Right Ventricular Function in Children with Tetralogy of Fallot before and after Aortic-to-Pulmonary Shunt JAY M. JARMAKANI, M.D., MAKOTO NAKAZAWA, M.D., JOSEPHINE ISABEL-JONES, M.D., AND RICHARD A. MARKS, Ph.D. SUMMARY Right and left ventricular volume variables were obtained in 43 tetralogy patients undergoing diagnostic cardiac catheterization. The patient population consisted of 25 preoperative patients (group 1) and 18 patients who had undergone aortic-topulmonary shunt procedure (group 2). Volumes were calculated from biplane cineangiocardiograms using Simpson's rule method for the right ventricle (RV) and the area-length methods for the left ventricle (LV). In group 1, RV end-diastolic volume (RVEDV) was not different from normal in the total group and averaged 93 ± 4% (SEM) of normal. In patients with hemoglobin (Hgb) ' 16 g%, however, this variable was significantly (P = 0.044) less than normal. Right ventricular ejection fraction was normal and RV systolic index was significantly (P < 0.001) reduced, averaging 3.35 ± 0.18 (sEM) L/min/m'. Left ventricular volume variables in this group were not significantly different from RV volume variables. In group 2, RVEDV in patients with Hgb ' 16 g% was significantly (P= 0.037) less than normal, but was normal in patients with Hgb < 16 g%. Right ventricular ejection fraction
averaged 0.52 ± 0.03 in this group and was significantly (P < 0.001) less than normal. Right ventricular systolic index (RVSI) averaged 3.51 ± 0.24 L/min/m' and was significantly (P = 0.009) less than normal. RVSI in patients with Hgb < 16 g% averaged 3.90 ± 0.31 and was not different from normal. In contrast, this variable in patients with Hgb >- 16 g% averaged 3.21 ± 0.34 and was significantly (P= 0.005) less than normal. Left ventricular enddiastolic volume (LVEDV) and LV systolic output in group 2 were significantly higher than RVEDV and RV systolic output. Right ventricular and LV ejection fractions in group 2 were not different. The relatively decreased ejection fraction in tetralogy patients, as compared with patients with valvular pulmonic stenosis and similar volumes and pressures, suggests that the decreased ejection fraction was not due to decreased preload or increased afterload and might be due to impaired ventricular function secondary to chronic hypoxia. Early corrective surgery in these patients might reverse this process. However, patients with severe tetralogy who have small ventricular volume and reduced output might benefit from shunt procedure rather than complete correction.
SIGNIFICANT ADVANCES have been made in the surgical technique and management of children with congenital heart disease in general and tetralogy of Fallot in particular.1 A significant number of tetralogy patients experience low cardiac output after complete correction.3 7 Postoperative low cardiac output and mortality were attributed to many factors such as anatomical defects with small main pulmonary artery annulus, severe hypoplasia or absent right or left pulmonary artery, ventriculotomy and right ventricular (RV) outflow patch, myocardial hypoxia during cardiopulmonary bypass, or pulmonary edema in the presence of normal left atrial pressure. In addition to these factors, Venugopal and Subramanian3 attributed death to a diminutive right ventricle in one patient and Kirklin and Karp7 suggested that a small left ventricle (LV) was a cause of death in some tetralogy patients postoperatively. Therefore, we believe that a quantitative determination of ventricular volume preoperatively might help in choosing the surgical procedure most likely to benefit the patient. A previous investigation in tetralogy patients before and after surgery" showed decreased left ventricular end-diastolic volume (LVEDV) in severe cases which subsequently increased after successful shunt procedure or complete correction. Both left ventricular ejection fraction (LVEF) and LV systolic output (LVSO) were significantly less than normal preoperatively. Many questions related to the effect of
the type and time of the surgical procedure on postoperative ventricular function remain unanswered. In addition, no data were available on right ventricular (RV) function in these patients. The purpose of this study was to: 1) quantitate right ventricular end-diastolic volume, ejection fraction, and systolic output in tetralogy patients preoperatively and 2) determine the effect of aortic-to-pulmonary shunt procedure on these variables. Right and left ventricular volume variables were compared in each patient. In addition, RV volume variables in all patients will be compared with normal values. Methods Patient Groups
Data were obtained in 43 tetralogy patients undergoing diagnostic cardiac catheterization. Tetralogy of Fallot in this study was defined as: large ventricular septal defect allowing equalization of the pressure in the two ventricles, and severe right ventricular outflow obstruction causing a bidirectional intraventricular shunt with a net right-to-left shunt. The net right-to-left shunt is the sum of the right-toleft minus the left-to-right shunt. Although some of the patients had patent foramen ovale, none of them had evidence of intra-atrial shunting by oximetry or cineangiography. In addition, there were no valvular lesions other than the pulmonic valve. Patients consisted of 25 pre-operative patients (group 1) and 18 patients (group 2) who had aorticto-pulmonary shunt (Blalock-Taussig = 16, Waterston = 2). The indication for shunt procedure in group 2 was small patient size (body weight < 15.0 kg) with one or more of the following: 1) hypercyanotic spells, 2) squatting, 3) markedly decreased exercise tolerance, and 4) rising hemoglobin (Hgb) concentration.
From the Department of Pediatrics, Division of Cardiology, UCLA Center for the Health Sciences, Los Angeles, California. Supported by research grant HL-16329 from the National Heart and Lung Institute; the American Heart Association, Greater Los Angeles affiliate; and a grant from the Children's Bureau. Address for reprints: Jay M. Jarmakani, M.D., Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90024. Received July 25, 1975; revision accepted for publication October 20, 1975.
