INTRODUCTION — Amyloidosis refers to the extracellular deposition of fibrils that are composed of low molecular weight subunits (5 to 25 kD) of a variety of serum proteins. These fibrils adopt a beta-pleated sheet configuration that leads to characteristic histologic changes. Amyloid deposits can occur in a variety of organs, with involvement of the heart, kidney, liver, and autonomic nervous system most often being responsible for morbidity and mortality. (See "Overview of amyloidosis".)
The frequency of cardiac involvement varies among types of amyloidosis. The prognosis of amyloid cardiomyopathy also varies among types of amyloidosis, with high mortality rates particularly in light-chain (AL) amyloidosis.
This topic will review the treatment of amyloid cardiomyopathy. The clinical manifestations and diagnosis of amyloid cardiomyopathy are discussed separately. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
NATURAL HISTORY AND PROGNOSIS
Cardiac ATTR amyloidosis
Wild-type ATTR amyloidosis — Original reports of wild-type transthyretin amyloidosis (ATTRwt) suggested a median survival of >5 years [1]; later studies [2-4] have reported worse outcomes, with median survival of 3.5 years [5].
Hereditary ATTR amyloidosis — The clinical phenotype of hereditary ATTR (ATTRm) varies among TTR variants and includes primary polyneuropathy (Val30Met), cardiomyopathy (Val122Ile, Leu111Met, Ile68Leu), and mixed phenotype (T60A). Peripheral neuropathy and autonomic dysfunction have a significant impact on quality of life, but cardiac involvement is the main determinant of prognosis with a median survival of four to five years when cardiac amyloidosis is present [6].
Cardiac AL amyloidosis — Natural history studies found that patients with cardiac AL amyloidosis and heart failure (HF) without disease-specific treatment had an overall median survival of only six months [7]. With contemporary management, the median survival for AL amyloidosis with cardiac involvement has significantly improved (eg, 5.5 years after diagnosis [8]). (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
STAGING
AL amyloidosis — Multiple staging systems have been proposed for AL amyloidosis, as discussed separately (table 1). (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Staging'.)
As an example, the Revised Mayo Stage system is based on serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T, and free light chains [9]. The scoring system assigns 1 point for NT-pro-BNP ≥1800 pg/mL, troponin T ≥0.025 ng/mL, and difference between the kappa and lambda free light chains ≥18 mg/dL. Median survival for stage III patients was 14 months and for stage IV patients was 5.8 months [9]. Within stage III, NT-proBNP >8500 pg/mL combined with a systolic blood pressure <100 mmHg identifies a group of patients with the highest mortality (IIIb).
In AL amyloidosis, changes in NT-proBNP have also been used to predict response to treatment and disease progression (table 2), with a decrease in NT-proBNP of >30 percent and >300 ng/L from a baseline value ≥650 ng/L associated with better prognosis [10].
ATTR amyloidosis — Two staging systems have been proposed in patients with ATTR amyloidosis:
●The first published staging system for ATTRwt is based on serum levels of NT-proBNP and cardiac troponin T [5]. Thresholds of troponin T (0.05 ng/ml) and NT-proBNP (3000 pg/ml) were used. The respective four-year overall survival estimates were 57, 42, and 18 percent for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively.
●The second staging system, validated in both ATTRwt and ATTRm, is based on serum levels of NT-proBNP and estimated glomerular filtration rate (eGFR) [11]. Stage I is defined as NT-proBNP ≤3000 ng/L and eGFR ≥45 mL/min, Stage III is defined as NT-proBNP >3000 ng/L and eGFR <45 mL/min, and the remainder were Stage II. Median survival among Stage I patients was 69.2 months, Stage II patients 46.7 months, and Stage III patients 24.1 months [11].
TREATMENT
General considerations — The treatment of symptomatic cardiac amyloidosis is twofold: therapy for HF and treatment of the underlying disease. Patients with ATTRm or ATTRwt generally respond better to HF therapy than patients with AL amyloidosis. However, there are more therapeutic options for addressing the underlying disease in AL amyloidosis, and if the plasma cell dyscrasia can be controlled, there is often a relatively rapid decrease in serum biomarkers of HF [12].
