In cardiac ATTR amyloidosis, amyloid is deposited in the myocardium by monomers of the transthyretin protein. The TTR protein is normally a tetramer (four smaller proteins form a stable large protein). In this disease, these tetramers break down into four small proteins (monomers) that are deposited as amyloid fibrils.

Read more: Specific cardiomyopathies – cardiac amyloidosis .

These drugs stop the production of TTR proteins in the liver by 'gene silencing '. This is blocking the TTR gene with a small interfering RNA ( siRNA ) that binds to the messenger RNA (mRNA) of the TTR gene and thereby blocking its synthesis. This results in an 80-90% reduction of TTR protein in the blood and thereby a strong reduction of new deposits of TTR proteins in the tissues.

Slowing the progression of the disease, both neurological and cardiac.

Due to the strong decrease in TTR protein, this effect is faster and greater than with TTR stabilizers.

Trials:

• Vutrisiran ( Amvuttra ): HELIOS-B (NEJM, 2025)
• Patisiran ( Onpattro ): APOLLO-B (NEJM, 2023)

In NYHA I-II patients:

• Stabilization of exercise capacity and quality of life with significantly less rapid progression of symptoms.
• Significantly less increasing NT- proBNP.
• HELIOS-B also showed reduction of cardiovascular events, progressive heart failure from a treatment duration of > 6 months and with longer treatment duration also a reduction of all-cause mortality.

• Both drugs are reimbursed for adults with peripheral polyneuropathy stage 1 and 2 caused by hereditary transthyretin -mediated amyloidosis (hATTR amyloidosis).
• Vutrisiran ( Amvuttra ) is also approved for use in hATTR cardiomyopathy.

• Infusion related reactions: rash , arthralgia, myalgia, ...
• Increased risk of upper respiratory tract infections.
• Vitamin A deficiency. The TTR protein plays an important role in vitamin A metabolism. Without TTR, blood levels of vitamin A will decrease with the risk of visual impairment. Daily vitamin A supplements will be prescribed.

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