MARK4 as a novel biomarker of acute myocardial ischemia-induced sudden cardiac death.

Abstract

Postmortem diagnosis of acute myocardial ischemia (AMI), especially early myocardial ischemia (EMI; ischemic insults occurring within minutes to a few hours, <6h), remains challenging due to nonspecific morphological changes. Microtubules affinity regulated kinase 4 (MARK4) is a serine/threonine kinase involved in the regulation of microtubule dynamics through the phosphorylation of microtubule-associated proteins. Emerging research has highlighted the significant involvement of MARK4 in cardiovascular diseases. The aim of this study is to evaluate whether MARK4 can serve as a postmortem diagnostic marker for sudden cardiac death (SCD) resulting from AMI. Using a mouse AMI model, hypoxia-treated AC16 cardiomyocytes, and human autopsy material (36 SCD hearts: 18 EMI, 18 myocardial infarction (MI) and 20 noncardiac controls), MARK4 expression was assessed by immunohistochemistry and western blotting, and diagnostic performance was examined by receiver operating characteristic (ROC) analysis. MARK4 expression increased with ischemia/hypoxia in vivo and in vitro, peaking at 3&#xa0;h. Human myocardial MARK4 was significantly elevated in EMI and MI versus controls, independently of age and postmortem interval. ROC analysis discriminated EMI from controls with an AUC of 0.8028 for MARK4, outperforming cardiac troponin I (cTnI; AUC = 0.7556), and combining both markers improved diagnostic accuracy. In hypoxic AC16 cells, MARK4 overexpression increased cytochrome c and phosphorylated Drp1, suggesting a role in ischemia-related mitochondrial dysfunction. These results indicate MARK4 is a promising postmortem biomarker for AMI-induced SCD.