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Noninvasive assessment of hemodynamic responses to exercise in pulmonary regurgitation after operations to correct pulmonary outflow obstruction
CONGENITAL
HEART DISEASE
NoninvasiveAssessment of HemodynamicResponses to Exercise in Pulmonary Regurgitation After Operations to Correct Pulmonary Outflow Obstruction GERALD R. MARX,
MD, RICHARD and STANLEY
W. HICKS, PhD, HUGH D. ALLEN, MD, J. GOLDBERG, MD
The influence of pulmonary regurgitation (PR) on exercise capacity is unknown. The hemodynamic responses to exercise in postoperative patients with PR was determined using Doppler-measured regurgitant fraction to indicate PR severity. Maximal heart rate, oxygen consumption and workload capacity were measured during upright cycle ergometry. Cardiac output was measured at rest and during submaximal supine cycle ergometry by pulsed Doppler echocardiography. Oxygen consumption was simultaneously measured and exercise factor was calculated as the change in cardiac output per change in oxygen consumption. Twenty-seven patients were compared with 17 age-, size- and sexmatched control subjects. Patients with PR had larger right ventricles (p 10.001), lower heart
rate response (p _<0.05), lower maximal oxygen consumption (p S0.005) and lower workloads (p 10.005) when compared with normal control subjects during maximal exercise testing. Exercise factor was the same for both groups. Patients with PR were then separated into mild, moderate and severe groups. Patients with mild PR had a normal response to exercise. However, patients with moderate and severe PR had lower maximal oxygen consumptions and maximal workloads than control subjects. Control, mild and moderate PR groups had similar exercise factors. Patients with severe PR had markedly low cardiac output responses. PR is associated with reduced exercise capability, which is related to the severity of the PR. (Am J Cardiol 1988;81:595-801)
P
ulmonary regurgitation (PR) is a common finding after surgery for critical pulmonary stenosis, tetralogy of Fallot or other defects that may require placement of a nonvalved conduit from the right ventricle to pulmonary arteries. Many of these patients have done well, but the influence of PR on exercise capacity is unknown. Inability to quantitate PR has impeded its investigati0n.l Pulsed Doppler echocardiography has recently been shown to accurately measure regurgitant fraction.z Magnitude of Doppler regurgitant frac-
tion has compared well to clinical determinants of disease severityn2 This study was designed to determine the hemodynamic responses to exercise in postoperative patients with PR using Doppler-measured regurgitant fraction to indicate severity of the PR.
Methods
From the Department of Pediatrics (Cardiology], University of Arizona, Health Sciences Center, Tucson, Arizona. This study was supported by a grant-in-aid from the American Heart Association, Arizona Affiliate. Manuscript received August 10, 1987; revised manuscript received and, accepted October 28,1987. Address for reprints: Gerald R. Marx, MD, Department of Pediatrics, University of Arizona, Health Sciences Center, Tucson, Arizona 85724. 595
Patient selection: Thirty-one patients with postoperative PR were chosen for study. Patients were at least 6 years of age and able to perform rigorous exercise testing. Patients were excluded if they had Doppler echocardiographic or catheterization findings of residual shunts, aortic, mitral or tricuspid regurgitation, stenosis or some combination of these. Patients with right ventricular outflow tract gradients >20 mm Hg, excluding peripheral stenosis, also were excluded. All patients had to be in sinus rhythm during exercise. An age- and sex-matched control group was also studied. Consent was obtained according to the guidelines of the University of Arizona Human Subjects Committee under an approved protocol.
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Doppler echocardiography technique: Standard &dimensional pulsed and continuous-wave Doppler echocardiograms (BioSound ND 2600) were performed at rest on all subjects. M-mode scans for measurement of cavity size and wall thickness were obtained with cursor alignment guided by &dimensional imaging. Two-dimensional images of the left and right ventricles were obtained from a short-axis parasternal plane at the level of the mitral valve chordae tendinae. The M-mode cursor was placed through the right and left ventricles perpendicular to the ventricular septum. The site of ventricular septal patch placement was avoided in patients who had surgical ventricular septal defect closure. Right and left ventricular enddiastolic dimensions, left ventricular end-systolic dimensions and left ventricular percent fractional shortening were calculated according to standard guidelines of the American Society of Echocardiography. All valves and right ventricular outflow tracts were interrogated by standard Doppler echocardiographic techniques for stenosis and regurgitation4r5 Regurgitation was considered insignificant if retrograde velocities were mapped only in a small area immediately proximal to the valves4T5 Pulmonary regurgitant fraction was measured by a previously reported pulsed Doppler techniquen2 Pul-
FIGURE 1. Pulsed Doppler tracings from the pulmonary outflow tract in 2 patients with pulmonary regurgitation (A and B). Anterograde, below baseline, and regurgitant, above baseline, velocities are sampled from the same flow area. Bdemonstrates baseline shift allowing simultaneous velocity measurement without signal aliasing.
monary forward and regurgitant velocities were obtained proximal to the bifurcation in the midpulmonary artery, right ventricular outflow tract patch or conduit. In some patients the conduit or patch was poorly visualized, and the Doppler sample volume was placed in the area of anticipated regurgitant flow. The sample volume was then maneuvered until both simultaneous negative velocities of anterograde flow and positive velocities of retrograde flow with 130% velocity spread were obtained (Figure 1). Modal positive and negative Doppler velocities were separately digitized over 3 beats using a dedicated software program, digitizing pad and microcomputer.4 The program determined positive and negative mean velocity by dividing the area under the time velocity curve by distance along the time axis. Percent pulmonary regurgitation was derived as regurgitant mean velocity/forward mean velocity X 100. Ascending aortic velocities were measured from the suprasternal notch both at rest and during 50% supine submaximal exercise for determination of average aortic acceleration and cardiac output6 At rest, a 3.5-MHz transducer was used to image and perform Doppler velocity interrogation. A smaller 2.25-MHz right angle transducer was used during exercise.6 Average aortic acceleration, averaged over 3 beats, was calculated by a previously reported method as the peak velocity divided by the time to reach peak velocity.7tE Aortic diameter was measured from the suprasternal notch at the sample volume site above the sinuses of Valsalva.g Maximal aortic diameter measured at rest was used for flow calculation during submaximal exercise. Cardiac output (ml/min) was calculated as4Jj mean velocity (cm/min) X cross-sectional area (cm2). Respiratory measurements: Expired respiratory gasses were continuously collected using a WilmoreCostill 3-way valve system.lO Fractional concentrations of oxygen and carbon dioxide were analyzed every 30 seconds using Beckman OM-11 and Godart Capnograph rapid gas analyzerslO Minute ventilation was measured using a Parkinson-Cowan CD-4 gas flow meter.lO These measurements allowed calculation of oxygen consumption, carbon dioxide production and respiratory exchange ratio. Exercise protocol: All subjects performed a graded maximal exercise test on a supine cycle ergometer (Spectrum Mode III) according to a standard protoc01.l~ Maximal exercise capacity was also determined with patients pedaling an upright cycle in 34 of 44 subjects using the same protocol. (Ten young subjects were unable to reach the pedals.] This upright test allowed calculation of relative maximal endurance index, a measure of work performed indexed for size, sex and age.ll The technician supervising the maximal exercise testing was blinded to patient’s medical history and magnitude of PR. An additional supine cycle exercise test was performed with the workload set to a level that corresponded to 50% of each individual’s previously determined maximal oxygen consumption6 Oxygen consumptions and Doppler cardiac outputs were mea-
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TABLE
I
Individual
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Control
Diag
Patch Cond.
