Contrast Ultrasound, Sonothrombolysis and Sonoperfusion in Cardiovascular Disease: Shifting to Theragnostic Clinical Trials.

Contrast ultrasound has a variety of applications in cardiovascular medicine, both in diagnosing cardiovascular disease as well as providing prognostic information. Visualization of intravascular contrast microbubbles is based on acoustic cavitation, the characteristic oscillation that results in changes in the reflected ultrasound waves. At high power, this acoustic response generates sufficient shear that is capable of enhancing endothelium-dependent perfusion in atherothrombotic cardiovascular disease (sonoperfusion). The oscillation and collapse of microbubbles in response to ultrasound also induces microstreaming and jetting that can fragment thrombus (sonothrombolysis). Several preclinical studies have focused on identifying optimal diagnostic ultrasound settings and treatment regimens. Clinical trials have been performed in acute myocardial infarction, stroke, and peripheral arterial disease often with improved outcome. In the coming years, results of ongoing clinical trials along with innovation and improvements in sonothrombolysis and sonoperfusion will determine whether this theragnostic technique will become a valuable addition to reperfusion therapy.

Feasibility of sonothrombolysis in the ambulance for ST-elevation myocardial infarction.

Patients with ST-elevation myocardial infarction (STEMI) due to coronary occlusion require immediate restoration of epicardial and microvascular blood flow. A potentially new reperfusion method is the use of ultrasound and microbubbles, also called sonothrombolysis. The oscillation and collapse of intravenously administered microbubbles upon exposure to high mechanical index (MI) ultrasound pulses results in thrombus dissolution and stimulates nitric oxide-mediated increases in tissue perfusion. The aim of this study was to assess feasibility of sonothrombolysis in the ambulance for STEMI patients. Patients presenting with chest pain and ST-elevations on initial electrocardiogram were included. Sonothrombolysis was applied in the ambulance during patient transfer to the percutaneous coronary intervention (PCI) center. Feasibility was assessed based on duration of sonothrombolysis treatment and number of high MI pulses applied. Vital parameters, ST-resolution, pre- and post-PCI coronary flow and cardiovascular magnetic resonance images were analyzed. Follow up was performed at six months after STEMI. Twelve patients were screened, of which three patients were included in the study. Sonothrombolysis duration and number of high MI pulses ranged between 12 and 17 min and 32-60 flashes respectively. No arrhythmias or changes in vital parameters were observed during and directly after sonothrombolysis, although one patient developed in-hospital ventricular fibrillation 20 min after sonothrombolysis completion but before PCI. In one case, sonothrombolysis on top of regular pre-hospital care resulted in reperfusion before PCI. This is the first report on the feasibility of performing sonothrombolysis to treat myocardial infarction in an ambulance. To assess efficacy and safety of pre-hospital sonothrombolysis, clinical trials with greater patient numbers should be performed. EU Clinical Trials Register (identifier: 2019-001883-31), registered 2020-02-25.

Efficacy of Sonothrombolysis Using Acoustically Activated Perflutren Nanodroplets versus Perflutren Microbubbles.

Nanoscale-diameter liquid droplets from commercially available microbubbles may optimize thrombus permeation and subsequent thrombus dissolution (TD). Thrombi were made using fresh porcine arterial whole blood and placed in an in vitro vascular simulation. A diagnostic ultrasound probe in contact with a tissue-mimicking phantom tested intermittent high-mechanical-index (HMI) fundamental multipulse (focused ultrasound [FUS], 1.8 MHz) versus harmonic single-pulse (HUS, 1.3 MHz) modes during a 10-min infusion of Definity nanodroplets (DNDs), Definity microbubbles (DMBs) or saline. The ability of FUS and intravenous DNDs to improve epicardial and microvascular flow was then tested in four pigs with left anterior descending thrombotic occlusion. Sixty in vitro thrombi were tested, 20 in each group. Percentage TD was significantly higher for DND-treated thrombi than DMB-treated thrombi and controls (DNDs: 42.4%, DMBs: 26.7%, saline: 15.0%; p < 0.0001 vs. control). The highest %TD was seen in the HMI FUS-treated DND group (51 ± 17% TD). HMI FUS detected droplet activation within the risk area in three of four pigs with left anterior descending thrombotic occlusion and re-canalized the epicardial vessel in two. DNDs with intermittent diagnostic HMI ultrasound resulted in significantly more intravascular TD than DMBs and have potential for coronary and risk area thrombolysis.

