Proteomics Profiling Reveals Circulating Biomarkers and Dysregulated Pathways in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND

Transthyretin amyloid cardiomyopathy (ATTR-CM) causes a restrictive cardiomyopathy resulting in heart failure (HF). Signaling pathways associated with ATTR-CM are not well defined. The purpose of this study was to identify signaling pathways that are dysregulated in ATTR-CM compared with controls.

METHODS

This was a case-control study of cases with ATTR-CM, internal controls with hypertensive left ventricular hypertrophy, and external controls with HF. For model development, ATTR-CM cases were age- and sex-matched with internal controls with hypertensive left ventricular hypertrophy. Plasma proteomics profiling of 7289 proteins was conducted. A sparse partial least squares discriminant analysis was performed to develop a proteomics-based discrimination model from 70% of the data (ie, the training set), and the discriminative ability was tested in the remaining 30% of the data (ie, the internal test set). External validation using HF controls was also conducted. Pathway analysis of significantly (ie, univariable P<10-6) dysregulated proteins was executed. Signaling pathways with a false discovery rate <0.05 were declared positive.

RESULTS

The analysis included 169 cases and 220 controls. A total of 211 discriminant proteins were identified in the training set from the proteomics-based model developed to distinguish ATTR-CM cases from 170 internal controls with hypertensive left ventricular hypertrophy. The area under the receiver-operating characteristic curve to discriminate ATTR-CM in the test set from 50 external controls with HF was 0.89 (95% CI, 0.82-0.96). The sensitivity was 0.90 (95% CI, 0.75-0.97), and the specificity was 0.86 (95% CI, 0.72-0.96). Pathway analysis revealed the PI3K-Akt (phosphoinositide-3-kinase-protein kinase) pathway and its related pathways (eg, JAK-STAT [Janus kinase-signal transducer and activator of transcription]) were dysregulated. Dysregulation of previously identified pathways, such as the complement and coagulation cascade pathways, was also observed.

CONCLUSIONS

This study reveals a distinct proteomic profile of ATTR-CM compared with controls with HF, and elucidates both novel and known signaling pathways that are differentially regulated in ATTR-CM.