PPS
RV/Ao
PR (%)
1 0.8 1 1 1 1.2 1.3 1.3 1.2 1.3 1.6 1.3 1.3 1.4 1.4 1.4 1.4 1.2 0.2
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7 9 12 12 19 8 13 14 16 12 4
0.7 1 1.3 1.1 1.5 0.7 1.4 1 1.6 1.1 0.3
TF TF TF TF TF PS PS PS PS
16 12 17 27 15 10 18 7 13 1
9 9 IO 15 17 25 7 a 9 13 12 6
0.7 0.8 1.2 1.4 1.4 1.5 0.9 i 0.9 1.6 1.1 0.3
TF TF TF TF TF TF DORV PS PS PS
20 6 3 22 26 21 30 11
10 11 11 12 7 7 9 11 10 2
1 0.9 1.1 1.3 0.8 0.9 1.1 0.9 1 0.2
TF TF,PA TF TF TGAt TA TA PS
Pt 62 64 63 66 65 61 43 45 41 47 52 44 46 42 48 51 53
Mean SD Mild
29 23 25 19 8 9 14 24 4
Mean SD Moderate
Mean SD Severe
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Data RVEDd
Group
JOURNAL
Age W
BSA On*)
8 a 9 IO IO IO 13 13 14 14 14 14 14 14 14 15 16 12 3
0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0
38 37 33 34 45
23 35 7.4
P P P P P 0 C 0 P 0
0 0 0 0 0 R&LPA RPA 0 0 0
33 39 48
RPA R&LPA
58 100
R&LPA R&LPA
75 64
40 55 60 46 32 44 10.1
74 18.7
LVEDd
R Act FS (%)
(mm/m*)
Ex Act
(cm/s*)
22 21 17 18 *
40 48 43 45
30 32 33 38
1,558 883 840 1,556
3,189 2,036 2,071 2,269
13 11 13 12 12 12 9 13 14 13 12 13 14 3.6
35 35 33 40 34 31 34 28 34 31 36 31 36 5.6
29 33 35 42 33 40 36 31 36 32 36 34 35 3.6
1,045 1,187 2,340 1,073 967 1,489 1,546 1,177 1,603 1,064 2,066 1,524 1,370 421
1,813 2,854 3,575 2,659 2,048 2,037 2,645 2,031 2,317 2,083 2,152 2,234 2,376 484
10 36 13 30 36 16 30 13 15 22 10.7
23 17 18 29 20 21 13 21 ia 20 4.4
47 44 32 32 30 34 32 40 28 35 6.6
39 27 36 34 33 40 38 38 36 36 4
1,516 1,195
4,344 1,739
661
1,012
626 1,955 1,603 1,371 1,275 490
4,548 2,855 2,482 4,333 3,045 1,402
48 43 44 44 51 53 44 51 46 54 48 4.2
43 34 17 25 26 21 33 20 27 18 26 8.2
40 35 32 26 22 24 36 35 34 25 31 6.1
29 32 29 38 32 31 37 29 32 25 31 3.9
1,254 935 757 1,151 865
2,422 2,429 1,315 1,477 3,865
1,266 1,881 1,273 1,173 349
2,863 4,457 3,158 2,748 1,084
83 80 81 82 68 72 76 70 77 5.9
30 41 38 25 44 34 34 38 36 6.1
34 36 34 38 40 46 31 30 36 5.8
32 38 37 34 28 30 29 44 34 5.4
1,243 1,674 964 868 970 971 948 1,556 1,149 309
2,539 1,707 816 2,385 1,943 3,106 1,436 2,390 2,040 718
MHR (bpm)
MVOs
RMEI
EF
165 200 ia0 150 180 150 195 198 190 180
30.2 45.2 43.5 27 35.4 24.8 44.2 45.8 45.5 40.5
111 193 192 75 150 38 150 210 241 174
5.9 a.3 6.8 6.5
192 192 195 195
43.1 30.4 38 48.6
193 150 168 191
170 182 17
47.6 39 7.9
167 160 52
180 168 190
38.8 25.8 27.2 39.6
142 82 135 158
182 160 188 178 12
33.1 43.7 47.5 37 8.2
134 187 238 154 49
160 190 155 160 186
28.1 25.1 25.1 20.1 38.4
37 84 84 53 137
ia0 172 15
28.6 28 6.1
86 80 34
160 140 152 160
29 17.8 24.7 22.1
40 -2 -18 98
172 148 155 11
27.8 30.8 25 4.8
50 89 43 47
8.2 6.7 5.3 6.9 5 5.7 5.3 6.9 6.5 6.2 5.7 4.9 6.3 1 10.3 5.9 6.3 5.5 5.7 5.3 6.3 6.5 1.7 8.3 6.1 6.2 9.8 8.7
6.8 7.9 7.4 7.6 1.2 4.7 4.7 3.8 3.4 3.7 5.8 4.4 2.6 4 i
bpm = beats/min; C = control; Cond = conduit; Diag = diagnosis; DORV = double-outlet right ventricle; EF = exercise factor; Ex Act = exercise mean acceleration; FS = fractional shortening: LPA = left pulmonary artery; LVEDd = left ventricular end-diastolic dimension; MHR = maximal heart rate: MV02 = maximal oxygen consumption; PA = pulmonary atresia; PPS = peripheral pulmonic stenosis; PR = pulmonary regurgitation; PS = pulmonic stenosis; R Act = resting mean acceleration: RMEI = relative maximal endurance index: RPA = right pulmonary artery: RV/Ao = right ventricularlaortic pressure ratio: RVEDd = right ventricular end-diastolic dimension; SD = standard deviation; TA = truncus arteriosus; TF = tetralogy of Fallot; TGA = transportation of the great vessels; VSD = ventricular septal defect. * = no echocardiographic data available; t = TGA, VSD and P.S.
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sured at rest and during the fifth minute of exercise at the predetermined workload. Exercise factor was calculated as the change in cardiac output between rest and exercise, divided by the simultaneous change in oxygen consumption.6 Statistical analysis: Grouped data for control and all PR subjects were compared using the unpaired Student t test. Data were then separated into control, mild, moderate and severe categories by magnitude of PR, according to a prior classification2: PR fraction <40% (mild), 40 to 60% (moderate) and >60% (severe). Statistical differences between groups were determined by analysis of variance and Scheffe post-hoc analyses. A p value of <0.05 was considered significant. Group data were expressed as mean and standard deviation,
Results Control group versus entire pulmonary regurgitation group: Seventeen control subjects and 31 patients with PR were enrolled in the study. Four patients with PR did not meet minimal requirements for study and were excluded from the protocol, leaving 27 PR patients for data analysis [Table I]. Control and PR groups were not significantly different in age, sex distribution and body surface area. Left ventricular enddiastolic dimension, percent fractional shortening and resting and exercise Doppler average aortic acceleration were not significantly different for both groups (Figure 2). The PR group had significantly larger right ventricles than control subjects (p 10.001, Figure 2). The PR group also had significantly lower maximal heart rate response (p 10.05), lower maximal oxygen consumption (p lO.005) and lower workload performed during maximal exercise testing (p LO.005, Figure 3). Exercise factor was not significantly different for both groups [Figure 3). Control group versus mild, moderate and severe groups: Population, age and size: Data were then analyzed by separating subjects into mild, moderate and severe PR groups [Table I). The control group consist-
ed of 17 subjects (mean age 12 years), mild group 9 patients (mean age 12 years), moderate group 10 patients [mean age 12 years] and severe group 8 patients (mean age 10 years]. Age and size were not significantly different for all 4 groups. Diagnoses in mild group: Five patients in the mild PR group had repair of tetralogy of Fallot. None required a transanular patch or conduit. Four patient had isolated valvar pulmonic stenosis. Three had surgical pulmonary valvotomies, and 1 patient underwent balloon dilation valvuloplasty. None of the 9 patients had significant peripheral pulmonic stenosis. Diagnoses in moderate group: Six patients in the moderate PR group had repaired tetralogy of Fallot; 5 required a transanular patch. The 1 patient without a patch had significant bilateral peripheral pulmonic stenosis. Three patients had pulmonary valvotomies in the newborn period for critical valvar pulmonic stenosis; 2 required a second operation. One had a repeat valvotomy, and the other placement of a transanular patch. One patient had a nonvalved conduit after Damas-Stansel-Kaye repair for double-outlet right ventricle. Diagnoses in severe group: Seven patients in the severe PR group had nonvalve conduits. Four of the 7 underwent recent cardiac catheterizations and all 4 had significant peripheral pulmonic stenosis. The eighth patient had transanular patch repair for tetralogy of Fallot and has not undergone postoperative catheterization. Baseline data: Magnitude of regurgitation: Mean PR fraction was 22% (lo.7 standard deviation [SD]] for the mild group; 48% (4.2 SD] for the moderate group; and 77% (5.9 SD) for the severe group, [p _
22s 2ca1
FIGURE 2. Echocardiographic Doppler data comparing control group versus entire pulmonary regurgitation group. Left ventricular end-diastolic dimension (LVEDd), left ventricular percent fractional shortening (%FS) and Doppler aortic (Ao) average acceleration at rest and exercise was similar for both groups. Patients had significantly larger right ventricular end-diastolic dimensions (RVEDd).
