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

      Highlights

      • The prevalence of the V122I transthyretin (TTR) variant in individuals with African ancestry is 3.2%.
      • In mid-life, carriers of the V122I TTR have subtle cardiac structural differences in comparison with noncarriers.
      • Over time, carriers of V122I have a greater increase in amino terminal pro-B-type natriuretic peptide in comparison with noncarriers.
      • In comparison with noncarriers, carriers of the V122I TTR are at a higher long-term risk of heart failure and death

      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.

      Graphical Abstract

      Key Words

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      References

        • Lane T
        • Fontana M
        • Martinez-Naharro A
        • Quarta CC
        • Whelan CJ
        • Petrie A
        • et al.
        Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis.
        Circulation. 2019; 140: 16-26
        • Maurer MS
        • Schwartz JH
        • Gundapaneni B
        • Elliott PM
        • Merlini G
        • Waddington-Cruz M
        • et al.
        Investigators A-AS. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.
        N Engl J Med. 2018; 379: 1007-1016
        • Judge DP
        • Heitner SB
        • Falk RH
        • Maurer MS
        • Shah SJ
        • Witteles RM
        • et al.
        Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy.
        J Am Coll Cardiol. 2019; 74: 285-295
        • Bokhari S
        • Castano A
        • Pozniakoff T
        • Deslisle S
        • Latif F
        • Maurer MS.
        (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses.
        Circ Cardiovasc Imaging. 2013; 6: 195-201
        • Syed IS
        • Glockner JF
        • Feng D
        • Araoz PA
        • Martinez MW
        • Edwards WD
        • et al.
        Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis.
        JACC Cardiovasc Imaging. 2010; 3: 155-164
        • Jiang X
        • Buxbaum JN
        • Kelly JW.
        The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis.
        Proc Natl Acad Sci U S A. 2001; 98: 14943-14948
        • Maurer MS
        • Hanna M
        • Grogan M
        • Dispenzieri A
        • Witteles R
        • Drachman B
        • et al.
        Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).
        J Am Coll Cardiol. 2016; 68: 161-172
        • Quarta CC
        • Buxbaum JN
        • Shah AM
        • Falk RH
        • Claggett B
        • Kitzman DW
        • et al.
        The amyloidogenic V122I transthyretin variant in elderly black Americans.
        N Engl J Med. 2015; 372: 21-29
        • Damrauer SM
        • Chaudhary K
        • Cho JH
        • Liang LW
        • Argulian E
        • Chan L
        • et al.
        Association of the V122I hereditary transthyretin amyloidosis genetic variant with heart failure among individuals of African or Hispanic/Latino ancestry.
        JAMA. 2019; 322: 2191-2202
        • Soares ML
        • Coelho T
        • Sousa A
        • Batalov S
        • Conceicao I
        • Sales-Luis ML
        • et al.
        Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease.
        Hum Mol Genet. 2005; 14: 543-553
        • Dorbala S
        • Ando Y
        • Bokhari S
        • Dispenzieri A
        • Falk RH
        • Ferrari VA
        • et al.
        ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
        J Card Fail. 2019; 25: e1-e39
        • Garg S
        • de Lemos JA
        • Matulevicius SA
        • Ayers C
        • Pandey A
        • Neeland IJ
        • et al.
        Association of concentric left ventricular hypertrophy with subsequent change in left ventricular end-diastolic volume: the Dallas Heart Study.
        Circ Heart Fail. 2017; 10
        • Drazner MH
        • Dries DL
        • Peshock RM
        • Cooper RS
        • Klassen C
        • Kazi F
        • et al.
        Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study.
        Hypertension. 2005; 46: 124-129
        • Abdalla M
        • Akwo EA
        • Bluemke DA
        • Lima JAC
        • Shimbo D
        • Maurer MS
        • et al.
        Association between reduced myocardial contraction fraction and cardiovascular disease outcomes: the Multi-Ethnic Study of Atherosclerosis.
        Int J Cardiol. 2019; 293: 10-16
        • Dewey FE
        • Murray MF
        • Overton JD
        • Habegger L
        • Leader JB
        • Fetterolf SN
        • et al.
        Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.
        Science. 2016; 354
        • Chang CC
        • Chow CC
        • Tellier LC
        • Vattikuti S
        • Purcell SM
        • Lee JJ.
        Second-generation PLINK: rising to the challenge of larger and richer datasets.
        Gigascience. 2015; 4: 7
        • de Lemos JA
        • McGuire DK
        • Khera A
        • Das SR
        • Murphy SA
        • Omland T
        • et al.
        Screening the population for left ventricular hypertrophy and left ventricular systolic dysfunction using natriuretic peptides: results from the Dallas Heart Study.
        Am Heart J. 2009; 157 (e2): 746-753
        • deFilippi CR
        • de Lemos JA
        • Christenson RH
        • Gottdiener JS
        • Kop WJ
        • Zhan M
        • et al.
        Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
        JAMA. 2010; 304: 2494-2502
        • de Lemos JA
        • Ayers CR
        • Levine BD
        • deFilippi CR
        • Wang TJ
        • Hundley WG
        • et al.
        Multimodality strategy for cardiovascular risk assessment: performance in 2 population-based cohorts.
        Circulation. 2017; 135: 2119-2132
        • Jacobson DR
        • Alexander AA
        • Tagoe C
        • Buxbaum JN.
        Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.
        Amyloid. 2015; 22: 171-174
        • Sinha A
        • Zheng Y
        • Nannini D
        • Qu Y
        • Hou L
        • Shah SJ
        • Yancy CW
        • et al.
        Association of the V122I transthyretin amyloidosis genetic variant with cardiac structure and function in middle-aged Black adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study.
        JAMA Cardiol. 2020; 6: 1-5
        • Gillmore JD
        • Maurer MS
        • Falk RH
        • Merlini G
        • Damy T
        • Dispenzieri A
        • et al.
        Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
        Circulation. 2016; 133: 2404-2412
        • Gillmore JD
        • Damy T
        • Fontana M
        • Hutchinson M
        • Lachmann HJ
        • Martinez-Naharro A
        • et al.
        A new staging system for cardiac transthyretin amyloidosis.
        Eur Heart J. 2018; 39: 2799-2806
        • Kristen AV
        • Maurer MS
        • Rapezzi C
        • Mundayat R
        • Suhr OB
        • Damy T
        • Investigators T
        Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - report from the Transthyretin Amyloidosis Outcome Survey (THAOS).
        PLoS One. 2017; 12e0173086
        • Sperry BW
        • Vranian MN
        • Hachamovitch R
        • Joshi H
        • McCarthy M
        • Ikram A
        • et al.
        Are classic predictors of voltage valid in cardiac amyloidosis? A contemporary analysis of electrocardiographic findings.
        Int J Cardiol. 2016; 214: 477-481
        • Grogan M
        • Scott CG
        • Kyle RA
        • Zeldenrust SR
        • Gertz MA
        • Lin G
        • et al.
        Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system.
        J Am Coll Cardiol. 2016; 68: 1014-1020