EXPEDITED REVIEW
Coronary vasodilation by noninvasive transcutaneous ultrasound
An in vivo canine study
Takashi Miyamoto, MD*,
Yoram Neuman, MD*,
Huai Luo, MD*,
Doo-Soo Jeon, MD*,
Sergio Kobal, MD*,
Fumiaki Ikeno, MD*,
Michael Horzewski, BS*,
Yasuhiro Honda, MD*,
James M. Mirocha, MS*,
Takahiro Iwami, MD*,
Debra Echt, MD, FACC*,
Michael C. Fishbein, MD, FACC and
Robert J. Siegel, MD, FACC*,*
* Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center Los Angeles, California USA;
Department of Pathology, UCLA School of Medicine, Los Angeles, California, USA
Manuscript received October 7, 2002;
revised manuscript received February 4, 2003,
accepted February 25, 2003.
* Reprint requests and correspondence: Dr. Robert J. Siegel, Division of Cardiology, Room #5335, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.
siegel{at}cshs.org
 |
Abstract
|
|---|
OBJECTIVES: We evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz) ultrasound (USD).
BACKGROUND: Ultrasound has been shown to affect vascular function.
METHODS: Ultrasound energy was administered transcutaneously to 12 dogs. Coronary arterial dimensions were assessed using intravascular coronary ultrasound (IVUS) and quantitative coronary angiography (QCA).
RESULTS: The IVUS mid-left anterior descending (LAD) luminal area was 6.77 ± 1.27 mm2 at baseline. After 30 s of ultrasound, this area increased by 9% (7.40 ± 1.44 mm2, p < 0.05), after 3 min by 19% (8.05 ± 1.72 mm2, p < 0.05) and after 5 min increased by 21% (8.16 ± 1.29 mm2, p < 0.05). The mean coronary diameter (2.69 ± 0.33 mm) at baseline (QCA of three segments of LAD and three segments of left circumflex coronary artery) increased by 19.3% (3.21 ± 0.28 mm) after 5 min of USD exposure. After a 90-min observation period there was a return to baseline values (p = NS). Intracoronary nitroglycerin (NTG) administered to five dogs revealed a similar magnitude of vasodilation as USD.
CONCLUSIONS: Noninvasive, transthoracic low-frequency USD energy results in coronary artery vasodilation within seconds of exposure. The vasodilation is reversible and is similar in magnitude to that induced by NTG. Further evaluation is needed to assess its potential applications in humans.
|
Abbreviations and Acronyms
| | IVUS | = intravascular coronary ultrasound | | LAD | = left anterior descending coronary artery | | LCx | = left circumflex coronary artery | | NTG | = nitroglycerin | | QCA | = quantitative coronary angiography | | USD | = ultrasound |
|
Invasive, catheter-delivered, low-frequency (20 kHz) high-intensity ultrasound (USD) has been shown to cause vasodilation in peripheral and coronary arteries in animals and in humans (1–3). However, there are no data on the vasomotor effects of transcutaneous USD. In this study, we evaluated the potential vasodilatory effects of transcutaneous low-frequency USD in canine coronary arteries, as such a noninvasive approach could represent a novel method for treatment of coronary syndromes.
|
Methods
|
|---|
Twelve dogs (20 to 30 kg) were anesthetized with thiopental and maintained by isoflurane inhalation. The dogs received heparin 1,000 U subcutaneously. Studies were performed according to the position of the American Heart Association on research animal use.
Transcutaneous USD device.
The device consists of a generator/amplifier and controller delivering 27-kHz pulsed-wave USD through a transducer placed over the mid-sternum of the thorax (Timi3 Systems, Inc., Santa Clara, California). The transducer-radiating surface faces the skin and it is coupled to the skin with USD gel. Ultrasound intensity is approximately 1.4 W/cm2 and the pulsed wave duty is cycle 30%. The beam shape of the USD field is diverging and covers the entire heart. Because of the diverging USD field, the acoustic pressure further away from the transducer face is lower than at 5 mm from the transducer. At 5 mm, the peak rarefactional (i.e., negative) pressure is 230 kPa, at 4 cm about 170 kPa, and at 10 cm about 100 kPa. In short, between 4 and 10 cm from the transducer face the peak rarefactional pressure decreases from about 170 kPa to about 100 kPa. The output of the transducer was measured with a calibrated hydrophone (model 8103 Brüel & Kæjr, Nærum, Denmark) in accordance with the existing guidelines and standards (4–6).
