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.

Acoustic Detection of Retained Perfluoropropane Droplets Within the Developing Myocardial Infarct Zone.

Perfluoropropane droplets (PDs) cross endothelial barriers and can be acoustically activated for selective myocardial extravascular enhancement following intravenous injection (IVI). Our objective was to determine how to optimally activate extravascular PDs for transthoracic ultrasound-enhanced delineation of a developing scar zone (DSZ). Ultrafast-frame-rate microscopy was conducted to determine the effect of pulse sequence on the threshold of bubble formation from PDs. In vitro studies were subsequently performed at different flow rates to determine acoustic activation and inertial cavitation thresholds for a PD infusion using multipulse fundamental non-linear or single-pulse harmonic imaging. IVIs of PDs were given in 9 rats and 10 pigs following prolonged left anterior descending ischemia to detect and quantify PD kinetics within the DSZ. A multipulse sequence had a lower myocardial index threshold for acoustic activation by ultrafast-frame-rate microscopy. Acoustic activation was observed at a myocardial index ≥0.4 below the inertial cavitation threshold for both pulse sequences. In rats, confocal microscopy and serial acoustic activation imaging detected higher droplet presence (relative to remote regions) within the DSZ at 3 min post-IVI. Transthoracic high-mechanical-index impulses with fundamental non-linear imaging in pigs at this time post-IVI resulted in selective contrast enhancement within the DSZ.

Influence of right ventricular pressure and volume overload on right and left ventricular diastolic function.

BACKGROUND: Ventricular interdependence may account for altered ventricular mechanics in congenital heart disease. The present study aimed to identify differences in load-dependent right ventricular (RV)-left ventricular (LV) interactions in porcine models of pulmonary stenosis (PS) and pulmonary insufficiency (PI) by invasive admittance-derived hemodynamics in conjunction with noninvasive cardiovascular magnetic resonance (CMR). METHODS: Seventeen pigs were used in the study (7 with PS, 7 with PI, and 3 controls). Progressive PS was created by tightening a Teflon tape around the pulmonary artery, and PI was created by excising 2 leaflets of the pulmonary valve. Admittance catheterization data were obtained for the RV and LV at 10 to 12 weeks after model creation, with the animal ventilated under temporary diaphragm paralysis. CMR was performed in all animals immediately prior to pressure-volume catheterization. RESULTS: In the PS group, RV contractility was increased, manifested by increased end-systolic elastance (mean difference, 1.29 mm Hg/mL; 95% confidence interval [CI], 0.57-2.00 mm Hg/mL). However, in the PI group, no significant changes were observed in RV systolic function despite significant changes in RV diastolic function. In the PS group, LV end-systolic volume was significantly lower compared with controls (mean difference, 25.1 mL; 95% CI, -40.5 to -90.7 mL), whereas in the PI group, the LV showed diastolic dysfunction, demonstrated by an elevated isovolumic relaxation constant and ventricular stiffness (mean difference, 0.03 mL-1; 95% CI, -0.02 to 0.09 mL-1). CONCLUSIONS: The LV exhibits systolic dysfunction and noncompliance with PI. PS is associated with preserved LV systolic function and evidence of some LV diastolic dysfunction. Interventricular interactions influence LV filling and likely account for differential effects of RV pressure and volume overload on LV function.

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

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

Delayed Echo Enhancement Imaging to Quantify Myocardial Infarct Size.

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

Selective infarct zone imaging with intravenous acoustically activated droplets.

