Once considered a rare and fatal disease, transthyretin amyloid cardiomyopathy (ATTR-CM) is now being transformed by advances in diagnosis and treatment, according to a recent review published in Current Cardiology Reports.
Improved imaging techniques — including echocardiography, cardiac magnetic resonance imaging and radionuclide bone scintigraphy — have significantly increased early detection over the past two decades.
What is ATTR-CM?
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare progressive disease of the heart muscle that leads to congestive heart failure. It occurs when the transthyretin protein produced by the liver is unstable. Symptoms include fatigue; shortness of breath; irregular heart rate or palpitations; swelling of the legs, ankles and stomach; brain fog; wheezing; and dizziness. It often goes underdiagnosed because of a lack of awareness and knowledge of the disease. There is currently no cure for ATTR-CM.
Emerging therapies target various stages of disease progression, and patients now have multiple options for managing ATTR-CM, potentially slowing progression and improving quality of life.
Read more about ATTR-CM therapies
“With burgeoning awareness and improved diagnostics, interest in clinical research surrounding ATTR-CM is rapidly accelerating,” review authors said. “Ongoing studies not only include additional TTR stabilizers but also silencers, and depleters.”
As the treatment landscape evolves, access to therapies and early diagnosis remain critical for improving patient outcomes. Ongoing research and clinical trials will determine how best to integrate novel treatments into routine care, offering patients greater hope for managing ATTR-CM effectively.
Transthyretin (TTR) stabilizers remain a cornerstone of treatment, preventing the dissociation of TTR tetramers and inhibiting amyloid formation.
Tafamidis, the first disease-modifying therapy approved for both wild-type and hereditary forms of the disease, has been shown to reduce rates of mortality and hospitalization while preserving mobility and kidney function.
Another stabilizer, acoramidis, has demonstrated superior stabilization of TTR in early studies and is pending FDA approval. Diflunisal and tolcapone, though less widely used, also show promise in stabilizing TTR and slowing progression of the disease.
TTR silencers offer another approach by reducing hepatic production of TTR. Small interfering RNA therapies such as patisiran and vutrisiran, as well as antisense oligonucleotides such as inotersen and eplontersen, have shown effectiveness in decreasing amyloid buildup.
These treatments work by targeting mRNA for TTR, preventing the production of misfolded proteins that contribute to cardiac damage. Revusiran was withdrawn because of concerns over worsening neuropathy, but other silencers continue to be explored in clinical trials.
One of the most innovative approaches is gene editing with CRISPR-Cas9 technology. NTLA-2001, an investigational therapy, has demonstrated durable reduction in levels of TTR in preclinical studies. If successful in human trials, it could offer a one-time treatment to prevent amyloid deposition altogether. But long-term safety and efficacy data are still needed before gene-editing therapies can become a standard treatment option.
TTR depleters, a new class of monoclonal antibody therapies, aim to remove existing amyloid fibril deposits, potentially reversing some of the damage caused by ATTR-CM. While still in early stages of development, these therapies could provide additional benefit for patients with advanced disease who have already experienced significant cardiac impairment.
“As more treatments are available, efforts will need to refocus on understanding long-term effects and improving reach and access for the most vulnerable populations,” the authors said. “We must intertwine in these missions: increased diversity in clinical trial enrollment, as well as develop affordable pathways to allow equitable access to ground-breaking therapies.”
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