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Reversible Myocardial Hypertrophy Induced by Tacrolimus in a Pediatric Heart Transplant Recipient: Case Report
Reversible Myocardial Hypertrophy Induced by Tacrolimus in a Pediatric Heart Transplant Recipient: Case Report A. Mano, T. Nakatani, Y. Yahata, T. Kato, S. Hashimoto, K. Wada, and H. Ishibashi-Ueda ABSTRACT Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement. ROGRESS in immunosuppressive drug therapy has improved the prognosis in patients after organ transplantation. Recent studies have reported that tacrolimus more efficiently prevents pediatric heart allograft rejection than cyclosporine.1 Thus, it is often used as rescue therapy for cyclosporine-resistant rejection.2 However, tacrolimus is cardiotoxic. Atkison et al3 demonstrated that tacrolimus induces hypertrophic cardiomyopathy in pediatric patients who have undergone liver or small bowel transplantation and that such myocardial hypertrophy is reversible. The findings of other investigations in similar recipients are similar.4,5 Herein we describe transient myocardial hypertrophy that developed in a pediatric heart transplant recipient undergoing tacrolimus therapy that was differentiated from allograft rejection and improved after adjustment of tacrolimus blood concentration.
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tacrolimus was controlled at around 10 ng/mL. A biopsy specimen obtained during the fifth annual evaluation again indicated grade 3A rejection (Fig 1A) that required methylprednisolone pulse therapy. The tacrolimus target concentration was increased to 11 to 13 ng/mL because of recurrent rejection episodes. The patient was discharged with no complications. Three weeks later at an outpatient clinic for a regular examination, the patient reported no symptoms; however, the plasma brain natriuretic peptide concentration had increased from 46.2 pg/mL at discharge to 141.4 pg/mL. Two-dimensional echocardiography revealed concentric myocardial hypertrophy without pericardial effusion (Fig 2). The thickness of the interventricular septum and the left ventricular posterior wall was increased by 3 and 4 mm, respectively compared with at the time of discharge and were 10 and 11 mm, respectively. Systolic function was preserved; however, there was mild diastolic dysfunction. Another allograft rejection was suspected, and endomyocardial biopsy was performed. However, the samples showed no evidence of either cellular or humoral
CASE REPORT A 14-year-old girl who had received a heart transplant because of end-stage idiopathic dilated cardiomyopathy 5 years previously was managed with an immunosuppressive regimen that included prednisolone, tacrolimus, and mycophenolate mofetil. She had been administered methylprednisolone pulse therapy to counteract ISHLT International Heart and Lung Transplantation (ISHLT) grade 3A rejection on 3 separate occasions. Endomyocardial biopsy specimens obtained 2 to 3 weeks after each treatment showed that the ISHLT grade was 0 to 1A. The target concentration of
From the Department of Emergency and Critical Care Medicine, Tokushima University, Tokushima (A.M.), and the Departments of Organ Transplantation (T.N., T.K.), Pathology (Y.Y., H.I.-U.), Physiology (S.H.), and Pharmacology (K.W.), National Cardiovascular Center, Osaka, Japan. Address reprint requests to Akiko Mano, MD, PhD, Department of Emergency and Critical Care Medicine, Tokushima University, 2-50-1, Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: [email protected]
© 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.05.040
Transplantation Proceedings, 41, 3831–3834 (2009)
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rejection, and ISHLT grade 0 was diagnosed (Fig 1B). At histologic analysis, interstitial edema in the myocardium was evident, and the cardiomyocytes were mildly hypertrophic. The nuclei were also larger (Fig 1B and Fig 3). Acute myocarditis was absent. At this time, we believed that the tacrolimus trough concentration of 16.9 ng/mL may have generated the myocardial wall thickening. Renal function was preserved, with normal concentrations of blood urea nitrogen and creatinine. The tacrolimus dosage was reduced to achieve a target blood concentration of around 12 ng/mL. Follow-up was with echocardiography. The myocardial wall thickening gradually improved after reducing the amount of tacrolimus in the blood, and completely resolved after 1 month (Fig 2 and Fig 4). Myocardial hypertrophy also improved in biopsy samples 6 months later (Fig 4). Thereafter, myocardial wall thickening did not recur.