Heart failure therapy
Approach to heart failure — Treatment of HF in patients with cardiac amyloidosis differs from the therapy generally recommended in patients with diastolic or systolic HF. While loop diuretics are a mainstay of treatment of cardiac amyloidosis, there is no evidence that beta blockers and angiotensin-converting enzyme (ACE) inhibitors are associated with prognostic benefit in cardiac amyloidosis despite their efficacy in other types of systolic HF. Furthermore, they are usually poorly tolerated, especially in AL amyloidosis. Similarly, calcium channel blockers that may be useful in treatment of diastolic HF are contraindicated in amyloid cardiomyopathy. Adverse responses to drugs in cardiac amyloidosis are likely due to its unique pathophysiologic features.
HF in patients with cardiac amyloidosis is secondary to complex pathophysiologic alterations. The pathologic changes that result from extensive amyloid infiltration result in a nondilated normal to small biventricular cavity size, with significant diastolic dysfunction because of decreased compliance. Systolic dysfunction is almost invariably present, and this usually affects first the longitudinal contraction (better assessed with longitudinal strain) and, in later stages, the radial contraction (reduced ejection fraction). In addition, the infiltration of the atria may severely impair atrial contraction, further decreasing ventricular filling. This combination results in a decreased stroke volume and cardiac output and marked elevation of intracardiac pressures with frequent occurrence of functional mitral and tricuspid regurgitation. In addition, there is experimental evidence that excessive circulating free light chains in AL amyloidosis are cardiotoxic, possibly explaining the worse prognosis in cardiac AL amyloidosis compared with ATTR. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Types of amyloidosis'.)
Medical therapy — Loop diuretics are a mainstay of the management of HF. If edema is severe, hospitalization and a course of intravenous diuretics should be strongly considered. This should be accompanied by careful monitoring of blood pressure and renal function, as overvigorous diuresis may result in progressive azotemia. Aldosterone antagonist therapy (eg, spironolactone) in conjunction with loop diuretics is generally tolerated without the development of excessive hypotension.
Although beta blockers reduce morbidity and mortality in patients with systolic HF generally, they have no proven benefit in patients with HF due to cardiac amyloidosis. Indeed, they are poorly tolerated in patients with cardiac amyloidosis in whom cardiac output is dependent on heart rate due to presence of a low, fixed stroke volume.
The safety and efficacy of ACE inhibitors or angiotensin receptor blockers (ARBs) in patients with cardiac amyloidosis is uncertain. There are no clinical trials of ACE inhibitors or ARBs in amyloidosis, but clinical experience has shown that these agents often provoke profound hypotension in AL amyloidosis, possibly by exposing a subclinical autonomic neuropathy. ACE inhibitors and ARBs appear to be better tolerated in patients with ATTRwt amyloidosis, in whom autonomic neuropathy is rare. Tolerability of ACE inhibitors and ARBs in ATTR cardiomyopathy due to a mutant protein depends on the presence or absence of concomitant autonomic dysfunction. If a trial of ACE inhibition is attempted in a patient with AL amyloidosis, initiation should be with a very low dose of captopril with careful blood pressure monitoring and slow, carefully monitored up-titration of the dose if tolerated.
Amyloid fibrils bind to digoxin and this interaction may account for increased susceptibility to digitalis toxicity [13]. Although digoxin has no role in treating HF due to amyloid cardiomyopathy, careful use of digoxin may be of value in a patient with atrial fibrillation and a rapid ventricular response, particularly when hypotension makes beta blocker use untenable [14]. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy".)
Calcium channel blockers such as verapamil or diltiazem that are used to slow heart rate and that may possibly improve ventricular relaxation in diastolic HF (eg, in hypertensive heart disease or hypertrophic cardiomyopathy) have not been proven to be effective in cardiac amyloidosis, and this is probably related to the different mechanism leading to diastolic dysfunction, as the diastolic dysfunction is due to the amyloid and not to myocardial cellular dysfunction. Indeed, these drugs are contraindicated, as their negative inotropic effects may be profound, possibly because of an abnormal binding to amyloid fibrils, and may depress compensatory heart rate responses to low stroke volume and cardiac output [13,15,16].
