Novel Protein-Based Biomarkers of Out-of-hospital Sudden Cardiac Death After Myocardial Infarction

BACKGROUND: Early identification of out-of-hospital high-risk sudden cardiac death (SCD) after acute myocardial infarction is crucial for timely therapeutic interventions. However, left ventricular ejection fraction as a standalone clinical stratification tool has major limitations, necessitating improved risk stratification strategies. METHODS: Mass spectrometry measured 6592 peptides and 522 proteins, from which targeted proteomics identified the optimal protein combination to assess out-of-hospital SCD risk. ELISA validated its predictive value by comparing it with a clinical stratification tool (left ventricular ejection fraction ≤35%) and 2 reported models (risk score and out-of-hospital cardiac arrest score) in 3 case-control cohorts nested within diverse contemporary postinfarction populations. RESULTS: In the discovery cohort (105 SCD cases and 105 survivors), mass spectrometry discovered 44 differential proteins associated with SCD, unveiling early circulating features characterized by inflammatory response and complement activation in out-of-hospital SCD cases. Targeted proteomics identified the optimal SCD-warning 3-protein combination, including coronin-1A, haptoglobin, and CFD (complement factor D), to assess out-of-hospital SCD risk. An ELISA-based SCD-warning 3-protein combination model significantly outperformed left ventricular ejection fraction alone (C statistic: 0.752 versus 0.548; P <0.001) and improved their performance (ΔC statistic, 0.281; categorical net reclassification improvement, 0.095; continuous net reclassification improvement, 0.952; integrated discrimination improvement, 0.291). Similar incremental discrimination metrics were observed in 2 reported stratification models (risk score and out-of-hospital cardiac arrest score), particularly within the left ventricular ejection fraction-preserved population. These findings were repeatably validated in 2 independent cohorts (n=234 and 48, respectively). CFD inhibition protection for mortality and pro-malignant arrhythmias in acute myocardial infarction mice supported the biological plausibility of the critical protein in SCD-warning 3-protein combination. CONCLUSIONS: In high-risk individuals for out-of-hospital SCD, the SCD-warning 3-protein combination may contribute to enhanced early identification for timely intensive management. These findings suggest pivotal proteins for improving understanding SCD pathophysiology.