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Eur J Cardiothorac Surg 2008;33:257-262. doi:10.1016/j.ejcts.2007.10.025
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Treatment options for severe cardiac amyloidosis: heart transplantation combined with chemotherapy and stem cell transplantation for patients with AL-amyloidosis and heart and liver transplantation for patients with ATTR-amyloidosis

Falk-Udo Sacka,*, Arnt Kristenb, Hartmut Goldschmidtc, Philipp A. Schnabeld, Thomas Denglerb, Achim Kocha, Matthias Karcka

a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
b Department of Cardiology, University of Heidelberg, Heidelberg, Germany
c Department of Hematology, University of Heidelberg, Heidelberg, Germany
d Institute of Pathology, University of Heidelberg, Germany

Received 2 April 2007; received in revised form 11 October 2007; accepted 16 October 2007.

* Corresponding author. Address: Department of Cardiac Surgery, INF 110, D-69120 Heidelberg, Germany. (Email: falk-udo.sack{at}urz.uni-heidelberg.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Objective: Cardiac amyloidosis (CA) is associated with a poor prognosis and a survival rate of less than 30% 2 years after clinical manifestation. Considered as a semi-malignant disease, CA is often a contraindication for HTx; however, depending on the type of CA, there are excellent treatment regimes that can be combined with HTx. In AL-amyloidosis, chemotherapy and stem cell transplantation are necessary and in TTR-amyloidosis, where the liver is the source of the pathologic protein, liver transplantation is recommended after HTx. Methods and Results: More than 60 patients with AL-amyloidosis and more than 25 patients with ATTR-amyloidosis have been investigated at our centre. Eighteen patients showed signs of end-stage heart failure. Four patients died within 1 month after listing for HTx. Seven patients with AL (mean age 41.8 years) and five patients with ATTR-amyloidosis (mean age 42.6 years) were successfully transplanted with an actual survival rate of 91.6%. One patient died 8 months after HTx due to infection. Five AL patients received chemotherapy and SCT and one ATTR patient was liver transplanted. Three AL patients showed complete remission of amyloidosis. Conclusions: Cardiac amyloidosis is a potentially curative disease after HTx when combined with either chemotherapy and SCT or LiverTx depending on the type of the amyloidosis. Due to the natural course of the disease, urgent HTx after cardiac manifestation is mandatory. With this approach, excellent survival rates and even remission of the underlying disease is possible.

Key Words: Amyloidosis • Heart failure • Transplantation • Stem cell therapy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Amyloidosis is a rare disease. The underlying pathological mechanism is the production of insoluble beta-fibrillar proteins that are then deposited in various organs [1,2]. The heterogeneity of its clinical appearance often leads to a delay in the appropriate diagnosis [3]. As soon as the heart gets involved, which is the case in more than 50% of the patients, prognosis is poor [4]. Survival rates of patients with symptomatic cardiac amyloidosis are less than 40% after 2 years. Despite the fact that cardiac involvement is such a limiting factor for survival, cardiac amyloidosis is often considered as a contraindication for heart transplantation, due to the semi-malignant nature of the disease. For a rational approach to this particular patient group, the underlying mechanism of amyloid production has to be analysed. There are more than 20 different amyloidotic proteins, but only two different sources of amyloid are responsible for the majority of cardiac involvement [5]. The most common form of amyloidosis is associated with plasma cell disorders. The pathologic protein is produced from clonal light chains, originating from plasma cells of patients with multiple myeloma [6]. Due to the origin from light chains the disease is referred to as AL-amyloidosis. Median survival rates after the first occurrence of congestive heart failure is <6 months [7–9]. Systemic high-dose chemotherapy with melphalan and autologous stem cell transplantation in patients with AL-amyloidosis is the only effective therapy with survival rates of more than 77% after 5 years [10,11]. However, this is only the case as long as cardiac symptoms are absent (NYHA < III). In patients in NYHA class III or IV, the formerly mentioned survival rates are reality [12].

Rationale for heart transplantation in immunoglobulin light-chain amyloidosis (AL)

Potential curative therapy: high dose chemotherapy: melphalan and autologous stem cell support

The other most significant form of amyloidosis affecting the heart is the hereditary amyloidosis ATTR. Transthyretin, a carrier protein for albumin, is predominantly produced by the liver. TTR is deposited as amyloid fibrils, causing neurodegeneration and organ failure.

Both wild-type and point mutations of thyretin are known to deposit amyloid [3,12]. Although transthyretin itself has only little influence on liver function, liver transplantation is currently the treatment of choice, in order to remove the source of the pathologic protein [13,14].

