Authors: Tanner Frahm, Eugene Kwan, Ravi Ranjan
Mentors: Ravi Ranjan
Insitution: University of Utah
Introduction:
Stereotactic body radiation therapy (SBRT) is a non-invasive treatment for ventricular tachycardia (VT) that acts as a promising alternative to the current gold-standard treatment, catheter ablation. Preliminary clinical successes indicate the promise of SBRT while subsequent animal studies suggest that the mechanism of SBRT is novel and unknown. We propose SBRT may alter Connexin-43 (Cx43) gap-junction distribution in cardiac myocyte walls, affecting electrical conduction and reducing VT episodes. A large animal model was used to evaluate Cx43 changes post-SBRT, aiming to elucidate its mechanism of action. Understanding this could expand SBRT's use in arrhythmia management and explore myocyte reprogramming.
Methods:
A large animal model (n=3) underwent cardiac SBRT on portions of their heart. Each animal provided control, untreated tissue, and treated tissues. Post-treatment, the hearts were excised, perfused, and preserved. Transmural sections were processed for histological and confocal microscopy analyses to assess scarring and Cx43 distribution. An algorithm for semi-automatic myocyte segmentation and Cx43 distribution analysis was developed and used. Two-sample student t-tests were conducted to compare Cx43 distribution between treated and control regions. All image and statistical analysis were performed in MATLAB.
Results/Discussion:
Preliminary results for the three preliminary animals indicate that treated regions of the myocardium had statistically significant differences in Cx43 distribution (p-values < 0.05). Treated values (mean standard deviation) were 48% 25%, 62% 26%, and 64% 17% of the distribution of Cx43 on the longitudinal ends while the untreated were 42% 30%, 44% 25% and 26% 16%. The proportion of Cx43 distributed along the longitudinal axis (the short ends of the myocyte) increased in all three animals. The results build on the findings of previous animal studies which suggested that the scarring like ablation was not the mechanism, but that Cx43 or other cellular components could be changing in response to therapy.
Conclusions:
The findings support the hypothesis that Cx43 distribution changes in response to SBRT indicating that the radiation could be inducing remodeling at the cellular level. Evidence of non-invasive cardiac reprogramming provides basic science credence to the preliminary and ongoing clinical studies evaluating the treatment in patients. The findings further inform and motivate more animal studies and analysis of changes to other cellular components.