Restoring microvascular circulation with diagnostic ultrasound and contrast agent: Rationale and Design of the REDUCE trial.

OBJECTIVES: 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 two 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 six 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.

Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Integrating hemodynamics with ventricular and valvular remodeling in aortic stenosis. A paradigm shift in therapeutic decision making.

Aortic valve stenosis (AS) has traditionally been approached in hemodynamic terms. Although hemodynamics and symptoms have formed the basis of recommending interventional treatment in AS, other factors reflecting left ventricular and valvular and/or vascular remodeling are equally important for the prognosis and outcome of patients with AS. Left ventricular and valvular/vascular remodeling in AS do not consistently correlate with hemodynamic severity of AS. Those remodeling changes are reflected and can be detected by a variety of novel laboratory and imaging techniques, including biomarkers, echocardiography, cardiac magnetic resonance and gated Computer Tomography (CT) imaging. Taking all those elements into Heart Team therapeutic decision making in patients with AS, can significantly improve appropriate patient selection for interventional treatment and patient outcomes. We review this novel approach and propose a simple algorithm for decision making by the Heart Team, in patients with moderate or severe AS.

Ultrasound Theranostics in Adult and Pediatric Cardiovascular Research.

Theranostics, the practice of systematically integrating diagnostics with treatment, has evolved as a field of medicine. In the context of ultrasound based theranostics, both traditional microbubbles and inorganic nanoparticles have emerged as technologies of clinical interest. Ultrasound induced microbubble cavitation has demonstrated efficacy in a variety of applications, including thrombolysis, tumor ablation, targeted microvascular flow enhancement, and targeted drug and gene delivery. This commentary summarizes the mechanisms and applications of ultrasound-based theranostics in cardiovascular medicine, including its impact in pediatric cardiology. It also provides an overview of ongoing clinical trials for theranostics in cardiovascular medicine.

Cardiovascular Sonothrombolysis.

PURPOSE OF REVIEW: This review will provide recent pre-clinical and initial clinical trials exploring the efficacy of sonothrombolysis as an adjunct to current emergent therapies in acute coronary syndromes. RECENT FINDINGS: The initial clinical trials examining the efficacy of short pulse duration diagnostic ultrasound (DUS) high mechanical index impulses in patients with ST segment elevation myocardial infarction (STEMI) have demonstrated that there is improved patency of the infarct vessel, and improved microvascular flow following percutaneous coronary intervention. Subsequent randomized prospective trials have confirmed that in patients with acute STEMI receiving an intravenous microbubble infusion, diagnostic high mechanical index impulses applied in the apical windows pre- and post-percutaneous coronary intervention have reduced myocardial infarction size, as assessed by magnetic resonance imaging at 72 h following presentation, and have been associated with better left ventricular systolic function at 6 month follow-up. Sonothrombolysis has potential for improving early epicardial coronary artery patency and reduce left ventricular remodeling when added to current interventional strategies in STEMI.

Conduction and Reactivity in Heterogeneous-Molecular Catalysis: New Insights in Water Oxidation Catalysis by Phosphate Cobalt Oxide Films.

Cyclic voltammetry of phosphate cobalt oxide (CoPi) films catalyzing O2-evolution from water oxidation as a function of scan rate, phosphate concentration and film thickness allowed for new insights into the coupling between charge transport and catalysis. At pH = 7 and low buffer concentrations, the film is insulating below 0.8 (V vs SHE) but becomes conductive above 0.9 (V vs SHE). Between 1.0 to 1.3 (V vs SHE), the mesoporous structure of the film gives rise to a large thickness-dependent capacitance. At higher buffer concentrations, two reversible proton-coupled redox couples appear over the capacitive response with 0.94 and 1.19 (V vs SHE) pH = 7 standard potentials. The latter is, at most, very weakly catalytic and not responsible for the large catalytic current observed at higher potentials. CV-response analysis showed that the amount of redox-active cobalt-species in the film is small, less than 10% of total. The catalytic process involves a further proton-coupled-electron-transfer and is so fast that it is controlled by diffusion of phosphate, the catalyst cofactor. CV-analysis with newly derived relationships led to a combination of the catalyst standard potential with the catalytic rate constant and a lower-limit estimation of these parameters. The large currents resulting from the fast catalytic reaction result in significant potential losses related to charge transport through the film. CoPi films appear to combine molecular catalysis with semiconductor-type charge transport. This mode of heterogeneous molecular catalysis is likely to occur in many other catalytic films.

