Discovery of potential plasma protein biomarkers for ventricular fibrillation due to first ST-elevation myocardial infarction via proteomics

Abstract

Abstract Background Although most sudden cardiac deaths are a consequence of ventricular fibrillation (VF) subsequent to myocardial infarction, the underlying biological mechanisms of VF in the setting of ischemia are largely unknown. We used an unbiased mass-spectrometry (MS)-based proteomic approach to improve our understanding of the molecular VF mechanisms. Purpose We aimed to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). Methods We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n=110) and without VF (control, n=120) before guided catheter insertion for primary percutaneous coronary intervention. Using MS-based proteomics on plasma samples collected within 24h of symptom onset, we investigated the plasma proteome. After quality control, one patient was excluded and the difference in the quantitative proteome composition between cases and controls were analysed using t-tests, and further corrected for multiple comparison using the Benjamini-Hochberg procedure (q-value). Cardiac enzymes and anterior infarct location were used in a subset as a proxy for large myocardial damage. Results In 229 STEMI patients (72% men, median age 62 years (interquartile range (IQR): 54-70)), a total of 401 unique proteins were identified with a median of 257 proteins (IQR: 244-281) quantified per patient. A total of 26 proteins were associated with VF, these proteins were involved in several biological processes. The most frequent processes were blood coagulation, hemostasis and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 (ACTBL2, FC 2.25, p<0.001, q=0.023) and coagulation factor XIII-A (F13A1, FC 1.48, p<0.001, q=0.023). The most up-regulated protein was ACTBL2, and the second most up-regulated protein was actin alpha 2 (ACTA2, FC 1.72, p=0.001, q=0.073). None of the three proteins were correlated with cardiac enzymes or anterior infarct location. Conclusion VF due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1). None of these proteins were correlated with infarct size which could reflect novel underlying molecular VF mechanisms.