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Ages ranged from three days to 17.0 years (mean = 4.46 i 0.73 SEM) in group 1, and from 1.08 to 13.00 years (mean = 6.93 ± 0.78) in group 2. Peak systemic pressure was similar in the two groups and was not different from normal. The heart rate in group 1 (mean = 109 ± 4) was not different from the heart rate in group 2 (101 ± 5), and both values were not significantly different from normal. Hemoglobin concentration in group 1 averaged 15.8 ± 0.6 g% and was not significantly different from Hgb concentration in group 2 (16.2 ± 0.6 g%). Hemoglobin concentration in both groups was significantly (P < 0.001) higher than normal. Eighteen patients in group 1 had a net right-to-left shunt in excess of 20%, while the other seven patients had balanced shunt (net shunt < 20%). The shunt in group 2 was calculated in 11 patients by the dye dilution method. In these 11 patients there was an inverse relation between the net leftto-right shunt and Hgb concentration. The shunt was also calculated in all patients using the Fick method, but was not included in group 2 because of the inaccuracy of this method in tetralogy patients with shunt. Data in tetralogy patients were compared with normal right ventricular volume parameters obtained from 42 patients which included normal heart, mild valvular pulmonary stenosis, peripheral pulmonary stenosis, bicuspid aortic valve with no significant gradient, systemic hypertension, vascular ring and mediastinal mass. None of the patients had detectable shunt and the peak RV pressure was less than 45 mm Hg. Data Acquisition
All data were obtained during diagnostic cardiac catheterization. Infants less than three months of age were not premedicated, and those three to 12 months old were given morphine (0.1 mg/kg) only. All other patients were premedicated with meperidine (1 mg/kg), promethazine (0.5 mg/kg) and chlorpromazine (0.5 mg/kg). Before the first cineangiocardiogram was taken, the left-to-right shunt and right-to-left shunt were quantified by the Fick and dye dilution methods in groups 1 and 2. The left and right ventricular pressures were recorded using the Millar Mikro-tip transducer catheter (Millar Instruments, Inc., P. 0. Box 18227, Houston, Texas 77023) or a side hole catheter (NIH No. 6F or 7F) connected to a Statham P23db transducer (Statham Instruments, Inc., 2230 Statham Boulevard, Oxnard, California). Zero pressure was referenced to mid chest. Right and left ventricular volumes were calculated from biplane cineangiocardiograms filmed after injecting 1.25 cc/kg of body weight of Renografin-76 into the right ventricle and left atrium or ventricle. Only normal sinus beats were analyzed. Right ventricular volume was calculated according to Simpson's rule method,'2 and LV volume was calculated according to the area length method of Dodge et al." Right and left ventricular volumes were calculated at end-diastole and end-systole. All values were corrected by separate regression equations described previously. 2," The following variables were calculated from end-diastolic (EDV) and end-systolic volume (ESV): RV stroke volume (RVSV) = RVEDV - RVESV RV ejection fraction (RVEF) = RVSV/RVEDV RV systolic output (RVSO) = RVSV X heart rate Identical variables were calculated for the left ventricle
and were compared with RV volume variables in each patient. The difference in heart rates between the LV and RV beats was less than 10%. The relation between RVEDV and body surface area (BSA) in children with normal right hearts was used to derive normal predicted values in each
patient. Results Normal Values for R V Volumes
The hemodynamic and RV volume variables are shown in table 1. Right ventricular volume parameters in normal children were similar to LV volume parameters and were not different from normal values reported previously."2 Right ventricular end-diastolic volume as a function of BSA was best fit by a curve (fig. 1) and can be expressed by the equation RVEDV = 75.1 (BSA)'43 (r = 0.97). This equation was used to calculate normal predicted values in all patients. Right ventricular EDV in each patient can then be expressed as percent of normal using the equation (RVEDV X 100)/predicted RVEDV. Right ventricular ejection fraction in normal patients averaged 0.61 ± 0.01 (SEM). Right ventricular output (RVO) as a linear function of BSA is shown in figure 2 and was best expressed (r = 0.90) by the equation: RVO = 4.61 (BSA)- 0.11. Tetralogy Patients
Right Ventricular Volume Variables. The patient's age, BSA, Hgb, heart rate, RV pressure (RVP) and RV volume variables are shown in table 1 and figures 3-7. Right ventricular end-diastolic volume averaged 93% ± 4% (mean ± SEM) of normal in group 1 and was not significantly different from normal (table 1, fig. 3). RVEDV/BSA averaged 57 ± 3 cm'/ml in group 1 and was significantly (P < 0.001) less than the average normal value.
.
c P)
a, EE
RVEDV = 75.1 (BSA) 143
E0
.
r = ,97
0 0 -2 .0
. 0
c .O.
.
.
0 ,9 0
a,
I I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
o
-II
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Body Surface Area ( m' )
1.8 2.0
I]
FIGURE 1. Right ventricular end-diastolic volume as afunction of body surface area in patients with normal right heart. The equation and the solid line represent the best fit for this relationship.
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RV FUNCTION IN TF/Jarmakani et al.
RVEDV in two patients (not shown in table 1) with superior vena cava (SVC) to right pulmonary artery (RPA) anastamosis (Glenn shunt) were significantly reduced (30, 37% of normal). In addition, one tetralogy patient with left
557
pulmonary artery (LPA) originating from the aorta had large RVEDV (169% of normal) and LVEDV (180% of normal). RVEDV averaged 102 ± 7% of normal in group 2 and was not significantly different from normal (table 1, fig. 4).
TABLE 1. Right Ventricular Volume Data Patients
Age (yrs)
BSA (m2)
Hgb (g%)
HR (B/min)
Normal (N = 42) Mean 5.87 0.78 13.2 112 SEM 0.74 0.06 0.2 5 Group 1. Tetralogy 1 A.G. 17.00 1.14 18.7 88 2 B.M. 2.10 0.48 13.5 77 3 B.K. 7.00 0.81 22.4 81 4 C.B. 10.40 1.20 23.4 100 5 C.D. 1.50 0.49 10.7 115 6 C.M. 2.20 0.46 18.0 103 7 D.D. 6.00 0.68 14.6 103 8 D.G. 2.80 0.55 15.4 95 9 E.C. 5.30 0.75 20.0 107 10 F.D. 5.00 0.78 14.0 94 11 G.S. 1.80 0.48 14.8 107 12 H.B. 8.00 0.65 19.6 94 13 H.J. 1.08 0.40 11.7 143 14 M.C. 3.00 0.57 10.4 100 15 M.T. 0.01 0.20 16.5 158 16 M.B. 5.00 0.71 16.7 100 17 M.R. 6.00 0.89 15.6 79 18 N.R. 3.40 0.64 16.5 100 19 O.S. 3.00 0.50 15.3 120 20 O.S. 5.00 0.70 17.6 133 21 O.W. 0.90 0.33 13.8 125 22 P.G. 5.00 0.83 16.7 125 23 S.J. 0.20 0.27 13.0 154 24 T.R. 5.60 0.77 13.2 130 25 V.J. 4.10 0.61 13.2 92 Mean 4.46 0.64 15.8 109 SEM 0.73 0.05 0.6 4 P (vs Normal) NS NS
volume in tetralogy patients. It is interesting that RVEDV in group 1 expressed as percent of normal was not different from normal and all but six values fell in the normal range (103 ± 25%), but was
FIGURE 7. Right ventricular end-diastolic volume (RVEDV) expressed as percent of normal (top panel), and R V systolic index (lower panel) in the two subgroups of each group. NS =not signifi-
was
L
P-0.0I2 P-0.003
T/F cant
NS
P-0.005
T/F + Shunt
(P > 0.05).
