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(Circulation. 1997;96:1507-1512.)
© 1997 American Heart Association, Inc.

Articles

Enalapril Does Not Enhance Exercise Capacity in Patients After Fontan Procedure

Amjad A. Kouatli, MD; Jorge A. Garcia, MD; Thomas M. Zellers, MD; Ellen M. Weinstein, MD; ; Lynn Mahony, MD

From the Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas.

	Abstract

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Background Angiotensin-converting enzyme inhibitors improve exercise capacity in adults with congestive heart failure by decreasing systemic vascular resistance and improving ventricular diastolic function. Patients who have undergone the Fontan procedure have decreased cardiac output, increased systemic vascular resistance, abnormal diastolic function, and decreased exercise capacity compared with normal people.

Methods and Results To test the hypothesis that afterload reduction therapy alters hemodynamic variables and augments exercise capacity in patients after a Fontan procedure, we compared the results of graded exercise with maximal effort from 18 subjects (14.5±6.2 years of age, 4 to 19 years after Fontan procedure) in a randomized, double-blind, placebo-controlled crossover trial using enalapril (0.2 to 0.3 mg · kg^-1 · d^-1, maximum 15 mg). Each treatment was administered for 10 weeks. Diastolic filling patterns at rest were assessed by Doppler determination of the systemic atrioventricular valve flow velocity at the conclusion of each therapy. No difference was detected in resting heart rate, blood pressure, or cardiac index. Diastolic filling patterns were also similar. Exercise duration was not different (6.4±2.6 [enalapril] versus 6.7±2.6 minutes [placebo]). The mean percent increase in cardiac index from rest to maximum exercise was slightly but significantly decreased in subjects after 10 weeks of enalapril therapy (102±34% [enalapril] versus 125±34% [placebo]; P<.02). At maximal exercise, cardiac index (3.5±0.9 [enalapril] versus 3.8±0.9 L · min^-1 · m² [placebo]), oxygen consumption (18.3±9 [enalapril] versus 20.5±7 mL · min^-1 · kg^-1 [placebo]), minute ventilation (57.5±17 [enalapril] versus 55.4±19 L/min [placebo]), and total work (247±181 [enalapril] versus 261±197 W [placebo]) were not different.

Conclusions We conclude that enalapril administration for 10 weeks does not alter abnormal systemic vascular resistance, resting cardiac index, diastolic function, or exercise capacity in patients who have undergone a Fontan procedure.

Key Words: heart defects, congenital • Fontan procedure • angiotensin • enzymes • exercise

	Introduction

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Many patients with single-ventricle physiology who have had a Fontan procedure do well from a clinical standpoint; however, numerous studies have shown that their exercise capacity is reduced compared with normal control subjects.^{1 2 3 4 5 6 7 8 9} In a Fontan circulation, vena caval blood flows passively through surgically created connections to the pulmonary arteries. The patient's ventricle pumps the pulmonary venous return to the systemic circulation. The reduced exercise capacity has been attributed in part to the failure of stroke volume to increase appropriately with exercise.^{1 2 3 5 8} A subnormal stroke volume may be related to impaired contractility, excessive afterload, limited preload, or a combination of these factors. Systolic function is depressed in some patients,^{7 10} and increased systemic vascular resistance has also been demonstrated.^{10 11} Assuming that there is no AV valve obstruction, preload to the ventricle in a Fontan circulation is determined by delivery of blood from the pulmonary vascular bed and by ventricular filling characteristics. The lack of a ventricular pumping chamber for the pulmonary circulation clearly contributes to the decreased stroke volume response to exercise. However, ventricular filling is dependent on the diastolic performance of the ventricle, and several studies have documented abnormal diastolic function in patients after the Fontan procedure.^{10 11 12} Thus, increased systemic vascular resistance and impaired diastolic function may contribute to the decreased exercise capacity observed in these patients.

ACE inhibitors are known to improve clinical status, hemodynamics, and exercise capacity in adults^{13 14 15 16} and children^{17 18 19 20} with left ventricular dysfunction. This clinical improvement results in part from a decrease in systemic vascular resistance^{13 14 21} and improvement in ventricular diastolic function.^{22 23} We hypothesized that ACE-inhibitor therapy in patients who have had a Fontan procedure would augment exercise capacity, and therefore we performed a randomized, double-blind, placebo-controlled study to test this hypothesis.

	Methods

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Inclusion and Exclusion Criteria
The subjects recruited were those patients who had undergone the Fontan procedure a minimum of 6 months before this study. The minimum age was set at 7 years to ensure cooperation with the exercise protocol. Patients were excluded from the study if they had congestive heart failure, were dependent on ACE inhibitors, were unable to exercise, had protein-losing enteropathy, had fixed-rate pacemakers, were pregnant, or had a history of angioedema. Informed consent under a protocol approved by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas was obtained from all subjects or their parents.

Study Design
This study was a randomized, double-blind, placebo-controlled crossover trial using a single dose of enalapril (0.2 to 0.3 mg · kg^-1 · d^-1, maximum 15 mg/d) or placebo every morning. This dose has been shown previously to be effective in pediatric and adult patients with both symptomatic and asymptomatic congestive heart failure.^{14 18 19 24 25} Each treatment was administered for 10 weeks. This time period was chosen because studies in adult patients have shown beneficial effects within 2 to 12 weeks of initiating therapy with ACE inhibitors.^{13 14 15 16} Randomization was accomplished by computer algorithm. Identical capsules containing either enalapril or placebo were prepared and dispensed by pharmacy personnel in vials identified by code. A cardiologist not otherwise involved in the study kept a list of vial codes so that the administered drug could be identified in the event of an emergency. One half of the study subjects received enalapril first, and the other half received placebo first. All personnel were unaware of whether study subjects were receiving enalapril or placebo. Pill counts were performed to assess compliance. Subjects were started initially on half the eventual dose of enalapril or placebo (0.1 to 0.15 mg · kg^-1 · d^-1). After 3 days, they were contacted by telephone by a physician to verify an absence of side effects. The dose of enalapril or placebo then was increased to 0.2 to 0.3 mg · kg^-1 · d^-1, and the subjects were contacted again in 3 days to assess side effects. At the conclusion of each treatment, a Doppler echocardiogram and an exercise test were performed, and the subjects were asked to complete a questionnaire concerning possible side effects.

Characteristics of the Study Subjects
Eighty-one consecutive patients who had undergone the Fontan procedure between 1984 and 1994 and who were 7 years old were screened for this study. One additional patient who had his surgery performed in 1975 at another institution was also included. Twenty-three patients were excluded because of significant congestive heart failure, dependence on ACE inhibitors, chronic pleural effusion, inability to exercise, or the fact that they were lost to follow-up. The study was thus offered to 59 patients, of whom 26 (44%) agreed to participate. Many of the patients who refused to participate either lived a long distance from Dallas or had full-time jobs and thus could not arrange to be available for the required procedures. Five patients were excluded after the practice exercise test because they were unable to follow adequately the steps of the exercise test or were unable to breath through the mouthpiece. Therefore, 21 patients who had undergone the Fontan procedure 4 to 19 years previously were enrolled in the study. All subjects denied having cardiorespiratory symptoms during their normal daily activities. Three female subjects withdrew from the study: a 27-year-old who was started on placebo complained of multiple somatic symptoms after one dose of placebo; an 8-year-old had successive viral illnesses that prevented completion of exercise tests; and a 14-year-old taking enalapril died of ventricular tachycardia while skiing at an altitude of 10 000 feet. This last patient had no previous history of arrhythmias, and her electrolytes were normal at the time of initial resuscitation.

Thus, 18 subjects completed the study. Their mean age was 14.5±6.2 years (range, 8 to 27 years), mean height was 152±19 cm, mean weight was 43±15 kg, and mean body surface area (BSA) was 1.35±0.32 m². Twelve subjects had tricuspid atresia, 2 had pulmonary atresia and hypoplastic right ventricle, 2 had d-transposition of the great arteries and hypoplastic right ventricle, and 2 had complex heart disease. One subject had an AV connection, and the remaining subjects had atriopulmonary connections. Eleven subjects had a classic Glenn procedure performed before undergoing a modified Fontan procedure. Two subjects had rate-responsive pacemakers. Fourteen subjects were taking digoxin, 3 were taking diuretics, 2 were taking antiarrhythmic agents, and 7 were taking antiplatelet agents. Pill counts were indicative of excellent compliance with the study medications.

Exercise Studies
Before beginning the study, all subjects underwent a practice exercise test to introduce them to the equipment and to familiarize them with the effort required for a maximal exercise test. Data obtained from the practice test were not included in the study. The exercise tests were performed on a previously calibrated, electronically braked, cycle ergometer (A.I.f. Ergometer, NASA Lyndon B. Johnson Space Center). The seat height was adjusted such that the angle of the knee was 160° when the pedal was at its lowest point. The pedaling rate was kept between 50 and 60 revolutions per minute. The subjects were encouraged to exercise to the point of exhaustion. All subjects were monitored for cardiac arrhythmia for 10 minutes after exercise. The initial workload was 25 W. The workload was increased every 2 minutes on the basis of BSA (10 W for BSA <1 m², 15 W for BSA 1 to 1.5 m², and 20 W for BSA >1.5 m²). Arterial oxygen saturation was measured continuously by use of forehead pulse oximetry (Nellcor Inc N-200). During the exercise test, heart rate, respiratory rate, ECG, and blood pressure were recorded continuously with the use of an Astro-Med MT-95000 Multi-Task Recorder at a paper speed of 5 mm/s. Blood pressure was measured at each workload interval by use of a recorded cuff pressure and Korotkoff sounds at the brachial artery (Narco Biosystems electrosphygmomanometer). A compression cuff of the appropriate size for each subject was used. All blood pressures were measured from the left arm unless a left Blalock-Taussig shunt had been performed previously. Cardiac output was determined by measurement of the effective pulmonary blood flow using the acetylene-helium rebreathing technique.²⁶ A gas mixture containing 0.6% acetylene, 9% helium, and 45% oxygen was used. Minute ventilation, oxygen consumption, carbon dioxide production (Douglas bag), and cardiac output were measured at rest while the subject was seated on the cycle ergometer and at maximal exercise. Gas fractions were determined with a Marquette 1100 Medical Gas Analyzer (mass spectrometer). Expired gas volume was measured by Tissot spirometry. Stroke volume was calculated from cardiac output using the heart rate determined during the rebreathing maneuver. Both cardiac output and stroke volume were indexed to BSA. We assumed that the right atrial mean pressure was 15 mm Hg^{1 5 27} and estimated systemic vascular resistance index from cardiac index and mean arterial blood pressure.

Doppler Echocardiogram Studies
Subjects underwent two-dimensional and Doppler echocardiographic examinations by use of a 128-element phased-array ultrasound system (Acuson) and a variety of transducers appropriate for body size. The ultrasound system has the capability of simultaneous echocardiographic imaging and Doppler interrogation. To evaluate ventricular diastolic function, pulsed- and continuous-wave Doppler recordings of the systemic AV valve inflow and semilunar valve outflow were used to measure the peak velocity during rapid ventricular filling (peak E), peak velocity during atrial contraction (peak A), and when possible, the isovolumic relaxation time.²⁸ The ratio of peak E to A velocities was calculated. All measurements were performed at end inspiration as assessed by a nasal thermistor. All Doppler examinations were recorded at a speed of 100 mm/s. The Doppler measurements were performed on line by tracing the outermost border of the spectral recording.¹²

Statistical Analysis
All variables are expressed as mean±SD. Variables measured while subjects were taking enalapril were compared with variables measured while subjects were taking placebo by use of two-tailed, paired Student's t tests. Echocardiographic measurements were performed by two echocardiographers who were not aware of which study medications the subjects were receiving. Three cardiac cycles were measured and averaged to obtain each AV valve Doppler measurement. Measurements obtained from patients taking placebo were also compared with previously published data from normal control subjects^{12 29} by use of two-tailed, unpaired Student's t tests. A value of P<.05 was considered significant.

We prospectively selected total exercise time and oxygen consumption at maximum exercise as the primary efficacy variables. Setting the type I error () at .05 and using SDs obtained from previously published² and unpublished data from our laboratory, we calculated that 12 to 28 subjects would be necessary to detect a 15% change in these variables with a type II error (ß) of .2 (80% power).

	Results

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Baseline Measurements
Enalapril therapy did not affect the heart rate, respiratory rate, systolic or diastolic blood pressure, arterial oxygen saturation, stroke volume, systemic vascular resistance, minute ventilation, or oxygen consumption measured at rest (Table 1). The calculated systemic vascular resistance was increased compared with that measured in normal control subjects.³⁰

View this table: [in this window] [in a new window]   Table 1. Exercise Data

Exercise Tests
All subjects exercised to the point of exhaustion. At maximum exercise, six subjects were unable to perform the maneuvers necessary to measure cardiac output. None of the subjects developed any arrhythmia or ST-segment abnormalities during exercise or recovery. After taking the placebo for 10 weeks, the subjects were able to increase their cardiac indices slightly more than twofold with maximum exercise (Table 1). Most of this increase in cardiac index was the result of an increase in heart rate, because the stroke volume increased by only 18%. However, the maximum heart rate achieved was only 78% of that predicted.³¹ This chronotropic incompetence has been observed by others.^{2 3 7}

Treatment with enalapril did not affect the heart rate, respiratory rate, systolic or diastolic blood pressure, cardiac index, or the decrease in systemic vascular resistance measured at maximum exercise (Table 1). Compared with values measured while subjects were taking the placebo, the mean percent change in cardiac index from rest to maximum exercise was slightly but significantly decreased in subjects after 10 weeks of enalapril therapy. We were able to obtain adequate blood pressure tracings on both enalapril and placebo at maximal exercise for only eight subjects. These eight subjects showed a normal systolic blood pressure response to exercise.³¹ Enalapril therapy did not affect the total exercise time, total work, or maximum power (Table 1).

Doppler Echocardiographic Studies
Echocardiographic and Doppler studies were performed on all but one of the study subjects. This subject had a rate-responsive ventricular pacemaker and was pacemaker dependent at the time of interrogation. Measurements of isovolumic relaxation time were obtained in eight subjects; the remaining subjects did not have clear simultaneous aortic and mitral valve Doppler tracings, in part because a large distance was often present between the aortic and mitral valves. Compared with normal values,^{12 32} the study subjects taking the placebo showed a decreased E/A ratio and isovolumic relaxation time (Table 2). These findings, which are similar to those reported by Frommelt et al,¹² are consistent with impaired ventricular relaxation. There were no differences in the diastolic filling patterns measured when subjects were taking enalapril compared with placebo (Table 2).

View this table: [in this window] [in a new window]   Table 2. Doppler/Echocardiographic Data

Questionnaire Evaluation
Perceived side effects were relatively frequent but not different when subjects were taking enalapril compared with placebo (Table 3).

View this table: [in this window] [in a new window]   Table 3. Side Effects

	Discussion

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This study evaluated for the first time the efficacy of enalapril therapy in patients who have had a Fontan procedure. The major findings of this randomized, double-blind, placebo-controlled trial are that treatment with enalapril did not affect baseline hemodynamic variables, augment exercise capacity, or alter diastolic function.

All subjects who participated in the present study denied having cardiorespiratory symptoms during their ordinary daily activities. As such, they were in New York Heart Association classification I. In addition, they showed no significant arterial desaturation at maximum exercise. This is in contrast to many other reports, including a study in a similarly well-compensated group of patients.⁴ Certainly the results of the present study should not be extrapolated to patients who have a less-than-ideal surgical outcome.

Despite what appeared to be an excellent functional result, we measured a decreased resting cardiac index and exercise capacity in the study subjects. These findings are consistent with those of other investigators.^{1 2 3 4 5 6 7 8 9} Thus, a discrepancy exists between the patient's assessment of functional capacity (which clearly depends on lifestyle) and objective evaluation of cardiac reserve by measuring response to exercise. Indeed, the oxygen consumptions measured at maximum exercise in the study subjects are similar to those measured in patients with functional classification B circulatory dysfunction.³³ In addition, increased systemic vascular resistance (as measured in the study subjects) is characteristic of patients with decreased functional capacity.

It is not clear why enalapril therapy failed to alter baseline hemodynamic variables or exercise capacity in the present study. It is possible that we did not see a beneficial effect because the renin-angiotensin system was not activated in the study subjects. Kelly et al²⁷ reported normal plasma renin activities in a small group of patients who had undergone a Fontan procedure despite the fact that they were all taking furosemide.

Other studies^{16 34} have shown that plasma renin activity is normal in adult patients with left ventricular dysfunction but no evidence of congestive heart failure. Despite this, enalapril therapy decreased the incidence of heart failure and the rate of hospitalization within 6 weeks of beginning therapy in these patients.²⁵ Furthermore, 6 weeks of treatment with lisinopril resulted in a small but statistically significant increase in oxygen consumption during maximum exercise in a group of asymptomatic patients in whom the plasma renin activity was normal.¹⁶ Interestingly, despite the observed increase in exercise capacity, lisinopril did not alter resting blood pressure or echocardiographic indices of systolic and diastolic function.

