(Circulation. 2000;101:2296.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Effect of 40-kHz Ultrasound on Acute Thrombotic Ischemia in a Rabbit Femoral Artery Thrombosis Model
Enhancement of Thrombolysis and Improvement in Capillary Muscle Perfusion
From the Vascular Medicine Unit, Department of Medicine, and Division of Laboratory Animal Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Correspondence to Charles W. Francis, MD, Vascular Medicine Unit, PO Box 610, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. E-mail charles_francis{at}urmc.rochester.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—We have shown previously that 40-kHz ultrasound (US) at low intensity accelerates fibrinolysis in vitro with little heating and good tissue penetration. These studies have now been extended to examine the effects of 40-kHz US on thrombolysis and tissue perfusion in a rabbit model.
Methods and Results—Treatment was administered with either US alone at 0.75 W/cm2, streptokinase alone, or the combination of US and streptokinase. US or streptokinase resulted in minimal thrombolysis, but reperfusion was nearly complete with the combination after 120 minutes. US also reversed the ischemia in nonperfused muscle in the absence of arterial flow. Tissue perfusion decreased after thrombosis from 13.7±0.2 to 6.6±0.8 U and then declined further to 4.5±0.4 U after 240 minutes. US improved perfusion to 10.6±0.5 and 12.1±0.5 U after 30 and 60 minutes, respectively. This effect was reversible and declined to pretreatment values after US was discontinued. Similarly, tissue pH declined from normal to 7.05±0.02 after thrombosis, but US improved pH to 7.34±0.03 after 60 minutes. US-induced improvement in tissue perfusion and pH also occurred after femoral artery ligation, indicating that thrombolysis did not cause these effects.
Conclusions—40-kHz US at low intensity markedly accelerates fibrinolysis and also improves tissue perfusion and reverses acidosis, effects that would be beneficial in treatment of acute thrombosis.
Key Words: ultrasonics • thrombolysis • tissue • perfusion • streptokinase • thrombosis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The expanding use of fibrinolytic therapy has resulted in improved outcomes in patients with myocardial infarction and peripheral vascular disease and the promise of reduced disability after stroke. These advances have also focused attention on the limitations of therapy and have stimulated efforts to improve effectiveness and decrease adverse effects. Thus, in patients with acute myocardial infarction, up to 20% do not achieve reperfusion, and the benefit decreases with longer periods of ischemia, emphasizing the need for rapidly acting therapy. For stroke, the need for very early treatment and the serious consequences of intracranial bleeding limit application. Problems with treatment of peripheral artery occlusion include the need for proper catheter replacement, a longer duration of treatment, and a requirement for subsequent endovascular or surgical reconstruction in most patients. Its limited use for venous thromboembolic disease reflects the high incidence of therapeutic failure and lower benefit-to-risk ratio. Efforts to overcome these obstacles have focused on development of new plasminogen activators, more effective dosing regimens, and adjunctive antiplatelet and anticoagulant therapy.
The use of ultrasound (US) represents a completely different,
nonpharmacological approach to improving fibrinolytic therapy and
offers unique potential to increase reperfusion and limit bleeding
complications. Several reports have shown marked acceleration of
fibrinolysis with low-intensity US in
vitro1 2 3 4 5 and in animal models.6 7 8 9 10
Miniaturized transducers have also been attached to catheters for
endovascular use,11 12 13 and this offers the potential to
deliver localized US at the site of thrombosis while limiting
insonification of normal tissue. The choice of US frequency is critical
for successful clinical application, because it influences both
efficacy and safety. Early studies used frequencies of 
500 kHz, but
poor tissue penetration and unacceptable heating were limiting. These
problems are smaller at lower frequencies, and we recently showed that
the enhancement of thrombolysis in vitro is greater at
40 kHz than at 1 MHz.5 In the present study,
therefore, we have extended these observations to a model of rabbit
femoral artery thrombosis. The findings indicate that 40-kHz US
accelerates thrombolysis, with little evidence of
tissue injury and minimal heating, and also improves tissue perfusion
and metabolism independent of clot lysis.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Preparation
Rabbits were anesthetized with ketamine 60 mg/kg, xylazine 6 mg/kg, and chlorpromazine 25 mg/kg, and sedation was maintained with sodium pentobarbital as needed. The femoral arteries were dissected 5 cm distal to the origin of the superficial branch, and the profunda femoris and superficial arteries were ligated close to their origin. A Doppler flow probe was placed distally around the isolated segment, and 2 parallel ligatures were placed around the femoral artery 1 cm distal to the profunda branch. These reduced flow by
50% and remained in place for the duration of the experiment.
