A recently published review in Trends in Cardiovascular Medicine summarized the advances in transthyretin amyloid cardiomyopathy (ATTR-CM) screening, diagnosis and treatment in the last decade and analyzed future perspectives.
“Increasing awareness, combined with the emergence of a growing blend of new
screening, diagnostic, and therapeutic modalities, has reshaped care for patients living with ATTR-CM,” the study’s authors noted.
A decade ago ATTR-CM was a severely underdiagnosed disease with no specific treatment and an abysmal prognosis. Thanks to medical research in the last 10 years, ATTR-CM is now understood as an important cause of heart failure and has specific treatments proven to increase patients’ longevity and quality of life. The study’s authors aimed to describe the medical advances responsible for this paradigm shift.
Advances in screening and diagnosis
Because disease-modifying treatments that perform better at early stages of the disease are now available, cardiological societies around the world are emphasizing the need for increased disease awareness and screening for ATTR-CM.
Read more about prognosis of ATTR-CM
Current guidelines recommend testing serum light chain levels as a first step in patients with clinical features suggestive of cardiac amyloidosis.
The presence of serum light chains, a protein produced by white blood cells, is suggestive of conditions such as light chain cardiac amyloidosis and multiple myeloma which can produce similar clinical manifestations as ATTR-CM.
A negative free light chain result increases the possibility of ATTR-CM and should prompt the realization of ATTR-CM–specific tests such as single photon emission computed tomography (SPECT) radionuclide scintigraphy or genetic testing for TRR gene mutations.
SPECT scintigraphy measures the cardiac muscle uptake of a marked radiomarker. It is based on the principle that the TRR fibrils responsible for ATTR-CM bind to certain radiotracers, therefore increased myocardial radiotracer uptake is diagnostic of ATTR-CM. Although SPECT scintigraphy was considered inadequate to assess progression or to perform risk stratification, recent advances in SPECT CT cameras are starting to change that perception.
Cardiac magnetic resonance imaging (CMRI), on the other hand, can’t distinguish ATTR-CM from light-chain cardiac amyloidosis but is a useful tool to assess progression in patients with an established diagnosis.
Advances in treatment
ATTR-CM results from TRR fibril deposition in cardiac muscle. Therefore, current treatment modalities are focused on slowing down or stopping TTR formation.
The first U.S. Food and Drug Administration (FDA) approved treatment for ATTR-CM was tafamidis, a TTR-stabilizing therapy. Tafamidis has been shown to reduce mortality while improving functional capacity and quality of life in patients with ATTR-CM. Acoramidis, another TTR-stabilizer, was the second treatment approved by the FDA for ATTR-CM. Clinical trial results found marked reductions in mortality after its use.
Vutrisiran, the most recent drug approved by the FDA as an ATTR-CM treatment, is a TTR-silencer. TTR-silencing therapy differs from TTR-stabilizing therapy in that it acts directly on the genetic material responsible for synthesizing TRR, thus halting its production completely. Although head-to-head comparisons of the drugs are currently not available, indirect comparisons suggest that vutrisiran could be superior to tafamidis.
Future perspectives
Drugs seeking not only to stop TRR production but also to remove previous TTR deposits are currently being investigated in clinical trials. For example, the phase 3 DepleTTR-CM clinical trial has shown promising results in mortality and CMRI changes.
Additionally, gene editing therapy with the CRISPR-Cas9 treatment nexiguran ziclumeran aims to produce long-lasting modifications in the TRR gene. Data from the MAGNITUDE trial suggests that gene editing treatment could decrease TRR production by 90% in a year with a single injection.
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