- Email: [email protected]
Hemoglobinopathies: an opportunity to study cardiac disease
Hemoglobinopathies: An Opportunity to Study Cardiac Disease Catherine S. Manno, MD, Mariell Jessup, MD
T
wo studies published in this issue of The American Journal of Medicine examine the cardiac manifestations of patients with separate hemoglobinopathies,  thalassemia major (1) and sickle  thalassemia (2). Important pathophysiologic and clinical lessons can be learned by a review of the investigators’ observations, with an eye toward improving the cardiac evaluation and therapies offered to these patients. Patients with  thalassemia major require lifelong support with red cell transfusions, whereas those with sickle cell disease (sickle  thalassemia) receive red cell transfusions on an episodic basis to treat acute disease complications, or on a chronic basis, usually to prevent recurrence of stroke. Recommendations for transfusion therapy are less uniform for patients with sickle  thalassemia (B0 or B⫹), and the clinical course for patients with sickle  thalassemia is similar to that observed in patients with homozygous sickle cell disease. Transfusion-derived iron overload with subsequent tissue iron deposition is a predictable result of multiple red cell transfusions in patients with  thalassemia major. Before the widespread availability of iron chelation therapy, the leading cause of death among patients with thalassemia major was cardiac arrhythmia or heart failure, secondary to iron-induced cardiomyopathy (3,4). Iron chelation with the parenteral medication deferoxamine was first introduced in 1973. With assiduous adherence to prescribed regimens, patients who regularly use deferoxamine are able to decrease total body iron loads and delay or prevent the onset of iron-induced organ dysfunction (5,6). The classic description of end-stage iron-induced cardiomyopathy was a combination of left ventricular diastolic dysfunction, pulmonary and peripheral edema, arrhythmias, and rapid progression to death months after the onset of congestive symptoms. Fortunately, this clinical presentation has been less likely as chelation is routinely applied. Indeed, until recently, patients dying from this symptom complex were thought to be primarily noncompliant with their chelation therapy. The last several years have witnessed a more complete description of the cardiac abnormalities accompanying  thalassemia maAm J Med. 2001;111:407– 408. From the Division of Hematology (CSM), Children’s Hospital of Philadelphia and the Division of Internal Medicine (MJ), Heart Failure/ Transplant Program, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Catherine S. Manno, MD, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. 䉷2001 by Excerpta Medica, Inc. All rights reserved.
jor, and may pertain to patients with other hemoglobinopathies as well (7). Important factors that contribute to cardiac dysfunction in  thalassemia major include the following: First, consequences of chronic hemolytic anemia: patients have elevated cardiac outputs, larger left ventricles, increased mitral annular size, and increased ventricular contractility (8). Second, iron-induced cardiomyopathy: quantitating the extent of myocardial damage with excessive tissue iron deposition in other organs, such as the liver, or by endomyocardial biopsy, has not been completely successful. For example, conduction and rhythm abnormities correlate poorly with conduction tissue infiltration in autopsy sections of patients dying from arrhythmias (9). And third, myocarditis and pericarditis: Kremastinos and colleagues, authors of one of the papers under discussion, earlier described a distinct clinical presentation of acute myocarditis in 4.5% of their thalassemia patients, with a high mortality rate in that group (10). Thus, it is possible that at least some of the cardiac deaths attributed to iron deposition in earlier series were related to a different pathophysiologic process. Add to these major factors the miscellaneous illnesses or acquired disorders common to this population, such as systemic infections, pulmonary embolus, thyroid disease, and arrhythmias (11), and it becomes apparent that despite very careful chelation of iron, cardiac function may never be normal in patients with  thalassemia major. It is in this context that the most recent work of Kremastinos et al. (1) is of interest, coming from one of the largest thalassemia centers in the world. They describe a 5-year follow-up of 52 patients with  thalassemia who had heart failure symptoms. Survival in this group was 48% at 5 years; and two subgroups became apparent. The larger subgroup (83%) had left-sided heart failure symptoms (nocturnal dyspnea, orthopnea, dyspnea on exertion); they were younger, and had lower serum ferritin levels and less right-side ventricular dilatation. The smaller subgroup (17%) had right-sided heart failure; they had more classic symptoms of iron-induced cardiomyopathy, with left ventricular restrictive physiology and high ferritin levels. Therefore, the etiology of the left ventricular dilatation in the younger, better chelated patients appears to be multifactorial. The authors suggest possible immunogenetic factors that may facilitate the development of myocarditis. Perhaps their findings will lead to other interventions in this population that may further decrease cardiac mortality (12). Interest continues in efforts to detect early cardiac de0002-9343/01/$–see front matter 407 PII S0002-9343(01)00943-3
