Glucocorticoid Receptor Antagonism and Cardiomyocyte Regeneration Following Myocardial Infarction: A Systematic Review.

Myocardial regeneration has been a topic of interest in literature and research in recent years. An evolving approach reported is glucocorticoid (GC) receptor antagonism and its role in the regeneration of cardiomyocytes. The authors of this study aim to explore the reported literature on GC receptor antagonism and its effects on cardiomyocyte remodeling, hypertrophy, scar formation, and ongoing cardiomyocyte death following cardiac injury. This article overviews cellular biology, mechanisms of action, clinical implications, challenges, and future considerations. The authors of this study conducted a systematic review utilizing the Cochrane methodology and PRISMA guidelines. This study includes data collected and interpreted from 30 peer-reviewed articles from 3 databases with the topic of interest. The mammalian heart has regenerative potential during its embryonic and fetal phases which is lost during its developmental processes. The microenvironment, intrinsic molecular mechanisms, and systemic and external factors impact cardiac regeneration. GCs influence these aspects in some cases. Consequently, GC receptor antagonism is emerging as a promising potential target for stimulating endogenous cardiomyocyte proliferation, aiding in cardiomyocyte regeneration following a cardiac injury such as a myocardial infarction (MI). Experimental studies on neonatal mice and zebrafish have shown promising results with GC receptor ablation (or brief pharmacological antagonism) promoting the survival of myocardial cells, re-entry into the cell cycle, and cellular division, resulting in cardiac muscle regeneration and diminished scar formation. Transient GC receptor antagonism has the potential to stimulate cardiomyocyte regeneration and help prevent the dreaded complications of MI. More trials based on human populations are encouraged to justify their applications and weigh the risk-benefit ratio.

Gene Editing as the Future of Cardiac Amyloidosis Therapeutics.

Cardiac Amyloidosis (CA) is a manifestation of a systemic disorder resulting from the deposition of transthyretin (TTR) in the myocardium. This leads to a myriad of manifestations ranging from conduction defects to heart failure. Previously CA was considered a rare disease, but recent advances in diagnostics and therapeutics have revealed the prevalence to be higher than estimated. There are two major classes of treatments for TTR cardiac amyloidosis (ATTR-CA): TTR stabilizers, such as tafamidis and AG10, and RNA interference (siRNA), such as patisiran and vutrisiran. Clustered regularly interspaced short palindromic repeats of genetic information-Cas9 endonuclease (CRISPR-Cas9) utilizes an RNA-guided endonuclease to target specific locations in the genome. Until recently, CRISPR-Cas9 was studied in small animal models for its ability to decrease extracellular deposition and accumulation of amyloid in tissues. Gene editing has demonstrated some early clinical promise as an emerging therapeutic modality in the treatment of CA. In an introductory human trial involving 12 subjects with TTR amyloidosis and amyloid cardiomyopathy (ATTR-CM), CRISPR-Cas9 therapy has demonstrated a reduction in approximately 90% of serum TTR proteins after 28 days. In this article, the authors review the current literature on therapeutic gene editing as a prospective curative treatment modality for CA.