Rationale for heart transplantation in hereditary amyloidosis (ATTR)

More than 99% of transthyretin is synthesized in the liver and secreted into the circulation.

Orthotopic liver transplantation would remove the source for the pathologic protein.

Manifest cardiac amyloidosis is associated with a high therapy-related mortality rate, such as arrhythmias or cardiac decompensation during chemotherapy for AL or perioperatively in patients undergoing liver transplantation for ATTR. The severity of symptoms and the lack of potential medical treatment for patients with cardiac amyloidosis and manifest heart failure, makes orthotopic heart transplantation followed by a specific treatment of the underlying disease, the only rational based help for these patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Appendix A
 References
 
Up until November 2006, more than 60 patients with AL-amyloidosis and more than 25 patients with ATTR-amyloidosis have been investigated in our institution. Among these patients, 18 patients showed signs of end-stage heart failure with NYHA classes III and IV. Twelve of these patients could be successfully transplanted, four patients died within 1 month after listing for HTx and two patients are still on the waiting list for heart transplantation. Demographic data, the type of amyloidosis, NYHA classification, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, time of first diagnosis in our centre, listing for HTx and waiting time are presented in Table 1 .


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  		Table 1 Baseline demographic and clinical characteristics of the patient population.
 
2.1 Clinical features
Due to the massive amyloid infiltration, stiffness of the left ventricle leads to an impairment of the diastolic filling. Signs of diastolic dysfunction are common in all patients. Systolic left ventricular function is sustained at early stages but decreases as organ involvement advances. Patients with cardiac amyloidosis often show rapidly progressive signs and symptoms. Clinical signs are predominantly right heart related with peripheral oedema and hepatomegaly. At later stages of the disease, dyspnoea is common and all our transplant patients suffered from shortness of breath. These symptoms are often associated with low cardiac output.

In patients with advanced cardiac amyloidosis, echocardiography shows signs of concentric left ventricular wall thickening without ventricular dilatation. The myocardial texture is often described as granular sparkling [15].

Due to the severity of left ventricular dysfunction, N-terminal pro-brain natriuretic peptide is extremely elevated in patients with end-stage cardiac amyloidosis (Table 1) [16].

The gold standard for diagnosis of cardiac amyloidosis is the detection of amyloid in Congo red staining of myocardial biopsies. In all our patients, cardiac amyloidosis was proven by endomyocardial biopsies. The majority of biopsies were taken from the left ventricle because the chance of perforation of the right ventricular wall and the development of a significant pericardial effusion is more than four times higher in patients with cardiac amyloidosis. The distribution patterns of amyloid within the heart are differentiated in a diffuse interstitial, subendocardial, vascular or nodular type. All patients with heart failure showed predominately diffuse, interstitial cardiac amyloidosis (Figs. 1 and 2 ).


Figure 1
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  		Fig. 1. Diffuse interstitial (endomysial) distribution of amyloid surrounding cardiac myocytes. Congo red staining, primary magnification x40 (light red, amyloid deposits; dark red, myocytes).

 

Figure 2
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  		Fig. 2. Diffuse interstitial distribution of amyloid. Endomyocardial biopsy from a patient with AL-amyloidosis, HE staining, primary magnification x200. Damage to cardiac myocytes surrounded by the amyloid fibres is clearly visible (arrows): partly atrophy, partly hypertrophy with vacuolisation and loss of myofibrils (arrows). In some areas a loss of cardiac myocytes is obvious.

 
As soon as the patients present with severe cardiac symptoms, evaluation for heart transplantation and consequent listing for HTx is mandatory. Due to the progressive nature of the disease, listing as high-urgency or urgency candidates is accepted according to the rules of Eurotransplant.

2.2 Orthotopic heart transplantation
There are no specific considerations for patients with cardiac amyloidosis undergoing orthotopic heart transplantation. However, the standard procedure in our institution is total heart transplantation with complete excision of the diseased cardiac tissue. As much of the atria as possible is resected. Bicaval anastomoses, anastomoses of the two pulmonary vein cuffs followed by end-to-end anastomoses of the great vessels, is the technique of choice [17].

Immediate postoperative care is no different to for standard HTx patients. Immunosuppression consists of triple therapy with antithymocyte immunoglobulin for induction, and corticosteroids, cyclosporine A and mycophenolic acid for maintenance.

2.3 Specific treatment of the amyloidosis
Patients with AL-amyloidosis are scheduled 4–6 months following heart transplantation for collection of CD 34+ cells for stem cell support and high dose chemotherapy with melphalan (140–200 mg/m2) followed by autologous stem cell support; immunosuppression is continued [18]. Patients with ATTR-amyloidosis are listed for orthotopic liver transplantation.

