Treatment of Cardiac Transthyretin Amyloidosis: An Update

Michele Emdin; Alberto Aimo; Claudio Rapezzi; Marianna Fontana; Federico Perfetto; Petar M. Seferović; Andrea Barison; Vincenzo Castiglione; Giuseppe Vergaro; Alberto Giannoni; Claudio Passino; Giampaolo Merlini


Eur Heart J. 2019;40(45):3699-3706. 

In This Article

Abstract and Introduction


Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.


Transthyretin (TTR) is a highly conserved protein involved in transportation of thyroxine (T4) and retinol-binding protein. TTR is synthesized mostly by the liver and is rich in beta strands with an intrinsic propensity to aggregate into insoluble amyloid fibres.[1] Fibrillogenesis requires the dissociation of TTR homotetrameric structure into misfolded monomers that self-assemble in soluble oligomeric species, presumably amyloid fibril precursors, which seem to exert significant cytotoxic effects in tissues.[2] Afterwards, oligomers aggregate into protofibrils and finally mature amyloid fibres, which deposit within tissue leading to the development of TTR-related amyloidosis (ATTR).[1]

ATTR can follow the deposition of either variant TTR (ATTRv, previously known as mutant ATTR)[3] or wild type TTR (ATTRwt). Single base substitutions resulting in missense mutations represent the majority of the genetic alterations in ATTRv.[4] More than 120 pathogenic mutations in the TTR gene have been described, resulting in a variable phenotypic presentation, ranging from pure polyneuropathy with autonomic dysfunction, to mixed neurological and cardiac presentation, and to selective cardiac involvement.[4] The variant most commonly associated to cardiomyopathy is V122I, which is found in 3.4% of African Americans.[5] Outside the US, the V30M is the most frequent pathogenetic variant, with the phenotype varying by region.[4] V30M is the most common TTR variant in patients with ATTRv with polyneuropathy, especially in endemic areas in Portugal, South America, Sweden, and Japan. In endemic areas, the disease may present as an early-onset (<50 years), rapidly progressive polyneuropathy, while in other regions it occurs as an isolated progressive polyneuropathy, apparently sporadic in elderly patients, frequently with a predominant cardiomyopathy.[6] Other variants affecting primarily the heart are T60A, L111M, and I68L.[4]

Accurate statistics on the prevalence of ATTRv are difficult to obtain. Among Americans of European descent, it has an estimated incidence of 0.4 per million people/year, while this condition is believed to be more common among people with African ancestry and in specific geographic areas, such as northern Portugal or some regions of West Africa.[4] Conversely, ATTRwt is a sporadic disorder with no specific biomarkers for its diagnosis, and most often affecting aged men (around 80% of cases).[4] An autopsy study reported amyloid deposition in 25% of patients older than 85 years,[7] although the clinical relevance of such deposits is undetermined, and it is reasonable to assume that only severe and widespread amyloid accumulation can produce disease manifestations by itself.

Cardiac ATTR should be searched in patients symptomatic for heart failure (HF), syncope, or bradyarrhythmia, with imaging findings suggestive of cardiac amyloidosis. In endemic areas, in patients with a positive family history, the diagnostic process is facilitated by the prototypic clinical presentation and the detection of the TTR variant, while the diagnosis is usually delayed in patients who have no family history. The presence of cardiac abnormalities including intracardiac conduction disorders, symptoms of dysautonomia, ruptured distal biceps tendon and carpal tunnel syndrome should suggest the diagnosis of ATTR amyloidosis. Cardiac involvement may manifest with left ventricular (LV) pseudohypertrophy and/or overt HF with preserved ejection fraction, possibly accompanied by conduction disturbances or arrhythmias. ATTR cardiomyopathy should be differentiated from ventricular hypertrophy secondary to pressure or volume overload, as well as from primary hypertrophy due to sarcomere gene mutations, other infiltrative conditions, or other aetiologies.[8] Cardiac ATTR should be considered in all patients who have LV wall thickening, especially when QRS voltages are normal or low and the LV is not enlarged; the likelihood of diagnosis increases when cardiac biomarkers (troponins and/or natriuretic peptides) are increased, and symptoms or history of peripheral or autonomic neuropathy coexist.[9,10] The diagnosis can be made either through the demonstration of TTR amyloid deposits on the endomyocardial biopsy or following a non-invasive algorithm in patients with no evidence of a monoclonal protein, where diphosphonate scintigraphy with 99mTc-labelled radiotracers play a central role[11] (Figure 1).

Figure 1.

Diagnostic algorithm for cardiac transthyretin amyloidosis. Dashed line indicates a suggested, non-mandatory step. AL, amyloid light-chain amyloidosis; ATTR, amyloid transthyretin amyloidosis (ATTRv, variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis); CMR, cardiac magnetic resonance; HF, heart failure. Modified from Gillmore et al.11

Cardiac ATTR has a favourable survival rate compared to light chain (AL) amyloidosis, with a median survival of 75 vs. 11 months.[9,10] On the other hand, ATTR cardiomyopathy is a progressive disorder with very limited therapeutic options until very recently. This field is rapidly evolving, with the positive results of a phase 3 trial on tafamidis,[12] and preliminary findings on patisiran[13] and inotersen[14] in patients with ATTR-related neuropathy and cardiac involvement, warranting a dedicated review.