BACKGROUND: Microbubbles (MB) can be compressed to nanometer-sized droplets and reactivated with diagnostic ultrasound; these reactivated MB possess unique imaging characteristics. OBJECTIVE: We hypothesized that droplets formed from compressing Definity MB may be used for infarct-enhancement imaging. METHODS: Fourteen rats underwent ligation of their left anterior descending (LAD) artery, and five pigs underwent 90 minute balloon occlusions of their mid LAD. At 48 hours in rats, transthoracic ultrasound was performed at two and four minutes following 200 µL intravenous injections (IVI) of Definity droplets (DD), at which point the MI was increased from 0.5 to 1.5 to assess for a transient contrast enhancement zone (TEZ) within akinetic segments. In pigs, 1.0 mL injections of DD were administered and low frame rate (triggered end systolic or 10 Hz) imaging 2-4 minutes post iVI to selectively activate and image the infarct zone (IZ). Infarct size was defined by delayed enhancement magnetic resonance imaging (DE-MRI) and post-mortem staining (TTC). RESULTS: Increasing MI to 1.5 (at two or four minutes after IVI) resulted in a TEZ in rats, which correlated with infarct size (r = 0.94, p<0.001). A TEZ was not seen at 2-4 minutes in any rat (n = 8) following Definity MB injections. Fluorescent staining confirmed DD presence within the infarct zone 10 minutes after intravenous injection. In pigs, selective enhancement within the IZ was achieved by using a low frame rate single pulse harmonic mode; IZ size matched the location seen with DE-MRI and correlated with TTC defect size (r = 0.90, p<0.05). CONCLUSION: DD formulated from commercially available MB can be acoustically activated for selective infarct enhancement imaging.

Right ventricular energetics and power in pulmonary regurgitation vs. stenosis using four dimensional phase contrast magnetic resonance.

OBJECTIVE: We investigated a full energetic profile of pressure and volume loaded right ventricle (RV) in porcine models by evaluating kinetic energy (KE), stroke power, power output and power loss across pulmonary valves with stenosis (PS) or with regurgitation (PR). METHODS: Fifteen pigs (6 PS and 6 PR, 3 unoperated controls) were studied. Phase-contrast 4D-flow MRI was performed in models of PS and PR at baseline and at 10-12 weeks, in conjunction with cardiac catheterization. Phase contrast velocities over 1 cardiac cycle were registered with a dynamic mask of the RV segmented from cine images. Mean KE and KE curve profiles were measured, normalized for RV volumes and compared between groups. Right heart catheterization pressures were used to calculate RV stroke power and power output, from which pulmonary valve power loss and RV power output ratio were calculated, and compared between groups. RESULTS: PS and PR groups had similar KE pre procedure but significant changes in KE post procedure. The PR group had higher RV power output ratio and KE (72.1% ±â€¯11.4%; 20.6 ±â€¯6.1) than PS group (25.6% ±â€¯4.7%; 13.8 ±â€¯5.0) post procedure. Volume loaded RV from PR had higher KE and power output ratio compared to pressure load from PS. CONCLUSIONS: In porcine models of PS and PR, the RV presents altered systolic and diastolic energetic profiles. Pulmonary valve efficiency appeared to decrease in the medium term with somatic growth, with increased power loss in all groups studied, and greatly within the PS group.

Location and structure of fibrous sheath formed after placing a tunneled hemodialysis catheter in a large pig model.

BACKGROUND AND OBJECTIVES: We evaluated the location and structure of the fibrous sheath formed after the placement of tunneled, cuffed hemodialysis catheters in large animals, 70 kg pigs. We focused on describing the location of the fibrous sheath in relation to the catheter. Its location explains the fibrous sheath's ability to cause catheter dysfunction by covering the catheter exit ports located at the catheter's tip. DESIGN: We used three animals. Each animal had a tunneled, cuffed, 15-French diameter hemodialysis catheter placed in the external jugular vein, with the tip at the junction of the superior vena cava and the right atrium. Two animals were sacrificed at 5 weeks and one animal at 17 weeks after catheter placement. The catheter and surrounding tissues were removed in one block. The fibrous sheath was dissected and longitudinally cut along the catheter to evaluate its extension in relation to the catheter. Relevant portions of the fibrous sheath were sent for pathology examination. RESULTS: The fibrous sheath covered the catheter in its entire length and circumference. It started at the entry site and continued without any interruption along the entire length of the catheter, including the tip. Its average thickness is 1 mm and has an inner cellular/inflammatory layer comprising lymphocytes, plasma cells, neutrophils, macrophages, multinucleated giant cells, and spindled cells and an outer layer comprising a mixture of collagen and fibroblasts. CONCLUSION: Our model showed that the fibrous sheath forms around all catheters and covers them in their entire length and circumference without any gaps.

