Perfluorocarbon-exposed Sonicated Dextrose Albumin Research Articles

Effectiveness of contrast-enhanced duplex ultrasound for detecting renal artery stenosis: A systematic review.

Contrast-enhanced duplex ultrasound (CEUS) might be a useful tool to diagnosing renal artery stenosis (RAS). We amalgamated and reviewed the evidence assessing the diagnostic accuracy of CEUS on detecting RAS compared to angiography. This preregistered systematic review included studies that compared the presence of RAS via CEUS with angiography. Sources were searched in November 2022 and included Scopus, EMBASE, MEDLINE, CINAHL, and Academic Search Premier (n = 1717). The Quality Assessment of Diagnostic Studies 2 tool assessed study quality. Results are presented narratively. The studies included (n = 11) had a total of 447 unique participants (193 females) and average age of 56 ± 9 years. Five of eleven studies investigated CEUS using SonoVue contrast agent and reported an average accuracy (91% ± 2%), sensitivity (91% ± 3%), specificity (90% ± 5%), negative predictive value (86% ± 6%), and positive predictive value (94% ± 1%) with all values >80%. The accuracy of CEUS using other types of contrast agent (n = 6), including Levovsit (n = 3/6), Definity (n = 1/6), perfienapent emulsion (n = 1/6), and perfluorocarbon-exposed sonicated dextrose albumin (n = 1/6) was mixed. These studies detected an average accuracy of 91 ± 11% (n = 2/3% > 80%), sensitivity of 98% ± 4%, (n = 3/3% > 80%), and specificity of 86% ± 10% (n = 2/3% > 80%). Included studies had generally low risk of bias and applicability concerns except for unclear flow and timing (n = 7/11) and applicability of patient selection (n = 4/11). Despite being limited by the heterogeneity of included studies, our review indicates a high overall diagnostic accuracy for CEUS to detect RAS compared to angiography, with the largest evidence-base for SonoVue contrast. Radiologists and hospital decision makers should consider CEUS as an acceptable alternative to angiography.

Phosphomimetic endothelial nitric oxide synthase-loaded microbubbles-mediated cardiac shock wave transfection therapy for angiogenesis in the ischemic myocardium

Abstract Background Cardiac shock wave therapy is a potential and effective remedy to promote revascularization in the ischemic myocardium of patients with refractory coronary heart disease (CHD). Although gene therapy holds great promise as a treatment for coronary heart disease, current clinical application is hampered by the development of safe and efficient systems for local gene delivery to a specific tissue or organ. Purpose In this study, we developed an experimental pulsed- focused electrohydraulic shock wave therapy system and investigated its effectiveness on myocardial angiogenesis in the hypercholesterolemic rabbit accompanied by phosphomimetic endothelial nitric oxide synthase-loaded microbubbles administration, wherein a high resolution diagnostic ultrasound is adjuncted with the therapy system, with a goal of increased safety. Methods Briefly, New Zealand white rabbits underwent 2% cholesterol rich diet injury for sixteen weeks. Histopathology results showed the formation of foam cells-rich soft atherosclerotic plaques with severe stenosis in all of the rabbits' coronary arteries. Then treatment group underwent extracorporeal electrohydraulic pulsed-focused shock waves (25kV, 0.5Hz, 150 pulses) accompanied by phosphomimetic endothelial nitric oxide synthase-loaded PESDA (Perfluorocarbon Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2.5x105 bubbles/ml) administration. Results Results from ultrasonography and histopathology showed a significant increase in the mean value for myocardial neovessels density in the treatment group compared with the control group (p<0.05). Conclusion Enhanced angiogenesis and sonoporation effect of electrohydraulic shock wave therapy, induced by inertial collapsed microbubbles, accompanied by phosphomimetic endothelial nitric oxide synthase-mediated shock wave transfection therapy, can cause to enhance the nitric oxide synthesis and VEGF, interleukin8 (IL8), stromal cell- derived factor 1 (SDF1) and matrix metalloproteinase 9 (MMP9) secretion in the hypercholesterolemic rabbits' coronary arteries, resulting in the differentiation and recruitment of endothelial progenitor cells (EPCs), promotion of revascularization in the ischemic myocardium and improvement of the cardiac function. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