Heart transplantation and ventricular assist devices — The great majority of patients with cardiac AL amyloidosis have significant noncardiac amyloidosis and are not suitable candidates for heart transplantation. For example, in one series, only 4 percent of patients had clinically isolated cardiac disease [17]. Early experience with cardiac transplantation in AL amyloidosis did not address the importance of a sustained clonal response and, not surprisingly, when the disease relapsed, the disease progressed in other organs and/or returned in the transplanted heart [18,19]. The few major centers that accept patients with AL amyloidosis for cardiac transplantation accept only those who have disease clinically isolated to the heart. Heart transplantation for AL amyloidosis in these centers is followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation within a 12-month period. Long-term follow-up data in these patients are not yet available, but several appear to have had excellent cardiac results and a durable hematologic response [20-24].
Patients with ATTRwt amyloidosis generally have the disease clinically isolated to the heart and as such would appear to be more suitable candidates. However, most patients are diagnosed in their seventh or eighth decade of life and are excluded based on their age. Nevertheless, successful heart transplantation has been carried out in a few patients with ATTRwt amyloidosis who presented at a younger age [25].
Patients with ATTRm cardiac amyloidosis are often younger than ATTRwt patients, and may be candidates for heart transplantation if amyloid neuropathy is absent or mild. However, since the mutant TTR is produced in the liver, most mutations may need a combined liver and heart transplant to prevent recurrence in the transplanted heart. Fourteen patients in a single center in Italy had combined liver-heart transplantation for familial amyloid cardiomyopathy between 1999 and 2012. Actuarial survival at one and five years was 93 and 82 percent, respectively, and the explanted liver was retransplanted into another (nonamyloid) recipient in 8 of 14 cases. No recurrent amyloid was reported in heart-liver recipients [26]. An exception to the requirement of liver transplantation is probably the Val122Ile mutation, common in African-Americans, in which isolated heart transplantation has been performed without documentation of recurrent disease [27].
Ventricular assist devices have been used very infrequently in cardiac amyloidosis, owing to technical difficulties when used in a restrictive cardiomyopathy as well as the presence of coexisting noncardiac amyloidosis [28].
Treatment of atrial fibrillation — If atrial fibrillation with a rapid ventricular response develops in a patient with AL or ATTR amyloidosis, low-dose beta blockade and careful digoxin use may help with rate control (notwithstanding the above concerns about beta blocker and digoxin use in amyloid cardiomyopathy generally). Despite severely impaired atrial contractile function, clinical improvement may occur after restoration of sinus rhythm in a patient with atrial fibrillation of recent onset, possibly due to a regularization of the heart rate. Amiodarone use to maintain sinus rhythm appears to be well tolerated without specific amyloidosis-related side effects. Experience with catheter ablation for atrial arrhythmias in patients with cardiac amyloidosis is limited. Results in 26 patients over two decades indicate symptomatic improvement but without evidence of change in disease-related mortality [29]. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "New onset atrial fibrillation".)
Anticoagulation — Amyloid cardiomyopathy is associated with high risk of intracardiac thrombus, predominantly in the atria [30]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiac involvement'.)
Anticoagulation is indicated if a patient with amyloid develops atrial fibrillation, since the risk of intracardiac thrombus is very high. The role of anticoagulation in patients in sinus rhythm is uncertain. Atrial failure, even in the presence of sinus rhythm, is very common in amyloidosis and is associated with atrial thrombus formation, particularly in patients with AL-type amyloidosis [30-32].
