Introduction
Cardiovascular disease is a leading cause of death and disability worldwide [1]. Although many pharmacological and device-based therapies have been developed for some cardiovascular diseases, such as resistant hypertension, heart failure, and myocardial infarction, many still have disappointing clinical outcomes. Use of ultrasound for cardiovascular diagnosis has been applied widely and might evolve similarly into a strategy for cardiovascular therapy because of its noninvasive and nonionizing characteristics. During the 1940s, researchers designed an efficient generator of focused ultrasound to produce focal heating, resulting in behavior disabilities in animals [2]. After that, ultrasound began to be used as a resource for device-based treatment in neurosurgery [3], cancers [4], and cardiology, alone or in combination with other interventions.
Biomedical Effects and Parameters of Ultrasound Interventions
Ultrasound is mainly produced by transducers in pulses or continuously as a mechanical wave, which thereby results in stress and strain through particle motion in mediums. The strong pressure wave can induce two major biomedical effects in local tissues that are exposed to it: thermal and nonthermal effects. Thermal effects are being widely explored in therapy. By concentration of ultrasound in deep zones of solid organs [5, 6], the temperature of the target can be elevated rapidly, accompanied by irreversible tissue injury in the form of coagulation necrosis, but nearby tissues are seldom affected. Nonthermal effects mainly refer to mechanical effects, which include oscillation and collapse of microbubbles, which cause several physical effects.
Sonication parameters, especially intensity and frequency, are mutually linked to induce different effects. Ultrasound can be defined as either low or high intensity according to whether the energy is below or above 1 W/cm2 [7]. High-intensity focused ultrasound (HIFU) is applied for ablation by producing thermal tissue lesion. Low-intensity ultrasound always promotes mechanical effects because of insufficient heat accumulation, and barely causes tissues necrosis [8]. Low-frequency and high-frequency ultrasound can be classified according to whether the frequency is below or above 1 MHz [9]. Low-frequency ultrasound has good penetration that can reach deeper targets, initiating predominantly mechanical effects on cell membranes with negligible temperature increase (<0.01 °C) [10], thereby depolarizing membranes to activate voltage-gated sodium channels and voltage-gated calcium channels and, furthermore, to influence cells’ excitability [11, 12]. High-frequency ultrasound has a shorter wavelength and better spatial resolution than low-frequency ultrasound. It is centrally deposited, which is helpful in imaging [13]. Fast attenuation may cause thermal loss and poor penetration when applied to delivery of skin treatment [9]. Besides the two main parameters, several variables, such as the mode of transmission, the pulse profile, and exposure times, are combined result in various biological effects, which strongly depend on the tissue type. Consequently, overall factors in practical application should be considered.
Effects of Ultrasound Intervention in Tissues
Different tissues undergo various biological effects during exposure to the same sonication parameters. A study compared the acoustic properties of bovine liver and heart muscle; the velocity, impedance, and density of heart muscle tissues are lower than those of liver in the frequency range from 20 to 40 MHz [14]. These differences may be connected to protein concentration and tissue structures, attenuation coefficient increases, and velocity decreases as the fat concentration increases [15]. Besides, the molecules vibrate greatly when ultrasound is propagating in the medium. Loosely organized structures, such as a thrombus or an atheroma, lacking the normal collagen and elastin fiber support [16], can be destroyed easily by ultrasound, but vascular walls contain a thick collagen and elastin matrix, so they tolerate ultrasound of higher intensity and lower frequency. These features are the foundation of sonothrombolysis. Furthermore, a nerve is a special structure whose activity is affected by ultrasound. Cell membranes of nerve fibers have a multilayer, lipid-water interface, which can be damaged easily by acoustic energy accumulation, changing the permeability and ionic transport of cell membranes [17]. Low-intensity ultrasound has been used to modulate neural activity or as a clinical analgesic by destroying nerves without injuring surrounding tissue (Table 1). In addition to the effects of tissular characteristics of ultrasound intervention, anatomical construction should be considered. Skin, soft tissues, and ribs can reflect, diffract, and absorb acoustic energy during ultrasound transmission in the treatment of cardiovascular diseases. Undesired lesions that occur along the acoustic path may be induced by ultrasound, causing energy loss during delivery of ultrasound to the target. These structural features of tissues are obstacles during ultrasound intervention to some degree, so further exploration of how to control acoustic energy effectively and safely is needed.
