Tomoo Nagai

Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity: comparison with stress myocardial perfusion imaging.

OBJECTIVES To validate intravascular ultrasound (IVUS) measurements for differentiating functionally significant from nonsignificant coronary stenosis. BACKGROUND To date, there are no validated criteria for the definition of a flow-limiting coronary artery stenosis by IVUS. METHODS Preinterventional IVUS imaging (30-MHz imaging catheter) of 70 de novo coronary lesions was performed. The lesion lumen area and three IVUS-derived stenosis indixes comparing lesion lumen area with the lesion external elastic lamina (EEL) area, the mean reference lumen area and the mean reference EEL area were compared with the results of stress myocardial perfusion imaging. RESULTS The lesion lumen area and three IVUS-derived stenosis indexes showed sensitivities and specificities ranging between 80% and 90% using stress myocardial perfusion imaging as the gold standard. The lesion lumen area < or =4 mm2 is a simple and highly accurate criterion for significant coronary narrowing. CONCLUSIONS Quantitative IVUS indices can be reliably used for identifying significant epicardial coronary artery stenoses.

Noninvasive, Transthoracic, Low-Frequency Ultrasound Augments Thrombolysis in a Canine Model of Acute Myocardial Infarction

BACKGROUND Recently it has been demonstrated that transcutaneous delivery of ultrasound combined with tissue plasminogen activator (tPA) is more effective than tPA alone in recanalizing acutely thrombosed canine coronary arteries. In the present study, we investigated the incidence of partial (> or =50%) and complete (> or =70%) ST-segment elevation resolution in the precordial leads of dogs with experimental acute myocardial infarction that were treated with tissue plasminogen activator (tPA) alone or in combination with noninvasive transcutaneous delivery of high-intensity low frequency (27[emsp3 ]kHz) ultrasound. METHODS Thrombotic coronary occlusions were induced in the midportion of left anterior descending (LAD) coronary artery by electrical injury in 24 dogs. All dogs were given intravenous heparin and tPA. Dogs were randomized to tPA alone (n=12) or combined tPA and adjunctive transcutaneous ultrasound (US) delivery (n=12). Electrocardiograms were recorded at 1) baseline, 2) after coronary occlusion just before initiation of therapy, 3) when coronary angiography showed recanalization of the coronary artery (or at 90 minutes after initiation of therapy if reperfusion did not occur before then) and 4) 90 minutes later. ST amplitude was measured in all 6 precordial leads. RESULTS ST-segment amplitude at baseline was comparable between the tPA and the US group. Before initiation of therapy, sum of ST-segment elevation tended to be higher in the US group. At reperfusion and 90 minutes thereafter, sum of ST-segment amplitude tended to be smaller for the US group than in the tPA group (p<0.001 for the time effect; p=0.118 for the time x group interaction). Up to 90 minutes after initiation of therapy >/=50% resolution of the sum of precordial ST elevation was detected in 7 out of 11 dogs (63.6%) in the tPA group versus 10 out of 11 dogs (90.9%) in the US group. Ninety minutes thereafter, 3 out of 7 dogs in the tPA group (42.9%) versus 9 of 11 dogs in the US group (81.8%) had >/=50% resolution of the sum of precordial ST elevation. CONCLUSIONS The combination of tPA with noninvasive transcutaneous delivery of low frequency high-intensity ultrasound resulted in greater resolution of ST-segment elevation when reperfusion occurs and 90 minutes thereafter, as well as a higher rate of epicardial coronary artery reperfusion.

