Current Treatment in Cardiac Amyloidosis Ivana Kholová, MD, PhD* Josef Kautzner, MD, PhD, FESC Address *Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail:
[email protected] Current Treatment Options in Cardiovascular Medicine 2006, 8:468–473 Current Science Inc. ISSN 1092–8464 Copyright © 2006 by Current Science Inc.
Opinion statement Involvement of the heart is a common finding in amyloidosis. The heart is usually infiltrated by amyloid fibrils in primary amyloidosis and age-related forms of amyloidosis, less commonly in transthyretin familial amyloidosis, and rarely in secondary amyloidosis. The most common clinical presentation is restrictive cardiomyopathy with right-sided heart failure. The second most frequent presentation is congestive heart failure due to systolic dysfunction, followed by arrhythmias and orthostatic hypotension. The diagnosis of amyloidosis requires tissue sample confirmation; at present, Congo red staining in polarized light is the diagnostic method of choice. The characterization of protein fibril type by immunohistochemistry or biochemistry is essential for patient prognosis and treatment. The therapeutic approach consists of specific treatment of amyloidosis and supportive treatment for cardiac-related symptoms. The treatment depends on the type of amyloidosis and the stage of disease. The mainstay of supportive treatment of cardiac failure is diuretic therapy. Primary amyloidosis treatment protocol includes melphalan and prednisone chemotherapy. Heart transplantation is only a palliative treatment. Stem cell transplantation is an emerging treatment alternative. Combination therapy of melphalan and stem cell transplantation has been shown to be a promising treatment strategy. Secondary amyloidosis requires aggressive treatment of the associated inflammatory and neoplastic process. Age-related (senile) amyloidosis benefits from supportive cardiac treatment when applicable. Transthyretin amyloidosis, the most common cardiac hereditary amyloidosis, is treated by liver or combined liver-heart transplantation. New therapies based on chemical and immunologic reaction with amyloid or its precursor are under intensive development.
Introduction The human heart is often affected by amyloidosis; this is a descriptive term encompassing a large group of diverse diseases rather than a single disease entity. Amyloidosis is characterized by extracellular deposition and accumulation of insoluble fibrillar proteins with concomitant destruction of normal tissue structure and function [1]. The pathogenesis of amyloid fibrils is related to amino acid substitutions in prefibrillar proteins and to protein instability caused by different stimuli that promote precipitation into the extracellular matrix. Despite the fact that morphologically proteinaceous deposits are identical, amyloid-forming proteins
are chemically different and can be identified and classified by immunohistochemical and biochemical analyses [2]. The current nomenclature of amyloid is based on the nature of the fibril protein; 18 proteins have been identified so far [3]. In clinical practice, five different types of amyloidosis have been described according to the underlying dise a s e : 1 ) I m m u n o g l o b u l i n ( A L ) a my l o i d o s i s i s associated with immunoglobulin light-chain proteins and includes primary amyloidosis, multiple myeloma, Waldenström’s macroglobulinemia, and so forth. It constitutes the vast majority of newly diagnosed cases
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Figure 1. Echocardiogram of a patient with AL amyloidosis (apical view) documents thickened ventricular walls, abnormal myocardial texture, and pericardial effusion. LV— left ventricle; RV— right ventricle.
Figure 2. Echocardiographic image from a patient with severe AL amyloidosis, showing significant dilation of hepatic veins (arrows) due to right-heart failure. RA—right atrium.
