- Email: [email protected]
Heart transplantation in a patient with chloroquine-induced cardiomyopathy
CASE REPORTS
Heart Transplantation in a Patient With Chloroquine-Induced Cardiomyopathy Jeffrey H. Freihage, MD,a Nehu C. Patel, MD,a William R. Jacobs, MD,a Maria Picken, MD, PhD,b Raoul Fresco, MD, PhD,b Krystyna Malinowska, PhD,a Barbara A. Pisani, DO,a Jose C. Mendez, MD,a Robert C. Lichtenberg, MD,a Bryan K. Foy, MD,c Mamdouh Bakhos, MD,c and G. Martin Mullen, MDa We present the first report of a patient who underwent heart transplantation (HT) after endomyocardial biopsy (EMB) and revealed chloroquine-induced cardiomyopathy (CIC). This patient, who was treated with chloroquine for 6 years, developed a restrictive cardiomyopathy that progressed to congestive heart failure (CHF) resistant to medical management. J Heart Lung Transplant 2004;23:252–255.
C
hloroquine is effective for the treatment of malaria. It is also used in the treatment of chronic conditions such as rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus and dermatologic disorders.1–3 However, long-term treatment with chloroquine can lead to irreversible retinopathy, myopathy and neuropathy.2,4,5 Cardiotoxic effects have also been reported.1– 8 Chloroquine at excessive doses can acutely effect the conduction system of the heart, leading to hypotension along with fatal arrhythmias.1 Its long-term use also can compromise the conduction system, leading to bundlebranch block or even complete heart block.1,6 Furthermore, long-term use can lead to cardiomyFrom the Divisions of aCardiology, bPathology and cThoracic and Cardiovascular Surgery, Department of Medicine, Loyola University Health System, Maywood, Illinois, USA. Submitted October 2, 2002; revised January 10, 2003; accepted January 15, 2003. Support by the Robert Donald Van Kampen Heart Transplant Resource Center. Reprint requests: Jeffrey H. Freihage, MD, Division of Cardiology, Department of Medicine, Loyola University Health System, 2160 South First Avenue, Maywood, Illinois 60153. Email: [email protected]. Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter doi:10.1016/S1053-2498(03)00108-6
252
opathy.4 Chloroquine-induced cardiomyopathy (CIC) was first reported in 1977,5 and, since then, roughly a dozen reports of CIC have been presented.1– 8 In half of these cases, the patients’ condition improved with discontinuation of chloroquine, but in the others the patients died despite its discontinuation.
CASE REPORT A 50-year-old woman with rheumatoid arthritis and unstable congestive heart failure (CHF) was transferred to our hospital for treatment of heart failure and evaluation for possible heart transplantation (HT). She had an 18-year history of rheumatoid arthritis (rheumatoid factor-positive) with moderate, but not lifestyle-limiting, joint deformities treated weekly with methotrexate and the addition of 500 mg/d chloroquine for the last 6 years, which had been discontinued 1 month before transfer. Two years prior to admission, she noted bilateral foot swelling after total knee replacements. One year later she experienced cardiac arrest from ventricular fibrillation. At that time she had normal coronary arteries and normal left ventricular (LV) function, and a defibrillator was placed. She was in compensated heart failure until 4 months before transfer when she developed dyspnea on exertion, peripheral edema
The Journal of Heart and Lung Transplantation Volume 23, Number 2
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FIGURE 1 Two-dimensional echocardiographic long-axis view demonstrating normal LV cavity size and thickened LV wall.
