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Objectives: To assess the accuracy of real-time myocardial contrast perfusion imaging (MCPI) for the diagnosis of restenosis and extent of coronary artery disease (CAD) in patients with previous percutaneous coronary intervention (PCI).Methods: 56 patients were studied 1.9 (SD 1.4) years after PCI. They underwent MCPI with commercially available ultrasound contrast agents (Optison or Definity) at rest and at peak dobutamine-atropine stress. Coronary angiography was performed within one month. Significant CAD was defined as >or= 50% stenosis in >or= 1 major epicardial coronary artery. Significant restenosis was defined as >or= 50% stenosis in a coronary segment with previous intervention.Results: Reversible perfusion abnormalities were detected in 40 of 43 patients with significant CAD and in 4 of 13 patients without (overall sensitivity 93%, 95% CI 85% to 99%; specificity 69%, 95% CI 44% to 94%; and accuracy 88%, 95% CI 79% to 96%). Significant restenosis in >or= 1 coronary artery with previous PCI was detected in 38 (68%) patients. Reversible perfusion abnormalities were present in 35 of them (sensitivity 92%, 95% CI 84% to 99%). Reversible perfusion abnormalities were detected in >or= 2 vascular distributions in 20 of 28 patients with multivessel CAD and in 3 of 28 patients without (sensitivity 71%, 95% CI 55% to 88%; specificity 89%, 95% CI 78% to 99%; and accuracy 80%, 95% CI 70% to 91%). Restenosis was detected in 41 coronary arteries. Sensitivity of MCPI for regional diagnosis of restenosis was 73% (95% CI 60% to 87%), specificity was 75% (95% CI 60% to 90%), and accuracy was 74% (95% CI 64% to 84%).Conclusion: Dobutamine stress MCPI is a useful technique for the evaluation of restenosis and extent of CAD after PCI. [ABSTRACT FROM AUTHOR]

Coronary artery disease is the underlying etiology of left ventricular dysfunction and arrhythmias in most patients who receive implantable cardioverter defibrillators (ICDs). The aim of this study was to assess the safety and feasibility of dobutamine stress echocardiography (DSE) in patients with an ICD. DSE (dobutamine up to 50 microg/kg/min, atropine up to 2 mg) was performed in 87 patients with an ICD and known or suspected coronary artery disease. The ICD was inactivated before the stress test and reactivated after the study; no serious complications occurred. DSE is a safe and feasible method for evaluating myocardial ischemia in patients with an ICD. [ABSTRACT FROM AUTHOR]

In a pilot study of 27 patients, those who presented with chest pain underwent 2 dobutamine stress echocardiographic studies, 1 with high mechanical index harmonic imaging to analyze wall motion without contrast and 1 with real-time low mechanical index perfusion imaging with intravenous Optison to assess myocardial perfusion and wall motion. All patients then underwent quantitative coronary angiography. Two independent reviewers demonstrated an improvement in sensitivity when analyzing myocardial perfusion. In the 21 patients who had significant coronary stenoses, 14 had abnormal myocardial perfusion detected at peak stress and 7 had abnormal wall motion detected by standard dobutamine stress echocardiography. There was decreased specificity with perfusion imaging by 1 reviewer. The addition of real-time perfusion imaging after intravenous contrast during dobutamine stress echocardiography has the potential to improve detection of coronary artery disease. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Conflicts of Interest K.N. reports honorarium from Daiichi-Sankyo, Otsuka Seiyaku, GE, and Philips, outside the submitted work. T.R.P. receives grant support from Lantheus Medical and Equipment Support from Philips Healthcare. The other authors have no conflict of interest to disclose., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: 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., Competing Interests: Conflicts of Interest T.R. Porter receives consultant fees from Lantheus Medical Imaging, and research equipment support from Philips Research North America. The other authors confirm that they have no competing interests., (Copyright © 2024 American Society of Echocardiography. All rights reserved.)

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 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., Competing Interests: Conflict of interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: 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)., Conclusion: Post-PCI sonothrombolysis had minimal effect on reducing myocardial infarct size but improved left ventricular systolic function in patients with acute anterior wall STEMI., (© 2024 Wiley Periodicals LLC.)

