Natural History of Exercise Capacity After the Fontan Operation: A Longitudinal Study

Alessandro Giardini MDa, ,Alfred Hager MDb, Carlo Pace Napoleone MDa and Fernando M. Picchio MDa
aPediatric Cardiology and Adult Congenital Unit, University of Bologna, Bologna, Italy
bDepartment of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Technische Universität, Munich, Germany
Accepted 2 November 2007.  Available online 18 February 2008.

Referred to by:		Invited Commentary The Annals of Thoracic Surgery, Volume 85, Issue 3, March 2008, Pages 821-822 Robert D. Ross

Background

Previous studies have shown that older Fontan patients and those with an underlying morphologically right ventricle have lower exercise capacity. We sought to assess the natural history of exercise capacity after the Fontan operation in individual patients, and to identify the factors influencing the rate of decrease of exercise capacity over time.

Methods

We studied, longitudinally, 53 Fontan patients with cardiopulmonary exercise tests (average 3.2 ± 1.1 tests for each patient). Age at the first test was 14 ± 6 years. Time intervals between tests ranged from 1 to 16 years (average, 7.7 ± 4.0 years). The morphology of the functionally single ventricle was left in 29 patients (55%) and right in 24 patients (45%). Twenty-two patients had undergone a total cavopulmonary connection (TCPC) at a mean age of 5.9 ± 2.8 years. Thirty-one patients had undergone an atriopulmonary or an atrioventricular connection at an age of 6.9 ± 4.4 years. Exercise capacity was expressed as percentage of predicted peak oxygen uptake (Vo2).

Results

Overall, peak Vo2 decreased at a rate of −2.6 ± 2.7%/year. Ventricular morphology (r = 0.525, p = 0.0001) and type of Fontan operation (r = 0.381, p = 0.0057) appeared as the only predictors of the rate of decrease of peak Vo2 at multivariate analysis. Patients with an underlying left ventricular morphology (−1.7 ± 2.0 vs −3.7 ± 3.2%/year, p = 0.005), and those who underwent a TCPC (−1.9 ± 1.8 vs −3.3 ± 3.2%/year, p = 0.042), had the lowest rate of decrease in peak Vo2.

Conclusions

Exercise capacity progressively declines in Fontan subjects. The decline of exercise capacity seems to be slower in patients with an underlying left ventricular morphology and in those who received a TCPC.

Article Outline

Patients and Methods
Cardiopulmonary Exercise Test
Statistical Analysis
Results
Comment
References

Because that observation was based on findings in different patients studied at different ages, it was unclear whether a patient’s maximal aerobic capacity decreased with time after the operation. The purposes of the present study are the following: (1) to assess whether there is deterioration of aerobic capacity over time after the Fontan operation in individual patients; and (2) to identify the factors that influence the rate of decrease of exercise capacity over time.

Patients and Methods

Since 1991, 53 Fontan patients have undergone two or greater exercise tests (average 3.2 ± 1.1 tests per patient) as part of their follow-up at the two institutions involved in the study. They represent the cohort analyzed in the present study. The Institutional Committee on Human Research approved the study on May 15, 2007 and waived the need for patient consent to participate.

There were 30 males (57%) and 23 females (43%). The preoperative diagnoses were made by echocardiography and cardiac catheterization. Details on underlying anatomy are shown in Table 1. Twenty-nine patients (55%) had a morphologically left ventricle and 25 patients (45%) had a morphologically right ventricle. Age at surgery was 6.7 ± 3.0 years. An atriopulmonary or atrioventricular connection was made in 31 patients (58%), a lateral-tunnel total cavopulmonary connection (TCPC) was performed in 11 patients (21%), and an extracardiac TCPC was made in 11 patients (21%). In 14 patients with a TCPC, at the time of operation a fenestration was made between the inferior vena cava pathway and the systemic atrium. The time interval between the operation and the first exercise test was nine years (range, 0.3 to 31 years). During follow-up two patients died, seven patients underwent conversion of atriopulmonary or atrioventricular Fontan to TCPC, and five patients underwent cardiac transplantation (peak Vo2 before heart transplantation 27 ± 5%). For these patients, the peak Vo2 value obtained at the time of the last test before death-transplantation or surgery was used in the subsequent analysis and follow-up was censored at that time. Seventeen patients developed arrhythmias during follow-up (atrial fibrillation in 10, atrial flutter in 4, and junctional rhythm in 3 patients), which became persistent in 14 patients. Eight patients needed the implantation of a permanent pace maker. Follow-up was not censored in case of arrhythmias or pacemaker implantation because these events represent frequent circumstances in the natural history of Fontan patients. The time interval between studies ranged from 1 to 16 years (average, 7.7 ± 4.0).

Table 1.

