Abstract Body: Background: Cardiac arrest (CA) affects over 600,000 Americans every year and remains a leading cause of death in the United States. After CA, myocardial dysfunction is a common occurrence leading to reduced cardiac output and cardiogenic shock. A broad milieu of molecular changes has been implicated in the post-arrest heart, including decreased ribosomal translation of nascent proteins. The translational changes in the post-arrest heart remain poorly understood.
Methods: Male and female C57 mice (n=8-10/group) were subjected to 8-min of asystole by direct injection of potassium chloride and were revived by cardiopulmonary resuscitation or sham surgery (anesthesia only). Mice were monitored for 24 hours post-arrest through serial neurologic exam, temperature monitoring, and echocardiography. One day after arrest, left-ventricles from sham and CA mice were collected for transcriptomic analysis including bulk RNA sequencing and ribosome profiling (Ribo-seq; n=6/group). Ribo-seq allowed high-resolution quantification of ribosome-associated mRNA fragments, enabling analysis of translation efficiency independent of transcript abundance.
Results: CA mice had reduced ejection fraction (48.9±4.1% in CA compared to ) compared to 60.9±2.7 in sham mice, p<0.05) as well as reduced neurologic score (7.0±0.5 in CA compared to 12.0±0.0 in sham, p<0.05) at one day after arrest. Ribosome profiling revealed widespread suppression of translation efficiency in cytosolic ribosomal genes following CA, including pronounced downregulation of core large subunit transcripts such as Rpl31. In contrast, genes involved in mitochondrial translation and stress adaptation, such as Lars2, Espn, and Cst6, exhibited increased translation efficiency, suggesting a selective shift toward organelle-specific and protective protein synthesis.
Conclusions
These findings demonstrate a post-arrest reprogramming of myocardial translation, marked by global cytosolic ribosomal suppression and targeted upregulation of mitochondrial and stress-responsive pathways. Ribosome profiling provides critical insight into translational regulation in the stunned heart and may identify novel targets to enhance myocardial recovery after cardiac arrest.