The Properties and Effects of Ultrasound.
| Main sonication parameters | Applications | |
|---|---|---|
| Intensity | High (≥1 W/cm2) | Thermal tissue lesion; tissue coagulative necrosis |
| Low (<1 W/cm2) | Neural activity modulating; clinical analgesic with mechanical effects | |
| Frequency | High (≥1 MHz) | Imaging; drug delivery for skin treatment |
| Low (<1 MHz) | Depolarizing membranes; influencing cells’ excitability | |
| Mode of transmission | Continuous wave Pulse wave | The choice of parameters depends on the tissue type and study design in practical application |
Challenges for External Ultrasound Therapy in Cardiology
There are some challenges in ultrasound-based therapy for cardiovascular diseases. The main concerns are to guarantee the efficacy and safety of external ultrasound applications in the treatment of such diseases. First, the heart and thoracic aorta are located in the thoracic cavity and are surrounded by the lungs. The rib and pulmonary alveoli will impede acoustic energy transmission from extracorporeal regions to intracorporeal regions, so acoustic energy delivery to these barriers may lead to undesired lesions and decrease the intensity of the energy that arrives at the targets [18]. Second, heart motion, respiratory movement, and blood circulation can reduce the target accuracy and acoustic energy accumulation. Third, the long acoustic pathway and undulating medium may reduce the required energy and induce nontarget injury, preventing achievement of the therapeutic goal. These challenges mainly increase the difficulty of controlling ultrasonic energy [19]. Although the inherent structural characteristics may be obstacles, ultrasound is still the ideal form of energy to realize noninvasive therapy in some cases. For instance, for hypertension intervention, acoustic ablation foci are set at the adventitia when ultrasound-based renal denervation is used, in favor of thermal accumulation and effective ablation for deeper nerves. Meanwhile, the intima and wall of the artery will be unaffected because of flowing blood that produces a cooling effect, so ultrasound-based renal denervation can have deeper penetration for deeper nerve injury and better preservation of the artery [20]. In general, controlling ultrasonic energy effectively is a crucial factor that propels the development of ultrasound-based treatment.
Ultrasound for Arrhythmia
In recent decades, catheter-based radiofrequency energy was widely used to ablate myocardium for arrhythmia therapy. However, some limitations had to be considered, such as the inadequately small ablation area target and imprecise and insufficient delivery of energy to target deep lesions, so other types of energy were explored. Ultrasonic energy was applied because it can focus centrally and enough energy can be delivered to the deeper target tissues. He et al. [21] created an ultrasound transducer mounted on a cardiac catheter that could produce well-circumscribed endocardial lesions for ablation of cardiac arrhythmia, which demonstrated that ultrasound was a potential alternative energy source for minimally invasive therapy. Researchers then examined the effects of an HIFU balloon catheter in patients with atrial fibrillation; about 50% of patients were free of symptomatic episodes of atrial fibrillation after pulmonary vein isolation [22, 23]. Despite so many advantages, there are still severe complications because of increased risks of the occurrence of thrombosis and eschar. Mechanical injury from the steerable sheath is unavoidable. A study reported that the long-term success rates of HIFU balloon catheter ablation were similar to those of radiofrequency-based catheter ablation [24]. The major problem of ultrasound balloon catheters is limited navigation ability, precluding the ability to target and isolate all pulmonary veins. Therefore, it is imperative to explore noninvasive, effective, and safe strategies for arrhythmia treatment.