Delayed Echo Enhancement Imaging to Quantify Myocardial Infarct Size.

BACKGROUND: Perfluoropropane droplets formulated from commercial microbubbles exhibit different acoustic characteristics than their parent microbubbles, most likely from enhanced endothelial permeability. This enhanced permeability may permit delayed echo-enhancement imaging (DEEI) similar to delayed enhancement magnetic resonance imaging (DE-MRI). We hypothesized this would allow detection and quantification of myocardial scar. METHODS: In 15 pigs undergoing 90 minutes of left anterior descending ischemia by either balloon (n = 13) or thrombotic occlusion (n = 2), DE-MRI was performed at 2-24 days postocclusion. Delayed echo-enhancement imaging was performed at 2-4 minutes following an intravenous injection of 1 mL of 50% Definity (Lantheus Medical) compressed into 180 nm droplets; DEEI was attempted in all pigs with single-pulse harmonic imaging at 1.7 transmit/3.4 MHz receive. Myocardial defects observed with DEEI were quantified (percentage of infarct area) and compared with DE-MRI as well as postmortem staining. In six pigs, multipulse low-mechanical index (MI) fundamental nonlinear imaging (FNLI) with intermittent high-MI impulses was performed to determine whether droplet activation within the infarct zone was achievable with a longer pulse duration. RESULTS: The range of infarct size area by DE-MRI ranged from 0% to 46% of total left ventricular area. Single-pulse harmonic imaging detected a contrast defect that correlated closely with infarct area by DE-MRI (r = 0.81, P = .0001). The FNLI high-MI impulses resulted in droplet activation in both the infarct and normal zones. Harmonic subtraction of the FNLI images resulted in infarct zone enhancement that also correlated closely with infarct size (r = 0.83; P = .04). Droplets were observed on postmortem transmission electron microscopy within myocytes of the infarct and remote normal zone. CONCLUSION: Intravenously Definity nanodroplets can be utilized to detect and quantify infarct zone at the bedside using DEEI techniques.

Determination and Interpretation of the QT Interval.

BACKGROUND: Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS. METHODS: Patients with a confirmed pathogenic variant in KCNQ1(LQT1), KCNH2(LQT2), or SCN5A(LQT3) genes and their family members were included. Genotype-positive patients were identified as LQTS cases and genotype-negative family members as controls. ECGs were analyzed with both methods, providing inter- and intrareader validity and diagnostic accuracy. Cutoff values based on control population's 95th and 99th percentiles, and LQTS-patients' 1st and 5th percentiles were established based on the method to correct for heart rate, age, and sex. RESULTS: We included 1484 individuals from 265 families, aged 33±21 years and 55% females. In the total cohort, QTTangent was 10.4 ms shorter compared with QTThreshold (95% limits of agreement±20.5 ms, P<0.0001). For all genotypes, QTTangent was shorter than QTThreshold ( P<0.0001), but this was less pronounced in LQT2. Both methods yielded a high inter- and intrareader validity (intraclass correlation coefficient >0.96), and a high diagnostic accuracy (area under the curve >0.84). Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity. QTc interval cutoff values of QTTangent were lower compared with QTThreshold and different depending on the correction for heart rate, age, and sex. CONCLUSION: The QT interval varies depending on the method used for its assessment, yet both methods have a high validity and can both be used in diagnosing LQTS. However, for diagnostic purposes current guideline cutoff values yield different results for these 2 methods and could result in inappropriate reassurance or treatment. Adjusted cutoff values are therefore specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for LQTS ( www.QTcalculator.org ) has been made available as an aid in the interpretation of the QT interval.