Electronic Structure of a Cu(II)-Alkoxide Complex Modeling Intermediates in Copper-Catalyzed Alcohol Oxidations.

In the copper-catalyzed oxidation of alcohols to aldehydes, a Cu(II)-alkoxide (Cu(II)-OR) intermediate is believed to modulate the αC-H bond strength of the deprotonated substrate to facilitate the oxidation. As a structural model for these intermediates, we characterized the electronic structure of the stable compound Tp(tBu)Cu(II)(OCH2CF3) (Tp(tBu) = hydro-tris(3-tert-butyl-pyrazolyl)borate) and investigated the influence of the trifluoroethoxide ligand on the electronic structure of the complex. The compound exhibits an electron paramagnetic resonance (EPR) spectrum with an unusually large gzz value of 2.44 and a small copper hyperfine coupling Azz of 40 × 10(-4) cm(-1) (120 MHz). Single-crystal electron nuclear double resonance (ENDOR) spectra show that the unpaired spin population is highly localized on the copper ion (≈68%), with no more than 15% on the ethoxide oxygen. Electronic absorption and magnetic circular dichroism (MCD) spectra show weak ligand-field transitions between 5000 and 12,000 cm(-1) and an intense ethoxide-to-copper charge transfer (LMCT) transition at 24,000 cm(-1), resulting in the red color of this complex. Resonance Raman (rR) spectroscopy reveals a Cu-O stretch mode at 592 cm(-1). Quantum chemical calculations support the interpretation and assignment of the experimental data. Compared to known Cu(II)-thiolate and Cu(II)-alkylperoxo complexes from the literature, we found an increased σ interaction in the Cu(II)-OR bond that results in the spectroscopic features. These insights lay the basis for further elucidating the mechanism of copper-catalyzed alcohol oxidations.

Synthesis, Radical Reactivity, and Thermochemistry of Monomeric Cu(II) Alkoxide Complexes Relevant to Cu/Radical Alcohol Oxidation Catalysis.

Two new monomeric Cu(II) alkoxide complexes were prepared and fully characterized as models for intermediates in copper/radical mediated alcohol oxidation catalysis: Tp(tBuR)Cu(II)OCH2CF3 with Tp(tBu) = hydro-tris(3-tert-butyl-pyrazol-1-yl)borate 1 or Tp(tBuMe) = hydro-tris(3-tert-butyl-5-methyl-pyrazol-1-yl)borate 2. These complexes were made as models for potential intermediates in enzymatic and synthetic catalytic cycles for alcohol oxidation. However, the alkoxide ligands are not readily oxidized by loss of H; instead, these complexes were found to be hydrogen atom acceptors. They oxidize the hydroxylamine TEMPOH, 2,4,6-tri-t-butylphenol, and 1,4-cyclohexadiene to the nitroxyl radical, phenoxyl radical, and benzene, with formation of HOCH2CF3 (TFE) and the Cu(I) complexes Tp(tBuR)Cu(I)-MeCN in dichloromethane/1% MeCN or 1/2 [Tp(tBuR)Cu(I)]2 in toluene. On the basis of thermodynamics and kinetics arguments, these reactions likely proceed through concerted proton-electron transfer mechanisms. Thermochemical analyses give lower limits for the "effective bond dissociation free energies (BDFE)" of the O-H bonds in 1/2[Tp(tBuR)Cu(I)]2 + TFE and upper limits for the free energies associated with alkoxide oxidations via hydrogen atom transfer (effective alkoxide α-C-H BDFEs). These values are summations of the free energies of multiple chemical steps, which include the energetically favorable formation of 1/2[Tp(tBuR)Cu(I)]2. The effective alkoxide α-C-H bonds are very weak, BDFE ≤ 38 ± 4 kcal mol(-1) for 1 and ≤44 ± 5 kcal mol(-1) for 2 (gas-phase estimates), because C-H homolysis is thermodynamically coupled to one electron transfer to Cu(II) as well as the favorable formation of the 1/2[Tp(tBuR)Cu(I)]2 dimer. Treating 1 with the H atom acceptor (t)Bu3ArO(•) did not result in the expected alkoxide oxidation to an aldehyde, but rather net 2,2,2-trifluoroethoxyl radical transfer occurred to generate an unusual 2-substituted dienone-ether product. Treating 2 with (t)Bu3ArO(•) gives no reaction, despite evidence that overall ligand oxidation and formation of 1/2[Tp(tBuMe)Cu(I)]2 is significantly exoergic. The origin of this lack of reactivity may be due to insufficient weakening of the alcohol α-C-H bond upon complexation to copper.

