Ultrasound is a diagnostic tool extensively used worldwide, which also has the potential to be used for therapeutic purposes by changing the intensity and irradiation time of the ultrasonic waves [1]. Ultrasonic waves have 2 biological actions, i.e, thermal (heating) and non-thermal (mainly cavitation) actions [1]. Heating occurs when the ultrasonic waves propagate and are scattered or absorbed, which results in the conversion of ultrasonic energy into thermal energy. Therefore, if the target lesion causes severe scattering, it will generate intense heat at the site. Moreover, there is a linear correlation between irradiation intensity and irradiation duration in the biological action of ultrasound waves. When a threshold value is exceeded, biological actions occur, and a therapeutic effect is elicited. High-intensity focused ultrasound (HIFU), which is a minimally invasive treatment that does not involve radiation exposure, has gained attention in recent years [2, 3], and expectations for its clinical application have been increasing. Regarding the indication for HIFU, patients should undergo HIFU for the following purposes: (1) to achieve tissue ablation and pain relief from malignant tumors, such as pancreas cancer, liver cancer, renal cancer, prostate cancer, bladder cancer, breast cancer, and soft tissue sarcoma; (2) to treat benign diseases, such as uterine myoma and prostatic hyperplasia; and (3) to treat neurological diseases, for thrombolysis, and for the hemostasis of vascular or organ hemorrhage [4]. The focal area of HIFU is heated to 80–100 °C, which causes coagulative necrosis of the tissue, through a combined mechanism of thermal actions and cavitation [4].

HIFU has also been applied in cardiovascular medicine. For example, the usefulness of HIFU in atrial septostomy for left-sided heart failure and resistant pulmonary hypertension was investigated in vitro [5]. On the other hand, the usefulness of HIFU for left ventricular septum ablation has been investigated in canine models [6]. In these studies, the ultrasound energy used was quite high, at an operating frequency of 5.25 MHz and at the focal point intensity of 4–23 kW/cm2.

In contrast to HIFU, which induces irreversible cell death, low-intensity focused ultrasound (LIFU), has recently been shown to be capable of reversibly modulating region-specific brain function [7]. In general, “low intensity” is regarded as a magnitude of ultrasonic intensity that is similar to or below that typically used for diagnostic ultrasound examinations. Sonication at low intensities (1–100 mW/cm2) was shown to lead to the activation of bioelectrical activity in the brain, whereas higher intensities (1–100 W/cm2) caused a decrease in electrocorticogram amplitude [7]. Several studies have demonstrated that LIFU can potentially suppress neuronal activity through the generation of action potentials in central neurons, i.e, the intracellular influx of Ca and Na ions, without any concomitant brain damage [8, 9]. Thus, there has been a rapidly growing interest in applying LIFU-mediated neuromodulation for treating neurological and psychiatric disorders [10]. Recently, autonomic nervous system modulation via the precise stimulation of the surgically exposed vagus nerve in rats has been reported [11]. This method improved autonomic nervous system function by activating the parasympathetic efferent pathway and inhibiting the sympathetic efferent pathway, which contributes to blood pressure reduction [12].

The present study by Jiang et al., which is a more advanced method than the above, demonstrates that downregulation of carotid body (CB) activity using LIFU irradiation has a substantial blood pressure lowing effect in a hypertensive rabbit model [13]. The LIFU operating parameters are described as a power of 6 W/cm², a focal region of 3.30 × 2.59 × 10.58 mm³, and a frequency of 650 kHz, with intravenous microbubbles for identifying the location of the CB. Precise irradiation of the CB caused unique histopathological results, such as nuclear shrinking, cytoplasmic vacuolization, and interstitial inflammatory cell infiltration in Hematoxylin & Eosin (H&E) staining, severe cell edema with membrane damage extensive matrix dissolution, and severe mitochondrial swelling in transmission electron microscopy, and significant increase in apoptotic cells on terminal transferase dUTP nick end labeling (TUNEL) staining 3 h after the intervention. Four weeks after the intervention, extensive fibrotic tissue formation on H&E staining and the reduced expression of cell markers for type 1and 2 cells of the CB on fluorescence staining were observed. Therefore, the present study demonstrated that LIFU is an effective method to reduce CB activity, lower sympathetic nervous system activity, and treat hypertension through the promotion of CB cell apoptosis in an animal models of hypertension.

Excessive activation of the sympathetic nervous system is a pathophysiological characteristics of hypertension. In treatment-resistant hypertension, conditions such as diabetes mellitus, chronic kidney disease, obesity, and sleep apnea syndrome commonly exist as comorbidities, and interventions should be performed as needed. Therapies requiring devices such as renal denervation (RDN) are antihypertensive treatments that can circumvent problems of drug adherence or drug intolerance [14]. However, such treatments are invasive and there are responder and non-responder issues, and it is hence necessary to carefully select patients who are expected to benefit from the procedure. Patient perspectives regarding treatment strategies are vital in controlling their hypertension and patients have the right to choose between medical therapy and device therapy. Almost all recently published consensus documents and papers on RDN have reported that patient preferences are considered when determining treatment strategies for hypertension through shared decision making. However, RDN itself is an invasive method, and patient preferences are greatly influenced by the information that is provided by the medical staff, so it is important to provide unbiased and up-to-date medical information [14, 15]. The downregulation of CB activity using LIFU which was reported in the present study has been considered to be a semi-invasive method. Considering its effectiveness and safety, the downregulation of CB activity using LIFU might have the potential to establish a status between medical treatment and RDN in refractory hypertension (Fig. 1). Although there are many challenges toward its clinical application, the downregulation of CB activity using LIFU can be one of an effective treatment method that shows promise for the future.

Fig. 1
figure 1

Future prospects of the treatment flow for refractory hypertension. CPAP Continuous positive airway pressure, LIFU Low-intensity focused ultrasound

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