After this, filter paper saturated with 20% ferric chloride was placed
on the femoral artery, and thrombosis was assessed by monitoring of
flow, which approached 0 after occlusion. In some animals, a completely
occlusive suture was placed around the artery.
Experimental Protocol
Rabbits received (1) US alone, (2) streptokinase alone, (3) both
US and streptokinase, or (4) no treatment. There were 7, 6, 6, and 9
rabbits in groups 1, 2, 3, and 4, respectively. The source of US was a
3.5-cm-diameter probe with a 1-cm-diameter transducer driven in
continuous mode at 0.75 W/cm2, and acoustic
pressures were measured before and after each experiment with a
hydrophone. A balloon filled with water at 37°C was placed over the
thrombosed segment for temperature control and US transduction. The
interface between the balloon and the artery was covered by a layer of
US transmission gel. Streptokinase was administered as an
intravenous bolus of 15 000 U/kg, followed by an infusion
of 15 000 U · kg-1 ·
h-1 for 2 hours. This dose was selected because
our previous experience with this model indicated that it was
relatively ineffective alone and that 1-MHz US enhanced its
effects,8 and data in vitro indicated that 40-kHz US had a
greater effect on thrombolysis than 1
MHz.5 The pH of the muscle was also monitored with a pH
meter (model HI 9023C, Hanna Instruments). Perfusion in the gracilis
muscle was measured with a laser-Doppler flowmeter (BFL 21,
Transonic Systems) with an output in units (TPU) that is linearly
related to the number of red cells times their velocity in the
hemispheric measuring volume.14 The measuring surface was
1 mm2, and the light penetration depth was
1 mm.
Temperature monitoring in 4 rabbits was performed with a copper-constantan fine-wire thermocouple placed under the femoral artery or on the exposed surface of the femur and connected to a temperature gauge. To assess the effects of heating on tissue perfusion, a balloon containing water at 32°C to 42°C was laid over the gracilis muscle. At the completion of each experiment, animals were euthanized, and samples for histology were excised and fixed in 10% buffered formalin. Specimens were processed in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin. The stained sections were encoded to obscure treatment and examined by an observer (R.B.B.) blinded as to code.
Statistical Methods
The 3 primary outcome measures that were used to assess the
effect of US were flow intensity, TPU, and pH. The mixed linear model
was used for statistical analysis of each of the primary
measures. The responses were grouped into clusters by the individual
animal (random effect) and were treated as repeated measurements taken
over time and/or at different distances. On the basis of these models,
the least-squares means, their standard errors, and covariances
were calculated, and the adjusted differences between treatment means
at different time points were obtained. They were used for testing for
treatment effect as well as for effect sizes for each level of grouping
variables.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Occlusive thrombi formed in all femoral arteries within 20 to 30 minutes of placement of the constriction and application of 20% ferric chloride. Arterial flow was 12.0±0.7 mL/min at baseline, declined to 5.8±0.4 mL/min after placement of the constriction, and was 0.1±0.1 mL/min after thrombosis. Three different treatment regimens were administered after thrombosis: US alone, streptokinase alone, or the combination of streptokinase and US. Flow in control vessels receiving no treatment remained at near 0 after 30, 60, and 120 minutes (Figure 1
). Treatment with US
alone resulted in no significant increase in flow, whereas treatment
with streptokinase alone resulted in a small but significantly
increased flow at 120 minutes to 0.4±0.1 mL/min (P<0.001).
The combination of streptokinase and US resulted in greater
reperfusion, with flow of 2.6±0.7 mL/min at 30 minutes, 4.6±0.4
mL/min at 60 minutes, and 4.8±0.6 mL/min at 120 minutes. The
120-minute flow represented 83% of the flow of 5.8±0.4
mL/min after placement of the external constrictor but before
thrombosis. These results indicate that the application of US markedly
accelerates arterial reperfusion compared with
streptokinase alone and that US by itself had no appreciable
effect.