and ascites. Despite medical management with digoxin, diuretics and angiotensin-converting enzyme inhibitors, she required multiple hospitalizations. Finally, she was admitted to a local hospital with CHF exacerbation that led to anuric renal failure. At the time of transfer to our hospital her physical exam revealed bitemporal wasting and a weight of 80 kg. Blood pressure was 90/60. She had elevated jugular venous pulse to the angle of the mandible at 45°. Heart rhythm was regular with a grade III/VI holosystolic murmur at the lower left sternal border radiating to the upper left sternal border, which increased with inspiration. The lungs were clear to auscultation and percussion. She had a pulsatile liver 3 cm below the costal margin and a grade 3⫹ pitting edema to the level of the knees. Neurologic examination was normal. Retinal examination done by an ophthalmologist was normal. The chest X-ray showed no infiltrates, only a slightly enlarged cardiac silhouette. Electrocardiogram (ECG) revealed a paced rhythm. Transthoracic echocardiography showed normal valvular anatomy with left and right atrial enlargement. The LV was normal in size but with thickened walls (Figure 1). Cardiac catheterization revealed normal coronary arteries and normal LV systolic function (ejection fraction 60%). LV end-diastolic pressure was 18 mm Hg. Right atrial (RA) pressures demonstrated a rapid y-descent. All right-sided pressures were elevated: RA, 18; right ventricle, (RV), 43/2; pulmonary artery, 46/13; and pulmonary
capillary wedge pressure, 22 mm Hg. RV enddiastolic pressure was 13 mm Hg. Right-and leftheart catheterization demonstrated dip-and-plateau pressure tracings. Ventricular inter-dependence was not shown. Right ventriculogram revealed wideopen tricuspid insufficiency. Transesophageal echocardiography demonstrated structurally normal tricuspid valves with one leaflet open causing moderate-to-severe regurgitation with an RV to RA gradient of 35 to 40 mm Hg. First-pass multiplegated acquisition (MUGA) scan revealed an RV ejection fraction of 40%. Computed tomography (CT) of the thorax demonstrated minimal pericardial thickening and no calcifications. Endomyocardial biopsy (EMB) stained negatively for iron and amyloid. Furthermore, all immunofluorescence (IF) studies were non-diagnostic (anti-human IgG, IgA, IgM, kappa and lambda light chains, C3, C1q, fibrinogen and albumin). Hematoxylin and eosin (H&E) sections showed a focal-feathery appearance of the myocytes. Electron microscopy (EM) revealed extensive loss of myocardial fibrils and accumulation of concentric lamellae (myelinoid bodies) as well as numerous curvilinear bodies. The diagnosis of restrictive cardiomyopathy secondary to chloroquine was based on the EM findings of the EMB (Figure 2). Due to the instability of the patient’s heart failure and the requirement of continuous inotropes, she was listed for HT. She underwent HT after being off chloroquine for ⬎3 months, during which time she
254
Freihage et al.
The Journal of Heart and Lung Transplantation February 2004
FIGURE 2 Space between 2 myocardial fibers showing numerous mitochondria
interspersed with myelinoid bodies (short arrows) and curvilinear bodies (long arrows). Original magnification ⫻7,000.
had shown no improvement. At the time of surgery the pericardium was normal. The explanted heart weighed 401 g and there was biventricular hypertrophy along with RV dilation. On histologic assessment, there was marked vacuolation of the subendocardial myocytes, which also involved the deeper myocardium to a lesser extent. All myocardial changes were consistent with CIC. At present, she was 1 year post-HT and doing very well. Although surveillance EMB revealed 2 focal moderate rejections, she was treated effectively with the pulse steroid therapy.