In order to detect reoccurrence of cardiac amyloid, routine myocardial biopsies are necessary.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Appendix A
 References
 
Of the 18 patients with a clear indication for orthotopic heart transplantation, 12 were successfully transplanted and 2 patients are still on the waiting list. Unfortunately, four patients died shortly after the diagnosis of cardiac amyloidosis was established and listing for HTx was initiated. All transplanted patients were in NYHA class III or IV with mean NT-proBNP levels of 5613.3 ± 2118.2 ng/l, thus reflecting the severe nature of the disease. There were no options for bridging devices due to the massive infiltration of the hearts with amyloid. All explanted hearts were extremely stiff. The cardiac tissue itself seemed to consist of hard rubber. Fig. 3a and b gives an impression of the appearance of cardiac involvement. After explantation, these hearts remain in shape. The stiff appearance can be seen in the figures. The shiny cutting surface shows the light-reflecting properties of the pathologic protein within the heart.


Figure 3
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  		Fig. 3. (a, b) Heart with end-stage AL-amyloidosis. Massive thickening of the ventricle walls can be seen. The yellow, light-reflecting cutting surface clearly shows the amyloid overload.

 
The postoperative survival is represented as a Kaplan–Meier curve in Fig. 4 . All patients except 1 are still alive. This patient died 201 days after heart transplantation due to infection. The patient had already received four cycles of chemotherapy prior to heart transplantation and he was scheduled for one cycle of melphalan and stem cell therapy in June 2006.


Figure 4
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  		Fig. 4. Survival after heart transplantation.

 
All surviving patients are free of cardiac symptoms. They are all in NYHA classes I and II. Table 2 gives an overview of the individual outcome for each of the 12 patients with main emphasis on curative therapy of amyloidosis.


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  		Table 2 Individual outcomes for each of the 12 patients
 
The clinical condition of the surviving patients following heart transplantation is excellent. They are all in NYHA classes I and II. There is no specific exercise testing protocol necessary for this patient group.

No complications occurred after chemotherapy and stem cell therapy in AL patients. The death due to infection of one patient of the AL group was not directly related to a cycle of chemotherapy. Five of the seven patients with AL-amyloidosis were treated with chemotherapy, one patient with additional autologous stem cells (CD 34+, G.W.). One patient declined stem cell therapy after harvesting of CD 34+ cells (V.P.). Her clinical condition is extremely good. The remaining patients are still scheduled for stem cell therapy. Regarding the amyloidosis, three patients showed complete remission of the disease. No amyloid is detectable in the heart. In addition, there are no free light chains detectable in the serum of these patients [19]. One patient showed only partial remission with light chains detectable in the serum but no amyloid in the cardiac biopsy (G.W.). Two patients are awaiting specific therapy after an interval of 4–6 months following heart transplantation (I.H.S., E.V.).

One of the ATTR patients has been successfully liver transplanted, while three patients are still on the waiting list. One patient declined liver transplantation, because she is feeling too well. Therefore, no specific therapy is planned for this patient.

Four of the five patients with ATTR amyloidosis show no signs of amyloid protein within the heart, proven by endomyocardial biopsy. In one patient, amyloid is detectable within the heart, however, only electronmicroscopically.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Appendix A
 References
 
Amyloidosis is a rare disease, the incidence being between 5 and 13 per million [10]. However, as soon as heart failure presents, mean survival rates are below 6 months [20]. Dubrey et al. have shown in a large series of patients, that the 2-year survival rate of patients with cardiac amyloidosis is less than 20% without HTx compared to a survival rate of 60% after heart transplantation [7]. The poor prognosis of the patients should be reason enough to include them in a transplant programme with a multidisciplinary follow-up and specific treatment for amyloidosis. Reported by the group of the Mayo clinic, the median survival rate of patients with cardiac amyloidosis and elevated NT-proBNP is 5.8 months in median despite their excellent expertise with chemotherapy and stem cell transplantation [21]. This reflects the severe nature of the disease and the urgent need for heart transplantation.

Total orthotopic heart transplantation seems to be the method of choice, because almost all the diseased cardiac tissue can be removed [17]. In cardiac amyloidosis, even the left and right atrial walls are extremely thick and very fragile. Anastomoses between the pulmonary veins and the left donor atrium and between the venae cavae and the right donor atrium are much easier and more safely performed as compared to the standard technique originally described by Lower and Shumway.

