Abstract
Background
Intravenous sonothrombolysis is an emerging strategy for management of acute coronary syndromes. This involves intravenous administration of echocardiographic ultrasound enhancing agents with subsequent ultrasound-induced microbubble rupture using echocardiography. However, it is challenging to isolate a specific cardiac distribution. We sought to overcome this with targeted coronary sonothrombolysis.
Case Summary
In a case of acute coronary syndrome with extensive thrombus burden, targeted coronary sonothrombolysis was performed with perflutren microbubbles injected directly into the thrombus and subsequently ruptured using echocardiography, leading to significant reduction in thrombus burden and normalization of coronary flow.
Discussion
Injection of perflutren microbubbles into the thrombus with subsequent opacification of only the myocardium supplied by the infarct-related artery is an effective means to deliver therapy to the appropriate location.
Take-Home Message
Targeted coronary sonothrombolysis helps overcome some of the difficulties observed with sonothrombolysis and may be a novel technique for management of coronary thrombus.
Key words: coronary thrombus, sonothrombolysis
Graphical Abstract
Treating large burden coronary thrombus remains a challenge with associated poor outcomes despite new devices and techniques dedicated to management.1,2 Sonothrombolysis is an emerging technique that is being investigated for its ability to disrupt thrombus and reduce microvascular obstruction to allow for reperfusion in the setting of acute ST-segment elevation myocardial infarction (STEMI).3 In limited clinical studies published, sonothrombolysis is conventionally performed by intravenous (IV) injection of ultrasound enhancing agents (UEAs) that comprise perflutren lipid microspheres, waiting for the UEAs to opacify the myocardium during transthoracic echocardiography (indicating that the UEAs entered the coronary circulation) and then delivering high mechanical index pulses via transthoracic echocardiography to rupture the microspheres within the thrombus and disrupt its biostructure.3,4 In standard clinical practice, perflutren lipid microspheres are injected intravenously during diagnostic echocardiography studies to provide contrast and enhance myocardial visualization. Injection of perflutren is typically very well tolerated with an excellent safety profile, with back pain and allergic reactions reported in rare cases as well as a theoretical risk of ventricular dysrhythmias potentially related to microbubble cavitation with end-systolic triggering.5 Initial results of sonothrombolysis performed before percutaneous coronary intervention demonstrated marked improvements in reperfusion (assessed by TIMI grade flow) on an order of magnitude similar to that appreciated in the initial trials studying streptokinase fibrinolytic therapy.3,6 Furthermore, sonothrombolysis before percutaneous coronary intervention in STEMI has been associated with a marked relative reduction in infarct size of up to 27.5%.3
Take-Home Messages
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Targeted coronary sonothrombolysis performed during percutaneous intervention represents another potential tool for the interventional cardiologist to treat refractory coronary thrombus in acute coronary syndromes.
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Targeted coronary sonothrombolysis helps to overcome many of the challenges associated with performing sonothrombolysis.
There are challenges associated with performing sonothrombolysis in the setting of STEMI. By administering the UEAs intravenously, the entire myocardium opacifies, and the only way for the sonographer to ensure that the culprit vessel is treated is to perform sonothrombolysis of the entire left ventricle. This can be time-consuming, requiring up to 90 separate high mechanical index pulses to achieve the results reported in initial trials,3 with no guarantee that the culprit lesion truly was subjected to the therapy. Additionally, simply owing to its distribution throughout the entire vasculature, only a small fraction of the UEAs injected actually reach the infarct artery when the UEAs are administered systemically.
We report targeted coronary sonothrombolysis as a unique approach to overcome these challenges. Through intracoronary injection of the UEAs directly into the culprit vessel immediately proximal to the thrombus, only the myocardium supplied by the infarct-related artery (IRA) opacifies, and therapy can be focused solely on the thrombus. A markedly increased proportion of the perflutren microbubbles can be ruptured in the thrombus,7 ideally leading to more rapid and complete degradation of the intracoronary thrombus. To our knowledge, we present the first-in-human experience of targeted coronary sonothrombolysis.
