UNASSIGNED: Despite advances in timely revascularisation of ST elevation myocardial infarction (STEMI) patients, there are several practical and unavoidable delays. Sonothrombolysis (administered during micro boluses of Perfluoropropane) initiated bedside as a point-of-care therapy during the initial evaluation of the patient may potentially mitigate this by producing early culprit vessel revascularisation.
UNASSIGNED: This was a prospective, single-centre study on hemodynamically stable patients presenting within 12 hours of a first STEMI who consented for study participation.
UNASSIGNED: Fifteen patients were recruited over a 1-month period. Eleven were male. Nine patients had anterior wall STEMI and left anterior descending as culprit vessel. There were no significant changes in safety outcomes. Median First Medical Contact (FMC)-Sono time was 12 min (10-15). Median duration of sonothrombolysis was 14 min (12-16). FMC-device time was 97 min (79-128). Six patients had culprit vessel recanalisation before primary percutaneous coronary intervention (PPCI) which was consistent with the reference rates of therapy-associated recanalisation (p = 0.535).
UNASSIGNED: Micro bolus sonothrombolysis maybe safely initiated as a point of care therapy adjunctive to PPCI in hemodynamically stable STEMI patients with reasonable efficacy. Further randomised trials are needed to ascertain its applicability in various geographical and clinical settings.

From its inception as a two-dimensional snapshot of the beating heart, echocardiography has become an indelible part of cardiovascular diagnostics. The integration of ultrasound enhancing agents (UEAs) marks a pivotal transition, enhancing its diagnostic acumen beyond myocardial perfusion. These agents have refined echocardiography\'s capacity to visualize complex cardiac anatomy and pathology with unprecedented clarity, especially in non-coronary artery disease contexts. UEAs aid in detailed assessments of myocardial viability, endocardial border delineation in left ventricular opacification, and identification of intracardiac masses. Recent innovations in UEAs, accompanied by advancements in echocardiographic technology, offer clinicians a more nuanced view of cardiac function and blood flow dynamics. This review explores recent developments in these applications and future contemplated studies.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation myocardial infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increases infarct vessel patency, improves microvascular flow, reduces infarct size, and improves ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel 3-arm sham-controlled randomized controlled trial to address this.
METHODS: Patients presenting with first STEMI undergoing pPCI within 6 hours of symptom onset were randomized 1:1:1 into 3 arms: sonothrombolysis pre-/post-pPCI (group 1), sham pre- sonothrombolysis post-pPCI (group 2), and sham pre-/post-pPCI (group 3). Our primary end point was infarct size (percentage of left ventricular mass) assessed by cardiac magnetic resonance imaging at day 4 ± 2. Secondary end points included myocardial salvage index (MSI) and echocardiographic parameters at day 4 ± 2 and 6 months.
RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (age 60, male 82%) were included postrandomization. Median sonothrombolysis took 5 minutes pre-pPCI and 15 minutes post-, without significant door-to-balloon delay. There was a trend toward reduction in median infarct size between group 1 (8% [interquartile range, 4,11]), group 2 (11% [7, 19]), or group 3 (15% [9, 22]). Similarly there was a trend toward improved MSI in group 1 (79% [64, 85]) compared to groups 2 (51% [45, 70]) and 3 (48% [37, 73]) No major adverse cardiac events occurred during hospitalization.
CONCLUSIONS: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicenter trials and health economic analyses are required before clinical translation.

OBJECTIVE: Approximately 50% of patients with ST elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) experience microvascular no-reflow. Pre- and post-PCI sonothrombolysis has been shown to decrease infarct size and improve left ventricular (LV) systolic function in STEMI patients receiving urgent PCI. The aim of this study was to investigate whether post-PCI sonothrombolysis alone in STEMI patients with persistent ST elevation could reduce no-reflow and infarct size.
METHODS: Patients with STEMI with symptoms <12 hours who had persistent ST elevation (≤70% ST resolution) after primary PCI were randomized to sonothrombolysis or control. The primary end point was summed (Σ) ST elevation 60 minutes after study intervention. Secondary end points included infarct size, myocardial perfusion score, LV ejection fraction on cardiovascular magnetic resonance imaging at 2 months follow-up, and clinical outcome at 6-month follow-up.
RESULTS: Sixty-seven STEMI patients with persistent ST elevation after PCI were randomized (49 left anterior descending, 18 right coronary/left circumflex artery). No difference was observed in Σ ST elevation 60 minutes after study intervention (mean difference, 0.6 mm; 95% CI, -1.1 to 2.2, P = .50). Complete ST resolution occurred in 14 (40%) of patients treated with sonothrombolysis compared to 6 (19%) of controls (P = .16). Myocardial perfusion score index (1.5 ± 0.3 vs 1.5 ± 0.3, P = .93), infarct size (18.0% ± 10% vs 16.8% ± 11%; P = .29) and LV ejection fraction on cardiovascular magnetic resonance (46% ± 8% vs 47% ± 11% in the control group; P = .86) were comparable. Incidence of all-cause death, acute coronary syndrome, and hospital admission for heart failure at 6-month follow-up was similar between the groups (sonothrombolysis, 2; control, 5).
CONCLUSIONS: In STEMI patients with persistent ST elevation after PCI, post-PCI sonothrombolysis did not result in more ST resolution or smaller infarct size compared to control subjects. The incidence of the combined clinical end points was remarkably low in this high-risk patient population.

