Cardiovasc Prev Pharmacother.  2021 Jan;3(1):1-9. 10.36011/cpp.2021.3.e1.

Tafamidis for Cardiac Transthyretin Amyloidosis

• Kim D
• Choi JO
• Jeon ES

• KMID: 2536946
• DOI: http://doi.org/10.36011/cpp.2021.3.e1

Abstract

Transthyretin amyloid (ATTR) cardiomyopathy is a progressive disease caused by the infiltration of ATTR fibrils in the myocardium. Although it is a rare disease, ATTR cardiomyopathy is an important cause of heart failure with preserved ejection fraction, and its incidence is increasing due to improved diagnostic imaging tools. There has been a breakthrough in the field of transthyretin amyloidosis, which opens a new therapeutic door for the patients. In this review, an overview of tafamidis therapy in ATTR cardiomyopathy with recent results from clinical trials will be discussed.

Keyword

Amyloid; Cardiomyopathy; Restrictive; Tafamidis

Figure

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  Figure 1. Schematic diagram of TTR amyloidogenesis. Each monomer consists of 127 amino acids with 1 alpha helix and 8 beta strands. Tetrameric TTR protein has 2 binding sites in a central channel called the T4 pocket; however, the T4 hormone preferentially binds to only 1 of the 2 sites. Stability of TTR tetramers is reduced by mutation or aging processes. As a result, TTR tetramers dissociate into dimeric or monomeric forms. Unstabilized monomers undergo misfolding and aggregation, forming amyloid fibrils.ATTR = transthyretin amyloidosis; TTR = transthyretin.

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  Figure 2. Clinical features of ATTR cardiomyopathy. A 47-year-old man visited the cardiology clinic complaining of dyspnea on exertion and bilateral pitting edema. The jugular vein was prominent. He had undergone surgery for bilateral carpal tunnel syndrome 3 years ago. He also complained of frequent episodes of diarrhea. The electrocardiography showed a pseudo-infarct pattern (A) and N-terminal prohormone brain natriuretic peptide was 3,600 pg/mL. Transthoracic echocardiography showed a thickened myocardium (15 mm at the septum), a relatively small left ventricle (end-diastolic dimension 45 mm), decreased e′ velocity (4.2 cm/s) with apical sparing of longitudinal strain (B-E). Cardiac magnetic resonance imaging revealed multifocal late gadolinium enhancement with subendocardial ring enhancement (F, G) Tc-99m-3,3-diphosphono-1,2-propanodicarboxylic acid scan showed grade 3 cardiac uptake with increased radioactive uptake in the gastrointestinal tract as well (H). Gene analysis was performed, and Asp58Val mutation was discovered. He was diagnosed with ATTR with involvement of the heart, gastrointestinal tract, and peripheral nerves.ATTR = transthyretin amyloidosis.

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  Figure 3. Molecular structure of tafamidis.14)

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  Figure 4. Clinical outcome in ATTR-ACT trial (modifications of Figures 2 and 4 from 20)) Reduction of all-cause mortality as well as reduction of functional decline was noted in patients treated with tafamidis when compared to those who received placebo.KCCQ-OS = Kansas City Cardiomyopathy Questionnaire–Overall Summary.

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