Published online before print March 2, 2009, doi: 10.1161/CIRCULATIONAHA.108.825067
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(Circulation. 2009;119:1378-1385.)
© 2009 American Heart Association, Inc.
Coronary Heart Disease |
Diagnostic Ultrasound Combined With Glycoprotein IIb/IIIa–Targeted Microbubbles Improves Microvascular Recovery After Acute Coronary Thrombotic Occlusions
From the Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center, Omaha (F.X., J.L., T.R.P.); Department of Radiology Research, University of Arizona, Tucson (T.M.); and ImaRx Therapeutics, Inc, Tucson, Ariz (R.Z.).
Correspondence to Feng Xie, MD, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha NE 68198-2265. E-mail fxie{at}unmc.edu
Received September 29, 2008; accepted December 29, 2008.
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Abstract |
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Background— The high mechanical index (MI) impulses from a diagnostic ultrasound transducer may be a method of recanalizing acutely thrombosed vessels if the impulses are applied only when microbubbles are channeling through the thrombus.
Methods and Results— In 45 pigs with acute left anterior descending thrombotic occlusions, a low-MI pulse sequence scheme (contrast pulse sequencing) was used to image the myocardium and guide the delivery of high-MI (1.9 MI) impulses during infusion of either intravenous platelet-targeted microbubbles or nontargeted microbubbles. A third group received no diagnostic ultrasound and microbubbles. All groups received half-dose recombinant prourokinase, heparin, and aspirin. Contrast pulse sequencing examined replenishment of contrast within the central portion of the risk area and guided the application of high-MI impulses. Angiographic recanalization rates, resolution of ST-segment elevation on ECG, and wall thickening were analyzed. Pigs receiving platelet-targeted microbubbles had more rapid replenishment of the central portion of the risk area (80% versus 40% for nontargeted microbubbles; P=0.03) and higher epicardial recanalization rates (53% versus 7% for prourokinase alone; P=0.01). Replenishment of contrast within the risk area (whether with platelet-targeted microbubbles or nontargeted microbubbles) was associated with both higher recanalization rates and even higher rates of ST-segment resolution (82% versus 21% for prourokinase alone; P=0.006). ST-segment resolution occurred in 6 pigs (40%) treated with microbubbles who did not have epicardial recanalization, of which 5 had recovery of wall thickening.
Conclusions— Intravenous platelet-targeted microbubbles combined with brief high-MI diagnostic ultrasound impulses guided by contrast pulse sequencing improve both epicardial recanalization rates and microvascular recovery.
Key Words: coronary disease • microbubbles • thrombolysis • ultrasonics
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Introduction |
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Coronary thrombosis on a ruptured coronary plaque is the main pathophysiological event that leads to acute coronary syndromes.1–3 Current recanalization therapies in these disease states include pharmacological thrombolysis and percutaneous coronary intervention, both of which have improved the prognosis of patients with ST-segment elevation myocardial infarction.4–6 Each of these therapeutic interventions, however, has significant limitations. The time required to open a coronary vessel successfully with percutaneous coronary intervention is, even at the most experienced centers, 90 minutes after presentation to the emergency department,7 during which time extensive myocardial necrosis may already have occurred. Reperfusion with the use of thrombolytics is most effective if given within the first hour after the onset of symptoms in ST-segment elevation myocardial infarction, but effective epicardial recanalization is achieved in <60% of patients.8 Furthermore, the doses of thrombolytics used in clinical trials have increased the risk for intracerebral hemorrhage, even if patients with previous stroke are excluded.9,10 Finally, neither percutaneous coronary interventions nor thrombolytic agents have reduced the risk for microvascular no reflow,11,12 a phenomenon in which there is a persistent perfusion abnormality within the risk area even after epicardial recanalization. This phenomenon correlates with lack of ST-segment resolution on the 12-lead ECG and is associated with postinfarction complications.13,14
Editorial p 1358
Clinical Perspective p 1385
Therapeutic ultrasound and intravenous microbubbles have been utilized to recanalize acute intravascular thrombi in peripheral vessels.15–23 Recently, we have demonstrated that a diagnostic ultrasound transducer has the capability to recanalize deeply located intravascular thrombi if the high–mechanical index (MI) impulses from this transducer are applied only when microbubbles are visualized channeling through the thrombus, with the use of a low-MI microbubble sensitive pulse sequence scheme as a guide.24 The ability of these guided high-MI impulses to recanalize acutely thrombosed coronary arteries may be impaired by the paucity of intravenous microbubbles reaching an occluded coronary vessel and the inability to directly visualize the small thrombosed coronary lumen. To overcome this limitation, we hypothesized that platelet glycoprotein IIb/IIIa–targeted microbubbles (platelet-targeted microbubbles) could be used to increase the avidity of microbubbles to thrombus in both the coronary artery and downstream microvasculature within the risk area. These microbubbles could then be visualized by examining for contrast within the central portion of the risk area, which would then guide the delivery of high-MI impulses. The purpose of this study was to determine whether a low-MI microbubble sensitive imaging system could be used to guide high-MI impulses from the same diagnostic transducer during a platelet-targeted microbubble infusion and improve both epicardial and microvascular flow in a pig model of acute coronary thrombosis.