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surface area (cardiac index), remained constant with age. The average cardiac index (CI) in our data is higher than the average CI in adults. This difference might, in part, be related to a higher metabolic rate per body surface area in children as compared with adults,'" and it has been shown by Astrand and co-workers17 that cardiac output was linearly related to metabolic rate. The fact that patients in group 1 with Hgb _ 16 g% had less than normal but equal RV and LV end-diastolic volumes indicates that both RV and LV volumes are equally decreased in patients with severe tetralogy. This finding, in addition to the equal LV and RV peak systolic and enddiastolic pressures, suggests that the two ventricles function as one unit. The significantly (P = 0.037) decreased RVEDV from normal in patients with increased Hgb (Hgb - 16 g%), as compared with the normal values in patients with normal Hgb (Hgb < 16 g%), suggests that pulmonary blood flow affects RV size. This theory is supported by the increased RVEDV (169% of normal) in one tetralogy patient with left pulmonary artery arising from the aorta, thus pulmonary venous return might contribute to RV filling. The validation of this observation should await documentation of RVEDV in patients before and after shunt procedure. The increase in LV size after shunt procedure, however, exceeds the increase in RV size. The decreased RVEDV in two patients with Glenn Shunt (. 37% of normal) indicates that RV size is dependent on systemic venous return to the RV. The significantly increased RV end-diastolic pressure (RVEDP) with decreased or normal RVEDV indicates a decreased RV compliance in these patients. It is interesting to note that RVEDV in severe tetralogy patients (Q S > Q P) was similar to LVEDV. After effective shunt procedure however, LVEDV exceeded RVEDV in the presence of an equal RV and LV end-diastolic pressure. This finding indicates that the RV is less compliant than the LV in these patients. Although the LV and RV ejection fractions in group 1 were identical, the LVEF was significantly less than normal and the RVEF was not different from normal. This was, in part, due to the slightly elevated normal LVEF, as compared with normal RVEF, and in part due to the slightly, but not significantly (P = 0.07) depressed RVEF in group 1 tetralogy patients. The decreased ejection fraction, in the presence of normal or decreased RVEDV and normal heart rate, resulted in a decreased RV output in 22 of the 25 patients in group 1 and seven of the 18 patients in group 2. Decreased RVEDV and RV output in severe tetralogy patients would be unexpected if we assumed that these patients had normal systemic flow and all systemic venous return filled the RV only. If the above assumption was correct, then RVEDV would have been normal or increased, but significantly larger than LVEDV. Levine and co-workers'8 showed a bidirectional intraventricular shunting in tetralogy patients. The equally decreased RV and LV volume suggests a significant diastolic right-to-left shunt. The decreased RV and LV end-diastolic volume and output in tetralogy patients emphasizes the potential risk of low cardiac output after complete correction. Parr et al.10
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showed that acute low cardiac output after surgical repair major cause of postoperative mortality. In one patient, Kirklin7 attributed death to a small LV which could not support adequate systemic blood flow. Venugopal and Subramanian3 observed high postoperative mortality in severe tetralogy patients, and death was attributed to a very small RV in at least one patient. Two of our patients with small RV (RVED < 57% of normal) had acute low cardiac output postoperatively despite a significant relief of RV outflow obstruction (RV/LV pressure < 0.60). The two patients were fully digitalized and the blood volume was augmented to achieve a normal left atrial pressure of 12 mm Hg and RV filling pressure of 17 mm Hg. There was no sustained improvement and additional Isuprel infusion was necessary to increase cardiac output. This management improved the patient's status for 6-8 hours which was followed by gradual deterioration and death. There is no doubt that these patients had severe lesions and difficult anatomical defects to correct, thus requiring long operative time. These factors, combined with small RV and LV, will further depress RV function. A successful shunt procedure might result in a normal RV output and an increased LV output. The decreased ejection fraction in the presence of normal preload and afterload is evidence of impaired ventricular function. Preload and afterload can, in turn, be calculated from ventricular pressure, ventricular radius, and wall thickness. Left ventricular end-diastolic volumes in severe tetralogy patients were less than normal volumes but were normal in acyanotic patients and were larger than normal after effective shunt procedure." Left ventricular enddiastolic stress remained normal due to proportional change in ventricular radius and wall thickness. RV end-diastolic volume was normal or less than normal in all patients. The geometry of the RV and the difficulty of determining RV wall thickness in living patients preclude determining RV end-diastolic stress (RVEDS). Right ventricular wall thickness in tetralogy patients was found to be increased in postmortem examination,9 20 which might result in a normal or decreased RVEDS. Peak LV and RV systolic pressures were equal and were not different from normal LV pressure. The change in LVEDV (radius) was similar to the change in LV mass (wall thickness) and resulted in a normal left ventricular systolic stress (normal afterload)." Previous work'8 21 has shown that LV ejection takes place during "isovolumic contraction" via the ventricular septal defect and RV outflow to the pulmonary artery. This indicates that LV ejection takes place at less than systemic pressure during "isovolumic contraction" and at less than normal radius after aortic valve opening. This is evidence of a decreased LV afterload in these patients, and should result in an increased LV ejection fraction in the presence of a normal myocardium and normal preload. Right ventricular systolic afterload could not be calculated; however, it might be normal if there were proportional change in RV pressure and wall thickness (i.e., RV wall thickness increased to three to four times normal). On the other hand, if the increase in wall thickness was less than the increase in RV pressure, then RV afterload would be significantly higher than normal. It has been shown that calculated left ventricular wall stress remained in the normal was a
