Thrombus-targeted perfluorocarbon-containing liposomal bubbles for enhancement of ultrasonic thrombolysis: in vitro and in vivo study.

BACKGROUND: External low-frequency ultrasound (USD) in combination with microbubbles has been reported to recanalize thrombotically occluded arteries in animal models. OBJECTIVE: The purpose of this study was to examine the enhancing effect of thrombus-targeted bubble liposomes (BLs) developed for fresh thrombus imaging during ultrasonic thrombolysis. METHODS: In vitro: after the administration of thrombus-targeted BLs or non-targeted BLs, the clot was exposed to low-frequency (27 kHz) USD for 5 min. In vivo: Rabbit iliofemoral arteries were thrombotically occluded, and an intravenous injection of either targeted BLs (n = 22) or non-targeted BLs (n = 22) was delivered. External low-frequency USD (low intensity, 1.4 W cm(-2) , to 12 arteries, and high intensity, 4.0 W cm(-2) , to 10 arteries, for both the targeted BL group and the non-targeted BL group) was applied to the thrombotically occluded arteries for 60 min. In another 10 rabbits, recombinant tissue-type plasminogen activator (rt-PA) was intravenously administered. RESULTS: In vitro: the weight reduction rate of the clot with targeted BLs was significantly higher than that of the clot with non-targeted BLs. In vivo: TIMI grade 3 flow was present in a significantly higher number of rabbits with USD and targeted BLs than rabbits with USD and non-targeted BLs, or with rt-PA monotherapy. High-intensity USD exposure with targeted BLs achieved arterial recanalization in 90% of arteries, and the time to reperfusion was shorter than with rt-PA treatment (targeted BLs, 16.7 ± 5.0 min; rt-PA, 41.3 ± 14.4 min). CONCLUSIONS: Thrombus-targeted BLs developed for USD thrombus imaging enhance ultrasonic disruption of thrombus both in vitro and in vivo.

Aortic valve replacement or heart transplantation in patients with aortic stenosis and severe left ventricular dysfunction.

INTRODUCTION: The decision to perform aortic valve replacement (AVR) or heart transplantation (HTx) for aortic stenosis (AS) with severe left ventricular dysfunction is difficult and may be affected by prior myocardial infarction (MI) and coronary artery disease (CAD). METHODS: Patients who underwent AVR from 1988 to 2001 with left ventricular ejection fraction (LVEF) <30% and severe AS (aortic valve area [AVA] < 1.0 cm(2); n = 51) were assessed for operative mortality, late survival, and predictors of outcome, and were compared with HTx. Subsequently, 131 patients with LVEF ≤ 35% who underwent AVR for critical AS (AVA < 0.8 cm(2)) were evaluated. RESULTS: In the first 51 patients, 3-year survival was 100% ± 0% with no CAD, and 45% ± 10% with CAD (P < .05); 3-year survival was 88% ± 12% with no bypass, 73% ± 12% with one to two grafts, and 18% ± 11% with three grafts (P < .01). Survival with HTx was 78% at 3 years. In the subsequent analysis of 131 patients, 90-day survivors were followed for a mean 4.6 ± 3.5 years. Advanced age (P = .001) was the only predictor of long-term mortality. LVEF improved from 28.5% ± 5.2% before AVR to 45.4% ± 13.2% at 1-month postoperatively (P < .0001). New York Heart Association (NYHA) class III/IV decreased from 94.2% pre-AVR to 12.8% at 1 year (P < .0001). Predictors of LVEF recovery were no previous MI (P = .007) and higher AS gradient (P = .03). CONCLUSIONS: In severe AS and LVEF <30% with no concomitant CAD or with CAD requiring one to two bypass grafts, AVR has a survival equal to or exceeding that of HTx. In patients with CAD requiring more than two bypass grafts, survival is significantly reduced, and HTx can be considered.

Predictors of reduction in mitral regurgitation in patients undergoing cardiac resynchronisation treatment.