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FIGURE 3. Exercise hemodynamics comparing control group with entire pulmonary regurgitation group. During maximal upright cycle ergometry patients had lower maximal heart rate (Max HR), oxygen consumption (maxir0,) and workload (RMEI) than the control group. Exercise factor measured during submaximal exercise was not significantly different.
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74% (18.7 SD] for the severe group (n = 4), (p 50.001). The severe group was significantly different from both mild and moderate PR groups; the latter 2 groups were not significantly different from each other. M-mode data: Mean left ventricular end-diastolic dimension indexed for body surface area and percent fractional shortening were not significantly different for the 4 groups [Figure 41. Mean right ventricular enddiastolic dimension was 14 mm/m2 (3.6 SD] for the control group: 20 mm/m2 (4.4 SD) for the mild group; 26 mm/m2 (8.2 SD) for the moderate group; and 36 mm/m2 (6.1 SD] for the severe group (p 50.001). All groups were significantly different from each other [Figure 4). Aortic average acceleration: Average resting and exercise aortic accelerations were not significantly different for all 4 groups (Figure 4). Exercise data: Not all patients were tall enough to reach the pedals of the upright cycle ergometer. Comparison of maximal upright cycle testing data was made in 15 patients in the control group, 7 in the mild, 6 in the moderate and 6 in the severe PR groups. Maximal heart rate: Mean maximal heart rate attained for the control group was 182 beats/min (17 SD); 178 (12 SD] for the mild group, 172 (15 SD] for the moderate group and 155 (11 SD) for the severe PR group (p 10.01). Only the control and severe groups were significantly different from each other (Figure 5). Maximal oxygen consumption: Mean maximal oxygen consumption was 39 ml/min/kg (7.9 SD) for the control group, 37 (8.2 SD) for the mild group, 28 (6.1 SD] for the moderate group and 25 (4.8 SD] for the severe PR group (p 10.005). Both the moderate and severe groups were significantly different from control. The severe group was also significantly different from the mild group (Figure 51. Relative maximal endurance index: Mean relative maximal endurance index for the control group was 160 kg-m/min/mz (52 SD], 154 (49 SD) for the mild group, 80 (34 SD] for the moderate and 43 (47 SD] for the severe group (p 50.001). Both moderate and severe PR groups were significantly different from the control group (Figure 5). Exercise factor: Mean exercise factor for the control group was 6.3 (1.0 SD], 6.5 (1.7) for the mild group, 7.6 (1.21 for the moderate group and 4.1 (1.0 SD] for the severe PR group (p 10.001). The severe group was significantly different from the other 3 groups (Figure 5).
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erate PR groups had similar increases in cardiac output per increase in oxygen consumption during submaximal exercise. However, some patients in the severe group had a markedly low cardiac output response. Patients with more severe PR had increased M-mode right ventricular end-diastolic dimensions. Right ventricular systolic pressures were increased at catheterization. The most severe PR occurred in patients who had pulmonary artery stenosis distal to their patches or nonvalved conduits. Results of this study are consistent with those of others who have reported increased right ventricular size,12 reduced radionuclide right ventricular ejection fraction12 and decreased exercise capacity13 in pa-
FIGURE 4. Echocardiographic Doppler data comparing control, mild, moderate and severe pulmonary regurgitation groups. Analysis of variance p values are shown in upper right of each panel. Left ventricular end-diastolic dimension (LVEDd); left ventricular percent fractional shortening (%FS) and Doppler aortic (Ao) average acceleration at rest and exercise were not significantly different for all groups. Right ventricular end-diastolic dimension was increased in relation to percent pulmonary regurgitation.
Discussion Results of this study demonstrated that subjects with PR had lower maximal heart rate responses, lower maximal oxygen consumptions and lower maximal workload capacities during upright bicycle ergometry compared with normal control subjects. In addition, the magnitude of response was related to the degree of PR. Subjects with mild PR had normal hemodynamic responses to exercise. Subjects with moderate and severe PR had lower maximal oxygen consumptions and maximal workload capacities. Control, mild and mod-
FIGURE 5. Exercise hemodynamic data comparing control, mild, moderate and severe pulmonary regurgitation groups. Analysis of variance p values are shown in upper righf of each panel. During maximal upright cycle ergometry the severe group and lower maximal heart rate than controls. Moderate and severe groups had lower maximal oxygen consumption (Max $0,) than the control group: the severe group was also lower than the mild group. Moderate and severe groups had lower workload (RMEI) than the control group. The severe group had lower exercise factor during submaximal exercise than each of the other 3 groups.
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tients with PR. Additionally, reduction in right ventricular size,14J5 improved right ventricular function14815 and exercise capacityl4J5 and improvement in clinical findings of right heart failure15J6 have been reported after pulmonary valve placement for severe PR. However, other investigators l7 have reported low exercise factor in postoperative tetralogy of Fallot patients regardless of the absence or presence of a pulmonary valve. In this study Doppler measurement of percent PR assumed a constant diameter throughout the cardiac cycle. A previous study confirms the validity of this premisee2 This calculation also appears valid in 15 of 27 subjects (56%) who had outflow tract patches or conduits. Nonetheless, the intent of this study was not to use measurement of Doppler PR fraction in absolute terms, but rather to separate subjects into broad categories of mild, moderate and severe PR. M-mode-derived left ventricular end-diastolic dimensions and percent fractional shortening were not significantly different for all 4 groups. However, right ventricular volume overload causing paradoxical septal wall motion18 and ventricular septal defect patches make absolute measurement of ventricular size difficult. Hence, reliance on comparison between groups of patients, and not on absolute values for ventricular size, is emphasized. In addition, percent fractional shortening has limitations as a determinant of ventricular function since it is both pre- and afterload dependent. An index for noninvasive measurement of ventricular function has been reported that is preload independent, incorporates afterload and is heart rate corrected. This index is the end-systolic wall stress/ heart rate corrected velocity of fiber shortening relation.lg Others have used this index to demonstrate that patients with conduit repair for transposition of the great arteries, ventricular septal defect and pulmonary stenosis have decreased left ventricular function.20 Use of this index may uncover differences in left ventricular performance between pulmonary regurgitation patients, Average aortic acceleration compares well with changes in dP/dt and dQ/dt under conditions of varying preload, heart rate and inotropic state in animals.21 Average aortic acceleration has also been used to differentiate adult patients with myocardial dysfunction.6 In our study, all patient groups had statistically similar average aortic accelerations at rest and at submaximal exercise, although the severe group tended to have a lower aortic acceleration during exercise. An exercise factor of 7.2, measured at catheterization, has been reported in pediatric patientsz2 One study in normal preadolescent boys6 measured cardiac output by pulsed Doppler during submaximal exercise and found an exercise factor of 6.4 (1.2 SD]. In our study only 4 patients (all in the severe PR group] had exercise factors lower than 2 SD below the previously reported normal mean value. Two of these patients had right ventricular to aortic pressure ratios >70% at catheterization. Excessive patient motion and respiratory effort prevented obtaining adequate Doppler ascending aortic velocity traces at higher workloads.
