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Heart transplantation in a patient with multiple sclerosis and mitoxantrone-induced cardiomyopathy
Heart Transplantation in a Patient With Multiple Sclerosis and Mitoxantrone-Induced Cardiomyopathy H. Na¨gele, MD, M.A. Castel, MD, O. Deutsch, MD, F.M. Wagner, MD, and H. Reichenspurner, MD, PhD We describe a 30-year-old man with end-stage heart failure after therapy with mitoxantrone for multiple sclerosis. A successful orthotopic heart transplantation was performed when intensified medical therapy failed to improve the patient’s hemodynamics. In spite of the severe underlying disease he did well on dual immunosuppression with methylprednisone and cyclosporine. Neurologic symptoms remained stable throughout the procedure and, after 2 months, he resumed preoperative ambulatory status. Eight years after the operation, the patient is now in New York Heart Association (NYHA) Class I status. Using canes, he is able to walk short distances. Repeated urinary tract infections caused by Escherichia coli became a problem, but have been controlled by long-term oral antibiotic prophylaxis with trimethoprim. J Heart Lung Transplant 2004;23:641–3.
The results of several studies have demonstrated mitoxantrone’s beneficial palliative effects on rapidly progressing multiple sclerosis.1–3 Mitoxantrone is structurally related to the anthracycline drugs doxorubicin and daunorubicin, and has also been used for the treatment of advanced metastatic cancer.4 Cardiotoxicity is a well-documented side effect of all anthracyclines.5 Tolerance of mitoxantrone was reported to be better than that of its analoges, predominantly exhibiting severe cardiac toxicity in combination with previous mediastinal irradiation, anthracycline therapy or cardiovascular disease.6 We describe a patient with severe cardiac failure after therapy with mitoxantrone for disabling multiple sclerosis and its successful treatment with orthotopic heart transplantation. CASE REPORT The patient was a 30-year-old man with a definitive diagnosis of multiple sclerosis since 1984. Cerebral magnetic resonance tomography in 1994 confirmed multiple sub-cortical demyelinating lesions compatible with encephalomyelitis. Clinical indications up to the time of operation included internuclear ophthalmoplegia, left-sided cerebellar dystaxia with kinetic tremor, left hemihypesthesia and extensor plantar responses bilaterally. In 1991, therapy with intravenous mitoFrom the aDepartment of Cardiovascular Surgery, University Clinic Eppendorf, Hamburg, Germany. Submitted February 19, 2003; revised June 17, 2003; accepted June 17, 2003. Reprint requests: H. Na¨gele, MD, Department of Cardiovascular Surgery, University Clinic Eppendorf, D-20246 Hamburg, Germany. Telephone: 49-40-42803-3471. Fax: 49-40-42803-4591. E-mail: naegele@uke. uni-hamburg.de Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ S1053-2498(03)00307-3
xantrone (Novantrone) every 2 months was initiated. By November 1993, a cumulative dose of 425 mg (236 mg/m2 body surface area) had been administered. His neurologic status remained stable under this regimen, although in 1992 a suprapubic catheter had to be inserted for bladder incontinence. Routinely performed echocardiographic studies first showed reduced systolic left ventricular function in December 1993 and mitoxantrone therapy was stopped. In January 1994 he was admitted to our hospital with severe biventricular cardiac decompensation. He had orthopnea, cyanosis, bilateral pleural effusions and ascites. His electrocardiogram showed sinus tachycardia of 100 beats/min; a left anterior fascicular block; and non-specific T-wave abnormalities in leads I, aVL and V4 to V6. Left and right heart catheterization with myocardial biopsy was performed. Coronary arteries were normal, left ventricular function was severely depressed (ejection fraction 15%), and histologic evaluation of the myocardial biopsy showed no signs of inflammation. Some focal sub-endocardial interstitial fibrosis was noted. Cardiac index (CI) at that investigation was 2.38 liters/min · m2 and pulmonary capillary wedge pressure (PCWP) was 20 mm Hg. Therapy with diuretics, digitalis and angiotensin-converting enzyme (ACE) inhibitors was initiated and the patient’s condition improved. In February 1994, he was able to leave the hospital. He was re-admitted the next month with another episode of cardiac decompensation and renal failure. Medical therapy was intensified on the basis of results from another right heart catheterization study. In that investigation, under maximal conventional therapy, a CI of 2.0 liters/min · m2 and a PCWP of 18 mm Hg were noted. Under additional pre-load and after-load reduction the patient’s status improved and he was again discharged. On April 13, 1994 he was re-admitted with dyspnea, jaundice and extreme fatigue. Echocardiographic study showed a hypokinetic heart with frac641