Enhancement of thrombolysis in vivo without skin and soft tissue damage by transcutaneous ultrasound

Previous studies have shown that transcutaneous ultrasound enhances thrombolysis by streptokinase in animals in vivo; however, skin and soft tissue damage induced by ultrasound energy has been a major limitation. The objective of this study was to examine the efficacy of thrombolysis and damage to skin and soft tissues using a newly designed concentrated ultrasound system with a cooling manifold. Using a rabbit model with iliofemoral arterial thrombotic occlusions, 15 pairs of arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Streptokinase (25,000 unit/kg) was given intravenously. Skin temperature was maintained at 25-33 degrees C when ultrasound energy was applied. The serum level of creatine kinase, lactate dehydrogenase, red blood cell counts, and platelet counts were checked at baseline, after thrombus induction, and after ultrasound treatment. Fifteen of fifteen (100%) iliofemoral arteries were angiographically recanalized after ultrasound treatment. In contrast, only 1/15 (6.7%) contralateral arteries were patent after 1 hour. After the subsequent hour with heparin the patency was 14/15 in the ultrasound treated group and 3/15 in the control group. Histologically, the patent arteries had only minimal focal mural thrombus, whereas the angiographically occluded arteries had occlusive thrombi. There was no histologic evidence of ultrasound induced damage to overlying skin, soft tissues, or arteries. In addition, there was no significant rise of creatine kinase, lactate dehydrogenase, or decrease in red blood cell counts and platelet counts induced by ultrasound. In conclusion, transcutaneous concentrated ultrasound which significantly enhances streptokinase induced thrombolysis in vivo can be delivered without concomitant tissue damage. This simple combination therapy has clinical potential for safely treating patients with arterial or venous thromboses.

Ultrasonic thrombolysis : catheter-delivered and transcutaneous applications

Ultrasonic thrombolysis has been proved to be an efficient and safe modality for the treatment of acute arterial occlusions in vitro and in vivo in animal studies. There have been and are ongoing parallel improvements in ultrasound technology and adjuvant pharmacological treatments for therapeutic applications. Thus therapeutic ultrasound for thrombolysis holds great promise in overcoming the limitations of current available therapies.

Noninvasive Transcutaneous Low Frequency Ultrasound Enhances Thrombolysis in Peripheral and Coronary Arteries

Previous studies have shown that external ultrasound with low frequencies and high intensities can enhance thrombolytic drug‐induced clot dissolution during in vitro experiments. In this series of studies, we evaluated the efficacy of peripheral and coronary thrombolysis in vivo in animals by using noninvasive transcutaneous ultrasound combined with thrombolytic drugs (streptokinase and tPA) and/or microbubbles agents (dodecafluoropentane [DDFP] and perfluorocarbon‐exposed sonicated dextrose albumin [PESDA]). Thrombotic occlusions were induced in 74 rabbit iliofemoral arteries and 24 canine left anterior descending (LAD) coronary arteries in this in vivo study. By using the combination of transcutaneous ultrasound and streptokinase, the angiographic patency rate in rabbit iliofemoral arteries was higher (56%–100%) than with ultrasound (6%; P ≤ 0.0036) and streptokinase alone (6%; P ≤ 0.0012). Also, with transcutaneous ultrasound and microbubbles, the angiographic patency rates were 76%–100% as compared with ultrasound alone (0%, P ≤ 0.0003) or microbubbles alone (9%, P ≤ 0.0001). In the canine study of acute myocardial infarction, thrombolysis in myocardial infarction (TIMI) grade flow at 90 minutes in the tPA alone group was 0.92 ± 1.4 as compared with 2.42 ± 1.9 in the tPA plus transthoracic ultrasound group (P = 0.006). There was much improved reperfusion with tPA plus ultrasound as compared with tPA alone. In vivo animal studies demonstrate that noninvasive transcutaneous ultrasound can greatly enhance the effect of clot dissolution with thrombolytic drugs and/or microbubbles, and has the potential for clinical application as an adjunctive method to improve arterial thrombolysis.

