BACKGROUND
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a fatal disease caused by destabilization
of the transthyretin (TTR) tetramer resulting in the formation of amyloid fibrils
that deposit in the heart, leading to heart failure and ultimately death. Tafamidis,
a specific stabilizer of TTR, binds to the thyroxine binding sites and inhibits TTR
dissociation, the rate limiting step in the amyloidogenic process. In ATTR-ACT, tafamidis
significantly reduced all-cause mortality and cardiovascular-related hospitalizations
in participants with ATTR-CM. Here, we evaluated the effects of tafamidis 80 mg on
TTR stabilization and TTR plasma concentrations compared to placebo-treated patients
in ATTR-ACT.
METHODS AND RESULTS
Patient blood samples were collected at baseline and Months 1, 6, 12, 18, 24 and 30.
TTR tetramer stability was measured using an immunoturbidimetric assay with urea denaturation.
The TTR tetramer plasma level was measured prior to and after urea denaturation. The
pre-denaturation TTR level provided the TTR plasma concentration at each time point.
A significantly greater proportion of participants in the tafamidis 80 mg group (144/164
[87.8%] demonstrated TTR stabilization at Month 1 than was observed for participants
in the placebo group (6/170 [3.5%] (p < 0.0001). The difference in stabilization remained
through month 30. Mean TTR plasma concentrations increased at Month 1 from baseline
and remained elevated throughout the study with tafamidis 80 mg. Tafamidis-treated
participants had a mean TTR concentration of 30.00 mg/dl (a 31% increase from baseline)
compared to placebo-treated participants with a mean of 21.88 mg/dl at 30 months.
CONCLUSION
These results suggest more TTR was conserved in its tetrameric structure and less
consumed in the amyloidogenic cascade supporting the robustness of tafamidis as a
TTR stabilizer. Tafamidis 80 mg resulted in almost 90% of participants demonstrating
TTR stabilization and mean TTR plasma levels were consistently elevated over the 30
months of ATTR-ACT. Stabilization of the TTR tetramer is an important consideration
in the treatment of ATTR-CM allowing for the preservation of functional transthyretin
in plasma for normal physiologic activity.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Article info
Identification
Copyright
© 2021 Published by Elsevier Inc.