Early stage atherosclerosis regression using combined sonotherapy and mitoxantrone-mediated sonoporation therapy

Abstract Background In atherosclerosis, local inflammation and associated macrophage activity can lead to foam cell-rich plaque formation, which results to plaque rupture and thrombosis, making inflammation an important therapeutic target in cardiovascular disease. The early stage of atherosclerosis is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells. Foam cells are generated by uncontrolled uptake of modified LDL, especially oxidized LDL (oxLDL). Purpose In this study, we developed an experimental focused ultrasound-based combined sonotherapy and sonoporation therapy system, and investigated its effectiveness on macrophage-derived foam cells reduction, wherein a high resolution diagnostic ultrasound is adjuncted with combination therapy system, with a goal of increased safety. Methods Briefly, New Zealand white rabbits underwent primary balloon dilatation injury at the right common carotid artery followed by a 1.5% cholesterol-rich diet injury for three weeks. Histopathology results showed the early stage atherosclerosis formation in all of the rabbits' arteries. Then common carotid arteries of the treatment group at the lesion region, treated using extracorporeal low-level pulsed-focused ultrasound (P=11 W, F=1.1 MHz, DF=50%) sonotherapy accompanied by mitoxantrone-loaded PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2–5x105 bubbles/ml)-mediated sonoporation therapy. Foam cells density were evaluated in the treatment group compared with the other groups using B-mode ultrasonography and histopathology. Results Results from B-mode ultrasonography and histopathology showed a significant reduction in the mean value for immune cells and foam cells density within the early stage atherosclerotic lesion in the treatment group compared with the other groups (p<0.05). Conclusion Enhanced sonoporation effect of ultrasound, induced by collapsed PESDA microbubbles accompanied by anti-inflammatory effect of sonotherapy and antineoplastic and cytotoxic effect of mitoxantrone can cause to reduce the immune cells and foam cells density within the lesion. These finding provide the basis for developing low-level pulsed-focused ultrasound-based combined sonotherapy and sonoporation therapy for a successful clinical application in the treatment of the early stage atherosclerosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

Sono- shock wave combination angiogenic therapy for cardiac function improvement in the hypercholesterolemic hamsters with myocardial ischemia

Background and Aims : Cardiac shockwave therapy is a novel, noninvasive approach that has been shown to ameliorate the myocardial ischemia and improve cardiac function. Cardiac shockwave therapy is a potential and effective remedy to promote revascularization in the ischemic myocardium of patients with refractory coronary heart disease. The technique is both safe and non-invasive.; however, the underlying molecular mechanism remains unclear. In this study, we developed an sono- shock wave combination therapy system and investigated its effectiveness on myocardial angiogenesis in the hamsters accompanied by PESDA (Perfluorocarbon- Exposed Sonicated Dextrose Albumin) microbubbles administration.

B- mode ultrasound- guided balloon angioplasty of occluded artery accompanied by combined focused ultrasound sonodynamic therapy and catheter- based 192Ir- mediated brachytherapy

Abstract Background and aims Three mechanisms are responsible for the development of restenosis: elastic recoil, intimal hyperplasia and late vascular constriction, all grouped under the catch phrase “negative remodeling”. Neointimal hyperplasia is usually defined in an artery as thickening of the intimal layer after an injury such as balloon angioplasty methods. The aim of this study was to evaluate the effect of combined ultrasound sonodynamic therapy and catheter- based 192Ir-mediated β-brachytherapy on restenosis reduction after balloon angioplasty. Methods Briefly, golden Syrian hamsters were submitted to common carotid artery advanced atherosclerotic occlusion by primary perivascular Co2 laser-mediated far-infrared injury followed by a 2% cholesterol-rich diet for six weeks. Histopathology results showed the formation of a thick-cap fibroatheromatic plaque, resulted to occlusion in all of the hamsters' arteries. Then treatment group (n=10) underwent B-mode ultrasound-guided balloon angioplasty followed by combined pulsed low level focused ultrasound (F=750 KHz, I=1.5 W/cm2, PD=120 ms)-mediated sonosensitizer protoporphyrin-IX-loaded PESDA (Perfluorocarbon Exposed Sonicated Dextrose Albumin) microbubbles (100ml/kg, 2–5×105 bubbles/ml) sonodynamic therapy and catheter- based β-brachytherapy (125I−, 18 Gy). Results Results from ultrasonography and histopathology showed a significant reduction in the mean value for macrophages and smooth muscle hyperplasia cells density after balloon angioplasty in the treated group compared with the other groups (p<0.05). Conclusions Enhanced anti-inflammatory effect of sonodynamic therapy, induced by collapsed microbubbles accompanied by apoptotic effect of β-brachytherapy, can cause to reduce the inflammation and smooth muscle hyperplasia cells in the intimal layer. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