Intravascular coronary ultrasound (IVUS).
As shown in Figure 1, after coronary angiography for baseline measurements, IVUS was performed in the mid-left anterior descending coronary artery (LAD) in 11 of 12 dogs. Luminal areas were continuously monitored during 5 min of USD exposure using a CVIS imaging system and coronary catheters (3 F, 40 MHz Atlantis SR and 3.2 F, 30 MHz, Ultracross, Boston Scientific, Massachusetts) (Fig. 2). In five dogs, intracoronary nitroglycerin (NTG) (100 µg) was administered 90 min after stopping USD. The IVUS recordings were analyzed by an independent core laboratory (7) blinded to the status of the dog, whether control period or during the NTG or USD exposure phase of the study (Cardiovascular Core Analysis Laboratory, Stanford University, Stanford, California).
View larger version (27K):
[in this window]
[in a new window]
|
Figure 1 The protocol and timing of coronary angiography, intravascular coronary ultrasound (IVUS), ultrasound (USD) exposure as well as nitroglycerin (NTG) administration. OB = observation.
|
|
View larger version (17K):
[in this window]
[in a new window]
|
Figure 2 Canine coronary artery segments. The canine left coronary angiogram was divided into six segments: three left anterior descending coronary artery (LAD) and three left circumflex coronary artery (LCx) segments. These segments were measured by quantitative coronary angiography. The intravascular coronary ultrasound (IVUS) was recorded as shown in the mid-LAD.
|
|
Coronary angiography protocol.
As noted in Figure 1, coronary angiograms were performed at baseline in the anterior-posterior and selected oblique projections after 5, 30, 60, and 90 min of USD, as well as 30, 60, and 90 min after stopping USD. In five dogs after the 90-min observation period, quantitative coronary angiography (QCA) was also performed 5 min after intracoronary NTG administration. Six segments (three LAD and three left circumflex [LCx]) were serially measured by QCA (Fig. 2). Arterial diameters were measured using a computer edge detection program (Advantx DXC Digital System, General Electric Medical Systems, Milwaukee, Wisconsin).
Safety testing.
During transcutaneous USD exposure, skin temperature below the transducer was measured by a thermocouple sensor (MedSource Inc., Santa Clara, California). Blood temperature within the LAD was measured with a thermocouple sensor (Timi3 Systems Inc.) mounted on a coronary guidewire placed in the mid-portion of the LAD.
Pathologic studies.
Dogs were euthanized; hearts were excised and fixed in formalin for 24 to 72 h and then cut transversely in 1-cm intervals from apex to base. Representative sections from the LAD and LCx arteries, as well as the skin, soft tissues, myocardium, and lung were submitted for microscopic examination.
Statistical analysis.
Continuous variables are expressed as mean ± standard deviation or percent change. Intraobserver and interobserver agreements were assessed using regression analysis and the Bland-Altman method. To assess changes from baseline to various time points, repeated measures analysis of variance was employed. Post hoc comparisons of all time points with baseline were performed using Dunnett’s procedure, which controls the experiment-wise type I error rate. A value of p < 0.05 was considered statistically significant.
|
Results
|
|---|
Ivus measurements. .
Figure 3 demonstrates mean mid-LAD luminal area at baseline, after 30 s, and each minute from 1 to 5 min as well as mean percent increase area after USD exposure. As shown, after 30 s of USD exposure, mean luminal area increased by 9% (from 6.77 ± 1.27 mm2 to 7.40 ± 1.44 mm2, p < 0.05), after 3 min by 19% (from 6.77 ± 1.27 mm2 to 8.05 ± 1.72 mm2, p < 0.05), and after 5 min by 21% (from 6.77 ± 1.27 mm2 to 8.16 ± 1.29 mm2, p < 0.05). Dunnett’s procedure indicated that the luminal areas after exposure to USD at all time points (30 s, 1 min, 2 min, 3 min, 4 min, 5 min) were significantly greater than baseline luminal area.
View larger version (47K):
[in this window]
[in a new window]
|
figure 3 The intravascular coronary ultrasound (ivus) mid-left anterior descending coronary artery (lad) area before and after ultrasound. on the vertical axis is the mid-lad ivus area; on the horizontal axis is the time (s/min) of ultrasound exposure. vasodilation increased incrementally with the duration of ultrasound. (inset upper left) baseline ivus image; (inset bottom right) ivus image of vasodilation seen after 5 min of ultrasound exposure. the ivus mid-lad areas in mm2 ± standard deviation (sd) are shown below each of the six time intervals at which the areas were measured.
|
|
Qca measurements.
