Radiation Treatment Persistently Alters Heart Cell Function to Produce Benefits in Heart Failure Patients

This paper is interesting as a first step on the way to further research into compensatory therapies that can reduce the cardiac muscle dysfunction of heart failure. One-time radiation therapy appears to persistently change cardiomyocyte behavior via altered epigenetic regulation of notch signaling, leading to modestly improved heart tissue function. Perhaps this should be taken as supportive of efforts to more directly target this regulatory pathway in the aging heart via other means.

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT.

Our study presents findings to suggest that radiation therapy, successfully used in patients with refractory VT, may increase levels of the cardiac sodium channel and improve conduction. Indeed, explanted cardiac specimens obtained from a treated patient with refractory VT revealed threefold higher NaV1.5 protein levels in the radiation-targeted region when compared to a nontargeted region of the same heart, restoring NaV1.5 to levels within the range of nonfailing myocardium. As an observation of the potential effect of RT on human physiology, we also report a non-significant decrease in mean QRS duration in the Electrophysiology-guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) patient cohort, as well as robustly shortened QRS intervals in at least 4 of the 19 patients.

Our findings have direct relevance for patient care. Most surviving patients continue to exhibit reduced VT burden 24 months after a single RT treatment. Our results demonstrate that the functional and molecular effects of RT and Notch reactivation are persistent and expected to directly translate into long-term durability of therapy.

Link: https://doi.org/10.1038/s41467-021-25730-0

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