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range in the presence of chronic pressure or volume overload.22' 23 If the relationship were to exist for the right ventricle, then we could assume that these patients have a normal preload and a normal afterload. Thus, the decreased LV and RV ejection fraction might be due to impaired ventricular function. A decreased RV preload or increased afterload could not be excluded and might be the cause for decreased RVEF. A possible explanation for the decreased RVEF in group 2 is the geometry of the RV which permits this ventricle to function normally at normal RV pressure but not at systemic pressure. RVEF in patients with valvular pulmonic stenosis with increased RV peak systolic pressure and normal RVEDV was significantly higher than normal (unpublished data). Furthermore, it is very unlikely that RV systolic stress (afterload) in PS patients is lower than RV afterload in tetralogy patients. Thus the decreased RVEF in tetralogy patients as compared with PS patients could not be explained by the geometry of the RV and the increased RV afterload alone and might be related to the depressed RV function in tetralogy patients. Although there was no correlation between arterial saturation and RVEF, it is interesting to speculate that chronic hypoxia might be the cause of depressed ventricular function in these patients. Additional support to this hypothesis is the decreased RVEF in patients with transposition of the great vessels."5' 24 The results of this study suggest the following conclusions: 1) The size of the right ventricle was significantly less than normal in severe tetralogy patients (Hgb _ 16 g%) before and after unsuccessful shunt procedure, but was normal in patients with Hgb < 16 g%. 2) Right and left ventricular systolic output is reduced in tetralogy patients preoperatively. After effective shunt procedure (Hgb < 16 g%) RV systolic output increases to normal value and LV systolic output to higher than normal. 3) The normal right ventricular ejection fraction in group 1 and less than normal right ventricular ejection fraction in group 2 were both significantly (P < 0.001) less than RVEF in patients with isolated valvular pulmonic stenosis (RVEF = 0.68 ± 0.02) who have similar RVEDV and pressures. The relative depression in RVEF might be due to the chronic hypoxia in tetra-
logy patients 4) Right and left ventricular volume determination is useful in identifying patients with critically small left or right ventricular chambers (< 60% of normal) where complete correction might be contraindicated. Long-term follow-up evaluation of these patients, taking into consideration ventricular function before surgery and the patient's age at the time of surgery, provides important information and could be beneficial in planning management of these and future patients.
Acknowledgment We wish to express our appreciation to the valuable technical assistance of Ms. Jean Gordon, Mr. George Oku, and Mrs. Kay Graetz and to Mrs. Cathy Heteniak for typing the manuscript.
References I. Barratt-Boyes BG, Simpson M, Neutze JR: Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 43 & 44 (suppl I): 1-25, 1971 2. Breckenridge IM, Oelert H, Graham GR, Stroh J, Waterston D, Bonham-Carter RE: Open heart surgery in the first year of life. J Thorac Cardiovasc Surg 65: 58, 1973 3. Venugopal P, Subramanian S: Intracardiac repair in tetralogy of Fallot under five years of age. Ann Thorac Surg 18: 228, 1974 4. Castaneda AR, Lamberti J, Sade RM, Williams RG, Nasas AS: Open heart surgery during the first three months of life. J Thorac Cardiovasc Surg 68: 719, 1974 5. Pacifico AD, Bargerson LM Jr, Kirklin JW: Primary total correction of tetralogy of Fallot in children less than four years of age. Circulation 48: 1085, 1973 6. Kirklin JW, Pacifico AD, Hannah H III, Allarde RR: Primary definitive intracardiac operations in infants: Intraoperative support techniques. In Advances in Cardiovascular Surgery, edited by Kirklin JW. New York, Gruen & Stratton, Inc., 1973 7. Kirklin JW, Karp RB: The Tetralogy of Fallot from a Surgical Viewpoint. Philadelphia, Saunders, 1970 8. Puga FJ, DuShane JW, McGoon DC: Treatment of tetralogy of Fallot in children less than four years of age. J Thorac Cardiovasc Surg 64: 247, 1972 9. Starr A, Bonchek LL, Sunderland CO: Total correction of tetralogy of Fallot in infancy. J Thorac Cardiovasc Surg 65: 45, 1973 10. Parr GVS, Blackstone EH, Kirklin JW: Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation 51: 867, 1975 11. Jarmakani JMM, Graham TP Jr, Canent RV Jr, Jewett PH: Left heart function in children with tetralogy of Fallot before and after palliative or corrective surgery. Circulation 46: 478, 1972 12. Graham TP Jr, Jarmakani JM, Atwood GF, Canent RV Jr: Right ventricular volume determinations in children. Circulation 47: 144, 1973 13. Dodge HT, Sandler J, Ballew DW, Lord JR Jr: Use of biplane angiocardiography for measurement of left ventricular volume in man. Am Heart J 60: 762, 1960 14. Graham TP Jr, Jarmakani JM, Canent RV Jr, Morrow MN: Left heart volume estimations in infancy and childhood. Re-evaluation of methodology and normal values. Circulation 43: 895, 1971 15. Jarmakani JMM, Canent RV Jr: Preoperative and postoperative right ventricular function in children with transposition of the great vessels. Circulation 49 (suppl II): II-39, 1974 16. DuBois EF: Basal Metabolism in Health and Disease. Philadelphia, Lea and Feiberg, 1936 17. Astrand P, Cuddy TE, Saltin B, Stenberg J: Cardiac output during submaximal and maximal work. J Appl Physiol 19: 268, 1964 18. Levine AR, Spach MS, Canent RV Jr, Boineau JP, Capp MP, Jain V, Barr RC: Intracardiac pressure-flow dynamics in isolated ventricular septal defects. Circulation 35: 430, 1967 19. Lev M, Eckner RAO: The pathologic anatomy of tetralogy of Fallot and its variations. Dis Chest 45: 251, 1964 20. Lev M, Rimoldi HAJ, Rowlatt UF: The quantitative anatomy of cyanotic tetralogy of Fallot. Circulation 30: 531, 1964 21. Jarmakani MM, Edwards SB, Spach MS, Canent RV Jr, Capp MP, Hagan MJ, Barr RC, Jain V: Left ventricular pressure-volume characteristics in congenital heart disease. Circulation 37: 879, 1968 22. Sandler H, Dodge HT: Left ventricular tension and stress in man. Circ Res 13: 91, 1963 23. Ross J Jr, McCullagh WH: The nature of enhanced performance of the dilated left ventricle during chronic volumne overloading. Circ Res 30: 549, 1972 24. Graham TP Jr, Atwood GF, Boucek RF Jr, Boerth RC, Nelson JH: Right heart volume characteristics in transposition of the great arteries. Circulation 51: 881, 1975
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Right ventricular function in children with tetralogy of Fallot before and after aortic-to-pulmonary shunt. J M Jarmakani, M Nakazawa, J Isabel-Jones and R A Marks Circulation. 1976;53:555-561 doi: 10.1161/01.CIR.53.3.555 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1976 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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averaged 0.52 ± 0.03 in this group and was significantly (P < 0.001) less than normal. Right ventricular systolic index (RVSI) averaged 3.51 ± 0.24 L/min/m' and was significantly (P = 0.009) less than normal. RVSI in patients with Hgb < 16 g% averaged 3.90 ± 0.31 and was not different from normal. In contrast, this variable in patients with Hgb >- 16 g% averaged 3.21 ± 0.34 and was significantly (P= 0.005) less than normal. Left ventricular enddiastolic volume (LVEDV) and LV systolic output in group 2 were significantly higher than RVEDV and RV systolic output. Right ventricular and LV ejection fractions in group 2 were not different. The relatively decreased ejection fraction in tetralogy patients, as compared with patients with valvular pulmonic stenosis and similar volumes and pressures, suggests that the decreased ejection fraction was not due to decreased preload or increased afterload and might be due to impaired ventricular function secondary to chronic hypoxia. Early corrective surgery in these patients might reverse this process. However, patients with severe tetralogy who have small ventricular volume and reduced output might benefit from shunt procedure rather than complete correction.