DISCUSSION We believe this is the first report of a patient with CIC to receive HT. Our patient received 500 mg/d for 6 years with a cumulative dose of 1,100 g. This dose is consistent with a report of patients receiving 600 to 2,280 g of chloroquine who developed cardiomyopathy due to toxicity from either high doses or prolonged treatment.4 Acute chloroquine toxicity can cause fatal arrhythmias due to interference with mitochondrial oxidative metabolism.7 The 2 known explanations for chronic chloroquine toxicity inducing cardiomyopathy are based on the finding that chloroquine is selectively taken up by lysosomes.1,6 A first explanation is that such progressive accumulation of chloroquine increases the pH in the lysosomes. The increased pH interferes with the activity of lysoso-
mal enzymes, leading to the accumulation of glycogen and phospholipids. A second explanation is that chloroquine directly binds to lysosomal enzymes, leading to decreased degradation of phospholipids. Both explanations demonstrate that the accumulation of glycogen and phospholipids leads to the formation of myelinoid and curvilinear bodies. Ultimately, these changes in structure destroy the ability of the myocytes to function properly. In one study restrictive cardiomyopathy induced by chloroquine was diagnosed by non-invasive methods (jugular venous pulse and cross-sectional echocardiography) and skeletal muscle biopsy, revealing curvilinear and myelinoid bodies.2 Five weeks after discontinuation of chloroquine, the patient expired and post-mortem EM of the cardiac tissue revealed myelinoid and curvilinear bodies. The use of skeletal muscle biopsy for diagnosis should be employed with caution because peripheral muscle and retinal involvement are inconsistent findings in the presence of cardiac disease.7 Although light microscopy has demonstrated vacuolated myocytes, the EM findings with myelinoid bodies as well as curvilinear bodies in our patient were both characteristic and diagnostic.3,8 The presence of curvilinear bodies in the cardiac myocytes is the most distinctive and reliable morphologic indicator of chloroquine-associated myocyte damage.3 Although many of the lysosomal storage diseases and toxic medications (e.g., amiodarone) cause sim-
The Journal of Heart and Lung Transplantation Volume 23, Number 2
ilar changes, curvilinear bodies have never been observed in these conditions.7 In a patient reported elsewhere with a restrictive cardiomyopathy, both clinical and histologic improvement occurred after discontinuation of chloroquine. The EMB demonstrated extensive myelinoid and curvilinear bodies.8 Subsequent EMBs in this patient were obtained at 6 weeks and 7 months after discontinuation of chloroquine therapy. An EMB at 6 weeks was unchanged, but the 7-month EMB showed that only half of the myocytes had myelinoid or curvilinear bodies. This patient had had a similar cumulative dose of chloroquine and length of treatment (500 mg/d for 6 years) to the patient in the present study. This partial improvement suggests that there could be the other factors responsible for the degree and progression of cardiac disease. At present there is no unanimity on how to screen for chloroquine-induced heart damage. One report recommends that an ECG be done before and at 6 months into chloroquine treatment.4 Annual ECGs should be performed if the total dose of chloroquine is ⬎100 g per year. Others recommend EMB for any patient who has cardiac symptoms while on or shortly after discontinuation of chloroquine.1 This
Freihage et al.
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report emphasizes the potential consequences of chloroquine toxicity: lack of improvement, even 3 months after discontinuation, and progression of heart failure requiring HT. REFERENCES 1. August C, Hohlzhausen HJ, Schmoldt A. Histological and ultrastructural findings in chloroquine-induced cardiomyopathy. J Mol Med 1995;73:73–7. 2. Cubero GI, Rodriguez Reguero JJ, Rojo Ortega JM. Restrictive cardiomyopathy caused by chloroquine. Br Heart J 1993; 69:451–2. 3. McAllister HA, Jr, Ferrans VJ, Jall RJ, et al. Chloroquine induced cardiomyopathy. Arch Pathol Lab Med 1987;111: 953–6. 4. Cervera A, Espinosa G, Cervera R, et al. Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis 2001;60:301. 5. Magnussen I, de Fine Olivarius B. Cardiomyopathy after chloroquine treatment. Acta Med Scand 1977;202:429 –34. 6. Veinot JP, Mai KT, Zarychanski R. Chloroquine related cardiac toxicity. J Rheumatol 1998;25:1221–5. 7. Baguet JP, Tremel F, Fabre M. Chloroquine cardiomyopathy with conduction disorders. Heart 1999;81:221–3. 8. Ratliff NB, Estes ML, Myles JL, et al. Diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy. N Engl J Med 1987;316:191–3.