Hemoglobinopathies/Manno and Jessup
terioration in patients with  thalassemia major so that intensified chelation regimens or more aggressive approaches, such as organ transplantation, can be employed. Unfortunately, routine cardiac imaging techniques have not always been successful in accurately predicting the clinical outcome of these patients (13). In a second paper from Athens, Aessopos et al. (2) describe the results of scintigraphic evaluation of myocardial perfusion in sickle  thalassemia patients during exercise. Eight patients (26.6%) developed reversible perfusion abnormalities during exercise; subsequent coronary angiograms were normal in all 8 patients. As a result of the exercise test, a sickling pain episode developed in 4 of the 30 patients. The authors concluded that physical stress induced myocardial ischemia in sickle  thalassemia patients, despite normal coronary arteries. The development of exercise-induced chest pain and electrocardiographic changes in sickle cell patients has been well described (14). Sickled erythrocytes are known to stack and agglutinate into obstructive masses within small arteries, capillaries, and venules of the heart and other organs of the body. Subsequent endothelial proliferation and fibromuscular dysplasia among many small coronary arteries may account for focal degeneration and fibrosis of the myocardium and conduction system (15). Whether this process can be accurately described as acute ischemia that is responsible for the reversible perfusion abnormalities (16), such as those seen in the study by Aessopos et al., is open to debate. Current recommendations in the United States do not call for exercise proscription, but rather for a regular form of aerobic exertion (17). Health care professionals may not routinely assess or manage adult patients with significant hemoglobinopathies. Moreover, applying cardiac imaging methods to these patients does not always provide accurate clues to the complete pathophysiologic abnormalities that may exist. Nevertheless, these two papers suggest that by acknowledging the unexpected results of such testing of these patients—two echocardiographic forms of heart failure in  thalassemia major patients in the first paper, and perfusion defects despite normal coronary arteries in the second article—we may find innovative approaches to their successful management.
408
October 1, 2001
THE AMERICAN JOURNAL OF MEDICINE威
REFERENCES 1. Kremastinos DT, Tsetsos GA, Tsiapras DP, et al. Heart failure in beta thalassemia: a 5-year follow-up study. Am J Med. 2001;111: 349 –354. 2. Aessopos A, Tsironi M, Vassiliadis I, et al. Exercise-induced myocardial perfusion abnormalities in sickle  thalassemia: Tc-99m tetrofosmin gated SPECT imaging study. Am J Med. 2001;111:355– 360. 3. Zurlo MG, DeStefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassemia major. Lancet. 1989;2:27–30. 4. Engle MA, Erlandson M, Smith CH. Late cardiac complications of chronic severe refractory anemia with hemochromatosis. Circulation. 1964;30:698–705. 5. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous -thalassemia. N Engl J Med. 1994;331:574–578. 6. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331:567–573. 7. Jessup M, Manno CS. Diagnosis and management of iron-induced heart disease in Cooley’s anemia. Ann NY Acad Sci. 1998;850: 242–250. 8. Bahl VK, Malhotra OP, Kumar D, et al. Noninvasive assessment of systolic and diastolic left ventricular function in patients with chronic severe anemia: a combined M-mode, two-dimensional, and Doppler echocardiographic study. Am Heart J. 1992;124: 1516–1523. 9. Schellhammer PF, Engle MA, Hagstrom TW. Histochemical studies of the myocardium and conduction tissue in acquired iron storage disease. Circulation. 1967;35:631– 637. 10. Kremastinos DT, Tiniakos G, Theodorakis GN, et al. Myocarditis in -thalassemia major. A cause of heart failure. Circulation. 1995; 91:66–71. 11. Vecchio C, Derchi G. Management of cardiac complications in patients with thalassemia major. Semin Hematol. 1995;32:288–296. 12. Rund D, Rachmilewitz E. Thalassemia major 1995: older patients, new therapies. Blood Rev. 1995;9:25–32. 13. Leon MB, Borer JS, Bacharach SL, et al. Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron-overload. N Engl J Med. 1979;301:1143–1148. 14. Covitz W, Espeland M, Gallagher D, et al. The heart in sickle cell anemia. The Cooperative Study of Sickle Cell Disease (CSSCD). Chest. 1995;108:1214–1219. 15. James TN. Homage to James B. Herrick: a contemporary look at myocardial infarction and at sickle-cell disease: the 32nd Annual Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2000;101:1874–1887. 16. Martin CR, Johnson CS, Cobb C, et al. Myocardial infarction in sickle cell disease. J Natl Med Assoc. 1996;88:428– 432. 17. Reid C, Charache S, Lubin B, et al. Management and Therapy of Sickle Cell Disease. 3rd ed. Bethesda: National Institutes of Health; 1995.