|
US application can cause heating, and temperature was monitored with a
thermocouple placed adjacent to the thrombosed vessel or at the surface
of the femur. With application of US, the average initial temperature
increase at the femoral artery was 0.02°C/min, and it was
0.04°C/min at the surface of the femur. The maximum temperature
increase after 60 minutes was 1.6±1.3°C at the femoral artery and
1.1±0.7°C at the femur. Histologically, examination
showed that vessels exposed to US, regardless of other treatment
components (streptokinase, ligation, clot), had a pronounced tendency
toward endothelial cell vacuolization, and some cells
lifted up off the underlying basement membrane (Figure 2). Occasionally, erythrocytes were seen
in direct contact with the basement membrane.
|
During these experiments, we observed that muscle adjacent to the
femoral artery lost its normal pink, vital color soon after thrombosis
and became a brownish-purple. Application of US restored the normal
pink color even when no thrombolysis occurred and
femoral artery flow remained near zero. Therefore, we characterized
perfusion in the gracilis muscle using a probe that is sensitive to
capillary blood flow (Figure 3). In
control experiments, tissue perfusion was stable for periods up to 60
minutes, indicating that application of the unactivated probe
by itself did not affect tissue perfusion. At baseline, before
vessel constriction or thrombosis, capillary perfusion was 13.7±0.4 U
(Figure 4A). This declined to 6.8±0.4 U
immediately after thrombosis and then declined progressively to
4.5±0.4 U after 240 minutes in animals receiving no treatment. The
application of US resulted in a significant increase in perfusion to
10.0±0.5 U at 30 minutes and a further increase to 12.1±0.5 U at 60
minutes (P<0.001 for both). To determine whether the effect
of US was reversible, the transducer was switched off at 60 minutes,
and perfusion then declined progressively to 9.7±0.2 U at 90 minutes
and to 8.5±0.2 U at 120 minutes (P<0.001 for both in
comparison with 60 minutes). At 120 minutes, the transducer was
reactivated, and this resulted again in improved perfusion to
11.8±0.8 U at 150 minutes and 12.7±0.4 U at 180 minutes
(P<0.001 for both compared with 120 minutes). When the
transducer was switched off at 180 minutes, perfusion again declined
and reached 8.2±0.8 U at 240 minutes. The Doppler flow probe
placed distally on the artery showed no flow for the duration of the
experiment. The same changes were observed when the vessel was ligated
completely with sutures to preclude any change in femoral artery flow.
Because tissue perfusion is sensitive to temperature, we investigated
whether US-induced heating could explain the changes. Muscle was heated
from 32°C to 42°C by use of warm water in a balloon, and TPU
increased from 6.2 to 7.2 U over this temperature range. Because the
maximum temperature increase with US was <2°C, heating alone could
not account for the US-induced increase in perfusion in the
ischemic area.
|
|
We hypothesized that the increased tissue perfusion after application
of US would improve the metabolism of ischemic
muscle and ameliorate acidosis, and this was investigated with a
similar experimental design with a pH probe (Figure 4B
). After
surgical exposure but before thrombosis, the baseline muscle pH was
7.41±0.02, but this declined to 7.05±0.02 after thrombotic occlusion.
In the absence of treatment, pH declined slowly but progressively to
reach 6.86±0.02 at 240 minutes. The application of US reversed the
acidosis, and muscle pH increased significantly to 7.31±0.02 after 30
minutes and to 7.34±0.03 after 60 minutes (P<0.001 for
both). At 60 minutes, the US was turned off, and muscle pH declined to
7.17±0.01 at 90 minutes and then showed little change to 7.16±0.02 at
120 minutes. The transducer was then turned on, and pH again improved
to 7.32±0.02 at 150 minutes and 7.30±0.03 at 180 minutes. At this
time, the transducer was again turned off, and pH declined to
7.13±0.04 at 210 minutes. The differences between means were all
significant (P<0.001).
