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. 2022 Mar;28(3):403-414.
doi: 10.1016/j.cardfail.2021.09.015. Epub 2021 Oct 9.

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

Julia Kozlitina  1 , Sonia Garg  2 , Mark H Drazner  2 , Susan A Matulevicius  2 , Colby Ayers  1 , John Overton  3 , Jeffrey Reid  3 , Aris Baras  3 , Krishnasree Rao  4 , Ambarish Pandey  2 , Jarett Berry  2 , James A de Lemos  2 , Justin L Grodin  5
Affiliations

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

Julia Kozlitina et al. J Card Fail. 2022 Mar.

Abstract

Background: 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 = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P > .05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P < .001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers.

Conclusions: V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.

Keywords: Cardiac amyloidosis; heart failure; transthyretin.

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Figures

Figure 1.
Figure 1.
Consort Diagram. Of the 1,818 DHS participants of African ancestry, n=1,532 had follow-up CV data, n=1,364 had CMR imaging data, and n=1,205 had both. Abbreviations are DHS-1, Dallas Heart Study Phase 1; WES, whole exome sequencing; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; and DHS-2, Dallas Heart Study Phase 2.
Figure 2.
Figure 2.
Kaplan-Meier Estimates of Cumulative Incidence of Fatal and Non-fatal Events Stratified by V122I TTR Carrier Status. Statistical comparisons are generated by the Log-rank test.
See this image and copyright information in PMC

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