Volume 111
T
wo studies published in this issue of The American Journal of Medicine examine the cardiac manifestations of patients with separate hemoglobinopathies,  thalassemia major (1) and sickle  thalassemia (2). Important pathophysiologic and clinical lessons can be learned by a review of the investigators’ observations, with an eye toward improving the cardiac evaluation and therapies offered to these patients. Patients with  thalassemia major require lifelong support with red cell transfusions, whereas those with sickle cell disease (sickle  thalassemia) receive red cell transfusions on an episodic basis to treat acute disease complications, or on a chronic basis, usually to prevent recurrence of stroke. Recommendations for transfusion therapy are less uniform for patients with sickle  thalassemia (B0 or B⫹), and the clinical course for patients with sickle  thalassemia is similar to that observed in patients with homozygous sickle cell disease. Transfusion-derived iron overload with subsequent tissue iron deposition is a predictable result of multiple red cell transfusions in patients with  thalassemia major. Before the widespread availability of iron chelation therapy, the leading cause of death among patients with thalassemia major was cardiac arrhythmia or heart failure, secondary to iron-induced cardiomyopathy (3,4). Iron chelation with the parenteral medication deferoxamine was first introduced in 1973. With assiduous adherence to prescribed regimens, patients who regularly use deferoxamine are able to decrease total body iron loads and delay or prevent the onset of iron-induced organ dysfunction (5,6). The classic description of end-stage iron-induced cardiomyopathy was a combination of left ventricular diastolic dysfunction, pulmonary and peripheral edema, arrhythmias, and rapid progression to death months after the onset of congestive symptoms. Fortunately, this clinical presentation has been less likely as chelation is routinely applied. Indeed, until recently, patients dying from this symptom complex were thought to be primarily noncompliant with their chelation therapy. The last several years have witnessed a more complete description of the cardiac abnormalities accompanying  thalassemia maAm J Med. 2001;111:407– 408. From the Division of Hematology (CSM), Children’s Hospital of Philadelphia and the Division of Internal Medicine (MJ), Heart Failure/ Transplant Program, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Catherine S. Manno, MD, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. 䉷2001 by Excerpta Medica, Inc. All rights reserved.
jor, and may pertain to patients with other hemoglobinopathies as well (7). Important factors that contribute to cardiac dysfunction in  thalassemia major include the following: First, consequences of chronic hemolytic anemia: patients have elevated cardiac outputs, larger left ventricles, increased mitral annular size, and increased ventricular contractility (8). Second, iron-induced cardiomyopathy: quantitating the extent of myocardial damage with excessive tissue iron deposition in other organs, such as the liver, or by endomyocardial biopsy, has not been completely successful. For example, conduction and rhythm abnormities correlate poorly with conduction tissue infiltration in autopsy sections of patients dying from arrhythmias (9). And third, myocarditis and pericarditis: Kremastinos and colleagues, authors of one of the papers under discussion, earlier described a distinct clinical presentation of acute myocarditis in 4.5% of their thalassemia patients, with a high mortality rate in that group (10). Thus, it is possible that at least some of the cardiac deaths attributed to iron deposition in earlier series were related to a different pathophysiologic process. Add to these major factors the miscellaneous illnesses or acquired disorders common to this population, such as systemic infections, pulmonary embolus, thyroid disease, and arrhythmias (11), and it becomes apparent that despite very careful chelation of iron, cardiac function may never be normal in patients with  thalassemia major. It is in this context that the most recent work of Kremastinos et al. (1) is of interest, coming from one of the largest thalassemia centers in the world. They describe a 5-year follow-up of 52 patients with  thalassemia who had heart failure symptoms. Survival in this group was 48% at 5 years; and two subgroups became apparent. The larger subgroup (83%) had left-sided heart failure symptoms (nocturnal dyspnea, orthopnea, dyspnea on exertion); they were younger, and had lower serum ferritin levels and less right-side ventricular dilatation. The smaller subgroup (17%) had right-sided heart failure; they had more classic symptoms of iron-induced cardiomyopathy, with left ventricular restrictive physiology and high ferritin levels. Therefore, the etiology of the left ventricular dilatation in the younger, better chelated patients appears to be multifactorial. The authors suggest possible immunogenetic factors that may facilitate the development of myocarditis. Perhaps their findings will lead to other interventions in this population that may further decrease cardiac mortality (12). Interest continues in efforts to detect early cardiac de0002-9343/01/$–see front matter 407 PII S0002-9343(01)00943-3
