rate, and 35% of the variation in % predicted VO2 at VAT” (2). This finding indicates that in Fontan patients, stroke volume reserve is the most important determinant of aerobic capacity. Whatever we as surgeons can do to preserve this stroke volume (myocardial protection) is quite important to the exercise tolerance of our patients. This conclusion was also reached by Anderson et al. (1) in the first study. They concluded that “effective strategies to preserve ventricular and valvar function, particularly for patients with RV morphology, are needed.” Perhaps the “hybrid” procedure, which avoids cardiopulmonary bypass in the neonate, will have this desired effect. Another particularly interesting finding in this study was that multiple linear regression analysis showed that the variables of male gender, post-pubertal age, and increased body mass index Z score were negatively associated with percent predicted peak VO2 and percent predicted peak O2 pulse (indicators of aerobic capacity and stroke volume). The authors hypothesize that this is due to the greater increase in male muscle mass during puberty and the inability of the male Fontan patient's circulatory system to meet the resulting higher demands of exercise.
The final article in this issue is by Meadows et al. (3) from Boston Children's Hospital. They sought to determine the effect of Fontan fenestration closure on exercise tolerance. They performed a prospective study of 20 consecutive patients referred for elective fenestration closure. All patients had a lateral tunnel Fontan with a 4-mm fenestration. Median age at fenestration closure was 10 years. Exercise tolerance was measured by expiratory gas analysis both before and after closure. Before fenestration closure, peak VO2 was depressed and, as expected, there was systemic desaturation at rest that worsened with exercise. Acute hemodynamic results of fenestration closure showed a 4% increase in systemic arterial saturation, an 11% increase in systemic venous pressure, no change in mixed venous O2 saturation, a 12% decrease in cardiac index, and a 10% decrease in systemic O2 delivery. This is consistent with the well-known fact that a fenestration increases systemic O2 delivery despite mild systemic desaturation by increasing cardiac output (6).
Of interest, the authors found no change in peak exercise capacity after fenestration closure as demonstrated by percent of predicted VO2, percent predicted ventilatory anaerobic threshold, heart rate, or O2 pulse. This is despite a 12% increase in O2 saturation at peak exercise, a finding “at odds” with the commonly held belief that improving arterial O2 saturation will improve exercise tolerance. The O2 pulse (VO2/heart rate) at peak exercise was unchanged. The authors explain that this finding demonstrates that exercise tolerance in the Fontan patient is limited by peak blood flow in the pulmonary vascular bed, which is passively perfused by systemic venous pressure. However, baseline ventilatory abnormalities showed significant but not normalized improvements with fenestration closure. Improvements demonstrated were a decrease in the minute ventilation/carbon dioxide elimination slope as well as an increase in the previously low end-tidal CO2 at the ventilatory anaerobic threshold. The authors speculate that these changes are due to a decrease in CO2-mediated respiratory drive after fenestration closure. The right-to-left shunt before fenestration closure led to systemic venous blood (rich in CO2) entering the arterial circulation during exertion. Chemoreceptors, sensing the increase in arterial partial pressure of CO2, caused an increase in respiratory drive. Alveolar hyperventilation followed in an attempt to normalize arterial partial pressure of CO2. Fenestration closure reduces this increase in respiratory drive, allowing the patient to breathe less during exercise and reducing the patient's feeling of dyspnea.
From a surgeon's perspective, this is truly fascinating physiology. The study supports fenestration closure in most patients. It is interesting, however, that as surgical strategies have evolved many of us are no longer using fenestrations as part of our surgical strategy. At Children's Memorial Hospital, we converted to the extracardiac Fontan technique in 1998 and have performed over 90 extracardiac Fontan procedures without fenestration with a 2.5% mortality rate.
The Fontan operation truly has come a very long way in the 40 years since the first procedure for tricuspid atresia performed by Fontan in 1968. The Fontan operation has now been applied to all types of single ventricle equivalents. The surgical technique has changed from an atriopulmonary anastomosis to either an extracardiac graft or a lateral tunnel procedure. The great majority of patients are now staged with a bidirectional cavopulmonary anastomosis. Intensive investigations in this issue of the Journal have demonstrated that although these patients do remarkably well, they do not keep up with age-matched control subjects in exercise ability. Continued detailed investigation by groups such as the Pediatric Heart Network will improve our understanding of these patients and will lead to surgical and medical therapies to improve their quality of life. Some examples of this that I believe have been demonstrated by the aforementioned studies are that younger age at Fontan improves incidence of normal sinus rhythm and freedom from AV valve insufficiency. The fact that stroke volume reserve is the most important determinant of aerobic capacity emphasizes the importance of myocardial preservation and early volume unloading. The use of a fenestration has not been applied by all institutions, but the article by Meadows et al. (3) clarifies the improvements that patients receive with exercise after having a Fontan fenestration closure. Fenestration closure does not improve exercise capacity but does improve the ventilatory response to exercise. The Fontan operation remains a palliative procedure, but for patients born with a single ventricle it is a dramatic improvement and a true milestone in the history of pediatric cardiac surgery. Studies such as the 3 in this issue of the Journal will allow us to continue to improve our strategies for the care of functional single ventricle patients.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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