In the 1990s, Strickberger et al. [25] reported extracardiac, focused ultrasound that can be used to create atrioventricular block within a beating canine heart. Noninvasive HIFU treatment was then explored to ablate the atrioventricular junction; the lesions were well demarcated and consistent with thermal necrosis, so complete atrioventricular block can be achieved extracorporeally, without any catheter or ionizing radiation [26]. Other successful studies of valves or pulmonary vein ablation have also been published [27, 28]. Although relative complications are seldom reported, a few cases still incur atrioesophageal fistula, pulmonary embolism, and phrenic nerve damage [29–31] in clinical trials. Furthermore, to decrease the risk of lung injury when ultrasound penetrates through the thoracic cavity to the heart, artificial pleural effusion is established [32]. This method has no significant complications, but transiently affects respiratory function. It is not suitable for some patients with pulmonary diseases. Because of these difficulties, recent studies in this field are declining; more novel and effective strategies should be considered and proposed in the future.
Ultrasound for Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is recognized to induce arterial fibrillation, heart failure, and even sudden cardiac death frequently. Alcohol septal ablation has been a promising, minimally invasive method to reduce hypertrophic myocardium, but may cause permanent atrioventricular block in about 20% of patients [33]. Then endocardial radiofrequency ablation is applied as therapy for hypertrophic cardiomyopathy, but the problem of a higher risk of a paradoxical increase in left ventricular outflow tract obstruction because of tissue edema should not be ignored [34]. From the beginning of the use of ultrasound-based myocardium ablation, use of HIFU rapidly emerged as a way to ablate myocardial tissues by way of an extracorporeal emission. Rong et al. [35] applied HIFU therapeutic systems to realize interventricular septum ablation. The average peak temperature at a power of 400 W for 4 seconds was 106.83±2.92 °C, and it remained greater than 50 °C for 10 seconds; small dot or large mass lesions were created, according to different parameter sets. Another study achieved similar results, and no procedure-related complications were observed [36]. HIFU may be effectively used for myocardium ablation. However, published studies are limited to animal models, so there is still lack of clinical data to show the efficacy of HIFU ablation for patients with hypertrophic cardiomyopathy. One possible explanation is that the number of patients of this type is not great enough, and the clinical importance is still relatively limited.
Ultrasound for Thrombolysis
Coronary thrombolysis is a desired method to restore occluded vessels, protect ventricular function, and reduce mortality. As a new approach, ultrasound-based thrombolysis has been developed in the form of a thermal or nonthermal effect within artery walls and atherosclerotic plaques, interfering with the growth of atherosclerotic plaques, further restoring or improving flow in thrombus-occluded vessels. Siegel et al. [37] first applied percutaneous, catheter-delivered ultrasonic energy for arterial recanalization in patients with peripheral vascular disease; the total arterial occlusions were restored. In a following study, they demonstrated that mean stenosis decreased and the minimum lumen diameter increased. Use of high-intensity, low-frequency, catheter-delivered ultrasound seemed safe and feasible in the treatment of coronary artery stenosis [38]. Other researchers reported similar results [39, 40], and there were no significant ultrasound-related complications. The mechanism of ultrasound thrombus disruption is damage to the fibrin matrix; atherosclerotic plaques are susceptible to ultrasound and can be disrupted easily. The fiber and cellular architecture of the media or adventitia are unaffected by ultrasound. One study suggested that the ultrasound intensity for thrombolysis is 1/20 of the intensity that induces arterial wall damage [41], so sonothrombolysis is an effective way to resolve luminal obstruction without damaging the integrity of vascular walls [42]. With the development of noninvasive technology, external ultrasound intervention has been developed for thrombolysis, and no other adverse interactions have been observed in animal and clinical experiments [43, 44]. Sonothrombolysis is an optional method for arterial recanalization. However, a clinical trial failed to increase the 60-minute Thrombolysis in Myocardial Infarction (TIMI) flow grade or degree of ST-segment resolution using thrombolysis plus transcutaneous ultrasound [45]. One reason for this negative result can be attributed to transcutaneous ultrasound devices not delivering enough energy to the intracoronary thrombus. The EkoSonic endovascular system (EKOS) has been approved by the FDA and applied to treat acute pulmonary embolism effectively [46, 47], so the development of ultrasound devices is helpful to increase the efficacy of sonothrombolysis. In addition, atheromatous, thrombotic, and complicated plaques contain different amounts of calcific elements as well as fatty fibrous tissue, and the energy requirements are different when ultrasound-based thrombolysis is conducted. Relative parameters, such as the frequency, duration of application, intensity, and mode of application of ultrasound, need to be optimized in practical applications [48]. The mechanism of sonothrombolysis may involve thermal, cavitation, and mechanical effects. Thermal injury and associated perforations can be observed [49]. In certain conditions, coagulation factors are activated to make atherosclerotic plaques unstable, increasing the risk of hemorrhage and reocclusion. To solve these problems, microbubble contrast agent–mediated sonothrombolysis was invented to increase the thrombolysis rate and minimize the required dose of thrombolytic drugs [50, 51], increasing the efficacy and safety of thrombolysis. Consequently, microbubble-mediated sonothrombolysis may be a promising strategy for the treatment of thrombo-occlusive diseases.
