Hereditary transthyretin amyloidosis (ATTRv) is characterized by the deposition of amyloid fibrils in different organs, mainly the heart and the somatic and autonomic peripheral nervous systems.1 Variants in the gene encoding transthyretin (TTR) are inherited in an autosomal dominant pattern and heterozygous carriers produce a mixture of variant and wild-type TTR. Mutated TTR is prone to destabilization of the tetrameric structure with consequent dissociation into monomers, misfolding and formation of amyloid fibril aggregates.2 The p.Val50Met variant (previously designated Val30Met) is the best-known TTR gene mutation, and is the most common variant in Europe, South America, and Japan.3 In Portugal, there is an endemic focus of the p.Val50Met variant and the mean incidence rate of ATTRv amyloidosis due to this variant reaches 0.87/100000 (95% confidence interval [CI]: 0.68–1.10), which corresponds to 71 new patients per year in the country. In 2016, the prevalence of ATTRv amyloidosis due to the p.Val50Met variant in Portugal was 22.93/100000 adult individuals (95% CI: 21.90–23.99).4

Orthotopic liver transplantation (OLT) was the first available treatment for ATTRv amyloidosis, eliminating production of the amyloidogenic mutated TTR. However, after OLT, some patients still develop cardiac amyloidosis due to the continued deposition of wild-type TTR amyloid fibrils in the heart.5

In recent years, several targeted disease-specific therapies have been developed and included in the armamentarium for the management of the disease.6 However, post-OLT patients were excluded from clinical trials on these therapies,7–9 which made an argument for the controversy on the use of specific treatment to patients with post-OLT cardiac amyloidosis. As a result, there are now several patients with ATTRv amyloidosis in Portugal with post-OLT cardiac amyloidosis, for whom a targeted disease-specific therapy is not available.

Considering this to be an important issue in the management of Portuguese ATTRv amyloidosis patients and in order to make access to treatment more uniform in the country, the Working Group on Myocardial and Pericardial Diseases of the Portuguese Society of Cardiology and the heads of the two national reference centers for familial amyloidosis wrote the present position statement, which addresses the diagnosis and treatment of post-OLT cardiac amyloidosis in patients with ATTRv amyloidosis.

In ATTRv amyloidosis, cardiac involvement is more severe in patients with type A fibrils (a mixture of full-length and fragmented short haphazard and weakly congophilic fibrils) than in those with type B fibrils (full-length long parallel and highly congophilic fibrils).10,11 As patients with late-onset V50M disease mainly present type A fibrils, cardiac involvement is more common and more severe in these patients than in those with the early-onset V50M phenotype, who present mainly type B fibrils.11–14

After OLT, pre-existing amyloid deposits of mutated TTR act as a substrate, priming new deposits of wild-type TTR in various organs, including the kidneys and nerves, but preferentially the heart.15 Post-OLT cardiac amyloidosis is thus more frequent in patients with pre-existing cardiac involvement, i.e., those with type A fibrils and with late-onset V50M disease.11,16 Furthermore, wild-type fibrils seem to be more easily incorporated in type A than in type B fibrils and liver transplantation may accelerate this cardiac amyloidosis process, as it provides a greater quantity of wild-type amyloid fibrils.6 Cardiac events, mainly end-stage heart failure but also sudden death, are the main cause of death in ATTRv amyloidosis patients after the year following OLT, accounting for about 38% of all deaths in follow-up.17

To aid the early diagnosis of post-OLT cardiac amyloidosis in ATTRv amyloidosis patients, periodic cardiac evaluation is advisable, based on clinical assessment, electrocardiogram (ECG), echocardiogram, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin levels, and Holter monitoring.18

If cardiac amyloidosis is suspected, single-photon emission computed tomography (SPECT) with 99mtechnetium (99mTc)-pyrophosphate (PYP), 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) or hydroxymethylene diphosphonate (HMDP) scintigraphy should be performed, and clonal dyscrasia should be excluded by performing serum free light chain assay and serum and urine protein immunofixation.19,20 In patients with the p.Val50Met variant, scintigraphy may not show myocardial radiotracer uptake, especially in patients with early-onset disease, because they present mainly type B fibrils, which produce false negative results on scintigraphy.21 In such cases, an endomyocardial biopsy should be performed to confirm the presence of TTR amyloid fibrils19,20,22,23 (Figure 1).

Figure 1.