Hence, exercise factor and aortic acceleration were measured only at submaximal exercise. Measurement of exercise factor and aortic acceleration at higher workloads may have more clearly differentiated the patient groups. Other variables, in addition to pulmonary regurgitation, may have contributed to the differences in patient groups. Patient age, age at surgery, type of repair and myocardial preservation could not be controlled between patient groups. The population was heterogeneous and included patients with different lesions. However, when we analyzed the data for tetralogy of Fallot patients alone, results were statistically similar to those for patients with other lesions. In addition, hemodynamically significant PR did not appear to occur as an isolated event. Absence of a functional valve in the pulmonary position and elevated distal pulmonary pressure appear to be requirements for hemodynamically significant PR, regardless of the type of underlying defect. Elevated distal pulmonary pressure occurred in our study as a result of peripheral pulmonary stenosis, but presumptively could occur secondary to pulmonary parenchymal or pulmonary vascular obstructive disease. Decreased pulmonary flow to 1 or both lungs, and associated ventilation-perfusion abnormalities, may also have contributed to decreased exercise capacity.13 As shown by catheterization data, available in two-thirds of the patients in this study, significant PR was associated with right ventricular hypertension. Decreased right ventricular ejection with exercise has been reported in patients with right ventricular hypertension from obstructed conduits alonesz3 In this study, patients with increasing severity of PR also had more right ventricular dilation. However, no direct measure of right ventricular systolic or diastolic function was made. Right ventricular dilation may have been an indicator of primary ventricular dysfunction related to large ventriculotomies for placement of noncontractile patches or conduits.24 Additionally, the more dilated right ventricles may have adversely affected left ventricular diastolic function.25 Similar to other investigators,13 we do not believe that PR alone caused the abnormal response to exercise, but rather a constellation of findings associated with significant PR were the probable etiologies. Many of our patients with moderate and severe PR were able to attend school and lead active lives. Although baseline Doppler echocardiograms demonstrated right ventricular dilation and increased regurgitant fractions, exercise testing most clearly differentiated the moderate and severe PR patients. Acknowledgment: We would like to express our sincere appreciation to Cheryl Czaplicki for typing and editing the manuscript.
References 1. Ebert PA. Second operations for pulmonary stenosis or insufficiency after repair of tetralogy of FaJJot. Am 1 CordioJ 1982;50:637-640. 2. Goldberg SJ. Allen HD. Quantitative assessment of Doppler echocardiogrophy of pulmonary or aortic regurgitation. Am [ CardioJ 1985;56:131-135. 3. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quontitation in M-mode echocardiography: results of o survey of echocordio-
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graphic measurements. Circulation 1978;58:1072-1083. 4. Goldberg SJ, Allen HD, Marx GR, Donnerstein RL. Doppler Echocardiography. Second edition. Philadelphia: Lea 8 Febiger, 1987, in press. 5. Hatle L, Angelsen B. Doppler Ultrasound in Cardiology. Second edition. Philadelphia: Lea & Febiger, 1985:153-188. 6. Marx GR. Hicks R. Allen HD. Measurement of cardiac outout and exercise factor by pulsed Doppler echocardiogrpahy durjng supine bicyle ergometry. IACC 1987:10:430-434. ?. Gardin JM, Burns CS, Childs WJ, Henry WL. Evaluation of blood flow velocity in the ascending aorta and main pulmonary artery of normal subjects by Doppler echocardiography. Am Heart J 1984; 107:310-319. 8. Gardin JM, Iseri LT, Elkaysam U, Tobis J, Childs W, Burns CS, Henry WL. Evaluation of dilated cardiomyopathy by pulsed Doppler echocardiography. Am Heart ~1983;106:1057-1065. 9. Marx GR, Goldberg SJ, Allen HD. Two methods for measurement of ascending aortic diameter by Z-D echocardiography as compared with cineangiography. Am Heart J 1986:112:172-173. 10. Wilmore JH Costill DL. Semiautomated systems approach to the assessment of oxygen uptake during exercise. J Appl Physiol 1974;36:618-620. 11. Goldberg SJ, Weiss R, Adams FH. A comparison of the .maximal endurance of normal children and patients with congenital cardiac disease. J Pediatr 1966;69:46-55. 12. Bove EL, Byrum CJ, Thomas FD, Kavey REW, Sondheimer HM, Blackman MS, Parker FB. The influence of pulmonary insufficiency on ventricular function following repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1983;85:691-696. 13. Wessel HU, Cunningham WJ, Paul MH, Bastanier CK, Muster AJ, Idriss FS. Exercise performance in tetralogy of Fallot after intracardiac repair. J Thorac Cardiovasc Surg 1980;80:582-593. 14. Bove EL, Kavey REW, Byrum CJ, Sondheimer HM, Blackman MS, Thomas FD. Improved right ventricular function following late pulmonary valve replacement for residual pulmonary insufficiency or stenosis. J Thorac Cardiovasc Surg 1985;90:50-55. 15. Ilbawi MN, Idriss FS, Muster AJ, Wessel HU, Paul MH, DeLeon SY.
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Tetralogy of Fallot with absent pulmonary valve: should valve insertion be part of the intracardiac repair? J Thorac Cardiovasc Surg 1981;81:906915. 16. Misbach GA, Turley K, Ebert PA. Pulmonary valve replacement for regurgitation after repair of tetralogy of Fallot. Ann Thorac Surg 1983;36:694691. 17. Rocchini AP. Hemodynamic abnormalities in response to supine exercise in patients after operative correction of tetrad of Fallot after early childhood. Am I Cardiol 1981;48:325-330. 18. Vick GW, Serwer GA. Echocardiographic evaluation of the postoperative tetralogy of Fallot patient. Circulation 1978;50:842-849. 19. Golan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load independent index of myo- , cordial contractility. JACC 1984;4:715-724. 20. Graham TP, Franklin RCG, Wyse RKH, Gooch V, Deanfield JE. Left ventricular wall stress and contractile function after Rastelli repair of transposition of the great arteries. r Thorac Cardiovasc Surg 1987;93:775784. 21. Wallmeyer K, Wann LS, Sagar KB, Kalbfleisch J, Klopfenstein HS. The influence of preload and heart rate on Doppler echocardiographic indexes of left ventricular performance: comparison with invasive indexes in an experimental preparation. Circulation 1986;74:181-186. 22. Lock JE, Einzig S, Moller JH. Hemodynamic responses to exercise in normal children. Am r Cardiol 1978;41:1278-1284, 23. Palik I, Graham TP, Burger J. Ventricular performance in patients with obstructed right ventricular-pulmonary artery conduits. Am Heart J 1986; 112:1271-1278. 24. Graham TP, Cordell D, Atwood GF. Boucek RJ, Boerth RC, Bender HW, Nelson JH Vaughn WK. Right ventricular volume characteristics before and after palliative and reparative operation in tetralogy of Fallot. Circulation 1976;54:417-423, 25. DePace NL, Nestico PF, Iskandrian AS, Morganroth J. Acute severe pulmonic valve regurgitation: pathophysiology, diagnosis, and treatment. Am Heart r 1984;108:567-573.