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., (© 2024 American Institute of Ultrasound in Medicine.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Small-for-gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood-based screening methods for determining SGA risk are available. We used a high-resolution MS/MS ALL shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals. Samples were acquired from 195 normal and 41 SGA pregnancies. Lipid profiles were determined serially across pregnancy. We identified specific lipid signatures of placental sEVs that define the trajectory of a normal pregnancy and their changes occurring in relation to maternal characteristics (parity and ethnicity) and birthweight centile. We constructed a multivariate model demonstrating that specific lipid features of circulating placental sEVs, particularly during early gestation, are highly predictive of SGA infants. Lipidomic-based biomarker development promises to improve the early detection of pregnancies at risk of developing SGA, an unmet clinical need in obstetrics., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

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 χ 2 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., (Copyright © 2023 American Society of Echocardiography. All rights reserved.)

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., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

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, (LBL 6 NDs and LBL 10 NDs) 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 LBL 6 NDs and LBL 10 NDs 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 LBL x NDs are significantly increased after incubation at 37 ∘ C and 45 ∘ C. Furthermore, the acoustic vaporization profiles the DFB-NDs, LBL 6 NDs, and LBL 10 NDs show that there is no statistically significant difference between the acoustic vaporization energy required to initiate acoustic droplet vaporization., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022. Published by Elsevier Inc.)