Ultrasound for Renal Sympathetic Denervation
The renal sympathetic nerve plays an important part in cardiovascular diseases through a cardiac-renal-neurological axis and renorenal reflexes. Renal denervation has been introduced as a treatment modality to control disorders associated with sympathetic overactivity, such as hypertension, heart failure, and sleep apnea. Since Kurm et al. [52] adopted radiofrequency catheter-based renal denervation to reduce blood pressure (BP) without serious adverse events, many clinical studies have been performed to verify its safety and efficiency [53, 54]. Because of individual anatomical variability of renal nerves, some limitations mainly related to insufficient energy and increased risk of vascular damage have been reported [55], thus spurring exploration of other types of energy. Ultrasonic energy seems to be suitable for renal denervation because enough energy can be delivered while avoiding direct contact of the energy source with the vessel wall (Table 2). Better preservation of the vessel wall and deeper denervation were observed with therapeutic intravascular ultrasound-based renal denervation compared with radiofrequency renal denervation [58, 64]. The endovascular ultrasound system offers easy tolerance and efficacy for patients [56, 57, 59]. In addition, renal denervation can be achieved with use of extracorporeal HIFU [65]. Clinical studies investigating the change of BP in patients by using noninvasive, HIFU-based renal denervation have demonstrated significant reduction in BP after ablation (Figure 1), and no intervention-related adverse events were found involving motor or sensory deficits [61, 62]. Ultrasound-based renal denervation may provide new insight into this procedure. However, the WAVE IV study failed to show the BP-lowering effect when using an external HIFU system [63]. One possible reason is the significant energy loss from the transducer to the target, which leads to incomplete renal denervation. The intensity of ablation energy will be decreased with deeper location of the target and more fat in the tissue, causing ineffective ablation in some patients. Another reason is the lack of a measure to evaluate specific target and denervation end points. Ultrasound may be the favored form of energy that can realize imaging and ablation at the same time. Hence, it can perform ablation immediately after positioning of the target, simplifying the operating procedure and avoiding ionizing radiation. Recently, the RADIANCE-HTN SOLO study showed BP-lowering efficacy of ultrasound-based renal denervation in patients with combined systolic and diastolic hypertension in the absence of antihypertensive medications compared with a sham control group [60]. The positive result inspired researchers’ confidence in ultrasound-based renal denervation therapy. The ongoing RADIANCE-HTN TRIO and REQUIRE studies concern ultrasound-based renal denervation and will provide more meaningful data in this field [66]. How to control acoustic energy to realize individualized treatment imposes a high demand on the ultrasound renal denervation system. The invention and improvement of ultrasound-based devices can be an effective method to overcome this difficulty.
Clinical Trials of Ultrasound Therapy for Hypertension.
