Left ventricular function in cyanotic congenital heart disease

Left Ventricular Function in Cyanotic Congenital Heart Disease

THOMAS HAROLD ROBERT ROBERT

P. GRAHAM, Jr., MD, FACC G. ERATH, Jr., MD J. BOUCEK, Jr., MD C. BOERTH, MD, PhD

Na.shville, Tennessee

Left ventricular function was studied with quantitative biplane cineangiocardiography in 39 preoperative and 23 postoperative patients with cyanotic congenital heart disease. Diagnoses included pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (group l), tricuspid atresia (group 2) and pulmonary atresia with ventricular septal defect (group 3). Preoperative patients ranged in age from 1 day to 7 years and postoperative patients from 7 weeks to 23 years. Left ventricular end-diadollc volume was increased in preoperative patients in groups 1 and 2 (132 and 136 percent of normal, respectively) but was normal in patients in group 3. Left ventricular ejection fraction was decreased to a similar extent in preoperative groups 1 to 3: 0.54,0.55 and 0.56, respectively. After a shunt procedure left ventricular end-diastolic volume increased to 226 and 266 percent of normal In groups 1 and 2, respectively, but remained within normal limits in group 3. Left ventricular ejection fraction was normal in postoperative group 1 patients, whose ages averaged 1.6 years, but remained decreased In group 2 and 3 patients, whose ages averaged 6.1 and 5.6 years, respectively. Duration of cyanosis and degree of left ventricular dilatation appear to be important variables In regard to pump function in patients with cyanotic congenital heart disease.

Abnormalities of cardiac function have been detected in various cyanotic congenital heart lesions including pulmonary atresia, transposition of the great arteries, tetralogy of Fallot and tricuspid atresia.l-g In some of these lesions, abnormalities also have been found after reparative surgery.a6y7 Despite these data, it is currently unclear whether either the degree or the duration of cyanosis is related to abnormalities of cardiac function in these patients. The purpose of this investigation was to estimate left ventricular function using quantitative biplane cineangiocardiography in patients with cyanotic congenital heart disease before and after palliative operation and to attempt to correlate any abnormalities with degree of cyanosis, duration of cyanosis and size of the left ventricle. Methods

From the Division of Pediatric: Cardiology, Vanderbilt University Medical Center, Nashville, Ten-. This work was supported in parl by Grarit 1 ROl HL21985-02 RAD of the National HeWLq,andBloodInstlMe,thefWionalHeart InstfWte, Bethesda, Maryland. Manuscript received October 23, 1979; revised manuscript received December 31, 1979, accepted January 9, 1980. Address for reprints: Thomas P. Graham, Jr., MD, Division of Pediatric Cardiology, Vanderbilt Medical Center, Nashville, Tennessee 37232.

Study patients: Patients with tricuspid atresia, pulmonary atresia or critical pulmonary stenosis with intact ventricular septum, and pulmonary atresia with ventricular septal defect were included in this analysis. All patients with these diagnoses who were studied at Vanderbilt Uuiversity from July 1971through July 1979 were included in the analysis provided they had biplane left ventricular cineaugiocardiograms that were adequate for analysis of left ventricular volume and ejection fraction. During this period, only 9 of 71 studies were excluded because of inadequate cineangiocardiograms. All data were obtained during diagnostic studies and none of the cineangiocardiograms were taken for the sole purpose of obtaining left ventricular function data. All data were obtained after any metabolic acidosis was corrected. Premature contractions and postpremature contractions were excluded from the analysis. Details of the methodology have been described previously together with normal values for comparison with different patient groups.l’J

