SICKLE CELL ANEMIA: DOES MYOCARDIAL ISCHEMIA OCCUR DURING CRISIS? Sharon Norris, MD, Cage S. Johnson, MD, and L. Julian Haywood, MD Los Angeles, California
The possibility that myocardial ischemia may be associated with chest pain during painful crises was evaluated prospectively in 20 patients (11 women and nine men) with sickle cell disease (19 SS, 1 Sp + thalassemia). Sixteen of 20 (80%) had abnormal ECGs, 7 (35%) had transient ST-T wave changes, and 3 (15%) had persistent ST-T wave changes, both consistent with ischemia; 6 (30%) had nonspecific ST-T changes, and 4 (20%) had normal tracings. Serum enzymes (CK, SGOT, LDH) were abnormal in 16 of 19 (84%); 1 had CK-MB detected, (5%) and 1 had LDH1 to LDH2 reversal. All 10 Tc-99m pyrophosphate scans performed were negative; 4 of 6 (66%) thallium-201 scans had focal defects, and 5 of 8 (63%) radionuclide angiograms (MUGAs) had focal wall motion abnormalities. Three of 8 (38%) MUGAs showed cardiac dilation, diffuse hypokinesis, and reduced ejection fractions. Thus, myocardial damage may be a potentially serious complication of patients with sickle cell anemia who present with chest pain during painful From the Department of Medicine, University of Southern California School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Dr L. Julian Haywood, Los Angeles County/University of Southern California Medical Center, 1200 N State St, Box 305, Los Angeles, CA 90033. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 3
crises. Studies are indicated to define the significance and pathophysiology of these observations. Key words * sickle cell anemia * sickle cell crisis* myocardial ischemia
INTRODUCTION Patients with sickle cell disease may come to the attention of cardiologists because of cardiac enlargement, murmurs, complaints of persistent dyspnea, or chest discomfort during painful crises. Nonspecific electrocardiographic abnormalities and auscultatory findings suggestive of organic heart disease have been noted frequently by clinicians, but only rarely has the issue of ischemia been raised. In 1944, Zimmerman and Barnett described a case of sickle cell anemia that appeared to be coronary occlusive disease.1 Diggs clearly demonstrated patchy free wall and papillary muscle fibrosis in a patient with sickle cell disease at post mortem.2 Small intramyocardial arteriolar occlusions with microthrombi and "agglutinized" sickled red cells have also been demonstrated in patients with sickle cell disease.3'4 The significance of small coronary arteriolar occlusion in the pathogenesis of myocardial fibrosis has remained speculative, as the thrombi found probably represented post mortem
events.5 At the Los Angeles County/University of Southern 209
SICKLE CELL ANEMIA
California Medical Center, an unequivocal case of acute myocardial infarction in a young woman with sickle cell disease was documented.6 We also found myocardial fibrosis associated with patent coronary arteries in a review of necropsies of sickle cell patients.7 Clinicopathological correlations have been analyzed in 52 patients,8 but the question of myocardial ischemia was not directly raised. The exact pathophysiologic mechanisms by which myocardial fibrotic lesions might be produced remain speculative. In this pilot study, we attempted to determine whether myocardial ischemia might occur in a significant number of patients with sickle cell disease who were admitted with protracted chest pain associated with painful "crises."
METHODS Patients over age 18 who had chest pain of at least 30 minutes duration during an episode of painful crisis were selected for serial studies. Diagnosis of sickle cell disease was established by electrophoresis on cellulose acetate at pH 8.6 and confirmed by citrate agar gel electrophoresis at pH 6.2; hemoglobin F was measured by alkali denaturation and hemoglobin A2 by DEAE microcolumn chromatography. Patients were excluded if: 1. they could not or would not give voluntary, informed consent, 2. they were pregnant, 3. they were under 16 years old, and 4. obvious pulmonary parenchymal or air space disease was evident by chest radiograph. Patients were studied within 1 to 5 days of onset of symptoms. Patients who qualified on the basis of symptoms and agreed to participate had a review of their medical history, admission chest radiograph, and physical examination. A complete blood count, serial serum enzymes (serum aspartate aminotransferase-SGOT, lactate dehydrogenase-LDH, creatine kinase-CK, and LDH or CK isoenzymes as appropriate), and serial 12-lead electrocardiograms (ECG) were then obtained. When possible, a technetium-99m pyrophosphate (Tc-99m pyro) myocardial scan with a simultaneous first-pass radionuclide ventriculogram was obtained 48 to 72 hours after onset of symptoms. Other noninvasive cardiac procedures, such as thallium-201 myocardial scintigrams, equilibrium radionuclide angiograms, and echocardiograms were obtained in some patients when feasible. Twenty mCi of Tc-99m pyro was administered by intravenous bolus with the patient positioned beneath 210
an Anger camera outfitted with a high-resolution collimator at a 20% window. Blood pool images were acquired in the anterior, modified 450 left anterior oblique, and left lateral views. Two-and-a-half to 4 hours later, the same camera views were repeated. Abnormal uptake was interpreted by visual inspection of the scintigrams9"10 One and one-half mCi of thallium-201 (T1-201) chloride were given intravenously. Five minutes after the injection, 500 000 count limited images were acquired with an Anger camera, high resolution collimator, and a dedicated interfaced nuclear computer at a 20% window. Images were obtained in the same positions used for the technetium-99m images. Images were inspected visually. Defects if present were located by regions.1"-'3 Equilibrium multigated radionuclide angiograms (MUGA) were obtained with the same nuclear camera, collimator, and computer, using red blood cells labeled with 20 mCi of technetium-99 in vitro.12'13 Resting gated images with an ECG reference signal were acquired in the three positions outlined above. The images were played in an endless loop fashion to assess regional wall motion abnormalities.'4,15 Data were expressed as means ± SE or SD and analyzed using the Student's t test; P