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Methods |
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Animal Preparation
Nine pigs died from refractory ventricular arrhythmias after left anterior descending thrombosis and thus were not randomized. Forty-five pigs (University of Nebraska–Lincoln Agricultural Research and Development Center, Mead, Neb) completed the randomized study protocol. The mean weight of the 45 pigs was 36±4 kg. The study was compliant with the guidelines of the Institutional Animal Care and Use Committee and the standards in the Guide for the Care and Use of Laboratory Animals. The animals were preanesthetized with an intramuscular mixture of Telazol (4.4 mg/kg), ketamine (2.2 mg/kg), and xylazine (2.2 mg/kg). Atropine (0.05 mg/kg IM) was used to dry oral-tracheal secretions and prevent bradycardia during intubation or surgery. After placement of a venous line in an ear vein (lateral or medial auricular vein), the animal was intubated, and isoflurane anesthesia (induction at 4%, maintained at 1.0% to 1.8%) was administered. The oxygen mixture was kept at <24% (slightly greater than room air) during intravenous ultrasound contrast infusions. The animal was intubated and placed on a respirator at a volume of 10 mL/kg of air and at a rate of 15 bpm.
Two femoral artery and 2 venous catheters were placed for hemodynamic monitoring and injections of microbubbles. The pigtail catheter was advanced over a guidewire with fluoroscopic guidance in a retrograde fashion from the femoral artery into the left ventricle and left atrium. The placement was confirmed by the typical left atrial pressure waveform (a and v waves) on the pressure recordings. An 8F guide catheter was introduced into the left main artery for digital angiograms and for balloon catheter insertion. Heart rate and oxygen saturation were also monitored throughout entire experiment. Low-dose intravenous dobutamine (1 to 3 µg/kg per minute) was used to maintain systolic arterial pressure >90 mm Hg during the acute coronary thrombotic occlusions.
Lidocaine boluses (40 mg IV followed by 20 mg IV boluses at periodic intervals) and a continuous lidocaine infusion (2 to 4 mg/min IV) were used in all animals to control arrhythmias. Isolated ventricular ectopic beats were observed in all animals after thrombotic occlusion.
Ultrasound System
A Siemens Acuson Sequoia with 4V1c transducer (1.5 MHz, Siemens Ultrasound Solutions, Calif) was used for all studies. The MI was adjusted for 2 settings: the low-MI setting (0.2 MI with the use of contrast pulse sequencing), for imaging of microbubbles within the risk area of the myocardial microcirculation, and the high-MI setting (1.9), for therapeutic applications over the risk area and epicardial location of the left anterior descending arteries. These 2 MI settings were alternated with the use of a foot pedal.
Microbubbles
Two formulations of lipid-encapsulated microbubbles with perfluorocarbon gas were provided by ImaRx Therapeutics, Inc (Tucson, Ariz): MRX-835, which are nontargeted microbubbles, and a platelet glycoprotein IIb/IIIa–targeted microbubble termed MRX-802. The targeting ligand was synthesized and purified with standard peptide chemistry techniques utilizing a Fmoc strategy. Briefly, MRX-802 was formulated with the use of phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine-polyethylene glycol 5000, and N,N’diaminobutyryl-a-amino, w-carboxy-polyethylene glycol 3400 (cyclo-CRGDWPC)-OH. The lipids and bioconjugate were dispersed in a mixture of propylene glycol, glycerol, and phosphate-buffered saline with intermittent heating to 50°C. Both formulations (MRX-835 and MRX-802) were then placed into 2-mL vials, sealed, and purged with perfluorobutane (Fluoromed, Round Rock, Tex). Samples were then activated by agitation on a modified dental amalgamator operating at 
4000 rpm. The mean diameter of the microbubbles was measured to be 1.0±0.1 µm, with concentration of 1.5 to 3.0x1010/mL. The microbubble infusion was prepared by diluting 2 mL of the MRX-835 or MRX-802 in 80 mL of 0.9% saline and infusing at a rate of 2.5 mL/min for 30 minutes.