HEART DISEASE
NoninvasiveAssessment of HemodynamicResponses to Exercise in Pulmonary Regurgitation After Operations to Correct Pulmonary Outflow Obstruction GERALD R. MARX,
MD, RICHARD and STANLEY
W. HICKS, PhD, HUGH D. ALLEN, MD, J. GOLDBERG, MD
The influence of pulmonary regurgitation (PR) on exercise capacity is unknown. The hemodynamic responses to exercise in postoperative patients with PR was determined using Doppler-measured regurgitant fraction to indicate PR severity. Maximal heart rate, oxygen consumption and workload capacity were measured during upright cycle ergometry. Cardiac output was measured at rest and during submaximal supine cycle ergometry by pulsed Doppler echocardiography. Oxygen consumption was simultaneously measured and exercise factor was calculated as the change in cardiac output per change in oxygen consumption. Twenty-seven patients were compared with 17 age-, size- and sexmatched control subjects. Patients with PR had larger right ventricles (p 10.001), lower heart
rate response (p _<0.05), lower maximal oxygen consumption (p S0.005) and lower workloads (p 10.005) when compared with normal control subjects during maximal exercise testing. Exercise factor was the same for both groups. Patients with PR were then separated into mild, moderate and severe groups. Patients with mild PR had a normal response to exercise. However, patients with moderate and severe PR had lower maximal oxygen consumptions and maximal workloads than control subjects. Control, mild and moderate PR groups had similar exercise factors. Patients with severe PR had markedly low cardiac output responses. PR is associated with reduced exercise capability, which is related to the severity of the PR. (Am J Cardiol 1988;81:595-801)
P
ulmonary regurgitation (PR) is a common finding after surgery for critical pulmonary stenosis, tetralogy of Fallot or other defects that may require placement of a nonvalved conduit from the right ventricle to pulmonary arteries. Many of these patients have done well, but the influence of PR on exercise capacity is unknown. Inability to quantitate PR has impeded its investigati0n.l Pulsed Doppler echocardiography has recently been shown to accurately measure regurgitant fraction.z Magnitude of Doppler regurgitant frac-
tion has compared well to clinical determinants of disease severityn2 This study was designed to determine the hemodynamic responses to exercise in postoperative patients with PR using Doppler-measured regurgitant fraction to indicate severity of the PR.
Methods
From the Department of Pediatrics (Cardiology], University of Arizona, Health Sciences Center, Tucson, Arizona. This study was supported by a grant-in-aid from the American Heart Association, Arizona Affiliate. Manuscript received August 10, 1987; revised manuscript received and, accepted October 28,1987. Address for reprints: Gerald R. Marx, MD, Department of Pediatrics, University of Arizona, Health Sciences Center, Tucson, Arizona 85724. 595
Patient selection: Thirty-one patients with postoperative PR were chosen for study. Patients were at least 6 years of age and able to perform rigorous exercise testing. Patients were excluded if they had Doppler echocardiographic or catheterization findings of residual shunts, aortic, mitral or tricuspid regurgitation, stenosis or some combination of these. Patients with right ventricular outflow tract gradients >20 mm Hg, excluding peripheral stenosis, also were excluded. All patients had to be in sinus rhythm during exercise. An age- and sex-matched control group was also studied. Consent was obtained according to the guidelines of the University of Arizona Human Subjects Committee under an approved protocol.
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Doppler echocardiography technique: Standard &dimensional pulsed and continuous-wave Doppler echocardiograms (BioSound ND 2600) were performed at rest on all subjects. M-mode scans for measurement of cavity size and wall thickness were obtained with cursor alignment guided by &dimensional imaging. Two-dimensional images of the left and right ventricles were obtained from a short-axis parasternal plane at the level of the mitral valve chordae tendinae. The M-mode cursor was placed through the right and left ventricles perpendicular to the ventricular septum. The site of ventricular septal patch placement was avoided in patients who had surgical ventricular septal defect closure. Right and left ventricular enddiastolic dimensions, left ventricular end-systolic dimensions and left ventricular percent fractional shortening were calculated according to standard guidelines of the American Society of Echocardiography. All valves and right ventricular outflow tracts were interrogated by standard Doppler echocardiographic techniques for stenosis and regurgitation4r5 Regurgitation was considered insignificant if retrograde velocities were mapped only in a small area immediately proximal to the valves4T5 Pulmonary regurgitant fraction was measured by a previously reported pulsed Doppler techniquen2 Pul-
FIGURE 1. Pulsed Doppler tracings from the pulmonary outflow tract in 2 patients with pulmonary regurgitation (A and B). Anterograde, below baseline, and regurgitant, above baseline, velocities are sampled from the same flow area. Bdemonstrates baseline shift allowing simultaneous velocity measurement without signal aliasing.
monary forward and regurgitant velocities were obtained proximal to the bifurcation in the midpulmonary artery, right ventricular outflow tract patch or conduit. In some patients the conduit or patch was poorly visualized, and the Doppler sample volume was placed in the area of anticipated regurgitant flow. The sample volume was then maneuvered until both simultaneous negative velocities of anterograde flow and positive velocities of retrograde flow with 130% velocity spread were obtained (Figure 1). Modal positive and negative Doppler velocities were separately digitized over 3 beats using a dedicated software program, digitizing pad and microcomputer.4 The program determined positive and negative mean velocity by dividing the area under the time velocity curve by distance along the time axis. Percent pulmonary regurgitation was derived as regurgitant mean velocity/forward mean velocity X 100. Ascending aortic velocities were measured from the suprasternal notch both at rest and during 50% supine submaximal exercise for determination of average aortic acceleration and cardiac output6 At rest, a 3.5-MHz transducer was used to image and perform Doppler velocity interrogation. A smaller 2.25-MHz right angle transducer was used during exercise.6 Average aortic acceleration, averaged over 3 beats, was calculated by a previously reported method as the peak velocity divided by the time to reach peak velocity.7tE Aortic diameter was measured from the suprasternal notch at the sample volume site above the sinuses of Valsalva.g Maximal aortic diameter measured at rest was used for flow calculation during submaximal exercise. Cardiac output (ml/min) was calculated as4Jj mean velocity (cm/min) X cross-sectional area (cm2). Respiratory measurements: Expired respiratory gasses were continuously collected using a WilmoreCostill 3-way valve system.lO Fractional concentrations of oxygen and carbon dioxide were analyzed every 30 seconds using Beckman OM-11 and Godart Capnograph rapid gas analyzerslO Minute ventilation was measured using a Parkinson-Cowan CD-4 gas flow meter.lO These measurements allowed calculation of oxygen consumption, carbon dioxide production and respiratory exchange ratio. Exercise protocol: All subjects performed a graded maximal exercise test on a supine cycle ergometer (Spectrum Mode III) according to a standard protoc01.l~ Maximal exercise capacity was also determined with patients pedaling an upright cycle in 34 of 44 subjects using the same protocol. (Ten young subjects were unable to reach the pedals.] This upright test allowed calculation of relative maximal endurance index, a measure of work performed indexed for size, sex and age.ll The technician supervising the maximal exercise testing was blinded to patient’s medical history and magnitude of PR. An additional supine cycle exercise test was performed with the workload set to a level that corresponded to 50% of each individual’s previously determined maximal oxygen consumption6 Oxygen consumptions and Doppler cardiac outputs were mea-
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TABLE
I
Individual
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Control
Diag
Patch Cond.