Heart Transplantation in a Patient With Chloroquine-Induced Cardiomyopathy Jeffrey H. Freihage, MD,a Nehu C. Patel, MD,a William R. Jacobs, MD,a Maria Picken, MD, PhD,b Raoul Fresco, MD, PhD,b Krystyna Malinowska, PhD,a Barbara A. Pisani, DO,a Jose C. Mendez, MD,a Robert C. Lichtenberg, MD,a Bryan K. Foy, MD,c Mamdouh Bakhos, MD,c and G. Martin Mullen, MDa We present the first report of a patient who underwent heart transplantation (HT) after endomyocardial biopsy (EMB) and revealed chloroquine-induced cardiomyopathy (CIC). This patient, who was treated with chloroquine for 6 years, developed a restrictive cardiomyopathy that progressed to congestive heart failure (CHF) resistant to medical management. J Heart Lung Transplant 2004;23:252–255.
C
hloroquine is effective for the treatment of malaria. It is also used in the treatment of chronic conditions such as rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus and dermatologic disorders.1–3 However, long-term treatment with chloroquine can lead to irreversible retinopathy, myopathy and neuropathy.2,4,5 Cardiotoxic effects have also been reported.1– 8 Chloroquine at excessive doses can acutely effect the conduction system of the heart, leading to hypotension along with fatal arrhythmias.1 Its long-term use also can compromise the conduction system, leading to bundlebranch block or even complete heart block.1,6 Furthermore, long-term use can lead to cardiomyFrom the Divisions of aCardiology, bPathology and cThoracic and Cardiovascular Surgery, Department of Medicine, Loyola University Health System, Maywood, Illinois, USA. Submitted October 2, 2002; revised January 10, 2003; accepted January 15, 2003. Support by the Robert Donald Van Kampen Heart Transplant Resource Center. Reprint requests: Jeffrey H. Freihage, MD, Division of Cardiology, Department of Medicine, Loyola University Health System, 2160 South First Avenue, Maywood, Illinois 60153. Email: [email protected]. Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter doi:10.1016/S1053-2498(03)00108-6
252
opathy.4 Chloroquine-induced cardiomyopathy (CIC) was first reported in 1977,5 and, since then, roughly a dozen reports of CIC have been presented.1– 8 In half of these cases, the patients’ condition improved with discontinuation of chloroquine, but in the others the patients died despite its discontinuation.
CASE REPORT A 50-year-old woman with rheumatoid arthritis and unstable congestive heart failure (CHF) was transferred to our hospital for treatment of heart failure and evaluation for possible heart transplantation (HT). She had an 18-year history of rheumatoid arthritis (rheumatoid factor-positive) with moderate, but not lifestyle-limiting, joint deformities treated weekly with methotrexate and the addition of 500 mg/d chloroquine for the last 6 years, which had been discontinued 1 month before transfer. Two years prior to admission, she noted bilateral foot swelling after total knee replacements. One year later she experienced cardiac arrest from ventricular fibrillation. At that time she had normal coronary arteries and normal left ventricular (LV) function, and a defibrillator was placed. She was in compensated heart failure until 4 months before transfer when she developed dyspnea on exertion, peripheral edema
The Journal of Heart and Lung Transplantation Volume 23, Number 2
Freihage et al.