Fig 1. Light microscopic findings of biopsy samples (hematoxylineosin; ⫻400). A, Myocardial sample obtained at annual evaluation shows that lymphocytes have injured the myocardium. This was diagnosed as ISHLT grade 3A rejection. B, Myocardial sample was obtained when echocardiography revealed myocardial hypertrophy. Interstitial edema and mild myocyte hypertrophy are evident. Cellular rejection was undetectable, and ISHLT grade 0 was diagnosed. Humoral rejection was also absent (data not shown).
Fig 2. Changes in 2-dimensional echocardiography. A, Before increasing target concentration of tacrolimus (⬃10 ng/mL), wall thickness is within normal limits. B, Maximal tacrolimus blood concentration (16.9 ng/mL). Concentric myocardial hypertrophy is evident. C, Adjusting tacrolimus blood concentration to around 12 ng/mL resulted in regression of myocardial hypertrophy.
TACROLIMUS-INDUCED REVERSIBLE MYOCARDIAL HYPERTROPHY
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Fig 3. Electron microscopic findings at discovery of concentric myocardial hypertrophy. Interstitial edema is moderate with mild myocyte hypertrophy.
DISCUSSION
Cardiotoxicity associated with tacrolimus is a lethal complication after organ transplantation. Atkison et al3 originally described 5 pediatric recipients who had undergone small bowel or liver transplantation and developed hypertrophic cardiomyopathy during tacrolimus treatment. Two developed hypertrophic obstructive cardiomyopathy with congestive heart failure, and the other 3 developed concentric hypertrophic cardiomyopathy. Changing tacrolimus therapy to cyclosporine therapy or decreasing the tacrolimus trough concentration caused regression or improvement in cardiac involvement. Nakata et al5 noted ventricular wall thickening with increasing dosage of tacrolimus, especially at doses greater than 15 ng/mL. Several reports have described similar findings, mostly in pediatric patients. Our 14-year-old patient initially developed myocardial hypertrophy when the tacrolimus trough concentration was higher than before. A myocardial biopsy specimen did not show any evidence of rejection. Medical management was the same as previous regimens except that the blood concentration of tacrolimus was increased. Concentric myocardial hypertrophy at echocardiography completely improved after lowering the blood tacrolimus concentration.
The patient has received enalapril maleate, 5 mg/d. Throughout the entire clinical course, blood pressure remained within normal limits. Thus, tacrolimus was thought to contribute to the myocardial hypertrophy, although an effect of steroid therapy was not completely excluded.6 Histologic analysis revealed that the myocardial hypertrophy disclosed at echocardiography was primarily due to interstitial edema, which might represent a pathologic feature in tacrolimus-induced myocardial hypertrophy. Furthermore, histologic analysis confirmed that myocyte hypertrophy regressed after adjusting the blood concentration of tacrolimus. Several mechanisms have been suggested to explain cardiac involvement in tacrolimus actions. Atkison et al4 suggested that tacrolimus alters intracellular calcium handling and causes myocardial hypertrophy FK506 binding protein is expressed in skeletal and cardiac muscles, where it binds to and stabilizes the ryanodine receptor– calcium release channel in the terminal cisternae of the sarcoplasmic reticulum.7 When tacrolimus is added, FK506 binding protein binds to tacrolimus and is released from the ryanodine receptor, thus enhancing calcium release from the sarcoplasmic reticulum.8 This calcium overload is believed
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Fig 4. Relationships between tacrolimus blood concentration and left ventricular wall thickness, myocyte size, brain natriuretic peptide (BNP), renal function, and blood pressure (BP). Left ventricular wall thickness, myocyte size, and BNP were decreased as tacrolimus blood concentration decreased. Renal function and BP were within normal limits throughout entire clinical course. Left ventricular wall thickness is represented as the mean of interventricular septum and posterior wall. Myocyte size is shown as a mean value of 50 myocytes. *P ⬍ .05 vs 20 December 20, 2005. †P ⬍ .05 vs January 5, 2006. BUN, Blood urea nitrogen; CRE, creatinine.