The two major forms affecting the heart are AL-amyloidosis and ATTR-amyloidosis [3,20]. Due to the semi-malignant character of the disease cardiac amyloidosis is often considered as a contraindication for heart transplantation. However, recent years have shown that amyloidosis is a disease with a good chance of remission as soon as aggressive treatment is initiated. Based on the two different types of amyloidosis affecting the heart, different therapeutic regimes are applied.

In AL-amyloidosis, high-dose chemotherapy with autologous stem cell therapy would be the optimal approach to these patients. In more than 50% of the cases, a complete haematological remission can be achieved [22,23]. The crucial point is the fact that high-dose chemotherapy with melphalan is an aggressive therapy that might be harmful to patients with symptoms of heart failure. Comenzo et al. had a 1-year mortality of 50% in the treatment group with cardiac involvement [9]. Therefore one must conclude that patients presenting with heart failure should be transplanted prior to specific chemotherapy and stem cell support for the AL-amyloidosis. In our small series, this approach seems to be promising (Fig. 5 ).


Figure 5
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  		Fig. 5. Schematic diagram of the therapeutic strategy for patients with AL-amyloidosis.

 
However, in clinical settings, this rational approach is limited by the patient decisions. Due to patients doing so well after heart transplantation and the short-term efficacy of chemotherapy, two of the patients rejected the options of an additional therapy, namely the stem cell transplantation. One patient even declined stem cell transplantation after harvesting the cells. Increasing expertise with this patient population might help to answer the question of necessity of stem cell therapy.

Patients with ATTR-amyloidosis and symptoms of heart failure should undergo heart transplantation first. There is no urgent need for liver transplantation, because amyloid production and deposition within the heart is a slow process. In our opinion combined liver and heart transplantation seems to be too much of a burden for severely ill patients [23]. There are only a few reports available addressing the issue of combined heart and liver transplantation; most of them are case reports [24–26]. The immunological advantage for transplantation of two solid organs from one donor is not convincing at that time. In patients with ATTR-amyloidosis and heart transplantation, progression of cardiac disease is very slow. There is no need for urgent liver transplantation as long as the liver function itself is not impaired. Following heart transplantation and extensive physiotherapy, there is the chance of bringing the patient to a point where an excellent physical condition might be an advantage for secondary liver transplantation.

With these strategies, we can offer a very promising therapy for patients with cardiac amyloidosis. However, maximum success can only be achieved if these patients are treated by a group of experienced physicians, consisting of cardiologists, haematologists, pathologists and surgeons. Therefore a multidisciplinary approach is the only effective way of helping these patients. The rational approach: AL-amyloidosis–heart transplantation–chemotherapy–stem cell transplantation and ATTR-amyloidosis–heart transplantation–liver transplantation will be proved in the future. At the moment, with our approach we are able to offer an effective treatment with excellent results in a patient group with a survival probability of less than 30% for 1 year without heart transplantation [21].


   Appendix A
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
References
 
Conference discussion

Dr C. McGregor (Rochester, Minnesota, USA): I’m simply amazed that your transplant team would consider amyloid heart disease as an indication for urgent transplantation. There are six patients in this series, one of whom has myeloma, and why would you do a heart transplant on somebody with myeloma? That's the first question.

The second thing is that you have two patients who have survived beyond a year. The 1-year survival is irrelevant. What really matters is 5-year survival. And the majority of reports that we are now seeing will change very dramatically when it comes to 5-year survival. The great challenge, I think, is the selection of patients with amyloid disease. So I wonder if you could briefly comment on that.

Dr Sack: The selection of patients was, in my opinion, it's very easy. As soon as you have a cardiac involvement of this disease, if the patients are really sick due to their heart disease, you have to decide or you have to carefully look what is the reason for it or what is the source for the amyloidosis. If you have a multiple myeloma patient, the results we have with chemotherapy and stem cell transplantation are pretty good. The only problem remains the heart and that can be solved.

Dr McGregor: Is there a single piece of evidence in the literature to suggest that's true?

Dr Sack: It is experience.

Dr McGregor: Can you show me any manuscript showing 5-year survival in myeloma with heart transplantation? Because I’m not aware of a single report.

Dr Sack: No. It is the experience of the groups performing this type of treatment. And the numbers are very small. You cannot expect evidence-based data for every treatment you offer to a patient. You have to do it in the patients who are sick and we have a challenge to help them.

Dr McGregor: I mean, I think that you’re taking on a tough problem. And groups have to do that, but I think they have to really specialize, as you’re doing, and continue to make the effort. But patient selection is the issue.


   Footnotes
 
\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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