Cardiac imaging: The biological effects of diagnostic cardiac ultrasound

Cardiac imaging: The biological effects of diagnostic cardiac ultrasound

ARTICLE IN PRESS Progress in Biophysics and Molecular Biology 93 (2007) 399–410 www.elsevier.com/locate/pbiomolbio Review Cardiac imaging: The biol...

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ARTICLE IN PRESS

Progress in Biophysics and Molecular Biology 93 (2007) 399–410 www.elsevier.com/locate/pbiomolbio

Review

Cardiac imaging: The biological effects of diagnostic cardiac ultrasound Maria Grazia Andreassi, Lucia Venneri, Eugenio Picano CNR Institute of Clinical Physiology, Pisa, Italy Available online 7 August 2006

Abstract Diagnostic cardiac ultrasounds are an environment-friendly and non-ionising imaging technology. However, ultrasounds are not biologically inert, and their use might have profound clinical impact. This paper summarizes the known effects of cardiac ultrasound—compared to other major imaging techniques—to exposed patients and to clinically exposed physicians practising ultrasound imaging. Furthermore, this review also provides an overview of the evidences on the biological effects of diagnostic ultrasound—which suggest that ultrasound with frequency, intensity and duration fully in the diagnostic range have significant molecular, cellular and organ effects. A better understanding of these effects may improve our understanding of the complex interactions between ultrasound and biological tissues and may open new avenues to therapeutic applications based on the ultrasound-modulated cell functions, such as membrane transduction, apoptosis, cell permeability and thrombolysis. r 2006 Elsevier Ltd. All rights reserved. Keywords: Diagnostic cardiac ultrasound; Biological effects; Clinical risks

Contents 1. 2. 3. 4. 5. 6.

7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The ultrasound energy spectrum in clinical approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasound and non-ultrasound imaging: the risk to patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasound and non-ultrasound imaging: the risk to chronically exposed physicians . . . . . . . . . . . . . . . . . . Below the regulating level: biological effects of diagnostic ultrasound. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological effects of diagnostic cardiac ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Molecular effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Cellular effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Organ effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical effects of diagnostic ultrasound. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +39 0585 493646; fax: +39 0585 493601.

E-mail address: [email protected] (M. Grazia Andreassi). 0079-6107/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pbiomolbio.2006.07.020

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1. Introduction A Renaissance of medical imaging occurred in the recent years, and the modern practise of the medicine heavily relies on imaging techniques. Every year, about 5 billion imaging exams are performed worldwide, and about 1 out of 3 are made with ultrasound (Roelandt et al., 1989) Most infants now born in the western countries were exposed to ultrasound before birth (NCRP, 2002). New medical imaging technologies allow the description of anatomy, function, perfusion, and metabolism in a polycrome, three-dimensional, overwhelming fashion, not without costs, however, and not without risks. We will briefly review the known effects of cardiac ultrasound—compared to other major imaging techniques—to exposed patients and to clinically exposed physicians practising ultrasound imaging. We will then review evidences on the biological effects of diagnostic ultrasound—which may be a conceptual link to a targeted use of ultrasound for therapeutics applications. 2. The ultrasound energy spectrum in clinical approaches The role of imaging techniques in defining the presence and the causes of heart disease is essential. Medical imaging began on 8 November 1895, when Professor Wilhelm Conrad Roentgen of the University of Wu¨rzburg discovered X-rays. There have been numerous refinements of X-ray techniques over the past 100 years with development of invasive radiology and computed tomography. In addition, entire new modalities have appeared including nuclear medicine, ultrasonography, magnetic resonance imaging (RP118, 2001). The ‘‘4 sisters’’ of cardiac imaging have very different biological and technological basis. It is important to operate a distinction, which is also relevant for the legal regulations of medical imaging between ‘‘ionising’’ and ‘‘nonionising’’ techniques. Ionising techniques use high-frequency electromagnetic waves, such as X-rays (radiology) and g-rays (nuclear medicine). Ionising radiations are only one part of the electromagnetic spectrum (Fig. 1). There are numerous other radiations (e.g., visible light, infra-red waves, radiofrequency electromagnetic waves) that do not posses the ability to ionise atoms of the absorbing matter. According to the general equation E ¼ hv radiation energy (E) is directly proportional to frequency (v). Higher energies can be toxic to the cell through the production of free radicals. Obviously, the use of high energies has also several advantages, including the possibility to go inside the body without obstacles represented by bone and air. However, the use of ionising testing is associated to environmental impact and definite biorisks for the patient and the operator (Cormack et al., 1998; ICRP, 2001). As always in medicine, a responsible use of these technologies clearly outweighs the risk (Picano 2004). Other technologies employed in cardiac imaging pose no environmental burden or known risk to the patient E=hxv

