Clinically, RT was associated with increased Na V1.5 expression in 1 of 1 explanted heart. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to Na V1.5 upregulation after RT. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in Na V1.5 and Cx43.
![]() ![]() Serial ECGs improve the sensitivity of ST elevation on the ECG for MI. All ST elevation (and T-wave size) should be assessed relative the QRS amplitude. Repolarization (ST-T) is proportional to depolarization. Serial Ecgs Series Reported ASimilar outcomes have since been replicated by several independent medical centers 10, 11, 12. More recently, a prospective Phase I/II trial of 19 patients who had either previously failed or were not eligible for CA reported a 94% reduction in episodes of VT or premature ventricular contractions and a 12-month survival rate of 72% in this very sick population 10. The first case series reported a 99.9% reduction in VT burden after treatment with 25 Gray (Gy) ionizing radiation 9. Recent clinical evidence has demonstrated the safety and efficacy of cardiac RT for treatment of refractory VT in patients 9, 10, 11. Hypothetically, ablative doses of radiation could noninvasively replicate effects of CA, with a fibrotic response expected over months to years 6, 7, 8. Posted by Steve Smith at 7:05 AM.Radiotherapy (RT) noninvasively delivers high-dose radiation to volumes of target tissue anywhere in the body, with minimal off-target exposure, and is well established for treating malignancies. ![]() In mice and patients, we find that 25 Gy persistently increases levels of cardiac conduction proteins and enhances ventricular conduction. Using explanted specimens from cardiac RT patients, we show that 25 Gy photon radiation, used in all clinical studies to date, was not sufficient to achieve CA-like scar. Though radiation is presumed to prevent arrhythmia by creating fibrosis in arrhythmogenic scar, the antiarrhythmic effects preventing reentry could potentially act through effects on ERP and/or CV.In this study, we evaluated effects of ionizing radiation on the heart. To date, there are no approved VT therapies that act through increasing CV. CA prevents reentry by terminating conduction substrates, while management with Class III AADs prolongs the action potential duration (APD) and ERP to increase wavelength 25. Hence, the presence of long, tortuous substrates, fast repolarization, and slowed CV all predispose to reentry. Percent fibrosis of the CA region for Patient A is shown in purple. D Percent fibrosis at the time of heart explant from 4 patients who received 25 Gy RT in control (left) and targeted (right) regions of myocardium. Experiment was independently repeated once on the same patient samples and produced similar results. Here we further discuss therapeutic strategies for reprogramming ventricular cardiomyocytes to a pro-conduction phenotype to prevent electrical reentry.A– c Representative Masson’s trichrome stains of regions of remote ( a), targeted ( b), and failed CA ( c) myocardium in the same patient who received 25 Gy ionizing radiation for treatment of refractory VT. We also report a statistically nonsignificant difference in QRS intervals, with a tendency toward QRS shortening, in 19 patients treated with RT. Nonenhanced, remote myocardium is adjacent to target region (white arrowhead). Top: the left ventricle with patchy, gadolinium-enhanced scar was transmurally targeted with 25 Gy between 3 and 6 O’clock (red brackets). F Gadolinium-enhanced MRI of a cardiac RT patient at baseline (left) and 3 months post-treatment (right). *Patient D’s values are divided by 20 to allow for comparisons on the same scale. Days post-treatment until specimen collection are shown in the legend. 1f), and there was no evidence of increased fibrosis on MRI post-RT in any patient. Representative contrast-enhanced magnetic resonance imaging (MRI) scans of Patient E revealed no change in gadolinium enhancement and preserved myocardial tissue between baseline and at 3-month follow-up in the RT-targeted region (Fig. Independent of fibrosis, all four patients experienced substantial reductions in VT episodes in the 6 months following RT (Fig. Using image-segmented analysis, we observed only minor differences in fibrosis between matched targeted and nontargeted regions of patients’ hearts, and fibrosis was lower in all radiation-targeted myocardium when compared to CA myocardium (Fig. Given that anatomic scarring is important for prescribing treatment locations and volumes 9, greater fibrosis is expected in radiation-targeted regions even prior to treatment. Source data are provided as a Source data file.At baseline, individual hearts exhibited distinct levels of underlying fibrosis. New games for mac septemberAt 6 weeks post-IR, we performed Masson’s trichrome staining to assess for gross evidence of fibrosis and did not detect significant collagen staining in either treatment condition after 6 weeks (Supplementary Fig. 2), a property of radioresistant tissues that demonstrates DNA repair and survival 27. Both percentages of γH2AX-positive nuclei and mean γH2AX intensity decreased with respect to time (Supplementary Fig. To test whether post-mitotic mammalian cardiomyocytes recover from 25 Gy radiation-induced DNA damage, murine hearts were stained at 30 min, 3 h, and 24 h post-IR for phosphorylated histone H2AX (γH2AX), a marker of double-stranded DNA breaks 26. Twenty-five Gy radiation reprograms cardiac electrophysiology and increases conductionTo further evaluate effects of 25 Gy irradiation (IR) to the heart, we assessed for structural and physiologic changes to the murine heart post-IR. Collectively, these data strongly suggest that fibrosis alone cannot explain the clinical timeline and magnitude of reduced VT burden observed after RT. Because RT reduces VT in the absence of profound CA-like structural change, we evaluated electrophysiologic mechanisms by which IR may prevent reentry. 3b).Electrophysiologic and structural remodeling both contribute to arrhythmogenic substrates in the setting of disease.
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