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Low Plasma Transthyretin Concentration and Risk of Heart Failure
Quick Takes
- Low plasma transthyretin concentrations and genetically determined transthyretin concentrations are both associated with a higher risk of incident HF in the general population.
- Plasma triglyceride level was the single most important covariable for baseline transthyretin concentrations.
- More data are needed to validate these important findings.
Study Questions:
Is low plasma transthyretin concentration associated with incident heart failure (HF) in the general population?
Methods:
This study includes two similar prospective cohorts from Denmark: the Copenhagen General Population Study (CGPS; n = 9,582) and the Copenhagen City Heart Study (CCHS; n = 7,385). The authors used data from these two cohorts to evaluate, first, whether low concentration of plasma transthyretin (concentration at or below the 5th percentile) was associated with increased risk of incident HF. They then evaluated whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF. They utilized concentrations between the 5th and 95th percentile as reference. Incident HF identified using the Danish National Patient Registry was the main outcome. To focus on extreme levels, the study authors partitioned individuals in percentiles of plasma transthyretin concentration: the 5th percentile or lower, the 5th-95th percentile (reference), and higher than the 95th percentile. Baseline characteristics were compared across the three plasma transthyretin groups using the Kruskal-Wallis test for continuous variables and the χ2 test for categorical variables.
Results:
The study investigators reported that of 9,582 individuals in the CGPS cohort, 53% (n = 5,077) were women, and the median (interquartile range [IQR]) age was 56 (47-65) years. Of 7,385 individuals in the CCHS cohort, 60.3% (n = 4,452) were women, and the median (IQR) age was 59 (46-70) years. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1,122 individuals (15.2%) in the CCHS, respectively, developed HF. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF (CGPS: hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.4; CCHS: HR, 1.4; 95% CI, 1.1-1.7). Men with low transthyretin levels had the highest risk of HF. Compared with p.T139M, a transthyretin-stabilizing variant, TTR genotype was associated with stepwise lower transthyretin concentrations for wild-type TTR (−16.5%), p.G26S (−18.1%), and heterozygotes for other variants (p.V142I, p.H110N, and p.D119N; −30.8%) (p for trend < 0.001). The corresponding HRs for incident HF were 1.14 (95% CI, 0.57-2.28), 1.29 (95% CI, 0.64-2.61), and 2.04 (95% CI, 0.54-7.67), respectively (p for trend = 0.04). Plasma triglyceride level was the single most important covariable for baseline transthyretin concentrations in both CGPS and CCHS.
Conclusions:
The study authors concluded that lower plasma and genetically determined transthyretin concentrations were associated with a higher risk of incident HF, suggesting a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population.
Perspective:
Low plasma transthyretin concentration has been shown to be an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as HF. Important considerations when evaluating and applying the results of diagnostic tests include: 1) Are the results valid? And 2) Will the results help me in caring for my patients? This is an important study because it suggests low plasma transthyretin concentration, which can be indicative of transthyretin protein misfolding, is an important predictor of HF. More data are needed to validate these important findings.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Amyloid Neuropathies, Familial, Biomarkers, Diagnostic Tests, Routine, Genotype, Heart Failure, Heterozygote, Prealbumin, Risk, Secondary Prevention, Triglycerides
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