http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(2): 120–123 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2013.853660
CASE REPORT
Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis Thenappan Thenappan1*, Savitri Fedson1, Jonathan Rich2, Catherine Murks1, Aliya Husain3, Jennifer Pogoriler3, and Allen S. Anderson2 1
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA, 2Division of Cardiology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, and 3Department of Pathology, University of Chicago, Chicago, IL, USA
Abstract
Keywords
Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation.
Endomyocardial biopsy, heart failure, liver transplantation History Received 8 April 2013 Revised 26 September 2013 Accepted 3 October 2013 Published online 5 February 2014
Abbreviations: MMF: mycophenolate mofetil; NYHA: New York Heart Association; TTR: transthyretin; VE: minute ventilation
Introduction Cardiac amyloidosis is characterized by infiltration of myocardium by amyloid protein resulting in conduction disturbances and progressive cardiomyopathy leading to biventricular failure and death. Two types of amyloid protein commonly infiltrate the heart: the immunoglobulin light chain (AL or systemic amyloidosis) and the transthyretin (TTR) amyloid protein [1]. TTR is a 127-amino acid, 56kDa-transport protein produced in the liver. TTR normally circulates in a homotetramer form. However, it can dissociate in to monomers either due to inherited genetic mutation (mutant or variant TTR) or due to sporadic changes from aging (wild-type TTR). Such monomers can misassemble as amyloid protein in the myocardium leading to TTR cardiac amyloidosis. Deposition of the mutant or variant TTR amyloid protein leads to familial amyloidosis syndrome, and deposition of the wildtype TTR leads to senile systemic amyloidosis [2]. The clinical manifestation of familial TTR amyloidosis depends on the type of mutation that affects the TTR gene located on chromosome 18q12.1. More than one hundred mutations have been reported to affect the TTR gene [3]. All *Current address: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA Address for correspondence: Dr Allen S. Anderson, MD, FACC, FAHA, Professor of Medicine, Feinberg School of Medicine, Medical Director, Center for Heart Failure, Bluhm Cardiovascular Institute of Northwestern, Northwestern Medical Faculty Foundation, 676 North Saint Clair Street, Suite 600, Chicago, IL 60611, USA. Tel: 312 695 0788. E-mail: [email protected]
have an autosomal dominant inheritance and predominantly affect either the peripheral nervous system called as familial amyloid neuropathy or the myocardium called as the familial cardiac amyloidosis. The most common TTR gene mutation that leads to familial amyloid cardiomyopathy is the valine-toisoleucine substitution at position 122 (V122I or Ile122) [4]. This mutation affects 3–4% of the African American population in the United States and it is extremely uncommon in Caucasians [5]. TTR amyloid protein deposition leads to a slowly progressing cardiomyopathy that usually takes decades to manifest clinically with heart failure and conduction disturbances [2]. Patients often do not present until the sixth or seventh decade. Currently, the only definitive treatment suggested for familial amyloid cardiomyopathy is the combined or sequential liver–heart transplantation in eligible patients. There are only a few case reports of isolated heart transplantation in patients with familial amyloid cardiomyopathy and minimal systemic manifestations [6]. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Our patient in this report underwent cardiac transplantation as he was thought to have idiopathic dilated cardiomyopathy prior to transplant.
