Transthyretin amyloidosis (ATTR) is a systemic disease resulting in a diverse number of conditions such as carpal tunnel syndrome (CTS), polyneuropathy, and restrictive cardiomyopathy. While they may seem unrelated, when it comes to ATTR, they are all connected by the deposition of amyloid fibrils in the affected organs and tissues.

Cuddy SAM, Falk RH. Amyloidosis as a systemic disease in context. Can J Cardiol. 2020;36(3):396–407.

 

 

ATTR cardiomyopathy

 

ATTR-CM is a restrictive cardiomyopathy caused by extracellular deposition of amyloid fibrils in the myocardium. In addition to causing a restrictive physiology, these fibrils disrupt the conduction system.

Di Lisi D, Di Stefano V, Brighina F, et al. Therapy of ATTR cardiac amyloidosis: current indications. Curr Probl Cardiol. 2023;48(2):101487.

 

Awareness of noncardiac manifestations, such as CTS, tendon ruptures, and polyneuropathy, may aid in raising diagnostic suspicion when a patient presents with cardiac symptoms.

For example, a history of CTS and biceps tendon rupture in a patient with symptoms of HF, especially if a restrictive cardiomyopathy is confirmed, should prompt suspicion of ATTR-CM, bringing it to the top of the differential diagnosis.

 

Current and emerging therapies for ATTR-CM

 

The last decade has witnessed significant advances in disease-modifying therapies for systemic ATTR and ATTR-CM. 

Currently available therapies include native transthyretin (TTR) stabilizers, RNA-interfering agents, and antisense oligonucleotides (ASOs). 

Treatment selection may depend upon classification by genetic testing of either wild-type (wtATTR) or hereditary (hATTR) amyloidosis, as well as by affected organ system.

Aimo A, Castiglione V, Rapezzi C, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. 2022;19(10):655–667.

 

 

Small interfering RNA agents like patisiran, along with ASOs such as inotersen and eplontersen, have been found to be highly effective inhibitors of hepatic TTR synthesis. Initially utilized for the treatment of ATTR polyneuropathy, phase 3 trials have also found these drugs to be superior to placebo in improving quality of life and functional capacity in patients with ATTR-CM.

Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553–1565.

 

Additional new agents are in the pipeline as well. An emerging TTR stabilizer, acoramidis, was found in a 2024 phase 3 trial to result in significant improvements in mortality, morbidity, and function in patients with ATTR-CM.

Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med. 2024;390(2):132-142.

 

 

Patient monitoring

 

In 2021, an international expert consensus report issued recommendations for monitoring the course of ATTR with measurable features across three domains:

Garcia-Pavia P, Bengel F, Brito D, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J Heart Fail. 2021;23(6):895–905.

 

 

1. Clinical and functional endpoints

2. Biomarkers and laboratory markers, and 

3. Imaging and electrocardiographic markers.

 

A brighter future

 

The emergence of disease-modifying therapies for ATTR-CM represents a pivotal advancement in treatment and management, and therefore an improved prognosis for patients with ATTR.  

The key is initiating treatment in the early stages of the disease, before severe, irreversible organ damage and advanced HF occur.

Ongoing research to optimize treatment strategies and uncover further novel agents promises to build on recent progress. With increased awareness, early diagnosis, and appropriate therapy, the future looks brighter for patients with ATTR-CM.