Plasma Proteomics Reveals Dysregulated Pathways Across the Spectrum Cardiomyopathy.

BACKGROUND

Pathogenic variants in the () gene cause an aggressive form of dilated cardiomyopathy (DCM), marked by higher rates of advanced conduction disease, malignant ventricular tachyarrhythmias, and advanced heart failure compared with other causes of nonischemic cardiomyopathy. However, the mechanisms that drive the development and progression of DCM are incompletely understood.

METHODS

To identify proteins and biological pathways associated with likely pathogenic/pathogenic variants, we measured ≈3000 plasma proteins using the OLINK platform in a genetic DCM cohort consisting of (n=41) and sarcomeric (n=18) DCM, along with phenotype-negative individuals from family-based cascade screening (n=55) with (, n=16; sarcomere, n=12) or without the family variant (genotype negative, n=27).

RESULTS

We identified several novel proteins associated with DCM compared with sarcomeric DCM, including EDA2R (ectodysplasin A2 receptor; per log2 fold change in relative protein abundance, β=3.0; =4×10³) and (myosin light chain 4; β=2.32; =5×10³). Among the proteins associated with DCM, 26 showed concordant differential gene expression from single-cell sequencing in cardiomyocytes from myocardial biopsies in advanced heart failure compared with control hearts (false discovery rate, <5%). We performed principal component analyses on these 26 proteins to identify proteomic signatures of DCM and found the first principal component to be associated with left ventricular ejection fraction and complete heart block in the DCM cohort. Six proteins-EDA2R, MYL4, CRIM1 (cysteine-rich transmembrane BMP regulator 1), TPR (translocated promoter region), FSTL3 (follistatin-like 3), and NFYA (nuclear transcription factor Y)-were associated with pathogenic variants across phenotype-negative individuals, DCM, and their respective cardiomyocyte RNA expression profiles in advanced heart failure.

CONCLUSIONS

Proteomic profiling in individuals with likely pathogenic/pathogenic variants illuminated integral pathways across the spectrum of DCM. These findings may help advance genotype-driven biomarker discovery and tailored therapeutic development in DCM.