Diagnosis and monitoring of cardiac amyloidosis in patients with hereditary transthyretin amyloidosis after orthotopic liver transplantation. CMR: cardiac magnetic resonance; DPD: 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid; ECV: extracellular volume; EQ-5D: five-dimension EuroQol instrument; HF: heart failure; HMDP: 99mtechnetium-hydroxymethylene diphosphonate; KCCQ: Kansas City Cardiomyopathy Questionnaire; LS: longitudinal strain; LV: left ventricular; 6MWT: six-minute walk test; NAC: UK National Amyloidosis Centre score; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; OLT: orthotopic liver transplantation; PYP: 99mtechnetium pyrophosphate; SPECT: single-photon emission computed tomography; SSFP: steady-state free precession; TTR: transthyretin; ULN: upper limit of normal.

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Cardiac magnetic resonance imaging plays a less important role in the diagnosis of cardiac amyloidosis, although it could be useful to determine the amyloid burden at baseline.23,24

Table 1 summarizes imaging findings suggestive of cardiac amyloidosis.

Post-OLT cardiac amyloidosis should be monitored based on clinical evaluation (including New York Heart Association [NYHA] class and cardiovascular hospitalizations), ECG, six-minute walk test (6MWT), NT-proBNP and troponin levels, and quality of life by the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score every six months, and echocardiogram and 24-hour Holter every year, in stable patients.22,25,26

Cardiac magnetic resonance may also be useful for quantifying amyloid burden and monitoring response to therapy.27,28 Furthermore, a change in cardiac tracer uptake on bone scintigraphy also appears to be a marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.29

The following signs have been proposed as criteria of cardiac disease progression: increase in NT-proBNP ≥30% and ≥300 ng/l; decrease in distance walked on the 6MWT; appearance of a restrictive transmitral filling pattern; and appearance or increase of pericardial effusion.30 More recently, a European expert consensus defined cardiac disease progression as the presence of at least one criterion of cardiac disease progression in each of three domains: a clinical and functional domain; a laboratory domain; and an imaging and ECG domain. The clinical and functional domain includes an increase in NYHA class, worsening indicated by any hospitalization related to HF decompensation, a decrease of 5–10 points in KCCQ score or of 10% on the five-dimension EuroQol instrument (EQ-5D), and a decrease in 6MWT distance of 30–40 m every six months. The laboratory domain, besides an increase in NT-proBNP of ≥30% and ≥300 pg/ml, also includes a ≥30% increase in troponin level and an advance in the UK National Amyloidosis Centre (NAC) staging score. The imaging and ECG domain includes echocardiographic parameters (≥2 mm increase in left ventricular [LV] wall thickness, increase in diastolic dysfunction grade, ≥5% decrease in LV ejection fraction, ≥5 ml decrease in stroke volume, and ≥1% increase in LV global longitudinal strain) and new-onset conduction abnormalities25 (Figure 1).

In Europe, based on current evidence, two formulations of tafamidis have been approved for ATTR amyloidosis: tafamidis 20 mg (tafamidis meglumine) for the treatment of adult patients with polyneuropathy in stage 1 related to ATTRv amyloidosis, and tafamidis 61 mg (equivalent to oral tafamidis meglumine 80 mg) for the treatment of cardiomyopathy related to ATTR amyloidosis, either variant or wild-type.

Patisiran is approved for the treatment of adult patients with ATTRv amyloidosis and stage 1 or 2 polyneuropathy (with or without cardiomyopathy). Vutrisiran is approved for the treatment of adult patients with ATTRv amyloidosis and stage 1 or 2 polyneuropathy.

Inotersen is approved for the treatment of adult patients with ATTRv amyloidosis and stage 1 or 2 polyneuropathy.

In view of the results of the above-mentioned phase 3 trials for ATTR cardiomyopathy, which included patients with ATTRv and ATTRwt, and taking into consideration that the progression of cardiac disease after OLT is secondary to deposition of wild-type fibrils, it may be postulated that well-tested targeted disease-specific therapy is potentially beneficial in this subset of patients.

Considering the poor prognosis conferred by cardiac disease progression and the favorable safety profile of these therapies, this Task Force recommends that targeted disease-specific therapy with documented benefit in ATTR cardiomyopathy should be considered in ATTRv amyloidosis patients with evidence of symptomatic cardiac involvement or progression after OLT, as its pathophysiology is similar to wild-type TTR cardiac amyloidosis, for which there is robust evidence of reductions in mortality and heart failure hospitalizations, and benefit in functional capacity and quality of life.7,9,52

Targeted disease-specific therapy should be considered in patients with an established diagnosis of post-OLT cardiac amyloidosis and at least one of the following criteria:

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  Clinical evidence of heart failure (with or without hospitalization) manifested by signs or symptoms of volume overload or elevated intracardiac pressures requiring treatment with a diuretic

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  NYHA functional class II or III

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  NT-proBNP level ≥500 pg/ml

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  Progressive cardiac conduction abnormalities or pacemaker implantation due to cardiac conduction abnormalities

Patients with the following characteristics are not candidates for this therapeutic approach:

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  NYHA functional class IV

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  Functional capacity <100 m on 6MWT (except if considered secondary to neuropathy and not cardiomyopathy)

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  Estimated life expectancy less than one year

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  Advanced dementia

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  Pregnancy and breastfeeding

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  Lack of therapeutic compliance

Periodic follow-up assessments should be performed by a multidisciplinary team to cover the wide range of manifestations of disease progression due to the continued deposition of wild-type TTR after OLT (Figure 2). At a minimum, this team should consist of a neurologist, a cardiologist and an ophthalmologist. Other specialists, including geneticists, gastroenterologists, nutritionists, physical therapists, nephrologists, and urologists, should be consulted as needed.53–55

Figure 2.

Targeted disease-specific therapy for patients with hereditary transthyretin amyloidosis and post-orthotopic liver transplantation cardiac amyloidosis. ATTRv: hereditary transthyretin amyloidosis; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; OLT: orthotopic liver transplantation; TTR: transthyretin.

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Patients in whom post-OLT cardiac amyloidosis is suspected or diagnosed can be followed at the nearest center with a dedicated cardiomyopathy clinic, in close communication with the reference center. The decision to start targeted disease-specific therapy in post-OLT cardiac amyloidosis should be a shared decision process with the involvement of the patient, the cardiologist specialized in Cardiomyopathies who follows the patient at the nearest center and the remaining multidisciplinary team of the Reference Center. Dispensation of oral medication or administration of intravenous medication should take place at the nearest center with a dedicated cardiomyopathy clinic, in order to simplify and improve patient care.

Cardiac assessment and follow-up of patients with post-OLT cardiac amyloidosis receiving targeted disease-specific therapy should also be performed in the nearest center with a dedicated cardiomyopathy clinic, in close communication with the reference center. Likewise, the decision whether to discontinue therapy should also be shared between the patient, the cardiomyopathy specialist following the patient at the nearest center, and the multidisciplinary team at the reference center.

Figure 3 summarizes the evaluation and follow-up of patients with post-OLT cardiac amyloidosis in the first year of targeted disease-specific therapy.

Figure 3.

Evaluation and follow-up of patients with post-orthotopic liver transplantation cardiac amyloidosis undergoing targeted disease-specific therapy. Laboratory tests should include hemogram, biochemistry (including renal and hepatic function), troponin, and NT-proBNP. 6MWT: six-minute walk test; CMR: cardiac magnetic resonance; KCCQ: Kansas City Cardiomyopathy Questionnaire.

a The frequency of follow-up may be adjusted in accordance with clinical status.

b In patients without cardiac devices.

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After the first year of treatment, surveillance should also be adapted on an individual basis, according to the patient's clinical course, but a biannual evaluation, as the one presented in figure 2 for the 6 and 12 months, may be appropriate. Other complementary tests may be used, depending on local availability and clinical indications.

A significant number of patients with ATTRv amyloidosis due to the p.Val50Met variant develop post-OLT cardiac amyloidosis, which constitutes the main cause of death in these patients. Targeted disease-specific therapy should be considered in symptomatic patients with an established diagnosis of post-OLT cardiac amyloidosis. Follow-up should be performed by a multidisciplinary team consisting of a cardiologist specializing in cardiomyopathies and the reference center team.

This article is part of a supplement entitled ‘Portuguese WGMPD Recommendations and consensus documents on Transthyretin Amyloidotic Cardiomyopathy’ which is sponsored by Grupo de Estudo de Doenças do Miocárdio e do Pericárdio da Sociedade Portuguesa de Cardiologia - Portuguese Society of Cardiology Working Group on Myocardial and Pericardial Diseases.