To determine whether the effect of US on tissue perfusion and pH was
limited to the insonified tissue, measurements were made at multiple
locations laterally and distally during insonification (Figure 5A). Perfusion measured from the center
of the transducer to 4 cm distally at baseline was between 12.4 and
13.6 U, and after thrombosis it decreased to between 6.3 and 6.5 U.
Perfusion measurements were then made after application of US for 30
and 60 minutes. At 0 cm (Figure 5A), perfusion increased to
11.1±0.5 U at 30 minutes and further to 14.0±0.6 U at 60 minutes. The
effect declined at sites distal from the center of the transducer. This
was most evident at 60 minutes, with values of 12.1±0.4, 8.3±0.3,
6.0±0.3, and 5.3±0.3 at 1, 2, 3, and 4 cm, respectively. The readings
at 3 and 4 cm were the same as those in control animals not exposed to
US. Because the diameter of the transducer was 1 cm, these findings
suggest that the US effect is limited to the insonified tissue. In
other experiments, the transducer was applied at sites 1, 2, 3, and 4
cm distally. Insonification at these sites resulted in normalization of
TPU, indicating that the effect could be induced at these sites but
required direct US exposure.
|
Similar experiments were performed measuring muscle pH (Figure 5B). At baseline and before thrombosis, muscle pH was between
7.36 and 7.42 within the 4-cm area. This declined to between 7.03 and
7.08 after thrombus formation. US application improved tissue pH at the
center of the transducer to 7.34±0.04 at 30 minutes and to 7.39±0.07
U at 60 minutes. As with perfusion (Figure 5A), the effect was
limited to the insonified area, and muscle pH at 3 and 4 cm was not
improved during insonification.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The results demonstrate that application of 40-kHz US at 0.75 W/cm2 greatly accelerates thrombolysis in a rabbit femoral artery thrombosis model. Streptokinase was chosen as the plasminogen activator for the study because the rabbit is relatively resistant to this activator, primarily as a result of slower activation of plasminogen to plasmin.15 This was confirmed by our findings showing <0.5 mL/min flow after 120 minutes of therapy with streptokinase alone (Figure 1
). US by itself resulted in no significant reperfusion,
but the combination of both US and streptokinase had a marked effect by
30 minutes, with restoration of flow to 83% of baseline by 120
minutes. The femoral artery thrombosis model was modified for these
experiments to avoid any endovascular instrumentation or injury to the
endothelium, and no injection of procoagulant was used.
Instead, thrombosis was induced by application of ferric chloride
externally. This avoided the possibility of injecting air into the
vessel, which would increase the potential for cavitation and possibly
increase the US effect artifactually. Therefore, clot lysis resulted
only from the interaction of plasminogen
activator and US with the thrombus. The magnitude of the US
effect appears to be greater than that previously demonstrated with a
similar model at 1 MHz,2 and this is consistent
with the demonstration of greater acceleration of
fibrinolysis in vitro with 40 kHz than with 1
MHz.5 The mechanism(s) by which US accelerates thrombolysis is complex. Transport of plasminogen activator into a thrombus is rate-limiting, because flow is obstructed.16 Drug access by diffusion is very slow, but previous studies in a static system have shown that US increases clot uptake of activator and results in greater depth of penetration.17 US also increases pressure-mediated perfusion through a fibrin matrix,18 and both of these effects would increase drug delivery and accelerate fibrinolysis. In addition, US reversibly alters fibrin fiber structure, generating a larger number of thinner fibers,19 and this may contribute to changes in equilibrium binding of activator to fibrin.20 The physical mechanism by which US accelerates fibrinolysis is nonthermal, and the ability of stabilized microbubbles to augment the effect21 suggests that cavitation plays a role, possibly by increasing fluid motion and thereby drug transport.
Previous reports have shown that US can accelerate fibrinolysis in vivo, but they differ from our findings in several respects. In some reports, thrombi were mechanically disrupted in vitro22 23 or in animal models23 24 with wires vibrating at US frequencies in the absence of plasminogen activator, and this approach has been tested in small studies in patients with coronary25 or peripheral26 27 arterial occlusion and with occluded coronary bypass grafts.28 This treatment requires endovascular positioning of the wire, and it can result in vessel wall damage, excessive heating, and distal embolization of clot fragments. Externally applied high-intensity US alone without plasminogen activator at 20 kHz has been used to recanalize femoral artery thrombi in a rabbit model, but excessive heating also occurred.21
In considering therapeutic application, the choice of US frequency is
of particular importance, because tissue penetration declines and
heating increases at higher frequencies. We have previously
demonstrated excellent transmission of US through bone at 40
kHz,5 and others have demonstrated that
40-kHz29 and 211.5-kHz30 US transmitted
through the skull can accelerate fibrinolysis in vitro.
Toxicity from US can result from heating or from the effects of
cavitation, but we found little evidence of adverse effects in our
study. Heating of <2°C at the bone surface would be of little
clinical consequence, and the endothelial changes
observed histologically (Figure 2) are similar
to those observed previously at 1 MHz8 and are likely to
be reversible. In those experiments, there was also evidence of
US-induced accumulation of platelets on the thrombus,8
a change that was not seen in the present experiments.