642
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tional shortening of approximately 7%, a left ventricular end-diastolic diameter of 6.4 cm and Grade I to II mitral and tricuspid regurgitation. His laboratory values showed a pattern of severe liver congestion with a bilirubin level of 6.5 mg/dl, alanine aminotransferase (ALAT) of 220 U/liter, aspartate aminotransferase (ASAT) of 277 U/liter and lactate dehydrogenase (LDH) of 795 U/liter. Despite severe underlying disease he was accepted for heart transplantation as the only remaining treatment option. On May 4, 1994, when a donor heart became available, orthotopic heart transplantation was performed. Induction immunosuppression was provided with rat anti-thymocyte globulin (rATG, Fresenius AG) and maintenance immunosuppression with 8 mg/day methylprednisone. Cyclosporine was then administered. Azathioprine was not used due to a gastrointestinal incompatibility. The peri-operative course was uneventful. The patient left the intensive care unit on Day 6 post-operatively. Repeated echocardiograms showed a normally functioning graft, whereas a right ventricular biopsy 30 days after the operation showed no signs of rejection (Hanover Stage A-1 F-0). A Xanthomonas maltophilia pulmonary infection at Week 2 post-operatively was successfully cured with ciprofloxacin. Because of sinus node syndrome of the donor heart, on Day 30 in the hospital a DDD pacemaker with leads in the recipient and donor atrium plus a short atrioventricular delay were inserted to restore a physiologic heart rate. No complications arose with this second intervention. By 2 to 3 months after the operation, it was possible to restore the patient’s mobility and he returned to pre-operative neurologic and overall health status. Histologic examination of the explanted heart from the recipient showed no signs of inflammation, but enlarged myocytes with severe interstitial fibrosis were seen. This finding was consistent with anthracycline toxicity. Unfortunately, no electron microscopic examination was performed. Eight years later, this patient is able to live alone in his flat and to work part-time as a programmer. Because azathioprine was not tolerated due to gastrointestinal problems, long-term immunosuppression consisted of methylprednisolone (4 mg/day) and cyclosporine (through levels 65 to 100 ng/ml). Annual myocardial biopsies showed no signs of rejection. Repeated coronary angiograms showed no signs of transplant vasculopathy. Several urinary tract infections have occurred, however, and these were obviously caused by the patient’s suprapubic catheter. Escherichia coli organisms were cultured several times. Long-term trimetophrim therapy at a dose of 50 mg/day has been prescribed since 1999, and has prevented any further re-infection. Another event
The Journal of Heart and Lung Transplantation May 2004
was a general convulsion in 2001 and, although no obvious reason was found, interference from cyclosporine therapy and the underlying disease were suspected as the causes. Additional therapy with carbamazepine was given, resulting in freedom from further convulsions up to the present. DISCUSSION To our knowledge this is the first case report on the long-term course of a patient with multiple sclerosis in whom cardiac transplantation was performed. His cardiomyopathy was very likely induced by the cardiotoxic effects of mitoxantrone. No other cause for the patient’s cardiomyopathy was found. This case again highlights the need for close cardiologic follow-up of patients receiving anthracyclines, including mitoxantrone.7 The lowest cumulative dose that provides sufficient therapeutic efficacy should be administered. Attempts to prevent anthracycline-induced cardiomyopathy with calcium channel blockers have been disappointing.8 Our patient received a relatively high cumulative dose, but cardiotoxic effects were described after doses of ⬍85 mg/m2 body surface area.9 In that report suppression of cardiac function was temporary and without any sequelae. By contrast, our patient suffered from irreversible, therapy-refractory cardiac damage. Mitoxantrone