Introduction

Echocardiography has evolved from a simple two-dimensional imaging modality to a sophisticated diagnostic tool integral to cardiovascular medicine [1]. Ultrasound enhancing agents (UEAs) have been pivotal in this evolution, significantly improving the visualization of cardiac anatomy and pathology [2]. Initially used to enhance myocardial perfusion imaging, UEAs now play crucial roles in various non-coronary artery disease contexts, including myocardial viability assessment, endocardial border delineation, and identification of intracardiac masses [3]. Recent advancements in UEAs and echocardiographic technology offer clinicians a more nuanced view of cardiac function and blood flow dynamics [4]. This review provides a comprehensive overview of the current applications of UEAs in cardiovascular imaging, particularly beyond coronary artery disease, and highlights recent advancements and future directions.

Techniques and protocols

UEAs are administered intravenously and consist of microbubbles that enhance ultrasound signals Fig. 1. Standard protocols involve specific imaging settings and safety precautions to maximize diagnostic yield while minimizing risks. Techniques such as low mechanical index imaging and harmonic imaging are commonly employed to optimize the visualization of UEAs.

Fig. 1
figure 1

Microbubble Oscillation and Cavitation Under Ultrasound in the Cardiovascular System

Full size image

Critical analysis of clinical data

Recent studies have demonstrated the efficacy of UEAs in various non-coronary artery disease contexts [5]. For example, UEAs have shown promise in improving tissue perfusion in peripheral artery disease (PAD) patients, as demonstrated by Mason et al. Additionally, innovations in endovascular ultrasound techniques have significantly enhanced limb perfusion in acute ischemia settings. Comparative analyses with established imaging modalities underscore the superior diagnostic capabilities of UEAs in specific clinical scenarios.

Addressing the research gap

The exploration of ultrasound enhancing agents (UEAs) beyond coronary artery disease (CAD) is still in its early stages. Despite significant potential, there is a noticeable gap between research advancements and their clinical application [6]. This review aims to bridge this gap by providing a comprehensive analysis of current UEA innovations, practical applications, and future directions in non-CAD conditions. We explore untapped UEA applications that go beyond traditional diagnostics, including enhancing pharmacological efficacy and targeted therapeutic delivery systems Table 1. These areas, sparsely covered in current literature, represent a frontier in cardiovascular treatment protocols. Additionally, we advocate for integrating UEAs with other imaging modalities to improve diagnostic accuracy and therapeutic outcomes in peripheral vascular disease, carotid artery disease, and other vascular anomalies.

Table 1. Central Table summarizing key studies of the use of contrast enhancing agent
Full size table

Underutilization of UEAs in clinical settings is often due to limited awareness among healthcare professionals and a lack of comprehensive, evidence-based guidelines. This review synthesizes fragmented evidence into a coherent narrative, promoting UEA integration into routine practice and emphasizing the need for extensive training programs highlighting their multifaceted benefits. We also project future advancements, discussing how next-generation microbubbles and improved ultrasound technology may expand UEAs' therapeutic window. The convergence of molecular imaging with UEAs offers a unique opportunity to understand pathophysiological processes at a cellular level, paving the way for personalized medicine in vascular diseases [7]. By highlighting these aspects, this review aims to provide actionable insights and concrete research directives, bridging the gap between theoretical promise and practical application in non-CAD therapeutic strategies.

Clinical applications and progress over the last 20 years

Despite the perception that considerable progress has not been made in the last 20 years, recent developments in UEAs and their clinical applications demonstrate significant advancements. Key studies have shown the efficacy of UEAs in various cardiovascular and non-cardiovascular contexts.

For instance, the application of UEAs in PAD has shown promising results. Mason et al. [8] demonstrated that microbubble cavitation significantly enhances tissue perfusion in PAD patients, leading to improved clinical outcomes. Additionally, advancements in catheter-based endovascular ultrasound techniques have increased limb perfusion in acute ischemia settings [9].

In the realm of myocardial viability, UEAs have refined the visualization of microvascular flow patterns, which is critical for the prognosis of myocardial recovery post-STEMI. Mathias et al. [10] highlighted the potential of diagnostic ultrasound impulses to improve microvascular flow, providing better myocardial recovery and patient outcomes.

Moreover, innovative approaches such as combining UEAs with molecular imaging have shown potential in elucidating pathophysiological processes at a cellular level. This integration opens new avenues for personalized medicine, particularly in vascular diseases.

Novel therapeutic techniques: sonothrombolysis and beyond

Sonothrombolysis represents a significant advance in the management of acute myocardial infarction (AMI), offering a less invasive yet effective means to alleviate thrombotic occlusion [11]. UEAs play a pivotal role in this technique, with their ability to oscillate and resonate under sonication, thus augmenting the thrombolytic effects [12]. This review expands upon the intricate mechanisms at play, detailing how the acoustic pressure waves generated by high mechanical index (MI) ultrasound interact with UEAs to induce microbubble cavitation [13]. This process facilitates the permeation and activation of thrombolytic agents within the thrombus structure, promoting dissolution and enhancing microvascular perfusion [14].

Beyond its application in AMI, sonothrombolysis, facilitated by UEAs, shows potential in other thrombotic conditions such as deep vein thrombosis and ischemic stroke, offering a paradigm shift in thrombolytic strategies [15]. The exploration extends to the latest research on optimizing sonication parameters and UEA formulations to maximize therapeutic efficacy while minimizing potential risks. Furthermore, the integration of UEAs with advanced imaging modalities holds promise for improving the precision of sonothrombolysis, potentially transforming the landscape of thrombus management across a spectrum of cardiovascular diseases.

