Clinical Implications of the Amyloidogenic V122I Transthyretin Variant in the General Population.

ABSTRACT AIMS. The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population. METHODS AND RESULTS. TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N=1,818), and either cardiac magnetic resonance imaging (CMR) (n=1,364), or long-term follow-up (n=1,532) were included. The prevalence of V122I TTR carriers (45±10 years) was 3.2% (n/N=59/1,818). V122I TTR carriers had higher baseline LV wall thickness (LVWT, 8.52±1.82 vs. 8.21±1.62 mm; adjusted P=0.038) than non-carriers, but no differences in other CMR measures (P>0.05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P=0.79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than non-carriers (median [interquartile range] 28.5 [11.4-104.1] vs. 15.9 [0.0–43.0] pg/mL; adjusted P=0.018). V122I TTR carriers were at a higher adjusted risk of heart failure (HF) (HR 3.82, 95% CI 1.80-8.13, P CONCLUSION. V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater LVWT, and a higher risk for HF, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.