SIGNIFICANT ADVANCES have been made in the surgical technique and management of children with congenital heart disease in general and tetralogy of Fallot in particular.1 A significant number of tetralogy patients experience low cardiac output after complete correction.3 7 Postoperative low cardiac output and mortality were attributed to many factors such as anatomical defects with small main pulmonary artery annulus, severe hypoplasia or absent right or left pulmonary artery, ventriculotomy and right ventricular (RV) outflow patch, myocardial hypoxia during cardiopulmonary bypass, or pulmonary edema in the presence of normal left atrial pressure. In addition to these factors, Venugopal and Subramanian3 attributed death to a diminutive right ventricle in one patient and Kirklin and Karp7 suggested that a small left ventricle (LV) was a cause of death in some tetralogy patients postoperatively. Therefore, we believe that a quantitative determination of ventricular volume preoperatively might help in choosing the surgical procedure most likely to benefit the patient. A previous investigation in tetralogy patients before and after surgery" showed decreased left ventricular end-diastolic volume (LVEDV) in severe cases which subsequently increased after successful shunt procedure or complete correction. Both left ventricular ejection fraction (LVEF) and LV systolic output (LVSO) were significantly less than normal preoperatively. Many questions related to the effect of
the type and time of the surgical procedure on postoperative ventricular function remain unanswered. In addition, no data were available on right ventricular (RV) function in these patients. The purpose of this study was to: 1) quantitate right ventricular end-diastolic volume, ejection fraction, and systolic output in tetralogy patients preoperatively and 2) determine the effect of aortic-to-pulmonary shunt procedure on these variables. Right and left ventricular volume variables were compared in each patient. In addition, RV volume variables in all patients will be compared with normal values. Methods Patient Groups
Data were obtained in 43 tetralogy patients undergoing diagnostic cardiac catheterization. Tetralogy of Fallot in this study was defined as: large ventricular septal defect allowing equalization of the pressure in the two ventricles, and severe right ventricular outflow obstruction causing a bidirectional intraventricular shunt with a net right-to-left shunt. The net right-to-left shunt is the sum of the right-toleft minus the left-to-right shunt. Although some of the patients had patent foramen ovale, none of them had evidence of intra-atrial shunting by oximetry or cineangiography. In addition, there were no valvular lesions other than the pulmonic valve. Patients consisted of 25 pre-operative patients (group 1) and 18 patients (group 2) who had aorticto-pulmonary shunt (Blalock-Taussig = 16, Waterston = 2). The indication for shunt procedure in group 2 was small patient size (body weight < 15.0 kg) with one or more of the following: 1) hypercyanotic spells, 2) squatting, 3) markedly decreased exercise tolerance, and 4) rising hemoglobin (Hgb) concentration.
From the Department of Pediatrics, Division of Cardiology, UCLA Center for the Health Sciences, Los Angeles, California. Supported by research grant HL-16329 from the National Heart and Lung Institute; the American Heart Association, Greater Los Angeles affiliate; and a grant from the Children's Bureau. Address for reprints: Jay M. Jarmakani, M.D., Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90024. Received July 25, 1975; revision accepted for publication October 20, 1975.
