TTR Destabilization:

The Source of ATTR‑CM

Discover the causes, symptoms, outcomes, and diagnostic methods of this relentlessly progressive heart disease.1

ATTR-CM is also known as ATTR cardiomyopathy, or ATTR cardiac amyloidosis (ATTR-CA).

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doctor and patient discussing ttr doctor and patient discussing ttr doctor and patient discussing ttr

TTR, also known as prealbumin, plays a role in processes vital to human health2,3:

  • Highly conserved transport protein produced in the liver
  • Distributes thyroxine and vitamin A throughout the body
  • Supports memory, neuroprotection, and cognitive function
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Click play to learn more about TTR.

TTR destabilization is the root cause of ATTR‑CM4,5

Factors such as aging or TTR gene variants can trigger a cascade of structural changes that destabilize the configuration of circulating TTR tetramers.4 These changes may cause the tetramers to break apart and misfold.5 Misfolded TTR proteins can aggregate into toxic amyloid fibrils that cause signs and symptoms indicative of transthyretin amyloidosis.5,6

ttr destabilization cycle

TTR Stability Impacts Disease Severity

Greater TTR destabilization is correlated with earlier disease onset and increased disease severity7

TTR gene variants strongly influence the rate of TTR tetramer dissociation, which is required for amyloid formation.7 Most known variants destabilize the tetramer, increasing the amyloidogenic potential of TTR and leading to poor clinical outcomes.7 However, variants shown to stabilize the tetramer have also been identified.6 These variants prevent amyloidogenesis by dramatically slowing the rate of tetramer dissociation and have been associated with disease protection.6,7

ttr stability versus disease severity graph

Relative tetramer stability based on denaturation midpoints measured via an in vitro dissociation/unfolding assay.7

The most beneficial TTR gene variant identified to date is T119M, which has been shown to confer protection against the development of ATTR even when coinherited with variants associated with poor outcomes7

Treating ATTR-CM

Learn about a TTR stabilizer treatment option.8

Discover a treatment

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References:
1.

Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16-26. 2. Liz MA, Coelho T, Bellotti V, Fernandez-Arias MI, Mallaina P, Obici L. A narrative review of the role of transthyretin in health and disease. Neurol Ther. 2020;9(2):395-402. 3. Vieira M, Saraiva MJ. Transthyretin: a multifaceted protein. Biomol Concepts. 2014;5(1):45-54. 4. Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2020;142(1):e7-e22. 5. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891. 6. Hornstrup LS, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy. Arterioscler Thromb Vasc Biol. 2013;33(6):1441-1447. 7. Hammarström P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci USA. 2002;99(suppl 4):16427-16432. 8. Morfino P, Aimo A, Vergaro G, et al. Transthyretin stabilizers and seeding inhibitors as therapies for amyloid transthyretin cardiomyopathy. Pharmaceutics. 2023;15(4):1129.