Liver Transplantation: Intraoperative Transesophageal Echocardiography Findings and Relationship to Major Postoperative Adverse Cardiac Events.

OBJECTIVE: The primary aim of the study was to describe the most common intraoperative transesophageal echocardiography (TEE) findings during the 3 separate phases of orthotopic liver transplantation (OLT). The secondary aim of the study was to determine if the abnormal TEE findings were associated with major postoperative adverse cardiac events (MACE) and thus may be amenable to future management strategies. DESIGN: Data were collected retrospectively from the electronic medical record and institutional echocardiography database. SETTING: Single university hospital. PARTICIPANTS: A total of 100 patients undergoing OLT via total cavaplasty technique. INTERVENTIONS: Intraoperative TEE was performed in all 3 phases of OLT. MEASUREMENT AND MAIN RESULTS: TEE findings of 100 patients who had TEE during OLT during the dissection, anhepatic, and reperfusion phases of transplantation were recorded after blind review. Findings then were analyzed to see if those findings were predictive of postoperative MACE. Intraoperative TEE findings varied among the different phases of OLT. Common TEE findings at reperfusion were microemboli (n = 40, 40%), isolated right ventricular dysfunction (n = 22, 22%), and intracardiac thromboemboli (n = 20, 20%). CONCLUSIONS: Intraoperative echocardiography findings during liver transplantation varied during each phase of transplantation. The presence of intracardiac thromboemboli or biventricular dysfunction on intraoperative echocardiography was predictive of short- and long-term major postoperative adverse cardiac events.

Contrast echocardiography: latest developments and clinical utility.

Ultrasound enhancing agents (UEAs) are being utilized for a growing number of applications with real-time very low mechanical index (MI) techniques in clinical cardiology today. This article will review recent developments on the safety of UEAs and their effectiveness in myocardial perfusion imaging, three-dimensional quantification of left ventricular function, and vascular imaging. UEAs are now being utilized in all age groups, with new indications that add incremental value to the currently approved by the Food and Drug Administration. These include the incremental value in cardiac imaging, where the off-label analysis of myocardial perfusion observed with UEAs adds to the enhanced endocardial border delineation. In carotid artery imaging, UEAs improve the detection of plaque but also can examine plaque neovascularization. Vascular surgeons now utilize UEAs in the evaluation of endovascular repair to detect endoleaks without the need of ionizing radiation. Newer applications are emerging in the detection of left atrial appendage thrombi and quantification of myocardial blood flow and volume in transplant patients.

Preparation, structural characterization, and thermochemistry of an isolable 4-arylphenoxyl radical.

The preparation and full characterization of the 4-(nitrophenyl)phenoxyl radical, 2,6-di-(t)butyl-4-(4'-nitrophenyl) phenoxyl radical ((t)Bu2NPArO(•)) is described. This is a rare example of an isolable and crystallographically characterized phenoxyl radical and is the only example in which the parent phenol is also crystallographically well-defined. Analysis of EPR spectra indicates some spin delocalization onto the secondary aromatic ring and nitro group. Equilibrium studies show that the corresponding phenol has an O-H bond dissociation free energy (BDFE) of 77.8 ± 0.5 kcal mol(-1) in MeCN (77.5 ± 0.5 kcal mol(-1) in toluene). This value is higher than related isolated phenoxyl radicals, making this a useful reagent for hydrogen atom transfer (HAT) studies. Additional thermochemical and spectroscopic parameters are also discussed.

Echocardiography-based hemodynamic management of left ventricular diastolic dysfunction: a feasibility and safety study.