Superiority of the Combination of Blood and Agitated Saline for Routine Contrast Enhancement

The purpose of this study was to evaluate the modification of the saline echo contrast method by mixing blood with agitated saline before intravenous injection. In 20 patients, contrast echocardiography was performed with a conventional technique from the apical 4-chamber view. We used 2 techniques: (1) the combination of blood (1 mL) withdrawn from the patients and air-agitated saline agitated, (2) air-agitated. In all patients, the blood combination technique was judged to make a greater contrast, with the agreement of all 3 reviewers. Peak echo intensity of the right ventricular cavity by the blood combination technique was significantly higher than that by agitated saline alone. In conclusion, the use of the combination of blood and agitated saline is superior to agitated saline alone for the opacification of the right atrium and ventricle in routine echocardiography.

Pacing stress echocardiography: an alternative to pharmacologic stress testing

OBJECTIVES We sought to evaluate the diagnostic accuracy and feasibility of bedside pacing stress echocardiography (PASE) as a potential substitute for pharmacologic stress echocardiography in patients admitted to the hospital with new-onset chest pain or worsening angina pectoris. BACKGROUND Accurate and rapid noninvasive identification and evaluation of the extent of coronary artery disease (CAD) is essential for optimal management of these patients. METHODS Bedside transthoracic stress echocardiography was performed in 54 consecutive patients admitted to a community hospital with new-onset chest pain, after acute myocardial infarction had been excluded. We used 10F transesophageal pacing catheters and a rapid and modified pacing protocol. The PASE results were validated in all patients by coronary angiography performed within 24 h of the test. Significant CAD was defined as > or =75% stenosis in at least one major epicardial coronary artery. RESULTS The sensitivity of PASE for identifying patients with significant CAD was 95%, specificity was 87% and accuracy was 92%. The extent of significant CAD (single- or multivessel disease) was highly concordant with coronary angiography (kappa = 0.73, p<0.001). Pacing stress echocardiography was well tolerated, and only 4% of the patients had minor adverse events. The mean rate-pressure product at peak pacing was 22,313+/-5,357 beats/min per mm Hg, and heart rate >85% of the age-predicted target was achieved in 94% of patients. The average duration of the bedside PASE test, including image interpretation, was 38+/-6 min. CONCLUSIONS Bedside PASE is rapid, tolerable and accurate for identification of significant CAD in patients admitted to the hospital with new-onset chest pain or worsening angina pectoris.

Ultrasound Has Synergistic Effects in Vitro with Tirofiban and Heparin for Thrombus Dissolution

Previous studies have shown synergism between ultrasound and thrombolytic agents or microbubbles on blood clot dissolution. It has not been investigated whether heparin or glycoprotein IIb/IIIa blockers enhance clot lysis by ultrasound. We compared the blood clot dissolution effect of saline, heparin, tissue plasminogen activator (tPA), tirofiban, and an echocardiographic contrast media (Optison) without and with ultrasound application. Human blood clots from four donors, 2 to 4 hours old, were cut into 200- to 400-mg sections, weighed, and immersed for 2 minutes in 1 L of normal saline 0.9% solution containing either heparin 1000 U, tirofiban 150 microg, tPA 20 mg, Optison 0.5 mL, or normal saline alone. Clots were randomized to 2 minutes ultrasound application or immersion alone without ultrasound. Ultrasound was applied with a 19.5 KHz catheter. After treatment, the clots were weighed, and the absolute and percent difference in weight was calculated. Immersion in heparin, tirofiban, and tPA without ultrasound did not augment clot disruption relative to normal saline alone. Immersion in Optison (p = 0.07) tended to result in less lysis than saline alone. Ultrasound enhanced clot dissolution compared to immersion alone with: saline (48.1+/-15.3% vs. 26.0+/-13.8%, p<0.0000002); heparin (60.8+/-17.5% vs. 30.8+/-15.1%, p = 0.000001); tirofiban (61.8+/-13.6% vs. 30.1+/-12.2%, p<0.0000001); tPA (53.1+/-15.3% vs. 30.2+/-11.5%, p<0.000002); and Optison (47.8+/-16.0% vs. 18.4+/-11.5%, p<0.0000001). The combination of tirofiban with ultrasound, as well as heparin with ultrasound, was associated with a significant augmentation of clot dissolution compared with the saline plus ultrasound group (p = 0.002, 0.013, respectively). Ultrasound with tPA or with Optison had no significant augmentation of clot dissolution over the ultrasound + saline effect. This in vitro study of catheter-delivered high-intensity low-frequency ultrasound demonstrates that: (1) tirofiban and heparin, as well as perfluorocarbon microbubbles, augment clot dissolution by ultrasound; (2) augmentation of clot dissolution is evident even after only brief exposure of ultrasound and the drug studied.

