Angina
Pectoris
in a Child With Sickle Cell Anemia
Wade Hamilton, M.D., Amnon Rosenthal, M.D., Donald Berwick, M.D., and Alexander
S. Nadas, M.D.
From the Departments of Cardiology and Medicine, The Childrens Hospital Medical Center, and the Department of Pediatrics, Harvard Medical School, Boston
ABSTRACT. A 7-year-old black boy with sickle cell disease, Wolff-Parkinson-White syndrome, mild left ventricular dysfunction, and normal coronary arteries developed angina pectoris five months after cessation of hypertransfusion
therapy. Exercise-induced ECG ST segment depression asso-ciated with angina disappeared following transfusion
ther-apy. Pediatrics 61:911-914, 1978, sickle cell anemia, angina pectoris, Wolff-Parkinaon-White syndrome, hypertransfusion
therapy, exercise testing.
Cardiovascular complications are common in
patients with sickle cell disease,’7 yet angina pectoris is an unusual manifestation in adults and,
heretofore, unreported in children with this
disease. This report describes a 7-year-old black
boy
with sickle cell disease and classical angina pectons which was responsive to transfusion ther-apy. The case is presented to stimulate awarenessof angina as a possible cause for chest pain in
patients with sickle cell (55) disease and to focus
attention on the diagnosis, management, and
prevention of coronary insufficiency in 55
disease.
CASE REPORT
A 7-year-old black boy with 55 anemia was admitted to
The Children’s Hospital Medical Center on March 1, 1977,
for evaluation of chest pain and excessive fatigability of eight
month’s duration. Chest pain with radiation to the left shoulder and left arm was induced by running, playing, and climbing stairs. The pain was often associated with mild shortness of breath, occasionally with mild dizziness, and was
relieved by five to ten minutes of rest. Pain, particularly in cold weather, was often so severe that the child had to be carried by his mother.
The child had multiple hospital admissions for febrile
illnesses, one of these associated with a transient hypoplastic
crisis. At age 4 years, he developed a spontaneous cerebro-vascular accident with a right hemiparesis. A left internal carotid angiogram eight days later was normal. There was gradual but almost complete resolution of neurologic abnor-malities. In an attempt to avoid further thrombotic episodes,
blood hypertransfusion therapy (10 dl/kg),’ designed to maintain a hematoent value greater than 30%, was begun
and continued for two years. In addition, he was placed on
sodium salicylate, 75 mg daily; folic acid, 1 mg daily; and
penicillin, 250 mg, twice daily. The boy remained
asymp-tomatic until the transfusions were discontinued in March 1976 and the hematocrit value dropped to 19%. Beginning in
October 1976, a series of four outpatient hospital visits for
exertional chest pain led to cardiac evaluation.
Physical examination disclosed a well-developed, pleasant, and cooperative child with mild scleral icterus and
right-sided weakness. Pulse rate was 104 beats per minute and
blood pressure was 110/70 mm Hg. There was a grade 2/6 systolic ejection murmur at the left upper sternal border, and the liver edge was palpable 6 cm below the right costal ma.rgin. The ECG revealed Wolff-Parkinson-White (WPW)
syndrome. The tracing was similar to that obtained at age 2#{189} years. A chest x-ray film showed mild cardiac enlargement and normal pulmonary vascularity. The echocardiogram
revealed mild dilatation of the left ventricle (end diastolic dimension was 4.2 cm), normal percent of dimension change
(33%), mild hypertrophy of the septum (7 mm), and posterior
left ventricular wall (8 mm). A graded treadmill exercise study using the Bruce’ protocol and simultaneous recording
of ECG were terminated after three minutes because of
severe chest pain and ST segment depression, both of which worsened during early recovery (Fig. 1). The patient went
home but was subsequently admitted to the hospital because of “crescendo angina” manifested by frequent episodes of severe chest pain with radiation to the left side of the neck
during minimal exercise.
A 24-hour Holter monitor tracing disclosed normal sinus
rhythm with no evidence for ectopy. A thallium
radionu-clide scan performed at rest was normal. Oxyhemoglobin dissociation curve was mildly shifted to the right (P 50 = 30
Received August 30; revision accepted for publication December 27, 1977.
Supported in part by Training Grant HL 05855 and program
project grant HL10436 from the National Institutes of Health.
Dr. Rosenthal is now at C.S. Mott Children’s Hospital, University of Michigan Medical Center, Ann Arbor. ADDRESS FOR REPRINTS: (W.H.) Department of Cardi-ology, The Children’s Hospital Medical Center, 300
I I
:
Im7
ISec
I
I _i I I I
I I I I
912 ANGINA PECTORIS
‘I , p
,
!
.1 , PI
. , 1
=
1_JTi
l____
I
L
:FIG. 1. Initial treadmill exercise study on February 17, 1977, when hematocrit value was 19.6%.
Tracing at rest shows Wolff-Parkinson-White syndrome and heart rate (HR) of 88 beats per minute. Exercise (EXER) was stopped because of severe chest pain. During early recovery
(RECOV) noticeable ST segment depression (arrow) to 0.8 mV is evident.
mm Hg at pH = 7.38), and 2,3 diphosphoglycerate was 0.70
M/M Hb (normal, 0.8 to 1.0). A lactic dehydrogenase electrophoresis revealed a cardiac band equal to 49%
(nor-mal, 20.0% to 37.3%); creatine phosphokinase level was
normal at 15 lU/liter with no MB band (cardiac muscle isoenzyme) detected. A serum lipoprotein electrophoresis
was normal. Serum cholesterol level was 159 mg/dl and triglyceride level was 60 mg/dl. The hematocrit value was 19.6% and WBC count was 11,200/cu mm with a normal differential count. There were ten nucleated RBCs per 100 WBCs and the reticulocyte count was 11.4%. Smear showed
occasional Howell-Jolly bodies, slight stippling and sickle forms, oval target forms, rare spherocytes, occasional
frag-ments, moderate polychromasia, and occasional giant
plate-lets. Hemoglobin electrophoresis showed 2.5% hemoglobin
A,, 41% hemoglobin A,, and 56.5% hemoglobin S.
On March 6, 1977, the patient received a transfusion of
packed RBCs to a hematocrit value of 38%. The angina and
dyspnea shown during exertion were no longer evident. A graded treadmill exercise test now revealed an endurance of eight minutes (normal value for patient’s age in our
labora-tory is 12.4 ± 1.6 minutes). There were no ST segment
changes or chest pain, and exercise was stopped because of
fatigue (Fig. 2).
Cardiac catheterization was performed on March 8.
Selec-live left ventricular cineangiogram revealed trivial mitral regurgitation, mild dyskinesis of the left ventricular apex, normal ejection fraction (78%), normal left ventricular mass
(65 gm/sq m), and a mildly increased left ventricular end diastolic volume (83 ml/sq m). Selective right and left coronary arteriograms were normal. There was
intrapul-monary right-to-left shunting. The Pao, in room air was 77
mm Hg and after the child inspired 100% oxygen for ten
minutes, the Pao2 was 373 mm Hg. All pressure
measure-ments were normal. Calculation of the coronary oxygen
supply and demand yielded a ratio (DPTI/SPTI) of 16.9,
:i-
:LJ-LLL
REST EXE R: 8 mit RECOV : 3 mm
HR 68 HR 136 HR 82
FIG. 2. Treadmill exercise study on March 7, 1977, after packed RBC transfusion when hematocrit value was 38%. Heart rate (HR) at rest is 68 beats per minute. There are no ST
segment or T wave changes during exercise (EXER) or recovery (RECOV) periods.
at Viet Nam:AAP Sponsored on September 8, 2020 www.aappublications.org/news
consistent with no subendocardial ischemia after transfu-sion.1#{176}
The child was discharged from the hospital. During the
first two weeks after transfusion, he remained asymptomatic.
On the third week, a slight decrease in exercise tolerance appeared and, by the fourth week, there was moderate
limitation in exercise tolerance with angina during moderate exertion. During the fifth and sixth weeks, angina occurred during minimal physical effort. Utilizing a reliable history,
serial treadmill exercise tests, and hematocnt measurements,
subsequent optimal management was determined.
Transfu-sion (15 dl/kg packed RBCs) every five to six weeks and
maintainance of the hematocnt value above 23% to 24%
resulted in a fairly normal age-related level of activity and no
angina.
DISCUSSION
The clinical history in this 7-year-old boy with
55 disease, coupled with documented typical
chest pain and ST segment depression during
treadmill exercise testing (Fig. 1), clearly
mdi-cates that he has angina pectoris. The angina
cannot be adequately explained by any single
factor. The mild myocardial dysfunction demon-strated at cardiac catheterization does not fully
explain the severe symptomatology. Coronary
arteries were normal by angiography. RBC 2,3
diphosphoglycerate level and hemoglobin oxydis-sociation curve were only mildly inappropriate
for the degree of anemia.”2 Hypoxemia was mild
and there were no ECG ST or T wave changes at
rest. The onset of angina after cessation of trans-fusion therapy and the subsequent relief of angina
and disappearance of exercise-induced ST and T
wave changes following packed RBC transfusions implicate a reduction in oxygen-carrying capacity in the etiology. Angina most likely developed as a
consequence of multiple factors leading to
inequality between myocardial oxygen demand
and supply. The increased demand for oxygen
generated by exercise, high cardiac output, and
tachycardia associated with chronic anemia could
not be adequately met because the supply was
limited by decreased oxygen-carrying capacity, hypoxemia associated with intrapulmonary right-to-left shunting, and the mild cardiac dysfunction. Transfusion of packed cells relieved angina both
by lowering myocardial demand for oxygen and
increasing the supply. Demand was reduced by
decreasing heart rate, cardiac output, and cardiac dilatation. The supply was improved by increas-ing oxygen-carrying capacity and reducing blood viscosity.13 Although alternative explanations for
the angina observed in our patient may exist,
these remain obscure in the absence of further documentation.
The presence of an ECG pattern of WPW
syndrome is unusual in 55 disease.5’7”4 WPW
syndrome commonly occurs as an isolated
congenital conduction defect, though it may
occur in children with cardiomyopathy or other
congenital cardiac defects.’5”6 The predilection for arrhythmias in patients with WPW syndrome is well recognized, but, despite multiple exercise
tests and Holter ECG monitoring, this was not
recognized in our patient. ST segment and T
wave depression during treadmill exercise has
been reported in apparently normal adults with
WPW
syndrome.’7 However, we have observedthe exercise of nine children with WPW
syndrome, two of whom have cardiomyopathy,
and none developed ST-T wave depression (A.
Rosenthal and M.D. Freed, unpublished data).
Furthermore, disappearance of exercise-induced ST segment depression after transfusion also
miti-gates against the WPW syndrome as the cause of
the ECG changes in our patient. Mild ST-T wave
changes at rest have been reported in asymptom-atic palients with 55 diseasel,7,14,18 and have been noted to revert after transfusion.’8
The cardiomyopathy in patients with 55
disease is not clearly defined. Pathological heart studies in young adults reveal a dilated, flabby
myocardium with microscopic evidence of
vacuolization of the sarcoplasm, disappearance of muscle striation, interstitial edema fluid, degener-ation of the myofibrils,5’7 and increased fibrous
lissue.’9 Evidence for myocardial infarction is
usually lacking,’ although it has been described in a few young adults.5
The enlarged cardiac silhouette seen on chest x-ray film, increased left ventricular electromo-live forces shown on ECG, and mildly increased left ventricular muscle mass and end diastolic dimension observed on the echocardiogram2#{176} are at least in
part
related to cardiac dilatation associated with chronic anemia.4’5’2’ Transfusion,particularly in children, frequently results in
return of the heart to normal size. Cardiac
catheterizalion studies in children with 55 disease have demonstrated mild systemic arterial
hypox-emia, normal pulmonary resistance, increased
cardiac output, and high coronary sinus blood
oxygen saturation.3’6
Angina pectoris has been rarely observed even
in adults with 55 anemia,4’7’22 though it is
common in patients with other anemias when
associated with arteriosclerotic cardiovascular
disease.5’23 Angina, however, may be more
common than presently appreciated in patients
with 55 disease. Some studies have excluded
patients with angina or arteriosclerotic cardiovas-cular disease.5’7’2#{176}Winsor and Burch reported a
914 ANGINA PECTORIS
sure if the pain was secondary to coronary
arteritis or pulmonary crises.7 Two patients with the lowest hemoglobin values, 7.0 and 6.3 mg/dl, reported by Shugin et al., had a history consistent with angina.3
Future assessment of myocardial performance
and ECG monitoring during episodes of chest or
abdominal pain often attributed to sickle cell
crises or pleurisy may indicate cardiac etiology.
. Exercise studies of asymptomatic 55 patients,
when correlated with cardiac physiologic
find-ings, may also define more clearly the relationship
between myocardial pathology and angina in this
disease. Such studies will have therapeutic impli-cations. Transfusion may produce transient relief from symptoms by increasing oxygen-carrying capacity and reducing viscosity.’3 The adverse
effects of transfusion iron overloading may
possibly
be prevented by simultaneous adminis-tration of desferrioxamine.24’25 The possibility that hypertransfusion therapy, if later discontinued, may predispose to angina also requires considera-lion.REFERENCES
1. Klinefelter HF: The heart in sickle cell anemia. Am I
Med Sci 203:34, 1942.
