Tafamidis for Transthyretin Amyloid Cardiomyopathy: The Solution or Just the Beginning of the End?

Rodney H. Falk


Eur Heart J. 2019;40(12):1009-1012. 

In This Article

Do Transthyretin Oligomers Have a Toxic Effect?

A seminal observation in patients with light chain amyloidosis was made over 20 years ago with the recognition that light chains, these precursor of the fibrils in AL amyloidosis, appeared to have an independent toxic effect on cardiac function.[14] Once circulating abnormal monoclonal proteins are abolished by successful chemotherapy, there is very often a clinical improvement, accompanied by a decrease in NT-proBNP and troponin levels, even though there is no obvious change in the left ventricular wall thickness. In TTR amyloidosis, the tetrameric transthyretin breaks down into monomers which misfold and produce oligomers. Oligomers are deposited in tissues along with the mature amyloid fibrils, and oligomeric deposition has been shown, experimentally, to produce toxic apoptotic cell death.[15] Although the toxic effect of amyloidogenic light chains in AL amyloidosis is widely accepted, it is still unclear whether oligomer deposition in transthyretin amyloid produces cardiac toxicity independent of the damage caused by the amyloid fibrils. To date, it has not been possible to clearly demonstrate this in vivo, as observations were limited by the unavailability of drugs that affected either the levels or stability of circulating TTR. Although the ATTR-ACT trial cannot directly answer this question, there are some data which might suggest a degree of organ toxicity related to active breakdown of transthyretin. Transthyretin has a half-life of approximately 48 h, and tafamidis stabilization should occur within days of drug initiation. Yet, the survival curves showed an equivalent mortality rate between the treated and untreated groups until 15–18 months, at which time the curves begin to diverge in favour of tafamidis. In contrast, tafamidis showed a clinical benefit in 6-min walk and quality-of-life well in advance of the mortality benefit. These observations parallel findings in patients with light chain amyloidosis treated with chemotherapy, in whom reduction of the amyloidogenic protein improves wellbeing before structural organ changes are seen. The delayed effect on mortality may simply reflect the time taken for the sicker, non-tafamidis responders to die in each group, with the effect of the drug on those less ill at study entry emerging later in the study. However, there may also be a role for oligomer toxicity, and these observations should encourage further basic science experiments in transthyretin amyloidosis.