253
FIGURE 1 Two-dimensional echocardiographic long-axis view demonstrating normal LV cavity size and thickened LV wall.
and ascites. Despite medical management with digoxin, diuretics and angiotensin-converting enzyme inhibitors, she required multiple hospitalizations. Finally, she was admitted to a local hospital with CHF exacerbation that led to anuric renal failure. At the time of transfer to our hospital her physical exam revealed bitemporal wasting and a weight of 80 kg. Blood pressure was 90/60. She had elevated jugular venous pulse to the angle of the mandible at 45°. Heart rhythm was regular with a grade III/VI holosystolic murmur at the lower left sternal border radiating to the upper left sternal border, which increased with inspiration. The lungs were clear to auscultation and percussion. She had a pulsatile liver 3 cm below the costal margin and a grade 3⫹ pitting edema to the level of the knees. Neurologic examination was normal. Retinal examination done by an ophthalmologist was normal. The chest X-ray showed no infiltrates, only a slightly enlarged cardiac silhouette. Electrocardiogram (ECG) revealed a paced rhythm. Transthoracic echocardiography showed normal valvular anatomy with left and right atrial enlargement. The LV was normal in size but with thickened walls (Figure 1). Cardiac catheterization revealed normal coronary arteries and normal LV systolic function (ejection fraction 60%). LV end-diastolic pressure was 18 mm Hg. Right atrial (RA) pressures demonstrated a rapid y-descent. All right-sided pressures were elevated: RA, 18; right ventricle, (RV), 43/2; pulmonary artery, 46/13; and pulmonary
capillary wedge pressure, 22 mm Hg. RV enddiastolic pressure was 13 mm Hg. Right-and leftheart catheterization demonstrated dip-and-plateau pressure tracings. Ventricular inter-dependence was not shown. Right ventriculogram revealed wideopen tricuspid insufficiency. Transesophageal echocardiography demonstrated structurally normal tricuspid valves with one leaflet open causing moderate-to-severe regurgitation with an RV to RA gradient of 35 to 40 mm Hg. First-pass multiplegated acquisition (MUGA) scan revealed an RV ejection fraction of 40%. Computed tomography (CT) of the thorax demonstrated minimal pericardial thickening and no calcifications. Endomyocardial biopsy (EMB) stained negatively for iron and amyloid. Furthermore, all immunofluorescence (IF) studies were non-diagnostic (anti-human IgG, IgA, IgM, kappa and lambda light chains, C3, C1q, fibrinogen and albumin). Hematoxylin and eosin (H&E) sections showed a focal-feathery appearance of the myocytes. Electron microscopy (EM) revealed extensive loss of myocardial fibrils and accumulation of concentric lamellae (myelinoid bodies) as well as numerous curvilinear bodies. The diagnosis of restrictive cardiomyopathy secondary to chloroquine was based on the EM findings of the EMB (Figure 2). Due to the instability of the patient’s heart failure and the requirement of continuous inotropes, she was listed for HT. She underwent HT after being off chloroquine for ⬎3 months, during which time she
254
Freihage et al.
The Journal of Heart and Lung Transplantation February 2004
FIGURE 2 Space between 2 myocardial fibers showing numerous mitochondria
interspersed with myelinoid bodies (short arrows) and curvilinear bodies (long arrows). Original magnification ⫻7,000.
had shown no improvement. At the time of surgery the pericardium was normal. The explanted heart weighed 401 g and there was biventricular hypertrophy along with RV dilation. On histologic assessment, there was marked vacuolation of the subendocardial myocytes, which also involved the deeper myocardium to a lesser extent. All myocardial changes were consistent with CIC. At present, she was 1 year post-HT and doing very well. Although surveillance EMB revealed 2 focal moderate rejections, she was treated effectively with the pulse steroid therapy.