Angiography
Angiography was performed with a cardiovascular mobile digital C-arm system (GE Healthcare, Salt Lake City, Utah) at 30, 60, and 90 minutes after treatment. If recanalization occurred, residual stenoses at the balloon injury site were quantified with a digital caliper, with the use of a nonbranching site proximal to the occlusion as the reference diameter. Angiographic recanalization was defined as evidence of contrast flow through the site of occlusion and normal runoff of flow distal to the occlusion.
ECG Measurements
Twelve-lead ECGs were used to compute changes in ST-segment deviation before and after any treatment, with the PR segment used as a reference point. The percent resolution of ST elevation with any randomized treatment was computed from the lead with the greatest degree of ST elevation immediately after angiographic occlusion occurred.
Measurements of wall thickening were obtained with the same diagnostic ultrasonic probe used for contrast imaging. A parasternal short-axis view of the left ventricle was obtained at the distal papillary muscle level with the use of tissue harmonic imaging. Percent wall thickening was calculated as the difference in end-systolic wall thickness and end-diastolic wall thickness within the central portion of the risk area divided by end-diastolic wall thickness. Improvement in wall thickening was defined as a >10% increase in this measurement after randomized treatment.
Protocol
A thrombotic occlusion in the left anterior descending artery was created with the use of simulation of the triad of Virchow as described previously.25 All occlusions had to persist for a total of 20 minutes before randomized treatments began. In 9 animals, refractory ventricular tachycardia, unresponsive to lidocaine infusion or repeated DC cardioversions, occurred after left anterior descending thrombotic occlusion. These animals were therefore not part of the randomized treatment groups. At 20 minutes after initial angiographic occlusion, a baseline angiogram was obtained, followed by a 12-lead ECG and baseline assessment of wall thickening with a short-axis view of the left ventricle obtained with the diagnostic transducer (Siemens Acuson; Mountain View, Calif). At this point, all pigs received 650 mg of aspirin via a nasogastric tube, an intravenous bolus of heparin (80 mg/kg), and 50 000 U/kg of recombinant prourokinase (Abbott Laboratories, Abbott Park, Ill). According to the package insert, this is one half of the recommended dose for systemic fibrinolysis. The prourokinase was given as an initial 25 000 U/kg bolus over 1 minute, followed by the remainder given as an infusion over 29 minutes. The pigs were randomized to (1) half-dose recombinant prourokinase only; (2) half-dose recombinant prourokinase with a continuous intravenous infusion of nontargeted microbubbles; or (3) half-dose recombinant prourokinase with a continuous infusion of intravenous platelet-targeted microbubbles.
In pigs receiving microbubbles, contrast pulse sequencing was utilized to visualize the left ventricular short axis until evidence of contrast within the central portion of the risk area was observed. At this point, the MI was increased to 1.9 and applied at a 20-Hz frame rate while scanning from apex to base in the short-axis plane. Then the MI was switched back to <0.3, and replenishment imaging was repeated. If no replenishment was observed anywhere within this central portion, high-MI impulses were repeated within 40 seconds. This sequence of high- and low-MI imaging was repeated for 30 minutes.
At 30, 60, and 90 minutes into treatment, a diagnostic angiogram and 12-lead ECG were repeated. At 60 minutes, wall thickening measurements were repeated within the risk area and compared with pretreatment wall thickening.