BACKGROUND: Patients with left ventricular diastolic dysfunction (LVDD) are at increased risk of postoperative adverse events. The primary aim of this study was to evaluate the safety and feasibility of using echocardiography-guided hemodynamic management (EGHEM) during surgery in subjects with LVDD compared to conventional management. The feasibility of using echocardiography to direct a treatment algorithm and clinical outcomes were compared for safety between groups. METHODS: Subjects were screened for LVDD by preoperative transthoracic echocardiography (TTE) and randomized to the conventional or EGHEM group. Subjects in EGHEM received hemodynamic management based on left ventricular filling patterns on transesophageal echocardiography (TEE). Primary outcomes measured were the feasibility to obtain TEE images and follow a TEE-based treatment algorithm. Safety outcomes also compared the following clinical differences between groups: length of hospitalization, incidence of atrial fibrillation, congestive heart failure (CHF), myocardial infarction, cerebrovascular accident, transient ischemic attack and renal failure measured 30 days postoperatively. RESULTS: Population consisted of 28 surgical subjects (14 in conventional group and 14 in EGHEM group). Mean subject age was 73.4 ± 6.7 years (36% male) in conventional group and 65.9 ± 14.4 years (36% male) in EGHEM group. Procedures included orthopedic (conventional = 29%, EGHEM 36%), general (conventional = 50%, EGHEM = 36%), vascular (conventional = 7%, EGHEM = 21%), and thoracic (conventional = 14%, EGHEM = 7%). There was no statistically significant difference in adverse clinical events between the 2 groups. The EGHEM group had less CHF, atrial fibrillation, and shorter length of stay. CONCLUSIONS: Echocardiography-guided hemodynamic management of patients with LVDD during surgery is feasible and may be a safe alternative to conventional management.

Reversible ischaemia and outcome after adjustment for coronary artery disease severity: a multicentre stress-echocardiography registry.

AIMS: To assess the potential association of reversible ischaemia and Doppler coronary flow velocity reserve in the left anterior descending coronary artery (CFVR-LAD) during stress echocardiography (SE) with all-cause mortality and non-fatal myocardial infarction (MI), after correction for anatomic coronary artery disease (CAD) burden and other significant clinical variables. METHODS AND RESULTS: We selected 3191 patients (mean age 66 ± 12 years) from our multicentre SE registry, who underwent both high-dose dipyridamole SE (comprehensive of CFVR-LAD measurement) and coronary angiography within 2 months. All-cause mortality and non-fatal MI were the primary end points. The association of the primary end point with ischaemia severity and CFVR-LAD was assessed, after multivariable adjustment for all other significant clinical and imaging variables, including anatomic CAD severity by the modified Duke Prognostic Index. The primary end point occurred in 767 (24%) patients (death in 409 and non-fatal MI in 375 patients) during a median follow-up of 42 months. Multivariable Cox regression analyses indicated that, among other significant variables, anatomic CAD severity, reversible ischaemia, and CFVR-LAD were all independently associated with the primary end point; reversible ischaemia was also associated with subsequent MI, while CFVR-LAD with mortality, independent of anatomic CAD severity. CONCLUSION: Our study suggests that reversible ischaemia by wall motion assessment and CFVR-LAD on dipyridamole SE are independently associated with dismal outcome in patients with suspected or known stable CAD, even after accounting for angiographic anatomic CAD severity and also independently from which coronary artery is diseased.

Effect of Ambient Conditions on Acoustic Activation of the Perfluoropropane Droplets Within the Infarct Zone.

