Feasibility of Microbubble-Accelerated Low-Dose Thrombolysis of Peripheral Arterial Occlusions Using an Ultrasound Catheter.

PURPOSE: Intra-arterial administration of microbubbles (MBs) through an ultrasound (US) catheter increases the local concentration of MBs into the thrombus and may further enhance outcomes of contrast-enhanced sonothrombolysis (CEST). The objective of this study was to evaluate the feasibility and lytic efficacy of intra-arterial infusion of MBs during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models. MATERIALS AND METHODS: SonoVue and Luminity MBs were infused at a flow rate of 20 mL/h through either the drug delivery lumen of the US catheter (DDC, n=20) or through the tube lumen of the vascular phantom (systematic infusion, n=20) during thrombolysis with a low-dose urokinase (UK) protocol (50 000 IU/h) with(out) US application to assess MB survivability and size by pre-treatment and post-treatment measurements. A human thrombus was placed into a vascular phantom of the flow system to examine the lytic effects of CEST by post-treatment D-dimer concentrations measurements of 5 treatment conditions (saline, UK, UK+US, UK+US+SonoVue, and UK+US+Luminity). Thrombolytic efficacy of localized MBs and US delivery was then investigated in vivo in 5 porcine models by arterial blood flow, microcirculation, and postmortem determined thrombus weight and remaining length. RESULTS: US exposure significantly decreased SonoVue (p=0.000) and Luminity (p=0.000) survivability by 37% and 62%, respectively. In vitro CEST treatment resulted in higher median D-dimer concentrations for the SonoVue (0.94 [0.07-7.59] mg/mL, p=0.025) and Luminity (0.83 [0.09-2.53] mg/mL, p=0.048) subgroups when compared with thrombolysis alone (0.36 [0.02-1.00] mg/mL). The lytic efficacy of CEST examined in the porcine model showed an improved median arterial blood flow of 21% (7%-79%), and a median thrombus weight and length of 1.02 (0.96-1.43) g and 2.25 (1.5-4.0) cm, respectively. One allergic reaction and 2 arrhythmias were observed due to the known allergic reaction on lipids in the porcine model. CONCLUSION: SonoVue and Luminity can be combined with an US catheter and could potentially accelerate thrombolytic treatment of peripheral arterial occlusions. CLINICAL IMPACT: Catheter-directed thrombolysis showed to be an effective alternative to surgery for acute peripheral arterial occlusions, but this technique is still associated with several limb and life-threatening complications. The effects of thrombolysis on clot dissolution may be further enhanced by intra-arterial administration of microbubbles through an ultrasound catheter. This study demonstrates the feasibility and lytic efficacy of intra-arterial infusion of microbubbles during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models.

Long-Term Prognostic Implications of Previous Silent Myocardial Infarction in Patients Presenting With Acute Myocardial Infarction.

OBJECTIVES: This study investigated the prevalence of silent myocardial infarction (MI) in patients presenting with first acute myocardial infarction (AMI), and its relation with mortality and major adverse cardiovascular events (MACE) at long-term follow-up. BACKGROUND: Up to 54% of MI occurs without apparent symptoms. The prevalence and long-term prognostic implications of previous silent MI in patients presenting with seemingly first AMI are unclear. METHODS: A 2-center observational longitudinal study was performed in 392 patients presenting with first AMI between 2003 and 2013, who underwent late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) examination within 14 days post-AMI. Silent MI was assessed on LGE-CMR images by identifying regions of hyperenhancement with an ischemic distribution pattern in other territories than the AMI. Mortality and MACE (all-cause death, reinfarction, coronary artery bypass grafting, and ischemic stroke) were assessed at 6.8 ± 2.9 years follow-up. RESULTS: Thirty-two patients (8.2%) showed silent MI on LGE-CMR. Compared with patients without silent MI, mortality risk was higher in patients with silent MI (hazard ratio: 3.87; 95% confidence interval: 1.21 to 12.38; p = 0.023), as was risk of MACE (hazard ratio: 3.10; 95% confidence interval: 1.22 to 7.86; p = 0.017), both independent from clinical and infarction-related characteristics. CONCLUSIONS: Silent MI occurred in 8.2% of patients presenting with first AMI and was independently related to poorer long-term clinical outcome, with a more than 3-fold risk of mortality and MACE. Silent MI holds prognostic value over important traditional prognosticators in the setting of AMI, indicating that these patients represent a high-risk subgroup warranting clinical awareness.