Case report A 64-year-old African American male presented to our institution for evaluation of heart transplantation for
DOI: 10.3109/13506129.2013.853660
non-ischemic dilated cardiomyopathy. He was diagnosed with dilated cardiomyopathy in 1998 and was treated with standard heart failure medical therapy including beta-blockers, angiotensin converting enzyme inhibitor, aldosterone receptor antagonist, and a dual chamber defibrillator for primary prevention of sudden cardiac death. His symptoms improved with medical therapy, and he remained as New York Heart Association (NYHA) functional class I for 7 years. However, a year prior to presenting to our institution, he had progressive worsening exercise tolerance (20–30 feet) and repeated hospitalizations for acute decompensated heart failure. His past medical history was remarkable for hypertension, obstructive sleep apnea, and gout. He had no history or features suggestive of peripheral neuropathy. He had no clinic features of systemic amyloidosis including bleeding, purpura, weight loss, dry mouth, hoarseness, periorbital ecchymosis, macroglossia, diarrhea, or constipation. He had no significant family medical history. His electrocardiogram showed sequential atrioventricular pacing and normal voltage. A trans-thoracic echocardiogram revealed severely reduced left ventricular systolic function with an estimated ejection fraction of 23%, moderately reduced right ventricular systolic function, and moderate biatrial enlargement. He had normal left and right ventricular wall thickness and no increased echogenicity suggestive of infiltrative diseases (Figure 1). His NT-proBNP was elevated at 384 pg/ml. The coronary arteries were angiographically normal. A right heart catheterization revealed a cardiac output of 2.6 l/min, a cardiac index of 1.28 l/min/m2, and elevated
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121
intracardiac filling pressures with moderate pulmonary hypertension that was completely reversible with acute vasodilator testing. His peak oxygen uptake was 12.6 ml/kg/ min, with a respiratory exchange ratio of 1.14, and a VE/ VCO2 ratio of 52. In light of these findings and symptoms of worsening heart failure leading to recurrent hospitalization, he was listed for heart transplantation and initiated on continuous intravenous home milirinone therapy. After 2 months in the waiting list, he underwent a cardiac transplantation using the total heart technique, our standard practice when possible. Histopathology of the explanted heart Microscopic examination of his explanted native heart showed significant myocyte hypertrophy, multifocal interstitial fibrosis, and eosinophilic deposits. A Congo red stain revealed apple–green birefringence under polarized light consistent with amyloid (Figure 2). Immunohistochemical stain for amyloid P component was positive. Immunohistochemical staining with antibodies against kappa light chain, lambda light chain, and amyloid-associated protein were negative. His urine and serum protein electrophoresis showed no evidence of monoclonal gammopathy. The sequencing of the TTR gene revealed heterozygous V122I mutation. Post-heart transplant course He underwent induction immunosuppression with rabbit antithymocyte globulin, corticosteroids, mycophenolate mofetil (MMF), and tacrolimus. Routine cytomegalovirus, pneumocystis carinii, and fungal prophylaxis were administered per protocol. Steroids were tapered and discontinued over 8 months. He has been on tacrolimus and MMF for maintenance immunosuppression. Pravastatin has also been prescribed chronically. Surveillance endomyocardial biopsies have shown no evidence of cellular- or antibody-mediated rejection or recurrent amyloidosis. Protocol screening coronary angiography has revealed no evidence of allograft vasculopathy. During his 5-year post transplant follow-up, he remains NYHA functional class I. His electrocardiogram shows no evidence of low voltage and an incomplete right bundle branch block with a left anterior fascicular block, present since immediately after his transplant. His most recent echocardiogram showed normal left ventricular size, wall thickness, systolic function with an estimated ejection fraction of 75%, and normal diastolic function. Right heart catheterization revealed a cardiac output of 5.2 l/min and a cardiac index of 2.5 l/min/m2. Five-year post transplant endomyocardial biopsy showed no evidence of recurrent amyloid deposits.
Discussion
Figure 1. Pretransplant echocardiogram showing dilated left ventricle with no evidence of increased echogenicity, ventricular wall thickening, or severe biatrial enlargement typical of cardiac amyloidosis: (A) parasternal short axis view (B) apical four chamber view.
We report a case of inadvertent but successful isolated heart transplantation for heterozygous Val122L mutated TTRrelated cardiac amyloidosis with good cardiac allograft function 5 years after transplantation with no evidence of recurrent amyloid deposition. This case along with the other limited literature suggests that isolated heart transplantation is an appropriate and effective treatment option for patients with Val122I mutated TTR-related cardiac amyloidosis with a low
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Figure 2. (A) Low power photomicrograph of explanted heart showing extensive amyloid deposits in the left ventricle wall (hematoxylin and eosin, 40), (B) high power photomicrograph of amyloid deposits (hematoxylin and eosin, 200), (C) high power photomicrograph staining positive for Congo red (200), (D) high power photomicrograph staining positive for Congo red with apple green birefringence on polarization (200). Arrow indicates amyloid deposits.