Hemoglobinopathies/Manno and Jessup
terioration in patients with  thalassemia major so that intensified chelation regimens or more aggressive approaches, such as organ transplantation, can be employed. Unfortunately, routine cardiac imaging techniques have not always been successful in accurately predicting the clinical outcome of these patients (13). In a second paper from Athens, Aessopos et al. (2) describe the results of scintigraphic evaluation of myocardial perfusion in sickle  thalassemia patients during exercise. Eight patients (26.6%) developed reversible perfusion abnormalities during exercise; subsequent coronary angiograms were normal in all 8 patients. As a result of the exercise test, a sickling pain episode developed in 4 of the 30 patients. The authors concluded that physical stress induced myocardial ischemia in sickle  thalassemia patients, despite normal coronary arteries. The development of exercise-induced chest pain and electrocardiographic changes in sickle cell patients has been well described (14). Sickled erythrocytes are known to stack and agglutinate into obstructive masses within small arteries, capillaries, and venules of the heart and other organs of the body. Subsequent endothelial proliferation and fibromuscular dysplasia among many small coronary arteries may account for focal degeneration and fibrosis of the myocardium and conduction system (15). Whether this process can be accurately described as acute ischemia that is responsible for the reversible perfusion abnormalities (16), such as those seen in the study by Aessopos et al., is open to debate. Current recommendations in the United States do not call for exercise proscription, but rather for a regular form of aerobic exertion (17). Health care professionals may not routinely assess or manage adult patients with significant hemoglobinopathies. Moreover, applying cardiac imaging methods to these patients does not always provide accurate clues to the complete pathophysiologic abnormalities that may exist. Nevertheless, these two papers suggest that by acknowledging the unexpected results of such testing of these patients—two echocardiographic forms of heart failure in  thalassemia major patients in the first paper, and perfusion defects despite normal coronary arteries in the second article—we may find innovative approaches to their successful management.
408
October 1, 2001
THE AMERICAN JOURNAL OF MEDICINE威
REFERENCES 1. Kremastinos DT, Tsetsos GA, Tsiapras DP, et al. Heart failure in beta thalassemia: a 5-year follow-up study. Am J Med. 2001;111: 349 –354. 2. Aessopos A, Tsironi M, Vassiliadis I, et al. Exercise-induced myocardial perfusion abnormalities in sickle  thalassemia: Tc-99m tetrofosmin gated SPECT imaging study. Am J Med. 2001;111:355– 360. 3. Zurlo MG, DeStefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassemia major. Lancet. 1989;2:27–30. 4. Engle MA, Erlandson M, Smith CH. Late cardiac complications of chronic severe refractory anemia with hemochromatosis. Circulation. 1964;30:698–705. 5. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous -thalassemia. N Engl J Med. 1994;331:574–578. 6. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331:567–573. 7. Jessup M, Manno CS. Diagnosis and management of iron-induced heart disease in Cooley’s anemia. Ann NY Acad Sci. 1998;850: 242–250. 8. Bahl VK, Malhotra OP, Kumar D, et al. Noninvasive assessment of systolic and diastolic left ventricular function in patients with chronic severe anemia: a combined M-mode, two-dimensional, and Doppler echocardiographic study. Am Heart J. 1992;124: 1516–1523. 9. Schellhammer PF, Engle MA, Hagstrom TW. Histochemical studies of the myocardium and conduction tissue in acquired iron storage disease. Circulation. 1967;35:631– 637. 10. Kremastinos DT, Tiniakos G, Theodorakis GN, et al. Myocarditis in -thalassemia major. A cause of heart failure. Circulation. 1995; 91:66–71. 11. Vecchio C, Derchi G. Management of cardiac complications in patients with thalassemia major. Semin Hematol. 1995;32:288–296. 12. Rund D, Rachmilewitz E. Thalassemia major 1995: older patients, new therapies. Blood Rev. 1995;9:25–32. 13. Leon MB, Borer JS, Bacharach SL, et al. Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron-overload. N Engl J Med. 1979;301:1143–1148. 14. Covitz W, Espeland M, Gallagher D, et al. The heart in sickle cell anemia. The Cooperative Study of Sickle Cell Disease (CSSCD). Chest. 1995;108:1214–1219. 15. James TN. Homage to James B. Herrick: a contemporary look at myocardial infarction and at sickle-cell disease: the 32nd Annual Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2000;101:1874–1887. 16. Martin CR, Johnson CS, Cobb C, et al. Myocardial infarction in sickle cell disease. J Natl Med Assoc. 1996;88:428– 432. 17. Reid C, Charache S, Lubin B, et al. Management and Therapy of Sickle Cell Disease. 3rd ed. Bethesda: National Institutes of Health; 1995.
Volume 111