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Cardio advancements: Improving outcomes in ATTR-CM

MDlinx Feb 29, 2024

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.


Until relatively recently, no effective treatment existed for ATTR. This was particularly true for ATTR cardiac amyloidosis with cardiomyopathy (ATTR-CM), the development of which has traditionally portended a poor prognosis. However, new and emerging therapies are finally offering a path forward in the management of ATTR.


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.


ATTR has an extremely poor prognosis in the absence of early treatment. In order to initiate early treatment, however, cardiologists must recognize the early signs and symptoms of ATTR and ATTR-CM, which are an under-recognized cause of heart failure (HF) in older patients, particularly in minority populations.

Ruberg FL, Blaner WS, Chiuzan C, et al. Design and rationale of the SCAN-MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study. J Am Heart Assoc. 2023;12(8):e028534.



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.



In a recent study of tafamidis (a TTR stabilizer) in patients with ATTR-CM, patients who received tafamidis as their initial treatment had significantly better survival at a median follow-up of 58.5 months than those who were first treated with placebo. The study authors concluded that this highlighted the “importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy.”

Elliott P, Drachman BM, Gottlieb SS, et al. Long-term survival with tafamidis in patients with transthyretin amyloid cardiomyopathy. Circ Heart Fail. 2022;15(1):e008193.


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.

To meet minimum requirements for assessing disease progression, at least one marker is needed from each of the three domains.


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.

What this means for you

As a cardiologist, being able to recognize the early signs and symptoms of ATTR-CM is imperative, as early diagnosis and treatment initiation are key to optimizing patient outcomes. Maintain a high index of suspicion for ATTR-CM, especially in older patients presenting with HF, particularly those with a history of CTS, tendon ruptures, or neuropathy. Confirming a restrictive cardiomyopathy on evaluation should prompt consideration of ATTR-CM as a leading differential diagnosis. Advanced cardiac imaging modalities should be used to aid in diagnosis when indicated. Stay up-to-date on the latest approved and emerging therapies for ATTR-CM to provide your patients with the best opportunity for prolonged survival and improved quality of life. 


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