Femoral artery thrombosis results in distal muscle ischemia and
metabolic changes, including acidosis. In the experiments
reported, muscle perfusion was measured with a probe sensitive to
movement of red blood cells to a depth of 1 mm in the regional
microcirculation.31 Unexpectedly, the application of US
improved tissue perfusion, and this resulted in reversal of acidosis.
Although the laser-Doppler measurement is limited to 1 mm in
depth, the prolonged duration of the US effect accompanied by
normalization of tissue pH and muscle color suggests that it was more
general. This occurred without clot lysis and was observed even when
the vessel was completely ligated, indicating that reperfusion with
flow through the femoral artery was not the explanation. The improved
perfusion was reversible, and the effect was limited to the insonified
area, with no discernible increase in perfusion either distally or
laterally. The proximal leg muscles receive their primary blood supply
from the femoral artery, and occlusion reduced perfusion to 50% of
baseline, but the residual perfusion after occlusion indicates that an
alternative arterial supply provided collateral flow. The
US-induced increase in perfusion in the absence of femoral artery flow
suggests that arterial supply through these collateral
vessels increased.
The mechanism of improved perfusion is unclear, but redistribution of collateral flow into the ischemic area may be modulated by neural or hormonal influences. Humoral mediators of vasomotor tone include endothelin, prostacyclin, and nitric oxide. The local secretion of nitric oxide is regulated by nitric oxide synthase, an enzyme that can be induced by mechanical stress on endothelial cells32 33 that could result from US. Thus, we hypothesize that nitric oxide–induced redistribution of flow may account for the effects of US, but further studies will be necessary to elucidate the physiological mechanisms. Therapeutic application will require careful attention to limiting application of US only to ischemic tissue, because inappropriate insonification to adjacent nonischemic tissues could result in redistribution of flow away from ischemic tissue, thereby extending ischemia.
Both the accelerated clot lysis and the increased tissue perfusion resulting from US have the potential to improve clinical outcomes with fibrinolytic therapy. Rapid reversal of tissue ischemia is essential in preventing myocardial necrosis and, in particular, neuronal loss with stroke. This could be achieved either through removal of the arterial obstruction or by an increased flow to the ischemic area through collateral vessels. The accelerated clot lysis with US offers the potential to accelerate clot dissolution and speed reperfusion, thereby preserving ischemic tissue. Alternatively, US could be used to achieve an equivalent rate of clot lysis with a lower concentration of plasminogen activator to reduce bleeding complications. The augmentation of collateral flow offers a new approach to increasing perfusion of ischemic tissue and limiting dysfunction and necrosis.
|
Acknowledgments |
|---|
This work was supported in part by grant HL-30616 from the NHLBI, NIH, Bethesda, Md, and by a Grant-in-Aid from the American Heart Association. We appreciate the statistical assistance provided by Vladimir Dragalin and the secretarial assistance of Carol Weed.
Received July 30, 1999; revision received December 9, 1999; accepted December 22, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lauer CG, Burge R, Tang DB, et al. Effect of ultrasound on tissue-type plasminogen activator–induced thrombolysis. Circulation. 1992;86:1257–1264.
2. Francis CW, Önundarson PT, Carstensen EL, et al. Enhancement of fibrinolysis in vitro by ultrasound. J Clin Invest. 1992;90:2063–2068.
3. Luo H, Steffen W, Cercek B, et al. Enhancement of thrombolysis by external ultrasound. Am Heart J. 1993;1125:1564–1569.
4. Tachibana K. Enhancement of fibrinolysis with ultrasound energy. J Vasc Interv Radiol. 1992;3:299–303.[Medline] [Order article via Infotrieve]
5.
Suchkova V, Siddiqi FN, Carstensen EL, et al.
Enhancement of fibrinolysis with 40-kHz ultrasound.
Circulation. 1998;98:1030–1035.
6. Hamano K. Thrombolysis enhanced by transcutaneous ultrasonic irradiation. Tokyo Jikekai Med J. 1991;106:533–542.
7.
Kornowski R, Meltzer RS, Chernine A, et al. Does
external ultrasound accelerate thrombolysis? Results
from a rabbit model. Circulation. 1994;89:339–344.