OBJECTIVE: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure.
BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear.
METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of 2 treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for 6 months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total.
CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

OBJECTIVE: Persistent microvascular obstruction (MVO) after successful percutaneous coronary intervention (PCI) in acute ST segment elevation myocardial infarction (STEMI) has been well-described. MVO predicts lack of recovery of left ventricular function and increased mortality. Sonothrombolysis utilizing diagnostic ultrasound induced cavitation of commercially available microbubble contrast has been effective at reducing infarct size and improving left ventricular ejection fraction (LVEF) when performed both pre- and post-PCI. However, the effectiveness of post-PCI sonothrombolysis alone after successful PCI has not been demonstrated.
METHODS: A prospective randomized controlled trial was performed in 50 consecutive consenting patients with anterior STEMI who underwent a continuous microbubble infusion immediately following successful PCI. Intermittent high mechanical index (MI) impulses were applied only in the sonthrombolysis group. Delayed enhancement magnetic resonance imaging (MRI) was performed at 48 h and again at 6-8 weeks to assess for differences in infarct size, LVEF, and MVO.
RESULTS: There were no differences between groups in age, gender, and cardiovascular risk factors. Significant (> 2 segments) MVO following successful PCI was observed in 66% of patients. Although sonothrombolysis reduced the extent of MVO acutely, there were no differences in infarct size, LVEF, or extent of MVO by MRI at 48 h. Twenty-eight patients returned for a follow up MRI at 6-8 weeks. LVEF improved only in the sonothrombolysis group (∆LVEF 7.81 ± 4.57% with sonothrombolysis vs. 1.77 ± 7.02% for low MI only, p = .011).
CONCLUSIONS: Post-PCI sonothrombolysis had minimal effect on reducing myocardial infarct size but improved left ventricular systolic function in patients with acute anterior wall STEMI.

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.

Microbubble-mediated sonothrombolysis has been proven to be a non-invasive and efficient method for thrombolysis. Nevertheless, there is a potential risk that the thrombus debris generated during the dissolution of the original thrombus are too large and can lead to hazardous emboli. Using a sonothrombolysis microfluidic platform, we investigated the effects of ultrasound power, thrombolytic agent and microbubble concentration on the size of thrombus debris with the example of microbubble-mediated sonothrombolysis of arterial thrombus. Additionally, we studied the effects of ultrasound power on the size and shape of thrombus debris produced by acute and chronic arterial sonothrombolysis. In acute arterial sonothrombolysis, ultrasound power has significant effect on the size of thrombus debris and steadily increases with the increase of ultrasound power. Conversely, in chronic arterial sonothrombolysis, the size of thrombus debris is minimally affected by ultrasound power. Using the sonothrombolysis microfluidic platform, the relationship between ultrasound power and the safety of sonothrombolysis has been illustrated, and the sonothrombolysis microfluidic platform is demonstrated to be a promising tool for further studies on the process of sonothrombolysis.

Thrombotic occlusions of large blood vessels are increasingly treated with catheter based mechanical approaches, one of the most prominent being to employ aspiration to extract clots through a hollow catheter lumen. A central technical challenge for aspiration catheters is to achieve sufficient suction force to overcome the resistance of clot material entering into the distal tip. In this study, we examine the feasibility of inducing cavitation within hollow cylindrical transducers with a view to ultimately using them to degrade the mechanical integrity of thrombus within the tip of an aspiration catheter. Hollow cylindrical radially polarized PZT transducers with 3.3/2.5 mm outer/inner diameters were assessed. Finite element simulations and hydrophone experiments were used to investigate the pressure field distribution as a function of element length and resonant mode (thickness, length). Operating in thickness mode (∼5 MHz) was found to be associated with the highest internal pressures, estimated to exceed 23 MPa. Cavitation was demonstrated to be achievable within the transducer under degassed water (10 %) conditions using hydrophone detection and high-frequency ultrasound imaging (40 MHz). Cavitation clouds occupied a substantial portion of the transducer lumen, in a manner that was dependent on the pulsing scheme employed (10 and 100 μs pulse lengths; 1.1, 11, and 110 ms pulse intervals). Collectively the results support the feasibility of achieving cavitation within a transducer compatible with mounting in the tip of an aspiration format catheter.

Stroke is a major cause of death and disability globally, with ischemic stroke being the predominant mechanism. While spontaneous recanalization may occur, significant neuronal injury would have occurred in the interim. Intravenous thrombolysis administered within the first 4.5 h after stroke onset and endovascular thrombectomy within 24 h in patients with a salvageable penumbra improves functional independence. Ultrasound has been shown in both in vivo and in vitro models to enhance clot lysis, even more-so in the presence of thrombolytic agents. The use of transcranial Doppler and transcranial color-coded Doppler ultrasound in acute IS has been reported in case series, case-controlled studies, and clinical trials. While ultrasound at a frequency of 300 kHz increases the risk of intracranial hemorrhage, the 2 MHz range ultrasound aids thrombolysis and improves recanalization without significantly increasing the risk of symptomatic intracranial hemorrhage. Despite this, functional independence was not increased in clinical trials, nor was a benefit shown with the adjunctive use of microbubbles or microspheres. Nonetheless, newer technologies such as endovascular ultrasound, endovascular delivery of microbubbles, and thrombolytic-filled microbubbles await clinical trials. More evidence is needed before sonothrombolysis can be routinely used in the hyperacute management of ischemic stroke.