risk of amyloid recurrence in the allograft over at least 5 years, perhaps similar to those with senile cardiac amyloidosis [7]. Currently, there is no effective medical treatment for either wild type or variant TTR cardiac amyloidosis, although several experimental therapies targeting tetramer-stabilization are in development including doxycycline, resveratrol, Epigallocatechin-3-gallate, diflunisal, and tafamidis [2]. Treatment is mostly supportive care for biventricular failure with diuretics [8]. These patients usually do not tolerate the standard heart failure therapy including angiotensin converting enzyme inhibitors and beta-blockers. Additionally, most patients with TTR cardiac amyloidosis present at an advanced age due to the slow progression of the disease, precluding them from consideration for heart transplantation. Simultaneous sequential or combined liver–heart transplantation have reported successful outcomes for those who present relatively early (565 years) with limited systemic manifestations from the amyloid deposits [9]. By performing combined or sequential liver–heart transplantation, the synthesis of the variant TTR is arrested, preventing further amyloid deposits in the cardiac allograft. We have a long experience with combined, sequential heart–liver transplantation [10] but do not consider older patients (465 years) suitable candidates for this complex, intensive operation. Isolated heart transplantation is an attractive option but it is not commonly performed in patients with Val122I mutated TTR-related cardiac amyloidosis due to the concern for
recurrence of amyloid deposits in the cardiac allograft as the native liver continues to synthesize variant TTR. However, since the rate of progression of cardiomyopathy from the mutant or variant TTR amyloid deposit is extremely slow, it is possible that this process would take longer than the reasonably expected life of the cardiac allograft and patient. There are case reports of isolated heart transplantation for familial TTR (V122I) cardiac amyloidosis with post transplant follow-up ranging from 10 months to 3 years [6,11]. Hamour et al. reported a patient with homozygous familial TTR (V122I) cardiac amyloidosis who underwent isolated heart transplantation and remained well with no evidence of recurrence amyloid deposit in the cardiac allograft or systemic amyloid deposition 3 years post heart transplantation [6]. Our patient is the first reported case of heterozygous TTR (V122I) cardiac amyloidosis who is doing well with good allograft function 5 years after isolated heart transplantation with no evidence of recurrent amyloid deposition in the cardiac allograft or other systemic organs. This case report adds further to this literature and reemphasizes the suitable role of isolated heart transplant in patients with familial TTR cardiac amyloidosis with successful outcome for at least 5 years. Historically isolated heart transplantation was not performed in our center for patients with senile cardiac amyloidosis or familial TTR cardiac amyloidosis; however, we are currently reconsidering this practice. Our patient in this report underwent cardiac transplantation as he was
DOI: 10.3109/13506129.2013.853660
thought to have idiopathic dilated cardiomyopathy. He had no typical clinical features of an infiltrative amyloid cardiomyopathy such as low voltage, increased ventricular wall thickness with increased echogenicity, or biatrial enlargement, prompting an endomyocardial biopsy (Figure 1). Cardiac magnetic resonance imaging was not performed as he had an implantable cardiac defibrillator for primary prevention of sudden cardiac death prior to being referred to our center. Cardiac amyloidosis was diagnosed only based on the histopathological evaluation of the explanted heart. If cardiac amyloidosis was recognized earlier, our patient would not have had undergone cardiac transplantation. This case also illustrates that physicians should have a high index of suspicion for diagnosing familial TTR (V122I) cardiac amyloidosis, especially in elderly African American patients with heart failure. Endomyocardial biopsy is considered the gold standard for diagnosing cardiac amyloidosis. Once congo red staining confirms amyloid deposition, immunohistochemical staining for AL, AA, and TTR protein is needed to identify the precursor protein [2]. In patients with TTR amyloid protein, further analysis with mass spectrometry and DNA sampling is required to differentiate variant from wild-type TTR protein [12]. Endomyocardial biopsy is not necessary if a tissue biopsy from a non-cardiac site (abdominal fat pad) demonstrates TTR amyloid deposits in the presence of an established TTR gene mutation, and non-invasive cardiac tests including electrocardiogram, echocardiogram, cardiac magnetic resonance imaging, and cardiac biomarkers (BNP and Troponin) demonstrates cardiac involvement. The presence of low QRS voltage on electrocardiography along with increased interventricular septal thickness on echocardiogram is 90% specific for the diagnoses of cardiac amyloidosis [13]. The typical echocardiographic features of amyloidosis include speckled appearance of the myocardium, increased ventricular wall thickness especially right ventricular wall thickening, small ventricular cavities, biatrial enlargement, thickened interatrial septum, valve thickening, and severe grade 3 diastolic dysfunction [12]. Cardiac output as measured by thermodilution or Fick technique at the time of right heart catheterization may show a profoundly low cardiac index despite relatively preserved ejection fraction. On cardiac magnetic resonance imaging, amyloidosis should be suspected whenever there is difficulty-suppressing signal from the myocardium on delayed late gadolinium enhancement images with standard inversion times [14]. Nuclear scintigraphy with technetium labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) is an emerging tool for diagnosing TTR cardiac amyloidosis. 99mTc-DPD has an increased avidity for TTR amyloid protein. Increased uptake of 99mTc-DPD in the heart of a patient with evidence of systemic amyloidosis is highly suggestive of TTR amyloid cardiomyopathy [15].