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Study groups: The 62 patients were classified into three groups on the basis of their clinical diagnosis (Table I). Group 1A included 16 patients with pulmonary atresia with intact ventricular septum or critical pulmonary stenosis defined as severe pulmonary stenosis with pressure at systemic levels or higher in the right ventricle and a right to left shunt at the atria1 level. In these patients, systemic oxygen saturation ranged from 30 to 85 percent at rest. Of the 16 patients in this group 6 had pulmonary stenosis and 10 pulmonary atresia. Twelve of the patients survived operation and six have had postoperative cardiac catheterization studies, as described subsequently. Group 1B consisted of 10 patients with pulmonary atresia with intact ventricular septum or pulmonary stenosis who were studied after successful palliation with valvulotomy (2 patients), shunt (2 patients) or valvulotomy plus shunt (6 patients). There were five Waterston shunts, two Potts shunts, one Glenn shunt and one Blalock-Taussig shunt, with one patient having two shunts. Eight patients underwent a second cardiac catheterization in the 1st year of life and two patients were restudied after 1 year of life. The time from operation to restudy ranged from 10 days to 11 years. The oldest patient was 11.8 years at the time of restudy. Three patients were restudied both before and after 1 year of age; only the data at the last recatheterization were included in the statistical comparisons of different groups. Group ZA consisted of 10 patients with tricuspid atresia who underwent cardiac catheterization studies before any shunting operation. All patients had associated pulmonary stenosis; seven had normally related great arteries and three had d-transposition. The patients’ ages ranged from 1 day to 2 years. Two patients had two cardiac catheterization studies before palliation. Systemic oxygen saturation ranged from 50 to 86 percent. Of six patients who had shunt procedures, five survived operation. Three patients await operation and one patient was lost to follow-up study. Only one patient had a postoperative study. Group 2B consisted of eight patients with tricuspid atresia who underwent cardiac catheterization studies after a shunt. These patients ranged in age from 1.7 to 23.1 years. Seven patients had pulmonary stenosis and one had pulmonary atresia; only one had transposed great arteries. One patient

had two studies at age 3.7 and age 9 years. Three patients had a prior Waterston anastomosis, two a Potts anastomosis, two a prior Glenn shunt and one prior Glenn and Blalock-Taussig shunts. All patients were restudied at least 1 year after their operative procedure. Group 3A consisted of I3 patients with pulmonary atresia with ventricular septal defect. All patients had at least a confluence of right and left pulmonary arteries supplied by either a ductus or anomalous systemic vessels. Their ages ranged from 1 day to 7 years at the time of initial cardiac catheterization, and two patients had a second study 5 months and 3 years later, respectively. All but two patients were studied initially in the first 3 months of life. Systemic oxygen saturation ranged from 32 to 85 percent. Six patients had shunts with one death, three patients had attempted repair with two deaths and three patients have had no operative procedure. Group 3B consisted of five patients who underwent cardiac catheterization 1 to 12 years after a shunt procedure (four Waterston and two Blalock-Taussig shunts [one patient had two shunts]). Two patients had preoperative shunts. Ventricular function data analyses: All left ventricular volume data from the patients with cyanosis were compared with normal data in two ways. First, the data were expressed, using previously derived regression equations, as a percent of the predicted normal value. However, individual patient data from the previous study were unavailable for direct statistical comparison of a normal group with the cyanotic patients, and therefore another group of normal patients was used for t tests, as will be described. This second group of patients with a presumed normal left ventricle included patients with mild valvular or peripheral pulmonary stenosis (right ventricular pressure 50 mm Hg or less), a small atria1 septal defect with a left to right shunt of less than 25 percent of pulmonary flow, mild tricuspid regurgitation and vascular ring. All normal data were obtained as part of diagnostic cardiac catheterization for cardiovascular anomalies presumed to be more serious. There were 21 patients less than 1 year of age and 15 patients greater than 1 year. Values of left ventricular end-diastolic volume, ejection fraction and systolic index were compared for normal subjects versus the patients with cyanosis using t tests for unpaired

TABLE I Patient Groups (mean f standard error of the mean and range) Croup 1. PAt or CPS, IVS A. Preop 0. Postop 2. TAt A. Preop

M 16 10

10

0. Postop

8

3. PAt, VSD A. Preop

13

B. Postop 4. Normal A. l

yr

5

21 15

Weight (kg)

Age (yr)

OsSat(%)

PCV (%)

59 f (30 84 f (71

52 f (42 48 f (40

0.04 l 0.02; (1 day to 4 mo) 1.8 f 1.1; (0.13 to 11.8)

3.6 f (2.5 8.7 f (4.8

0.37 f 0.24; (1 dayto2yr) 8.1 f 2.2: (1.7 to 23.1)

4.6 f 0.9; (2.5 to 9.7) 25.2 f 4.7; (9.3 to 75.9)

68 f 4; (50 to 86) Sih33; (72 to 9 1)

53 f 3; (41 to 65) 52f3; (43 to 84)

0.74 f 0.59; (1 day to 7 yr) 5.6 f 2.0; (2.2 to 13.0)

4.7 f 1.4; (2.2 to 6.4) 19.0 f 7.3; (8.0 to 47.6)

68 f (32 81 f (67

49 f (34 55 f (44

0.35 f 0.06; (2dayto 11 mo) 5.8 f 0.8; (1.2 to 13.0)

5.8 f 0.4; (1.7 to 10.0) 19.5 f 2.1; I1 1.0 to 42.7)

0.2; to 5.0) 1.8; to 23.9)

5; to 85) 3; to 96)

6; to 85) 4; to 87)

2; to 62) 2: to 53)

3; to 62) 41; to 66)

...

...

...

. .

PAt = pulmonary atresia; CPS = critical pulmonary stenosis; IVS = intact ventricular septum; postop = postoperative; preop = preoperative; Sat = saturation: TAt = tricuspid atresia; VSD = ventricular septal defect; PGV = packed cell volume.

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data. In addition, the various groups of patients with cyanosis were compared with each other as described under Results. Finally, linear regression analysis was used in an attempt to determine if ejection fraction was related to age, end-diastolic volume, systemic oxygen saturation or hematocrit. Values are expressed as mean f standard error of the mean.

Results Preoperative Studies

Left ventricular endl-diastolic volume: This variable averaged 47 f 3 ml/m2 or 132 percent of the predicted normal value in patients in group 1A with pulmonary atresia or critical pulmonary stenosis and intact ventricular septum; both values’were significantly different from normal (Fig. 1, Table II). There were no significant differences in this or in other variables between patients with pulmonary atresia and those with pulmonary stenosis (p >.0.05), and therefore their data were combined for comparison with the normal subjects and other groups. Left ventricular end-diastolic volume was also increased from normal patients in group 2A with tricuspid atresia, averaging 52 f 4 ml/m2 or 136 percent of predicted normal. These values were not significantly different from those found in patients with pulmonary atresia or pulmonary stenosis. Left ventricular enddiastolic volume averaged 39 f 5 ml/m2 or 105 percent of normal in patients in group 3A with pulmonary atresia and ventricular septal defect. These values were not significantly different from normal values, from those in patients with pulmonary stenosis or atresia and intact ventricular septum, or from those in patients with triauspid atresia.

D

200

7

i

I

5w

H

n,z

*la 2:’

150

u E F-“’ Z&k w+o ‘(n< +Q” l&o Y

-

100

-

50

-

----------

---

109% NORMAL RANGE

---

--

0

136%

132%

__

--_

TAt (n=IO)

PALI, iPS IVS

(tl=16)

---

PA1 VSD in : \3)

FIGURE 1. Left ventricularend-diastolicvolume as a percent of the predicted normal value* for the three preoperative patient groups. PAt = pulmonary atresia; CPS = critical pulmonary stenosis; IVS = intact ventricular septum; TAt = tricuspid atresia; VSD = ventricular septal defect.

Ejection fraction: Left ventricular ejection fraction averaged 0.54 f 0.01 in group lA, 0.54 f 0.03 in group 2A and 0.56 f 0.02 in group 3A; all values were significantly less than normal (Table II, Fig. 2). These values were not different from each other. Left ventricular systolic index averaged 3.5 f 0.3,3.8 f 0.5 and 3.1 i. 0.4 liters/min per m2 in groups lA, 2A and 3A, respectively. These values were not different from normal or from each other. Postoperative Studies

Left ventricular end-diastolic volume: This variable’kveraged 107 f 18 ml/m2 or 228 percent of normal

TABLE II Left Ventricular Volume Data (mean f standard error of the mean) LVEDV (ml/m*)

LVEDV (% normal)

LVEF

LVSI (literslmin per m2)

LVSI (% normal)

138N$ 3

47 f 3 p <0.05

132 f 8 p
0.54 f 0.01 p
3.5 f 0.3 NS

94 f 6 NS p vs normal

2A. TAt

132 f 6 NS

52 f 4 p
136f8 p (0.001

0.54 f 0.03 p
3.8 f 0.5 NS

108 f 12 NS p vs normal

3A. PAt, VSD

13’N:

105 f 12 NS

0.56 f 0.02 p
3.1 f 0.4 NS

86f 11 NS p vs normal

13

228 f 27 p
0.63 f 0.03 NS p
8.2 f 1.0 p
199 f 24 p
172 f 37

266 f 60 p
o.5::O!02 NS

9.8 f 2.2 p
236 f 57 p
120 l 15

0.58 l 0.05

4.4 f 0.7

107 f 16 NS p vs normal NS p vs preoperative

Group PreQperative 1A. PAt or CPS, IVS

Postoperative 1B. PAt or CPS. IVS

2B. TAt

HR

7

120f6 NS NS

111 f

39 f 5 NS 107 f

10

K

30. PA& VSD

; <
78f

17

lo3N: 6 p
str

p zzo2

p z&O5

p zo5

!Z

= critical pulmonary stenosis; HR = head rate; IVS = intact ventricular septum; LVEF = left ventricular ejection fraction; LVSI = left ventricular = not significant; p = probability; PAt = pulmonary atresia; TAt = tricuspid atresia; VSD = ventricular septal defect.

