Abstract
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally, placing an immense burden on health care costs worldwide. The emergence of therapeutic ultrasound-based therapies in the CVD management represents a promising innovative strategy beyond current established approaches. This paper explores three distinct modalities of ultrasound-based therapies—high-intensity focused ultrasound, extracorporeal shock wave therapy, and low-intensity pulsed ultrasound—each characterized by unique acoustic parameters and mechanisms of action tailored to specific therapeutic outcomes. High-intensity focused ultrasound was shown to be beneficial as an adjunct in the treatment of myocardial infarction and arrhythmias. It has also been investigated for the in vivo treatment of resistant hypertension, symptomatic aortic valve stenosis, arterial stenosis, tumors, hypertrophic cardiomyopathy, and external cardiac pacing. Extracorporeal shock wave therapy was shown to be beneficial in the treatment of chronic refractory angina pectoris, while low-intensity pulsed ultrasound was shown to be beneficial in dissolving blood clots and improving blood flow in the treatment of acute pulmonary embolism, despite its association with an increased risk of bleeding. Ultrasound-based therapies are, therefore, a potential adjunct and comparatively safe adjuncts for managing challenging CVD cases. Further investigations are essential to validate their long-term effectiveness and safety, particularly for high-risk individuals susceptible to postprocedural complications.
Highlights
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Ultrasound-based therapies emerge as an add-on treatment for cardiovascular diseases.
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Indications: myocardial infarction, arrhythmias, hypertension, valve stenosis, clot lysis.
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Tolerable adjunct option for challenging cardiovascular diseases.
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Needs validation in high-risk patients (protocols and long-term effects).
Introduction
Cardiovascular diseases (CVDs) continue to be the world’s leading causes of morbidity and mortality, with a major impact on health care expenditure. , Diagnostic medical ultrasound with frequencies in the megahertz range (MHz), including Doppler ultrasonography, has established clinical utility in the diagnosis of cardiovascular structural and functional abnormalities, including intracardiac and blood flow hemodynamics within the heart and blood vessels. The physical properties of ultrasound, which are acoustic energy waves with mechanical and thermal effects on insonated biological tissues, can be harnessed for diagnostic medical imaging as well as therapeutic purposes. The acoustic energy of ultrasound consists of mechanical longitudinal waves with pressure amplitudes that can be spatially directed and focused as a geometric beam with acoustic power and intensity, is measured in joules or watts per square centimeter (W/cm 2 ). Ultrasound can be transmitted as intermittent pulses (pulsed-wave ultrasound) or continuously (continuous-wave ultrasound). During transmission and interaction with tissues, portions of the acoustic energy within the ultrasound beam are reflected, transmitted, and absorbed, depending on the acoustic impedance of the insonated tissues. The extent of these interactions is also influenced by the ultrasound instrumentation and technique, including operating mode, transducer design, application technique, and the total acoustic energy output. ,
For several years, researchers have investigated the therapeutic use of ultrasound. More recently, there has been a surge of interest in therapeutic ultrasound for the treatment of CVDs. Advances in bioengineering and endovascular treatments have allowed for more accurate delivery of high-powered ultrasound, opening new avenues for the therapeutic use of ultrasound ( Figure 1 ). The therapeutic benefits of ultrasound are determined by its frequency, power, and whether it is targeted. This paper presents a contemporary overview of therapeutic applications of ultrasound in patients with CVDs.
Ultrasound-Based Therapies: Mechanisms of Action in CVDs
Ultrasound-based therapies are commonly associated with physical therapy. In the realm of CVDs, ultrasound is seldom used therapeutically and is still under investigation. Its mechanism of action is further summarized in Tables 1 and 2 , Figure 1 , and below, based on the type of sound waves.
| Therapy | Type | Mechanism | Applications |
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| High-intensity focused ultrasound (HIFU) | Thermal | High-energy focused ultrasound waves induce tissue coagulation and ablation, concentrating energy to elevate temperature precisely in targeted areas, sparing surrounding tissue. |
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| Extracorporeal shock wave therapy (ESWT) | Nonthermal | Utilizes mechanical effects of ultrasound waves such as vibration and pressure to stimulate biological responses without significant heat generation. , |
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| Low-intensity pulsed ultrasound (LIPUS) | Nonthermal | Low-energy pulsed ultrasound waves activate cellular processes and promote microbubble cavitation, facilitating healing and perfusion enhancement. |
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| Pulsed cavitational ultrasound therapy | Nonthermal | Ultrasound pulses create cavitation bubbles that mechanically disrupt tissues on a microscale for therapeutic benefits. |
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| Therapy | Type | Method | Applications | Specific considerations |
|---|---|---|---|---|
| Extracorporeal shock wave therapy (ESWT) | Noninvasive | Therapy applied externally without the need for surgical intervention. , |
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| Pulsed cavitational ultrasound therapy | Noninvasive | Uses external devices to deliver therapeutic ultrasound waves. |
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| Low-intensity pulsed ultrasound (LIPUS) | Noninvasive | Ultrasound therapy is delivered through the skin using portable or fixed devices. |
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| High-intensity focused ultrasound (HIFU) | Invasive | Therapy requiring surgical exposure or insertion into the body. |
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| HIFU (invasive approaches) | Invasive | Invasive applications during interventional procedures. |
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High-Intensity Focused Ultrasound
High-intensity focused ultrasound (HIFU) is a noninvasive therapeutic technique that delivers high-powered, focused ultrasound energy to targeted tissues. In 1942, Lynn first introduced HIFU for focal tissue ablation with minimal/no effects on surrounding tissue. The ultrasound parameters of HIFU include continuous waves with generally low frequencies (frequency: 0.7-9 MHz) and high intensities (30 W/cm 2 and acoustic power: 6-150 W). , , Lower frequencies enable deeper penetration for transthoracic approaches with less tissue attenuation and low thermal index , whereas higher frequencies (3.8-9 MHz) are suited for more superficial structures due to lower depth of penetration caused by greater attenuation. Ultrasound at frequencies in the MHz range can be safe and effective for treating ischemic stroke, as reported in 57 small clinical trials and in a meta-analysis of 10 studies. , The biological effects of HIFU are generated in situ based on the properties of tissues and mediated by thermal and/or mechanical effects. HIFU’s thermal effects can be harnessed in cardiovascular medicine to ablate and isolate focal tissues that trigger atrial fibrillation, as well as in noncardiac applications such as renal denervation and malignancies. Khokhlova et al. (2014) investigated HIFU for noninvasive cardiac ablation in a porcine model, demonstrating its potential for precise cardiovascular tissue interventions not often associated with ultrasound techniques. In the “boiling histotripsy” method, HIFU mechanically generates mm-sized boiling bubble that interact with the ultrasonic field to fractionate porcine tissue into subcellular debris without producing additional thermal effects. Pulsed cavitational ultrasound therapy (thrombotripsy) has also been investigated for the recanalization of proximal deep venous thrombosis in a swine model.