BACKGROUND: Acoustically activated perfluoropropane droplets (PD) formulated from lipid encapsulated microbubble preparations produce a delayed myocardial contrast enhancement that preferentially highlights the infarct zones (IZ). Since activation of PDs may be temperature sensitive, it is unclear what effect body temperature (BT) has on acoustic activation (AA). OBJECTIVE: We sought to determine whether the microvascular retention and degree of myocardial contrast intensity (MCI) would be affected by BT at the time of intravenous injection. METHODS: We administered intravenous (IV) PD in nine rats following 60 min of ischemia followed by reperfusion. Injections in these rats were given at temperatures above and below 36.5°C, with high MI activation in both groups at 3 or 6 min following IV injection (IVI). In six additional rats (three in each group), IV PDs were given only at one temperature (<36.5°C or ≥36.5°C), permitting a total of 12 comparisons of different BT. Differences in background subtracted MCI at 3-6 min post-injection were compared in the infarct zone (IZ) and remote zone (RZ). Post-mortem lung hematoxylin and eosin (H&E) staining was performed to assess the effect potential thermal activation on lung tissue. RESULTS: Selective MCI within the IZ was observed in 8 of 12 rats who received IVI of PDs at <36.5°C, but none of the 12 rats who had IVI at the higher temperature (p < 0.0001). Absolute MCI following droplet activation was significantly higher in both the IZ and RZ when given at the lower BT. H&E indicated significant red blood extravasation in 5/7 rats who had had IV injections at higher BT, and 0/7 rats who had IV PDs at <36.5°C. CONCLUSIONS: Selective IZ enhancement with AA of intravenous PDs is possible, but temperature sensitive. Thermal activation appears to occur when PDs are given at higher temperatures, preventing AA, and increasing unwanted bioeffects.

Sonothrombolysis in patients with ST-elevation myocardial infarction with electrocardiographic no-reflow after percutaneous coronary intervention: a randomized controlled trial.

BACKGROUND AND AIMS: Approximately 50% of patients with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) suffer from microvascular no-reflow. Pre- and post-PCI sonothrombolysis has 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: STEMI patients with symptoms <12 hours, who had persistent ST-elevation (≤70% ST-resolution) after primary PCI. were randomized to sonothrombolysis or control. The primary endpoint was summed (Σ) ST-elevation 60 minutes after study intervention. Secondary endpoints included infarct size, myocardial perfusion score, LV ejection fraction on cardiovascular magnetic resonance (CMR) imaging at two months follow up, and clinical outcome at six months follow up. RESULTS: 67 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: 0.6mm, 95% CI: -1.1 - 2.2, p=0.50). Complete ST-resolution occurred in 14 (40%) of patients treated with sonothrombolysis compared to six (19%) of controls (p=0.16). Myocardial perfusion score index (1.5 ±0.3 vs. 1.5 ±0.3, p=0.93), infarct size (18.0±10% vs. 16.8±11%; p=0.29) or LV ejection fraction on CMR (46±8% vs.47±11% in the control group; p=0.86) were comparable. Incidence of all-cause death, acute coronary syndrome and hospital admission for heart failure at six months follow up was similar between the groups (sonothrombolysis: 2, control: 5). CONCLUSION: 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 endpoints was remarkably low in this high-risk patient population.

Sonothrombolysis before and after percutaneous coronary intervention provides the largest myocardial salvage in ST-segment Elevation Myocardial Infarction.

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), increase infarct vessel patency, improve microvascular flow, reduce infarct size, and improve ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel three-arm sham-controlled randomised controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within six hours of symptom onset were randomised 1:1:1 into three arms: sonothrombolysis pre/post pPCI (Group 1), Sham pre & sonothrombolysis post pPCI (Group 2), and Sham pre/post pPCI (Group 3). Our primary endpoint was infarct size (% LV mass) assessed by Cardiac MRI at day 4±2. Secondary endpoints included myocardial salvage index (MSI) and echocardiographic parameters at Day 4±2 and six 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 post randomisation. Median sonothrombolysis took 5 minutes pre pPCI and 15 minutes post, without significant door-to-balloon delay. There was a trend towards reduction in median infarct size between Group 1 (8%[IQR 4,11]), Group 2 (11%[7,19]) or Group 3 (15%[9,22]). Similarly there was a trend towards 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. CONCLUSION: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicentre trials and health economic analyses are required before clinical translation.

Prognostic value of high-dose dipyridamole stress myocardial contrast perfusion echocardiography.