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100

$5 g- 060

g: Eff z

ET AL.

I

c-______-__--_------__\

( 060:

-

-

054 _____________

0.54

0 56

NORMAL RANGE

YE $040. Y= 020

-

0’

PAl.CPS

ILS

TAt

In =lO)

In=161

PAt VSD (n:l3)

FIGURE 2. Left ventricular ejection fraction for the three preoperative patients groups. Abbreviations as in Figure 1.

in group 1B patients studied after operation for pulmonary atresia or critical pulmonary stenosis (Fig. 3). These values are significantly different from normal as well as from preoperative values (Table II). Left ventricular end-diastolic volume was also increased in patients with tricuspid atresia after a shunt procedure, averaging 172 f 37 ml/m2 or 266 percent of normal (Fig. 3). These values were significantly different from normal values, from preoperative values and from those of patients in group 1B with pulmonary stenosis or atresia and intact ventricular septum. Left ventricular end-diastolic volume averaged 78 f 17 ml/m2 or 120 f 15 percent in five postoperative patients with pulmonary atresia and ventricular septal defect. For this small number of patients, end-diastolic volume in ml/m2 was not different from normal but was different from the preoperative value (p <0.02). However, the pre- and postoperative groups were different in age, which probably accounts for the end-diastolic volume difference when expressed in ml/m2. Left ven-

”

PAl,CPS IVS (n:IO)’

TAI ill=t3)

PAl VSD (fl c 51

FIGURE 3. Left ventricular end-diastolic volume for the three postoperative patient groups. Abbreviations as in Figure 1.

1234

tricular end-diastolic volume as a percent of the predicted normal value was increased from normal but not from preoperative values. Finally, it was significantly less for patients with pulmonary atresia and ventricular septal defect than for patients in either group 1B or 2B (Fig. 3). Ejection fraction: Left ventricular ejection fraction averaged 0.63 f 0.03 in patients in group 1B and was not different from normal but was different from the preoperative value (Fig. 4, Table II). Patients with postoperative tricuspid atresia had an average ejection fraction value of 0.53 f 0.02, which was different from the normal value and from that in patients in group lB, but not from that in patients with preoperative tricuspid atresia. Similarly, patients in group 3B with pulmonary atresia and ventricular septal defect had a lower than normal ejection fraction of 0.58 f 0.05, which was not different from the preoperative value. This value also was not different from that for patients with postoperative tricuspid atresia but was different from that of patients with postoperative pulmonary atresia with an intact ventricular septum. Left ventricular systolic index was significantly greater than normal for both group 1B and 2B patients but was not different from normal in patients in group 3B (Table II).

June 1980

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Volume

Correlation of Left Ventricular Ejection Fraction With Other Variables

The relations between ejection fraction and ventricular size, patient age, systemic oxygen saturation and hematocrit values were examined in the entire group of patients after a shunt procedure (n = 24). Linear regression analysis of left ventricular ejection fraction (LVEF) with age showed a weak negative relation, with older patients having a lower ejection fraction (LVEF = -0.0068 [age] + 0.61, standard error of the estimate f 0.09, p <0.05, r = 0.441). This relation was also examined by classifying the group into 12 patients who were 4 years of age or less and 12 patients older than 4 years. Figure 5 shows that the mean ejection fraction in the older patients was 0.54 and was significantly less than the ejection fraction in the younger group, 0.61 (p CO.01). Neither end-diastolic volume nor systemic oxygen saturation was different in the two age groups (p >0.05). Ejection fraction was also examined as a function of end-diastolic volume (LVEDV). Again there was a negative correlation between these variables, and lower ejection fractions were associated with larger left ventricles (LVEF = -0.00025 [LVEDV] + 0.63, standard error of the estimate f 0.09, p = 0.05, r = 0.339). Multiple regression analysis using both end-diastolic volume and age as independent variables yielded a more significant relation (LVEF = -0.0085 [age] - 0.00034 [LVEDV] + 0.70, standard error of the estimate f 0.08, p <0.05, r = 0.634). The relations between left ventricular ejection fraction and systemic oxygen saturation and hematocrit also were examined. There was no statistically significant relation between these variables. 45

VENTRICULAR FUNCTION IN CONGENITAL HEART DISEASE--GRAHAM

Discussion Left ventricular function in cyanotic heart disease nd effect of shunt operation: Abnormal left ventr cular pump function as defined by a low ejection fracti bn was demonstrated before operation in patients with cyanotic congenital heart disease associated with decreased pulmonary blood flow. Similar data were reported by Sauer et a1.s for infants with pulmonary atresia or critical pulmonary stenosis with intact ventricular septum. Although the defects studied differ in terms of intracardiac anatomy, they were considered together because of their similarities in terms of decreased systemic oxygen isaturation and initial similar therapy in most instances. Postoperative studies revealed a decreased left ventricular ejection fraction in patients with tricuspid atresia or pulmonary atresia and ventricular septal defect but a normal ejection fraction in patients with pulmonary atresia and an intact ventricular septum. The latter patients were considerably younger than the other patients, which may explain the differences in ejection fraction. LaCorte et al.5 showed a mild increase in left ventricular end-diastolic volume and a small decrease in ejection fraction in 13 infants with tricuspid atresia and decreased pulmonary blood flow who were not operated on. In 12 patients with surgical shunts, end-diastolic volume was increased and ejection fraction decreased. Four of five postoperative patients less than 10 years of age had a normal ejection fraction, whereas six of seven patients greater than 10 years of age had a decreased ejection fraction. Sauer and Mocelling reported similar findings with their postshunt patients who averaged 12.8 years showing the most significant reduction in left ventricular ejection fraction. Our data are in agreement with these findings and suggest that an extension of this phenomenon of a depression of ejection fraction with long-standing volume overload can be applied in more general terms to cyanotic patients with either tricuspid or pulmonary atresia. LaCorte et a1.5 also reported that two patients with a Glenn shunt had the least abnormal values for volumes and ejection fractilon. Our three patients with a Glenn shunt were 1.7,18 and 23 years of age, respectively. These patients had the smallest volumes among our patients with postshunt tricuspid atresia, that is, 170, 127 and 90 percent of normal, and had ejection fractions of 0.52,0.58 and 0.45, respectively, with the oldest patient having the smallest volume and lowest ejection fraction. Thus, the presence of only mild volume overload in shunted cyanotic patients does not appear to prevent deteroriation of ventricular pump function. Hemodynamic determinants of low ejection fraction: The use of ejection fraction to characterize pump performance can be misleading when preload and afterload are not considered. Preload has a definite effect on ejection fraction in acute studies with an increase in volume associated with an increase in ejection fraction. In our studies end-diastolic volume was generally increased, and thus a decrease in ejection fraction could not be accounted for by preload changes. Afterload has

9:

ET AL.

0.63

na + L 0.60

-

0.53

cl2 >O $040!i3 020-

0

PAi,CPS

TAt

IVS

VSD

FIGURE 4. Left ventricular ejection fraction for the postoperative patient groups. Abbreviations as in Figure 1.

a marked effect on ejection fraction with an increase in afterload associated with a decrease in ejection fraction. In an attempt to estimate afterload, systemic vascular resistance was determined in nine patients with no ventricular septal defect, and aortic and right atria1 pressures were obtained before angiography. Resistance was calculated as (D - RAP)/LVSI, where D = mean aortic pressure, RAP = mean right atrial pressure and LVSI = left ventricular stroke index in liters per minute per square meter. The nine patients ranged in age from 1 day to 11.8 years, and resistance ranged between 5.0 and 29.8 units/m2 (mean 15.6). None of these values are increased.ll Four patients with a large aorticopulmonary shunt had low values for resistance (15 units or less/m2, mean 8.0 units/m2), whereas five other patients had normal resistance (mean 21.4 units/m2). Ejection fraction averaged 0.55 in each subgroup. Thus, elevation in afterload could not account for the low ejection fraction in our studies and a depression of pump performance cannot be explained on the basis of abnormal loading of the left ventricle.

0.80

r 0.61 P< 0801

0.54

9e -I * I,Pyr

<4YR

S4YR

FIGURE 5. Left ventricular ejection fraction in postoperative shunt patients:~~entslessthan4yeersversusthose4yeersorolder.LvEDv = left ventricular end-diastolic volume: O2 SAT = oxygen saturation.

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Causes of low ejection fraction: It is our hypothesis that the low ejection fraction in preoperative patients is related to the low systemic oxygen saturation. The normal ejection fraction in patients studied in the 1st year after operation for pulmonary atresia or critical pulmonary stenosis with an oxygen saturation of 84 percent versus a preoperative value of 57 percent lends indirect support to this hypothesis. The low ejection fraction in older patients undergoing palliative surgery is probably related to either longstanding severe volume overload or to repeated hypoxic myocardial damage. Long-standing volume overload would be associated with increased left ventricular wall tension. Tachycardia, elevated blood pressure and decreased systemic oxygen saturation all could occur during times of stress with resultant repeated episodes of myocardial hypoxia and subsequent fibrosis.lsJ3

Another possible detrimental factor in patients with a large aorticopuhnonary shunt is the low aortic diastolic pressure, which could be associated with an abnormal ratio of myocardial oxygen supply to demand (DPTI/ SPTI).14 Subendocardial hypoxia might well occur in these patients under conditions of relatively minor stress. Implications: The data reported support the hypothesis that both duration of cyanosis and degree of volume overload are contributing factors to abnormal left ventricular function. Further long-term follow-up studies both in older cyanotic patients undergoing palliative surgery as well as in patients who have had relief of cyanosis are needed in an attempt to clarify the relation between duration and extent of cyanosis and myocardial function in patients with congenital heart disease.

References 1. Graham Tp Jr, Bender HW, Atwood OF, Page DL, Sell CGR. Increase in right ventricular volume following valvulotomy for pulmonary atresia or stenosis with intact ventricular septum. Circulation 1974;50:69-79. 2. Graham TP Jr, Atwood OF, Boucek RJ Jr, Boerth RC. Right heart volume characteristics in transposition of the great arteries. Clrculation 1975;51:681-9. 3. Jarmakanl JM, Graham TP, Canent RV Jr, Jewett PH. Left heart function in children with tetralogy of Fallot before and after palliative or corrective surgery. Circulation 1972;46:478-90. 4. Graham TP Jr, Faulkner S, Bender HW, Weeder CM. Hypoplasia of the left ventricle: rare cause of postoperative mortality in tetralogy of Fallot. Am J Cardiol 1977;40:454-7. 5. LaCorle MA, Mck M, Soheer 0, LaFarge CO, Fyler DC. Left ventricular function in tricuspid atresia. Circulation 1975;9961000. 6. Jarmakanl JM, Canent RV Jr. Preoperative and postoperative right ventricular function in children with transposition of the great vessels. Circulation 1974;49, 50:11-39-11-45. 7. Graham TP Jr, Atwood GF, Boucek RJ Jr, Boerth RC, Bender HW Jr. Abnormalities of right ventricular function following Mustards operation for transposition of the great arteries. Circulation

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1975;52:678-84. 8. Sauer U, Mooellln R, Hengleln. Pulmonalkloppenatresie and hochgradige (kritische) Pulmonalklappenstenose nit intaken Ventrikelseptum. Herz Kardlovasculare Erkrankungen 1977;2: 398-410. 9. Sauer U, Mooellln R. Angiocardiographic left ventricular volume determination in tricuspid atresia. Herz Kardiovasculare Erkrankungen 1979;4:248-55. 10. Graham TP Jr, Jarmakanl JM, Canent RV Jr, Morrow MM. Left heart volume estimation in infancy and childhood: m-evaluation of methodology in normal values. Circulation 1971;43:895-904. 11. Radotph AM. Congenital diis of the heart. Chicago: Year Book Publishers, 1974: 153. 12. Krymskll LD. Pathological anatomy of the tetralogy, pentology, and trilogy of Fallot. Arkh Patol 1962; 24:T1160-T1168. 13. Jones M, Ferrans VJ. Myocardttl degeneration in congenital heart disease: a comparison of morphological findings in young and old patients with congenital heart diseases associated with muscular obstruction to right ventricular outflow. Am J Cardiol 1977;39: 1051-63. 14. Heffman JIE, Buckburg GD. The myocardial oxygen supply: demand ratio-a critical review. Am J Cardiol 1978;41:327-32.

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