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Ages ranged from three days to 17.0 years (mean = 4.46 i 0.73 SEM) in group 1, and from 1.08 to 13.00 years (mean = 6.93 ± 0.78) in group 2. Peak systemic pressure was similar in the two groups and was not different from normal. The heart rate in group 1 (mean = 109 ± 4) was not different from the heart rate in group 2 (101 ± 5), and both values were not significantly different from normal. Hemoglobin concentration in group 1 averaged 15.8 ± 0.6 g% and was not significantly different from Hgb concentration in group 2 (16.2 ± 0.6 g%). Hemoglobin concentration in both groups was significantly (P < 0.001) higher than normal. Eighteen patients in group 1 had a net right-to-left shunt in excess of 20%, while the other seven patients had balanced shunt (net shunt < 20%). The shunt in group 2 was calculated in 11 patients by the dye dilution method. In these 11 patients there was an inverse relation between the net leftto-right shunt and Hgb concentration. The shunt was also calculated in all patients using the Fick method, but was not included in group 2 because of the inaccuracy of this method in tetralogy patients with shunt. Data in tetralogy patients were compared with normal right ventricular volume parameters obtained from 42 patients which included normal heart, mild valvular pulmonary stenosis, peripheral pulmonary stenosis, bicuspid aortic valve with no significant gradient, systemic hypertension, vascular ring and mediastinal mass. None of the patients had detectable shunt and the peak RV pressure was less than 45 mm Hg. Data Acquisition
All data were obtained during diagnostic cardiac catheterization. Infants less than three months of age were not premedicated, and those three to 12 months old were given morphine (0.1 mg/kg) only. All other patients were premedicated with meperidine (1 mg/kg), promethazine (0.5 mg/kg) and chlorpromazine (0.5 mg/kg). Before the first cineangiocardiogram was taken, the left-to-right shunt and right-to-left shunt were quantified by the Fick and dye dilution methods in groups 1 and 2. The left and right ventricular pressures were recorded using the Millar Mikro-tip transducer catheter (Millar Instruments, Inc., P. 0. Box 18227, Houston, Texas 77023) or a side hole catheter (NIH No. 6F or 7F) connected to a Statham P23db transducer (Statham Instruments, Inc., 2230 Statham Boulevard, Oxnard, California). Zero pressure was referenced to mid chest. Right and left ventricular volumes were calculated from biplane cineangiocardiograms filmed after injecting 1.25 cc/kg of body weight of Renografin-76 into the right ventricle and left atrium or ventricle. Only normal sinus beats were analyzed. Right ventricular volume was calculated according to Simpson's rule method,'2 and LV volume was calculated according to the area length method of Dodge et al." Right and left ventricular volumes were calculated at end-diastole and end-systole. All values were corrected by separate regression equations described previously. 2," The following variables were calculated from end-diastolic (EDV) and end-systolic volume (ESV): RV stroke volume (RVSV) = RVEDV - RVESV RV ejection fraction (RVEF) = RVSV/RVEDV RV systolic output (RVSO) = RVSV X heart rate Identical variables were calculated for the left ventricle
and were compared with RV volume variables in each patient. The difference in heart rates between the LV and RV beats was less than 10%. The relation between RVEDV and body surface area (BSA) in children with normal right hearts was used to derive normal predicted values in each
patient. Results Normal Values for R V Volumes
The hemodynamic and RV volume variables are shown in table 1. Right ventricular volume parameters in normal children were similar to LV volume parameters and were not different from normal values reported previously."2 Right ventricular end-diastolic volume as a function of BSA was best fit by a curve (fig. 1) and can be expressed by the equation RVEDV = 75.1 (BSA)'43 (r = 0.97). This equation was used to calculate normal predicted values in all patients. Right ventricular EDV in each patient can then be expressed as percent of normal using the equation (RVEDV X 100)/predicted RVEDV. Right ventricular ejection fraction in normal patients averaged 0.61 ± 0.01 (SEM). Right ventricular output (RVO) as a linear function of BSA is shown in figure 2 and was best expressed (r = 0.90) by the equation: RVO = 4.61 (BSA)- 0.11. Tetralogy Patients
Right Ventricular Volume Variables. The patient's age, BSA, Hgb, heart rate, RV pressure (RVP) and RV volume variables are shown in table 1 and figures 3-7. Right ventricular end-diastolic volume averaged 93% ± 4% (mean ± SEM) of normal in group 1 and was not significantly different from normal (table 1, fig. 3). RVEDV/BSA averaged 57 ± 3 cm'/ml in group 1 and was significantly (P < 0.001) less than the average normal value.
.
c P)
a, EE
RVEDV = 75.1 (BSA) 143
E0
.
r = ,97
0 0 -2 .0
. 0
c .O.
.
.
0 ,9 0
a,
I I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
o
-II
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Body Surface Area ( m' )
1.8 2.0
I]
FIGURE 1. Right ventricular end-diastolic volume as afunction of body surface area in patients with normal right heart. The equation and the solid line represent the best fit for this relationship.
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RV FUNCTION IN TF/Jarmakani et al.
RVEDV in two patients (not shown in table 1) with superior vena cava (SVC) to right pulmonary artery (RPA) anastamosis (Glenn shunt) were significantly reduced (30, 37% of normal). In addition, one tetralogy patient with left
557
pulmonary artery (LPA) originating from the aorta had large RVEDV (169% of normal) and LVEDV (180% of normal). RVEDV averaged 102 ± 7% of normal in group 2 and was not significantly different from normal (table 1, fig. 4).
TABLE 1. Right Ventricular Volume Data Patients
Age (yrs)
BSA (m2)
Hgb (g%)
HR (B/min)
Normal (N = 42) Mean 5.87 0.78 13.2 112 SEM 0.74 0.06 0.2 5 Group 1. Tetralogy 1 A.G. 17.00 1.14 18.7 88 2 B.M. 2.10 0.48 13.5 77 3 B.K. 7.00 0.81 22.4 81 4 C.B. 10.40 1.20 23.4 100 5 C.D. 1.50 0.49 10.7 115 6 C.M. 2.20 0.46 18.0 103 7 D.D. 6.00 0.68 14.6 103 8 D.G. 2.80 0.55 15.4 95 9 E.C. 5.30 0.75 20.0 107 10 F.D. 5.00 0.78 14.0 94 11 G.S. 1.80 0.48 14.8 107 12 H.B. 8.00 0.65 19.6 94 13 H.J. 1.08 0.40 11.7 143 14 M.C. 3.00 0.57 10.4 100 15 M.T. 0.01 0.20 16.5 158 16 M.B. 5.00 0.71 16.7 100 17 M.R. 6.00 0.89 15.6 79 18 N.R. 3.40 0.64 16.5 100 19 O.S. 3.00 0.50 15.3 120 20 O.S. 5.00 0.70 17.6 133 21 O.W. 0.90 0.33 13.8 125 22 P.G. 5.00 0.83 16.7 125 23 S.J. 0.20 0.27 13.0 154 24 T.R. 5.60 0.77 13.2 130 25 V.J. 4.10 0.61 13.2 92 Mean 4.46 0.64 15.8 109 SEM 0.73 0.05 0.6 4 P (vs Normal) NS NS
volume in tetralogy patients. It is interesting that RVEDV in group 1 expressed as percent of normal was not different from normal and all but six values fell in the normal range (103 ± 25%), but was
FIGURE 7. Right ventricular end-diastolic volume (RVEDV) expressed as percent of normal (top panel), and R V systolic index (lower panel) in the two subgroups of each group. NS =not signifi-
was
L
P-0.0I2 P-0.003
T/F cant
NS
P-0.005
T/F + Shunt
(P > 0.05).
