Will Heavy Ion Irradiation, a New Tissue Modification Technology, Open New Horizons for Arrhythmia Therapy?
Article ID: CJ-22-0793
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Article ID: CJ-22-0793
In the field of clinical irradiation therapy, 2 types of beams are used. One is the photon beam, which is electromagnetic beam such as X-rays and gamma rays, and the other one is a particle beam, which comprises hyper-accelerated nuclei.1 Thanks to recent advances in nuclei accelerators, various nuclei, including hydrogen to uranium, can be accelerated to considerable levels of speed. In contrast to smaller nuclei, such as hydrogen, helium, etc., larger ions than these light ions are called heavy ions. When these accelerated heavy ions collide with target materials, damage occurs from the mechanical and radiation energies, although the precise mechanism of causation of such injuries is still unclear (Figure 1).2,3 In the clinical setting, carbon nuclei are used as a heavy ion beam that can be accelerated up to 70% of light speed.2
Carbon molecule and heavy ion. Each carbon molecule contains 1 nucleus and 6 electrons. The carbon nucleus comprises 6 protons and 6 neutrons, and its molecular weight is 12. When its nucleus is accelerated, it becomes a heavy ion. When this heavy ion collides with the target material, the impact area is damaged by mechanical and electromagnetic energies. In clinical radiation therapy, hyper-acceleration of the carbon nucleus up to 70% light speed is used as a heavy ion beam.
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The biggest difference between photon and particle beams are the patterns of injury under irradiation (Figure 2). Photon beams injure all tissues along the route of the beam and the severity of injury depends on the distance from the irradiation source. To avoid unnecessary injury to surrounding organs as well as achieving sufficient irradiation of the target, helical scanning technology is necessary (Figure 2). In contrast, particle beams can produce pinpoint damage. They go through the human body at high speed leaving minimal damage, and release large amounts of energy just before stopping. This selective peak of injury is called the “Bragg peak” and it can be set at any point in the body as the distance from the irradiation source.1–3
Distribution of irradiation damage with photon and particle beams. Photon beams injure all tissues along the route of the beam and the severity of injury depends on the distance from the irradiation source. To avoid unnecessary injury to surrounding organs as well as achieving sufficient irradiation of the target, helical scanning technology is important (IMRT and/or VMAT). In contrast, particle beams can produce pinpoint damage in the body. Particle beams go through the human body at high speed leaving minimal damage, and they release a large amount of energy just before stopping, which is called the “Bragg peak”. This selective peak of injury can be set at any point in the body.
Another essential point of clinical irradiation is the accuracy of targeting. Most of the historical clinical usage, such as the “gamma-knife”, began with brain surgery because brain tissue is practically stationary during the irradiation procedure.2 The problem for the application of this irradiation technique to the total body is movement of organs during irradiation,1–3 and this has been solved by gating technology with controlled respiration during the procedure.1 With gating as well as helical scanning control, total body irradiation has been applied to any type of tumor in the human body.1–3
Considering Irradiation of the Beating MyocardiumHowever, when considering myocardial tissue as the target of irradiation, it is obvious that the “heart beat” is a problem for accurate targeting of the beam. Even though the gating technologies have been developed for cardiac magnetic resonance imaging, their application is not easy because of continuous linear irradiation and the time delay between movement sensor and irradiation.
However, in 2017 Cuculich et al4 in Washington University sought to try to irradiate ventricular tissue with the aim of reducing ventricular arrhythmias in the human heart. They used a single 25-Gy X-ray application using a stereotactic body radiation technique, and achieved a marked reduction in the ventricular tachycardia burden in clinical patients. Although ethical issues of a human study may arise, they continued a subsequent prospective phase I/II trial in 19 patients (ENCORE-VT trial) and also reported supportive results.5 The precise mechanisms of the results were not well discussed, but neither complete ablation nor elimination but rather some modification of the electrophysiological properties of arrhythmogenic substrate is speculated as the mechanism because the larger surrounding areas were irradiated during their protocols.4 Other investigators have performed experimental studies to evaluate the mechanisms underlying this interesting phenomenon and reported that modification of gap junctions could be a possible mechanism of such electrophysiological changes.6 However, the target and methodology themselves have to be evaluated in future studies for further usage in the clinical field.
Using Heavy Ion Irradiation as Antiarrhythmic TherapyAmino et al focused on using a heavy ion beam of carbon nuclei instead of an X-ray beam, which may have some potential benefits.7 As described above, a heavy ion beam may be able to produce highly selective pinpoint damage in the human body in comparison with photon beams. In addition, as described in this issue of the Journal,8 they have focused on atrial tissue, instead of ventricular tissue, as therapy for atrial fibrillation. Because the movement of atrial tissue with the heart beat is much less than for ventricular tissue, the targeting of the irradiation may be easier. They present beautiful results in an experimental study using hypercholesterolemic rabbits to demonstrate the possible underlying mechanism. Inducibility of atrial arrhythmia was markedly reduced after heavy ion irradiation, which was considered to normalize the distribution of connexin expression as well as suppressing sympathetic hyper-innervation in the rabbits. These results clearly coincide well with the results from a murine experiment.6 Therefore, the myocardial changes produced by heavy ion irradiation could be considered as modification of atrial tissue to an appropriate level for antiarrhythmic purpose.8
Possibly this result might have been chance hitting of the sweet spot for irradiation power (i.e., targeted point and area, strength of irradiation, setting of Bragg peak point, etc.), but it clearly opens a new possible horizon for arrhythmic therapy. There will be various questions about the irradiation methodology, but appropriate clinical usage must be investigated in future studies.