Surgical technique of placement of an external jugular tunneled hemodialysis catheter in a large pig model.

BACKGROUND: Currently, there is insufficient knowledge about the surgical anatomy and surgical techniques in large animals that can be used to test medical devices designed for human use. We encountered this problem in our study requiring the placement of jugular vein, tunneled, cuffed hemodialysis catheter in 70 kg pigs. Despite the operator's extensive expertise in placing tunneled hemodialysis catheters in humans, the important differences in anatomy made the procedure and choosing the appropriate catheter length challenging. METHODS: The following article describes the anatomy and our technique for the placement of tunneled hemodialysis catheter in the pig model. RESULTS: We consider our surgical technique to be sound because in all animals the catheters were placed in the desired location, the procedures were well tolerated by the animals, and there were no immediate or late complications. CONCLUSION: We present our experience to help other researchers who might encounter the same problem.

The Thrombolytic Effect of Diagnostic Ultrasound-Induced Microbubble Cavitation in Acute Carotid Thromboembolism.

BACKGROUND: Acute ischemic stroke is often due to thromboembolism forming over ruptured atherosclerotic plaque in the carotid artery (CA). The presence of intraluminal CA thrombus is associated with a high risk of thromboembolic cerebral ischemic events. The cavitation induced by diagnostic ultrasound high mechanical index (MI) impulses applied locally during a commercially available intravenous microbubble infusion has dissolved intravascular thrombi, especially when using longer pulse durations. The beneficial effects of this in acute carotid thromboembolism is not known. MATERIALS AND METHODS: An oversized balloon injury was created in the distal extracranial common CA of 38 porcine carotid arteries. After this, a 70% to 80% stenosis was created in the mid common CA proximal to the injury site using partial balloon inflation. Acute thrombotic CA occlusions were created just distal to the balloon catheter by injecting fresh autologous arterial thrombi. After angiographic documentation of occlusion, the common carotid thrombosis was treated with either diagnostic low MI imaging alone (0.2 MI; Philips S5-1) applied through a tissue mimicking phantom (TMP) or intermittent diagnostic high MI stable cavitation (SC)-inducing impulses with a longer pulse duration (0.8 MI; 20 microseconds' pulse duration) or inertial cavitation (IC) impulses (1.2 MI; 20 microseconds' pulse duration). All treatment times were for 30 minutes. Intravenous ultrasound contrast (2% Definity; Lantheus Medical) was infused during the treatment period. Angiographic recanalization in 4 intracranial and extracranial vessels downstream from the CA occlusion (auricular, ascending pharyngeal, buccinator, and maxillary) was assessed with both magnetic resonance 3-dimensional time-of-flight and phase contrast angiography. All magnetic resonance images were interpreted by an independent neuroradiologist using the thrombolysis in cerebral infarction (TICI) scoring system. RESULTS: By phase contrast angiography, at least mild recanalization (TICI 2a or higher) was seen in 64% of downstream vessels treated with SC impulses compared with 33% of IC treated and 29% of low MI alone treated downstream vessels (P = 0.001), whereas moderate or complete recanalization (TICI 2b or higher) was seen in 39% of SC treated vessels compared with 10% IC treated and 21% of low MI alone treated vessels (P = 0.001). CONCLUSIONS: High MI 20-microsecond pulse duration impulses during a commercial microbubble infusion can be used to recanalize acutely thrombosed carotid arteries and restore downstream flow without anticoagulants. However, this effect is only seen with SC-inducing impulses and not at higher mechanical indices, when a paradoxical reversal of the thrombolytic effect is observed. Diagnostic ultrasound-induced SC can be a nonsurgical method of dissolving CA thrombi and preventing thromboembolization.