has a palliative role in controlling multiple sclerosis. In the light of our case and published data,3 close and careful cardiologic monitoring of patients undergoing this tentative treatment is necessary. Administration of the drug should also be discontinued immediately if any signs or symptoms of impending heart failure develop. Most importantly, the present case report shows that cardiac transplantation can be performed with good results in a patient with advanced multiple sclerosis. As for necessary immunosuppression, it is emphasized that prednisone and azathioprine as well as cyclosporine and FK 506 are also being used or evaluated in the treatment of multiple sclerosis.10 Such therapy may therefore even have a favorable effect on the underlying neurologic disease. For our patient, the stable clinical peri-operative course fortunately persisted in long-term follow-up. He has enjoyed a good quality of life for the past 8 years after heart transplantation. The sole, major problem in this patient is the occurrence of urinary tract infections due to suprapubic fistula. After initiation of long-term antibiotic therapy with trimethoprim, no further infections were noted. In conclusion, we suggest that heart transplantation should not be withheld from patients with multiple sclerosis and end-stage heart failure when no other
The Journal of Heart and Lung Transplantation Volume 23, Number 5
treatment options exist. However, in light of the ongoing crisis in heart transplantation (lack of donor organs), this single experience can obviously not be used to suggest general expansion of the recipient pool. REFERENCES 1. Noseworthy JH, Hopkins MB, Vandervoort MK, et al. An open-trial evaluation of mitoxantrone in the treatment of progressive MS. Neurology 1993;43:1401–6. 2. Mauch E, Kornhuber HH, Krapf H, Fetzer U, Laufen H. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci 1992;242:96 –102. 3. Ben-Zacharia AB, Lublin FD. Palliative care in patients with multiple sclerosis. Neurol Clin 2001;19:801–27. 4. Koeller J, Eble M. Mitoxantrone: a novel anthracycline derivative. Clin Pharmacol 1988;7:574 –81.
Na¨ gele et al.
643
5. Goebel M, Kaplan E. Anthracycline-induced cardiotoxicity—a review. Oncology 1992;15:198 –204. 6. van der Graaf WT, de Vries EG. Mitoxantrone: bluebeard for malignancies. Anti-Cancer Drugs 1990;1:109 –25. 7. Ghalie RG, Edan G, Laurent M, et al. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology 2002;59:909 –13. 8. Kraft J, Grille W, Appelt M, et al. Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial. Hematol Blood Transf 1990;33:566 –70. 9. Villani F, Galimberti M, Crippa F. Evaluation of ventricular function by echocardiography and radionuclide angiography in patients treated with mitoxantrone. Drugs Exp Clin Res 1989;15:501–6. 10. Hughes RA. Immunotherapy for multiple sclerosis. J Neurol 1994;57:3–6.
The results of several studies have demonstrated mitoxantrone’s beneficial palliative effects on rapidly progressing multiple sclerosis.1–3 Mitoxantrone is structurally related to the anthracycline drugs doxorubicin and daunorubicin, and has also been used for the treatment of advanced metastatic cancer.4 Cardiotoxicity is a well-documented side effect of all anthracyclines.5 Tolerance of mitoxantrone was reported to be better than that of its analoges, predominantly exhibiting severe cardiac toxicity in combination with previous mediastinal irradiation, anthracycline therapy or cardiovascular disease.6 We describe a patient with severe cardiac failure after therapy with mitoxantrone for disabling multiple sclerosis and its successful treatment with orthotopic heart transplantation. CASE REPORT The patient was a 30-year-old man with a definitive diagnosis of multiple sclerosis since 1984. Cerebral magnetic resonance tomography in 1994 confirmed multiple sub-cortical demyelinating lesions compatible with encephalomyelitis. Clinical indications up to the time of operation included internuclear ophthalmoplegia, left-sided cerebellar dystaxia with kinetic tremor, left hemihypesthesia and extensor plantar responses bilaterally. In 1991, therapy with intravenous mitoFrom the aDepartment of Cardiovascular Surgery, University Clinic Eppendorf, Hamburg, Germany. Submitted February 19, 2003; revised June 17, 2003; accepted June 17, 2003. Reprint requests: H. Na¨gele, MD, Department of Cardiovascular Surgery, University Clinic Eppendorf, D-20246 Hamburg, Germany. Telephone: 49-40-42803-3471. Fax: 49-40-42803-4591. E-mail: naegele@uke. uni-hamburg.de Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ S1053-2498(03)00307-3