BACKGROUND: CRT causes reduction in MR due to left ventricular (LV) remodelling, but determinants of clinically meaningful MR reduction acutely after CRT have not been evaluated. OBJECTIVES: We evaluated echocardiographic predictors of significant reduction in functional mitral regurgitation (MR) by cardiac resynchronisation treatment (CRT). METHODS: 35 patients with >or= moderate to severe MR underwent CRT for presence of electrical and/or mechanical dyssynchrony. Significant reduction in MR post-CRT was defined as reduction to less than moderate MR (MR jet area/left atrial area <25%, group 1) on follow-up echocardiogram at 1.7 (SD 2.8) months post-CRT. RESULTS: Significant MR reduction of 62% (28%) from baseline MR occurred in 18 patients vs 22% (16%) in the remaining patients (group 2), p<0.01). Follow-up left ventricular ejection fraction (LVEF) was 0.43 (0.09) in group 1 patients vs 0.29% (0.1%) in group 2 patients (p<0.001). On multivariate analysis, time to peak strain in the mid inferior segment was the only significant predictor of MR reduction post-CRT (p = 0.008, OR = 1.023 (CI 1.006 to 1.041). The sensitivity and specificity of the combined variable of time to peak strain of >400 ms in the mid inferior segment and peak negative strain of >or=9% and 8% in the basal and mid posterior segments, respectively, to predict follow-up MR was 88% and 93% respectively and positive and negative predictive value was 94% and 87%. CONCLUSION: In patients with cardiomyopathy and significant MR, the presence of delayed longitudinal strain in the mid inferior LV segment along with preserved negative systolic strain in the basal and mid posterior segments predicts substantial reduction in MR post-CRT.

Mitral annular calcification: a marker of severe coronary artery disease in patients under 65 years old.

BACKGROUND: Mitral annular calcification has been associated with various systemic and cardiac diseases, with a higher prevalence in women and patients over 70. A possible association between mitral annular calcification and coronary artery disease has recently been suggested. OBJECTIVE: To determine the prevalence of severe coronary artery disease in younger patients with mitral annular calcification. METHODS: Consecutive patients aged or= 70% stenosis of at least one major epicardial coronary artery. PATIENTS: 17 735 patients were screened. Of these, 6207 (35%) had mitral annular calcification and 885 (5%) were also

Comparison of myocardial tissue Doppler with transmitral flow Doppler in left ventricular hypertrophy.

We sought to determine the most useful echocardiographic measurements for assessment of diastolic function in patients with left ventricular hypertrophy (LVH) and normal systolic function. We compared myocardial Doppler velocities of the basal inferoposterior wall with mitral inflow pulsed wave Doppler velocities in 11 healthy volunteers (age, 36 +/- 6 years), 25 patients (age, 64 +/- 14 years) without LVH, and 37 patients (age, 67 +/- 14 years) with LVH and otherwise normal echocardiograms. The discriminatory measurements were myocardial A-wave duration (120 +/- 18 versus 98 +/- 20 and 92 +/- 12 ms, P <.0001), myocardial isovolumetric relaxation time (124 +/- 45 versus 95 +/- 48 and 78 +/- 25 ms, P =.0035), mitral A-wave velocity (0.98 +/- 0.37 versus 0.73 +/- 0.28 m/s and 0.61 +/- 0.22 m/s, P =.009), and mitral E-wave deceleration time (257 +/- 93 versus 201 +/- 85 ms and 184 +/- 83 ms, P =.015), which were significantly increased, and myocardial E-wave velocity (0.84 +/- 0.04 m/s versus 0.13 +/- 0.03 m/s and 0.14 +/- 0.03 m/s, P <.0001), which was significantly decreased, in patients with LVH compared with patients without LVH and normal volunteers, respectively. Left ventricular posterior wall thickness correlated with myocardial isovolumetric relaxation time (r = 0.52, P <.0001) and myocardial A-wave duration (r = 0.59, P <.0001), negatively with myocardial E wave (r = -0.43, P <.0001), and showed no correlation with mitral inflow parameters except mitral inflow A wave (r = 0.43, P =.002). On multivariate analysis using these variables, myocardial isovolumetric relaxation time (P =.0014) and A-wave duration (P =.001) were the only 2 variables that correlated with posterior wall thickness (multiple R = 0.71). In the presence of LVH and preserved left ventricular systolic function, myocardial relaxation time and velocities are more sensitive than mitral Doppler inflow parameters in detecting abnormal left ventricular relaxation.

Association of mitral annulus calcification, aortic valve sclerosis and aortic root calcification with abnormal myocardial perfusion single photon emission tomography in subjects age < or =65 years old.