Figure 4 shows the data on QCA mean luminal diameter of the LAD and LCx. There was a 19.3% mean increase in all segments from 2.69 ± 0.33 mm to 3.21 ± 0.28 mm (p < 0.05) after 5 min of USD. After a 60-min observation period, mean diameter resolved to 5.6% above baseline values (p = NS). After the 60-min observation period, USD treatment was initiated again for 90 min and angiograms as shown in Figure 5 were performed at 30-, 60-, and 90-min intervals during USD exposure. The mean increase in QCA coronary arterial diameters was 12.6% (from 2.69 ± 0.33 mm to 3.03 ± 0.30 mm, p < 0.05) at 30 min, 12.3 % (to 3.02 ± 0.28 mm, p < 0.05) at 60 min, and 8.2% (to 2.91 ± 0.28 mm, p = NS) at 90 min. During a subsequent 90-min observation period (no USD), angiographic evaluation of luminal diameter in each of the segments studied was repeated every 30 min. There was a decrease in the coronary artery luminal diameter towards baseline during the observation period after USD exposure.
View larger version (34K):
[in this window]
[in a new window]
|
Figure 4 Quantitative coronary angiography (QCA) measurements. The mean percent change of left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCx) diameter at baseline and after ultrasound (USD) exposure are shown. The vertical axis indicates the mean diameter of the coronary artery by QCA analysis; horizontal axis shows the baseline and the eight subsequent times of measurement during and after USD exposure. Percent change in angiographic diameter is plotted, and the average diameter in mm with standard deviation (SD) is shown below each of the nine time intervals. 1: Baseline 1 (before USD exposure). 2: After 5 min of USD exposure. 3: Baseline 2 (after 5 min of USD exposure followed by a 60-min observation [OB] period). 4: After 30 min of USD exposure. 5: After 60 min of USD exposure. 6: After 90 min of USD exposure. 7: After 30 min of OB. 8: After 60 min of OB. 9: After 90 min of OB. The table below the figure indicates the coronary artery diameter for each of the nine time intervals plotted on the graph.
|
|
View larger version (72K):
[in this window]
[in a new window]
|
Figure 5 Coronary angiogram before (a) and after (b) ultrasound (USD). As shown in (b), after USD the coronary artery luminal diameter increases.
|
|
Both QCA and IVUS regression analyses indicated strong intraobserver and interobserver correlations (r  0.98). The Bland-Altman method indicated good agreement. The averaged limits of agreement (mean difference) for IVUS were 0.24 (0.01) mm2 and 0.58 (0.10) mm2, and for QCA it was 0.14 (0.02) mm and 0.27 (0.11) mm. The mean absolute percentage difference (SD) ranged from 1.0% (1.0%) for IVUS to 4.2% (3.6%) for QCA.
Ntg effect.
Baseline mean luminal area measured by IVUS in the mid-LAD was 6.95 ± 1.40 mm2. After 100 µg intracoronary NTG, maximal luminal area increase within 5 min was 21% (8.40 ± 1.21 mm2) over baseline. Mean luminal QCA diameter of the LAD and LCx 5 min after NTG administration increased 16.6% from baseline luminal diameter (from 2.47 ± 0.39 mm to 2.88 ± 0.45 mm, p < 0.05). Dunnett’s procedure indicated that the luminal areas at 1 min and 2 min were significantly greater than the luminal area at baseline.
Temperature measurements.
Skin temperature below the transducer in four dogs was 34.9 ± 1.08°C at baseline and 34.8 ± 1.92°C (p = 0.85) after 90 min of USD. Intracoronary temperature in one dog showed no change during USD exposure (37.0°C at baseline and 36.9°C after 60 min).
Pathologic studies.
No USD-mediated injury to the coronary arteries, skin, soft tissue, myocardium, or lung was detected. Specifically, there was no thermal injury, necrosis, or inflammatory changes in the tissues.
|
Discussion
|
|---|
This is the first study to demonstrate that noninvasive, transcutaneous low-frequency USD causes coronary artery vasodilation. Both IVUS and QCA were used to document that transcutaneous USD exposure results in coronary artery vasodilation in a canine model.