Case Summary
A 78-year-old man with no known prior medical history presented with chest pain while mowing his lawn. After presenting to the emergency department, he was found to be in sustained monomorphic ventricular tachycardia (Figure 1), which resolved with a 150-mg bolus of amiodarone. Electrocardiography demonstrated diffuse T-wave inversions, and cardiac biomarkers were elevated (high-sensitivity troponin T: 261 ng/L), prompting urgent coronary angiography. Initial angiography (Video 1) revealed an aneurysmal left circumflex artery with a large mobile filling defect consistent with thrombus and TIMI distal flow grade 2 (Figure 2). He was treated with 24 hours of continuous IV heparin for anticoagulation and returned to the cardiac catheterization laboratory the following day for repeat angiography, which demonstrated no change. Intravascular ultrasound (Video 2) demonstrated a large mobile intraluminal mass of mixed echogenicity (Figure 3), and optical coherence tomography (Video 3) confirmed a low-attenuation mass with no evidence of atherosclerosis (Figure 4). The differential diagnosis included either a coronary embolus or thrombosis in situ within the coronary aneurysm. Conventional management strategies were attempted, including aspiration thrombectomy and IV glycoprotein IIb/IIIa administration, with minimal effect on thrombus burden. The patient was then treated with targeted coronary sonothrombolysis (Video 4), with subsequent angiography (Video 5) and optical coherence tomography (Video 6) demonstrating a marked improvement in thrombus burden and TIMI distal flow grade 3. Balloon angioplasty and stenting were deferred following targeted sonothrombolysis. The patient developed no complications from the procedure and experienced no side effects related to the therapy, and he was discharged from the hospital 1 day after percutaneous coronary intervention. He recovered completely and remains angina-free at 6 months.
Figure 1.
Initial Electrocardiogram Demonstrating a Wide Complex Tachycardia Consistent With Ventricular Tachycardia
Figure 2.
Initial Angiography Demonstrating Thrombus in an Aneurysmal Circumflex Artery
Figure 3.
Initial Intravascular Ultrasound Demonstrating a Large Mobile Intraluminal Mass of Mixed Echogenicity Consistent With Thrombus
Figure 4.
Initial Optical Coherence Tomography Showing an Intraluminal Low-Attenuation Mass With No Evidence of Atherosclerosis Consistent With Thrombus
Technique of Targeted Coronary Sonothrombolysis
After the vessel was wired with a standard coronary workhorse wire, an aspiration catheter was positioned in the culprit circumflex artery with the aspiration port immediately proximal to the thrombus. Any single- or dual-lumen microcatheter or over-the-wire balloon could be similarly employed. Using two-dimensional transthoracic echocardiography, from the apical window (4-chamber view), the lateral wall of the heart was visualized. Diluted perflutren lipid microspheres (1.3 mL of Definity UEA mixed with 8.7 mL of saline) were injected directly into the left circumflex artery proximal to the thrombus through an aspiration catheter in 0.2-mL aliquots by the interventional cardiologist. As this technique had not been previously described or performed to our knowledge, the optimal UEA and dosage were unknown to us. Perflutren was selected as this had been safely and effectively used in prior IV sonothrombolysis trials, and 0.2-mL aliquots were injected as this is the dose that our team had safely used with intracoronary injections for evaluation of perforation localization.
Following injection, the sonographer adjusted the transducer to ensure that the targeted area of myocardium opacified was optimally visualized using low mechanical index diagnostic UEA echocardiography. Following this, a high mechanical index pulse was applied to rupture the microspheres directly in the thrombus and disrupt it. Additional 0.2-mL aliquots were injected, and high mechanical index pulses were repeated 16 times in multiple views from the apical and parasternal windows to definitively ensure that the thrombus in the circumflex artery and all of its major branches were treated. After 16 cycles of sonothrombolysis, it appeared that the circumflex artery and the entirety of the myocardium that it supplied were adequately treated, so angiography and intravascular ultrasound were each performed once, with both demonstrating marked improvement in thrombus burden. Based upon these imaging results, the team decided to defer further therapies and completed the case.