of amyloidosis and cardiac involvement is common. 2) Secondary amyloidosis is related to reactive amyloid fibrils that are produced as acute-phase proteins in cases of systemic inflammation. 3) Hereditary amyloidosis is caused by an autosomal-dominant mutation, usually in the transthyretin gene. 4) Senile systemic amyloidosis that is associated with advanced age is derived from normal transthyretin and mainly affects atrial cardiac tissue. 5) Hemodialysis-associated amyloidosis occurs with chronic hemodialysis and is characterized by the deposits of the β2 microglobulin amyloid fibril subunit in skeleton and joints [4,5]. Isolated atrial amyloidosis without systemic involvement is a common finding at autopsy, particularly in the elderly. It can be associated with atrial fibrillation; amyloid was found in atria and myocardial sleeves on pulmonary veins in patients with atrial fibrillation [6,7]. Clinical symptoms of amyloidosis are often nonspecific. Restrictive cardiomyopathy is the leading finding in cardiac amyloid involvement and results from the replacement of normal contractile elements by interstitial deposits of amyloid. Affected myocardium becomes firm and noncompliant [8]. The second frequent presentation is congestive heart failure due to systolic dysfunction, followed by arrhythmias and orthostatic hypotension [4,5]. Amyloid deposits in pulmonary vessels can lead to pulmonary hypertension and cor pulmonale [9]. The identification of amyloidogenic proteins is of a great importance both for the treatment and prognosis. The diagnostic approach is multidisciplinary and includes clinical examination, electrocardiography, imaging (echocardiography, chest radiography, and MRI), biochemical tests, genetic analysis, and histopathologic evaluation of tissue samples [10–12]. Cardiac amyloidosis should be suspected in any patient
who presents with restrictive cardiomyopathy (Fig. 1), prominent signs of right-sided heart failure (Fig. 2), or left-sided heart failure in the absence of coronary artery disease [12]. Amyloid can be diagnosed and classified in any affected tissue specimen by special stains and biochemical analysis. Samples from extracardiac tissue sites can be obtained less invasively before heart specimens. However, endomyocardial biopsy was found to be a safe and effective method for the cardiac amyloid involvement [13]. According to the American College of Cardiology/American Heart Association criteria, endomyocardial biopsy is recommended in patients with heart failure in whom an inflammatory or infiltrative disorder of the heart is suspected [14]. Both formalin-fixed and fresh/frozen tissue samples can be used for the biochemical analysis [15,16]. At light microscopy, all forms of amyloid deposits appear amorphous, homogenous, and pale eosinophilic when stained with hematoxylin and eosin. At present, Congo red is the standard staining method. Congo red-stained amyloid has an orange or red color at light microscopy and has an apple-green birefringence under polarized light. Immunohistochemical staining enables the classification of amyloid deposits and seems to have increasing importance in amyloid diagnosis. Furthermore, a wide range of anti-amyloid fibril protein antibodies is commercially available [2,17].
ACKNOWLEDGMENT Dr. Kholová is supported by the Finnish Foundation for Cardiovascular Research. Dr. Kautzner can be contacted at the following address: Department of Cardiology, Institute for Clinical and Experimental Medicine, Vídenská 1958/9, CZ-140 21 Prague, Czech Republic; email:
[email protected].
Treatment • The treatment and prognosis of cardiac amyloidosis depends on the type of amyloidosis and the stage of disease. Treatment of amyloidosis can be divided into specific treatment directed to the amyloidogenic process and supportive treatment focusing on the resulting cardiac dysfunction [4,5].
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Valvular, Myocardial, Pericardial, and Cardiopulmonary Disease • Treatment of heart failure is ruled by general principles. Careful use of diuretics and vasodilators may provide symptomatic benefit; however, orthostatic hypotension and intravascular volume contraction caused by concomitant nephrotic syndrome make diuretic therapy challenging [4,5,18]. Angiotensin-converting enzyme inhibitors, long-acting nitrate, and other vasodilatators have showed varying responses, whereas calcium channel blockers, β blockers, and digoxin are relatively contraindicated or should be used with extreme caution in cardiac amyloidosis. Digoxin is bound extracellullarly by amyloid fibrils and may cause hypersensitivity and toxicity. Calcium channel blockers and β blockers may worsen symptoms of heart failure because of their negative inotropic effects. • A pacemaker may be indicated to treat symptomatic bradyarrhythmias [4]. In case of atrial fibrillation, ibutilide and/or amiodarone were shown to be effective. Moreover, patients with atrial fibrillation benefit from anticoagulant therapy. The same holds true for patients with atrial standstill due to amyloid infiltration.