Effect of short duration USD exposure.
In this closed-chest canine model, noninvasive USD exposure caused significant vasodilation of the coronary arteries. As measured by IVUS, the vasodilation effect was apparent within 30 s of USD exposure. As shown in Figure 3, luminal area gradually increased, resulting in a 21% increase after 5 min. By QCA, the coronary arterial diameter also increased by 19.3% after 5 min of USD. Sixty minutes after stopping USD, there was resolution of vasodilation, indicating that this is a reversible phenomenon.
Effect of prolonged duration USD exposure.
In the second part of the study, the effect of the duration of USD exposure was evaluated. After 30 and 60 min of USD exposure, there was an increase in the mean luminal diameter by QCA but it was less prominent than the increase after the first short exposure of 5 min. Subsequent arterial size reduction towards normal at 90 min despite continuation of USD exposure indicates that vasodilation becomes attenuated over time. The QCA luminal diameter significantly increased in response to ultrasound in all the LAD and LCx segments studied.
Thermal analysis.
Tissue heating can cause vasodilation (8). High-intensity USD can heat tissue (9,10). Although USD-induced vasodilation could be mediated by heating, we found no evidence of USD tissue heating even after 90 min of USD exposure. Thus, vasodilation was not thermally mediated in this study.
Relative vasodilatory effects of USD and NTG.
The magnitude of coronary artery vasodilation induced by USD exposure and NTG was similar. There was a 21% increase in luminal area by IVUS for both USD and NTG and a 19.3% and 16.6% increase, respectively, in QCA diameter. Similar mechanisms could be responsible for USD- and NTG-induced vasodilation.
Mechanism of USD-induced vasodilation.
We believe that the coronary artery vasodilation is most likely a direct effect of USD on coronary vasomotor tone. Previously studies from our laboratory demonstrated that catheter-delivered, low-frequency USD (20-kHz) induced vasodilation in rabbit aortas (2), canine coronary arteries (1), and human peripheral arteries (1,3). The magnitude of increase in arterial diameter using intravascular versus external USD was comparable, i.e., a 21% increase in canine coronary artery diameter with intravascular delivery at 20 kHz (1) and 19.3% in this study using a 27-kHz, noninvasive, transcutaneous USD device. These comparable results are consistent with a similar mechanism for transcatheter and transcutaneous USD-induced vasodilation. In these studies of catheter-delivered USD, the effect was limited to the exposed artery. Recently, Suchkova et al. (11) demonstrated that externally applied low-frequency USD (40 kHz) improves tissue perfusion to muscle in ischemic limbs as well as increasing capillary size in the exposed tissue. In addition, they showed that when the animals were pretreated with the nitric oxide synthase inhibitor N -nitro-L-arginine methyl-ester, the USD enhancement of tissue perfusion as well as capillary dilation was completely blocked. Thus, it seems likely that the USD-induced capillary dilation and enhanced tissue perfusion are due to a nitric oxide-dependent mechanism. As USD energy may increase mechanical shear stress on the endothelial cells, it could promote local release of the potent vasodilator nitrous oxide (12). It is possible that low-frequency USD could induce an increase in cardiac contractility and stroke volume and secondarily an increase in coronary arterial size to account for the vasodilation detected in our study. However, the results of catheter-based, USD-induced vasodilation, as well as the findings of Suchkova et al. (11) showing USD enhancement of tissue perfusion and capillary size which can be blocked by inhibition of nitric oxide synthase, are consistent with transthoracic low-frequency USD inducing coronary vasodilation by a nitric oxide-dependent mechanism.
Study limitations.
While we did measure coronary arterial lumen size by IVUS and QCA, we did not measure the effect of USD on coronary blood flow or velocity, or myocardial oxygen consumption. Nonetheless, we believe the findings of the current study are novel. Further studies are required to delineate the time course of action and to identify the mechanism responsible for the coronary vasodilation effect of transcutaneously applied, low-frequency USD.
Conclusions.