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CIRCULATION
surface area (cardiac index), remained constant with age. The average cardiac index (CI) in our data is higher than the average CI in adults. This difference might, in part, be related to a higher metabolic rate per body surface area in children as compared with adults,'" and it has been shown by Astrand and co-workers17 that cardiac output was linearly related to metabolic rate. The fact that patients in group 1 with Hgb _ 16 g% had less than normal but equal RV and LV end-diastolic volumes indicates that both RV and LV volumes are equally decreased in patients with severe tetralogy. This finding, in addition to the equal LV and RV peak systolic and enddiastolic pressures, suggests that the two ventricles function as one unit. The significantly (P = 0.037) decreased RVEDV from normal in patients with increased Hgb (Hgb - 16 g%), as compared with the normal values in patients with normal Hgb (Hgb < 16 g%), suggests that pulmonary blood flow affects RV size. This theory is supported by the increased RVEDV (169% of normal) in one tetralogy patient with left pulmonary artery arising from the aorta, thus pulmonary venous return might contribute to RV filling. The validation of this observation should await documentation of RVEDV in patients before and after shunt procedure. The increase in LV size after shunt procedure, however, exceeds the increase in RV size. The decreased RVEDV in two patients with Glenn Shunt (. 37% of normal) indicates that RV size is dependent on systemic venous return to the RV. The significantly increased RV end-diastolic pressure (RVEDP) with decreased or normal RVEDV indicates a decreased RV compliance in these patients. It is interesting to note that RVEDV in severe tetralogy patients (Q S > Q P) was similar to LVEDV. After effective shunt procedure however, LVEDV exceeded RVEDV in the presence of an equal RV and LV end-diastolic pressure. This finding indicates that the RV is less compliant than the LV in these patients. Although the LV and RV ejection fractions in group 1 were identical, the LVEF was significantly less than normal and the RVEF was not different from normal. This was, in part, due to the slightly elevated normal LVEF, as compared with normal RVEF, and in part due to the slightly, but not significantly (P = 0.07) depressed RVEF in group 1 tetralogy patients. The decreased ejection fraction, in the presence of normal or decreased RVEDV and normal heart rate, resulted in a decreased RV output in 22 of the 25 patients in group 1 and seven of the 18 patients in group 2. Decreased RVEDV and RV output in severe tetralogy patients would be unexpected if we assumed that these patients had normal systemic flow and all systemic venous return filled the RV only. If the above assumption was correct, then RVEDV would have been normal or increased, but significantly larger than LVEDV. Levine and co-workers'8 showed a bidirectional intraventricular shunting in tetralogy patients. The equally decreased RV and LV volume suggests a significant diastolic right-to-left shunt. The decreased RV and LV end-diastolic volume and output in tetralogy patients emphasizes the potential risk of low cardiac output after complete correction. Parr et al.10
VOL. 53, No. 3, MARCH 1976
showed that acute low cardiac output after surgical repair major cause of postoperative mortality. In one patient, Kirklin7 attributed death to a small LV which could not support adequate systemic blood flow. Venugopal and Subramanian3 observed high postoperative mortality in severe tetralogy patients, and death was attributed to a very small RV in at least one patient. Two of our patients with small RV (RVED < 57% of normal) had acute low cardiac output postoperatively despite a significant relief of RV outflow obstruction (RV/LV pressure < 0.60). The two patients were fully digitalized and the blood volume was augmented to achieve a normal left atrial pressure of 12 mm Hg and RV filling pressure of 17 mm Hg. There was no sustained improvement and additional Isuprel infusion was necessary to increase cardiac output. This management improved the patient's status for 6-8 hours which was followed by gradual deterioration and death. There is no doubt that these patients had severe lesions and difficult anatomical defects to correct, thus requiring long operative time. These factors, combined with small RV and LV, will further depress RV function. A successful shunt procedure might result in a normal RV output and an increased LV output. The decreased ejection fraction in the presence of normal preload and afterload is evidence of impaired ventricular function. Preload and afterload can, in turn, be calculated from ventricular pressure, ventricular radius, and wall thickness. Left ventricular end-diastolic volumes in severe tetralogy patients were less than normal volumes but were normal in acyanotic patients and were larger than normal after effective shunt procedure." Left ventricular enddiastolic stress remained normal due to proportional change in ventricular radius and wall thickness. RV end-diastolic volume was normal or less than normal in all patients. The geometry of the RV and the difficulty of determining RV wall thickness in living patients preclude determining RV end-diastolic stress (RVEDS). Right ventricular wall thickness in tetralogy patients was found to be increased in postmortem examination,9 20 which might result in a normal or decreased RVEDS. Peak LV and RV systolic pressures were equal and were not different from normal LV pressure. The change in LVEDV (radius) was similar to the change in LV mass (wall thickness) and resulted in a normal left ventricular systolic stress (normal afterload)." Previous work'8 21 has shown that LV ejection takes place during "isovolumic contraction" via the ventricular septal defect and RV outflow to the pulmonary artery. This indicates that LV ejection takes place at less than systemic pressure during "isovolumic contraction" and at less than normal radius after aortic valve opening. This is evidence of a decreased LV afterload in these patients, and should result in an increased LV ejection fraction in the presence of a normal myocardium and normal preload. Right ventricular systolic afterload could not be calculated; however, it might be normal if there were proportional change in RV pressure and wall thickness (i.e., RV wall thickness increased to three to four times normal). On the other hand, if the increase in wall thickness was less than the increase in RV pressure, then RV afterload would be significantly higher than normal. It has been shown that calculated left ventricular wall stress remained in the normal was a
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RV FUNCTION IN TF/Jarmakani et al.