Sonothrombolysis of embolic carotid artery, using pesda microbubbles- mediated B-mode ultrasound- guided extracorporeal pulsed low- level focused confocal dual frequency ultrasound accompanied by streptokinase administration

Background and Aims: Therapeutic ultrasound was found to selectively lyse thrombi with a wide margin of safety. Ultrasound effects sonothrombolysis by selective disruption of the fibrin matrix of the thrombus. In this study, we developed an experimental sonothrombolysis system, and investigated its effectiveness on carotid artery recanalization, accompanied by intravenous streptokinase and PESDA (perfluorocarbon exposed sonicated dextrose albumin) microbubbles administration, wherein diagnostic ultrasound imaging system is combined with the therapy system, with a goal of increased safety.

Ultrasound Imaging in an Animal Model of Vascular Inflammation Following Balloon Injury

Cardiovascular disease is a major cause of morbidity and mortality in the world and better prevention and treatment strategies are needed. Studies from this laboratory have shown that perfluorocarbon exposed sonicated dextrose albumin (PESDA) microbubbles bind to inflamed vasculature through interactions with scavenger receptors (SR). This current study details the use of PESDA as a tool for accessing and quantifying the extent of vascular inflammation. Angioplastied rat aortas were evaluated with low mechanical index microbubble imaging techniques contrast pulse sequencing (CPS); Siemens Acuson Sequoia 15L8, 7–15 MHz ultrasound probe with a mechanical index of 0.09 to detect microbubble binding. Real-time polymerase chain reaction (RT-PCR) analysis of angioplastied aortas demonstrated a significantly (p < 0.01) increased expression of both SRs and Interleukin 6 (IL-6). Vessel wall enhancement was quantified using densitometry of CPS ultrasound images and correlated with the upregulated expression of scavenger receptors, Toll-like receptors and IL-6. This study demonstrates that PESDA, in conjunction with CPS ultrasound, is an effective imaging technique to better detect early vascular inflammation and potential cardiovascular disease.

A method for the making and utility of gadolinium-labeled albumin microbubbles

Objective Perfluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA) binds scavenger receptors and can be noninvasively imaged. To enhance imaging, gadolinium (Gd)-labeled PESDA was developed and tested in a model of vascular inflammation by magnetic resonance imaging (MRI). Methods and Results Purified human serum albumin (HSA) (5%) was labeled with Gd via the covalent binding of diethylenetriaminepentacetic acid. Abdominal aortic tissues in Sprague–Dawley rats ( n=5 per group) were analyzed by 7-T MRI and scanning electron microscopy to evaluate PESDA binding. Labeling-purified 5% human albumin resulted in an average of 16.1 Gd atoms per albumin molecule as determined by atomic absorption. Forty-eight hours after balloon angioplasty, aortic tissue was enhanced with Gd-PESDA as compared to control tissue. 7-T MRI of explanted tissues was sensitive to the detection of retained PESDA. Enhancement of aortic tissue in vivo was present albeit to a lesser extent than explanted tissue from the same animals. Conclusions HSA was successfully labeled, and an albumin-based microbubble with Gd was synthesized. This contrast agent, Gd-PESDA, may serve as an additional agent for the MRI evaluation of innate inflammation and used to noninvasively image early vascular pathophysiologic processes. Condensed Abstract In this study, Gd-PESDA microbubbles and were synthesized and shown to detect the binding of these microbubbles using MRI in injured aortic tissue. The method for synthesizing Gd-PESDA is detailed, and the proposed utility of this new contrast agent is discussed.