PPS
RV/Ao
PR (%)
1 0.8 1 1 1 1.2 1.3 1.3 1.2 1.3 1.6 1.3 1.3 1.4 1.4 1.4 1.4 1.2 0.2
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
C C C C C C C C C C C C C C C C C
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7 9 12 12 19 8 13 14 16 12 4
0.7 1 1.3 1.1 1.5 0.7 1.4 1 1.6 1.1 0.3
TF TF TF TF TF PS PS PS PS
16 12 17 27 15 10 18 7 13 1
9 9 IO 15 17 25 7 a 9 13 12 6
0.7 0.8 1.2 1.4 1.4 1.5 0.9 i 0.9 1.6 1.1 0.3
TF TF TF TF TF TF DORV PS PS PS
20 6 3 22 26 21 30 11
10 11 11 12 7 7 9 11 10 2
1 0.9 1.1 1.3 0.8 0.9 1.1 0.9 1 0.2
TF TF,PA TF TF TGAt TA TA PS
Pt 62 64 63 66 65 61 43 45 41 47 52 44 46 42 48 51 53
Mean SD Mild
29 23 25 19 8 9 14 24 4
Mean SD Moderate
Mean SD Severe
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Data RVEDd
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Age W
BSA On*)
8 a 9 IO IO IO 13 13 14 14 14 14 14 14 14 15 16 12 3
0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0
38 37 33 34 45
23 35 7.4
P P P P P 0 C 0 P 0
0 0 0 0 0 R&LPA RPA 0 0 0
33 39 48
RPA R&LPA
58 100
R&LPA R&LPA
75 64
40 55 60 46 32 44 10.1
74 18.7
LVEDd
R Act FS (%)
(mm/m*)
Ex Act
(cm/s*)
22 21 17 18 *
40 48 43 45
30 32 33 38
1,558 883 840 1,556
3,189 2,036 2,071 2,269
13 11 13 12 12 12 9 13 14 13 12 13 14 3.6
35 35 33 40 34 31 34 28 34 31 36 31 36 5.6
29 33 35 42 33 40 36 31 36 32 36 34 35 3.6
1,045 1,187 2,340 1,073 967 1,489 1,546 1,177 1,603 1,064 2,066 1,524 1,370 421
1,813 2,854 3,575 2,659 2,048 2,037 2,645 2,031 2,317 2,083 2,152 2,234 2,376 484
10 36 13 30 36 16 30 13 15 22 10.7
23 17 18 29 20 21 13 21 ia 20 4.4
47 44 32 32 30 34 32 40 28 35 6.6
39 27 36 34 33 40 38 38 36 36 4
1,516 1,195
4,344 1,739
661
1,012
626 1,955 1,603 1,371 1,275 490
4,548 2,855 2,482 4,333 3,045 1,402
48 43 44 44 51 53 44 51 46 54 48 4.2
43 34 17 25 26 21 33 20 27 18 26 8.2
40 35 32 26 22 24 36 35 34 25 31 6.1
29 32 29 38 32 31 37 29 32 25 31 3.9
1,254 935 757 1,151 865
2,422 2,429 1,315 1,477 3,865
1,266 1,881 1,273 1,173 349
2,863 4,457 3,158 2,748 1,084
83 80 81 82 68 72 76 70 77 5.9
30 41 38 25 44 34 34 38 36 6.1
34 36 34 38 40 46 31 30 36 5.8
32 38 37 34 28 30 29 44 34 5.4
1,243 1,674 964 868 970 971 948 1,556 1,149 309
2,539 1,707 816 2,385 1,943 3,106 1,436 2,390 2,040 718
MHR (bpm)
MVOs
RMEI
EF
165 200 ia0 150 180 150 195 198 190 180
30.2 45.2 43.5 27 35.4 24.8 44.2 45.8 45.5 40.5
111 193 192 75 150 38 150 210 241 174
5.9 a.3 6.8 6.5
192 192 195 195
43.1 30.4 38 48.6
193 150 168 191
170 182 17
47.6 39 7.9
167 160 52
180 168 190
38.8 25.8 27.2 39.6
142 82 135 158
182 160 188 178 12
33.1 43.7 47.5 37 8.2
134 187 238 154 49
160 190 155 160 186
28.1 25.1 25.1 20.1 38.4
37 84 84 53 137
ia0 172 15
28.6 28 6.1
86 80 34
160 140 152 160
29 17.8 24.7 22.1
40 -2 -18 98
172 148 155 11
27.8 30.8 25 4.8
50 89 43 47
8.2 6.7 5.3 6.9 5 5.7 5.3 6.9 6.5 6.2 5.7 4.9 6.3 1 10.3 5.9 6.3 5.5 5.7 5.3 6.3 6.5 1.7 8.3 6.1 6.2 9.8 8.7
6.8 7.9 7.4 7.6 1.2 4.7 4.7 3.8 3.4 3.7 5.8 4.4 2.6 4 i
bpm = beats/min; C = control; Cond = conduit; Diag = diagnosis; DORV = double-outlet right ventricle; EF = exercise factor; Ex Act = exercise mean acceleration; FS = fractional shortening: LPA = left pulmonary artery; LVEDd = left ventricular end-diastolic dimension; MHR = maximal heart rate: MV02 = maximal oxygen consumption; PA = pulmonary atresia; PPS = peripheral pulmonic stenosis; PR = pulmonary regurgitation; PS = pulmonic stenosis; R Act = resting mean acceleration: RMEI = relative maximal endurance index: RPA = right pulmonary artery: RV/Ao = right ventricularlaortic pressure ratio: RVEDd = right ventricular end-diastolic dimension; SD = standard deviation; TA = truncus arteriosus; TF = tetralogy of Fallot; TGA = transportation of the great vessels; VSD = ventricular septal defect. * = no echocardiographic data available; t = TGA, VSD and P.S.
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sured at rest and during the fifth minute of exercise at the predetermined workload. Exercise factor was calculated as the change in cardiac output between rest and exercise, divided by the simultaneous change in oxygen consumption.6 Statistical analysis: Grouped data for control and all PR subjects were compared using the unpaired Student t test. Data were then separated into control, mild, moderate and severe categories by magnitude of PR, according to a prior classification2: PR fraction <40% (mild), 40 to 60% (moderate) and >60% (severe). Statistical differences between groups were determined by analysis of variance and Scheffe post-hoc analyses. A p value of <0.05 was considered significant. Group data were expressed as mean and standard deviation,
Results Control group versus entire pulmonary regurgitation group: Seventeen control subjects and 31 patients with PR were enrolled in the study. Four patients with PR did not meet minimal requirements for study and were excluded from the protocol, leaving 27 PR patients for data analysis [Table I]. Control and PR groups were not significantly different in age, sex distribution and body surface area. Left ventricular enddiastolic dimension, percent fractional shortening and resting and exercise Doppler average aortic acceleration were not significantly different for both groups (Figure 2). The PR group had significantly larger right ventricles than control subjects (p 10.001, Figure 2). The PR group also had significantly lower maximal heart rate response (p 10.05), lower maximal oxygen consumption (p lO.005) and lower workload performed during maximal exercise testing (p LO.005, Figure 3). Exercise factor was not significantly different for both groups [Figure 3). Control group versus mild, moderate and severe groups: Population, age and size: Data were then analyzed by separating subjects into mild, moderate and severe PR groups [Table I). The control group consist-
ed of 17 subjects (mean age 12 years), mild group 9 patients (mean age 12 years), moderate group 10 patients [mean age 12 years] and severe group 8 patients (mean age 10 years]. Age and size were not significantly different for all 4 groups. Diagnoses in mild group: Five patients in the mild PR group had repair of tetralogy of Fallot. None required a transanular patch or conduit. Four patient had isolated valvar pulmonic stenosis. Three had surgical pulmonary valvotomies, and 1 patient underwent balloon dilation valvuloplasty. None of the 9 patients had significant peripheral pulmonic stenosis. Diagnoses in moderate group: Six patients in the moderate PR group had repaired tetralogy of Fallot; 5 required a transanular patch. The 1 patient without a patch had significant bilateral peripheral pulmonic stenosis. Three patients had pulmonary valvotomies in the newborn period for critical valvar pulmonic stenosis; 2 required a second operation. One had a repeat valvotomy, and the other placement of a transanular patch. One patient had a nonvalved conduit after Damas-Stansel-Kaye repair for double-outlet right ventricle. Diagnoses in severe group: Seven patients in the severe PR group had nonvalve conduits. Four of the 7 underwent recent cardiac catheterizations and all 4 had significant peripheral pulmonic stenosis. The eighth patient had transanular patch repair for tetralogy of Fallot and has not undergone postoperative catheterization. Baseline data: Magnitude of regurgitation: Mean PR fraction was 22% (lo.7 standard deviation [SD]] for the mild group; 48% (4.2 SD] for the moderate group; and 77% (5.9 SD) for the severe group, [p _
22s 2ca1
FIGURE 2. Echocardiographic Doppler data comparing control group versus entire pulmonary regurgitation group. Left ventricular end-diastolic dimension (LVEDd), left ventricular percent fractional shortening (%FS) and Doppler aortic (Ao) average acceleration at rest and exercise was similar for both groups. Patients had significantly larger right ventricular end-diastolic dimensions (RVEDd).