Grading of Myocardial Contrast Replenishment Within the Risk Area After High-MI Impulses
Similar to the methods described by Coggins et al,26 the size of the planimetered perfusion defect at the papillary muscle level within 3 seconds of the completed high-MI impulse was defined as the risk area. Subsequent to this, replenishment of the risk area was noted in 4 different patterns (Figures 1 and 2
): (1) none=no replenishment seen within either the central or lateral portions of the risk area at 20 to 25 seconds after the high-MI impulses (Figure 1); (2) lateral replenishment only=replenishment of myocardial contrast only within the lateral portions of the risk area (Figure 1); (3) partial replenishment=replenishment of myocardial contrast within the subepicardial portion of the central risk area as well as laterally (Figure 2); and (4) complete replenishment=complete transmural opacification of the risk area after high-MI impulses (Figure 2). The central portion of the risk area was arbitrarily defined as that portion of the risk area that did not enhance from ingrowth along the lateral margins after high-MI impulses. This central portion either filled along the epicardial rim only (Figure 2, top) or filled completely (Figure 2, bottom). Early central risk area replenishment was defined as either partial or complete contrast appearance within the central portion of the risk area by 15 minutes into treatment with microbubbles. These replenishment patterns were graded by an experienced reviewer blinded to the type of microbubbles used, angiographic results, and ECG or wall thickening changes.
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Statistical Analysis
All data are expressed as mean±SD values or number and percentages. 
2 tests were used to compare differences in recanalization rates, ECG resolution, and wall thickening improvement at 30, 60, and 90 minutes after documented occlusion. This test was also used when we compared partial or complete contrast replenishment within the risk area at 5, 10 to 15, and 25 to 30 minutes into treatment with pigs that had no or only lateral risk area replenishment at this point in treatment. One-way ANOVA was used for comparisons of quantitative wall thickening measurements and ECG ST-segment changes. The Bonferroni method was used to adjust probability values for multiple comparisons made at multiple time points during the experiment. A probability value <0.05 was considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Hemodynamic Comparisons
Table 1 summarizes the hemodynamic, heart rate, and oxygen saturation measurements in the 3 groups after coronary occlusion just before treatment and at 60 minutes after initiation of treatment. There were no differences among the 3 groups in these parameters.
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Angiographic Recanalization, ST-Segment Resolution, and Wall Thickening Responses in the 3 Different Treatment Groups
The pigs who had the guided diagnostic ultrasound treatment regimen with platelet-targeted microbubbles had a 53% recanalization rate at 30 minutes (P=0.02 compared with half-dose lytic therapy alone) and 53% and 60% recanalization rates at 60 and 90 minutes (Figure 3). In comparison, the pigs randomized to guided diagnostic ultrasound and nontargeted microbubbles with half-dose lytics had recanalization rates of 33%, 40%, and 33% at 30, 60, and 90 minutes after initiation of treatment. Recanalization rates for prourokinase alone were 7%, 20%, and 20% at these same time periods. A residual 
70% diameter stenosis was present after reperfusion in 4 of the 5 (80%) recanalized vessels treated with nontargeted microbubbles, in 6 of the 8 (75%) recanalized vessels treated with platelet-targeted microbubbles, and in all 3 of the recanalized vessels of the pigs treated with half-dose lytic therapy alone. Figure 4 is an example of a coronary angiogram of a recanalized left anterior descending artery after 30 minutes of treatment with intravenous platelet-targeted microbubbles.
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Wall thickening within the central portion of the risk area and maximal ST-segment deviation were similar between groups before treatment (Table 2). Follow-up 12-lead ECGs were not available in 2 pigs: 1 pig in the platelet-targeted microbubbles group and 1 pig in the prourokinase only group who died before the 12-lead ECG could be obtained, leaving 14 for comparison in each of these groups. ST-segment resolution occurred in 9 of the 14 pigs (64%) treated with platelet-targeted microbubbles and 9 of 15 treated with nontargeted microbubbles (60%) compared with 3 of 14 control pigs (21%). Wall thickening within the central risk area increased in 9 pigs treated with platelet-targeted microbubbles (60%) and 8 pigs (53%) in the nontargeted microbubbles group compared with 5 pigs (36%) in the control group. Figure 5 demonstrates ST-segment resolution observed in a pig randomized to diagnostic ultrasound and platelet-targeted microbubbles, even though no epicardial recanalization occurred in this particular pig.