Ongoing Challenges and Future Directions
The use of sonothrombolysis in general for coronary thrombus in acute coronary syndromes remains an intriguing option for management of microvascular obstruction in addition to primary reperfusion. Studies have, however, delivered mixed results, with some studies demonstrating that sonothrombolysis reduces infarct size in acute coronary syndromes and others showing limited effect on microvascular obstruction in cases of no-reflow phenomenon.8,9 These discrepancies may be related to the challenges in rapidly performing high-quality contrast echocardiography in patients actively experiencing acute STEMI and subsequently attempting to direct sonothrombolysis to the IRA. To overcome these challenges, typically 60 to 90 pulses have been administered across the multiple different views in a broad-spectrum approach to attempt to deliver at least some of the therapy to the IRA and the thrombus.3,8,9 This results in added time and effort, and it still remains unclear how many high mechanical index pulses are actually delivered to the IRA as well as the number of microbubbles that are able to be ruptured in the thrombus. Echocardiography depends heavily on both the patient's imaging windows and the skill of the sonographer, and successful sonothrombolysis depends on the sonographer being able to repeatedly target and deliver high mechanical index pulses to the IRA.
We present this novel method of focusing sonothrombolysis on the IRA and the myocardium at risk, which in this case yielded a marked reduction in thrombus burden after conventional methods for thrombus management failed. Intracoronary administration of UEAs has been previously demonstrated to be safe in the setting of perforation management10 and alcohol septal ablation,11 and although further studies will be required to confirm the safety of targeted coronary sonothrombolysis, there is no identifiable underlying mechanism for adverse effects or significant complications. This technique should be evaluated further in future studies to better understand its safety and efficacy compared with IV sonothrombolysis or other traditional therapies such as aspiration thrombectomy.
Conclusions
Targeted coronary sonothrombolysis is a novel method for delivery of UEAs to the IRA in the setting of acute coronary syndromes and refractory coronary thrombus through direct intracoronary injection. Although this increases the technical complexity of sonothrombolysis compared with simple IV administration, this method ensures that all therapy is directed at the IRA and the myocardium that it supplies.
Ethical Approval
As this was an urgent intraprocedural decision to treat a refractory coronary thrombus by modifying an existing technique, we were unable to obtain ethical/institutional review board approval in the periprocedural setting. The patient was informed of the potential unknown risks of off-label device use and agreed to proceed.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental videos, please see the online version of this paper.
Appendix
Initial Angiography of the Left Coronary System Demonstrating Thrombus in an Aneurysmal Circumflex Artery
Initial Intravascular Ultrasound Demonstrating a Large Mobile Intraluminal Mass of Mixed Echogenicity Consistent With Thrombus
Initial Optical Coherence Tomography Showing an Intraluminal Low-Attenuation Mass With No Evidence of Atherosclerosis Consistent With Thrombus
Echocardiogram With Focus on the Inferolateral Wall With Subsequent Bolus of Perflutren Microbubbles Followed by Repeated High Mechanical Index “Flashes”
Final Angiography Following Targeted Sonothrombolysis Demonstrating Marked Improvement in Coronary Flow and Reduction in Thrombus Burden
Final Optical Coherence Tomography After Targeted Sonothrombolysis With Improvement in Thrombus Burden
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Associated Data
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Supplementary Materials
Initial Angiography of the Left Coronary System Demonstrating Thrombus in an Aneurysmal Circumflex Artery
Initial Intravascular Ultrasound Demonstrating a Large Mobile Intraluminal Mass of Mixed Echogenicity Consistent With Thrombus
Initial Optical Coherence Tomography Showing an Intraluminal Low-Attenuation Mass With No Evidence of Atherosclerosis Consistent With Thrombus
Echocardiogram With Focus on the Inferolateral Wall With Subsequent Bolus of Perflutren Microbubbles Followed by Repeated High Mechanical Index “Flashes”
Final Angiography Following Targeted Sonothrombolysis Demonstrating Marked Improvement in Coronary Flow and Reduction in Thrombus Burden
Final Optical Coherence Tomography After Targeted Sonothrombolysis With Improvement in Thrombus Burden