Background: Reduced global longitudinal strain (GLS) of the left ventricle is associated with adverse prognosis in healthy subjects and in different cardiovascular conditions. Resting GLS may enable risk assessment independently from stress echocardiography (SE). We assessed whether there is an association of GLS measured at rest before SE with long-term outcome, independent of clinical parameters or reversible wall motion abnormalities and Doppler coronary flow velocity reserve., Methods: Five hundred thirty patients who underwent SE for ischemia evaluation between 2010 and 2012 and who had rest images available were selected. Resting GLS was measured off-line (absolute value <15% was considered abnormal). Cox models were used to examine the association between clinical variables, ejection fraction, SE variables, and resting GLS with mortality and cardiac events (cardiac death and nonfatal myocardial infarction). The independent prognostic value of GLS over known rest and stress variables was assessed., Results: Over a median follow-up of 7.5 years, 137 patients died from any cause and 50 had a nonfatal myocardial infarction. Patients with resting GLS <15% had significantly lower event-free survival (log-rank P < .0001). Resting GLS was significantly associated with risk of all-cause death and hard cardiac events, after adjustment for clinical risk factors, reversible wall motion abnormalities, and coronary flow velocity reserve. Adding resting GLS into a model with clinical, rest, and stress imaging variables significantly increased the model C index (P = .031)., Conclusions: In a large cohort of patients with suspected coronary artery disease referred for SE, resting GLS <15% was independently associated with mortality and hard cardiac events, incremental to SE data. Model discrimination including resting GLS measurement was comparable to discrimination including SE results., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents (UEAs) in echocardiography, based on more than two decades of experience in the use of UEAs for cardiac imaging. The protocols reflect current clinical CEUS practice in many modern echocardiography laboratories throughout the world. Specific attention is given to preparation and dosing of three UEAs that have been approved by the United States Food and Drug Administration (FDA) and additional regulatory bodies in Europe, the Americas and Asia-Pacific. Consistent with professional society guidelines (J Am Soc Echocardiogr 31:241-274, 2018; J Am Soc Echocardiogr 27:797-810, 2014; Eur Heart J Cardiovasc Imaging 18:1205, 2017), these protocols cover unapproved "off-label" uses of UEAs-including stress echocardiography and myocardial perfusion imaging-in addition to approved uses. Accordingly, these protocols may differ from information provided in product labels, which are generally based on studies performed prior to product approval and may not always reflect state of the art clinical practice or guidelines., (© 2022. The Author(s).)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: We aimed to identify, among Chronic Chagas Cardiomyopathy (CCC) patients with left ventricular dysfunction (LVD) and non-left bundle branch block (non-LBBB), subgroups with different functional and mechanical patterns of global longitudinal strain (GLS) and intraventricular dyssynchrony (IVD) at rest and after exercise stress test, and reclassify them using a new echocardiographic approach., Methodology: In this single-center cross-sectional study, 40 patients with CCC, left ventricular ejection fraction (LVEF) ≤ 35% and non-LBBB underwent rest echocardiography and then treadmill exercise stress echocardiography with GLS and IVD analysis. The sample was divided into four groups, based on GLS and IVD significant variation between rest and exercise: GLS + IVD+ (9 patients); GLS + IVD- (9 patients); GLS-IVD+ (10 patients); GLS-IVD- (10 patients)., Results: At rest, median LVEF was 28% (21.3%-33%) and GLS (-7% (-5%/-9.3%), were not different among groups. The average response of GLS was an increase of 0.74% over rest values, and the average response of IVD was a decrease of 6.9 ms. Group GLS-IVD+ presented more dyssynchrony at rest (p = 0.01). Left atrial (LA) volume (higher in GLS-IVD-) (p = 0.022) and TAPSE (higher in GLS + IVD+) (p = 0.015) were also different among groups at baseline. Of the 40 patients evaluated, 27 (67.5%) had very severe LVD (GLS < -8%). In addition, among these patients, 11 patients had contractile reserve after undergoing stress echocardiography., Conclusions: In patients with CCC, severe LVD and non-LBBB, the evaluation of GLS and IVD between rest and exercise was able to reclassify myocardial function and to identify subgroups with contractile reserve and significant dyssynchronopathy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., Competing Interests: Funding Support and Author Disclosures This study is in part funded by the Theodore F. Hubbard Foundation (Omaha, Nebraska) and National Institutes of Health RO1 146489-01A1 grant. Dr Porter has received consultant fees from Lantheus Medical Imaging; and research equipment support from Philips Research North America. Dr Kamp has received research support from Lantheus Medical Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Complex insertion-deletion (indel) events in the globin genes manifest in widely variable clinical phenotypes. Many are incompletely characterized because of a historic lack of efficient methods. A more complete assessment enables improved prediction of clinical impact, which guides emerging therapeutic choices. Current methods have limited capacity for breakpoint assignment and accurate assessment of mutation extent, especially in cases containing duplications or multiple deletions and insertions. Technology, such as long-read sequencing, holds promise for significant impact in the characterization of indel events because of read lengths that span large regions, resulting in improved resolution. Four known complex β-globin gene cluster indel types were assessed using single-molecule, real-time sequencing technology and showed high correlation with previous reports, including the Caribbean locus control deletion (g.5,305,478&#95;5,310,336del), a large β-gene duplication containing the Hb S mutation (g.4,640,335&#95;5,290,171dup with g.5,248,232T>A, c.20A>T; variant allele fraction, 64%), and two nested variants (double deletions with intervening inversion): the Indian G γ( A γδβ) 0 -thalassemia (g.5,246,804-5,254,275del, g.5,254,276&#95;5,269,600inv, and g.5,269,601&#95;5,270,442del) and the Turkish/Macedonian (δβ) 0 thalassemia (g.5,235,064&#95;5,236,652del, g.5,236,653&#95;5,244,280inv, and g.5,244,281&#95;5,255,766del). Our data confirm long-read sequencing as an efficient and accurate method to identify these clinically significant complex events. Limitations include high-complexity sample preparation requirements, which hinder routine use in clinical laboratories. Continued improvements in sample and data workflow processes are needed to accommodate volumes in a tertiary clinical laboratory., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Methemoglobin (MetHb) and sulfhemoglobin (SHb) measurements are useful in the evaluation of cyanosis. When one or both values are elevated, additional analysis is important to establish the etiology of the disorder. Methemoglobinemia occurs from acquired or hereditary causes with diverse treatment considerations, while true sulfhemoglobinemia is only acquired and treatment is restricted to toxin removal. Some toxic exposures can result in a dual increase in MetHb and SHb. Hereditary conditions, such as M-Hemoglobin variants (M-Hbs), can result in increased MetHb and/or SHb values but are clinically compensated and do not require treatment if they are cyanotic but otherwise clinically well., Methods: Herein, we report 53 hemoglobin variant cases that have associated MetHb and SHb levels measured by an adapted Evelyn-Malloy laboratory assay method., Results: Our data indicate M-Hbs cause variable patterns of MetHb and SHb elevation in a fairly reproducible pattern for the particular variant. In particular, α globin chain M-Hbs can mimic acquired sulfhemoglobinemia due to an isolated increased SHb value., Conclusion: If the patient appears clinically well other than cyanosis, M-Hbs should be considered early in the evaluation process to differentiate from acquired conditions to avoid unnecessary testing and treatment regimens and prompt genetic counseling., (© 2021 John Wiley & Sons Ltd.)

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., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflict of interest disclosure TRP discloses that currently he receives consultant fees from Lantheus Medical Imaging and research equipment support from Philips Research North America., (Copyright © 2021. Published by Elsevier Inc.)