OBJECTIVES: We examined the hypothesis that mitral annulus calcification (MAC), aortic valve sclerosis (AVS) and aortic root calcification (ARC) are associated with coronary artery disease (CAD) in subjects age < or =65 years. BACKGROUND: Mitral annulus calcification, AVS and ARC frequently coexist and are associated with coronary risk factors and CAD in the elderly. METHODS: We studied 338 subjects age < or =65 years who underwent evaluation of chest pain with myocardial perfusion single photon emission computed tomography (SPECT) and a two-dimensional transthoracic echocardiogram for other indications. The association of MAC, AVS and ARC with abnormal SPECT was evaluated by using chi-square analyses and logistic regression analyses. RESULTS: Compared with no or one calcium deposit and no or one coronary risk factor other than diabetes, multiple (> or =2) calcium (or sclerosis) deposits with diabetes or multiple (> or =2) coronary risk factors were significantly associated with abnormal SPECT in women age < or =55 years old (odds ratio [OR], 20.00), in women age >55 years old (OR, 10.00) and in men age < or =55 years old (OR, 5.55). Multivariate analyses identified multiple calcium deposits as a significant predictor for an abnormal SPECT in women (p < 0.001), younger subjects age < or =55 years (p < 0.05) and the total group of subjects (p < 0.01). CONCLUSIONS: When coronary risk factors are also taken into consideration, the presence of multiple calcium deposits in the mitral annulus, aortic valve or aortic root appears to be a marker of CAD in men < or =55 years old and women.

Aortic root dilatation in patients with emphysema.

BACKGROUND: Abdominal aortic aneurysms have been recognized to occur more frequently in patients with emphysema. However, the prevalence of aortic root dilatation in patients with emphysema and its relationship to risk factors for aortic enlargement have not been previously described. METHODS: We studied 47 patients, past smokers (aged 67 +/- 6 years, 18 women) with severe emphysema diagnosed by a pulmonary function test and an ultrafast computed tomographic scan. Two-dimensional echocardiography was used to measure the aortic root at the aortic annulus, sinus of Valsalva, sinotubular junction and proximal part of the ascending aorta. Measured mean values were compared with published normal values and age- and sex-matched patients without emphysema. The relationship between aortic root size and cardiac risk factors (hypertension, hypercholesterolemia, and diabetes) was also examined. RESULTS: In patients with emphysema the mean aortic root dimensions were significantly larger than normal values at each measured site (P <.0001) and those of patients without emphysema (P <.05 to.0001). A substantial percentage of patients with emphysema had larger sinus of Valsalva (43%) and proximal ascending aorta (59%) than the upper limit of normal. In the multivariable regression model, emphysema was a significant determinant of aortic root size at all measured sites and hypertension was associated with additional dilatation at the sinus of Valsalva, sinotubular junction, and proximal ascending aorta. CONCLUSIONS: (1) In patients with emphysema the aortic root dimension is significantly larger than in patients without emphysema. (2) Systemic hypertension is associated with additional enlargement of the proximal ascending aorta, the sinus of Valsalva, and the sinotubular junction.

The effects of streptokinase and hydroxyethyl starch on in vitro clot disruption by ultrasound.

BACKGROUND: In vitro studies showed that low-frequency ultrasound (US) causes blood clot dissolution. This effect is augmented with thrombolytics, microbubbles and microparticles. However, in animal models of transcutaneous delivery, US alone is not effective, probably due to attenuation of US energy by overlying skin. When combined with thrombolytics or microbubbles, transcutaneous US is highly effective. PURPOSE: To assess the synergistic effect of low-intensity low-frequency US and saline, hydroxyethyl starch (HAES) (a non-gas filled microparticle containing solution), streptokinase (STK), and their combination on blood clot disruption. METHODS: Human blood clots from 4 healthy donors, 2-4 hours old, were immersed for 0, 15, or 30 min in 37 degrees C in 10 ml of the above-mentioned solutions, and then were randomized to 10 sec of 20 kHz US or no US. The % difference in weight was calculated. RESULTS: Immersion for 30 min without US resulted in 13.8 +/- 1.2% clot lysis in saline, and 22.0 +/- 1.3%, 21.7 +/- 2.1%, and 23.2 +/- 1.9% in STK, HAES, and STK + HAES, respectively (p = 0.002). US augmented clot lysis in all groups and at all time points. With low-intensity US, HAES was not better than saline. However, the combination of HAES + STK with US resulted in larger clot disruption at 15 sec incubation time (46.7 +/- 3.2%) than with saline (29.6 +/- 2.1%), HAES (29.6 +/- 2.5%), and STK (32.8 +/- 3.6%) (p < 0.001). CONCLUSION: low-frequency, low-intensity US combined with HAES and STK resulted in greater clot disruption at short incubation times. This combination may assist in achieving faster reperfusion in in vivo models.

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

BACKGROUND: 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.

Noninvasive transthoracic low frequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction--evaluation of the extent of ST-segment resolution.

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.

Myocardial Doppler tissue imaging: findings in inferior myocardial infarction and left ventricular hypertrophy--wall motion assessment.

BACKGROUND: Because of the geometry of the basal inferior wall and its relation with the posterior medial papillary muscle, differentiating abnormal from normal basal inferior wall motion can be challenging. METHODS: We performed pulsed wave Doppler echocardiography of the basal inferior wall and basal interventricular septum in 26 patients (63 +/- 14 years) with a normal echocardiogram, 33 patients (67 +/- 14 years) with inferior myocardial infarction (MI) associated with hypokinesis to dyskinesis of the basal inferior wall, and 38 patients (67 +/- 14 years) with left ventricular hypertrophy (LVH). RESULTS: Systolic velocity was significantly lower in the basal interventricular septum (0.071 +/- 0.013 m/s versus 0.084 +/- 0.023 m/s) and basal inferior wall (0.075 +/- 0.014 m/s versus 0.085 +/- 0.019 m/s) in the MI group compared with the LVH group, and both were significantly lower compared with normal values at the interventricular septum (0.090 +/- 0.023 m/s, P <.001, analysis of variance) and basal inferior wall (0.095 +/- 0.014 m/s, P <.0001, analysis of variance). The sum of the systolic (S), early diastolic (E'), and late diastolic (A') velocities of 0.30 m/s at the basal inferior wall had 91%, 76%, and 84% sensitivity, specificity, and accuracy, respectively, for the differentiation of a normal wall from an infarcted basal inferior wall, and 76%, 73%, and 75% sensitivity, specificity, and accuracy, respectively, for the differentiation of a normal wall from a hypertrophied basal inferior wall. The sum of systolic and diastolic velocities of 0.25 m/s at the basal interventricular septum had 70%, 66%, and 68% sensitivity, specificity, and accuracy, respectively, for the differentiation of an infarcted from a hypertrophied basal interventricular septum. Mitral inflow early-filling wave deceleration time by pulsed wave Doppler was the most sensitive parameter for the differentiation of LVH from MI (P <.0001). CONCLUSION: Doppler tissue imaging velocities of the basal inferior wall and basal interventricular septum may help differentiate normal from infarcted and hypertrophied myocardium.

There is synergism between high-intensity, low-frequency ultrasound and streptokinase but not with eptifibatide, heparin, and aspirin. Differential effects on fresh and aged blood clots. An in vitro study.

OBJECTIVE: Ultrasound is emerging as a promising modality for recanalization of acutely thrombosed blood vessels, especially when associated with fibrinolytics. We assessed the efficacy of ultrasound combined with saline, heparin, eptifibatide, aspirin, and streptokinase in disruption of fresh as well as aged human blood clots, using an in vitro model. METHODS: Blood clots from five donors, 2-4 or 48 hours old, were cut into 250-400 mg slices and immersed for 1, 15, or 30 min in 10 ml saline containing either heparin, eptifibatide, aspirin, streptokinase, or saline alone. Clots were then randomized to 10 s of 20 kHz ultrasound or immersion alone. After treatment, the percentage difference in weight was calculated. RESULTS: Immersion of fresh clots without ultrasound in eptifibatide and heparin resulted in significantly more clot lysis than immersion in saline, aspirin, and streptokinase. Immersion of aged thrombi without ultrasound in heparin, eptifibatide, and aspirin had no additive effect over immersion in saline. Ultrasound enhanced clot disruption in all five solutions, in each immersion time and both in fresh and aged clots. Heparin and aspirin had no additive effect, compared with saline, on ultrasound disruption of both fresh and aged clots, whereas eptifibatide was less effective than saline. In contrast, streptokinase greatly enhanced disruption of both fresh (P=.004) and aged (P<.001) thrombi by ultrasound. The combinations of ultrasound with saline, heparin, eptifibatide, and aspirin were less effective on aged than fresh thrombi, whereas the combination of ultrasound with streptokinase was equally effective on fresh and aged thrombi. CONCLUSIONS: Using a simple in vitro model, we found that the combination of streptokinase and low-frequency ultrasound had a synergistic effect on disruption of both fresh and aged blood clots. Further studies are needed to assess the role of heparin and antiplatelet agents in augmenting clot disruption by ultrasound in in vivo models of acute and subacute thrombosis.

Arterial thrombus dissolution in vivo using a transducer-tipped, high-frequency ultrasound catheter and local low-dose urokinase delivery.

PURPOSE: To examine the hypothesis that a transducer-tipped high-frequency ultrasound drug-delivery catheter may augment the thrombolytic effects of locally delivered low-dose urokinase and result in improved recanalization rates and reduced residual thrombotic burden. METHODS: Thrombi were induced in situ bilaterally in 5- to 6-cm-long segments of the superficial femoral arteries in 9 dogs by intraluminal thermal damage and injection of thrombin. A transducer-tipped high-frequency local drug-delivery catheter was applied at 1.1 MHz and 0.6 W for 60 minutes to one superficial femoral artery segment, and an identical catheter with an inactivated ultrasound transducer was used to treat the contralateral control segment. Urokinase (5000 IU/kg) was delivered bilaterally into the thrombi during the treatment interval. RESULTS: Angiography documented TIMI grade 2 or 3 flow in 9 (100%) segments in the ultrasound-treated group versus 6 (67%) of the controls (no ultrasound) (p = 0.058). Angiographically detected distal embolization was found in 2 ultrasound-treated segments compared with 5 controls (p = 0.02). Protruding or occlusive thrombi were seen angioscopically in 8 (89%) control segments but in only 1 (11%) of the ultrasound-treated arteries (p < 0.001). By histopathology, 7 (78%) segments in the control group had occlusive thrombi, whereas only 3 nonocclusive thrombi were found in the ultrasound-treatment group (p < 0.001). CONCLUSIONS: Catheter-delivered high-frequency ultrasound and local low-dose urokinase infusion is efficacious for the treatment of acute thrombotic occlusions as evaluated by angiography, angioscopy, and histopathology.

Milrinone echocardiographic viability test: a pilot study.

We assessed the utility of milrinone to predict recovery of function after surgical myocardial revascularization in patients with severe baseline left ventricular systolic dysfunction caused by coronary artery disease (CAD). Prediction of viable myocardial segments that will regain function after revascularization may help in the selection of patients who will benefit from coronary artery bypass graft surgery (CABG) as well as aid in the choice of target sites for coronary revascularization. We investigated 20 consecutive patients with CAD and left ventricular ejection fraction < or = 40% who had evidence of myocardial viability by either thallium scan or dobutamine viability test and were candidates for elective CABG. Left ventricular regional wall motion and global ejection fraction were assessed by transesophageal echocardiography in the operating room. Measurements were done before and 10 minutes after milrinone infusion, and immediately after CABG. Left ventricular wall motion score was derived by means of a 12-segment model. Functional improvement for each segment was defined as a wall motion change > 1. Baseline ejection fraction was 27% +/- 5% (mean +/- SD). Ejection fraction increased to 35% +/- 5% after milrinone infusion (P < .0001) and to 36% +/- 6% after CABG (P < .0001). Post-CABG ejection fraction was significantly correlated with postmilrinone ejection fraction (r = 0.65, P < .0001). Milrinone infusion resulted in augmentation of contraction in 98 of the 209 abnormal segments (wall motion score > or = 2); 91 (92.9%) of these improved after CABG. One hundred nine of the 111 segments that showed no improvement with milrinone did not improve after revascularization (98.2%). Seventy-three segments were akinetic or dyskinetic at baseline; 46 (63.0%) of these improved with milrinone. Improvement in regional wall motion after revascularization was detected in 84.8% of the segments that improved with milrinone versus only 3.7% of the segments that did not improve with milrinone. In patients with ischemic cardiomyopathy, improvement in left ventricular function (segmental wall motion and global ejection fraction) during milrinone infusion is highly predictive of improvement after CABG.

Ultrasound as treatment for coronary artery disease.

Therapeutic ultrasound is already established in the treatment of diverse surgical conditions, such as cataract, liver cancer, and stones, without danger to healthy tissue. Clinical trials of catheter-delivered, high energy, low frequency (kHz) ultrasound undertaken over the last decade have demonstrated the safety of ultrasound in the treatment of peripheral and coronary artery disease, and have identified a number of indications in which it may be particularly advantageous. The dispersal of thrombus, the recanalization of chronic total occlusions, and the favorable modification of the distensibility of small, atherosclerotic vessels are three promising areas. The authors review developments in these fields.

The use of transducer-tipped ultrasound catheter for recanalization of thrombotic arterial occlusions.

Ultrasound energy is currently being used and intensively investigated for recanalization of thrombotically occluded arteries. The ultrasonic energy is mainly applied either by a transcutaneous approach or by a percutaneous approach through a catheter with an external ultrasound transducer. Catheter-delivered transducer-tipped ultrasound thrombolysis is a new and innovative method. In this article we summarize the current available data on the use of this new type of catheter and discuss future directions and clinical applications.

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 < or = 0.0036) and streptokinase alone (6%; P < or = 0.0012). Also, with transcutaneous ultrasound and microbubbles, the angiographic patency rates were 76%-100% as compared with ultrasound alone (0%, P < or = 0.0003) or microbubbles alone (9%, P < or = 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.