Pharmacologic treatment • The principle of systemic chemotherapy in the treatment of AL amyloidosis was established 30 years ago. Most commonly, a combined chemotherapy regimen of melphalan and prednisone was used [19•,20]. However, this standard protocol has been shown to be unsatisfactory (response rate ~ 30%) with a long time to response (> 1 year) [21]. More recently, low-dose regimens of melphalan have been found to be more effective in patients with heart failure who do not tolerate prednisone or more aggressive chemotherapy [22]. In another study, a combination of oral melphalan and high-dose dexamethasone showed complete remission in 33% of patients ineligible for stem cell transplantation [23]. Therefore, alkylating agent– based therapy is the standard therapy to which new treatment should be compared [19•]. Vincristine, dexamethasone, doxorubicin, and colchicine either in combination (VAD regimen) or single therapy has also been used with variable results [5,19•]. Another effective alternative, although quite toxic, appears to be thalidomide. The combination of thalidomide and dexamethasone has been used in patients refractory to the above therapy [24,25]. Alternative drugs under consideration are 4′-iodo-4′-deoxydoxorubicin and interferon-α [5,12]. • Secondary amyloidosis requires aggressive treatment of the underlying inflammatory or neoplastic process. The cardiac symptoms are rare and require supportive treatment [4,5]. Yet, cardiac involvement carries a poor prognosis. • Until recently, no specific drugs were available for familiar amyloidosis. Because abnormal proteins are produced predominantly by the liver, liver transplantation remains the most important therapeutic option. Recently, drugs that stabilize the transthyretin molecule are under intensive evaluation [26]. Several nonsteroidal anti-inflammatory drugs, including diclofenac, diflunisal, and flufenamic acid, were shown to stabilize the native tetramer and strongly inhibit transthyretin amyloid fibril formation in vitro [27–29]. • Senile systemic amyloidosis is associated with the most favorable prognosis and congestive heart failure is responsive to medical treatment more than in other types of amyloidosis.
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Heart and liver transplantation • Heart transplantation for cardiac amyloidosis remains controversial because of the systemic involvement and the potential for amyloid deposition in the graft [30,31•]. Long-term prognosis is poor (39% survival at 4 years in one study and 30% at 5 years in another) [8,30]. Heart transplantation in primary amyloidosis is only a palliative procedure and consequent supportive chemotherapy should be considered [30]. Recurrence of amyloid in graft in patients with primary amyloidosis is common; however, the recurrence influences neither the function nor the prognosis [31•]. Recently, a series of five patients successfully treated by sequential heart and autologous stem cell transplantation for primary amyloidosis was reported [32]. • Liver transplantation is one of seldom effective treatments for the most common hereditary amyloidosis, transthyretin amyloidosis. Liver transplantation provided before cardiac involvement can prevent cardiomyopathy onset [33]. Successful combined heart-liver and liver-kidney transplantation were reported for hereditary transthyretin, fibrinogen, and apolipoprotein AI amyloidosis, respectively [34–38].
Stem cell transplantation • Stem cell transplantation can be divided into allogeneic and syngeneic transplantation and autologous peripheral blood stem cell transplantation [19•]. Stem cell transplantation is used exclusively for primary amyloidosis. The use of stem cell transplantation in the management of amyloidosis is logical because patients with multiple myeloma benefit from stem cell transplantation. Autologous stem cell transplantation is associated with a high mortality rate (21% at referral centers) and toxicity. Patients with multiorgan involvement are at very high risk of treatment-related toxicity and toxic death [39]. The organ involvement before stem cell transplantation for primary amyloidosis is the most important predictive survival factor [40]. To prevent the possible risks, transplant centers have recently introduced measures such as mobilization with growth factors alone, infusion of dimethylsulfoxide-depleted grafts, cardiac monitoring, and prophylactic antiarrhythmia treatments [39]. Patients indicated for stem cell transplantation should fulfill all of the following parameters: age ≤ 80 years, compensated congestive heart failure, cardiac ejection fraction ≥ 0.40, lack of pleural effusions, systolic blood pressure ≥ 90 mm Hg, and oxygen saturation ≥ 95% [41]. Stem cell transplantation may be complicated by multiorgan failure, kidney failure, cardiac arrhythmia, pulmonary embolia, fungal infection, pneumonia, and gastrointestinal tract bleeding [40,42]. Spontaneous rupture of the spleen has recently been reported in patients with AL amyloidosis during stem cell mobilization; this can be successfully treated in the early post-transplant period [43]. • The Calgary Bone Marrow Transplantation Program revealed a 67% complete hematologic response and a 27% complete organ response in a series of 15 patients. Overall survival rate was 75%. They concluded autologous stem cell transplantation is feasible for patients with multisystem involvement [44]. A combination of high-dose melphalan chemotherapy and autologous stem cell support was also suggested [41,45].
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Future perspectives in therapy • Despite all the advances mentioned in this paper, the treatment of cardiac amyloidosis remains unsatisfactory and the prognosis of affected patients is generally poor. Future perspectives include therapies based on precursor stabilization (transthyretin), prevention of formation by cross-linking, elimination of the synthesizing cells (light chains), antisense oligonucleotides inhibiting monoclonal immunoglobulin production, and immunization to induce host-mediated reaction (light chains) [10,46–48].
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