8. Riggs PN, Francis CW, Bartos RS, et al. Ultrasound enhancement of rabbit femoral artery thrombolysis. Cardiovasc Surg. 1997;5:201–207.[Medline] [Order article via Infotrieve]
9.
Luo H, Nishioka T, Fishbein MC, et al. Myocardial
ischemia/ infarction/thrombolysis:
transcutaneous ultrasound augments lysis of arterial
thrombi in vivo. Circulation. 1996;94:775–778.
10. Kashyap A, Blinc A, Marder VJ, et al. Acceleration of fibrinolysis by ultrasound in a rabbit ear model of small vessel injury. Thromb Res. 1994;76:475–485.[Medline] [Order article via Infotrieve]
11.
Birnbaum Y, Luo H, Nagai T, et al. Noninvasive in vivo
clot dissolution without a thrombolytic drug:
recanalization of thrombosed iliofemoral arteries
by transcutaneous ultrasound combined with intravenous
infusion of microbubbles. Circulation. 1998;97:130–134.
12. Shlansky-Goldberg RD, Cines DB, Sehgal CM. Catheter-delivered ultrasound potentiates in vitro thrombolysis. J Vasc Interv Radiol. 1996;7:313–320.[Medline] [Order article via Infotrieve]
13. Sehgal CM, Leven RF, Shlansky-Goldberg RD. Ultrasound-assisted thrombolysis. Invest Radiol. 1993;28:939–943.[Medline] [Order article via Infotrieve]
14. Haberl RL, Heizer ML, Marmarou A, et al. Laser-Doppler assessment of brain microcirculation: effect of systemic alterations. Am J Physiol. 1989;256:1247–1254.
15.
Summaria L, Arzadon L, Bernabe P, et al. The
interaction of streptokinase with human, cat, dog, and rabbit
plasminogens. J Biol Chem. 1974;249:4760–4769.
16. Blinc A, Francis CW. Transport processes in fibrinolysis and fibrinolytic therapy. Thromb Haemost. 1996;76:481–491.[Medline] [Order article via Infotrieve]
17. Francis CW, Blinc A, Lee S, et al. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. US Med Biol. 1995;21:419–424.
18. Siddiqi F, Blinc A, Braaten J, et al. Ultrasound increases flow through fibrin gels. Thromb Haemost. 1995;73:495–498.[Medline] [Order article via Infotrieve]
19. Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost. 1997;78:1063–1068.[Medline] [Order article via Infotrieve]
20.
Siddiqi F, Odrljin TM, Fay PJ, et al. Binding of
tissue-plasminogen activator to fibrin: effect
of ultrasound. Blood. 1998;91:2019–2025.
21. Nishioka T, Luo H, Fishbein MC, et al. Dissolution of thrombotic arterial occlusion by high intensity, low frequency ultrasound and dodecafluoropentane emulsion: an in vitro and in vivo study. J Am Coll Cardiol. 1997;30:561–568.[Abstract]
22. Rosenschein U, Bernstein JJ, DiSegni E, et al. Experimental ultrasonic angioplasty: disruption of atherosclerotic plaque and thrombi in vitro and arterial recanalization in vivo. J Am Coll Cardiol. 1990;15:711–717.[Abstract]
23.
Ariani M, Fishbein MC, Chae JS, et al. Dissolution of
peripheral arterial thrombi by ultrasound.
Circulation. 1991;84:1680–1688.
24. Trubstein G, Engel C, Etzerl F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med. 1976;51:697s–698s.
25. Eccleston DS, Cumpston GN, Hodge AJ, et al. Ultrasonic coronary angioplasty during coronary artery bypass grafting. J Am Coll Cardiol. 1996;78:1172–1175.
26.
Rosenschein U, Rozenszajn LA, Kraus L, et al.
Ultrasonic angioplasty in totally occluded peripheral
arteries: initial clinical, histological, and
angiographic results. Circulation. 1991;83:1976–1986.
27. Siegel RJ, Gaines P, Crew JR, et al. Clinical trial of percutaneous peripheral ultrasound angioplasty. J Am Coll Cardiol. 1993;22:480–488.[Abstract]
28.
Rosenschein U, Gaul G, Erbel R, et al.
Percutaneous transluminal therapy of occluded saphenous
vein grafts: can the challenge be met with ultrasound
thrombolysis? Circulation. 1999;99:26–29.
29. Behrens S, Daffertshofer M, Spiegel D, et al. Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol. 1999;25:269–273.[Medline] [Order article via Infotrieve]
30. Akiyama M, Ishibashi T, Yamada T, et al. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery. 1998;43:828–833.[Medline] [Order article via Infotrieve]
31. Stern MD, Lappe DL, Bowen PD, et al. Continuous measurement of tissue blood flow by laser-Doppler spectroscopy. Am J Physiol. 1977;232:441–448.
32. Corson MA, James NL, Latta SE, et al. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res. 1996;9:984–991.
33. Uematsu M, Ohara Y, Navas JP, et al. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol. 1995;269:1371–1378.
This article has been cited by other articles:
 |
|
 |
|
  S. Kaul Sonothrombolysis: A Universally Applicable and Better Way to Treat Acute Myocardial Infarction and Stroke? Who Is Going to Fund the Research? Circulation, March 17, 2009; 119(10): 1358 - 1360. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Eggers, I. R. Konig, B. Koch, G. Handler, and G. Seidel Sonothrombolysis With Transcranial Color-Coded Sonography and Recombinant Tissue-Type Plasminogen Activator in Acute Middle Cerebral Artery Main Stem Occlusion: Results From a Randomized Study Stroke, May 1, 2008; 39(5): 1470 - 1475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wilhelm-Schwenkmezger, P. Pittermann, K. Zajonz, O. Kempski, M. Dieterich, and M. Nedelmann Therapeutic Application of 20-kHz Transcranial Ultrasound in an Embolic Middle Cerebral Artery Occlusion Model in Rats: Safety Concerns Stroke, March 1, 2007; 38(3): 1031 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Iida, H. Luo, K. Hagisawa, T. Akima, P. K. Shah, T. Z. Naqvi, and R. J. Siegel Noninvasive Low-Frequency Ultrasound Energy Causes Vasodilation in Humans J. Am. Coll. Cardiol., August 1, 2006; 48(3): 532 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Schneider, T. Gerriets, M. Walberer, C. Mueller, R. Rolke, B. M. Eicke, J. Bohl, O. Kempski, M. Kaps, G. Bachmann, et al. Brain Edema and Intracerebral Necrosis Caused by Transcranial Low-Frequency 20-kHz Ultrasound: A Safety Study in Rats Stroke, May 1, 2006; 37(5): 1301 - 1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ogata, T. Kitazono, J. Kuroda, K. Kamei, M. Kamouchi, H. Ooboshi, S. Ibayashi, and M. Iida A Case of Recanalized Cardioembolic Stroke: Possible Effect of Transcranial Color-Coded Real-time Sonography on Thrombolytic Therapy J. Ultrasound Med., April 1, 2005; 24(4): 561 - 565. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Eggers, G. Seidel, B. Koch, and I. R. Konig Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA Neurology, March 22, 2005; 64(6): 1052 - 1054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Siegel, V. N. Suchkova, T. Miyamoto, H. Luo, R. B. Baggs, Y. Neuman, M. Horzewski, V. Suorsa, S. Kobal, T. Thompson, et al. Ultrasound energy improves myocardial perfusion in the presence of coronary occlusion J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1454 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miyamoto, Y. Neuman, H. Luo, D.-S. Jeon, S. Kobal, F. Ikeno, M. Horzewski, Y. Honda, J. M. Mirocha, T. Iwami, et al. Coronary vasodilation by noninvasive transcutaneous ultrasound: An in vivo canine study J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1623 - 1627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nedelmann, B. M. Eicke, E. G. Lierke, A. Heimann, O. Kempski, and H. C. Hopf Low-Frequency Ultrasound Induces Nonenzymatic Thrombolysis In Vitro J. Ultrasound Med., June 1, 2002; 21(6): 649 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Z. Goldhaber Echocardiography in the Management of Pulmonary Embolism Ann Intern Med, May 7, 2002; 136(9): 691 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishibashi, M. Akiyama, H. Onoue, T. Abe, and H. Furuhata Can Transcranial Ultrasonication Increase Recanalization Flow With Tissue Plasminogen Activator? Stroke, May 1, 2002; 33(5): 1399 - 1404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W Francis and V. N Suchkova Ultrasound and thrombolysis Vascular Medicine, August 1, 2001; 6(3): 181 - 187. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||