DISCUSSION We believe this is the first report of a patient with CIC to receive HT. Our patient received 500 mg/d for 6 years with a cumulative dose of 1,100 g. This dose is consistent with a report of patients receiving 600 to 2,280 g of chloroquine who developed cardiomyopathy due to toxicity from either high doses or prolonged treatment.4 Acute chloroquine toxicity can cause fatal arrhythmias due to interference with mitochondrial oxidative metabolism.7 The 2 known explanations for chronic chloroquine toxicity inducing cardiomyopathy are based on the finding that chloroquine is selectively taken up by lysosomes.1,6 A first explanation is that such progressive accumulation of chloroquine increases the pH in the lysosomes. The increased pH interferes with the activity of lysoso-
mal enzymes, leading to the accumulation of glycogen and phospholipids. A second explanation is that chloroquine directly binds to lysosomal enzymes, leading to decreased degradation of phospholipids. Both explanations demonstrate that the accumulation of glycogen and phospholipids leads to the formation of myelinoid and curvilinear bodies. Ultimately, these changes in structure destroy the ability of the myocytes to function properly. In one study restrictive cardiomyopathy induced by chloroquine was diagnosed by non-invasive methods (jugular venous pulse and cross-sectional echocardiography) and skeletal muscle biopsy, revealing curvilinear and myelinoid bodies.2 Five weeks after discontinuation of chloroquine, the patient expired and post-mortem EM of the cardiac tissue revealed myelinoid and curvilinear bodies. The use of skeletal muscle biopsy for diagnosis should be employed with caution because peripheral muscle and retinal involvement are inconsistent findings in the presence of cardiac disease.7 Although light microscopy has demonstrated vacuolated myocytes, the EM findings with myelinoid bodies as well as curvilinear bodies in our patient were both characteristic and diagnostic.3,8 The presence of curvilinear bodies in the cardiac myocytes is the most distinctive and reliable morphologic indicator of chloroquine-associated myocyte damage.3 Although many of the lysosomal storage diseases and toxic medications (e.g., amiodarone) cause sim-
The Journal of Heart and Lung Transplantation Volume 23, Number 2
ilar changes, curvilinear bodies have never been observed in these conditions.7 In a patient reported elsewhere with a restrictive cardiomyopathy, both clinical and histologic improvement occurred after discontinuation of chloroquine. The EMB demonstrated extensive myelinoid and curvilinear bodies.8 Subsequent EMBs in this patient were obtained at 6 weeks and 7 months after discontinuation of chloroquine therapy. An EMB at 6 weeks was unchanged, but the 7-month EMB showed that only half of the myocytes had myelinoid or curvilinear bodies. This patient had had a similar cumulative dose of chloroquine and length of treatment (500 mg/d for 6 years) to the patient in the present study. This partial improvement suggests that there could be the other factors responsible for the degree and progression of cardiac disease. At present there is no unanimity on how to screen for chloroquine-induced heart damage. One report recommends that an ECG be done before and at 6 months into chloroquine treatment.4 Annual ECGs should be performed if the total dose of chloroquine is ⬎100 g per year. Others recommend EMB for any patient who has cardiac symptoms while on or shortly after discontinuation of chloroquine.1 This
Freihage et al.
255
report emphasizes the potential consequences of chloroquine toxicity: lack of improvement, even 3 months after discontinuation, and progression of heart failure requiring HT. REFERENCES 1. August C, Hohlzhausen HJ, Schmoldt A. Histological and ultrastructural findings in chloroquine-induced cardiomyopathy. J Mol Med 1995;73:73–7. 2. Cubero GI, Rodriguez Reguero JJ, Rojo Ortega JM. Restrictive cardiomyopathy caused by chloroquine. Br Heart J 1993; 69:451–2. 3. McAllister HA, Jr, Ferrans VJ, Jall RJ, et al. Chloroquine induced cardiomyopathy. Arch Pathol Lab Med 1987;111: 953–6. 4. Cervera A, Espinosa G, Cervera R, et al. Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis 2001;60:301. 5. Magnussen I, de Fine Olivarius B. Cardiomyopathy after chloroquine treatment. Acta Med Scand 1977;202:429 –34. 6. Veinot JP, Mai KT, Zarychanski R. Chloroquine related cardiac toxicity. J Rheumatol 1998;25:1221–5. 7. Baguet JP, Tremel F, Fabre M. Chloroquine cardiomyopathy with conduction disorders. Heart 1999;81:221–3. 8. Ratliff NB, Estes ML, Myles JL, et al. Diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy. N Engl J Med 1987;316:191–3.