Preclinical studies have demonstrated that high mechanical index (MI) impulses from a diagnostic ultrasound (DUS) transducer during an intravenous microbubble infusion (sonothrombolysis) can restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). The investigators propose to demonstrate the clinical effectiveness of sonothrombolysis in multiple centers and in a wide scenario of acute coronary syndromes.

Initial safety and feasibility human studies demonstrated that intermittent high MI aimed at the myocardial microcirculation could improve capillary blood flow within the risk area and epicardial recanalization rates. In light of this, the investigators published the first prospective randomized human study showing the added value of sonothrombolysis to percutaneous coronary intervention (PCI). Sonothrombolysis improved recanalization rates and reduced infarct size, leading to sustained improvements in systolic function after STEMI. Since both diagnostic ultrasound and intravenous infusions of microbubbles are Class I indication to assess regional and global left ventricular function and risk area in patients with STEMI, the purpose of this study is to 1) demonstrate the clinical effectiveness of sonothrombolysis in multiple centers and in a wide scenario of acute coronary syndromes including pre-hospital care setting; and 2) develop a portable non-imaging ultrasound device prototype, simple-to-handle and capable of generating intermittent ultrasound pulses for sonothrombolysis.

A total of 540 subjects will be included in this study. Subjects will be randomized to either receive DUS guided high MI impulses within and outside the risk area during a continuous infusion of intravenous 3% Definity® or placebo. Comparisons between the two groups will be made on door to dilation times, survival, angiographic recanalization rates at initial angiography and reduction in microvascular obstruction and in infarct size determined by the salvageability index at cardiac magnetic resonance imaging (MRI) post-STEMI and using myocardial perfusion imaging. The effect of high-energy ultrasound therapy and microbubbles on the outcome of sympathetic hyperactivation and autonomic imbalance after MI will be also evaluated. Cardiac remodeling assessed by left atrial and ventricular volumes indexes and myocardial strain imaging will also be measured. Overall survival defined as the time from the start of treatment to death from any cause as well as new MIs events will be assessed.