Risks and benefits of cavitation in contrast-enhanced ultrasound

While the theoretical benefits of cavitation in sonothrombolysis are well-documented, it is essential to address the potential risks associated with this technique. Cavitation can cause microcirculatory disruption and hemorrhage, which necessitates a balanced discussion of both benefits and risks.

Recent studies have explored the optimization of sonication parameters to maximize therapeutic efficacy while minimizing potential risks. For example, Bader et al. [16] investigated the safety profile of sonothrombolysis and found that appropriate control of acoustic pressure waves and microbubble concentrations can significantly reduce adverse effects.

Furthermore, innovative ideas in the development of new ultrasound contrast agents focus on enhancing safety and efficacy. Next-generation microbubbles with improved stability and targeting capabilities are being designed to reduce the likelihood of microcirculatory disruption and hemorrhage while enhancing the therapeutic benefits of cavitation.

The potential of targeted bubbles in clinical applications has also seen significant advancements. Despite the slow progress since Dr. Lindner's report, recent research has demonstrated the feasibility of using targeted bubbles for site-specific drug delivery and imaging, thereby improving clinical outcomes without increasing the risk of adverse effects [17].

Sonothrombolysis

The challenge of persistent microvascular obstruction (MVO) post-revascularization in acute STEMI is a well-documented prognosticator of adverse outcomes [10, 18]. Despite successful angiographic recanalization, MVO is a harbinger of diminished left ventricular function, an increased propensity for heart failure, and a greater likelihood of mortality [19, 20]. Current clinical markers, including angiographic and electrocardiographic indicators, inadequately represent the prevalence of MVO, a limitation that has been elucidated through more sensitive diagnostic modalities such as cardiac magnetic resonance imaging and myocardial contrast echocardiography (MCE) [21, 22].

Pharmacological strategies and interventional tactics aimed at preventing MVO have largely fallen short in reducing the sequelae of reperfusion injury. Notably, conventional therapies like high-intensity statins and beta blockers post-percutaneous coronary intervention (PCI) are not universally effective, with substantial microvascular perfusion abnormalities persisting in a significant cohort of patients [22]. The advent of sonothrombolysis, utilizing ultrasound-induced microbubble cavitation, has shown potential to mitigate these issues. By disintegrating both large vessel thrombi and microthrombi, sonothrombolysis presents a viable solution to restore microvascular flow, as evidenced by pre-clinical large animal models and initial clinical trials [23, 24].

The implications of sonothrombolysis extend beyond the coronary arteries, addressing conditions like atherosclerotic peripheral arterial disease (PAD) where perfusion deficits are paramount. The diagnostic capability of ultrasound, when coupled with microbubble cavitation, has been demonstrated to augment tissue perfusion through mechanisms such as convective shear and purinergic signaling pathways. Studies reveal that these phenomena mediate the release of endogenous vasodilators, enhancing regional blood flow even with limited exposure [8].

Further research in animal models underscores the versatility of sonothrombolysis in PAD. Endovascular ultrasound catheters have been employed to facilitate limb perfusion, presenting promising findings of substantial flow increases in ischemic limbs. These outcomes suggest that such non-cavitating ultrasound modalities, commonplace in human thrombolysis, can ameliorate vascular resistance and augment perfusion in acute ischemic conditions [25].

Moreover, contrast-enhanced ultrasound (CEUS) has been instrumental in discerning microvascular flow alterations in pathologies such as sickle cell disease, capturing physiological changes inherent to vaso-occlusive crises. These findings, although preliminary, provide a foundation for the role of CEUS in capturing dynamic blood flow changes associated with vascular pathophysiology [26].

New and emerging applications of UEAs

Advancements in microbubble physics and imaging techniques are driving new applications in ultrasound contrast imaging, particularly in the realm of sonothrombolysis Graphical Abstract. The development of non-invasive procedures that estimate hepatic fibrosis and portal hypertension with second-generation microbubbles marks a significant leap from traditional, more invasive diagnostic methods. Furthermore, clinicians now have at their disposal new techniques for directly estimating the attenuation coefficient of UCAs, streamlining and improving the efficiency of ultrasound diagnostic procedures in clinical settings [27].

In parallel, activatable contrast agents responsive to biological stimuli are enhancing the capabilities of optoacoustic imaging, with potential adaptations for targeted sonothrombolysis therapies. These agents could revolutionize cancer detection and treatment, allowing for more precise and personalized approaches based on each tumor's molecular phenotype. In addition, novel frequency mixing ultrasound imaging methods using nanobubbles present a new frontier for high-resolution imaging, which could greatly benefit real-time monitoring during sonothrombolytic interventions [28, 29].

The potential of UCAs extends to targeting ErbB2 ( +) gastric cancer cells, indicating new therapeutic pathways for sonothrombolysis in cancer treatment. These targeted approaches could lead to significant advancements in patient outcomes, especially when combined with technologies like ultrasound-switchable fluorescence for deep tissue imaging. This multifaceted development signifies UCAs' expanding role beyond cardiovascular applications, stepping into areas such as oncology, hepatology, and molecular imaging with promising clinical implications [30].

Conclusion

The scope of this review extends beyond merely highlighting the potential of sonothrombolysis; it advocates for a paradigm shift in the management of cardiovascular disorders. By harnessing the power of ultrasound-induced microbubble cavitation, we can transcend traditional barriers in the treatment of MVO and PAD, reshaping the therapeutic landscape for patients afflicted with these conditions.