Identification of Biomarkers of Arrhythmogenic Cardiomyopathy (ACM) by Plasma Proteomics

Abstract

Background and Objectives: The pathophysiology of arrhythmogenic cardiomyopathy (ACM), previously known as arrhythmogenic right ventricular cardiomyopathy (ARVC), and its specific biological features remain poorly understood. High-throughput plasma proteomic profiling, a powerful tool for gaining insights into disease pathophysiology at the systems biology level, has not been used to study ACM. This study aimed at characterizing plasmatic protein changes in patients with ACM, which were compared with those of healthy controls, and at exploring the potential role of the identified proteins as biomarkers for diagnosis and monitoring. Materials and Methods: Blood samples were collected from six ACM patients, four patients with other cardiomyopathies, and two healthy controls. Plasma was processed to remove high-abundance proteins and analyzed by two-dimensional gel electrophoresis. Differential protein expressions were assessed using PDQuest software, Bio-Rad US version 8.0.1. Results: The analysis revealed several proteins with altered expressions between ACM patients and controls, including plakophilin-2, junctional plakoglobin, desmoplakin, desmin, transmembrane protein 43, and lamin A/C. Conclusions: The plasma proteomic profiling of ACM suggests that ACM is a distinct disease entity characterized by a unique dysregulation of desmosomal proteins. The identification of plasma biomarkers associated with ACM underscores their potential to improve diagnostic accuracy and facilitate early intervention strategies. Further exploration of mutations in desmosomal proteins and their phosphorylation states may provide deeper insights into the pathophysiology of ACM.

Keywords: arrhythmogenic cardiomyopathy; biomarkers; desmosomal proteins; phosphorylation; proteomics.

Figure 1

Protein profiles obtained by 2DE pH 3-10. The figures (A–D) are for the gel proteins profiles (A) Gel A Protein profile of female control (TF), (B) Gel B Protein profile of patient A2, the arrow 2 represent LMNA, (C) Gel C Protein profiles of patient A8, the arrow 1 represented PKP2; the arrow 2 represent LMNA and the arrow 6 represent TMEM43, (D) Gel D Protein profiles of patient A9; the arrow 1 represent PKP2 and the arrow 6 represent TMEM43). The arrow numbers 1, 2, 3, 4, 5, and 6 represent the proteins: 1: PKP2, 2: LMNA, 3: DSP, 4: JUP, 5: DES, 6: TMEM43. The X-axis stands for the isoelectric point (PI), and the Y-axis for the molecular mass (MM).

Figure 2

Protein profiles obtained by 2DE pH 3–10. The figures (A–D) are for the gel proteins profiles: (A) Gel E Protein profile patient A12, (B) Gel F Protein profile male control, (C) Gel G Protein profiles of patient A11, the arrow 1 represented PKP2; the arrow 3 represent DSP, (D) Gel H Protein profiles of patient A13; the arrow 1 represent PKP2, the arrow 2 represent LMNA the arrow 3 represent DSP, the arrow 4 represent JUP and the arrow 5 represent DES. The arrow numbers 1, 2, 3, 4, 5, and 6 are for the proteins: 1: PKP2, 2: LMNA, 3: DSP. The X-axis stands for the isoelectric point (PI), and the Y-axis for the molecular mass (MM).