BACKGROUND: The addition of myocardial perfusion (MP) imaging during dipyridamole real-time contrast echocardiography improves the sensitivity to detect coronary artery disease, but its prognostic value to predict hard cardiac events in large numbers of patients with known or suspected coronary artery disease remains unknown. METHODS AND RESULTS: We studied 1252 patients with the use of dipyridamole real-time contrast echocardiography and followed them for a median of 25 months. The prognostic value of MP imaging regarding death and nonfatal myocardial infarction was determined and related to wall motion (WM), clinical risk factors, and rest ejection fraction by the use of Cox proportional-hazards models, C index, and risk reclassification analysis. A total of 59 hard events (4.7%) occurred during the follow-up (24 deaths, 35 myocardial infarctions). The 2-year event-free survival was 97.9% in patients with normal MP and WM, 91.9% with isolated reversible MP defects but normal WM, and 67.4% with both reversible MP and WM abnormalities (P<0.001). By multivariate analysis the independent predictors of events were age (hazard ratio 1.05, 95% confidence interval [CI], 1.02-1.08), sex (hazard ratio, 2.36; 95% CI, 1.32-4.23), reversible MP defects (hazard ratio, 3.88; 95% CI, 1.83-8.21), and reversible WM abnormalities with reversible MP defects (hazard ratio, 4.51; 95% CI, 2.25-9.07). Reversible MP defects added incremental predictive value and reclassification benefit over WM response and clinical factors (P=0.001). CONCLUSIONS: MP imaging using real-time perfusion echocardiography during dipyridamole real-time contrast echocardiography provides independent, incremental prognostic information regarding hard cardiac events in patients with known or suspected coronary artery disease. Patients with normal MP responses have better outcome than patients with normal WM; patients with both reversible WM and MP abnormalities have the worst outcome.

Thermal and Acoustic Stabilization Of Volatile Phase-Change Contrast Agents Via Layer-By-Layer Assembly.

OBJECTIVE: Phase-change contrast agents (PCCAs) are perfluorocarbon nanodroplets (NDs) that have been widely studied for ultrasound imaging in vitro, pre-clinical studies, and most recently incorporated a variant of PCCAs, namely a microbubble-conjugated microdroplet emulsion, into the first clinical studies. Their properties also make them attractive candidates for a variety of diagnostic and therapeutic applications including drug-delivery, diagnosis and treatment of cancerous and inflammatory diseases, as well as tumor-growth tracking. However, control over the thermal and acoustic stability of PCCAs both in vivo and in vitro has remained a challenge for expanding the potential utility of these agents in novel clinical applications. As such, our objective was to determine the stabilizing effects of layer-by-layer assemblies and its effect on both thermal and acoustic stability. METHODS: We utilized layer-by-layer (LBL) assemblies to coat the outer PCCA membrane and characterized layering by measuring zeta potential and particle size. Stability studies were conducted by; 1) incubating the LBL-PCCAs at atmospheric pressure at 37∘C and 45∘C followed by; 2) ultrasound-mediated activation at 7.24 MHz and peak-negative pressures ranging from 0.71 - 5.48 MPa to ascertain nanodroplet activation and resultant microbubble persistence. The thermal and acoustic properties of decafluorobutane gas-condensed nanodroplets (DFB-NDs) layered with 6 and 10 layers of charge-alternating biopolymers, (LBL6NDs and LBL10NDs) respectively, were studied and compared to non-layered DFB-NDs. Half-life determinations were conducted at both 37∘C and 45∘C with acoustic droplet vaporization (ADV) measurements occurring at 23∘C. DISCUSSION: Successful application of up to 10 layers of alternating positive and negatively charged biopolymers onto the surface membrane of DFB-NDs was demonstrated. Two major claims were substantiated in this study; namely, (1) biopolymeric layering of DFB-NDs imparts a thermal stability up to an extent; and, (2) both LBL6NDs and LBL10NDs did not appear to alter particle acoustic vaporization thresholds, suggesting that the thermal stability of the particle may not necessarily be coupled with particle acoustic vaporization thresholds. CONCLUSION: Results demonstrate that the layered PCCAs had higher thermal stability, where the half-lifes of the LBLxNDs are significantly increased after incubation at 37∘C and 45∘C. Furthermore, the acoustic vaporization profiles the DFB-NDs, LBL6NDs, and LBL10NDs show that there is no statistically significant difference between the acoustic vaporization energy required to initiate acoustic droplet vaporization.