range in the presence of chronic pressure or volume overload.22' 23 If the relationship were to exist for the right ventricle, then we could assume that these patients have a normal preload and a normal afterload. Thus, the decreased LV and RV ejection fraction might be due to impaired ventricular function. A decreased RV preload or increased afterload could not be excluded and might be the cause for decreased RVEF. A possible explanation for the decreased RVEF in group 2 is the geometry of the RV which permits this ventricle to function normally at normal RV pressure but not at systemic pressure. RVEF in patients with valvular pulmonic stenosis with increased RV peak systolic pressure and normal RVEDV was significantly higher than normal (unpublished data). Furthermore, it is very unlikely that RV systolic stress (afterload) in PS patients is lower than RV afterload in tetralogy patients. Thus the decreased RVEF in tetralogy patients as compared with PS patients could not be explained by the geometry of the RV and the increased RV afterload alone and might be related to the depressed RV function in tetralogy patients. Although there was no correlation between arterial saturation and RVEF, it is interesting to speculate that chronic hypoxia might be the cause of depressed ventricular function in these patients. Additional support to this hypothesis is the decreased RVEF in patients with transposition of the great vessels."5' 24 The results of this study suggest the following conclusions: 1) The size of the right ventricle was significantly less than normal in severe tetralogy patients (Hgb _ 16 g%) before and after unsuccessful shunt procedure, but was normal in patients with Hgb < 16 g%. 2) Right and left ventricular systolic output is reduced in tetralogy patients preoperatively. After effective shunt procedure (Hgb < 16 g%) RV systolic output increases to normal value and LV systolic output to higher than normal. 3) The normal right ventricular ejection fraction in group 1 and less than normal right ventricular ejection fraction in group 2 were both significantly (P < 0.001) less than RVEF in patients with isolated valvular pulmonic stenosis (RVEF = 0.68 ± 0.02) who have similar RVEDV and pressures. The relative depression in RVEF might be due to the chronic hypoxia in tetra-
logy patients 4) Right and left ventricular volume determination is useful in identifying patients with critically small left or right ventricular chambers (< 60% of normal) where complete correction might be contraindicated. Long-term follow-up evaluation of these patients, taking into consideration ventricular function before surgery and the patient's age at the time of surgery, provides important information and could be beneficial in planning management of these and future patients.
Acknowledgment We wish to express our appreciation to the valuable technical assistance of Ms. Jean Gordon, Mr. George Oku, and Mrs. Kay Graetz and to Mrs. Cathy Heteniak for typing the manuscript.
References I. Barratt-Boyes BG, Simpson M, Neutze JR: Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 43 & 44 (suppl I): 1-25, 1971 2. Breckenridge IM, Oelert H, Graham GR, Stroh J, Waterston D, Bonham-Carter RE: Open heart surgery in the first year of life. J Thorac Cardiovasc Surg 65: 58, 1973 3. Venugopal P, Subramanian S: Intracardiac repair in tetralogy of Fallot under five years of age. Ann Thorac Surg 18: 228, 1974 4. Castaneda AR, Lamberti J, Sade RM, Williams RG, Nasas AS: Open heart surgery during the first three months of life. J Thorac Cardiovasc Surg 68: 719, 1974 5. Pacifico AD, Bargerson LM Jr, Kirklin JW: Primary total correction of tetralogy of Fallot in children less than four years of age. Circulation 48: 1085, 1973 6. Kirklin JW, Pacifico AD, Hannah H III, Allarde RR: Primary definitive intracardiac operations in infants: Intraoperative support techniques. In Advances in Cardiovascular Surgery, edited by Kirklin JW. New York, Gruen & Stratton, Inc., 1973 7. Kirklin JW, Karp RB: The Tetralogy of Fallot from a Surgical Viewpoint. Philadelphia, Saunders, 1970 8. Puga FJ, DuShane JW, McGoon DC: Treatment of tetralogy of Fallot in children less than four years of age. J Thorac Cardiovasc Surg 64: 247, 1972 9. Starr A, Bonchek LL, Sunderland CO: Total correction of tetralogy of Fallot in infancy. J Thorac Cardiovasc Surg 65: 45, 1973 10. Parr GVS, Blackstone EH, Kirklin JW: Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation 51: 867, 1975 11. Jarmakani JMM, Graham TP Jr, Canent RV Jr, Jewett PH: Left heart function in children with tetralogy of Fallot before and after palliative or corrective surgery. Circulation 46: 478, 1972 12. Graham TP Jr, Jarmakani JM, Atwood GF, Canent RV Jr: Right ventricular volume determinations in children. Circulation 47: 144, 1973 13. Dodge HT, Sandler J, Ballew DW, Lord JR Jr: Use of biplane angiocardiography for measurement of left ventricular volume in man. Am Heart J 60: 762, 1960 14. Graham TP Jr, Jarmakani JM, Canent RV Jr, Morrow MN: Left heart volume estimations in infancy and childhood. Re-evaluation of methodology and normal values. Circulation 43: 895, 1971 15. Jarmakani JMM, Canent RV Jr: Preoperative and postoperative right ventricular function in children with transposition of the great vessels. Circulation 49 (suppl II): II-39, 1974 16. DuBois EF: Basal Metabolism in Health and Disease. Philadelphia, Lea and Feiberg, 1936 17. Astrand P, Cuddy TE, Saltin B, Stenberg J: Cardiac output during submaximal and maximal work. J Appl Physiol 19: 268, 1964 18. Levine AR, Spach MS, Canent RV Jr, Boineau JP, Capp MP, Jain V, Barr RC: Intracardiac pressure-flow dynamics in isolated ventricular septal defects. Circulation 35: 430, 1967 19. Lev M, Eckner RAO: The pathologic anatomy of tetralogy of Fallot and its variations. Dis Chest 45: 251, 1964 20. Lev M, Rimoldi HAJ, Rowlatt UF: The quantitative anatomy of cyanotic tetralogy of Fallot. Circulation 30: 531, 1964 21. Jarmakani MM, Edwards SB, Spach MS, Canent RV Jr, Capp MP, Hagan MJ, Barr RC, Jain V: Left ventricular pressure-volume characteristics in congenital heart disease. Circulation 37: 879, 1968 22. Sandler H, Dodge HT: Left ventricular tension and stress in man. Circ Res 13: 91, 1963 23. Ross J Jr, McCullagh WH: The nature of enhanced performance of the dilated left ventricle during chronic volumne overloading. Circ Res 30: 549, 1972 24. Graham TP Jr, Atwood GF, Boucek RF Jr, Boerth RC, Nelson JH: Right heart volume characteristics in transposition of the great arteries. Circulation 51: 881, 1975
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Right ventricular function in children with tetralogy of Fallot before and after aortic-to-pulmonary shunt. J M Jarmakani, M Nakazawa, J Isabel-Jones and R A Marks Circulation. 1976;53:555-561 doi: 10.1161/01.CIR.53.3.555 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1976 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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