to induce myocardial hypertrophy. Atkison et al4 also found extensively calcified cardiac tissue in an autopsy sample from a liver-bowel transplant recipient who had been treated with tacrolimus. Tacrolimus may cause capillary leak syndrome, and induces interstitial edema followed by myocardial hypertrophy in rabbits. Tacrolimus induced vasculitis in several dogs and baboon organs, including the heart.9 This vasculitis may be responsible for the myocardial toxicity of tacrolimus. Although tacrolimus is an important immunosuppressive drug after organ transplantation, blood concentration must be carefully maintained. Repeated echocardiography is useful to detect and avert tacrolimus-induced cardiac hypertrophy. REFERENCES 1. Kino T, Hatanaka H, Hashimoto M, et al: FK506, a novel immunosuppressant isolated from a Streptomyces, I: fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249, 1987 2. Jarzembowski TM, John E, Panaro F, et al: Reversal of tacrolimus-related hypertrophic obstructive cardiomyopathy 5 years after kidney transplant in a 6-year-old recipient. Pediatr Transplant 9:117, 2005
3. Atkison P, Joubert G, Barron A, et al: Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients [published online September 16, 2003]. Lancet 345:894, 1995 4. Atkison P, Joubert G, Guiraudon C, et al: Arteritis and increased intracellular calcium as a possible mechanism for tacrolimusrelated cardiac toxicity in a pediatric transplant recipient. Transplantation 65:773, 1997 5. Nakata Y, Yoshibayashi M, Yonemura T, et al: Tacrolimus and myocardial hypertrophy. Transplantation 69:1960, 2000 6. Skelton R, Gill AB, Parsons JM: Cardiac effects of short course dexamethasone in preterm infants. Arch Dis Child Fetal Neonatal Ed 78:F133, 1998 7. Mayrleitner M, Timerman AP, Wiederrecht G, et al: The calcium release channel of sarcoplasmic reticulum is modulated by FK-506 binding protein: effect of FKBP-12 on single channel activity of skeletal muscle ryanodine receptor. Cell Calcium 15:99, 1994 8. Timerman AP, Jayaraman T, Wiederrecht G, et al: The ryanodine receptor from canine heart sarcoplasmic reticulum is associated with a novel FK-506 binding protein. Biochem Biophys Res Commun 198:701, 1994 9. Thiru S, Collier DSJ, Calne R: Pathological studies in canine and baboon renal allograft recipients immunosuppressed with FK-506. Transplant Proc 19(suppl):98, 1987
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tacrolimus was controlled at around 10 ng/mL. A biopsy specimen obtained during the fifth annual evaluation again indicated grade 3A rejection (Fig 1A) that required methylprednisolone pulse therapy. The tacrolimus target concentration was increased to 11 to 13 ng/mL because of recurrent rejection episodes. The patient was discharged with no complications. Three weeks later at an outpatient clinic for a regular examination, the patient reported no symptoms; however, the plasma brain natriuretic peptide concentration had increased from 46.2 pg/mL at discharge to 141.4 pg/mL. Two-dimensional echocardiography revealed concentric myocardial hypertrophy without pericardial effusion (Fig 2). The thickness of the interventricular septum and the left ventricular posterior wall was increased by 3 and 4 mm, respectively compared with at the time of discharge and were 10 and 11 mm, respectively. Systolic function was preserved; however, there was mild diastolic dysfunction. Another allograft rejection was suspected, and endomyocardial biopsy was performed. However, the samples showed no evidence of either cellular or humoral
CASE REPORT A 14-year-old girl who had received a heart transplant because of end-stage idiopathic dilated cardiomyopathy 5 years previously was managed with an immunosuppressive regimen that included prednisolone, tacrolimus, and mycophenolate mofetil. She had been administered methylprednisolone pulse therapy to counteract ISHLT International Heart and Lung Transplantation (ISHLT) grade 3A rejection on 3 separate occasions. Endomyocardial biopsy specimens obtained 2 to 3 weeks after each treatment showed that the ISHLT grade was 0 to 1A. The target concentration of