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Conclusion We present a patient with heterozygous Val122I mutated TTR-related cardiac amyloidosis who underwent only heart transplantation with good cardiac allograft function 5 years after transplantation with no evidence of recurrence. This case report demonstrates that isolated heart transplantation alone is a safe and effective strategy that should be strongly considered for patients with Val122I mutated TTR-related cardiac amyloidosis.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart 2011;97:75–84. 2. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126:1286–300. 3. Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 2007;36:411–23. 4. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466–73. 5. Yamashita T, Hamidi Asl K, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. Amyloid 2005;12:127–30. 6. Hamour IM, Lachmann HJ, Goodman HJ, Petrou M, Burke MM, Hawkins PN, Banner NR. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant 2008;8:1056–9. 7. Fuchs U, Zittermann A, Suhr O, Holmgren G, Tenderich G, Minami K, Koerfer R. Heart transplantation in a 68-year-old patient with senile systemic amyloidosis. Am J Transplant 2005;5:1159–62. 8. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart 2012;98:1546–54. 9. Dubrey SW, Burke MM, Hawkins PN, Banner NR. Cardiac transplantation for amyloid heart disease: the United Kingdom experience. J Heart Lung Transplant 2004;23:1142–53. 10. Te HS, Anderson AS, Millis JM, Jeevanandam V, Jensen DM. Current state of combined heart-liver transplantation in the United States. J Heart Lung Transplant 2008;27:753–9. 11. Ammirati E, Marziliano N, Vittori C, Pedrotti P, Bramerio MA, Motta V, Orsini F, et al. The first Caucasian patient with p.Val122Ile mutated-transthyretin cardiac amyloidosis treated with isolated heart transplantation. Amyloid 2012;19:113–17. 12. Kapoor P, Thenappan T, Singh E, Kumar S, Greipp PR. Cardiac amyloidosis: a practical approach to diagnosis and management. Am J Med 2011;124:1006–15. 13. Rahman JE, Helou EF, Gelzer-Bell R, Thompson RE, Kuo C, Rodriguez ER, Hare JM, et al. Noninvasive diagnosis of biopsyproven cardiac amyloidosis. J Am Coll Cardiol 2004;43:410–15. 14. van den Driesen RI, Slaughter RE, Strugnell WE. MR findings in cardiac amyloidosis. AJR Am J Roentgenol 2006;186:1682–5. 15. Chen W, Dilsizian V. Molecular imaging of amyloidosis: will the heart be the next target after the brain? Curr Cardiol Rep 2012;14: 226–33.
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CASE REPORT
Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis Thenappan Thenappan1*, Savitri Fedson1, Jonathan Rich2, Catherine Murks1, Aliya Husain3, Jennifer Pogoriler3, and Allen S. Anderson2 1
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA, 2Division of Cardiology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, and 3Department of Pathology, University of Chicago, Chicago, IL, USA
Abstract
Keywords
Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation.
