Unexpected High Incidence of Coronary Vasoconstriction in the Reduction of Microvascular Injury Using Sonolysis (ROMIUS) Trial

Roos, Sebastiaan T.; Juffermans, Lynda J.M.; Royen, Niels van; Rossum, Albert C. van; Xie, Feng; Appelman, Yolande; Porter, Thomas R.; Kamp, Otto

doi:10.1016/j.ultrasmedbio.2016.03.032

Cited by 24 publications

(22 citation statements)

References 39 publications

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“…These fluid jets may have produced endothelial and platelet injury, resulting in thromboxane or serotonin release, inducing vasoconstriction that inhibited any return of flow from thrombus dissolution. Vasoconstriction in response to the high MI longer pulse durations used in this study have been observed following transthoracic applications in patients with acute ST segment elevation myocardial infarction (29). The potential role for platelet induced vasoconstriction is supported by studies in animal models of coronary injury and arterial thrombus formation.…”

Section: Discussionmentioning

confidence: 90%

“…The potential role for platelet induced vasoconstriction is supported by studies in animal models of coronary injury and arterial thrombus formation. In this setting, diagnostic transthoracic high MI impulses (>1.0) at 20 usec pulse duration produced vasodilation of balloon injured coronary artery segments, but this vasodilatory effect was reversed when intra-arterial thrombus was also present (29). The peak negative pressure that produced penetrating tunnel-forming clots in vitro in the study by Acconcia et.al.…”

Section: Discussionmentioning

confidence: 99%

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

Porter¹,

Xie²,

Lof³

et al. 2017

Invest Radiol

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Background Acute ischemic stroke is often due to thromboembolism forming over ruptured atherosclerotic plaque in the carotid artery (CA). The presence of intraluminal carotid artery thrombus is associated with a high risk of thromboembolic cerebral ischemic events. The cavitation induced by diagnostic ultrasound (DUS) high mechanical index (MI) impulses applied locally during a commercially available intravenous microbubble (IV MB) 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 carotid artery of 38 porcine carotid arteries. Following this, a 70-80% stenosis was created in the mid common carotid artery 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. Following 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 usec pulse duration) or inertial cavitation (IC) impulses (1.2 MI; 20 usec 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 four intra-and extracranial vessels downstream from the CA occlusion (auricular, ascending pharyngeal, buccinator, and maxillary) was assessed with both magnetic resonance three dimensional time of flight (TOF) and phase contrast (PCA) angiography. All magnetic resonance images were interpreted by an independent neuroradiologist using the TICI scoring system. Results By PCA, at least mild recanalization (TICI 2a or higher) was seen in 64% of downstream vessels treated with SC impulses compared to 33 % of IC treated and 29% of low MI alone treated downstream vessels (p=0.001), while moderate or complete recanalization (TICI 2b or higher) was seen in 39% of SC treated vessels compared to 10% IC treated and 21% of low MI alone treated vessels (p=0.001). Conclusions High MI 20 usec 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. DUS induced SC can be a non-surgical method of dissolving carotid artery thrombi and preventing thromboembolization.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Porter¹,

Xie²,

Lof³

et al. 2017

Invest Radiol

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“…Our group and others have been investigating the use of longer tone burst to achieve sonothrombolysis, which demonstrated improved efficacy with longer pulses in preclinical studies 15 , 16 , 35 , 36 . However, a small phase-2 clinical trial 37 using longer tone burst ultrasound (20 μs) was aborted prematurely (6 patients were enrolled) after the angiographic observation of vasoconstriction in three patients following MB+US therapy. It is important to note that all patients responded well to PCI after the transient vasoconstriction incident.…”

Section: Discussionmentioning

confidence: 99%

The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction

Chen

Straub

et al. 2017

Theranostics

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Rationale: Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies, is associated with additional myonecrosis, and is linked to worse prognosis, including death. We have shown, both in in vitro and in vivo models, that ultrasound (US) and microbubble (MB) therapy (termed “sonoreperfusion” or “SRP”) is a theranostic approach that relieves MVO and restores perfusion, but the underlying mechanisms remain to be established.Objective: In this study, we investigated the role of nitric oxide (NO) during SRP.Methods and results: We first demonstrated in plated cells that US-stimulated MB oscillations induced a 6-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation in vitro. We then monitored the kinetics of intramuscular NO and perfusion flow rate responses following 2-min of SRP therapy in the rat hindlimb muscle, with and without blockade of eNOS with LNAME. Following SRP, we found that starting at 6 minutes, intramuscular NO increased significantly over 30 min and was higher than baseline after 13 min. Concomitant contrast enhanced burst reperfusion imaging confirmed that there was a marked increase in perfusion flow rate at 6 and 10 min post SRP compared to baseline (>2.5 fold). The increases in intramuscular NO and perfusion rate were blunted with LNAME. Finally, we tested the hypothesis that NO plays a role in SRP by assessing reperfusion efficacy in a previously described rat hindlimb model of MVO during blockade of eNOS. After US treatment 1, microvascular blood volume was restored to baseline in the MB+US group, but remained low in the LNAME group. Perfusion rates increased in the MB+US group after US treatment 2 but not in the MB+US+LNAME group.Conclusions: These data strongly support that MB oscillations can activate the eNOS pathway leading to increased blood perfusion and that NO plays a significant role in SRP efficacy.

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“…Pre-treatment using therapeutic ultrasound on top of regular treatment might enhance reperfusion prior to coronary intervention, but could also be cause for side-effects. It has already been shown that an increase in pulse duration might be responsible for coronary vasoconstriction in the clinical application of SRP therapy in human STEMI patients (Roos et al 2016). While our experiments showed that 5000 cycles was optimal in vitro , the effects of ultrasound on living tissue, such as possible hemolysis and hemorrhaging, should not be discarded and future studies will have to consider safety as an important trial outcome.…”

Section: Discussionmentioning

confidence: 99%

Sonoreperfusion Therapy Kinetics in Whole Blood Using Ultrasound, Microbubbles and Tissue Plasminogen Activator

Roos

Kamp

et al. 2016

Ultrasound in Medicine & Biology

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Coronary intervention for myocardial infarction often results in microvascular embolization of thrombus. Sonoreperfusion therapy (SRP) using ultrasound and microbubbles restored perfusion in our in vitro flow model of microvascular obstruction. In this study, we assessed SRP efficacy using whole blood as the perfusate with and without tissue plasminogen activator (tPA). In a phantom vessel bearing a 40-μm pore mesh to simulate the microvasculature, microthrombi were injected to cause microvascular obstruction and were treated using SRP. Without tPA, the lytic rate increased from 2.6±1.5 mmHg/min with 1000 cycles to 7.3±3.2 mmHg/min with 5000 cycles ultrasound pulses (p<0.01). The lytic index was similar between tPA-only [(2.0±0.5)×10−3 mmHg−1min−1] and 5000 cycles without tPA [(2.3±0.5)×10−3 mmHg−1min−1] (p=0.5) but increased [(3.6±0.8)×10−3 mmHg−1min−1] with tPA in conjunction with 5000 cycles ultrasound (p<0.01). In conclusion, SRP restored microvascular perfusion in whole blood and SRP lytic rate in experiments without tPA increased with ultrasound pulse length and efficacy increased with the addition of tPA.

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Unexpected High Incidence of Coronary Vasoconstriction in the Reduction of Microvascular Injury Using Sonolysis (ROMIUS) Trial

Cited by 24 publications

References 39 publications

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

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

The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction

Sonoreperfusion Therapy Kinetics in Whole Blood Using Ultrasound, Microbubbles and Tissue Plasminogen Activator

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