Early Changes in Rat Heart After High‐Dose Irradiation: Implications for Antiarrhythmic Effects of Cardiac Radioablation

Background Noninvasive cardiac radioablation is employed to treat ventricular arrhythmia. However, myocardial changes leading to early‐period antiarrhythmic effects induced by high‐dose irradiation are unknown. This study investigated dose‐responsive histologic, ultrastructural, and functional changes within 1 month after irradiation in rat heart. Methods and Results Whole hearts of wild‐type Lewis rats (N=95) were irradiated with single fraction 20, 25, 30, 40, or 50 Gy and explanted at 1 day or 1, 2, 3, or 4 weeks’ postirradiation. Microscopic pathologic changes of cardiac structures by light microscope with immunohistopathologic staining, ultrastructure by electron microscopy, and functional evaluation by ECG and echocardiography were studied. Despite high‐dose irradiation, no myocardial necrosis and apoptosis were observed. Intercalated discs were widened and disrupted, forming uneven and twisted junctions between adjacent myocytes. Diffuse vacuolization peaked at 3 weeks, suggesting irradiation dose‐responsiveness, which was correlated with interstitial and intracellular edema. CD68 immunostaining accompanying vacuolization suggested mononuclear cell infiltration. These changes were prominent in working myocardium but not cardiac conduction tissue. Intracardiac conduction represented by PR and QTc intervals on ECG was delayed compared with baseline measurements. ST segment was initially depressed and gradually elevated. Ventricular chamber dimensions and function remained intact without pericardial effusion. Conclusions Mononuclear cell–related intracellular and extracellular edema with diffuse vacuolization and intercalated disc widening were observed within 1 month after high‐dose irradiation. ECG indicated intracardiac conduction delay with prominent ST‐segment changes. These observations suggest that early antiarrhythmic effects after cardiac radioablation result from conduction disturbances and membrane potential alterations without necrosis.

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PO-1914 Early changes in rat heart after high dose irradiation

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)08365-1 ◽

2021 ◽

Vol 161 ◽

pp. S1632-S1633

Author(s):

J.H. Chang

Keyword(s):

Rat Heart ◽

High Dose ◽

Dose Irradiation

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TL dosimetry of natural quartz sensitized by heat-treatment and high dose irradiation

Radiation Measurements ◽

10.1016/j.radmeas.2008.01.028 ◽

2008 ◽

Vol 43 (2-6) ◽

pp. 487-491 ◽

Cited By ~ 14

Author(s):

H.J. Khoury ◽

P.L. Guzzo ◽

L.B.F. Souza ◽

T.M.B. Farias ◽

S. Watanabe

Keyword(s):

Heat Treatment ◽

High Dose ◽

Natural Quartz ◽

Dose Irradiation

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Response of Bone Subjected to Optimized High Dose Irradiation

Journal of Biomaterials Applications ◽

10.1177/0885328208097088 ◽

2008 ◽

Vol 24 (5) ◽

pp. 387-400 ◽

Cited By ~ 4

Author(s):

H. Wilson Burgess ◽

James Mackrell ◽

Derek Toms ◽

Anuradha Karunanidhi ◽

Swaroopa Vaidya ◽

...

Keyword(s):

High Dose ◽

Dose Irradiation

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Improved cellular automata model shows that indirect apoptotic cell death due to vascular damage enhances the local control of tumors by single fraction high-dose irradiation

Biomedical Physics & Engineering Express ◽

10.1088/2057-1976/ac4466 ◽

2021 ◽

Author(s):

Daisuke Kawahara ◽

Yasushi Nagata ◽

Yoichi Watanabe

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Radiation Damage ◽

Apoptotic Cell ◽

Vascular Damage ◽

High Dose ◽

Oxygen Level ◽

Cellular Automata Model ◽

Apoptotic Death ◽

Dose Irradiation

Abstract We investigated the effects of indirect apoptotic cell death due to vascular damage on tumor response to a single large dose with an improved two-dimensional cellular automata model. The tumor growth was simulated by considering the oxygen and nutrients supplied to the tumor through the blood vessels. The cell damage processes were modeled by taking account of the direct cell death and the indirect death due to the radiation-induced vascular damages. The radiation increased the permeation of oxygen and nutrients through the blood vessel or caused the breakdown of the vasculature. The amount of oxygen in cancer cells affected the response of cancer cells to radiation and the tumor growth rate after irradiation. The lack of oxygen led to the apoptotic death of cancer cells. We calculated the tumor control probability (TCP) at different radiation doses, D, the probability of apoptotic death, PO2_ap, the threshold of the oxygen level for indirect apoptotic death, O2t, the average oxygen level in cancer cells, [O2]av, and the vessel survival probability after radiation damage, Pv. Due to the vessel damage, indirect cell death led to a 4% increase in TCP for the dose ranging from 15 Gy to 20 Gy. TCP increased with increasing PO2_ap and O2t due to increased apoptotic death. The variation of TCP as a function of [O2]av exhibited the minimum at [O2]av of 2.7%. The apoptosis increased as [O2]av decreased, leading to an increasing TCP. On the other hand, the direct radiation damage increased, and the apoptosis decreased for higher [O2]av, resulting in a higher TCP. We showed by modeling the radiation damage of blood vessels in a 2D CA simulation that the indirect apoptotic death of cancer cells, caused by the reduction of the oxygen level due to vascular damage after high dose irradiation, increased TCP.