Magnetic Resonance ELECTROMAGNETIC SPECTRUM

106

109

Nuclear Radiology Medicine 4.1 * 1014 7.5 * 1014

5 * 1028 XRay

Radio-waves

Frequency (hertz)

γ-Ray

Echography ACOUSTIC WAVES 20,000

1 MHz

5 MHz 10 MHz

Fig. 1. Electromagnetic and acoustic spectrum. Only high-energy electromagnetic waves (used in radiology and nuclear medicine) are ionising.

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Intensity W/cm2

2000

50

fibrinolysis 5

drug /gene delivery target lesion production/ valvular decalcification diagnostic US HIFU

2 1 20KHz

1 MHZ 2 MHZ

10 MHZ

40 MHZ

Frequency Fig. 2. The range of energies within broadly specified limits of different frequency and intensity ranges employed in clinical diagnostic and therapeutic ultrasound.

or to the operator (RP118, 2001). They include magnetic resonance, which uses low-frequency electromagnetic waves and ultrasound. Both these forms of physical energy are not capable to produce ionising phenomena (Fig. 1). Ultrasounds are mechanical vibrations with frequencies above human limit of audibility (Nyborg, 2001). Ultrasound is used widely as both a diagnostic and therapeutic tool in various medical specialties by using its mechanical vibrations, localized cavitations, microstream formation, physicochemical changes and thermal energy (Dalecki, 2004). In the area of cardiovascular diseases, ultrasound could be used for thrombolysis, adjunct to coronary interventions, drug delivery, local gene transfer, and creating therapeutic lesions. The range of energies and frequencies employed in diagnostic and therapeutic application of cardiac ultrasound are reported in Fig. 2. The biological effects of cardiac ultrasound are varied from the use of low- to medium-range frequency and low to focused high intensity. In this review, we will focus and discuss various biological aspects of ultrasound in the frequency and intensity energy range of diagnostic ultrasound. 3. Ultrasound and non-ultrasound imaging: the risk to patients The National Council on Radiation Protection and Measurements formulate and widely disseminated recommendations on radiation protection and measurements, considering medical radiation of all types: ionising radiation (such as X-rays and nuclear medicine) and non-ionising radiation (such as ultrasound and magnetic resonance imaging) (ICRP, 2001, NCRP, 2002). Doses of common radiological imaging examinations are reported in Fig. 3, as multiples of chest X-ray, as recommended by the Imaging Guidelines of the European Medical Commission (RP118, 2001). The corresponding risk values are based on the official estimates of the International Commission of Radiation Protection (ICRP, 2001). To date, researches have not identified any adverse biological effects caused by ultrasound, even while million people have been exposed to ultrasound for nearly half a century; and three million babies born each year have had ultrasound scans in utero (Stephenson, 2005). There are epidemiological studies looking for association between ultrasound exposure and various traits, such as low Apgar scores at birth, birth defects, speech or hearing disorders, chromosomal abnormalities, childhood cancers, etc. (Salvesen, 2002). There is no conclusive evidence that any of these traits were caused by in utero ultrasound exposure. However, a possible association between ultrasound during pregnancy and subsequent

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1 in 1,000 Interventional Fluoroscopic procedures

Additive risk of cancer/exam

Risk category

Cardiac radiofrequency ablation

Zero Negligible Minimal Verylow Low

Coronary stenting

Abdominal computed tomography

1 in 2,000

Thallium scan

Chest computed tomography

Sestamibi cardiac scintigraphy

Barium enema

Bone scintigraphy 1 in 20,000

Lung scintigraphy 50

MRI, US

500 Equivalent number of chest x-rays

1000

Fig. 3. Presentation of cancer risk and radiation dose (in multiples of dose from a single chest X-rays) for some common radiological and nuclear medicine examinations (modified from Picano, 2004).

