Cardiovascular disease is currently the most common cause of death worldwide, affecting approximately twice as many people as cancer, with increasing social and economic burden as the population ages [15] .Hypertrophic cardiomyopathy (HCM) is a myocardial disease of unknown cause, characterised by asymmetric hypertrophy of the ventricular wall, invasion of the interventricular septum, diminution of the intraventricular cavity, obstruction of left ventricular blood filling, and decreased left ventricular diastolic compliance. According to the presence or absence of obstruction of the left ventricular outflow tract, it is divided into obstructive and non-obstructive hypertrophic cardiomyopathy, which may be related to heredity. It is a common hereditary cardiomyopathy, with an incidence rate of approximately 0.2% of the total population༻16༽. About 70% of HCMs present with left ventricular outflow tract obstruction in resting or stimulated states, leading to dyspnea, chest pain, atrial fibrillation, heart failure, and even sudden death. Interventricular septal myocardial reduction (SRT) is effective for treating HCM, including surgical treatment༻17༽, alcohol isolation༻18༽, and RFA༻19༽. All current myocardial volume reduction strategies are invasive, with high surgical risk and the possibility of serious surgical complications; therefore, most patients with HCM choose medication instead of surgery.
HIFU transmits low ultrasonic energy from outside the body, which transmits through the skin and the corresponding tissues to reach a target area in the body, so that the energy focused in the target area is extremely high. HIFU can cause target tissue cells to undergo coagulative necrosis in a short time through thermal, cavitation, and mechanical effects, and other mechanisms, and has little or no damage to the tissues on the acoustic channel and around the target area, thereby achieving non-invasive ablation. Third, mechanical effect refers to the mechanical effect that ultrasonic energy can generate with high-speed vibrations back and forth, which can cause cell autolysis, DNA molecular degradation, and apoptosis [20]. Thermal effects play a major role in the mechanism of HIFU ablation. Ultrasonic energy is absorbed by the tissue and converted into heat, which causes the temperature of the target tissue to rise to the threshold temperature of irreversible damage in a short time, leading to irreversible tissue cell death. Cavitation also plays an important role in this process. Cavitation is a dynamic process in which tiny bubbles in the target tissue repeatedly oscillate, expand, contract, and finally break under the action of ultrasound. A large amount of energy is released during this process because of the cavitation effect of the tissue. When the cavitation microbubbles collapse, extreme physical effects (such as high temperature, high pressure, strong shock waves, etc.) can be locally generated to destroy cell membrane structures and organelles, resulting in cell death༻21༽. Finally, ultrasonic waves generate mechanical action with high-speed oscillation, which can cause cell autolysis, DNA molecular degradation, and apoptosis, thereby killing cells. Based on these mechanisms of action of HIFU, HIFU shows the advantages of non-invasive and accurate positioning in clinical treatment, and has been widely used in the treatment of clinical tumours༻22༽. Intracardiac lesions using HIFU were demonstrated for the first time in an in vitro study, in which 2-6 mm focal lesions in the medial wall of the myocardium were produced without damage to surrounding tissues༻23༽.In the last 20 years, the application of HIFU in the cardiovascular field has been ongoing. In 2007, Otsuka used HIFU with ECG-gated technology to ablate the interventricular septum myocardium in dogs after thoracotomy, and confirmed that HIFU could produce targeted and well-demarcated thermal damage in the moving heart༻24༽. Boris Schmidt first reported the clinical application of the HIFU catheter for pulmonary vein isolation to treat atrial fibrillation in 2007༻25༽. However, later clinical studies showed that complications such as phrenic nerve injury and left atrial esophageal fistula may occur after surgery. In 2013, Elodie Constanciel designed a HIFU probe guided by transesophageal ultrasound, which verified the safety and feasibility of the transesophageal approach༻26༽. In 2013, Huang Jing used pleural effusion to establish an artificial channel, and HIFU was used to ablate the ventricular septal myocardium in dogs through the thoracic cavity༻5༽. Although previous studies have been performed via multiple pathways, including thoracotomy, transthoracic, and transesophageal, they have not been clinically applied due to various limitations.
Due to the anatomical location and particularity of the heart, it was once considered a restricted area for HIFU ablation. The main reasons for this are as follows. First, the heart is surrounded by gas-rich lungs in the thoracic cavity, which consists of the sternum, ribs, and thoracic vertebrae. It is difficult for ultrasonic energy to penetrate these tissues to reach the heart and may cause damage to the surrounding tissues. Second, the heart is an organ with rapid and rhythmic movement, and its movement affects the accurate positioning of HIFU and energy deposition. Third, the heart is rich in blood flow, and owing to the cooling effect of blood flow, it is difficult for the heat generated by HIFU to precipitate in the myocardium. Therefore, these factors have hindered the application of HIFU in cardiovascular diseases. Previous studies have chosen transesophageal and intravascular pathways to avoid the influence of cardiac anatomical location and have made substantial progress.
Because the heart moves continuously and rhythmically, and there is no effective method for the focal area of HIFU to continuously track the moving target area, the pulse method can be used for HIFU ablation of myocardial tissue in motion. The pulse mode is discontinuous transmission, which adjusts the working and intermittent time according to the change in the cardiac cycle. The ventricular systolic period is about 0.2-0.3 s, when the ventricular wall and ventricular septum are thickened, which is convenient for target location. Moreover, the blood supply to the heart is in the diastolic period, and there is almost no blood flow in the systolic period. At this time, the heat generated by HIFU is not removed by the blood flow, and it is easily absorbed by the myocardium. Otsuka et al. reported that HIFU using electrocardiogram gating can provide more accurate ablation in a beating heart [24]. Rong et al. reported that electrocardiogram-triggering ablation can further eliminate the influence of cardiac motion and believed that this technique could be applied to the treatment of cardiovascular diseases by HIFU༻5༽.
The heart is a dynamic three-dimensional structure with abundant blood flow in the heart cavity and myocardium. The adult heart accounts for 0.5% of the body weight, while coronary blood flow accounts for 5% of the cardiac output. Therefore, the abundant blood flow in the myocardium seriously affects the ablation effect of HIFU. Previous studies have found that under the conditions of the same HIFU intensity and irradiation time, the heat generated in the blood-rich tissues would be quickly removed by the blood flow, and the extent of tissue necrosis would be affected [27]. An abundant vascular bed can not only reduce the peak temperature rise caused by HIFU, but also reduce the size and change the shape of the injury. This study shows that with a decrease in blood perfusion in the treatment area, the effect of hyperthermia is significantly improved, which is the same as in previous studies. Therefore, medical strategies to reduce or prevent blood flow into the treatment area have been proposed as areas of improvement for clinical treatment regimens. For example, when HIFU is used to treat uterine fibroids, the heat dissipation effect of fibroid blood vessels is reduced through the injection of oxycontin, which causes uterine contraction༻28༽. Myocardial ablation is an effective treatment for arrhythmia and hypertrophic cardiomyopathy, and transcatheter RFA has achieved great clinical success. HIFU may be a method for the treatment of hypertrophic obstructive cardiomyopathy in the future.
The myocardium of the left ventricular outflow tract was mainly supplied by the septal branches of the left coronary artery. When ablating the hypertrophic myocardium in the left ventricular outflow tract, septal branch occlusion can be used to reduce the blood supply to the hypertrophic myocardium and make the heat generated by HIFU more easily precipitate in the myocardium in this area, thereby increasing the effect of HIFU ablation.