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

Looking Ahead: Is Transthyretin Cardiomyopathy a Rare Disease, or is it Only Rare in the Eyes of the Beholder?

Beauty is the eye of the beholder, but if the eyes remain closed, then nothing is beautiful. Similarly, if we do not look for a disease, we will not see it. Both transthyretin and AL amyloidosis cardiomyopathy are considered rare diseases, but, undoubtedly, transthyretin amyloidosis is an underdiagnosed disease and far commoner than recognized. About one in 30 patients of African descent in the USA and UK carry a mutation of transthyretin, Val122Ile, which may cause amyloid cardiomyopathy with an estimated survival of 3–4 years following the onset of heart failure. Despite the typical amyloid appearance on the echocardiogram, the disease was not described until 1997[16] and it remains underdiagnosed despite estimates that it is the fourth commonest cause of congestive heart failure in this population.[17]

Only a minority of patients with the Val122Ile mutation gene develop typical echocardiographic appearance of amyloid cardiomyopathy, but the prevalence of heart failure is 50% higher in this population than in African-American controls without the gene.[18] This suggests that amyloid may be deposited to a degree that is inadequate to produce typical echocardiographic appearances, but that it may add a 'second hit' to a clinically vulnerable ventricle, resulting in the development of heart failure with atypical imaging features—a form of a hidden amyloid cardiomyopathy. Massive infiltration resulting in heart failure was only described as a specific disease in the mid-1980s and was considered so rare that the authors doubted that it could ever be diagnosed during life.[19] However, smaller amounts of wild-type transthyretin-derived amyloid have long been recognized as a common pathological feature in the aging heart and it likely that too act as a "second hit" trigger for heart failure, without the typical echocardiographic appearance of amyloidosis.[20] Today, ATTRwt with the classical appearance of an infiltrative cardiomyopathy is undoubtedly the most commonly recognized form of amyloid cardiomyopathy. With the widespread diagnostic use of cardiac magnetic resonance imaging for diagnosis of unexplained heart failure, and the adoption of technetium MDP/PYP as a highly sensitive and specific tool for diagnosis of ATTR,[21] it is possible that atypical presentations may even become the dominant form of the disease (Figure 1). Should this be the case, it will remain to be seen whether these forms respond positively to drugs designed specifically to slow or stop transthyretin deposition.

Figure 1.

Early transthyretin amyloidosis in an echocardiogram without typical amyloid appearance, in a patient with recent-onset CHF. (Left panel) Parasternal long-axis echocardiogram showing minimal increase in septal thickness, and no typical features of cardiac amyloidosis (Supplementary material online, Video S1A). (Middle panel) Strain imaging (same patient) in apical four-chamber view, showing reduced strain in all segments, but best-preserved in apical segments, which have an average strain of −17% compared with −6.5% at base (Supplementary material online, Video S1B). (Right panel) Individual strain curves and colour-coded strain showing bullseye appearance suggestive of amyloidosis and rarely seen in other diseases (Supplementary material online, Video S1B). The patient had a technetium pyrophosphate scan that showed uptake equal to the ribs, suggesting transthyretin amyloidosis (normal, no isotope uptake). Cardiac biopsy showed small foci of amyloid, with a density much less than is usually seen in patients with the classical echocardiographic appearance of amyloidosis.

Take Home Figure.

Schematic showing the effect of tafamidis on the transthyretin (TTR) tetramer. In the serum the tetramer exists in equilibrium with monomers. In amyloidogenesis, monomers misfold, producing aggregation-prone monomers. These may then produce oligomers which can have direct cellular toxicity (proteotoxicity) in the heart or may further aggregate in the extracellular space as amyloid fibrils, causing cellular compression and dysfunction, and decreasing the compliance of the heart. Bottom Left: Tafamidis binds to the site at which thyroxine is transported (small black arrow). In doing so, monomer formation is blocked or markedly reduced (TTR stabilization) and the cascade of misfolding to amyloid formation shown above is interrupted. Not to scale.

The data on tafamidis represent a breakthrough in the treatment of amyloid cardiomyopathy. Tafamidis has few side-effects and is likely to be prescribed widely, but the cost is also likely to be high, and it is important to determine more precisely whether there is a subgroup of patients with more advanced disease who do not benefit from the drug. A major thrust needs to be made to persuade cardiologists that this is a far commoner disease than most believe, that early diagnosis is critical for best outcomes, and that simple nuclear imaging, easily performed in any nuclear medicine facility has a high diagnostic sensitivity and specificity, without the need for a cardiac biopsy.[21,22] Finally, it is critical to move forward with clinical trial of newer agents, whether more potent stabilizers, TTR silencers or their combination, to determine whether the current breakthrough in therapy can be further improved.