X-ray irradiation of the apex of the heart affects cardiac function by modulating the sympathetic nervous system and calcium transients

Epidemiological studies indicate that breast cancer (BC) patients treated with X-ray irradiation (IR) have an increased risk of long-term cardiovascular disease, including arrhythmia, atrial fibrillation and conduction disorders after radiotherapy (RT).

This study examined the effects of low to moderate doses of IR on the cardiac sympathetic nervous system (CSNS), ventricular remodeling, and calcium homeostasis involved in heart rhythm.

To replicate RT for left breast cancer, female C57Bl/6J mice received X-ray doses of 0.5 and 2 Gy targeting 40% of the cardiac apex.

Sixty weeks after IR, Doppler ultrasound revealed reduced ejection fraction, impaired myocardial strain at 2 Gy in the apex and mid-heart region and contractility dyssynchronization at 0.5 Gy. Increased heart rate, combined with shortened RR intervals, indicated impaired left ventricular function and heart rhythm. Proteins involved in calcium transport (RYR2, SERCA2a) were up-regulated. All these results indicate impaired left ventricular function and heart rhythm. Proteins involved in calcium transport (RYR2, SERCA2a) were up-regulated in the atria and ventricles at 2 Gy, while NAK and Kir2.1 were increased only in the ventricles at 0.5 and 2 Gy. Micro-tomography analysis also showed a reduction in diastolic volumes of the aorta at all doses and of the pulmonary artery only at 2 Gy, suggesting vascular dysfunction.

Connexin 40 (Cx40) protein expression increased in a dose-dependent manner and correlated with susceptibility to atrial fibrillation observed at 2 Gy. 3D imaging based on the iDISCO method, revealed a reduction in areas positive for contactin-2 (a marker of the Purkinje cell network), an increase in ventricular sympathetic innervation (tyrosine hydroxylase: TH) and a reorientation of nerve fibres associated with a change in the expression of SEMA3a, which is involved in axonal guidance.

In conclusion, irradiation of the cardiac apex induced long-term alterations in calcium homeostasis, CSNS, and electrical conduction, promoting arrhythmogenic mechanisms and cardiac dysfunction. These findings could help identify preventive strategies against radiotherapy-induced arrhythmias in breast cancer patients and encourage future studies to consider combination treatments of radiotherapy and chemotherapy or immunotherapy that add additional cardiotoxicity.