From the Department of Emergency and Critical Care Medicine, Tokushima University, Tokushima (A.M.), and the Departments of Organ Transplantation (T.N., T.K.), Pathology (Y.Y., H.I.-U.), Physiology (S.H.), and Pharmacology (K.W.), National Cardiovascular Center, Osaka, Japan. Address reprint requests to Akiko Mano, MD, PhD, Department of Emergency and Critical Care Medicine, Tokushima University, 2-50-1, Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: [email protected]
© 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.05.040
Transplantation Proceedings, 41, 3831–3834 (2009)
3831
3832
MANO, NAKATANI, YAHATA ET AL
rejection, and ISHLT grade 0 was diagnosed (Fig 1B). At histologic analysis, interstitial edema in the myocardium was evident, and the cardiomyocytes were mildly hypertrophic. The nuclei were also larger (Fig 1B and Fig 3). Acute myocarditis was absent. At this time, we believed that the tacrolimus trough concentration of 16.9 ng/mL may have generated the myocardial wall thickening. Renal function was preserved, with normal concentrations of blood urea nitrogen and creatinine. The tacrolimus dosage was reduced to achieve a target blood concentration of around 12 ng/mL. Follow-up was with echocardiography. The myocardial wall thickening gradually improved after reducing the amount of tacrolimus in the blood, and completely resolved after 1 month (Fig 2 and Fig 4). Myocardial hypertrophy also improved in biopsy samples 6 months later (Fig 4). Thereafter, myocardial wall thickening did not recur.
Fig 1. Light microscopic findings of biopsy samples (hematoxylineosin; ⫻400). A, Myocardial sample obtained at annual evaluation shows that lymphocytes have injured the myocardium. This was diagnosed as ISHLT grade 3A rejection. B, Myocardial sample was obtained when echocardiography revealed myocardial hypertrophy. Interstitial edema and mild myocyte hypertrophy are evident. Cellular rejection was undetectable, and ISHLT grade 0 was diagnosed. Humoral rejection was also absent (data not shown).
Fig 2. Changes in 2-dimensional echocardiography. A, Before increasing target concentration of tacrolimus (⬃10 ng/mL), wall thickness is within normal limits. B, Maximal tacrolimus blood concentration (16.9 ng/mL). Concentric myocardial hypertrophy is evident. C, Adjusting tacrolimus blood concentration to around 12 ng/mL resulted in regression of myocardial hypertrophy.
TACROLIMUS-INDUCED REVERSIBLE MYOCARDIAL HYPERTROPHY
3833
Fig 3. Electron microscopic findings at discovery of concentric myocardial hypertrophy. Interstitial edema is moderate with mild myocyte hypertrophy.
DISCUSSION
Cardiotoxicity associated with tacrolimus is a lethal complication after organ transplantation. Atkison et al3 originally described 5 pediatric recipients who had undergone small bowel or liver transplantation and developed hypertrophic cardiomyopathy during tacrolimus treatment. Two developed hypertrophic obstructive cardiomyopathy with congestive heart failure, and the other 3 developed concentric hypertrophic cardiomyopathy. Changing tacrolimus therapy to cyclosporine therapy or decreasing the tacrolimus trough concentration caused regression or improvement in cardiac involvement. Nakata et al5 noted ventricular wall thickening with increasing dosage of tacrolimus, especially at doses greater than 15 ng/mL. Several reports have described similar findings, mostly in pediatric patients. Our 14-year-old patient initially developed myocardial hypertrophy when the tacrolimus trough concentration was higher than before. A myocardial biopsy specimen did not show any evidence of rejection. Medical management was the same as previous regimens except that the blood concentration of tacrolimus was increased. Concentric myocardial hypertrophy at echocardiography completely improved after lowering the blood tacrolimus concentration.
