Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Abstract

Background: Myocarditis-induced inflammation disrupts the intricate genetic architecture governing cardiomyocyte development and function. Understanding the specific disruptions in key regulators, such as Isl1, Nkx2–5, GATA4, and signaling pathways like Wnt and BMPs, is crucial for unraveling the molecular underpinnings of cardiac dysfunction. This investigation holds paramount importance in informing targeted therapeutic strategies to mitigate inflammation-induced genetic disruptions, offering potential breakthroughs in the management of myocarditis and improving outcomes for affected individuals. Methods: Databases, including PubMed, MEDLINE, and Google Scholar, were searched for published articles without any date restrictions, focusing on cardiac genes, signaling pathways, and transcription factors, with an emphasis on NF-κB in myocarditis. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study reveals profound disruptions in the genetic architecture of cardiomyocytes. Transcriptional regulatory networks crucial for cardiomyocyte differentiation, including Isl1, Nkx2–5, GATA4, and Tbx5, exhibit altered expression patterns, suggesting compromised maturation processes. The Brg1/Baf60 – Smarcd3 complex, HAND1/2, and MYOCD, essential for cardiogenic regulation, are susceptible to inflammatory damage, impacting cell fate determination. NF-κB-mediated damage to BMPs and the Wnt-signaling pathway results in downstream shifts, affecting gene expression dynamics. These disruptions, coupled with compromised survival mechanisms and heightened apoptotic susceptibility, contribute to cardiac dysfunction and increased arrhythmogenic risk. Altered ECM remodeling and fibrosis further underscore the complexity of myocarditis-induced genetic alterations. Insights from these results hold implications for developing targeted therapeutic strategies aimed at mitigating inflammation-induced genetic disruptions and preserving cardiac health in the context of myocarditis. Conclusion: Myocarditis-induced inflammation disrupts the intricate genetic architecture of cardiomyocytes, compromising key regulators like Isl1, Brg1/Baf60 complex, Nkx2–5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt signaling, Notch, FGF, and BMPs. This disruption leads to impaired cardiomyocyte differentiation, compromised survival mechanisms, dysregulated ECM remodeling, and heightened pro-inflammatory responses, collectively resulting in cardiac dysfunction and structural abnormalities. Targeted therapeutic interventions to mitigate inflammation-induced genetic disruptions are crucial for preserving optimal cardiac function in the challenging landscape of myocarditis.