Extracorporeal Shock Wave Therapy (ESWT)
Extracorporeal shock wave therapy (ESWT) techniques employ high-pressure, high-energy, short duration pulses of sound called shock waves generated outside the body (extracorporeally) to deliver energy to tissues. ESWT produces a mechanical action in the tissue, resulting in rapid pressure changes, tissue deformation, and cellular mechano-transduction. As shockwaves propagate through body tissues, it is the properties of the shockwave, e.g., its pressure, focus, and frequency that determine the depth of penetration and interaction with the target tissue. Best practice ESWT clinical treatment parameters and protocols are generally categorized into three energy categories based on total energy dose and the energy per unit area or energy flux density using the following ranges: low (<0.08-10 mJ/mm2), medium (0.08-0.28 mJ/mm 2 ), and high (>0.29-0.60 mJ/mm 2 ). The ESWT protocols include exposure to separate pulses with high amplitude and predominant nonthermal biomechanical effects (frequency: individual shock waves; acoustic power: 0.9 mJ/mm 2 ; and delivery protocol: 200 shock waves per spot, 40 to 60 spots per session, three sessions per week for 3 months). ,
Low-Intensity Pulsed Ultrasound (LIPUS)
Low-intensity pulsed ultrasound (LIPUS) is a therapeutic modality that harnesses low-power, low-intensity ultrasound (intensities typically around 30 mW/cm 2 , frequencies 1 to 3 MHz, pulse duration of 200 μs, and pulse repetition frequency of 1 kHz) to exert a nonthermal biological effects on tissues, including reduced inflammation, improved blood flow, and healing by direct stimulation of tissues or indirectly by harnessing the therapeutic potential of lipid-coated or drug-loaded microbubbles. , , Microbubbles are microscopic, highly reflective gas-filled bubbles encapsulated in a stabilizing protein, lipid, or polymer shell that oscillate and cavitate when exposed to the mechanical pressures from ultrasound insonation.
Clinical Applications of Ultrasound-Based Therapy in CVDs
Cardiovascular ultrasound-based therapies are a fast-developing discipline with the potential to become useful adjuncts in the treatment of CVDs. Therapeutic ultrasound may be utilized alone, as in stroke (sonolysis) to cause clot lysis and then recanalization, or combined with tissue-type plasminogen activator treatment to increase its effects (sonothrombolysis), or in conjunction with microbubbles. , The following discourse and Table 2 summarize various clinical applications of therapeutic ultrasound modalities based on the mode of delivery, which includes invasive and noninvasive techniques.
Noninvasive Techniques
Sonothrombolysis
Sonothrombolysis holds significant promise due to its potential to eliminate or significantly reduce reliance on thrombolytic agents for clot dissolution. The primary mechanism of action of sonothrombolysis is mediated through acoustic radiation force, localized tissue displacement, and clot deformation. Animal studies showed that LIPUS could be beneficial in stroke , ischemic heart disease, and contractile dysfunction, likely through upregulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase. The ultrasonic vibrations induce cells to release proteins and other chemicals that aid in healing and inflammation reduction. A study found that lower-frequency ultrasound is more effective at dissolving blood clots than higher-frequency ultrasound. This finding is important because it suggests that ultrasound-induced blood clot dissolution may be a viable alternative to thrombolytic drugs in certain settings.
Sonothrombolysis in Myocardial Infarction
Sonothrombolysis is a therapeutic intervention that combines ultrasound techniques combined with thrombolytic therapy to enhance the treatment of myocardial infarction, particularly ST-segment-elevation myocardial infarction. It is conducted by a trained medical professional and lasts for approximately 20 minutes or until the patient reaches the hospital or interventional laboratory. The procedure involves the use of proprietary microbubble infusions with simultaneous transthoracic echocardiography. High mechanical index (MI) instrument settings (MI of approximately 1.0 to 1.2) with transmit frequency of 1.6 MHz and pulse duration less than 5 μs with imaging averaging 20 frames ( Figure 2 A). Typically, 30 to 60 impulses are administered, with 4 to 8 seconds between each high MI pulse to ensure sufficient replenishment of the microbubble contrast within the perfusion beds.