Augmentation of in-vitro clot dissolution by low frequency high-intensity ultrasound combined with antiplatelet and antithrombotic drugs

AbstractBackground: Glycoprotein IIb/IIIa antagonists and heparin are increasingly used for treatment of acute coronary syndromes. There is no data on the effect of these drugs on clot dissolution when combined with low frequency high-intensity ultrasonic energy. We examined a possible additive effect of low frequency high-intensity ultrasound with an antithrombotic, an antiplatelet and a fibrinolytic agent alone or in combinations for in vitro blood clot dissolution. Methods: Human blood clots were incubated for 10′, 15′ and 30′ in normal saline containing commonly used concentrations of heparin, tirofiban, t-PA and Optison (echocardiographic contrast agent) alone and in combinations. Clots were then randomly exposed to low frequency high-intensity ultrasound (27[emsp3 ]kHz) for 5 minutes. The percent difference in clot weight and the incremental effect of ultrasound energy were calculated. Results: The most significant additive effect of ultrasound energy was detected with the combination of tirofiban and heparin (39±2% augmentation after 10′ of incubation, p<0.0001). The greatest magnitude of percent clot weight reduction was observed with ultrasound energy combined with either t-PA alone (72±1% after 30′ incubation, p=0.0016) or with the combination of t-PA, tirofiban, heparin and Optison (68±4% after 30′ incubation, p=0.015). Conclusions: Application of low frequency high-intensity ultrasound has an additive effect to antiplatelet, antithrombotic and fibrinolytic drugs, specifically with the combination of tirofiban and heparin or with t-PA; this effect is observed after a short incubation period.

Cooling System Permits Effective Transcutaneous Ultrasound Clot Lysis In Vivo Without Skin Damage

Previous in vivo studies have shown that transcutaneous ultrasound enhances clot dissolution in the presence of either streptokinase or microbubbles. However, ultrasound-induced skin damage has been a major drawback. The objective was to evaluate the effect of a cooling system to prevent the skin damage that has heretofore been associated with transcutaneous low-frequency, high-intensity ultrasound clot dissolution. After thrombi were induced in both iliofemoral arteries in 15 rabbits, streptokinase (25,000 U/kg) was given intravenously and dodecafluoropentane was injected slowly (2 mL/15 min) through an infusion catheter into the abdominal aorta. One iliofemoral artery was randomized to receive ultrasound treatment, and the contralateral artery was treated as a control (receiving streptokinase and dodecafluoropentane alone). In six rabbits (group 1), the skin below the ultrasound transducer was protected by the use of a balloon cooling system, and in the other nine rabbits (group 2), ultrasound was used without a cooling system. Seven of nine (78%) arteries treated without the cooling system, and six of six (100%) arteries treated with the cooling system were angiographically recanalized after ultrasound + streptokinase + dodecafluoropentane treatment. Thermal damage was present in the skin and soft tissues of all nine rabbits treated without a cooling system. However, the skin and soft tissues were grossly and histologically normal in the six rabbits in which the transcutaneous ultrasound was used with the cooling system. Low-frequency, high-intensity ultrasound energy can be delivered transcutaneously for clot dissolution without concomitant tissue damage when coupled with the use of a cooling system to prevent thermal injury.