Albumin-based Microbubbles Bind Up-regulated Scavenger Receptors following Vascular Injury

We have shown previously that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind to injured vascular tissue and can be detected with ultrasound imaging techniques. Prior studies have shown that scavenger receptors (SRs) are regulators of innate and adaptive immune responses and are involved in the progression of vascular disease such as atherosclerosis. In this study, we sought to determine the molecular mechanism of PESDA binding to balloon-injured vasculature. RT-PCR analysis of angioplastied aortas demonstrated a significantly (p ≤ 0.01) increased expression of SRs. Binding to SRs was confirmed using SR-expressing CHO cells, and this binding was blocked by competitive inhibition with the SR-binding ligands oxidized LDL and malondialdehyde-acetaldehyde-modified LDL. Confocal imaging confirmed the co-localization of PESDA microbubbles to CD36, SRB-1, and Toll-like receptor 4, but not to monocytes/macrophages. This study demonstrates that PESDA binds to SRs and that this binding is in major part dependent upon the oxidized nature of PESDA microbubble shell proteins. The extent of SR mRNA expression was increased with injury and associated with microbubble retention as defined by scanning electron microscopy and immunohistochemistry. These findings clarify the mechanisms of how albumin-based microbubbles bind to injured and inflamed vasculature and further support the potential of this imaging technique to detect early vascular innate inflammatory pathophysiologic processes.

Comparison of Myocardial Contrast Echocardiography Versus Rest Sestamibi Myocardial Perfusion Imaging in the Early Diagnosis of Acute Coronary Syndrome

It remains unclear whether myocardial contrast echocardiography (MCE) is as accurate as myocardial perfusion imaging with technetium-99m sestamibi (MPI) for the diagnosis of acute coronary syndrome (ACS). We sought to directly compare the diagnostic accuracy of MCE with resting MPI in a head-to-head fashion. We prospectively enrolled 98 consecutive patients (mean age; 59+/-9 years, 68 males) who presented to the emergency department with chest pain suggestive of acute myocardial ischemia. Early MCE was performed by using continuous infusion of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) during intermittent power Doppler harmonic imaging. Myocardial perfusion defects observed in at least one coronary territory were considered positive. Sestamibi was injected immediately after MCE and MPI was obtained within 6 hours of tracer injection. ACS was confirmed in 67 patients. There were 32 patients with acute myocardial infarction (AMI) and 35 patients with unstable angina requiring urgent revascularization. The sensitivities of MCE and MPI for the diagnosis of ACS were 72% and 61%, respectively, which were significantly higher than those of ST segment change (24%, p<0.001 vs. MCE and vs. MPI) and troponin I (27%, p<0.001 vs. MCE and vs. MPI), with similar specificities of 90% to 100%. On a receiveroperating characteristics curve demonstrating diagnostic accuracy for ACS, the area under the curve of MCE was significantly larger than that of MPI (0.86 vs. 0.77, respectively; p=0.019). MCE and MPI overcome the low sensitivity of routine triage tests for detecting ACS, and MCE is more accurate than MPI for the diagnosis of ACS in the emergency department.

Bioeffects of albumin-encapsulated microbubbles and real-time myocardial contrast echocardiography in an experimental canine model

Myocardial contrast echocardiography has been used for assessing myocardial perfusion. Some concerns regarding its safety still remain, mainly regarding the induction of microvascular alterations. We sought to determine the bioeffects of microbubbles and real-time myocardial contrast echocardiography (RTMCE) in a closed-chest canine model. Eighteen mongrel dogs were randomly assigned to two groups. Nine were submitted to continuous intravenous infusion of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) plus continuous imaging using power pulse inversion RTMCE for 180 min, associated with manually deflagrated high-mechanical index impulses. The control group consisted of 3 dogs submitted to continuous imaging using RTMCE without PESDA, 3 dogs received PESDA alone, and 3 dogs were sham-operated. Hemodynamics and cardiac rhythm were monitored continuously. Histological analysis was performed on cardiac and pulmonary tissues. No hemodynamic changes or cardiac arrhythmias were observed in any group. Normal left ventricular ejection fraction and myocardial perfusion were maintained throughout the protocol. Frequency of mild and focal microhemorrhage areas in myocardial and pulmonary tissue was similar in PESDA plus RTMCE and control groups. The percentages of positive microscopical fields in the myocardium were 0.4 and 0.7% (P = NS) in the PESDA plus RTMCE and control groups, respectively, and in the lungs they were 2.1 and 1.1%, respectively (P = NS). In this canine model, myocardial perfusion imaging obtained with PESDA and RTMCE was safe, with no alteration in cardiac rhythm or left ventricular function. Mild and focal myocardial and pulmonary microhemorrhages were observed in both groups, and may be attributed to surgical tissue manipulation.

Value of adenosine infusion for infarct size determination using real-time myocardial contrast echocardiography

BackgroundMyocardial contrast echocardiography has been used for determination of infarct size (IS) in experimental models. However, with intermittent harmonic imaging, IS seems to be underestimated immediately after reperfusion due to areas with preserved, yet dysfunctional, microvasculature. The use of exogenous vasodilators showed to be useful to unmask these infarcted areas with depressed coronary flow reserve. This study was undertaken to assess the value of adenosine for IS determination in an open-chest canine model of coronary occlusion and reperfusion, using real-time myocardial contrast echocardiography (RTMCE).MethodsNine dogs underwent 180 minutes of coronary occlusion followed by reperfusion. PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) was used as contrast agent. IS was determined by RTMCE before and during adenosine infusion at a rate of 140 mcg·Kg-1·min-1. Post-mortem necrotic area was determined by triphenyl-tetrazolium chloride (TTC) staining.ResultsIS determined by RTMCE was 1.98 ± 1.30 cm2 and increased to 2.58 ± 1.53 cm2 during adenosine infusion (p = 0.004), with good correlation between measurements (r = 0.91; p < 0.01). The necrotic area determined by TTC was 2.29 ± 1.36 cm2 and showed no significant difference with IS determined by RTMCE before or during hyperemia. A slight better correlation between RTMCE and TTC measurements was observed during adenosine (r = 0.99; p < 0.001) then before it (r = 0.92; p = 0.0013).ConclusionRTMCE can accurately determine IS in immediate period after acute myocardial infarction. Adenosine infusion results in a slight better detection of actual size of myocardial damage.

Targeted vascular delivery of antisense molecules using intravenous microbubbles

Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind the antisense to the c-myc protooncogene (anti-c-myc) which prevents neointimal hyperplasia following vascular endothelial injury. The microbubbles also adhere to sites of damaged vascular endothelium and thus may be a method of systemically targeting delivery of anti-c-myc. Laser scanning microscopy was performed on the aorta of 10 mice (five which were complement depleted) that received intravenous FITC-PESDA following aortic endothelial injury. C-myc expression was quantified following selective intracoronary injury in nine pigs that received intravenous (IV) anti-c-myc bound to PESDA. Finally, neointimal formation was measured following intracoronary stent deployment in 30 pigs that received either IV anti-c-myc alone or the same dose bound to PESDA. Fluorescent microscopy confirmed selective PESDA microbubble adherence to aortic endothelium in all mice with aortic injury. This binding was nearly abolished when serum complement was depleted prior to injury. C-myc expression at the site of coronary endothelial injury was significantly lower in pigs treated with systemic anti-c-myc bound to PESDA. There was a 33% reduction in % stenosis and a 28% reduction in intimal area at 45 days post-stent deployment in pigs that received IV antisense plus PESDA. The stent margins also had reduced neointimal formation. Systemic administration of anti-c-myc bound to PESDA microbubbles may be a good method for preventing coronary neointimal formation within and around implanted stents.

Effect of Different Conditioning on Perfluorocarbon Exposed Sonicated Dextrose Albumin Manufacture

Effect of Different Conditioning on Perfluorocarbon Exposed Sonicated Dextrose Albumin Manufacture

Efficacy of Myocardial Contrast Echocardiography in the Diagnosis and Risk Stratification of Acute Coronary Syndrome

We examined the hypothesis that myocardial contrast echocardiography (MCE) is superior to conventional electrocardiographic, echocardiographic, and troponin I criteria for the diagnosis of acute coronary syndrome. We prospectively enrolled 114 consecutive patients (60+/-10 years of age, 73 men) who presented to the emergency room with chest pain on exertion and at rest. Exclusion criteria included an age<40 years, presence of Q wave or ST-segment elevation, and a poor echocardiographic window. Echocardiography and MCE were performed to assess regional wall motion abnormalities (RWMAs) and myocardial perfusion defects by using continuous infusion of perfluorocarbon-exposed sonicated dextrose albumin. Acute coronary syndrome was confirmed in 87 patients. There were no deaths; 46 patients had acute myocardial infarction, and 41 patients required urgent revascularization. On multiple logistic regression analysis, myocardial perfusion defect (odd ratio 87, p<0.001) was the only independent variable for diagnosing acute coronary syndrome. Myocardial perfusion defect (odd ratio 21, p=0.001) and troponin I levels (odd ratio 3, p=0.009) were independent predictors for acute myocardial infarction. The sensitivity of myocardial perfusion defect for diagnosing acute coronary syndrome was 77%, which is significantly higher than the sensitivities of ST change, troponin I increase, and RWMA (28%, 34%, and 49%, respectively), with similar specificities of 85% to 96%. In conclusion, MCE is more sensitive than the currently used electrocardiographic and troponin I criteria, and evaluation of myocardial perfusion defect by MCE complements RWMA analysis by conventional echocardiography for accurate diagnosis of acute coronary syndrome.

Targeting vascular endothelium with avidin microbubbles

Targeting microbubbles (MBs) to specific vascular beds enables contrast ultrasound to be used for molecular imaging. There are several methods for attaching targeting moieties to the surface of MBs. In the present study, we demonstrate that avidin (Av) can be incorporated into the shell of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) MBs (Av-PESDA-MBs) and serve as an anchor that links Av-PESDA-MBs to biotinylated monoclonal antibodies (mAbs). This novel linking strategy was used to conjugate Av-PESDA-MBs to mAbs specific for endoglin (CD105) or a control IgG. MBs targeted to CD105 specifically bound to endothelial cells, but not to fibroblasts, in vitro but Av-PESDA-MBs conjugated with the control IgG did not specifically target either cell type. We conclude that Av-PESDA-MBs represent a novel and attractive tool to conjugate MBs with biotinylated mAbs for the purposes of vascular targeting and molecular imaging. (E-mail: rolf.brekken@utsouthwestern.edu)

Incidence of Cardiac Arrhythmias With Therapeutic Versus Diagnostic Ultrasound and Intravenous Microbubbles

The purpose of this study was to determine the type of arrhythmias induced with therapeutic versus diagnostic transthoracic low-frequency ultrasound (TLFUS) transducers in the presence of intravenous microbubbles. Intravenous perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles were infused or given as a bolus injection while TLFUS was applied in the standard parasternal and apical views with either a 1-MHz therapeutic ultrasound transducer or high-mechanical-index diagnostic ultrasound (1.7 MHz). Significantly more ectopy was produced by the therapeutic transducer, especially at higher-intensity settings in the continuous wave mode after bolus injections of PESDA (P < .001 compared with lower intensities and lower continuous infusion rates). Six patients (15%) had either clinical supraventricular tachycardia or nonsustained ventricular tachycardia after intravenous PESDA with therapeutic TLFUS. In comparison, diagnostic high-mechanical-index ultrasound produced only isolated ventricular ectopy and no sustained ventricular arrhythmias. Intravenously injected microbubbles and low-frequency therapeutic transducers operating at longer duty cycles and wide beam widths have the capability of eliciting clinically important arrhythmias in patients at high risk for such events.

Noninvasive detection of coronary allograft vasculopathy by myocardial contrast echocardiography

Noninvasive detection of coronary allograft vasculopathy is still challenging. To determine the accuracy of myocardial contrast echocardiography (MCE) in detecting coronary allograft vasculopathy after heart transplantation, we studied 35 asymptomatic patients (30 men, aged 46 +/- 12.7 years) with normal left ventricular function. Patients underwent MCE with continuous contrast (perfluorocarbon-exposed sonicated dextrose albumin) administration. Images were obtained at baseline and during peak dobutamine (up to 40 mg/kg/min) with intermittent harmonic imaging. Areas failing to increase contrast enhancement during peak stress were regarded as abnormal. Coronary artery obstructions greater than 50% at angiography were considered significant. Seven out of 10 patients with coronary artery disease had a positive MCE and one patient with a positive MCE had no angiographically detected disease (sensitivity = 70%, specificity = 96%, accuracy = 88.6%). Agreement between the vascular territory and perfusion defects was good for the left anterior descending coronary artery (kappa = 0.56), but not for other arteries. Although 5 patients had multivessel disease, multiple perfusion defects were detected in only one patient. MCE showed good accuracy in detecting the presence of coronary allograft vasculopathy after heart transplantation; however, it failed to identify the extent of the disease.

Microbubble responses to a similar mechanical index with different real-time perfusion imaging techniques.

The purpose of this study was to determine differences in contrast enhancement and microbubble destruction rates with current commercially available low-mechanical index (MI) real-time perfusion imaging modalities. A tissue-mimicking phantom was developed that had vessels at 3 cm (near field) and 9 cm (far field) from a real-time transducer. Perfluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA) were injected proximal to a mixing chamber, and then passed through these vessels while the region was insonified with either pulses of alternating polarity with pulse inversion Doppler (PID) or pulses of alternating amplitude by power modulation (PM) at MIs of 0.1, 0.2 and 0.3. Effluent microbubble concentration, contrast intensity and the slope of digital contrast intensity vs. time were measured. Our results demonstrated that microbubble destruction already occurs with PID at an MI of 0.1. Contrast intensity seen with PID was less than with PM. Therefore, differences in contrast enhancement and microbubble destruction rates occur at a similar MI setting when using different real-time pulse sequence schemes.

Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion-induced myocardial tumor necrosis factor-alpha

Ultrasound contrast agents are now emerging as effective vehicles for delivering therapeutic agents to target tissues. In the present study, we used ultrasound-targeted, contrast-bound antisense oligonucleotides to inhibit the expression of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine with negative inotropic effects. We compared the efficacy of left ventricular vs. intravenous administration and determined the optimal time for delivery. WKY rats were treated with perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microspheres incubated with 100 μg of antisense oligonucleotide directed against TNF-α. Contrast was infused into either the superior vena cava or the left ventricular cavity along with simultaneous application of ultrasound. Twenty-four hours later, the animals underwent 15 min of ischemia and 2 h reperfusion. Control animals underwent sham operation only, ischemia/reperfusion only, or received PESDA only. A second group received treatment just prior to, or immediately after the onset of ischemia. At the end of the experimental period, hearts were removed and analyzed for TNF-α by northern and western blotting. While no TNF-α expression was detected in sham-operated animals, robust expression of TNF-α mRNA and protein was seen in controls treated with ultrasound and PESDA alone. In contrast, intravenous or left ventricular administration of antisense oligonucleotides significantly inhibited ischemia/reperfusion-induced TNF-α expression. Direct delivery into the left ventricular cavity was more effective than intravenous administration, and delivery just prior to ischemia was most effective in attenuating TNF-α expression. Furthermore, attenuation of TNF-α expression also significantly inhibited other post-ischemic inflammatory mediators including IL-1β and intercellular adhesion molecule-1 (ICAM-1). Thus, ultrasound-targeted antisense oligonucleotides can effectively attenuate post-ischemic cytokine expression when delivered in a clinically relevant time frame, obviating the need for pretreatment.