Diagnostic Ultrasound High Mechanical Index Impulses Restore Microvascular Flow in Peripheral Arterial Thromboembolism.

We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p < 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses.

Targeted Transthoracic Acoustic Activation of Systemically Administered Nanodroplets to Detect Myocardial Perfusion Abnormalities.

BACKGROUND: Liquid core nanodroplets containing condensed gaseous fluorocarbons can be vaporized at clinically relevant acoustic energies and have been hypothesized as an alternative ultrasound contrast agent instead of gas-core agents. The potential for targeted activation and imaging of these agents was tested with droplets formulated from liquid octafluoropropane (C3) and 1:1 mixtures of C3 with liquid decafluorobutane (C3C4). METHODS AND RESULTS: In 8 pigs with recent myocardial infarction and variable degrees of reperfusion, transthoracic acoustic activation was attempted using 1.3 to 1.7 MHz low (0.2 mechanical index [MI]) or high MI (1.2 MI) imaging in real time (32-64 Hertz) or triggered 1:1 at end systole during a 20% C3 or C3C4 droplet infusion. Any perfusion defects observed were measured and correlated with delayed enhancement magnetic resonance imaging and postmortem staining. No myocardial contrast was produced with any imaging setting when using C3C4 droplets or C3 droplets during low MI real-time imaging. However, myocardial contrast was observed in all 8 pigs with C3 droplets when using triggered high MI imaging and in 5 of 6 pigs that had 1.7 MHz real time-high MI imaging. Although quantitative myocardial contrast was lower with real-time high MI imaging than 1:1 triggering, the correlation between real-time resting defect size and infarct size was good (r=0.97; P<0.001), as was the correlation with number of transmural infarcted segments by delayed enhancement imaging. CONCLUSIONS: Targeted transthoracic acoustic activation of infused intravenous C3 nanodroplets is effective, resulting in echogenic and persistent microbubbles which provide real-time high MI visualization of perfusion defects.

Sheep Model of Hemodialysis Arteriovenous Fistula Using Superficial Veins.

Current models of animal arteriovenous fistula (AVF) are swine models of femoral vein terminolaterally anastomosed to femoral artery, creating a deep AVF. This feature sets it aside from human AVFs using superficial veins. Our AVF model uses sheep superficial veins to create an AVF almost identical to human model. AVFs were created in six sheep using basilic veins sutured terminolaterally to brachial artery. Presurgery vein and artery diameters were measured. We measured AVFs and feeding arteries blood flows and diameters at 1, 3, and 5 weeks postsurgery. At 5 weeks we performed angiograms, euthanized animals, and harvested AVFs. Four animals completed the study. Three AVFs developed and were patent at 5 weeks; one thrombosed. Animal weight and presurgery vessels diameters predicted AVFs blood flows and diameters. Despite using vessels with diameters smaller than the ones recommended for human AVF, the Fistulas developed. Two animals died before the study conclusion for causes unrelated to surgery. This AVF model is anatomically almost identical to the human AVF and has a good maturation rate. It is a viable model for studying AVF maturation, devices intended to improve AVF maturation, AVF related procedures and can even support hemodialysis needles.

Utilization of modified diagnostic ultrasound and microbubbles to reduce myocardial infarct size.