The possibility that myocardial ischemia may be associated with chest pain during painful crises was evaluated prospectively in 20 patients (11 women and nine men) with sickle cell disease (19 SS, 1 Sp + thalassemia). Sixteen of 20 (80%) had abnormal ECGs, 7 (35%) had transient ST-T wave changes, and 3 (15%) had persistent ST-T wave changes, both consistent with ischemia; 6 (30%) had nonspecific ST-T changes, and 4 (20%) had normal tracings. Serum enzymes (CK, SGOT, LDH) were abnormal in 16 of 19 (84%); 1 had CK-MB detected, (5%) and 1 had LDH1 to LDH2 reversal. All 10 Tc-99m pyrophosphate scans performed were negative; 4 of 6 (66%) thallium-201 scans had focal defects, and 5 of 8 (63%) radionuclide angiograms (MUGAs) had focal wall motion abnormalities. Three of 8 (38%) MUGAs showed cardiac dilation, diffuse hypokinesis, and reduced ejection fractions. Thus, myocardial damage may be a potentially serious complication of patients with sickle cell anemia who present with chest pain during painful From the Department of Medicine, University of Southern California School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Dr L. Julian Haywood, Los Angeles County/University of Southern California Medical Center, 1200 N State St, Box 305, Los Angeles, CA 90033. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 3
crises. Studies are indicated to define the significance and pathophysiology of these observations. Key words * sickle cell anemia * sickle cell crisis* myocardial ischemia
INTRODUCTION Patients with sickle cell disease may come to the attention of cardiologists because of cardiac enlargement, murmurs, complaints of persistent dyspnea, or chest discomfort during painful crises. Nonspecific electrocardiographic abnormalities and auscultatory findings suggestive of organic heart disease have been noted frequently by clinicians, but only rarely has the issue of ischemia been raised. In 1944, Zimmerman and Barnett described a case of sickle cell anemia that appeared to be coronary occlusive disease.1 Diggs clearly demonstrated patchy free wall and papillary muscle fibrosis in a patient with sickle cell disease at post mortem.2 Small intramyocardial arteriolar occlusions with microthrombi and "agglutinized" sickled red cells have also been demonstrated in patients with sickle cell disease.3'4 The significance of small coronary arteriolar occlusion in the pathogenesis of myocardial fibrosis has remained speculative, as the thrombi found probably represented post mortem
events.5 At the Los Angeles County/University of Southern 209
SICKLE CELL ANEMIA
California Medical Center, an unequivocal case of acute myocardial infarction in a young woman with sickle cell disease was documented.6 We also found myocardial fibrosis associated with patent coronary arteries in a review of necropsies of sickle cell patients.7 Clinicopathological correlations have been analyzed in 52 patients,8 but the question of myocardial ischemia was not directly raised. The exact pathophysiologic mechanisms by which myocardial fibrotic lesions might be produced remain speculative. In this pilot study, we attempted to determine whether myocardial ischemia might occur in a significant number of patients with sickle cell disease who were admitted with protracted chest pain associated with painful "crises."
METHODS Patients over age 18 who had chest pain of at least 30 minutes duration during an episode of painful crisis were selected for serial studies. Diagnosis of sickle cell disease was established by electrophoresis on cellulose acetate at pH 8.6 and confirmed by citrate agar gel electrophoresis at pH 6.2; hemoglobin F was measured by alkali denaturation and hemoglobin A2 by DEAE microcolumn chromatography. Patients were excluded if: 1. they could not or would not give voluntary, informed consent, 2. they were pregnant, 3. they were under 16 years old, and 4. obvious pulmonary parenchymal or air space disease was evident by chest radiograph. Patients were studied within 1 to 5 days of onset of symptoms. Patients who qualified on the basis of symptoms and agreed to participate had a review of their medical history, admission chest radiograph, and physical examination. A complete blood count, serial serum enzymes (serum aspartate aminotransferase-SGOT, lactate dehydrogenase-LDH, creatine kinase-CK, and LDH or CK isoenzymes as appropriate), and serial 12-lead electrocardiograms (ECG) were then obtained. When possible, a technetium-99m pyrophosphate (Tc-99m pyro) myocardial scan with a simultaneous first-pass radionuclide ventriculogram was obtained 48 to 72 hours after onset of symptoms. Other noninvasive cardiac procedures, such as thallium-201 myocardial scintigrams, equilibrium radionuclide angiograms, and echocardiograms were obtained in some patients when feasible. Twenty mCi of Tc-99m pyro was administered by intravenous bolus with the patient positioned beneath 210
an Anger camera outfitted with a high-resolution collimator at a 20% window. Blood pool images were acquired in the anterior, modified 450 left anterior oblique, and left lateral views. Two-and-a-half to 4 hours later, the same camera views were repeated. Abnormal uptake was interpreted by visual inspection of the scintigrams9"10 One and one-half mCi of thallium-201 (T1-201) chloride were given intravenously. Five minutes after the injection, 500 000 count limited images were acquired with an Anger camera, high resolution collimator, and a dedicated interfaced nuclear computer at a 20% window. Images were obtained in the same positions used for the technetium-99m images. Images were inspected visually. Defects if present were located by regions.1"-'3 Equilibrium multigated radionuclide angiograms (MUGA) were obtained with the same nuclear camera, collimator, and computer, using red blood cells labeled with 20 mCi of technetium-99 in vitro.12'13 Resting gated images with an ECG reference signal were acquired in the three positions outlined above. The images were played in an endless loop fashion to assess regional wall motion abnormalities.'4,15 Data were expressed as means ± SE or SD and analyzed using the Student's t test; P