Background: Treatment of ST-elevation myocardial infarction (STEMI) has improved over the years. Current challenges in the management of STEMI are achievement of early reperfusion and the prevention of microvascular injury. Sonothrombolysis has emerged as a potential treatment for acute myocardial infarction, both for epicardial recanalisation as well as improving microvascular perfusion. This study aims to determine safety and feasibility of sonothrombolysis application in STEMI patients in the ambulance., Methods: Ten patients with STEMI will be included and treated with sonothrombolysis in the ambulance during transfer to the PCI centre. Safety will be assessed by the occurrence of ventricular arrhythmias and shock during sonothrombolysis intervention. Feasibility will be assessed by the extent of protocol completion and myocardial visibility. Efficacy will be determined by angiographic patency rate, ST-elevation resolution, infarct size and left ventricular volumes, and function measured with cardiovascular magnetic resonance imaging, and contrast and strain echocardiography. A comparison will be made with matched controls using an existing STEMI database., Discussion: Sonothrombolysis is a novel technique for the treatment of cardiovascular thromboembolic disease. The first clinical trials on its use for STEMI have demonstrated promising results. This study will be the first to examine the feasibility of in-ambulance sonothrombolysis for STEMI., Trial Registration: EU Clinical Trials Register (identifier: 2019-001883-31), registered 2020-02-25.

Aims: To evaluate the prognostic value of myocardial perfusion (MP) imaging during contrast stress echocardiography (cSE) in patients with known or suspected coronary artery disease (CAD)., Methods and Results: A search in PubMed, Embase databases, and the Cochrane library was conducted through May 2019. The Cochran Q statistic and the I2 statistic were used to assess heterogeneity, and the results were analysed by RevMan V5.3 and Stata V15.1 software. Twelve studies (seven dipyridamole and five exercise/dobutamine) without evidence of patient overlap (same institution publishing results over a similar time period) enrolling 5953 subjects (47% female, 8-80 months of follow-up) were included in the analysis. In all studies, total adverse cardiovascular events were defined as either cardiac death, non-fatal myocardial infarction (NFMI), or need for urgent revascularization. Hazard ratios (HRs) revealed that a MP abnormality [pooled HR 4.75; 95% confidence interval (CI) 2.47-9.14] was a higher independent predictor of total events than abnormal wall motion (WM, pooled HR 2.39; 95% CI 1.58-3.61) and resting left ventricular ejection fraction (LVEF, pooled HR 1.92; 95% CI 1.44-2.55) with significant subgroup differences (P = 0.002 compared with abnormal WM and 0.01 compared with abnormal LVEF). Abnormal MP was associated with higher risks for death [Risk ratio (RR) 5.24; 95% CI 2.91-9.43], NFMI (RR 3.09; 95% CI 1.84-5.21), and need for coronary revascularization (RR 16.44; 95% CI 6.14-43.99)., Conclusion: MP analysis during stress echocardiography is an effective prognostic tool in patients with known or suspected CAD and provides incremental value over LVEF and WM in predicting clinical outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Intermittent high-mechanical index (MI) impulses from a transthoracic ultrasound transducer are recommended for regional wall motion analysis and assessment of myocardial perfusion following intravenous administration of ultrasound enhancing agents (UEAs). High-MI impulses (>1.0) applied in this setting have also been shown to increase microvascular blood flow through a purinergic signaling pathway, but their effects on left ventricular (LV) myocardial function are unknown. Therefore, the aim of this study was to investigate the effect of transthoracic intermittent high-MI impulses during intravenous UEA infusion in patients with normal and abnormal resting systolic function., Methods: Fifty patients referred for echocardiography to evaluate LV systolic function during continuous infusion of UEAs (Definity 3% infusion) were prospectively assigned to low-MI (<0.2) imaging alone (group 1) or low-MI (<0.2) imaging with intermittent high-MI impulses (five frames, 1.8 MHz, MI = 1.0-1.2) applied at least two times in each apical window to clear myocardial contrast (group 2). Global longitudinal strain (GLS) measurements were obtained at baseline before UEA administration and at 5-min intervals up to 10-min after infusion completion., Results: There were no differences between groups with respect to age, gender, resting GLS, biplane LV ejection fraction, or cardiac risk factors. Resting GLS in group 1 was -15.5 ± 5.2% before UEA infusion and -15.5 ± 5.4% at 10 min after UEA infusion. In comparison, GLS increased in group 2 (-15.3 ± 5.0 before infusion and -16.8 ± 4.8% at 10 min, P < .00001). Improvements in GLS were seen in patients with normal and abnormal systolic function. Regional analysis demonstrated that the increase in strain in patients with abnormal LV ejection fractions was primarily in the apical segments (-12.0 ± 2.7% before infusion and -13.4 ± 3.4% at 10 min, P = .001)., Conclusions: High-MI impulses during infusion of a commercially available contrast agent can improve LV systolic function and may have therapeutic effect in patients with LV dysfunction., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)