2. Manuel NGL, Liebman J, Anslovar J, Gross S:
Cardio-vascular findings in children with sickle cell anemia. Die Chest 52:788, 1967.
3. Shugin H, Kaufman R, Shapiro M, et al: Cardiovascular findings in children with sickle cell anemia. Am I Cardiol 6:875, 1960.
4. Higgins WH: The heart in sickle cell anemia. South Med
I 42:39, 1949.
5. Uzsoy NK: Cardiovascular findings in patients with sickle cell anemia. Am I Cardiol 13:320, 1964.
6. Sproule BJ, Malden R, Miller WF: A study of cardiopul-monary alterations in patients with sickle cell disease and its variants. I Clin Invest 37:486,
1958.
7. Winsor T, Burch GE: The electrocardiogram and
cardiac state in sickle cell anemia. Am Heart I
29:684, 1945.
8. Lusmer JM, Haghighat H, Khalifa AS: A prophylactic transfusion program for children with sickle cell
anemia complicated by CNS infarction. Am I Hematol 1:265, 1976.
9. Bruce BA: Exercise testing of patients with coronary heart disease: Principles and normal standards for
evaluation. Ann Clin Res 3:323, 1971.
10. Lewis AB, Heymann MA, Stanger P, et al: Evaluation of subendocardial ischemia in valvar aortic stenosis in
children. Circulation 49:978, 1974.
11. Eaton JW, Brewer GJ: The relationship between red cell
2,3 diphosphoglycerate and levels of hemoglobin in
the human. Proc Nat Acad Sci USA 61:756, 1968.
12. Torrance J, Jacobs P. Restrepo A, et al: Interaerythro-cytic adaptation to anemia. New Engl I Med
283:165, 1970.
13. Murphy JR, Wengard M, Brereton W: Rheological studies of hemoglobin 55 blood: Influence of hema-tocnt, hypertonicity, separation of cells, deoxygen-ation and mixture with normal cells. I Lab Gun Med
87:475, 1976.
14. Lindo CL, Doctor MD: The electrocardiogram in sickle cell anemia. Am Heart I 50:218, 1955.
15. Nadas AS, Fyler DC: Pediatric Cardiology, ed 3.
Phil-adelphia, WB Saunders, 1972, p 242.
16. Gallagher JJ, Gilbert M, Svenson RH, et al:
Wolff-Parkinson-White syndrome: The problem,
evalua-lion and surgical correction. Circulation 51:767, 1975.
17. Gazes P: False-positive exercise test in the presence of
the Wolff-Parkinson-White syndrome. Am Heart I
78:13, 1969.
18. Henderson AB: Sickle cell anemia. Am I Med 9:757, 1950.
19. Murphy RC, Shapiro 5: The pathology of sickle cell
anemia. Ann Intern Med 23:376, 1946.
20. Gerry JL, Baird MJ, Fortuin NJ: Evaluation of left
ventricular function in patients with sickle cell anemia. Am I Med 60:968, 1976.
21. Rosenthal A, Restieaux NJ, Feig SA: Influence of acute
variations in hematocrit on the QRS complex of the Frank electrocardiogram. Circulation 44:456, 1971.
22. Zimmerman SL, Bwinett R: Sickle cell simulating coro-nary occlusion. Ann Intern Med 21:1045, 1944.
23. Pickering GW, Wayne EJ: Observations in angina pectoris and intermittent clauduation in anemia.
Clin Sci 1:305, 1934.
24. Model CB, Beck J: Long term desferrioxamine therapy in thalassemia. Ann NY Acad Sci 232:201, 1974. 25. Propper 1W, Cooper B, Rufo RR, et al: Continuous
subcutaneous administration of desferrioxamine in patients with iron overload. New Engi I Med
297:418, 1977.
at Viet Nam:AAP Sponsored on September 8, 2020 www.aappublications.org/news
1978;61;911
Pediatrics
Wade Hamilton, Amnon Rosenthal, Donald Berwick and Alexander S. Nadas
Angina Pectoris in a Child With Sickle Cell Anemia
Services
Updated Information &
http://pediatrics.aappublications.org/content/61/6/911
including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or in its
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
1978;61;911
Pediatrics
Wade Hamilton, Amnon Rosenthal, Donald Berwick and Alexander S. Nadas
Angina Pectoris in a Child With Sickle Cell Anemia
http://pediatrics.aappublications.org/content/61/6/911
the World Wide Web at:
The online version of this article, along with updated information and services, is located on
American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1978 by the
been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
at Viet Nam:AAP Sponsored on September 8, 2020 www.aappublications.org/news