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

Abstract

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.

Cardiac stereotactic ablative radiotherapy for control of refractory ventricular tachycardia: initial UK multicentre experience

“…33 Data taken at serial timepoints up to 4 weeks post irradiation in a rat model did not show necrosis or apoptosis, rather interstitial and intracellular oedema, reflected in slowed conduction with prolongation of PR and QT intervals. 34 However, any perturbation of myocardial conduction whether increase or decrease may be sufficient to prevent re-entrant VT and most recent data again points to a 'supraphysiologic' phenotype induced by radiation. 35 The acute and late side effects of radiotherapy also need consideration, including those affecting the heart itself.…”

Leveraging Radiobiology for Arrhythmia Management: A New Treatment Paradigm?

“…In the absence of fibrosis, several phenotypic changes have been observed in a subset of clinical and preclinical studies, including the presence of vacuolar degeneration [44,60,69,85], nuclear atypia [17], necrosis [44], celljunction disruption [44,85], immune cell infiltrates [69,85] and microvascular haemorrhaging [69]. These phenotypic changes are presumed to have potential physiological consequences.…”

“…The precise biology behind radiation-induced functional ablation is unclear but may be attributed to some combination of oxidative stress, mitochondrial dysfunction [44,88,89], endoplasmic reticulum dysfunction [56,90,91], inflammation [57,85,92] and/or dysregulated intercellular coupling [44,85]. Excessive ROS production after radiation therapy can alter mitochondrial membrane stability, create local redox imbalances and cause substantial mitochondrial dysfunction or genomic instability.…”

“…Excessive ROS production after radiation therapy can alter mitochondrial membrane stability, create local redox imbalances and cause substantial mitochondrial dysfunction or genomic instability. Although long-term mitochondrial dysfunction may lead to cytochrome c release and induction of apoptosis [85,93,94], as evidenced by the detection of caspase-3 in porcine ventricles treated with >30 Gy after 12e16 weeks [70], short-term dysfunction may cause an acute conduction block in highly metabolic cardiomyocytes. These potential mechanisms may be consistent with several of the phenotypic changes described to date, and the progression from these subacute observations to collagen deposition and scar formation is still under investigation [70].…”

“…Radiation is observed to cause chronic dose-dependent interruptions in electric conduction in the dose ranges of 20e55 Gy [36e40, 68,85,94,95] and robust conduction block was consistently observed at higher doses (Figure 2). Yet, these observations are primarily reported in studies that targeted the atrioventricular node and pulmonary vein.…”