Underlying Anatomic Findings in the Study Cohort

Cardiac Lesion	Associated Anomalies	Number of Patients	Death or HTx	Fontan Conversion
Tricuspid atresia	Concordant VA connections	11	−	3
	Discordant VA connections	3	2	−
PA – intact septum	−	6	−	1
Double inlet left ventricle	Discordant VA connections	7	1	3
	Concordant VA connections	2	−	−
Double outlet right ventricle	Hypoplastic mitral valve	6	1	1
HLHS	Mitral atresia	2	−	−
	Aortic atresia	1	1	−
	Mitral + aortic atresia	1	−	−
Double intlet right ventricle	Aorta from the RV + PA/S	2	−	−
	Double outlet right ventricle + PA/S	1
Complete AVSD	Right ventricular dominance	3	−	−
	Double outlet right ventricle	2	−	−
Right univentricular heart	Aorta from the RV + PA/S	3	1	−
	Double outlet right ventricle + PA/S	3	1	−

AV = atrioventricular; AVSD = atrioventricular septal defect; HLHS = hypoplastic left heart syndrome; HTx = heart transplantation; PA/S = pulmonary atresia/stenosis; RV = right ventricle; VA = ventriculoarterial.

Cardiopulmonary Exercise Test

Exercise tests were performed on an electronically braked cycle ergometer (Ergoline, Germany). Oxygen uptake (Vo2), carbon dioxide elimination, and minute ventilation were measured with a computerized breath-by-breath analyzer (VMax; Sensor-Medics, Yorba Linda, CA). Patients performed a maximal exercise test using a one-minute incremental bicycle protocol. Work rate increment was variable, from 10 to 20 W/minute, with the aim of achieving exhaustion in about 10 minutes of exercise. Patient exhaustion with a respiratory exchange ratio greater than 1.09 was considered a criterion for test ending. A 12-lead electrocardiogram and transcutaneous oxygen saturation were continuously monitored throughout the study and cuff blood pressure was determined every two minutes. The technical details of measurement of peak Vo2 were published previously [5]. Standard equations were used to generate predicted values for peak exercise Vo2 [6]. All patients or legal guardians provided written informed consent before the exercise tests.

Statistical Analysis

To index for the physiologic change in peak Vo2 when expressed in mL/Kg/minute during normal growth, we expressed peak Vo2 as the percent of predicted normal values for age, weight, and gender. For each single patient, the rate of change in peak Vo2% across studies was calculated by linear regression. Univariate and stepwise multivariate regression analyses were used to identify the demographic, anatomic, and surgical variables associated with a higher rate of peak Vo2 decrease. For each of the variables identified at multivariate regression, a subgroup analysis was performed by averaging the individual rates of peak Vo2 change of patients included in each subgroup. The rates of change in peak Vo2 over time, observed in different subgroups, were compared by unpaired t test. Baseline characteristics of different subgroups, stratified according to the predictors identified by multivariate analysis, were compared by unpaired t test. A 2-tailed p value of 0.05 or less was used as the criterion for statistical significance.

Results

Age and peak Vo2 at the time of the first exercise test were 14 ± 6 years and 61 ± 11%, respectively. Overall, peak Vo2 decreased during follow-up at a rate of –2.6 ± 2.7% each year of follow-up.

At univariate analysis, ventricular morphology (Table 2), type of Fontan operation, and peak Vo2 at the first exercise test, appeared to be associated with the rate of decrease of peak Vo2. However, at multivariate analysis, ventricular morphology (r = 0.525, p = 0.0001) and type of Fontan operation (r = 0.381, p = 0.0057) were the only independent predictors of the rate of decrease in peak Vo2. Gender, age at first test, age at surgery, and peak Vo2 at the first test were not associated with the rate of decline of peak Vo2 at multivariate analysis. Patients with underlying left ventricular morphology (Table 3), and those with a TCPC, had higher peak Vo2 values at the first test when compared with patients with underlying right ventricular morphology or those with an atriopulmonary or atrioventricular connection, respectively. The rate of decrease in peak Vo2 appeared to be lower in patients with an underlying morphologically left ventricle than in those patients with right ventricular morphology (−1.7 ± 2.0 vs −3.7 ± 3.2%/year, p = 0.005; Fig 1), and also in patients who received a TCPC when compared with patients with an atriopulmonary or atrioventricular connection (−1.9 ± 1.8 vs −3.3 ± 3.2%/year, p = 0.042; Fig 2).

Table 2.

Univariate and Multivariate Predictors of the Slope of Decline of Peak Vo2 in the Study Cohort (n = 53)

	r	p Value
Univariate Analysis
Ventricular morphology	0.531	<0.0001
Type of Fontan operation	0.367	0.0058
Gender	−0.247	0.0682
Age at surgery	0.3470	0.3997
Age at first test	−0.1836	0.1797
Peak VO2 at first test	−0.3172	0.0183
Multivariate analysis:
Ventricular morphology	0.525	0.0001
Type of Fontan operation	0.381	0.0057

Vo2 = oxygen uptake.

Table 3.