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Analysis of Myocardial Contrast Replenishment in the Pigs Randomized to Nontargeted Versus Platelet-Targeted Microbubbles
The baseline risk area was 2.38±0.83 cm2 in the pigs treated with platelet-targeted microbubbles versus 2.49±0.42 cm2 in the pigs treated with nontargeted microbubbles (P=0.64). The pigs who received platelet-targeted microbubbles exhibited more rapid replenishment of myocardial contrast within the central risk area over the time course of treatment compared with pigs receiving nontargeted microbubbles (Figure 6). Although there were no differences in central risk area replenishment at the initiation of treatment, partial or complete replenishment of myocardial contrast was observed in 12 of 15 pigs treated with platelet-targeted microbubbles at 10 minutes of treatment versus 6 of 15 pigs receiving nontargeted microbubbles (P=0.04). At 30 minutes, all pigs receiving platelet-targeted microbubbles had partial or complete central risk area replenishment (P=0.04 compared with nontargeted microbubbles).
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Regardless of whether the microbubbles were targeted or nontargeted, early central risk area replenishment was associated with a higher epicardial recanalization rate and even higher rate of ST-segment resolution. Pigs who had early risk area replenishment had a 56% epicardial recanalization rate at 30 minutes compared with 25% who did not have early central risk area replenishment and 7% for prourokinase alone (P=0.03). ST-segment resolution at 60 minutes occurred in 14 pigs (82%) who had early central risk area replenishment compared with 5 of 12 pigs (42%) who did not and 3 of 14 pigs (21%) receiving prourokinase alone (P=0.01). Wall thickening improved in 13 of the 18 pigs (72%) with early risk area replenishment compared with 5 of 12 (42%) who did not and 5 of 14 pigs (37%) receiving prourokinase alone (P=0.08).
In the 14 pigs treated with platelet-targeted microbubbles or nontargeted microbubbles that had epicardial recanalization at 60 minutes, 13 (93%) had ST-segment resolution and wall thickening recovery. However, in the 16 pigs treated with platelet-targeted microbubbles or nontargeted microbubbles that did not have epicardial recanalization by 60 minutes, ST-segment resolution still occurred in 6 (38%). Five of these 6 pigs also had recovery of wall thickening.
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Discussion |
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In this study, we demonstrated that intravenous platelet-targeted microbubbles combined with guided applications of high-MI impulses from a diagnostic transthoracic ultrasound transducer significantly improved epicardial recanalization rates and microvascular recovery after acute coronary thrombotic occlusion. Furthermore, ST-segment resolution and wall thickening improvement occurred even in the absence of epicardial recanalization, indicating that the beneficial effects of ultrasound at the capillary level may occur even in the absence of restored epicardial flow. This could have important implications for improving current pharmacological and interventional treatment regimens in acute myocardial infarction.
Mechanism for Improved Early Recanalization
In vivo studies have shown in acute peripheral artery or dialysis graft thromboses that the addition of intravenous microbubbles increases the effectiveness of ultrasound in dissolving the thrombus.18,23,27,28 Although the ultrasound we used for this study is routinely used for diagnostic imaging, the frequency and MI emitted from this transducer have been shown to induce cavitational activity in the presence of microbubbles.24,29 Cavitation has generally been classified into 2 subtypes: stable and inertial, with the stable form being induced at a lower peak negative pressure.30 This stable form of cavitation induces microstreaming and appears to be the main mechanism by which ultrasound potentiates thrombolysis in vitro.30,31 Recent data have demonstrated that cavitation must be achieved for significant thrombolysis to occur in the presence of intravenously infused microbubbles.24
Microvascular Recovery
In acute coronary syndromes, thrombi from within the epicardial vessel embolize downstream, leading to microthrombi that can reduce capillary perfusion even after epicardial recanalization.32,33 ST-segment resolution has served as an important marker of microvascular recovery in acute myocardial infarction.13,34 In our study, ST-segment resolution occurred in >80% of the pigs exhibiting early central risk area contrast replenishment, irrespective of whether treatment was with platelet-targeted microbubbles or nontargeted microbubbles and even though epicardial recanalization was observed in 56% of these pigs. There are at least 2 potential mechanisms by which diagnostic ultrasound and microbubbles may improve microvascular flow in this setting. Low-frequency ultrasound alone has been shown to improve tissue perfusion distal to occluded coronary arteries, a phenomenon that appeared to be nitric oxide mediated.35 Alternatively, the guided high-MI impulses and microbubbles may be dissolving the microthrombi within the capillaries. Reopening capillaries within the risk area would potentially reduce capillary resistance, which would then facilitate either anterograde coronary flow or collateral flow to these regions.36
Clinical Implications