OBJECTIVE: We sought to determine whether guided high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion could augment low-dose fibrinolytic therapy in treating acute myocardial infarction (ST segment elevation myocardial infarction, STEMI). METHODS: Acute thrombotic occlusions of the left anterior descending were created in 32 atherosclerotic pigs. Fourteen historical control pigs received half dose of tissue plasminogen activator alone (half tPA), while the subsequent 18 were randomised to (a) 1.0 mg/kg tPA (full-dose tPA); (b) low-dose tPA (0.5 mg/kg) and an intravenous microbubble infusion where guided transthoracic high MI impulses were applied intermittently to the risk area (guided high MI/half tPA) or (c) guided high MI impulses and microbubbles alone (guided high MI alone). Angiographic recanalisation, ST segment resolution and wall thickening (WT) at 60 min were compared between all pigs, while indexed infarct size at 48 h was compared in the 18 randomised pigs. RESULTS: Recanalisation rates improved from 36% for half dose tPA alone to 83% with the addition of guided high MI impulses, while it was 50% for full-dose tPA and guided high MI alone. WT recovery within the risk area following treatment was highest for guided high MI/half tPA (p=0.007 compared with full-dose tPA; ANOVA), and indexed infarct size was lowest (p<0.05 compared to full-dose tPA). CONCLUSIONS: Guided high MI-induced microbubble cavitation from a diagnostic transducer added to low-dose tPA can immediately improve regional function and reduce infarct size in acute STEMI. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT02170103.

Improvements in cerebral blood flow and recanalization rates with transcranial diagnostic ultrasound and intravenous microbubbles after acute cerebral emboli.

OBJECTIVES: Intravenous microbubbles (MBs) and transcutaneous ultrasound have been used to recanalize intra-arterial thrombi without the use of tissue plasminogen activator. In the setting of acute ischemic stroke, it was our objective to determine whether skull attenuation would limit the ability of ultrasound alone to induce the type and level of cavitation required to dissolve thrombi and improve cerebral blood flow (CBF) in acute ischemic stroke. MATERIALS AND METHODS: In 40 pigs, bilateral internal carotid artery occlusions were created with 4-hour-old thrombi. Pigs were then randomized to high-mechanical index (MI = 2.4) short-pulse (5 microseconds) transcranial ultrasound (TUS) alone or a systemic MB infusion (3% Definity) with customized cavitation detection and imaging system transmitting either high-MI (2.4) short pulses (5 microseconds) or intermediate-MI (1.7) long pulses (20 microseconds). Angiographic recanalization rates of both internal carotids were compared in 24 of the pigs (8 per group), and quantitative analysis of CBF with perfusion magnetic resonance imaging was measured before, immediately after, and at 24 hours using T2* intensity versus time curves in 16 pigs. RESULTS: Complete angiographic recanalization was achieved in 100% (8/8) of pigs treated with image-guided high-MI TUS and MBs, but in only 4 of 8 treated with high-MI TUS alone or 3 of 8 pigs treated with image-guided intermediate-MI TUS and MBs (both P < 0.05). Ipsilateral and contralateral CBF improved at 24 hours only after 2.4-MI 5-microsecond pulse treatments in the presence of MB (P < 0.005). There was no evidence of microvascular or macrovascular hemorrhage with any treatment. CONCLUSIONS: Guided high-MI impulses from an ultrasound imaging system produce sustained improvements in ipsilateral and contralateral CBF after acute cerebral emboli.

Improved sonothrombolysis from a modified diagnostic transducer delivering impulses containing a longer pulse duration.

Although guided high-mechanical-index (MI) impulses from a diagnostic ultrasound transducer have been used in preclinical studies to dissolve coronary arterial and microvascular thrombi in the presence of intravenously infused microbubbles, it is possible that pulse durations (PDs) longer than that used for diagnostic imaging may further improve the effectiveness of this approach. By use of an established in vitro model flow system, a total of 90 occlusive porcine arterial thrombi (thrombus age: 3-4 h) within a vascular mimicking system were randomized to 10-min treatments with two different PDs (5 and 20 µs) using a Philips S5-1 transducer (1.6-MHz center frequency) at a range of MIs (from 0.2 to 1.4). All impulses were delivered in an intermittent fashion to permit microbubble replenishment within the thrombosed vessel. Diluted lipid-encapsulated microbubbles (0.5% Definity) were infused during the entire treatment period. A tissue-mimicking phantom 5 cm thick was placed between the transducer and thrombosed vessel to mimic transthoracic attenuation. Two 20-MHz passive cavitation detection systems were placed confocal to the insonified vessel to assess for inertial cavitational activity. Percentage thrombus dissolution was calculated by weighing the thrombi before and after each treatment. Percentage thrombus dissolution was significantly higher with a 20-µs PD already at the 0.2 and 0.4 MI therapeutic impulses (54 ± 12% vs. 33 ± 17% and 54 ± 22% vs. 34 ± 17%, p < 0.05 compared with the 5-µs PD group, respectively), and where passive cavitation detection systems detected only low intensities of inertial cavitation. At higher MI settings and 20-µs PDs, percentage thrombus dissolution decreased most likely from high-intensity cavitation shielding of the thrombus. Slightly prolonging the PD on a diagnostic transducer improves the degree of sonothrombolysis that can be achieved without fibrinolytic agents at a lower mechanical index.