I
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FIGURE 3. Exercise hemodynamics comparing control group with entire pulmonary regurgitation group. During maximal upright cycle ergometry patients had lower maximal heart rate (Max HR), oxygen consumption (maxir0,) and workload (RMEI) than the control group. Exercise factor measured during submaximal exercise was not significantly different.
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74% (18.7 SD] for the severe group (n = 4), (p 50.001). The severe group was significantly different from both mild and moderate PR groups; the latter 2 groups were not significantly different from each other. M-mode data: Mean left ventricular end-diastolic dimension indexed for body surface area and percent fractional shortening were not significantly different for the 4 groups [Figure 41. Mean right ventricular enddiastolic dimension was 14 mm/m2 (3.6 SD] for the control group: 20 mm/m2 (4.4 SD) for the mild group; 26 mm/m2 (8.2 SD) for the moderate group; and 36 mm/m2 (6.1 SD] for the severe group (p 50.001). All groups were significantly different from each other [Figure 4). Aortic average acceleration: Average resting and exercise aortic accelerations were not significantly different for all 4 groups (Figure 4). Exercise data: Not all patients were tall enough to reach the pedals of the upright cycle ergometer. Comparison of maximal upright cycle testing data was made in 15 patients in the control group, 7 in the mild, 6 in the moderate and 6 in the severe PR groups. Maximal heart rate: Mean maximal heart rate attained for the control group was 182 beats/min (17 SD); 178 (12 SD] for the mild group, 172 (15 SD] for the moderate group and 155 (11 SD) for the severe PR group (p 10.01). Only the control and severe groups were significantly different from each other (Figure 5). Maximal oxygen consumption: Mean maximal oxygen consumption was 39 ml/min/kg (7.9 SD) for the control group, 37 (8.2 SD) for the mild group, 28 (6.1 SD] for the moderate group and 25 (4.8 SD] for the severe PR group (p 10.005). Both the moderate and severe groups were significantly different from control. The severe group was also significantly different from the mild group (Figure 51. Relative maximal endurance index: Mean relative maximal endurance index for the control group was 160 kg-m/min/mz (52 SD], 154 (49 SD) for the mild group, 80 (34 SD] for the moderate and 43 (47 SD] for the severe group (p 50.001). Both moderate and severe PR groups were significantly different from the control group (Figure 5). Exercise factor: Mean exercise factor for the control group was 6.3 (1.0 SD], 6.5 (1.7) for the mild group, 7.6 (1.21 for the moderate group and 4.1 (1.0 SD] for the severe PR group (p 10.001). The severe group was significantly different from the other 3 groups (Figure 5).
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erate PR groups had similar increases in cardiac output per increase in oxygen consumption during submaximal exercise. However, some patients in the severe group had a markedly low cardiac output response. Patients with more severe PR had increased M-mode right ventricular end-diastolic dimensions. Right ventricular systolic pressures were increased at catheterization. The most severe PR occurred in patients who had pulmonary artery stenosis distal to their patches or nonvalved conduits. Results of this study are consistent with those of others who have reported increased right ventricular size,12 reduced radionuclide right ventricular ejection fraction12 and decreased exercise capacity13 in pa-
FIGURE 4. Echocardiographic Doppler data comparing control, mild, moderate and severe pulmonary regurgitation groups. Analysis of variance p values are shown in upper right of each panel. Left ventricular end-diastolic dimension (LVEDd); left ventricular percent fractional shortening (%FS) and Doppler aortic (Ao) average acceleration at rest and exercise were not significantly different for all groups. Right ventricular end-diastolic dimension was increased in relation to percent pulmonary regurgitation.
Discussion Results of this study demonstrated that subjects with PR had lower maximal heart rate responses, lower maximal oxygen consumptions and lower maximal workload capacities during upright bicycle ergometry compared with normal control subjects. In addition, the magnitude of response was related to the degree of PR. Subjects with mild PR had normal hemodynamic responses to exercise. Subjects with moderate and severe PR had lower maximal oxygen consumptions and maximal workload capacities. Control, mild and mod-
FIGURE 5. Exercise hemodynamic data comparing control, mild, moderate and severe pulmonary regurgitation groups. Analysis of variance p values are shown in upper righf of each panel. During maximal upright cycle ergometry the severe group and lower maximal heart rate than controls. Moderate and severe groups had lower maximal oxygen consumption (Max $0,) than the control group: the severe group was also lower than the mild group. Moderate and severe groups had lower workload (RMEI) than the control group. The severe group had lower exercise factor during submaximal exercise than each of the other 3 groups.
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tients with PR. Additionally, reduction in right ventricular size,14J5 improved right ventricular function14815 and exercise capacityl4J5 and improvement in clinical findings of right heart failure15J6 have been reported after pulmonary valve placement for severe PR. However, other investigators l7 have reported low exercise factor in postoperative tetralogy of Fallot patients regardless of the absence or presence of a pulmonary valve. In this study Doppler measurement of percent PR assumed a constant diameter throughout the cardiac cycle. A previous study confirms the validity of this premisee2 This calculation also appears valid in 15 of 27 subjects (56%) who had outflow tract patches or conduits. Nonetheless, the intent of this study was not to use measurement of Doppler PR fraction in absolute terms, but rather to separate subjects into broad categories of mild, moderate and severe PR. M-mode-derived left ventricular end-diastolic dimensions and percent fractional shortening were not significantly different for all 4 groups. However, right ventricular volume overload causing paradoxical septal wall motion18 and ventricular septal defect patches make absolute measurement of ventricular size difficult. Hence, reliance on comparison between groups of patients, and not on absolute values for ventricular size, is emphasized. In addition, percent fractional shortening has limitations as a determinant of ventricular function since it is both pre- and afterload dependent. An index for noninvasive measurement of ventricular function has been reported that is preload independent, incorporates afterload and is heart rate corrected. This index is the end-systolic wall stress/ heart rate corrected velocity of fiber shortening relation.lg Others have used this index to demonstrate that patients with conduit repair for transposition of the great arteries, ventricular septal defect and pulmonary stenosis have decreased left ventricular function.20 Use of this index may uncover differences in left ventricular performance between pulmonary regurgitation patients, Average aortic acceleration compares well with changes in dP/dt and dQ/dt under conditions of varying preload, heart rate and inotropic state in animals.21 Average aortic acceleration has also been used to differentiate adult patients with myocardial dysfunction.6 In our study, all patient groups had statistically similar average aortic accelerations at rest and at submaximal exercise, although the severe group tended to have a lower aortic acceleration during exercise. An exercise factor of 7.2, measured at catheterization, has been reported in pediatric patientsz2 One study in normal preadolescent boys6 measured cardiac output by pulsed Doppler during submaximal exercise and found an exercise factor of 6.4 (1.2 SD]. In our study only 4 patients (all in the severe PR group] had exercise factors lower than 2 SD below the previously reported normal mean value. Two of these patients had right ventricular to aortic pressure ratios >70% at catheterization. Excessive patient motion and respiratory effort prevented obtaining adequate Doppler ascending aortic velocity traces at higher workloads.