| Authors | Therapy method | Ultrasound device | Product design | Outcomes | Year | |
|---|---|---|---|---|---|---|
| Efficacy | Safety | |||||
| Mabin et al. [56] | Endovascular ultrasound | Paradise ultrasound catheter | Ultrasound balloon catheter | Office BP and home BP decreased by 36/17 mmHg and 22/12 mmHg, respectively, at 6 months, compared with the baseline | There was no device-related serious adverse event. There was no change in renal function | 2012 |
| Shetty et al. [57] | Endovascular ultrasound | TIVUS ultrasound catheter | Ultrasound autoregulating balloon catheter | Mean SBP and DBP were lower than baseline BP. Mean office BP decreased by 25/10 mmHg at the 3-month follow-up | The procedures were technically uneventful, with no device-related complications | 2014 |
| Stiermaier et al. [58] | Endovascular ultrasound | Paradise ultrasound catheter | Ultrasound balloon catheter | Mean daytime SBP changed from 161.7±14.6 mmHg at the baseline to 151.6±11.0 mmHg at 6 months. Mean 24-hour SBP was 158.6±13.5 mmHg at the baseline and 148±9.8 mmHg at 6 months | There were no deaths, neurological complications, alterations in kidney function, or other severe events | 2016 |
| Fengler et al. [59] | Endovascular ultrasound | Paradise ultrasound catheter | Ultrasound balloon catheter | Ambulatory 24-hour mean/daytime/nighttime SBP change at 3 months was −9.7±12.6/−10.6 ±13.7/−8.2±15.2 mmHg and DBP changed by −5.1±7.4/−5.8±7.8/−3.9±10.3 mmHg | No new renal artery stenosis was detected after renal denervation | 2017 |
| Azizi et al. [60] | Endovascular ultrasound | Paradise ultrasound catheter | Ultrasound balloon catheter | The reductions in daytime ambulatory SBP were greater with renal denervation than with the sham procedure; the baseline-adjusted difference between groups was −6.3 mmHg | No major adverse events were reported in the renal denervation group or the sham control group | 2018 |
| Rong et al. [61] | External ultrasound | Model JC HIFU tumor therapeutic system | Focused ultrasound ablation system | The mean reductions in the 24-hour ambulatory BP from the baseline to 6 months were 11.4±4.8/4.8±4.8 mmHg; the mean reductions in office BP were 29.2±6.8/11.2±9.7 mmHg at 6 months | No serious complications or myalgias, back pain, or hematuria were observed. Renal function was not significantly altered | 2015 |
| Neuzil et al. [62] | External ultrasound | Kona medical ultrasound system | Focused ultrasound ablation system | Decreases of at least 10 and 20 mmHg in office SBP were observed in 75% and 56% of the 69 patients, respectively, at 1 year. Twenty-four-hour ambulatory BP dropped by 20.6±2.2/10.9±2.6 mmHg at 6-months (WAVE I, II, III) | No intervention-related adverse events involving motor or sensory deficits were reported. Renal function was not altered | 2016 |
| Schmieder et al. [63] | External ultrasound | Kona medical ultrasound system | Focused ultrasound ablation system | No significant difference in the change in office BP and ambulatory BP was observed between the renal denervation group and the sham group | No safety concern about renal denervation | 2018 |
BP, Blood pressure; DBP, diastolic blood pressure; HIFU, high-intensity focused ultrasound; SBP, systolic blood pressure.
The Direction for Ultrasound-Based Treatment of Cardiovascular Diseases
As a mechanical wave, ultrasound has the ability to ablate deep targets of the body without any ionizing radiation, but its efficacy and treatment safety are impaired by an inappropriate acoustic environment, poor energy delivery, and inaccurate ultrasound parameter set. To understand it clearly and evaluate the acoustic environment in the body carefully, we should foster strengths and circumvent weaknesses for the acoustic treatment of cardiovascular diseases. Ultrasound can be a powerful form of energy for safe cardiovascular treatment through real-time temperature monitoring of targets and the pathway under X-ray, ultrasound, or magnetic resonance imaging guidance. Besides, the second generation of the Paradise endovascular ultrasound renal denervation system could deliver ablative energy targeted to 1 mm below the luminal surface, which provides a shorter time and higher precision for therapy when compared with the first generation. Therefore, the improvement of ultrasound-based devices is also very important to enhance effects, shorten the duration, and guarantee safety in the treatment of cardiovascular diseases.
Conclusions
Ultrasound as a potential form of energy has been explored for cardiovascular disease therapy. The acoustic energy can be delivered in a minimally or noninvasive mode, which achieves the aims of improving the patient’s medical experience and decreasing damage. Despite this, some difficulties remain with regard to technical aspects and application that need to be overcome, but ultrasound-based treatment should be a good and promising strategy in the future.