Noninvasive, transthoracic, low-frequency USD induces vasodilation in canine coronary arteries. The onset of coronary vasodilation is relatively rapid ( 30 s). The magnitude of the effect is similar to that found with intracoronary NTG. This phenomenon of vasodilation that is caused by externally applied USD energy might have the potential to reduce myocardial ischemia in patients with acute coronary syndromes.
|
Appendix
|
|---|
The ultrasonic power and intensity emitted by the Timi3 Systems ultrasound (USD) transducer were measured using a calibrated hydrophone. The USD transducer was connected to the Timi3 USD console and placed against an acoustic window of a tank containing degassed water. The water tank was lined with anechoic material to minimize effects of standing waves. The USD field was mapped using scanning techniques, and single-point hydrophone measurements were made at the point of maximum intensity at 5 mm from the applicator face. The hydrophone used for these measurements is a B&K type 8103 (Brüel & Kæjr, Nærum, Denmark). The hydrophone diameter is 9.5 mm. Its sensitivity at around 30 kHz is –212.7 ± 0.25 dB re 1 V/µPa, and its calibration is traceable to the National Institute of Standards and Technology. The hydrophone was scanned under computer control using a stepper motor XY-positioning system. The distance of the scan from the applicator face was 5 mm, and all measurements were made in a 25 by 25 rectangular grid across to the applicator face with the step increment of 0.200 inch (5.08 mm). The USD pressure was also measured as a function of distance from the transducer face from 5 to 155 mm. The hydrophone signal was digitized, and various acoustic parameters were calculated according to International Electrotechnical Commission standards (5,6) (IEC Publication 60601-2-5), and the Food and Drug Administration’s guidance document (4).
|
References
|
|---|
- Steffen W, Cumberland D, Gaines P, et al. Catheter-delivered high intensity, low frequency ultrasound induces vasodilation in vivo. Eur Heart J. 1994;15:369–376[Abstract/Free Full Text]
- Fischell TA, Abbas MA, Grant GW, et al. Ultrasound energy: effects on vascular function and integrity. Circulation. 1991;84:1783–1795[Abstract/Free Full Text]
- Siegel RJ, Gaines P, Procter A, et al. Clinical demonstration that catheter-delivered ultrasound energy reverses arterial vasoconstriction. J Am Coll Cardiol. 1992;20:732–735[Abstract]
- CFR 1050.10. Food and Drug Administration, Center for Devices and Radiological Health, 4-1-87 edition
- Measurement and characterization of ultrasonic fields using hydrophones in the frequency range 0.5 MHz to 5 MHz. Geneva: International Electrotechnical Commission, 1991:Publ. IEC 61102
- Ultrasonics—physiotherapy systems—performance requirements for the safety of ultrasonic physiotherapy equipment. Geneva: International Electrotechnical Commission, 1996:Publ. IEC 61689
- Metz JA, Yock PG, Fitzgerald PJ. Intravascular ultrasound: basic interpretation. Cardiol Clin. 1997;15:1–15[CrossRef][Medline]
- Osawa F. Actin-actin bond strength and conformational change of F-actin. Biorheology. 1977;14:11–19[Medline]
- Luo H, Nishioka T, Fishbein MC, et al. Transcutaneous ultrasound augments lysis of arterial thrombi in vivo. Circulation. 1996;94:775–778[Abstract/Free Full Text]
- Suchkova VN, Baggs RB, Francis CW. 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. Circulation. 2000;101:2296–2301[Abstract/Free Full Text]
- Suchkova VN, Baggs RB, Sahni SK, et al. Ultrasound improves tissue perfusion in ischemic tissue through a nitric oxide dependent mechanism. Thromb Haemost. 2002;88:865–870[Medline]
- Corson MA, James NL, Latta SE, et al. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res. 1996;79:984–991[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
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]
|
|
|
|
|
|
|
M. Daffertshofer, A. Gass, P. Ringleb, M. Sitzer, U. Sliwka, T. Els, O. Sedlaczek, W. J. Koroshetz, and M. G. Hennerici
Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia: Increased Risk of Hemorrhage With Combined Ultrasound and Tissue Plasminogen Activator: Results of a Phase II Clinical Trial
Stroke,
July 1, 2005;
36(7):
1441 - 1446.
[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]
|
|
|
|
|
|
|
N. Kipshidze and N. N. Kipshidze
Therapeutic transcutaneous ultrasound: long overdue therapy
J. Am. Coll. Cardiol.,
July 7, 2004;
44(1):
210 - 211.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Siegel, H. Luo, Y. Birnbaum, M. C. Fishbein, and T. Miyamoto
Reply
J. Am. Coll. Cardiol.,
July 7, 2004;
44(1):
211 - 211.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods