Tetralogy of Fallot

Patients are often asymptomatic after operative correction of an atrial septal defect (ASD) or tetralogy of Fallot (TF). However, the maximal functional capacity of their hearts relative to that of normal subjects has not been defined. Twelve asymptomatic patients who had ASDs closed and 10 asymptomatic patients who had total correction of tetralogy of Fallot were evaluated by catheterization studies at rest and during mild and intense treadmill exercise. Except for small right ventricular outflow gradients in the tetralogy of Fallot group (2-21 mm Hg), data recorded at rest were normal or nearly so in each subject. However, at a level of upright exercise sufficiently intense to lower pulmonary arterial oxygen saturation to 30%, cardiac output was below that attained by normal subjects (mean, 8.9 -+0.3 liters/min/M2) in seven of 12 ASD patients (mean, 6.6 -0.6 liters/min/m2) and in eight of 10 tetralogy of Fallot patients (mean, 6.1 + 0.3 liters/min/m2). Right ventricular (RV) outflow gradients, measured during upright exercise in six TF patients, increased in each; RV systolic pressures reached levels of 75-106 mm Hg in four of the six patients studied. No outflow gradients were observed in the ASD group. Thus, patients with operative closure of an ASD and normal hemodynamic findings at rest may have impairment of their cardiac output response to intense upright exercise in the absence of residual shunts, arrhythmias, or pulmonary arterial hypertension. Although the cardiac output response in patients with corrected tetralogy of Fallot is consistently reduced, it is remarkably good considering the complicated nature of their defect and operative repair; however, the RV outflow gradient and RV systolic pressure may increase markedly with exercise. The longterm significance of these findings remains to be determined.

below that attained by normal subjects (mean, 8.9 -+-0.3 liters/min/M2) in seven of 12 ASD patients (mean, 6.6 --0.6 liters/min/m2) and in eight of 10 tetralogy of Fallot patients (mean, 6.1 + 0.3 liters/min/m2). Right ventricular (RV) outflow gradients, measured during upright exercise in six TF patients, increased in each; RV systolic pressures reached levels of 75-106 mm Hg in four of the six patients studied. No outflow gradients were observed in the ASD group. Thus, patients with operative closure of an ASD and normal hemodynamic findings at rest may have impairment of their cardiac output response to intense upright exercise in the absence of residual shunts, arrhythmias, or pulmonary arterial hypertension. Although the cardiac output response in patients with corrected tetralogy of Fallot is consistently reduced, it is remarkably good considering the complicated nature of their defect and operative repair; however, the RV outflow gradient and RV systolic pressure may increase markedly with exercise. The longterm significance of these findings remains to be determined.

Additional Indexing Words: Asymptomatic
Cardiac output Right ventricular pressure gradient OVER THE PAST decade, several follow-up reports have indicated that operative correction of an atrial septal defect (ASD) or the tetralogy of Fallot usually produces considerable symptomatic and hemodynamic improvement. [1][2][3][4][5][6][7][8][9][10][11][12][13] In these previous studies, however, hemodynamic evaluations were performed with the patients either at rest or during only mild supine exercise. Under these conditions aberrations of cardiac function may go unrecognized despite marked reductions of the maximal pumping capacity of the heart as assessed during intense exercise.14 Moreover, circulatory responses may differ considerably when exercise is performed in the supine and upright positions.15 To evaluate the pumping performance of the heart under exercise stresses commonly experienced during normal activities, the circulatory responses to both mild and intense exercise performed in the upright position were studied in 12 asymptomatic patients after closure of an atrial septal defect, and in 10 asymptomatic patients in whom complete operative repair of tetralogy of Fallot had been carried out.

Methods
Twelve patients, nine women and three men aged 14 to 56 years, were studied 6-15 months following operative closure of an uncomplicated secundum ASD. Preoperatively, many of the patients complained of exertional dyspnea, easy fatiguability, and frequent palpitations; they were in functional classes I-III (New York Heart Association). Postoperatively, all patients were asymptomatic and in functional class I. The 10 patients with tetralogy of Fallot, four women and six men, ranging in age from 12 to 36 years, were evaluated 6 months to 4 years after operative correction. All patients were in either functional class II or III before operation with exertional dyspnea, fatigue, and, in most cases, cyanosis at rest. Postoperatively, all patients were completely free of symptoms (functional class I). Four of the patients (S.C., P.G., E.M., and M.C.) had functioning subelavian-pulmonary arterial anastomoses that were closed at the time of total correction. One of these patients (E.M.) and another patient without a prior shunt operation (L.S.) were acyanotic at rest and during most activities before operation. Five patients (L.K., L.S., M.C., L.S., and H.K.) had a loud murmur of pulmonic regurgitation after operation, due to either excision of the valve or extensive operative repair of the right ventricular outflow tract. Several factors affected selection of patients for study: patients had to be asymptomatic postoperatively and in normal sinus rhythm; they had to be at least 12 years of age; and they (with parental consent if the patient was less than 21 years of age) had to be willing to participate in the study after the procedure was explained to them in detail.
Each patient underwent routine postoperative cardiac catheterization followed immediately by treadmill exercise. During the routine catheterization performed at rest in the supine position, the pulmonic-to-systemic flow (Qp/Qs) and resistance (Rp/Rs) ratios were calculated. After the routine catheterization was completed, the patients were taken to the exercise laboratory. Exercise was performed on a motor-driven treadmill at varying speeds and grades. Total body oxygen uptake (V02) was recorded by means of a continuous flow system utilizing a paramagnetic oxygen analyzer,14 and cardiac output was measured by the Fick principle. Mixed venous blood was obtained by sampling through a catheter previously introduced into the pulmonary artery, and arterial blood was withdrawn through a short Teflon catheter inserted percutaneously into the brachial artery. Arterial and mixed venous oxvgen contents were estimated by the method of Van Slyke and Neill.16 Svstemic and pulmonary arterial pressures were recorded with 23Db Statham pressure transducers with zero pressure set 10 cm below the stemal angle and rechecked at each exercise intensity before recordings were taken. In eight ASD patients and six tetralocy patients a no. 8 double-lumen catheter was employed for the simultaneous recording of right ventricular and pulmonary arterial pressures. Measurements were obtained at rest in the sitting position and in the fifth minute of a mild level of treadmill exercise. The exercise was then increased with no intervening period of rest to a level that had been determined at previous trials to produce exhaustion in 53l-6 min (maximal exercise). Measurements were again obtained in the fifth minute of exercise. The reliability of this method for measuring cardiac output under these conditions of exercise has been documented previously. '4 Comparison between the ASD and tetralogy patients with a group of 16 normal subjects (ages 19-44 years) previously evaluated in our laboratory was made by plotting the cardiac index against the pulmonary arterial (PA) 02 saturation. This technic has been shown to provide a sensitive measure of cardiac function during strenuous upright exercise.14 A group of 20 patients in functional class II or III with impaired cardiac performance due to valvular or primary myocardial disease was also included for comparison.14 The cardiac index at a PAO2 saturation of 30%14 was obtained from the observed values by either interpolation or extrapolation.
In separate studies of seven of the ASD patients, the 02 uptake during maximal exercise (maximal VO2) was determined both before and after operation. Maximal V02 was also measured in a group of eight unoperated patients with tetralogy of Fallot (three were patients who subsequently had hemodynamic studies after operation) and in 11 patients after total correction (10 of the 11 patients were studied hemodynamically). Results are expressed as the mean + SEM. Data were analyzed statistically using Student's paired or unpaired t test, where applicable.

Results
Atrial Septal Defect Pre-and Postoperative Hemodynamics during Supine Rest The hemodynamic data obtained at rest are summarized in table 1. Preoperatively, all patients had significant left-to-right shunts at the atrial level. Pulmonic-to-systemic flow ratios ranged from 1.6/1 to 3.0/1. Pulmonary arterial pressure was slightly increased (systolic above 40 mm Hg) in four patients, and markedly elevated in one (systolic = 90 mm Hg, E.W.). Cardiac index at rest was either normal or slightly diminished. Right ventricular end-diastolic and mean right atrial pressures were mildly elevated (over 6 mm Hg) in seven patients before operation. All but one patient had a normal left ventricular end-diastolic pressure and no clinical evidence of left ventricular failure. The one exception was a patient (L.T.) in overt right and left heart failure several months before operation with marked elevation of atrial and ventricular enddiastolic pressures. The patient improved markedly on a vigorous program of diuretics and salt restriction, and follow-up catheterization (shown in table 1) showed only a slight increase in right ventricular end-diastolic pressure.
Postoperative catheterization demonstrated the absence of any shunt. Pulmonary arterial pressures at rest were all within the normal range. Slight elevations in mean right atrial pressure were present in two patients, and in right ventricular end-diastolic pressure in five patients. Mean pulmonary capillary wedge pressure was normal in 11 patients and borderline high in one (J.G.). Abbreviations: BSA = body surface area; I = preoperative evaluation; II = postoperative evaluation; CI = cardiac index; RAP = mean right atrial pressure; LAP = mean left atrial pressure; LVP = left ventricular systolic and end-diastolic pressure; RVP = right ventricular systolic and end-diastolic pressure; Qp/Qs = ratio of pulmonary-to-systemic blood flow; Rp/Rs = ratio of pulmonary vascular resistance to systemic vascular resistance.

Postoperative Studies during Upright Exercise
The cardiac output response to the intense level of treadmill exercise was below the normal range in seven of the 12 patients with closed atrial septal defects (table 2, fig. 1). The low cardiac output during exercise was due primarily to an inadequate augmentation in stroke volume. When the cardiac indices achieved at a PAO2 saturation of 30% were compared to those of normal subjects ( fig. 2), the average cardiac index, 6.6 + 0.6 liters/min/m2, in the 12 patients with closed atrial septal defects was significantly lower than the average of 8.9 0.3 liters/min/m2 in the group of 16  thus, four of the seven subjects with a reduced cardiac output response to exercise were under 34 years of age. Systemic arterial 02 saturations remained unchanged from rest to maximal exercise, averaging 97% at both times.
In all but one patient there was a modest diminution in cardiac diameter when the pre-and postoperative chest X-rays were compared. However, there was no significant difference in these changes or in the cardiac diameters between the five patients with a normal cardiac output response to exercise postoperatively and the seven patients with an abnormal response. Similarly, the routine pre-and postoperative electrocardiograms were of no help in predicting whether the exercise response would be normal or abnormal.  Abbreviations: Q02/m2 = oxygen uptake/m2; CI = cardiac index; SVI = stroke volume index; A-V 02 diff = arterial-venous oxygen difference; PAO2 sat = % pulmonary arterial oxygen saturation; CI at 30% = cardiac index at pulmonary arterial oxygen saturation of 30%r7 (obtained by interpolation); PAP = mean pulmonary arterial pressures; RYP = right ventricular systolic pressure; R = rest; E' = mild exercise: E2 = intense exercise.
Mildly abnormal increases in mean pulmonary arterial pressures occurred in three of the ASD patients during intense exercise ( fig. 5). Two of these subjects had pulmonary hypertension during routine catheterization preoperatively (E .H., E.W.). The third patient (L.T.) did not have pulmonary hypertension but, as previously mentioned, did have clinical evidence of left ventricular decompensation and a high left ventricular enddiastolic pressure at an earlier preoperative catheterization study.
In eight patients in whom a double-lumen catheter was used, no systolic gradients between the right ventricle and pulmonary artery were observed during the exercise studies.

Tetralogy of Fallot
Pre-and Postoperative Hemodynamics during Supine Rest Before total correction, all but two of the patients with tetralogy of Fallot had an abnormally low arterial 02 saturation with a corresponding increase Circulation, Volume XLVII, May 1973 POST OP ASD ents between the right ventricle and main pulmonary artery were present at rest in the supine position in all patients (table 3). The resting cardiac index was within the normal range, and there was a slight increase in the right ventricular end-diastolic pressure in all but one subject. Arterial 02 saturations were normal, and hemoglobin concentrations were not elevated.

Postoperative Studies during Upright Exercise
The cardiac output response to intense exercise fell just below the normal range in nine of the 10 patients with total correction of tetralogy of Fallot. As with the patients with an atrial septal defect, the d area depicts the range of performance in a group of impairment in cardiac output was due primarily to I subjects.
an inadequate stroke volume response to exercise. Although the patient with the lowest cardiac output moglobin concentration (table 3) Cardiac indices at a pulmonary arterial (PA) 02 saturation of 30% in a group of normal subjects, a group of patients with congestive heart failure (CHF) due to valvular or primary myocardial disease in functional classes II or III, patients with total correction of tetralogy of Fallot, and patients with closed atrial septal defects. Maximum oxygen uptake (V02) in seven patients before and after operative closure of an atrial septal defect.
this malformation, maximal V02 averaged 18.8+ 2.4 ml/min/kg and 28.3 + 1.8 ml/min/kg, respectively, a difference of 51% (P < 0.005). In three patients who had both pre-and postoperative determinations, maximal V02 increased from mean 20.3 + 5.4 to 27.3 + 4.8 ml/min/kg (P < 0.02). In contrast to the ASD patients, systemic arterial 02 saturation decreased in the TF patients from an average value of 96.7 + 0.8% at rest to 93.2 + 1.2% during maximal exercise (P<0.025). The arterial 02 saturation during intense exercise was significantly lower in the tetralogy patients than in the ASD patients (P < 0.05).
Mean pulmonary arterial pressure at rest and during exercise was normal in all of the tetralogy    Relatior oxygen tense tr patients in contrast to only 45.0 ± 2.8 in the ASD patients (P < 0.005). The elevated right ventricular systolic pressures in the tetralogy patients were due to an increase in the gradient from right ventricle to pulmonary artery from a mean value of 17+2.5 mm Hg at rest to 28.7 + 5.7 mm Hg during mild exercise, and to 41.8 + 9.5 mm Hg during intense exercise. An illustration of the pressures recorded from a double-lumen catheter in one of the patients is shown in figure 9.   Abbreviations: V02/m2 = oxygen uptake/'m2; Cl = cardiac index; SVI = stroke volume index; A-V 02 diff = arterial-venous oxygen difference; PAO2 sat = % pulmonary arterial oxygen saturation; CI at 30% = cardiac index at pulmonary arterial oxygen saturation of 30% (obtained by interpolation). PAP = mean pulmonary arterial pressures; RVP = right ventricular systolic pressure; RV-PA gradient = right ventricle-to-pulmonary artery peak systolic pressure; R = rest; El = mild exercise; E2 = intense exercise.
Thus, the cardiac output response to intense treadmill exercise was below the normal range in seven of the 12 patients with closed atrial septal defects. Five of the seven patients had normal hemodynamic function at rest; the sixth had only minimal elevations of right atrial mean and right ventricular end-diastolic pressures, and the seventh had a borderline-low cardiac index. Of interest, the patient with the most impaired cardiac response to intense exercise (F.B.) was only 23 years of age, was asymptomatic and in normal sinus rhythm, and at cardiac catheterization had normal right heart pressures and a cardiac index that was only minimally depressed (table 5). Based on these routine assessments, therefore, his markedly abnormal response to intense exercise would have been unsuspected. Hence, the presence or absence of a defect in the pumping capacity of the heart cannot be predicted in ASD patients on the basis of symptoms or routine catheterization studies. In addition, neither an abnormal rhythm nor an excessive increase in pulmonary arterial pressure could be evoked to explain the abnormal cardiac output response to intense exercise manifest by some of the patients following closure of the ASD. Therefore it would appear that the contractile response during exercise or the compliance characteristics of the ventricular myocardium is abnormal in these subjects.
Previous studies have suggested that abnormal hemodynamics at rest or during supine exercise occur commonly in older subjects following repair of an atrial septal defect.4' 7However, our findings demonstrate that abnormal cardiac function, as assessed in the present study, does not correlate with age in asymptomatic patients who have had atrial septal defects closed after 11 years of age (fig. 3); thus, subjects in their early and mid-20s may m1ES 1073 manifest as low a cardiac output response to intense exercise as older individuals. Whether normal myocardial function is preserved more consistently in patients having their defects closed at a younger age is unknown.
In the patients with tetralogy of Fallot, two rather interesting hemodynamic abnormalities were observed after complete repair. First, although the cardiac output response to intense upright exercise was unequivocally normal in only one of the 10 patients, the response of all but one of the remaining patients was remarkably good, considering the complicated anatomic deformity present preoperatively and the extensive operative procedures employed. Moreover, the cardiac output response of the patient who had the lowest output during intense exercise (M.C.) was no worse than that of the patient displaying the lowest output response following repair of an atrial septal defect (K.G.). Indeed, the mean cardiac index achieved at a pulmonary arterial oxygen saturation of 30% was similar in the postoperative tetralogy and atrial septal defect groups ( fig. 2). On the other hand, the range of cardiac output responses of the ASD patients was greater, and several ASD patients had a cardiac output response in the upper limits of normal; this was not seen in any of the patients with tetralogy of Fallot.
A second abnormal response to intense upright exercise observed in the postoperative tetralogy patients was the development of sizeable gradients across the right ventricular outflow tract, often leading to markedly elevated right ventricular systolic pressures. In most previous studies in which the hemodynamics following operative repair of MILD EXERCISE INTENSE EXERCISE Figure 9 Simultaneous right ventricular and pulmonary arterial pressure recordings in patient E.M. at supine and sitting rest and during mild and intense exercise. The level of intense exercise used in this recording was less than that employed in the hemodynamic study recorded in table 4. The apparent baseline shift seen during intense exercise was due to respiratory variation.  tetralogy of Fallot were evaluated, the results were considered to be excellent if peak systolic gradients across the right ventricular outflow tract were less than 15-20 mm Hg, measured at rest in the supine position.8 10, 13 It was therefore interesting to find that, despite the absence of what would be considered important gradients across the right ventricular outflow tract during routine right heart catheterization, patients developed large gradients during both mild and intense upright exercise with right ventricular systolic pressure reaching levels of 75-106 mm Hg in four of the six patients so evaluated. The patient who had a right ventricular systolic pressure during intense upright exercise of 106 mm Hg had a right ventricular-to-pulmonary artery gradient during rest in the supine position of only 15 mm Hg. The patients with tetralogy of Fallot studied in this investigation were evaluated 6 months to 4 years after correction of their congenital abnormality, and it is possible that the remarkable increase in right ventricular outflow gradient during exercise will be resolved in time. Although there is some information in the literature relating to this point, the evidence is conflicting and pertains only to observations with patients at rest. One report noted that patients studied 6 years after operation (5 years after their first postoperative investigation) did not manifest significant change in the gradient,9 while another indicated that postoperative gradients measured 4-8 weeks postoperatively may be unchanged. increased, or decreased when catheterization is repeated at a later time. 8 There has been considerable speculation as to the adequacy of the pulmonary vascular bed in patients with tetralogy of Fallot.9' 17, 18 None of the 10 patients studied in the present investigation, however, developed pulmonary hypertension during intense exercise. Although we limited our studies to postoperative patients who were asymptomatic, these results attest to the functional competence in such patients of both the left ventricle and the pulmonary vascular bed. The presence of an abnormal reduction in arterial saturation with intense exercise, however, in the absence of shunt or pulmonary hypertension suggests that some abnormality of pulmonary blood flow distribution may be present in the postoperative state.
In conclusion, patients with operatively closed atrial septal defects who have essentially normal routine catheterization studies may have residual reduction of their cardiac output response to intense upright exercise in the absence of residual shunts, arrhythmias, or pulmonary arterial hypertension, a finding which suggests that myocardial function is impaired. Patients with operatively corrected tetralogy of Fallot do not have normal cardiac output responses to exercise. Their output response is remarkably good, however, when the complex nature of their defect and the extensive surgical procedures employed in its correction are considered. Nevertheless, these patients often will develop a large gradient across the right ventricular outflow tract resulting in considerable elevations of right ventricular systolic pressure during moderate and intense upright exercise. The long-term significance of the impaired cardiac output response to exercise in patients with atrial septal defects, and of the pressure stress on the right ventricle in patients with tetralogy of Fallot remains to be determined.