The patient has received enalapril maleate, 5 mg/d. Throughout the entire clinical course, blood pressure remained within normal limits. Thus, tacrolimus was thought to contribute to the myocardial hypertrophy, although an effect of steroid therapy was not completely excluded.6 Histologic analysis revealed that the myocardial hypertrophy disclosed at echocardiography was primarily due to interstitial edema, which might represent a pathologic feature in tacrolimus-induced myocardial hypertrophy. Furthermore, histologic analysis confirmed that myocyte hypertrophy regressed after adjusting the blood concentration of tacrolimus. Several mechanisms have been suggested to explain cardiac involvement in tacrolimus actions. Atkison et al4 suggested that tacrolimus alters intracellular calcium handling and causes myocardial hypertrophy FK506 binding protein is expressed in skeletal and cardiac muscles, where it binds to and stabilizes the ryanodine receptor– calcium release channel in the terminal cisternae of the sarcoplasmic reticulum.7 When tacrolimus is added, FK506 binding protein binds to tacrolimus and is released from the ryanodine receptor, thus enhancing calcium release from the sarcoplasmic reticulum.8 This calcium overload is believed
3834
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Fig 4. Relationships between tacrolimus blood concentration and left ventricular wall thickness, myocyte size, brain natriuretic peptide (BNP), renal function, and blood pressure (BP). Left ventricular wall thickness, myocyte size, and BNP were decreased as tacrolimus blood concentration decreased. Renal function and BP were within normal limits throughout entire clinical course. Left ventricular wall thickness is represented as the mean of interventricular septum and posterior wall. Myocyte size is shown as a mean value of 50 myocytes. *P ⬍ .05 vs 20 December 20, 2005. †P ⬍ .05 vs January 5, 2006. BUN, Blood urea nitrogen; CRE, creatinine.
to induce myocardial hypertrophy. Atkison et al4 also found extensively calcified cardiac tissue in an autopsy sample from a liver-bowel transplant recipient who had been treated with tacrolimus. Tacrolimus may cause capillary leak syndrome, and induces interstitial edema followed by myocardial hypertrophy in rabbits. Tacrolimus induced vasculitis in several dogs and baboon organs, including the heart.9 This vasculitis may be responsible for the myocardial toxicity of tacrolimus. Although tacrolimus is an important immunosuppressive drug after organ transplantation, blood concentration must be carefully maintained. Repeated echocardiography is useful to detect and avert tacrolimus-induced cardiac hypertrophy. REFERENCES 1. Kino T, Hatanaka H, Hashimoto M, et al: FK506, a novel immunosuppressant isolated from a Streptomyces, I: fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249, 1987 2. Jarzembowski TM, John E, Panaro F, et al: Reversal of tacrolimus-related hypertrophic obstructive cardiomyopathy 5 years after kidney transplant in a 6-year-old recipient. Pediatr Transplant 9:117, 2005
3. Atkison P, Joubert G, Barron A, et al: Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients [published online September 16, 2003]. Lancet 345:894, 1995 4. Atkison P, Joubert G, Guiraudon C, et al: Arteritis and increased intracellular calcium as a possible mechanism for tacrolimusrelated cardiac toxicity in a pediatric transplant recipient. Transplantation 65:773, 1997 5. Nakata Y, Yoshibayashi M, Yonemura T, et al: Tacrolimus and myocardial hypertrophy. Transplantation 69:1960, 2000 6. Skelton R, Gill AB, Parsons JM: Cardiac effects of short course dexamethasone in preterm infants. Arch Dis Child Fetal Neonatal Ed 78:F133, 1998 7. Mayrleitner M, Timerman AP, Wiederrecht G, et al: The calcium release channel of sarcoplasmic reticulum is modulated by FK-506 binding protein: effect of FKBP-12 on single channel activity of skeletal muscle ryanodine receptor. Cell Calcium 15:99, 1994 8. Timerman AP, Jayaraman T, Wiederrecht G, et al: The ryanodine receptor from canine heart sarcoplasmic reticulum is associated with a novel FK-506 binding protein. Biochem Biophys Res Commun 198:701, 1994 9. Thiru S, Collier DSJ, Calne R: Pathological studies in canine and baboon renal allograft recipients immunosuppressed with FK-506. Transplant Proc 19(suppl):98, 1987