IMPORTANCE Rare mutations in the transthyretin gene lower plasma transthyretin levels and cause hereditary transthyretin cardiac amyloidosis, which may manifest as heart failure (HF). Plasma transthyretin levels also decrease with age, and so-called wildtype transthyretin cardiac amyloidosis is a likely underdiagnosed phenomenon of aging. However, whether low plasma transthyretin levels confer increased risk of incident HF in community-dwelling individuals is unknown.
OBJECTIVE To determine if low plasma transthyretin levels herald increased risk of incident HF in the general population.
DESIGN, SETTING, AND PARTICIPANTS In two similar prospective studies of the Danish general population, we identified 16,967 individuals without clinically recognized HF, high-sensitivity C-reactive protein (hsCRP) <10mg/L and consecutively ascertained plasma transthyretin. Of the total study subjects, 9,582 were participants in the Copenhagen General Population Study (CGPS) and 7,385 in the Copenhagen City Heart Study (CCHS). 
EXPOSURES To focus on extreme levels, participants were divided by transthyretin in percentiles: ≤5th, >5-95th, and >95th. 
MAIN OUTCOME AND MEASURE Incident HF was the main endpoint. Participants meeting endpoint were identified using the national Danish electronic patient registry.
RESULTS During a median follow-up of 13 and 22 years, respectively, 441(5%) individuals in the CGPS and 1,122(15%) individuals in the CCHS developed HF. In individuals with plasma transthyretin levels ≤5th versus >5-95th percentiles(=reference), multivariable adjusted hazard ratios for HF were 1.6 (95% confidence interval (CI): 1.1-2.3) in the CGPS and 1.3 (95% CI: 1.1-1.7) in the CCHS. In further stratification by hsCRP, the corresponding hazard ratios were 1.6 (1.1-2.3) and 1.3 (1.1-1.7) in the CGPS and CCHS, respectively. In contrast, hazard ratios for HF in individuals with transthyretin >95th versus >5-95th percentiles did not differ in either study (both p≥0.13).
CONCLUSIONS AND RELEVANCE In two large studies of the general population, plasma transthyretin levels ≤5th percentile were independently associated with increased risk of incident HF.

06 - PLASMA TRANSTHYRETIN AND RISK OF INCIDENT HEART FAILURE