Misfolded transthyretin: a novel risk factor for heart failure, JAMA study

Several studies have established that low plasma transthyretin concentration is an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both these entities manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown.

In this regard, Greve et al in the current issue of JAMA cardiology have shown that individuals with low concentration of plasma transthyretin (at the fifth percentile or lower, corresponding to values <19.0 mg/dL) had a 1.4-fold to 1.6-fold increased risk of incident HF on long-term follow-up and men with low transthyretin levels were at higher risk than women.

This study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385).

Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested.

The results from this study were:

1. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1122 individuals (15.2%) in the CCHS, respectively, developed HF.

2. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF.

3. Risk of HF was highest in men with low transthyretin levels.

4. Furthermore, there was a stepwise association between TTR variants, transthyretin levels, and incident HF, such that variants associated with the lowest transthyretin levels were associated with the highest risk of incident HF and the stabilizing variant (T139M) was associated with the highest transthyretin levels and lowest risk of incident HF.

Together, these findings are compelling for 2 reasons: they provide novel insight into the pathogenesis of HF that could be associated with ATTR-CM in the general population, and they open the possibility that low concentrations of transthyretin may be useful as a test that could alert clinicians to the possibility of a patient being at risk for or having overt ATTR-CM, which could lead to confirmatory tests and earlier diagnosis.

In conclusion, in this study, lower plasma concentrations and genetically determined transthyretin concentrations were associated with higher risk of incident HF.

"These results are compatible with a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population", noted the authors.

Source: JAMA cardiology: JAMA Cardiol. 2021;6(3):258-266. doi:10.1001/jamacardio.2020.5969