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TTR Destabilization:

The Source of ATTR‑CM

Destabilization of the transthyretin (TTR) protein, also known as prealbumin, leads to low levels of serum TTR and has been correlated with earlier disease onset and poor clinical outcomes in people with transthyretin amyloid cardiomyopathy (ATTR‑CM) — a relentlessly progressive disease.*^,1-3

*Also known as ATTR cardiomyopathy, or ATTR cardiac amyloidosis (ATTR-CA).

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What Is TTR?

TTR, also known as prealbumin, plays a role in processes vital to human health:^4,5

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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TTR Destabilization in ATTR‑CM

*Amyloid fibrils can also accumulate in areas of the body outside of the heart.^6,7

TTR destabilization is the root cause of ATTR‑CM^6,7

Factors such as aging or TTR gene variants can trigger a cascade of structural changes that destabilize the configuration of circulating TTR tetramers.⁶ These changes may cause the tetramers to break apart and misfold.⁷ Misfolded TTR proteins can aggregate into toxic amyloid fibrils that cause signs and symptoms indicative of transthyretin amyloidosis.^7,8

TTR Stability Impacts Disease Severity

Greater TTR destabilization is correlated with earlier disease onset and increased disease severity¹

TTR gene variants strongly influence the rate of TTR tetramer dissociation, which is required for amyloid formation.¹ Most known variants destabilize the tetramer, increasing the amyloidogenic potential of TTR and leading to poor clinical outcomes.¹ However, variants shown to stabilize the tetramer have also been identified.⁸ These variants prevent amyloidogenesis by dramatically slowing the rate of tetramer dissociation and have been associated with disease protection.^1,8

The most beneficial TTR gene variant identified to date is T119M, which has been shown to confer protection against the development of ATTR‑CM even when coinherited with variants associated with poor outcomes¹

Relative tetramer stability based on denaturation midpoints measured via an in vitro dissociation/unfolding assay.¹

References:

Hammarström P, et al. Proc Natl Acad Sci U S A. 2002;99 Suppl 4(Suppl 4):16427-32. 2. Hanson JLS, et al. Use of Serum Transthyretin as a Prognostic Indicator and Predictor of Outcome in Cardiac Amyloid Disease Associated With Wild-Type Transthyretin. Circ Heart Fail. 2018;11(2):e004000. 3. Lane T, et al. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation. 2019;140(1):16-26. 4. Liz MA, et al. A Narrative Review of the Role of Transthyretin in Health and Disease. Neurol Ther. 2020;9(2):395-402. 5. Vieira M, Saraiva MJ. Transthyretin: A Multifaceted Protein. Biomol Concepts. 2014;5(1):45-54. 6. Kittleson MM, et al. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020;142(1):e7-e22. 7. Ruberg FL, et al. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-2891. 8. Hornstrup LS, et al. Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy. Arterioscler Thromb Vasc Biol. 2013;33(6):1441-7.