• Senthil Selvaraj, Brian Claggett, Svati H Shah, Robert J Mentz, Michel G Khouri, Ani W Manichaikul, Sadiya S Khan, Stephen S Rich, Thomas H Mosley, Emily B Levitan, Pankaj Arora, Parag Goyal, Bernhard Haring, Charles B Eaton, Richard K Cheng, Gretchen L Wells, JoAnn E Manson, Marianna Fontana, and Scott D Solomon.
• Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
• JAMA. 2024 Jun 4; 331 (21): 182418331824-1833.

ImportanceIndividual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments.ObjectivesTo better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population.Design, Setting, And ParticipantsA total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024.ExposureV142I carrier status (n = 754, 3.2%).Main Outcomes And MeasuresHospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data.ResultsAmong the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant.Conclusions And RelevanceAmong self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

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