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

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-cycle pulses to 7.3 ± 3.2 mmHg/min with 5000-cycle ultrasound pulses (p < 0.01). The lytic index was similar for tPA-only ([2.0 ± 0.5] × 10-3 mmHg-1 min-1) and 5000 cycles without tPA ([2.3 ± 0.5] × 10-3 mmHg-1 min-1) (p = 0.5) but increased ([3.6 ± 0.8] × 10-3 mmHg-1 min-1) with tPA in conjunction with 5000-cycles ultrasound (p < 0.01). In conclusion, SRP restored microvascular perfusion in whole blood, SRP lytic rate in experiments without tPA increased with ultrasound pulse length and efficacy increased with the addition of tPA.

No benefit of additional treatment with exenatide in patients with an acute myocardial infarction.

OBJECTIVES: This double blinded, placebo controlled randomized clinical trial studies the effect of exenatide on myocardial infarct size. The glucagon-like peptide-1 receptor agonist exenatide has possible cardioprotective properties during reperfusion after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. METHODS: 191 patients were randomly assigned to intravenous exenatide or placebo initiated prior to percutaneous coronary intervention using 10µg/h for 30min followed by 0.84µg/h for 72h. Patients with a previous myocardial infarction, Trombolysis in Myocardial Infarction flow 2 or 3, multi-vessel disease, or diabetes were excluded. Magnetic resonance imaging (MRI) was performed to determine infarct size, area at risk (AAR) (using T2-weighted hyperintensity (T2W) and late enhancement endocardial surface area (ESA)). The primary endpoint was of 4-month final infarct size, corrected for the AAR measured in the acute phase using MRI. RESULTS: After exclusion, 91 patients (age 57.4±10.1years, 76% male) completed the protocol. There were no baseline differences between groups. No difference was found in infarct size corrected for the AAR in the exenatide group compared to the placebo group (37.1±18.8 vs. 39.3±20.1%, p=0.662). There was also no difference in infarct size (18.8±13.2 vs. 18.8±11.3% of left ventricular mass, p=0.965). No major adverse cardiac events occurred during the in-hospital phase. CONCLUSION: Exenatide did not reduce myocardial infarct size expressed as a percentage of AAR in ST elevated myocardial infarction patients successfully treated with percutaneous coronary intervention.

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

High-mechanical-index ultrasound and intravenous microbubbles might prove beneficial in treating microvascular obstruction caused by microthrombi after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). Experiments in animals have revealed that longer-pulse-duration ultrasound is associated with an improvement in microvascular recovery. This trial tested long-pulse-duration, high-mechanical-index ultrasound in STEMI patients. Non-randomly assigned, non-blinded patients were included in this phase 2 trial. The primary endpoint was any side effect possibly related to the ultrasound treatment. The study was aborted after six patients were included; three patients experienced coronary vasoconstriction of the culprit artery, unresponsive to nitroglycerin. Therefore, coronary artery diameter was measured in five pigs. Coronary artery diameters distal to the injury site decreased after application of ultrasound, after balloon injury plus thrombus injection (from 1.89 ± 0.24 mm before to 1.78 ± 0.17 after ultrasound, p = 0.05). Long-pulse-duration ultrasound might cause coronary vasoconstriction distal to the culprit vessel location.

Fluoroscopy Assisted Scoring of Myocardial Hypoperfusion (FLASH) ratio as a novel predictor of mortality after primary PCI in STEMI patients.

BACKGROUND: The aim of this study was to investigate whether Fluoroscopy Assisted Scoring of Myocardial Hypoperfusion (FLASH) enabled a more accurate assessment of coronary blood flow and prediction of cardiac mortality after primary PCI (pPCI), than the presently used angiographic scores of reperfusion. METHODS: We included 453 STEMI patients who received pPCI at our hospital. Using the novel FLASH algorithm, based on contrast passage time and quantitative coronary analysis, FLASH flow was measured after pPCI and was used to calculate FLASH ratio of culprit and reference artery. In 28 of the 453 patients, FLASH flow was compared to Doppler-derived-flow. RESULTS: FLASH flow had a good correlation with Doppler derived flow (Pearson's R=0.65, p<0.001) and had a high inter-observer agreement (ICC=0.83). FLASH flow was significantly lower in patients that died of cardiac death within six months (25.9±17.7 ml/min vs. 38.2±18.8 ml/min, p=0.004). FLASH ratio had a high accuracy of predicting cardiac mortality with a significant higher area under the curve as compared with CTFC and QuBe (p=0.041 and p=0.008). FLASH ratio was an independent predictor of mortality at 6 months (HR=0.98 per 1% increase, p=0.014). CONCLUSION: FLASH is a simple non-invasive method to estimate coronary blood flow and predict mortality directly following pPCI in STEMI patients, with a higher accuracy compared to the presently used angiographic scores.