What is ATTR cardiomyopathy?

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a condition in which a protein called transthyretin (TTR) misfolds and forms deposits in the heart, gradually thickening and stiffening the heart muscle. The result is heart failure, often with preserved ejection fraction (the heart pumps normally but does not relax properly).

The two forms. Wild-type ATTR amyloidosis (formerly called senile systemic amyloidosis) occurs in older adults, predominantly men, with normal TTR genetics. Hereditary ATTR amyloidosis is caused by inherited variants in the TTR gene; some variants cause cardiomyopathy, some cause polyneuropathy, some cause both.

Why it has been underdiagnosed. ATTR-CM has classically been confused with other causes of heart failure with preserved ejection fraction or with hypertensive heart disease. The diagnostic workup (bone scintigraphy, blood and urine tests for monoclonal protein, sometimes genetic testing) requires clinical suspicion, and that suspicion has only become widespread in the past several years. As awareness has grown, the apparent prevalence of ATTR-CM has increased substantially.

The therapy options.

Stabilisers: tafamidis and acoramidis are oral medicines that bind TTR and prevent it from breaking apart and forming amyloid deposits. They slow disease progression and improve outcomes.

Silencers: vutrisiran, eplontersen, and patisiran are injectable medicines that reduce the amount of TTR the liver produces in the first place. With less TTR around, less amyloid forms. Vutrisiran is the silencer specifically approved for ATTR cardiomyopathy; eplontersen and patisiran are approved for the polyneuropathy form of ATTR (eplontersen has cardiac trial data pending).

Emerging one-time options: CRISPR gene-editing therapy designed to knock out the TTR gene in liver cells is in late-stage trials. If it works, a single treatment could replace ongoing therapy.

What to expect. With modern therapy, ATTR-CM is increasingly a treatable condition rather than the relentlessly progressive disease it used to be. Earlier diagnosis is one of the most important things that determines outcomes; many patients first identified with ATTR-CM today have several therapy options that did not exist five years ago.