The study will be divided into 6 subprojects: subproject 1 (n=70 in each group) - safety and efficacy of the therapeutic use of intermittent high-energy ultrasound and microbubbles in the recanalization of acute STEMI treated with primary PCI. Additionally, the investigators will assess the effect of sonothrombolysis on autonomic function, cardiac function and intracellular signaling. All patients will receive conventional PCI approach, including aspirin 325 milligram, clopidogrel 600 milligrams and heparin bolus (5000 units), followed by primary PCI using glycoprotein 2b/3a inhibitors as anti-thrombotic agents using established protocols. Besides angiographic recanalization rates at the time of presentation to the catheterization laboratory, participants will have a fully echocardiography study including myocardial perfusion imaging and strain imaging, serum microRNAS for detecting endothelial cells shear-stress and autonomic control assessment (heart rate and systolic blood pressure variability) at the baseline, 72-96 hours, 30 days and 6 months of follow up. A iodine-123 meta-iodobenzylguanidine (MIBG) cardiac scintigraphy will be carried out at 30 days and 6 months follow up, and exercise echocardiogram at 6 months. Subproject 2 (n=70 in each group) - safety and efficacy of the therapeutic use of intermittent high-energy ultrasound and microbubbles in the recanalization of acute STEMI in patients initially treated in a primary hospital with fibrinolytic therapy within 12 hours. Angiographic recanalization rates at initial angiography and in infarct size determined by the salvageability index at cardiac MRI post-STEMI, and cardiac death and a new MI episode are the main objectives. Participants will receive STEMI/PCI treatment as per current guidelines using standard protocols similar to subproject 1. In addition, both groups will undergo elective PCI after fibrinolytic therapy. Besides angiographic recanalization rates at the time of presentation to the catheterization laboratory, a comprehensive echocardiography study including myocardial perfusion and strain imaging, MRI and exercise echocardiogram will be performed at the time of presentation and during 72-96 hours, 30 days, 3 months and 6 months of follow up. Subproject 3 (n=70 in each group) - safety and efficacy of the therapeutic use of intermittent high-energy ultrasound and microbubbles in the recanalization of acute myocardial infarction without segment elevation or with high-risk unstable angina (NSTEMI). Subjects presenting without persistent ST-segment elevation acute coronary syndromes undergoing early invasive strategy within 24 hours will be randomized to either receive diagnostic ultrasound guided high MI impulses during a continuous infusion of intravenous 3% Definity® or placebo. Participants will receive conventional medical treatment, including aspirin 325 milligram, clopidogrel 600 milligrams and unfractionated heparin weight-adjusted iv. bolus or in combination with glycoprotein 2b/3a inhibitors followed by primary PCI using established protocols as per current guidelines. A comprehensive echocardiography study including myocardial perfusion echocardiography and exercise echocardiogram will be carried out at the baseline, 72-96 hours, 30 days- and 6 months of follow up. Subproject 4 (n=30 in each group): safety and efficacy of the therapeutic use of intermittent high-energy ultrasound and microbubbles in reducing microvascular obstruction and myocardial infarction size after primary PCI in patients with anterior wall myocardial infarction. Participants will receive STEMI/PCI approach as per guidelines likewise subprojects 1 and 2. In order to assess microvascular obstruction and no reflow phenomenon, a comprehensive echocardiography study, including myocardial perfusion imaging and myocardial strain will be performed at baseline, 2 months and 6 months of follow up. MRI will be performed at 3 days and 3 months of follow up. Subproject 5: this subproject will be dedicated to the development of an automated hands-free portable prototype emitting ultrasound waves of intermittent high-energy capable of promoting sonothrombolysis. Subproject 6 (n=30 in each group): a pilot study on the therapeutic use of intermittent high-energy ultrasound and microbubbles in the recanalization of acute STEMI in the pre-hospital setting (ambulances). Subjects with acute STEMI will be randomized to either receive diagnostic ultrasound guided high MI impulses during a continuous infusion of intravenous 3% Definity® or placebo while routing from the ambulance to the emergency department. At the admission hospital, all patients will receive conventional PCI approach, including aspirin 325 milligram, clopidogrel 600 milligrams and heparin bolus (5000 units), followed by primary PCI using glycoprotein 2b/3a inhibitors as anti-thrombotic agents using established protocols as per aforementioned subprojects. A complete echocardiography study including myocardial perfusion and strain, and exercise echocardiogram will be carried out at baseline, 72-96 hours, 30 days- and 6 months of follow up.

Inclusion Criteria:

• Age ≥30 years with STEMI with less than 12 hours of chest pain onset.
• Age ≥30 years with STEMI initially treated in a primary setting by fibrinolytic therapy within 12h
• Age ≥30 years with NSTEMI with high-risk unstable angina who will undergo elective PCI
• Eligible for emergent PCI therapy.
• No contraindications or hypersensitivities to ultrasound contrast agents

Exclusion Criteria:

• Known or suspected hypersensitivity to ultrasound contrast agent used for the study.
• Cardiogenic Shock.
• Life expectancy of less than two months or terminally ill.
• Known bleeding diathesis or contraindication to glycoprotein 2b/3a inhibitors, anticoagulants, or aspirin.
• Known large right to left intracardiac shunts or severe pulmonary hypertension.
• Patients who received thrombolytic therapy previously to enrollment.
• Women of childbearing potential.

Patients with acute ST elevation myocardial infarction (STEMI) with less than 12 hours of chest pain onset, STEMI initially treated with fibrinonilytic therapy, NSTEMI or high-risk angina undergoing early invasive PCI, anterior wall (LAD territory) acute STEMI, and acute STEMI with less than 12 hours of chest pain onset in the pre-care setting (ambulance) eligible for emergent percutaneous coronary intervention therapy.

The data will be saved into a research encrypted platform available only to study group researchers. Participants will be non-identifiable and results will be blinded to reviewers. The platforms included are RedCap and Castor.