Association Between Segmental Noninvasive Myocardial Work and Microvascular Perfusion in ST-Segment Elevation Myocardial Infarction: Implications for Left Ventricular Functional Recovery and Clinical Outcomes.

BACKGROUND: Predicting left ventricular recovery (LVR) after acute ST-segment elevation myocardial infarction (STEMI) is of prognostic importance. This study aims to explore the prognostic implications of segmental noninvasive myocardial work (MW) and microvascular perfusion (MVP) after STEMI. METHODS: In this retrospective study, 112 patients with STEMI who underwent primary percutaneous coronary intervention and transthoracic echocardiography after percutaneous coronary intervention were enrolled. Microvascular perfusion was analyzed by myocardial contrast echocardiography, and segmental MW was analyzed by noninvasive pressure-strain loops. A total of 671 segments with abnormal function at baseline were analyzed. The degrees of MVP were observed following intermittent high-mechanical index impulses: replenishment within 4 seconds (normal MVP), replenishment >4 seconds and within 10 seconds (delayed MVP), and persistent defect (microvascular obstruction). The correlation between MW and MVP was analyzed. The correlation of the MW and MVP with LVR (normalization of wall thickening, >25%) was assessed. The prognostic value of segmental MW and MVP for cardiac events (cardiac death, admission for congestive heart failure, or recurrent myocardial infarction) was evaluated. RESULTS: Normal MVP was seen in 70 segments, delayed MVP in 236, and microvascular obstruction in 365. The segmental MW indices were independently correlated with MVP; 244 (36.4%) segments had segmental LVR at 3-month follow-up. Segmental MW efficiency and MVP were independently associated with segmental LVR (P < .05). The χ2 of combination of segmental MW efficiency and MVP was higher than either index alone for identifying segmental LVR (P < .001). At a median follow-up of 42.0 months, cardiac events occurred in 13 patients; all regional MW parameters, high sensitivity troponin I, regional longitudinal strain, and so on were associated with cardiac events. CONCLUSIONS: Segmental MW indices are associated with MVP within the infarct zone following reperfused STEMI. Both are independently associated with segmental LVR, and regional MW is associated with cardiac events, providing prognostic value in STEMI patients.

The Impact of Sonothrombolysis on Left Ventricular Diastolic Function and Left Atrial Mechanics Preventing Left Atrial Remodeling in Patients With ST Elevation Acute Myocardial Infarction.

BACKGROUND: The diagnostic ultrasound-guided high mechanical index impulses during an intravenous microbubble infusion (sonothrombolysis) improve myocardial perfusion in acute ST segment elevation myocardial infarction, but its effect on left ventricular diastolic dysfunction (DD), left atrial (LA) mechanics and remodeling is unknown. We assessed the effect of sonothrombolysis on DD grade and LA mechanics. METHODS: One hundred patients (59 ± 10 years; 34% women) were randomized to receive either high mechanical index impulses plus percutaneous coronary intervention (PCI) (therapy group) or PCI only (control group) (n = 50 in each group). Diastolic dysfunction grade and LA mechanics were assessed immediately before and after PCI and at 48 to 72 hours, 1 month, and 6 months of follow-up. Diastolic dysfunction grades were classified as grades I, II, and III. The LA mechanics was obtained by two-dimensional speckle-tracking echocardiography-derived global longitudinal strain (GLS). RESULTS: As follow-up time progressed, increased DD grade was observed more frequently in the control group than in the therapy group at 1 month and 6 months of follow-up (all P < .05). The LA-GLS values were incrementally higher in the therapy group when compared with the control group at 48 to 72 hours, 24.0% ± 7.3% in the therapy group versus 19.6% ± 7.2% in the control group, P = .005; at 1 month, 25.3% ± 6.3% in the therapy group versus 21.5% ± 8.3% in the control group, P = .020; and at 6 months, 26.2% ± 8.7% in the therapy group versus 21.6% ± 8.5% in the control group, P = .015. The therapy group was less likely to experience LA remodeling (odds ratio, 2.91 [1.10-7.73]; P = .03). LA-GLS was the sole predictor of LA remodeling (odds ratio, 0.79 [0.67-0.94]; P = .006). CONCLUSION: Sonothrombolysis is associated with better DD grade and LA mechanics, reducing LA remodeling.