Ribosomal Remodeling and Translational Suppression in the Post-Arrest Heart
Background: Cardiac arrest (CA) is a leading cause of death and disability in the United States, and no pharmacologic therapies improve post-arrest outcomes. Acute myocardial dysfunction is a highly prevalent CA complication that contributes to post-arrest mortality, yet the molecular mechanisms that drive this dysfunction remain incompletely understood. Prior work in our laboratory has suggested that ribosome-associated pathways are altered after CA in the heart and that translational dysregulation may be a central feature of post-arrest myocardial injury. Objectives: To define the impact of CA on myocardial ribosome biology and protein synthesis across experimental models of CA and determine how transcriptome, ribosome-bound transcriptome, translational efficiency, and proteome changes evolve after CA in the heart. Methods: We studied complementary porcine and murine models of CA. In pigs, left ventricular myocardium was collected from naive controls, cardiac arrest with return of spontaneous circulation (Arrest), and cardiac arrest with pulseless electrical activity (PEA) re-arrest in a myocardial infarction-induced CA model and analyzed tissue by RNA sequencing. In mice, left ventricular tissue was collected at various time points after potassium chloride-induced asystole and resuscitation for ribosome activity and multi-omic profiling including RNA sequencing, ribosome profiling, and proteomics. Results: In the porcine model, myocardial transcriptomes demonstrate enrichment of cytosolic ribosomal protein transcripts and translation-related pathways that increase with ischemic burden. In contrast, a functional assay of ribosome activity in mice demonstrates suppression of protein synthesis after CA with gradual recovery over days. Multi-omic profiling in the mouse model demonstrates that ribosome- and translation-related pathways are among the most consistently altered programs across time points and modalities. While 6 h studies note prevalent inflammatory signals, 24 h studies find disruptions to ion homeostasis and conduction-related pathways that are likely related to translational suppression. Conclusions: CA induces marked remodeling of myocardial ribosome biology, characterized by increasing ribosomal transcripts with ischemic burden in the pig model. However, functional studies in the mouse model demonstrate that ribosome activity is suppressed following CA and remains suppressed for at least 24 h after resuscitation, contributing to reduced nascent protein synthesis and may limit critical functions of the heart. These findings identify translational control as a central feature of post-arrest myocardial injury and suggest that ribosome-dependent recovery pathways may represent a novel therapeutic target in post-arrest cardiac dysfunction.