Integrative Proteomic and Transcriptomic Profiling Identifies Candidate Biomarkers for Discriminating Anaphylactic from Cardiac Sudden Death

TL;DR

This study identifies potential blood markers to help distinguish sudden deaths caused by anaphylaxis from those caused by heart disease.

Contribution

The study introduces a novel multi-marker framework for forensic diagnosis of sudden death using proteomic and transcriptomic data.

Findings

FN1, GP1BA, and PF4 were identified as candidate biomarkers for distinguishing ASD from SD-CHD.

FN1 was significantly upregulated in SD-CHD myocardial samples and in ASD airway epithelium.

PRM, ELISA, and IHC validated the biomarkers in mouse models and human post-mortem tissues.

Abstract

To address the forensic diagnostic challenge of distinguishing Anaphylactic Sudden Death (ASD) from Sudden Death from Coronary Heart Disease (SD-CHD), this study established Ldlr−/− mouse models of Atherosclerosis (AS) and ovalbumin-induced Anaphylaxis (AP). LC-MS/MS-based serum proteomic analysis of Atherosclerosis (AS) and Anaphylaxis (AP) mice identified fibronectin 1 (FN1), platelet glycoprotein Ibα chain (GP1BA), and platelet factor 4 (PF4) as candidate biomarkers. These candidates were validated by parallel reaction monitoring (PRM), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC) in a combined AS + AP mouse model and in post-mortem human cardiac and bronchiolar epithelial tissue. In mice, serum FN1, GP1BA, and PF4 levels were significantly elevated in the AS group, whereas only FN1 was markedly downregulated in AP mice. In human tissues, FN1, GP1BA, and PF4 were all upregulated in Sudden death from coronary heart disease (SD-CHD) myocardial samples, with FN1 showing the greatest increase. In airway epithelium, FN1 was upregulated in anaphylactic sudden death (ASD) and anaphylactic sudden death (ASD) with Coronary Atherosclerosis (ASD + CAS) groups, while GP1BA was downregulated. These results indicate that FN1 serves as a key differential mouse serum biomarker, while PF4 and GP1BA aid in Sudden death from coronary heart disease (SD-CHD) diagnosis. Collectively, this multimarker, multilevel framework provides a molecular diagnostic strategy for the forensic identification of complex sudden death.

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