Proteomics in Cardiovascular Deaths, a Postmortem Pilot Study: The Diagnostic Efficacy of α-1 Antitrypsin and Apolipoprotein A-IV in Ischemic and Congestive Deaths

Background/Objectives: Determining the cardiovascular cause of death, particularly distinguishing ischemic from congestive mechanisms, remains challenging in forensic practice, especially in early ischemia without definitive histological findings. Proteomic techniques and molecular profiling may provide complementary diagnostic information beyond conventional autopsy. Methods: We applied an untargeted high-resolution proteomic approach to postmortem cardiac tissue samples from cardiovascular (ischemic and congestive) and non-cardiovascular deaths. Identified proteins were analyzed using bioinformatic and differential expression workflows. Selected candidates were evaluated in peripheral blood samples for translational validation using statistical modeling, including regression analyses and receiver operating characteristic (ROC) curve assessment. Results: A total of 572 proteins were identified. Although no proteins fulfilled strict exclusivity criteria for a single cause-of-death group, differential expression analysis revealed distinct molecular patterns distinguishing ischemic, congestive, and non-cardiovascular deaths. Thirty-one proteins were differentially expressed between ischemic and congestive cases, including α-1 antitrypsin (AAT), plasma levels did not demonstrate statistically significant discrimination. In contrast, plasma Apolipoprotein A-IV (ApoA-IV) levels were significantly associated with ischemic death in regression models, and ROC analysis yielded a cutoff point with complete separation between ischemic and selected non-cardiovascular cases. However, the limited sample size warrants cautious interpretation due to potential overfitting. Conclusions: Postmortem cardiac proteomic profiling reveals biologically coherent molecular signatures associated with different cardiovascular causes of death. Although further validation in larger independent cohorts is required, ApoA-IV emerges as a promising candidate biomarker for ischemic cardiac death. Multimarker proteomic strategies may complement traditional autopsy to enhance diagnostic accuracy in forensic investigations, particularly in cases with equivocal morphological findings.