xantrone (Novantrone) every 2 months was initiated. By November 1993, a cumulative dose of 425 mg (236 mg/m2 body surface area) had been administered. His neurologic status remained stable under this regimen, although in 1992 a suprapubic catheter had to be inserted for bladder incontinence. Routinely performed echocardiographic studies first showed reduced systolic left ventricular function in December 1993 and mitoxantrone therapy was stopped. In January 1994 he was admitted to our hospital with severe biventricular cardiac decompensation. He had orthopnea, cyanosis, bilateral pleural effusions and ascites. His electrocardiogram showed sinus tachycardia of 100 beats/min; a left anterior fascicular block; and non-specific T-wave abnormalities in leads I, aVL and V4 to V6. Left and right heart catheterization with myocardial biopsy was performed. Coronary arteries were normal, left ventricular function was severely depressed (ejection fraction 15%), and histologic evaluation of the myocardial biopsy showed no signs of inflammation. Some focal sub-endocardial interstitial fibrosis was noted. Cardiac index (CI) at that investigation was 2.38 liters/min · m2 and pulmonary capillary wedge pressure (PCWP) was 20 mm Hg. Therapy with diuretics, digitalis and angiotensin-converting enzyme (ACE) inhibitors was initiated and the patient’s condition improved. In February 1994, he was able to leave the hospital. He was re-admitted the next month with another episode of cardiac decompensation and renal failure. Medical therapy was intensified on the basis of results from another right heart catheterization study. In that investigation, under maximal conventional therapy, a CI of 2.0 liters/min · m2 and a PCWP of 18 mm Hg were noted. Under additional pre-load and after-load reduction the patient’s status improved and he was again discharged. On April 13, 1994 he was re-admitted with dyspnea, jaundice and extreme fatigue. Echocardiographic study showed a hypokinetic heart with frac641
642
Na¨gele et al.
tional shortening of approximately 7%, a left ventricular end-diastolic diameter of 6.4 cm and Grade I to II mitral and tricuspid regurgitation. His laboratory values showed a pattern of severe liver congestion with a bilirubin level of 6.5 mg/dl, alanine aminotransferase (ALAT) of 220 U/liter, aspartate aminotransferase (ASAT) of 277 U/liter and lactate dehydrogenase (LDH) of 795 U/liter. Despite severe underlying disease he was accepted for heart transplantation as the only remaining treatment option. On May 4, 1994, when a donor heart became available, orthotopic heart transplantation was performed. Induction immunosuppression was provided with rat anti-thymocyte globulin (rATG, Fresenius AG) and maintenance immunosuppression with 8 mg/day methylprednisone. Cyclosporine was then administered. Azathioprine was not used due to a gastrointestinal incompatibility. The peri-operative course was uneventful. The patient left the intensive care unit on Day 6 post-operatively. Repeated echocardiograms showed a normally functioning graft, whereas a right ventricular biopsy 30 days after the operation showed no signs of rejection (Hanover Stage A-1 F-0). A Xanthomonas maltophilia pulmonary infection at Week 2 post-operatively was successfully cured with ciprofloxacin. Because of sinus node syndrome of the donor heart, on Day 30 in the hospital a DDD pacemaker with leads in the recipient and donor atrium plus a short atrioventricular delay were inserted to restore a physiologic heart rate. No complications arose with this second intervention. By 2 to 3 months after the operation, it was possible to restore the patient’s mobility and he returned to pre-operative neurologic and overall health status. Histologic examination of the explanted heart from the recipient showed no signs of inflammation, but enlarged myocytes with severe interstitial fibrosis were seen. This finding was consistent with anthracycline toxicity. Unfortunately, no electron microscopic examination was performed. Eight years later, this patient is able to live alone in his flat and to work part-time as a programmer. Because azathioprine was not tolerated due to gastrointestinal problems, long-term immunosuppression consisted of methylprednisolone (4 mg/day) and cyclosporine (through levels 65 to 100 ng/ml). Annual myocardial biopsies showed no signs of rejection. Repeated coronary angiograms showed no signs of transplant vasculopathy. Several urinary tract infections have occurred, however, and these were obviously caused by the patient’s suprapubic catheter. Escherichia coli organisms were cultured several times. Long-term trimetophrim therapy at a dose of 50 mg/day has been prescribed since 1999, and has prevented any further re-infection. Another event