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Prenatal ethanol exposure impairs the conduction delay at the atrioventricular junction in the looping heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00107.2021 ◽

2021 ◽

Author(s):

Shan Ling ◽

Michael W Jenkins ◽

Michiko Watanabe ◽

Stephanie M Ford ◽

Andrew M Rollins

Keyword(s):

Heart Development ◽

Molecular Mechanisms ◽

Early Stage ◽

Heart Defects ◽

Ethanol Exposure ◽

Cardiac Conduction ◽

Conduction Delay ◽

Prenatal Ethanol Exposure ◽

Endocardial Cushions ◽

Atrioventricular Junction

The etiology of ethanol-related congenital heart defects has been the focus of much study, but most research has concentrated on cellular and molecular mechanisms. We have shown with optical coherence tomography (OCT) that ethanol exposure led to increased retrograde flow and smaller atrioventricular (AV) cushions compared to controls. Since AV cushions play a role in patterning the conduction delay at the atrioventricular junction (AVJ), this study aims to investigate whether ethanol exposure alters the AVJ conduction in early looping hearts and whether this alteration is related to the decreased cushion size. Quail embryos were exposed to a single dose of ethanol at gastrulation, and Hamburger-Hamilton stage 19 - 20 hearts were dissected for imaging. Cardiac conduction was measured using an optical mapping microscope and we imaged the endocardial cushions using OCT. Our results showed that, compared with controls, ethanol-exposed embryos exhibited abnormally fast AVJ conduction and reduced cushion size. However, this increased conduction velocity (CV) did not strictly correlate with decreased cushion volume and thickness. By matching the CV map to the cushion size map, we found that the slowest conduction location was consistently at the atrial side of the AVJ, which had the thinner cushions, not at the thickest cushion location at the ventricular side as expected. Our findings reveal regional differences in the AVJ myocardium even at this early stage in heart development. These findings reveal the early steps leading to the heterogeneity and complexity of conduction at the mature AVJ, a site where arrhythmias can be initiated.

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Abstract 16851: ST Segment Variability as a Predictor of Clinical Deterioration in Hypoplastic Left Heart Syndrome

Circulation ◽

10.1161/circ.130.suppl_2.16851 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Eric L Vu ◽

Craig G Rusin ◽

Dan J Penny ◽

Kathy K Kibler ◽

Ronald B Easley ◽

...

Keyword(s):

Hypoplastic Left Heart Syndrome ◽

Clinical Deterioration ◽

Cardiac Conduction ◽

Control Group ◽

High Risk Population ◽

Left Heart ◽

Hypoplastic Left Heart ◽

St Segment ◽

Icu Discharge ◽

Left Heart Syndrome

Introduction: The interstage mortality rate for hypoplastic left heart syndrome (HLHS) is high at 12%. Modalities to predict clinical decline would be useful in this high risk population. Due to cardiac conduction system anomalies in HLHS, electrocardiogram (ECG) monitoring of the ST segment is confounded. Our aim is to develop a monitor of ST variability that predicts deterioration despite the presence of an abnormal ST segment baseline. Hypothesis: Increased ST variability is associated with clinical deterioration in HLHS. Methods: A prospective, observational study was conducted at Texas Children’s Hospital using interstage recordings of 5 lead ECG. From January 2013 to January 2014, 25 subjects were admitted with HLHS; 21 had requisite ECG data for inclusion. In 11 subjects, there were 17 deterioration events, defined as rapid response team (RRT) activation. Events included 13 instances of respiratory failure with intubation and 4 instances of chest compressions. The control group included 10 subjects with no deterioration. An approach to quantify variability was developed where the ST segment vector was resolved using 3 orthogonal leads (II, V5, and aVF) and variability quantified with two metrics: 1) Displacement: distance between ST vector tips at 30 s intervals and 2) Component range: sum of ST vector tip movement in 3 dimensions over 10 min intervals. Comparison was made with the four hour window prior to RRT activation in the deterioration group against the four hour window prior to ICU discharge in the control group. Results: Four hours prior to clinical deterioration, increased ST variability was noted in both methods. For the 30 s displacement method, subjects with deterioration had a median value of 0.059 mm [IQR: 0.039 - 0.075] compared with 0.037 mm [IQR: 0.025 - 0.053] in the control group (p = 0.023). For the 10 min component range method, subjects with deterioration had a median value of 3.0 mm [IQR: 1.8 - 4.5] compared with 1.9 mm [IQR: 1.0 - 2.8] in the control group (p = 0.031). Conclusions: ST variability is increased in HLHS subjects prior to deterioration. Although conduction abnormalities limit the utility of ST monitoring in this population, quantification of ST variability may have a role in advanced systems to monitor clinical deterioration.

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