Although amyloidosis is associated with increased hemorrhagic risk due to amyloid angiopathy, intestinal or bladder amyloid, or coagulopathy, major bleeding in anticoagulated patients does not seem to exceed that seen in other patients with similar nonamyloid degrees of illness, so anticoagulation should not be withheld if indicated unless a clear-cut contraindication exists. There are no controlled data on bleeding risk of oral anticoagulants in cardiac amyloidosis, but bleeding has not been found to be excessive, and warfarin or one of the newer oral anticoagulants have been used (oral direct thrombin inhibitor or direct factor Xa inhibitor) without unanticipated problems. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
Conduction disease — Patients with amyloid cardiomyopathy are at risk of conduction system disease with the potential requirement for pacemaker therapy; general indications for cardiac pacing should be applied. (See "Permanent cardiac pacing: Overview of devices and indications".)
Implantable cardioverter-defibrillator — The efficacy of implantable cardioverter-defibrillator (ICD) therapy in patients with cardiac amyloidosis is uncertain. Sudden cardiac death (SCD) is common in patients with cardiac AL amyloidosis and prophylactic ICDs have been suggested as an option to reduce this risk. However, electromechanical dissociation appears to be a significant cause of SCD in these patients, so the role of ICD therapy in preventing SCD in this population is unclear.
This issue was illustrated by a study in which 19 cardiac AL amyloidosis patients with history of syncope (n = 4) or high-grade ventricular arrhythmias (n = 10), or both (n = 5) received an ICD [33]. Two subsequently underwent cardiac transplant, and one died of an unrelated disease. There were six cardiac deaths, all sudden despite the ICD. One patient received appropriate shocks but later died of electromechanical dissociation, which was also the cause of death in the other five. Only one patient received appropriate ICD shocks with long-term survival.
Similar findings were reported in a retrospective analysis of a cohort of 53 patients with amyloid cardiomyopathy (33 with cardiac AL amyloidosis confirmed by endomyocardial biopsy) who had undergone ICD implantation (77 percent for primary prevention) at a single center between 2000 and 2009 [34]. Over a mean follow-up of 23 months, 15 patients (12 with cardiac AL amyloidosis) received at least one appropriate ICD shock, with none of these shocks occurring in patients who received the ICD strictly for primary prevention due to a reduced left ventricular ejection fraction. However, there was no significant difference in survival between patients who received an appropriate ICD shock and those who did not receive ICD shock.
Thus, the limited available clinical data do not support use of ICDs for primary prevention of SCD in patients with cardiac amyloidosis of any etiology. In the patient with cardiac amyloidosis who is resuscitated from a life-threatening ventricular arrhythmia, implantation of an ICD should be considered.
TREATMENT OF THE UNDERLYING PROTEIN MISFOLDING DISORDER — Treatment of the underlying protein misfolding disorder varies with the cause of excess fibril production.
Specific therapy for AL amyloidosis — As discussed in detail separately, survival in patients with AL amyloidosis varies with the extent of organ involvement, and median survival is as short as four to six months in those with HF (see "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Prognosis' and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis"). However, with earlier diagnosis, careful patient selection, and use of currently available chemotherapeutic regimens, survival can be significantly prolonged [12]. The available medical regimens are discussed separately, but the basic principles will be reviewed here. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
In general, therapy involves the administration of chemotherapy and/or autologous stem cell transplantation (ASCT) in an attempt to treat the underlying plasma cell clone responsible for AL amyloid formation. The goal of therapy in patients with cardiac involvement is to achieve a 90 percent or greater reduction in serum free light chain levels, but not all patients may be able to attain this level of response. The intensity and type of therapy chosen is affected by the number and extent of organ involvement. The most common initial chemotherapy regimens used are now bortezomib-based regimens such as daratumumab, cyclophosphamide, bortezomib, dexamethasone (dara-CyBorD) or cyclophosphamide, bortezomib, dexamethasone (CyBorD). For patients who are candidates for stem cell transplantation, ASCT involves administration of high-dose melphalan followed by stem cell rescue. The risk of treatment-related mortality associated with ASCT in AL amyloidosis restricts the use of this procedure to a small group of selected patients.
New York Heart Association (NYHA) functional class III or IV HF is generally considered a contraindication to ASCT in patients with AL amyloidosis. These patients have also been classified as stage III AL amyloidosis (table 1). (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
The prognosis of such individuals, who have been excluded from many of the clinical therapeutic studies, was evaluated in a study of 346 Stage III patients treated with standard chemotherapeutic regimens. The median survival was seven months, with 24 percent surviving until 24 months [35]. The overall hematologic response rate was 33 percent, including a complete response rate of 12 percent. N-terminal pro-B-type natriuretic peptide (NT-proBNP) >8500 ng/L and systolic blood pressure <100 mmHg predicted a poor outcome. However, these patients were treated before the widespread use of bortezomib, and it is likely that current regimens are superior in terms of survival [36].
Specific therapy for ATTR amyloidosis — For ATTR cardiomyopathy, options include:
●For patients with ATTR cardiomyopathy with NYHA functional class I to III, we recommend treatment with tafamidis. In this population, a randomized trial found that tafamidis therapy reduced mortality as well as cardiovascular-related hospitalizations, and reduced declines in functional capacity and quality of life [37]. (See 'Tafamidis' below.)
●In addition, patients diagnosed with ATTRm cardiomyopathy should undergo evaluation for liver transplantation, as this can be curative in selected patients with ATTRm but not in ATTRwt, as discussed below.
Tafamidis — The multicenter randomized ATTR-ACT trial demonstrated that tafamidis is an effective therapy for patients with ATTR cardiomyopathy [37]. Tafamidis stabilizes the transthyretin tetramer and may thus reduce formation of TTR amyloid [38,39]. In the ATTR-ACT trial, 441 patients with ATTR (variant or wild-type) amyloid cardiomyopathy were randomly assigned in a 2:1:2 ratio to receive tafamidis 80 mg, tafamidis 20 mg, or placebo once daily for 30 months [37]. Exclusion criteria included NYHA functional class IV HF or an estimated glomerular filtration rate less than 25 mL per minute per 1.73 m2 of body-surface area. Tafamidis reduced mortality compared with placebo (29.5 versus 42.9 percent; hazard ratio 0.70, 95% CI 0.51-0.96) and also reduced cardiovascular-related hospitalizations (0.48 versus 0.70 per year; risk ratio 0.68, 95% CI 0.56-0.81). Tafamidis also reduced the rate of decline in six-minute walk distance and Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS). The incidence of adverse events was similar in the tafamidis and placebo groups.
Consistent effects on mortality and cardiovascular hospitalization were observed across subgroups of TTR type, tafamidis dose, and NYHA functional class at baseline, except for patients with NYHA class III at baseline, for whom the risk of cardiovascular-related hospitalization was higher with tafamidis. This finding may be due to longer survival in severely symptomatic patients.
The US Food and Drug Administration (FDA) approved doses and formulations of tafamidis for amyloid cardiomyopathy are an 80 mg daily dose of tafamidis meglumine (Vyndaqel) for amyloid cardiomyopathy, or alternatively, a 61 mg daily dose of tafamidis (Vyndamax). The 80 mg dose of tafamidis meglumine was approved by the FDA because a pooled analysis of 11 studies found that ex vivo stabilization of transthyretin tetramers was greater with the 80 mg dose than with the 20 mg dose, and safety results were similar for the two doses [40]; the clinical significance of this surrogate endpoint is uncertain.
Liver transplantation — In ATTR amyloidosis, the source of the amyloidogenic protein is the liver. Transplantation of the liver removes the mutant amyloidogenic TTR in ATTRm, but in ATTRwt the precursor protein is native TTR, and thus liver transplantation is not indicated. Unfortunately, cardiac disease has progressed after liver transplantation in some patients with familial ATTR, even though deposits elsewhere may stabilize [41]. Examination of the composition of TTR in the heart of patients with progressive cardiomyopathy after liver transplantation reveals that the mechanism is enhanced deposition of wild-type TTR on a template of amyloid derived from variant TTR. Patients with advanced heart disease may be treated with combined heart and liver transplantation [42].
Once a patient with a transthyretin mutation is found to have a positive biopsy for amyloid, he or she should undergo evaluation for liver transplantation, with the goal to receive the transplant as early in the disease as possible. If an amyloid cardiomyopathy is present with significant HF, isolated liver transplantation is contraindicated and consideration should be given to a combined liver-heart transplant or just heart alone.
This appears to be particularly true in patients with the Ala60 mutation in whom cardiomyopathy is almost always present and in whom liver transplant alone does not stop progressive cardiomyopathy [43].
Investigational agents — Several investigational agents for ATTR amyloidosis are in active trials, but effects on cardiovascular outcomes have not been established. RNA-targeted therapies that interfere with hepatic TTR synthesis and thus reduce the availability of misfolded monomer to form amyloid deposits include patisiran and inotersen, which are discussed further separately (see "Overview of amyloidosis", section on 'Treatment'):
●Patisiran is an anti-TTR small interfering ribonucleic acid (siRNA) formulation of lipid nanoparticles. A randomized trial comparing patisiran with placebo in patients with ATTRm amyloidosis with polyneuropathy found that patisiran significantly reduced symptoms and impairment from neuropathy and improved quality of life [44]. In a cardiac subgroup, patisiran significantly reduced NT-proBNP levels and LV wall thickness and reduced worsening of longitudinal strain. The drug was generally well tolerated.
●Inotersen is an antisense oligonucleotide construct that inhibits hepatic production of TTR. A randomized trial comparing inotersen with placebo found that inotersen significantly reduced symptoms and impairment from neuropathy and improved quality of life [45]. The most frequent serious adverse events were glomerulonephritis and severe thrombocytopenia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac amyloidosis" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: AL amyloidosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The treatment of symptomatic cardiac amyloidosis is twofold: therapy for heart failure (HF) and treatment of the underlying disease. (See 'General considerations' above.)
●Treatment of HF in patients with cardiac amyloidosis differs from the therapy generally recommended in patients with diastolic or systolic HF. While loop diuretics are a mainstay of treatment of cardiac amyloidosis, beta blockers and angiotensin-converting enzyme inhibitors are often not tolerated despite their efficacy in other types of systolic HF. Similarly, calcium channel blockers that may be useful in treatment of diastolic HF are contraindicated in amyloid cardiomyopathy. (See 'Heart failure therapy' above.)
●Anticoagulation is recommended in patients with amyloid cardiomyopathy with atrial fibrillation, intracardiac thrombi, or an embolic event. (See 'Anticoagulation' above.)
●The efficacy of implantable cardioverter-defibrillator therapy in patients with severe cardiac amyloidosis is unclear. (See 'Implantable cardioverter-defibrillator' above.)
●The main treatment option in patients with light-chain (AL) amyloidosis is chemotherapy. A variety of regimens are used, including high-dose melphalan with autologous hematopoietic stem cell transplantation. Bortezomib-based regimens are first-line therapy for most patients who are not candidates for hematopoietic stem cell transplantation, even in patients with advanced cardiac disease (New York Heart Association [NYHA] functional class III or IV) (table 3). (See 'Specific therapy for AL amyloidosis' above.)
●For transthyretin amyloidosis (ATTR) cardiomyopathy, options include (see 'Specific therapy for ATTR amyloidosis' above):
•For patients with ATTR cardiomyopathy with NYHA functional class I to III, we recommend treatment with tafamidis (Grade 1B). In this population, a randomized trial found that tafamidis therapy reduced mortality as well as cardiovascular-related hospitalizations, and reduced declines in functional capacity and quality of life. (See 'Tafamidis' above.)
•In addition, patients diagnosed with familial ATTR (ATTRm) cardiomyopathy should undergo evaluation for liver transplantation, as this can be curative in selected patients with ATTRm but not in those with wild-type ATTR (ATTRwt) amyloidosis. However, cardiac disease has progressed after liver transplantation in some patients with ATTRm. Patients with advanced heart disease with ATTRm may be treated with combined heart and liver transplantation. (See 'Liver transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledge Rodney H Falk, MD, who contributed to earlier versions of this topic review.