The Journal of Heart and Lung Transplantation May 2004
was a general convulsion in 2001 and, although no obvious reason was found, interference from cyclosporine therapy and the underlying disease were suspected as the causes. Additional therapy with carbamazepine was given, resulting in freedom from further convulsions up to the present. DISCUSSION To our knowledge this is the first case report on the long-term course of a patient with multiple sclerosis in whom cardiac transplantation was performed. His cardiomyopathy was very likely induced by the cardiotoxic effects of mitoxantrone. No other cause for the patient’s cardiomyopathy was found. This case again highlights the need for close cardiologic follow-up of patients receiving anthracyclines, including mitoxantrone.7 The lowest cumulative dose that provides sufficient therapeutic efficacy should be administered. Attempts to prevent anthracycline-induced cardiomyopathy with calcium channel blockers have been disappointing.8 Our patient received a relatively high cumulative dose, but cardiotoxic effects were described after doses of ⬍85 mg/m2 body surface area.9 In that report suppression of cardiac function was temporary and without any sequelae. By contrast, our patient suffered from irreversible, therapy-refractory cardiac damage. Mitoxantrone has a palliative role in controlling multiple sclerosis. In the light of our case and published data,3 close and careful cardiologic monitoring of patients undergoing this tentative treatment is necessary. Administration of the drug should also be discontinued immediately if any signs or symptoms of impending heart failure develop. Most importantly, the present case report shows that cardiac transplantation can be performed with good results in a patient with advanced multiple sclerosis. As for necessary immunosuppression, it is emphasized that prednisone and azathioprine as well as cyclosporine and FK 506 are also being used or evaluated in the treatment of multiple sclerosis.10 Such therapy may therefore even have a favorable effect on the underlying neurologic disease. For our patient, the stable clinical peri-operative course fortunately persisted in long-term follow-up. He has enjoyed a good quality of life for the past 8 years after heart transplantation. The sole, major problem in this patient is the occurrence of urinary tract infections due to suprapubic fistula. After initiation of long-term antibiotic therapy with trimethoprim, no further infections were noted. In conclusion, we suggest that heart transplantation should not be withheld from patients with multiple sclerosis and end-stage heart failure when no other
The Journal of Heart and Lung Transplantation Volume 23, Number 5
treatment options exist. However, in light of the ongoing crisis in heart transplantation (lack of donor organs), this single experience can obviously not be used to suggest general expansion of the recipient pool. REFERENCES 1. Noseworthy JH, Hopkins MB, Vandervoort MK, et al. An open-trial evaluation of mitoxantrone in the treatment of progressive MS. Neurology 1993;43:1401–6. 2. Mauch E, Kornhuber HH, Krapf H, Fetzer U, Laufen H. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci 1992;242:96 –102. 3. Ben-Zacharia AB, Lublin FD. Palliative care in patients with multiple sclerosis. Neurol Clin 2001;19:801–27. 4. Koeller J, Eble M. Mitoxantrone: a novel anthracycline derivative. Clin Pharmacol 1988;7:574 –81.
Na¨ gele et al.
643
5. Goebel M, Kaplan E. Anthracycline-induced cardiotoxicity—a review. Oncology 1992;15:198 –204. 6. van der Graaf WT, de Vries EG. Mitoxantrone: bluebeard for malignancies. Anti-Cancer Drugs 1990;1:109 –25. 7. Ghalie RG, Edan G, Laurent M, et al. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology 2002;59:909 –13. 8. Kraft J, Grille W, Appelt M, et al. Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial. Hematol Blood Transf 1990;33:566 –70. 9. Villani F, Galimberti M, Crippa F. Evaluation of ventricular function by echocardiography and radionuclide angiography in patients treated with mitoxantrone. Drugs Exp Clin Res 1989;15:501–6. 10. Hughes RA. Immunotherapy for multiple sclerosis. J Neurol 1994;57:3–6.