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Cardiac Radiotherapy-Induced Epigenetic Memory Underlies Electrophysiologic and Metabolic Reprogramming [RNA-seq]

ABSTRACT: Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate via modulating ion channel expression, though the mechanisms whereby single-fraction radiation mediates durable changes in gene expression are incompletely understood. The DNA damage response (DDR) recruits epigenetic regulators during the repair process after irradiation (IR). Here, we demonstrate acute changes in the cardiomyocyte epigenome and transcriptome after IR in vivo and in vitro. A subset of changes persist as late as 6 weeks post-IR in mice, including increased Scn5a expression and chromatin accessibility (encoding the alpha subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity increases observed after STAR. Transcriptomic and epigenetic sequencing further identify dynamic changes to gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. Gene expression changes are mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration after IR, highlighting important cellular processes which may mediate both therapeutic and toxic effects of STAR. Cardiomyocyte-specific knockout of p53 failed to blut conduction velocity changes post-IR, and improved ROS scavenging via SOD2 overexpression had minimal impact on the post-IR transcriptome. Overall, we find that cardiomyocytes exposed to a single fraction of high-dose IR exhibit epigenetic reprogramming that mediates broad and dynamic physiologic responses.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE291280 | GEO | 2026/01/28

REPOSITORIES: GEO

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Project description:Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a leading cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological host immune responses. However, little is known regarding how viral infection can acutely induce an arrhythmogenic substrate prior to significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology. We have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy. By optical mapping of infected hearts we find decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against MAdV-3 induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.

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Cardiac Radiotherapy-Induced Epigenetic Memory Underlies Electrophysiologic and Metabolic Reprogramming [RNA-seq]

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