Hence, exercise factor and aortic acceleration were measured only at submaximal exercise. Measurement of exercise factor and aortic acceleration at higher workloads may have more clearly differentiated the patient groups. Other variables, in addition to pulmonary regurgitation, may have contributed to the differences in patient groups. Patient age, age at surgery, type of repair and myocardial preservation could not be controlled between patient groups. The population was heterogeneous and included patients with different lesions. However, when we analyzed the data for tetralogy of Fallot patients alone, results were statistically similar to those for patients with other lesions. In addition, hemodynamically significant PR did not appear to occur as an isolated event. Absence of a functional valve in the pulmonary position and elevated distal pulmonary pressure appear to be requirements for hemodynamically significant PR, regardless of the type of underlying defect. Elevated distal pulmonary pressure occurred in our study as a result of peripheral pulmonary stenosis, but presumptively could occur secondary to pulmonary parenchymal or pulmonary vascular obstructive disease. Decreased pulmonary flow to 1 or both lungs, and associated ventilation-perfusion abnormalities, may also have contributed to decreased exercise capacity.13 As shown by catheterization data, available in two-thirds of the patients in this study, significant PR was associated with right ventricular hypertension. Decreased right ventricular ejection with exercise has been reported in patients with right ventricular hypertension from obstructed conduits alonesz3 In this study, patients with increasing severity of PR also had more right ventricular dilation. However, no direct measure of right ventricular systolic or diastolic function was made. Right ventricular dilation may have been an indicator of primary ventricular dysfunction related to large ventriculotomies for placement of noncontractile patches or conduits.24 Additionally, the more dilated right ventricles may have adversely affected left ventricular diastolic function.25 Similar to other investigators,13 we do not believe that PR alone caused the abnormal response to exercise, but rather a constellation of findings associated with significant PR were the probable etiologies. Many of our patients with moderate and severe PR were able to attend school and lead active lives. Although baseline Doppler echocardiograms demonstrated right ventricular dilation and increased regurgitant fractions, exercise testing most clearly differentiated the moderate and severe PR patients. Acknowledgment: We would like to express our sincere appreciation to Cheryl Czaplicki for typing and editing the manuscript.
References 1. Ebert PA. Second operations for pulmonary stenosis or insufficiency after repair of tetralogy of FaJJot. Am 1 CordioJ 1982;50:637-640. 2. Goldberg SJ. Allen HD. Quantitative assessment of Doppler echocardiogrophy of pulmonary or aortic regurgitation. Am [ CardioJ 1985;56:131-135. 3. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quontitation in M-mode echocardiography: results of o survey of echocordio-
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graphic measurements. Circulation 1978;58:1072-1083. 4. Goldberg SJ, Allen HD, Marx GR, Donnerstein RL. Doppler Echocardiography. Second edition. Philadelphia: Lea 8 Febiger, 1987, in press. 5. Hatle L, Angelsen B. Doppler Ultrasound in Cardiology. Second edition. Philadelphia: Lea & Febiger, 1985:153-188. 6. Marx GR. Hicks R. Allen HD. Measurement of cardiac outout and exercise factor by pulsed Doppler echocardiogrpahy durjng supine bicyle ergometry. IACC 1987:10:430-434. ?. Gardin JM, Burns CS, Childs WJ, Henry WL. Evaluation of blood flow velocity in the ascending aorta and main pulmonary artery of normal subjects by Doppler echocardiography. Am Heart J 1984; 107:310-319. 8. Gardin JM, Iseri LT, Elkaysam U, Tobis J, Childs W, Burns CS, Henry WL. Evaluation of dilated cardiomyopathy by pulsed Doppler echocardiography. Am Heart ~1983;106:1057-1065. 9. Marx GR, Goldberg SJ, Allen HD. Two methods for measurement of ascending aortic diameter by Z-D echocardiography as compared with cineangiography. Am Heart J 1986:112:172-173. 10. Wilmore JH Costill DL. Semiautomated systems approach to the assessment of oxygen uptake during exercise. J Appl Physiol 1974;36:618-620. 11. Goldberg SJ, Weiss R, Adams FH. A comparison of the .maximal endurance of normal children and patients with congenital cardiac disease. J Pediatr 1966;69:46-55. 12. Bove EL, Byrum CJ, Thomas FD, Kavey REW, Sondheimer HM, Blackman MS, Parker FB. The influence of pulmonary insufficiency on ventricular function following repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1983;85:691-696. 13. Wessel HU, Cunningham WJ, Paul MH, Bastanier CK, Muster AJ, Idriss FS. Exercise performance in tetralogy of Fallot after intracardiac repair. J Thorac Cardiovasc Surg 1980;80:582-593. 14. Bove EL, Kavey REW, Byrum CJ, Sondheimer HM, Blackman MS, Thomas FD. Improved right ventricular function following late pulmonary valve replacement for residual pulmonary insufficiency or stenosis. J Thorac Cardiovasc Surg 1985;90:50-55. 15. Ilbawi MN, Idriss FS, Muster AJ, Wessel HU, Paul MH, DeLeon SY.
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Tetralogy of Fallot with absent pulmonary valve: should valve insertion be part of the intracardiac repair? J Thorac Cardiovasc Surg 1981;81:906915. 16. Misbach GA, Turley K, Ebert PA. Pulmonary valve replacement for regurgitation after repair of tetralogy of Fallot. Ann Thorac Surg 1983;36:694691. 17. Rocchini AP. Hemodynamic abnormalities in response to supine exercise in patients after operative correction of tetrad of Fallot after early childhood. Am I Cardiol 1981;48:325-330. 18. Vick GW, Serwer GA. Echocardiographic evaluation of the postoperative tetralogy of Fallot patient. Circulation 1978;50:842-849. 19. Golan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load independent index of myo- , cordial contractility. JACC 1984;4:715-724. 20. Graham TP, Franklin RCG, Wyse RKH, Gooch V, Deanfield JE. Left ventricular wall stress and contractile function after Rastelli repair of transposition of the great arteries. r Thorac Cardiovasc Surg 1987;93:775784. 21. Wallmeyer K, Wann LS, Sagar KB, Kalbfleisch J, Klopfenstein HS. The influence of preload and heart rate on Doppler echocardiographic indexes of left ventricular performance: comparison with invasive indexes in an experimental preparation. Circulation 1986;74:181-186. 22. Lock JE, Einzig S, Moller JH. Hemodynamic responses to exercise in normal children. Am r Cardiol 1978;41:1278-1284, 23. Palik I, Graham TP, Burger J. Ventricular performance in patients with obstructed right ventricular-pulmonary artery conduits. Am Heart J 1986; 112:1271-1278. 24. Graham TP, Cordell D, Atwood GF. Boucek RJ, Boerth RC, Bender HW, Nelson JH Vaughn WK. Right ventricular volume characteristics before and after palliative and reparative operation in tetralogy of Fallot. Circulation 1976;54:417-423, 25. DePace NL, Nestico PF, Iskandrian AS, Morganroth J. Acute severe pulmonic valve regurgitation: pathophysiology, diagnosis, and treatment. Am Heart r 1984;108:567-573.