Diagnostic ultrasound–facilitated thrombolysis could affect current therapies in several ways. First, it could improve the success rate of existing treatment regimens used in acute coronary syndromes. Ultrasound and microbubbles could potentially be administered outside of the hospital before reaching interventional facilities where definitive treatment occurs. Even if epicardial recanalization is not achieved with ultrasound and microbubbles, the improvements in microvascular flow may limit infarct size and relieve symptoms. This ultrasound treatment regimen could also be applied to non–ST-segment elevation infarctions and acute coronary syndromes. In this setting, thrombus on a ruptured plaque is still the primary pathophysiological event, and microbubbles have already been utilized to diagnose these entities in the emergency department.37 The addition of ultrasound and microbubbles may also permit lower doses of fibrinolytic agents to be administered while still achieving an equivalent pharmacological effect. Furthermore, the enhanced thrombolytic effects would be targeted to just the region being insonified, which could reduce the risk of bleeding at remote locations. Third, unlike other treatment modalities, this study indicates that ultrasound and microbubbles have the potential to improve microvascular flow, which must be achieved if there is to be recovery of regional function within the risk area.12
Limitations of the Study
Although we were able to successfully recanalize the coronary arteries, there was still a significant residual stenosis noted in the epicardial vessel of a majority of pigs that recanalized. Because no underlying atherosclerotic disease was present in this model, this stenosis was most likely residual thrombus. The ischemia/reperfusion process is associated with endothelial activation producing receptors that further propagate both thrombus formation and leukocyte adherence and activation.38 Additional antiplatelet and antiinflammatory agents may need to be added to counter this activation and prevent reocclusion.
The diagnostic transducer used in this study has an elevation plane of 5 mm, and thus we manually moved the sector from the apical short-axis plane to the base during the high-MI impulses to cover the entire coronary artery and risk area affected. This 2-dimensional approach may result in certain segments of the risk area being not completely exposed to these impulses. A 3-dimensional application of high-MI impulses may improve the likelihood that the entire volume of the risk area and upstream coronary artery is being insonified.
Because ultrasound and microbubbles were part of the randomized therapeutic regimen, we did not use myocardial contrast echocardiography as an end point in examining microvascular perfusion. Although this is a preferred method to assess microvascular recovery, ST-segment resolution has correlated closely with myocardial contrast measurements of microvascular perfusion in acute myocardial infarction34,39 and thus served as an independent marker that could be compared among the 3 treatment groups.
Conclusions/Future Directions
We have shown that intravenous platelet-targeted microbubbles combined with a diagnostic transthoracic ultrasound transducer rapidly improve microvascular flow to the risk area, as well as improve epicardial recanalization rates. The improvement in microvascular flow was observed even when epicardial recanalization did not occur and correlated with improvements in wall thickening within the risk area. Although ultrasonic methods targeting coronary artery thrombus will be challenging, methods to improve targeting to the microcirculation are easier to achieve with transthoracic ultrasound. For example, a 3-dimensional ultrasound volumetric probe may increase microvascular coverage when the high-MI impulses are applied and improve visualization of the risk area (or risk volume) when in the low-MI imaging mode. Additional targeting ligands can be added to the microbubbles, such as targeting to both glycoprotein IIb/IIIa receptor inhibitor and fibrin. This may increase the number of microbubbles adherent to microthrombi, resulting in greater amounts of thrombus fragmentation with the high-MI impulses, leading to a higher rate of microvascular recovery.
Even without these modifications, the ultrasound settings used in this study are already within Food and Drug Administration limits, and even nontargeted microbubbles were partially effective at improving microvascular recovery. Therefore, it is possible that this supplemental treatment regimen could be tested in a clinical scenario with nontargeted commercially available microbubbles to determine whether the addition of guided diagnostic ultrasound and intravenous microbubbles to fibrinolytic therapy will result in improved regional function and better clinical outcomes compared with treatment regimens focused on recanalizing the epicardial vessel.
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Acknowledgments |
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We thank Elizabeth Stolze and Gretchen Fry for their expert technical assistance. We also thank Lynette M. Smith, MS, for her statistical support in this manuscript.
Sources of Funding
This work was supported by the National Institutes of Health SBIR grant (2R44HL071433-02).
Disclosures
Dr Porter reports grant support from Bristol-Myers Squibb Medical Imaging and Siemens Medical Solutions and has served as a consultant for ImaRx Therapeutics, Inc. The other authors report no conflicts.
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