Prevention of arteriovenous shunt occlusion using microbubble and ultrasound mediated thromboprophylaxis.

BACKGROUND: Palliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion. High mechanical index (MI) impulses from a modified diagnostic ultrasound (US) transducer during a systemic microbubble (MB) infusion have been used to dissolve intravascular thrombi without anticoagulation, and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts. METHODS AND RESULTS: Heparin-bonded ePTFE tubular vascular shunts of 4 mm×2.5 cm (Propaten; W.L Gore) were surgically placed in 18 pigs: a right-sided side-to-side arteriovenous (AV, carotid-jugular) shunt, and a left-sided arterio-arterial (AA, carotid-carotid) interposition shunt in each animal. After shunt implantation, animals were randomly assigned to one of 3 groups. Transcutaneous, weekly 30-minute treatments (total of 4 treatments) of either guided high MI US+MB (Group 1; n=6) using a 3% MRX-801 MB infusion, or US alone (Group 2; n=6) were given separately to each shunt. The third group of 6 pigs received no treatments. The shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area (mm2) for the length of each shunt. No pigs received antiplatelet agents or anticoagulants during the treatment period. The median overall thrombus burden in the 3 groups for AV shunts was 5.10 mm2 compared with 4.05 mm(2) in AA (P=0.199). Group 1 pigs had significantly less thrombus burden in the AV shunts (median 2.5 mm2) compared with Group 2 (median 5.6 mm2) and Group 3 (median 7.5 mm2) pigs (P=0.006). No difference in thrombus burden was seen between groups for AA shunts. CONCLUSION: Transcutaneous US with intravenous MB is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents, and may be a method of preventing progressive occlusion of palliative shunts.

Combination of real time three-dimensional echocardiography with diagnostic catheterization to derive left ventricular pressure-volume relations.

AIMS: The aim of this study was to investigate the left ventricular (LV) myocardial contractility index-Emax using transesophageal real time three-dimensional echocardiography (RT3DE) combined with catheterization. METHODS: Transesophageal RT3DE (single beat, X7-2 × matrix, iE33, Philips) was used to obtain real time LV volumes in pigs. Volumes were integrated with LV pressures from conductance catheterization (CC) to create RT3DE pressure-volume relations. At the same time, CC was used for measuring conventional pressure-volume relations that served as reference. The slope Emax was determined from RT3DE and CC end-systolic pressure-volume relations. All measurements were made at rest and during dobutamine infusion. RESULTS: In six pigs, the mean ± SD (mmHg/mL) values were Emax-CC 1.86 ± 1.1 and Emax-RT3DE 1.78 ± 1.2 (P = 0.502) at baseline. On dobutamine, mean Emax-CC was 3.43 ± 1.5 and Emax-RT3DE 3.60 ± 1.23 (P = 0.171). Bland-Altman analysis showed good agreements between the RT3DE- and CC-derived Emax for measurements performed at baseline and on dobutamine. CONCLUSIONS: Emax can be determined from RT3DE integrated with catheterization-derived pressures. RT3DE is a promising method for enhancing clinical applicability of pressure-volume relations for assessment of myocardial contractility.

Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction.

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) ½ dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction.