Original article

Double organ transplantation in cardiac amyloidosis Aggeliki Gkouzioutaa, Dimitrios Farmakisb,c, Athanassios Manginasd, Petros Sfyrakisa, Georgios Sarogloua, Stamatis Adamopoulosa and Efstathios K. Iliodromitisb Background Cardiac amyloidosis, particularly primary or AL amyloidosis, is the most common infiltrative cardiomyopathy and is associated with a poor prognosis. The outcome of cardiac transplantation is generally poor, and almost half of patients die while waiting for the procedure to be done. Patient We report here the remarkable case of a 63-year-old man with heart failure caused by AL amyloidosis. After a long course, which included rapid deterioration of preexisting heart failure, cardiac arrest, cardiogenic shock, biventricular assist device support, heart transplantation, renal failure, kidney transplantation and finally a life-threatening H1N1 virus pneumonia, the patient managed not only to survive but also to return fully to his previous demanding duties and lifestyle.

Introduction Cardiac amyloidosis refers to the disease state wherein the heart is infiltrated by amyloid protein, whether as part of systemic amyloidosis (as is most commonly the case) or as a localized phenomenon. It is the most common of the infiltrative cardiomyopathies (i.e. sarcoidosis, hemochromatosis) and is associated with a poor prognosis.1 We report here the case of a 63-year-old man with end-stage heart failure caused by idiopathic amyloidosis, who underwent successful sequential cardiac and renal transplantation following bridging with biventricular assist device support.

Case report The patient’s adventure began in November 2008, when he was investigated for effort dyspnea and palpitations started a few months before. Echocardiography revealed left ventricular hypertrophy with interventricular and posterior wall thickening (16 and 14 mm, respectively) with sparkling appearance, an impaired left ventricular ejection fraction of 45%, as well as left atrial dilatation (46 mm), impaired right ventricular function and increased pulmonary artery pressure (right ventricular systolic pressure, 47 mmHg; Fig. 1). Holter monitoring showed short episodes of nonsustained ventricular tachycardia. Cardiovascular MRI showed a typical image of cardiac amyloidosis. Cardiopulmonary exercise test yielded a VO2max of 17.9 ml/kg/min. The patient was referred to the National Amyloidosis Center, where he 1558-2027 ß 2016 Italian Federation of Cardiology. All rights reserved.

Discussion Early use of left ventricular or biventricular mechanical circulatory support may be beneficial as a bridge to transplantation in patients with cardiac AL amyloidosis. J Cardiovasc Med 2016, 17:126–129 Keywords: amyloidosis, biventricular assist device, heart failure, left ventricular assist device, renal failure, transplantation a Onassis Cardiac Surgery Center, bSecond Department of Cardiology, Attikon University Hospital, cFirst Department of Internal Medicine, Laiko Hospital and d Department of Cardiology, Mediterraneo Hospital, Athens, Greece

Correspondence to Dimitrios Farmakis, MD, PhD, FESC, First Department of Internal Medicine, University of Athens Medical School, Laiko Hospital, Athens, Greece Tel: +30 210 7456432; fax: +30 210 7788830; e-mail: [email protected] Received 25 December 2013 Revised 2 August 2014 Accepted 13 August 2014

was diagnosed as having systemic amyloidosis of AL type with subtle lambda (l) light-chain-secreting plasma cell dyscrasia. No evidence of clinically significant extracardiac involvement was present, and no visceral deposits were revealed by amyloid P component scintigraphy. A bone marrow biopsy showed a 12% monoclonal plasma cell infiltration (type l), and a serum-free light-chain assay revealed an elevated concentration of serum-free l light chains. He received no specific treatment for amyloidosis at that time. A few months later, in March 2009, and despite medical therapy, he was admitted with severe dyspnea of New York Heart Association Class III–IV, fatigue, and syncope. Left heart catheterization revealed normal coronary arteries and increased left ventricular end-diastolic pressure (27 mmHg). Right catheterization showed increased pressures (left atrium 21 mmHg, right ventricle 56/24 mmHg, pulmonary artery 56/31/42 mmHg, pulmonary capillary wedge 33 mmHg, transpulmonary gradient 9 mmHg, pulmonary vascular resistance 2.0 Wood Units and cardiac index 2.2 l/min/m2). Endomyocardial biopsy was positive for amyloidosis (Fig. 2). A new bone marrow biopsy showed an 18% monoclonal plasma cell infiltration. It was decided that the patient would receive chemotherapy (bortezomib and dexamethasone) with the aim of halting the ongoing amyloid progression. He was discharged and the first scheme of chemotherapy was successfully administered. DOI:10.2459/JCM.0000000000000216

© 2016 Italian Federation of Cardiology. All rights reserved

Double organ transplantation in cardiac amyloidosis Gkouziouta et al. 127

Fig. 1

Fig. 2

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LV

RV

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LA

TV

RA

ICON Endomyocardial biopsy specimen, stained with hematoxylin and eosin, from the described patient. The amyloid is stained pinkish red and is seen as an amorphous material that separates the darker staining myocytes.

RA

IAS LA

(a) Apical four-chamber transthoracic echocardiogram demonstrating a thickened tricuspid valve (TV) and a rounded area of thickening of the endocardial surface of the right atrium (arrow). (b) Transesophageal view showing marked thickening of the interatrial septum. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

A few weeks later, in mid-April 2009, after the first dose of chemotherapy, the patient suffered an episode of cardiac arrest. He was resuscitated successfully, intubated and due to hemodynamic instability, started on high-dose inotropes and vasopressants. He was admitted to the Cardiac Care Unit (CCU) in cardiogenic shock and an intra-aortic balloon pump was inserted. He was unable to be weaned due to frequent episodes of sustained ventricular tachycardia and 2 weeks later, in early May 2009, a Berlin Heart Biventricular Assist Device (BiVAD) was implanted uneventfully. As bone marrow biopsy showed a remission of amyloidosis, with a residual 8% plasma cell infiltration, the chemotherapy was continued; the second scheme was administered a few days after BiVAD implantation and the third one in late June 2009. In mid-July 2009, he was discharged home on mechanical assistance. After 116 days of BiVAD support, in September 2009, the patient was finally transplanted successfully, the graft

offered from a 35-year-old donor who suffered a car accident with brain injury. His renal function, however, deteriorated due to perioperative hemorrhagic shock and low cardiac output. He was on dialysis three times per week posttransplantation. Candidaemia was detected 2 days posttransplantation with PCR and was successfully treated. A month later, bone marrow biopsy revealed total remission of amyloidosis. The patient was finally discharged in November 2009. The patient was subsequently referred for kidney transplantation. In March 2010, he underwent surgery for an inguinal hernia. Finally, in April 2010, a year after his admission to the CCU for cardiogenic shock and 8 months after cardiac transplantation, he successfully underwent kidney transplantation. The donor was his HLA-identical 66-year-old brother. The graft functioned immediately and the perioperative course was generally uneventful, although support with small doses of vasopressors was needed for several days. The patient was discharged 12 days postsurgery with an immunosuppressive regimen (cyclosporine, prednisone, and mycophenolic acid). In January 2011, the patient developed rapidly deteriorating severe dyspnea. He was hospitalized again and diagnosed as having pneumonia due to H1N1 virus infection. He was treated successfully with antiviral medication with no need for mechanical ventilatory support. Today, 5 years after his initial presentation, he is well and has completely resumed his previous demanding duties.

© 2016 Italian Federation of Cardiology. All rights reserved

128 Journal of Cardiovascular Medicine 2016, Vol 17 No 2

Discussion This is the remarkable case of a 63-year-old man with rapidly deteriorating heart failure caused by a serious systemic disorder that required BiVAD support followed by sequential heart and kidney transplantation. The patient also suffered subsequently a life-threatening viral pneumonia and, against the available evidence, not only did he manage to survive, but he even resumed his previous demanding career. Cardiac amyloidosis is a potentially life-threatening condition. Primary systemic or AL amyloidosis is the most commonly diagnosed form of clinical amyloid disease in developed countries.2 The AL fibrils are derived from monoclonal immunoglobulin light chains, and multiorgan infiltration is typical. Although the other forms of amyloid deposits are less commonly associated with clinically significant cardiac disease,3,4 end-stage heart failure has also been reported for patients with senile and familial amyloidosis.5 The extent of cardiac involvement with amyloid deposition is the major determinant of outcome and an important determinant of treatment options.3,6 The presence and the pattern of late gadolinium enhancement in cardiac MRI are strongly associated with clinical and functional markers of prognosis. The combination of elevated biomarkers (troponin T and B-type Natriuretic Peptide) and most importantly clinical heart failure, particularly low cardiac output heart failure, with elevated left ventricular filling pressure, as in our case, is associated with a dismal prognosis of typically several weeks to months. The outcome of cardiac transplantation in patients with AL amyloidosis is poor. The major risk associated with heart transplantation for patients with end-stage cardiac amyloidosis is progression in other major organ systems, including recurrence in the cardiac allograft leading to decreased l-year and 5-year posttransplant survival.7,8 Early transplant experience from the United Kingdom in 24 cases (the majority due to AL amyloidosis) without adjunctive chemotherapy showed a dismal 1-year and 5-year survival of 50 and 20%, respectively.7 Thus, compared with the current US national postheart-transplant benchmarks (1-year survival around 89%, 5-year survival around 75%), heart transplantation for cardiac amyloidosis has historically been associated with the poorest posttransplant survival.9 However, the implementation of light-chain reductive chemotherapy and posthearttransplant autologous hematopoietic stem cell transplant has improved postheart-transplant outcome. Studies in small patient populations reported posttransplant 1-year and 5-year survival rates as high as 82 and 65%, respectively.7,10,11 Patients with severe cardiac amyloidosis forms of restrictive cardiomyopathies are represented either in trials that established Assist Device therapy as a therapeutic

and other largely not Ventricular option for

end-stage heart disease or in the INTERMACS registry to provide definitive recommendations on its the safety and efficacy as a bridge to transplantation or destination therapy.12 An established risk factor for post- Left Ventricular Assist Device (LVAD) morbidity and mortality relates to preexisting right-sided heart failure reflected by a high right-atrial pressure,13,14 which is not uncommon in end-stage cardiac amyloidosis, thereby leading potentially to higher early postoperative risk compared with patients with nonamyloid dilated cardiomyopathies. Ideal mechanical circulatory support options for patients with end-stage cardiac amyloidosis who have biventricular failure include BiVADs and the total artificial heart.15 The feasibility of placing a permanent, continuous-flow LVAD has been reported in six patients with end-stage cardiac amyloidosis.5,10,16 In contrast, there is a paucity of data regarding biventricular circulatory support as a bridge to heart transplantation in patients with end-stage systemic amyloidosis, whereas the use of biventricular mechanical support as destination therapy not linked to heart transplantation is associated overall with a 1-year survival rate of less than 50%.13 It should be stressed that there may be some technical difficulties regarding LVAD implantation in particular cardiomyopathies characterized by small-sized left ventricle, such as that related to cardiac amyloidosis. These difficulties may be addressed by the smaller newgeneration devices. Unfortunately, patients with end-stage amyloidosis listed for heart transplantation continue to have an extraordinarily poor prognosis, with 50% death on the waiting list. Death on the waiting list is often due to progressive biventricular failure and/or complications of systemic amyloidosis coupled with long waiting times for a donor heart. The timely diagnosis of the condition along with the intensified care using all available means may give even an almost desperate case the chance not only to survive in the long term but also to lead a normal life, despite the significant comorbidities and the dismal prognosis. In addition to the medical and social implications, this case may also be interesting from a financial point of view, as the high cost of such an intensive approach is compensated and may be outweighed by the fact that a middle-aged individual resumed his profession and productivity.

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Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004; 22:3751–3757. Dubrey SW, Burke MM, Hawkins PN, Banner NR. Cardiac transplantation for amyloid heart disease: the United Kingdom experience. J Heart Lung Transplant 2004; 23:1142–1153. Pelosi F Jr, Capehart J, Roberts WC. Effectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol 1997; 79:532–535. Johnson MR, Meyer KH, Haft J, et al. Heart transplantation in the United States, 1999–2008. Am J Transplant 2010; 10:1035–1046. Dey BR, Chung SS, Spitzer TR, et al. Cardiac transplantation followed by dose-intensive melphalan and autologous stem-cell transplantation for light chain amyloidosis and heart failure. Transplantation 2010; 90:905–911. Lacy MQ, Dispenzieri A, Hayman SR, et al. Autologous stem cell transplant after heart transplant for light chain (Al) amyloid cardiomyopathy. J Heart Lung Transplant 2008; 27:823–829.

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Kirklin JK, Naftel DC, Kormos RL, et al. The Fourth INTERMACS Annual Report: 4000 implants and counting. J Heart Lung Transplant 2012; 31:117–126. Kirklin JK, Naftel DC, Kormos RL, et al. Third INTERMACS Annual Report: the evolution of destination therapy in the United States. J Heart Lung Transplant 2011; 30:115–123. Kormos RL, Teuteberg JJ, Pagani FD, et al., HeartMate II Clinical Investigators. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010; 139:1316– 1324. Copeland JG, Smith RG, Arabia FA, et al., CardioWest Total Artificial Heart Investigators. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med 2004; 351:859–867. Siegenthaler MP, Westaby S, Frazier OH, et al. Advanced heart failure: feasibility study of long-term continuous axial flow pump support. Eur Heart J 2005; 26:1031–1038.

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Double organ transplantation in cardiac amyloidosis.

Cardiac amyloidosis, particularly primary or AL amyloidosis, is the most common infiltrative cardiomyopathy and is associated with a poor prognosis. T...
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