Endomyocardial biopsy, heart failure, liver transplantation History Received 8 April 2013 Revised 26 September 2013 Accepted 3 October 2013 Published online 5 February 2014
Abbreviations: MMF: mycophenolate mofetil; NYHA: New York Heart Association; TTR: transthyretin; VE: minute ventilation
Introduction Cardiac amyloidosis is characterized by infiltration of myocardium by amyloid protein resulting in conduction disturbances and progressive cardiomyopathy leading to biventricular failure and death. Two types of amyloid protein commonly infiltrate the heart: the immunoglobulin light chain (AL or systemic amyloidosis) and the transthyretin (TTR) amyloid protein [1]. TTR is a 127-amino acid, 56kDa-transport protein produced in the liver. TTR normally circulates in a homotetramer form. However, it can dissociate in to monomers either due to inherited genetic mutation (mutant or variant TTR) or due to sporadic changes from aging (wild-type TTR). Such monomers can misassemble as amyloid protein in the myocardium leading to TTR cardiac amyloidosis. Deposition of the mutant or variant TTR amyloid protein leads to familial amyloidosis syndrome, and deposition of the wildtype TTR leads to senile systemic amyloidosis [2]. The clinical manifestation of familial TTR amyloidosis depends on the type of mutation that affects the TTR gene located on chromosome 18q12.1. More than one hundred mutations have been reported to affect the TTR gene [3]. All *Current address: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA Address for correspondence: Dr Allen S. Anderson, MD, FACC, FAHA, Professor of Medicine, Feinberg School of Medicine, Medical Director, Center for Heart Failure, Bluhm Cardiovascular Institute of Northwestern, Northwestern Medical Faculty Foundation, 676 North Saint Clair Street, Suite 600, Chicago, IL 60611, USA. Tel: 312 695 0788. E-mail: [email protected]
have an autosomal dominant inheritance and predominantly affect either the peripheral nervous system called as familial amyloid neuropathy or the myocardium called as the familial cardiac amyloidosis. The most common TTR gene mutation that leads to familial amyloid cardiomyopathy is the valine-toisoleucine substitution at position 122 (V122I or Ile122) [4]. This mutation affects 3–4% of the African American population in the United States and it is extremely uncommon in Caucasians [5]. TTR amyloid protein deposition leads to a slowly progressing cardiomyopathy that usually takes decades to manifest clinically with heart failure and conduction disturbances [2]. Patients often do not present until the sixth or seventh decade. Currently, the only definitive treatment suggested for familial amyloid cardiomyopathy is the combined or sequential liver–heart transplantation in eligible patients. There are only a few case reports of isolated heart transplantation in patients with familial amyloid cardiomyopathy and minimal systemic manifestations [6]. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Our patient in this report underwent cardiac transplantation as he was thought to have idiopathic dilated cardiomyopathy prior to transplant.
Case report A 64-year-old African American male presented to our institution for evaluation of heart transplantation for
DOI: 10.3109/13506129.2013.853660
non-ischemic dilated cardiomyopathy. He was diagnosed with dilated cardiomyopathy in 1998 and was treated with standard heart failure medical therapy including beta-blockers, angiotensin converting enzyme inhibitor, aldosterone receptor antagonist, and a dual chamber defibrillator for primary prevention of sudden cardiac death. His symptoms improved with medical therapy, and he remained as New York Heart Association (NYHA) functional class I for 7 years. However, a year prior to presenting to our institution, he had progressive worsening exercise tolerance (20–30 feet) and repeated hospitalizations for acute decompensated heart failure. His past medical history was remarkable for hypertension, obstructive sleep apnea, and gout. He had no history or features suggestive of peripheral neuropathy. He had no clinic features of systemic amyloidosis including bleeding, purpura, weight loss, dry mouth, hoarseness, periorbital ecchymosis, macroglossia, diarrhea, or constipation. He had no significant family medical history. His electrocardiogram showed sequential atrioventricular pacing and normal voltage. A trans-thoracic echocardiogram revealed severely reduced left ventricular systolic function with an estimated ejection fraction of 23%, moderately reduced right ventricular systolic function, and moderate biatrial enlargement. He had normal left and right ventricular wall thickness and no increased echogenicity suggestive of infiltrative diseases (Figure 1). His NT-proBNP was elevated at 384 pg/ml. The coronary arteries were angiographically normal. A right heart catheterization revealed a cardiac output of 2.6 l/min, a cardiac index of 1.28 l/min/m2, and elevated
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121
intracardiac filling pressures with moderate pulmonary hypertension that was completely reversible with acute vasodilator testing. His peak oxygen uptake was 12.6 ml/kg/ min, with a respiratory exchange ratio of 1.14, and a VE/ VCO2 ratio of 52. In light of these findings and symptoms of worsening heart failure leading to recurrent hospitalization, he was listed for heart transplantation and initiated on continuous intravenous home milirinone therapy. After 2 months in the waiting list, he underwent a cardiac transplantation using the total heart technique, our standard practice when possible. Histopathology of the explanted heart Microscopic examination of his explanted native heart showed significant myocyte hypertrophy, multifocal interstitial fibrosis, and eosinophilic deposits. A Congo red stain revealed apple–green birefringence under polarized light consistent with amyloid (Figure 2). Immunohistochemical stain for amyloid P component was positive. Immunohistochemical staining with antibodies against kappa light chain, lambda light chain, and amyloid-associated protein were negative. His urine and serum protein electrophoresis showed no evidence of monoclonal gammopathy. The sequencing of the TTR gene revealed heterozygous V122I mutation. Post-heart transplant course He underwent induction immunosuppression with rabbit antithymocyte globulin, corticosteroids, mycophenolate mofetil (MMF), and tacrolimus. Routine cytomegalovirus, pneumocystis carinii, and fungal prophylaxis were administered per protocol. Steroids were tapered and discontinued over 8 months. He has been on tacrolimus and MMF for maintenance immunosuppression. Pravastatin has also been prescribed chronically. Surveillance endomyocardial biopsies have shown no evidence of cellular- or antibody-mediated rejection or recurrent amyloidosis. Protocol screening coronary angiography has revealed no evidence of allograft vasculopathy. During his 5-year post transplant follow-up, he remains NYHA functional class I. His electrocardiogram shows no evidence of low voltage and an incomplete right bundle branch block with a left anterior fascicular block, present since immediately after his transplant. His most recent echocardiogram showed normal left ventricular size, wall thickness, systolic function with an estimated ejection fraction of 75%, and normal diastolic function. Right heart catheterization revealed a cardiac output of 5.2 l/min and a cardiac index of 2.5 l/min/m2. Five-year post transplant endomyocardial biopsy showed no evidence of recurrent amyloid deposits.
Discussion
Figure 1. Pretransplant echocardiogram showing dilated left ventricle with no evidence of increased echogenicity, ventricular wall thickening, or severe biatrial enlargement typical of cardiac amyloidosis: (A) parasternal short axis view (B) apical four chamber view.
We report a case of inadvertent but successful isolated heart transplantation for heterozygous Val122L mutated TTRrelated cardiac amyloidosis with good cardiac allograft function 5 years after transplantation with no evidence of recurrent amyloid deposition. This case along with the other limited literature suggests that isolated heart transplantation is an appropriate and effective treatment option for patients with Val122I mutated TTR-related cardiac amyloidosis with a low
122
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Amyloid, 2014; 21(2): 120–123
Figure 2. (A) Low power photomicrograph of explanted heart showing extensive amyloid deposits in the left ventricle wall (hematoxylin and eosin, 40), (B) high power photomicrograph of amyloid deposits (hematoxylin and eosin, 200), (C) high power photomicrograph staining positive for Congo red (200), (D) high power photomicrograph staining positive for Congo red with apple green birefringence on polarization (200). Arrow indicates amyloid deposits.
risk of amyloid recurrence in the allograft over at least 5 years, perhaps similar to those with senile cardiac amyloidosis [7]. Currently, there is no effective medical treatment for either wild type or variant TTR cardiac amyloidosis, although several experimental therapies targeting tetramer-stabilization are in development including doxycycline, resveratrol, Epigallocatechin-3-gallate, diflunisal, and tafamidis [2]. Treatment is mostly supportive care for biventricular failure with diuretics [8]. These patients usually do not tolerate the standard heart failure therapy including angiotensin converting enzyme inhibitors and beta-blockers. Additionally, most patients with TTR cardiac amyloidosis present at an advanced age due to the slow progression of the disease, precluding them from consideration for heart transplantation. Simultaneous sequential or combined liver–heart transplantation have reported successful outcomes for those who present relatively early (565 years) with limited systemic manifestations from the amyloid deposits [9]. By performing combined or sequential liver–heart transplantation, the synthesis of the variant TTR is arrested, preventing further amyloid deposits in the cardiac allograft. We have a long experience with combined, sequential heart–liver transplantation [10] but do not consider older patients (465 years) suitable candidates for this complex, intensive operation. Isolated heart transplantation is an attractive option but it is not commonly performed in patients with Val122I mutated TTR-related cardiac amyloidosis due to the concern for
recurrence of amyloid deposits in the cardiac allograft as the native liver continues to synthesize variant TTR. However, since the rate of progression of cardiomyopathy from the mutant or variant TTR amyloid deposit is extremely slow, it is possible that this process would take longer than the reasonably expected life of the cardiac allograft and patient. There are case reports of isolated heart transplantation for familial TTR (V122I) cardiac amyloidosis with post transplant follow-up ranging from 10 months to 3 years [6,11]. Hamour et al. reported a patient with homozygous familial TTR (V122I) cardiac amyloidosis who underwent isolated heart transplantation and remained well with no evidence of recurrence amyloid deposit in the cardiac allograft or systemic amyloid deposition 3 years post heart transplantation [6]. Our patient is the first reported case of heterozygous TTR (V122I) cardiac amyloidosis who is doing well with good allograft function 5 years after isolated heart transplantation with no evidence of recurrent amyloid deposition in the cardiac allograft or other systemic organs. This case report adds further to this literature and reemphasizes the suitable role of isolated heart transplant in patients with familial TTR cardiac amyloidosis with successful outcome for at least 5 years. Historically isolated heart transplantation was not performed in our center for patients with senile cardiac amyloidosis or familial TTR cardiac amyloidosis; however, we are currently reconsidering this practice. Our patient in this report underwent cardiac transplantation as he was
DOI: 10.3109/13506129.2013.853660
thought to have idiopathic dilated cardiomyopathy. He had no typical clinical features of an infiltrative amyloid cardiomyopathy such as low voltage, increased ventricular wall thickness with increased echogenicity, or biatrial enlargement, prompting an endomyocardial biopsy (Figure 1). Cardiac magnetic resonance imaging was not performed as he had an implantable cardiac defibrillator for primary prevention of sudden cardiac death prior to being referred to our center. Cardiac amyloidosis was diagnosed only based on the histopathological evaluation of the explanted heart. If cardiac amyloidosis was recognized earlier, our patient would not have had undergone cardiac transplantation. This case also illustrates that physicians should have a high index of suspicion for diagnosing familial TTR (V122I) cardiac amyloidosis, especially in elderly African American patients with heart failure. Endomyocardial biopsy is considered the gold standard for diagnosing cardiac amyloidosis. Once congo red staining confirms amyloid deposition, immunohistochemical staining for AL, AA, and TTR protein is needed to identify the precursor protein [2]. In patients with TTR amyloid protein, further analysis with mass spectrometry and DNA sampling is required to differentiate variant from wild-type TTR protein [12]. Endomyocardial biopsy is not necessary if a tissue biopsy from a non-cardiac site (abdominal fat pad) demonstrates TTR amyloid deposits in the presence of an established TTR gene mutation, and non-invasive cardiac tests including electrocardiogram, echocardiogram, cardiac magnetic resonance imaging, and cardiac biomarkers (BNP and Troponin) demonstrates cardiac involvement. The presence of low QRS voltage on electrocardiography along with increased interventricular septal thickness on echocardiogram is 90% specific for the diagnoses of cardiac amyloidosis [13]. The typical echocardiographic features of amyloidosis include speckled appearance of the myocardium, increased ventricular wall thickness especially right ventricular wall thickening, small ventricular cavities, biatrial enlargement, thickened interatrial septum, valve thickening, and severe grade 3 diastolic dysfunction [12]. Cardiac output as measured by thermodilution or Fick technique at the time of right heart catheterization may show a profoundly low cardiac index despite relatively preserved ejection fraction. On cardiac magnetic resonance imaging, amyloidosis should be suspected whenever there is difficulty-suppressing signal from the myocardium on delayed late gadolinium enhancement images with standard inversion times [14]. Nuclear scintigraphy with technetium labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) is an emerging tool for diagnosing TTR cardiac amyloidosis. 99mTc-DPD has an increased avidity for TTR amyloid protein. Increased uptake of 99mTc-DPD in the heart of a patient with evidence of systemic amyloidosis is highly suggestive of TTR amyloid cardiomyopathy [15].
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Conclusion We present a patient with heterozygous Val122I mutated TTR-related cardiac amyloidosis who underwent only heart transplantation with good cardiac allograft function 5 years after transplantation with no evidence of recurrence. This case report demonstrates that isolated heart transplantation alone is a safe and effective strategy that should be strongly considered for patients with Val122I mutated TTR-related cardiac amyloidosis.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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