Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS)

Abstract

Aim: Cardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking.

Methods and results: Patients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5-194.9), NT-proBNP 337.9 pg/mL (IQR 73.0-2584.0), troponin T 0.03 μg/L (IQR 0.01-0.05), and troponin I 0.08 μg/L (IQR 0.04-0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1-Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR.

Conclusions: In this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR.

Trial registration: ClinicalTrials.gov NCT00628745.

Conflict of interest statement

Competing Interests: A. V. K. has received research support from and served on advisory boards for Pfizer Inc. including the THAOS scientific advisory board. M. S. M. has received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, as a clinical investigator and for scientific meeting expenses. His institution has received grant support from Pfizer Inc. He serves on the THAOS scientific advisory board. C. R. has received unrestricted research grants from Pfizer Inc. He serves on the THAOS scientific advisory board. R. M. is an employee of Pfizer Inc. and holds stock options in Pfizer Inc. O. B. S. served as an advisor for Alnylam Pharmaceuticals, Isis Pharmaceuticals, and Pfizer Inc. as well as having served as an advisor and receiving support as a clinical investigator from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010. He currently serves on the THAOS (natural history disease registry) scientific advisory board. T. D. has received research support from and served on advisory boards for Pfizer Inc. including the THAOS scientific advisory board. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Unadjusted comparison of cardiac biomarkers in patients with ATTR by genotype, mutation, and age at disease onset.

(A) BNP in patients with wild type (WT) vs. mutant type (MT); (B) NT-proBNP in patients with WT vs. MT; (C) Troponin I in patients with WT vs. MT; (D) Troponin T in patients with WT vs. MT; (E) BNP in patients with Val30Met vs. non-Val30Met mutations; (F) NT-proBNP in patients with Val30Met vs. non-Val30Met mutations; (G) Troponin I in patients with Val30Met vs. non-Val30Met mutations; (H) Troponin T in patients with Val30Met vs. non-Val30Met mutations; (I) BNP in patients with early vs. late onset of ATTR due to Val30Met mutation; (J) NT-proBNP in patients with early vs. late onset of ATTR due to Val30Met mutation; (K) Troponin I in patients with early vs. late onset of ATTR due to Val30Met mutation; (L) Troponin T in patients with early vs. late onset of ATTR due to Val30Met mutation.

Fig 2. Association of survival and plasma levels of natriuretic peptides in patients with ATTR using unadjusted log-rank test.

Survival stratified by natriuretic peptides (BNP/NT-proBNP) optimal cut-off values (A) in the whole cohort; (B) in patients with wildtype ATTR; (C) in patients with mutant type ATTR; (D) in patients with Val30Met; (E) in patients with early onset of Val30Met; (F) in patients with late onset of Val30Met; (G) in patients with non-Val30Met; (H) in patients with Val122Ile. P-values are for the comparison between the combination of above vs. below the cut-off value.

Fig 3. Association of survival and plasma levels of cardiac biomarkers in patients with ATTR using unadjusted log-rank test.

Survival stratified by combination of troponin T/I cut-off values as well as NT-proBNP/BNP quartiles cut-off values (A) in the whole cohort; (B) in patients with wildtype ATTR; (C) in patients with mutant type ATTR; (D) in patients with Val30Met; (E) in patients with early onset of Val30Met; (F) in patients with late onset of Val30Met; (G) in patients with non-Val30Met; (H) in patients with Val122Ile. P-values are for the comparison between the combination of patients with values above vs. below the cut-off value. Stage A: both natriuretic peptides AND troponins above; Stage B both natriuretic peptides AND troponins below; Stage C: either of the natriuretic peptides OR troponins is above.