These data are suggestive that actions other than inhibition of plasma ACE activity may contribute to the beneficial effects of ACE inhibitors. Other effects of ACE inhibitors include increased bradykinin and prostaglandin concentrations, decreased norepinephrine release, sympathetic withdrawal, and alterations in tissue ACE.³⁵ In particular, venous dilation occurs secondary to smooth muscle relaxation potentiated by the bradykinin system. In postinfarction patients, this results in decreased preload because of venous pooling.^{21 36}

It is possible that enalapril-induced venous dilation could have adversely affected our study subjects. Inasmuch as central venous pressure is the driving force for pulmonary blood flow, cardiac output in the Fontan circulation is dependent on relatively high central venous pressures. A recent study²⁷ showed decreased venous capacitance in patients who had undergone a Fontan procedure and proposed that the increased venous tone may limit mobilization of blood from capacitance vessels during exercise. The increase in cardiac index from rest to maximum exercise was slightly but significantly decreased when subjects were taking enalapril compared with placebo. It is possible that this difference in exercise-induced augmentation of cardiac index is consistent with a further limitation in the ability to mobilize blood from capacitance vessels as a result of venous dilation from enalapril.

Compared with other studies,³⁷ the frequency of side effects in the present study was somewhat high. This may reflect the fact that subjects were asked about each specific side effect at the end of both treatment periods. The proportion of subjects who reported side effects was no higher when they were taking enalapril than when they were taking the placebo.

Study Limitations
This study has several limitations that must be recognized. First, we studied a relatively small number of subjects who were heterogeneous with respect to congenital heart defect and precise type of surgery. However, Driscoll and colleagues² showed no difference in exercise capacity after Fontan procedure between patients with tricuspid atresia and those with other forms of functional single ventricle.

Second, it could be argued that the lack of beneficial effects of enalapril therapy in our study is related to an inadequate dose of this agent. To the best of our knowledge, the only previous studies concerning enalapril treatment in children involved patients with moderate to severe congestive heart failure.^{17 18 19 20} The dose used in the present study (0.2 to 0.3 mg · kg^-1 · d^-1) was comparable or larger than doses used previously. Furthermore, these doses are comparable to doses used in studies demonstrating efficacy in adult patients. For example, the SOLVD investigators^{23 24 25} administered 20 mg of enalapril daily to patients with average weights of 80 kg; this is 0.25 mg · kg^-1 · d^-1. Recently, some investigators have emphasized the need for higher doses of ACE inhibitors to achieve maximal therapeutic benefit, at least in adult patients with severe congestive heart failure.³⁸ We were reluctant to give higher doses of enalapril to asymptomatic subjects because of our concern about side effects. Despite these considerations, we cannot exclude the possibility that higher doses of enalapril might have been beneficial to the study subjects.

Third, a longer treatment time may be necessary to show improvement in exercise capacity. The time period of 10 weeks was chosen because studies in adult patients have shown beneficial effects within 2 to 12 weeks of initiating therapy with ACE inhibitors.^{13 14 15 16} However, it is also known that longer periods of treatment result in attenuation of ventricular dilation and remodeling in patients who have had myocardial infarctions.²¹ Whether long-term administration of ACE inhibitors to patients with a functional single ventricle would affect ventricular remodeling is not known at this time.

Finally, despite the fact that this study failed to show significant beneficial or harmful effects of enalapril in our subjects, the power to say that no difference existed was low. Although we estimated the sample size necessary to detect what we defined as clinically important differences in maximal oxygen consumption and duration of exercise, our SDs were higher than expected, and not all subjects were able to perform the maneuvers necessary to measure maximum oxygen consumption. Thus, real differences may have escaped detection.

Conclusions
This placebo-controlled, double-blind study showed that treatment of well-compensated patients after Fontan procedure with enalapril for 10 weeks failed to alter their abnormal systemic vascular resistance, resting cardiac index, diastolic function, or exercise capacity. These results emphasize the need to continue to explore the pathophysiology of these abnormalities so that therapy can be optimized.

	Acknowledgments

 
The authors gratefully acknowledge support for this project from the VASOTEC Medical School Grants Committee at Merck & Co, Inc, West Point, Pa. In addition, we are indebted to William A. Scott, MD, and David E. Fixler, MD, for their critical reviews of the manuscript, to the personnel at the Cardiovascular Physiology and Space Medicine Laboratory at The University of Texas Southwestern Medical Center at Dallas for their assistance during exercise tests, and to Michelle Kromelis, RPh, of the Pharmacy Department, Childrens Medical Center at Dallas for assistance in preparing, randomizing, and dispensing study drugs.

	Footnotes

 
Reprint requests to Lynn Mahony, MD, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-9063.

Received December 31, 1996; revision received March 24, 1997; accepted April 8, 1997.

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