Angina Pectoris in a Child With Sickle Cell Anemia

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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


with sickle cell disease and classical angina pectons which was responsive to transfusion ther-apy. The case is presented to stimulate awareness

of 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



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







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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,



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.

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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



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


syndrome.’7 However, we have observed

the 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


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



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


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.


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Wade Hamilton, Amnon Rosenthal, Donald Berwick and Alexander S. Nadas

Angina Pectoris in a Child With Sickle Cell Anemia


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