Demographic Characteristics of the Overall Study Cohort (n = 53) and of Different Subgroups According to Gender, Ventricular Morphology, and Type of Fontan Operation

Variable	Gender		Ventricular Morphology		Type of Fontan Operation
	Male	Female	Left	Right	TCPC	Other Types
	(n = 30)	(n = 23)	(n = 29)	(n = 24)	(n = 22)	(n = 31)
Age at first exercise test, years	15.4 ± 6.3	12.5 ± 5.4	15.0 ± 6.3	13.0 ± 4.5	12.3 ± 6.3	15.4 ± 6.5
Peak Vo2 at first exercise test, %	59 ± 11	63 ± 9	64 ± 11	56 ± 10a	64 ± 11	58 ± 10a
Number of exercise tests	3.0 ± 1.1	3.5 ± 1.3	3.2 ± 1.1	3.2 ± 1.0	3.4 ± 1.1	3.1 ± 0.8
Time interval between first and last test, years	9.3 ± 3.3	9.5 ± 3.3	9.8 ± 3.3	8.9 ± 2.9	9.9 ± 3.3	9.0 ± 2.7
Age at surgery, years	6.6 ± 3.8	5.9 ± 3.7	6.3 ± 3.2	6.5 ± 4.3	5.9 ± 2.8	6.9 ± 4.4

Data were compared by unpaired t test.

TCPC = total cavopulmonary connection; Vo2 = oxygen uptake.
a p < 0.05.

Display Full Size version of this image (24K)

Fig 1. Change in peak VO2 over time in individual Fontan patients according to the presence of morphologically right (solid circles) or left (empty circles) ventricle. Solid and dashed lines indicate the average of the individual slopes of decrease of peak Vo2 in patients with morphologically right versus left ventricles, respectively. (Vo2 = oxygen uptake.)

Display Full Size version of this image (26K)

Fig 2. Change in peak Vo2 over time in individual Fontan patients according to the type of Fontan surgery. Solid circles indicate atriopulmonary or atrioventricular connections; empty circles refer to intracardiac or extracardiac TCPC. The dashed and solid lines, respectively, indicate the average of the individual slopes of decrease of peak Vo2 in patients with, versus without, a TCPC. (TCPC = total cavopulmonary connection; Vo2 = oxygen uptake.)

Comment

This study shows that after Fontan operation there is a progressive decline in exercise capacity over time. This finding could be suspected looking at previously published cross-sectional studies. Indeed, those studies provided evidence that maximal aerobic capacity after this operation is lower in older than in younger patients [[1], [2] and [3]]. However, because that observation was based on findings in different patients studied at different ages, it was unclear whether a patient’s maximal aerobic capacity decreased with time after the operation. The only two studies that assessed the change in peak Vo2 over time in Fontan patients included 25 and 32 patients, respectively. However, patients were studied only at short time intervals between tests [[4] and [7]]. Furthermore, one of these studies did not include patients with the current “gold standard” surgical treatment represented by the TCPC [7]. In addition to expanding the findings of Nir and colleagues [7] our results show, also, that the performance of the TCPC in terms of preserving exercise capacity over time might be superior to that provided in the past by the atriopulmonary or atrioventricular connections.

Ohuchi and colleagues [4] studied 95 Fontan children by cardiopulmonary exercise testing. They showed that ventricular morphology is related to exercise capacity, so that Fontan patients with a morphologically left ventricle have the highest exercise capacity. In those 32 children who underwent a second exercise test after an average of 4.3 years, they showed a reduction in exercise capacity over time. However, likely as a consequence of the short time between the two tests, the reduction of peak Vo2 appeared to be significant only in patients with a morphologically right ventricle. Our results confirm that patients with an underlying morphologically left ventricle have higher exercise capacity. However, we could also show that progressive decrease in exercise capacity appears to be slower in patients with an underlying morphologically left ventricle. Interestingly, multivariate analysis excluded peak Vo2 at baseline as a predictor of the rate of peak Vo2 decrease, possibly suggesting that the slower worsening of exercise capacity in patients with morphologically left ventricles is not related to a higher exercise capacity at baseline, but rather to the presence of a left ventricle supporting the systemic circulation.

The present study is retrospective and shares all the limitations of a retrospective study. Another limitation of the present study is represented by the potential for a selection bias. Indeed, there is the chance that patients with advanced exercise intolerance and heart failure symptoms had been included in the analysis, whereas asymptomatic patients with normal exercise capacity had undergone a single exercise testing and therefore have been excluded. Assignment to TCPC was not random. Indeed, this type of Fontan operation was offered only to the most recent patients. Therefore, even though the length of follow-up was similar in the two groups, we cannot exclude that other factors, such as improved intraoperative or postoperative care, might have led to a better preservation of cardiac function and improved exercise capacity in TCPC patients. Furthermore, the lack of longitudinal echocardiographic data prevented us from assessing whether the decrease in exercise capacity was associated with a decrease in ventricular function.

References

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