more left-handedness among boys has been suggested (Kieler et al., 2001; Salvesen, 2002). As clearly showed by the European Medical Imaging guidelines, all agree that medical ultrasound is safer than other imaging techniques, and certainly to be preferred over ionising imaging techniques, wherever the clinical information provided is comparable. However, the National Council on Radiation Protection and Measurements advocates further studies of ultrasound safety, improvements in the safety features of ultrasound systems and more safety education for ultrasound system operators to ensure that the benefits of ultrasound continue to outweigh any risks (NCRP, 2002). This is especially true when contrast agents are used to enhance the ultrasound signal in clinical diagnostic echocardiography There is a number of studies evidencing that in presence of contrast agents, ultrasound exposure may induce significant tissue damage, particularly of microvasculature (Mornstein, 1997). In vitro and animal studies (Ay et al., 2001) showed significant myocardial damage, but the large clinical experience accumulated so far in thousand of patients with ultrasound contrast agents have failed to demonstrate any clinically detectable adverse effects (Cosyns et al., 2005; Tsutsui et al., 2005; Hayat and Senior 2005). 4. Ultrasound and non-ultrasound imaging: the risk to chronically exposed physicians Ionising procedures expose not only patients but also medical staff to the highest radiation levels in diagnostic radiology, and recently, as the number of diagnostic and interventional cardiac catheterisation procedures has greatly increased, serious radiation-induced skin injuries and an excess of cataract development have been reported in exposed staff. There are data suggesting that fluoroscopic procedures may be a health hazard and increase the risk for brain tumours in interventional cardiologists (Read, 1992; Andreassi, 2004). In contrast to ionising radiation, ultrasound do not cause ionisation, but mainly interact with human tissue by generating heat and by determining cavitation. The latter process includes ultrasound mechanical effects leading to hydrodynamic breaks of hydrogen bonds and oscillation of hydrogen ions, and chemical effects produced by the occurrence of free radicals. Theoretically, free radicals may interfere with DNA molecule, causing DNA and chromosomal damage, as shown in Fig. 4 (Fuciarelli et al., 1995). Several biomarkers of chromosomal and DNA damage are currently employed in order to study human exposure to environmental mutagen and carcinogen agents (Fenech, 2002; Andreassi, 2004).

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·OH+·OH

Apoptosis

H2O2

H2O·

403

DNA damage ·H + ·H

H2

Elimination

Repair

Inefficient Repair

Corrected sequence

Mutation

Fig. 4. Ultrasound mechanical effects may lead to hydrodynamic breaks of hydrogen bonds and oscillation of hydrogen ions producing free radicals. Theoretically, free radicals may interfere with DNA, causing chromosomal damage (modified from Andreassi, 2004).

Indeed, a large number of studies investigated the potential genotoxicity from exposure to therapeutic and diagnostic ultrasound using several methodological approaches (Miller et al., 1983, 1991; Stella et al., 1984; Barnett et al., 1987; Carrera et al., 1990; Martin et al., 1991; Sahin et al., 2004). In particular, Stella et al. (1984) reported that ultrasound induce a significant increase in sister chromatid exchanges (SCEs) in human lymphocytes after treatment both in vitro and in vivo. In the same study, no increase in chromosomal aberrations was observed during and after ultrasound exposure. Subsequently, some reports on human cells indicated that diagnostic ultrasound was not able to induce SCEs or other type of chromosomal damage (Table 1). Thus, there is at present no indication that exposure to medical ultrasound is capable of inducing genetic effects and representing a serious health hazard for clinical staff. However, very little information is available on the genetic effects of individuals occupationally exposed to chronic ultrasound. Medical staff can be exposed to hand transmitted ultrasound waves in the workplace. Indeed, ultrasound sources do not transmit acoustic energy into air, and only low-level ultrasound reaches medical personnel through handling of the probe (Nyborg, 1996). Probably, occupational exposure to ultrasound occurs during training procedures (Nyborg, 1996). In fact, medical personnel often apply diagnostic ultrasound to themselves during training or during technique demonstrations (Nyborg, 1996). Consequently, ultrasound is not harmful like the other types and sources of radiation. However, a recent investigation indicated that medical personnel from a cardiology unit working with colour Doppler ultrasonic equipment had an increased genotoxic damage compared to the control subjects (Garaj-Vrhovac and Kopjar 2000). Plonska et al. (2005) demonstrated that in the literature there are few works referring to harmful effects of making an echocardiographic examination. The most common referred symptoms, such as musculoscheletal pain, spine pain, wrist pain, appear to be connected to the forced body posture. Among the clinical symptoms, the author includes aspecifica symptoms and signs, such as heart palpitations and the chest pain, but did not demonstrate any relation with ultrasound exposure (Plonska et al., 2005). Therefore, this observation requires further studies in order to determine if chronic exposure to ultrasound might induce genotoxic and clinical effects. Until more exhaustive data obtained in vivo become available, a prudent extension to personnel working in ultrasound imaging of the universal ALARA principle-by which radiation exposure should be kept ‘‘As low as reasonably achievable’’— is probably warranted. 5. Below the regulating level: biological effects of diagnostic ultrasound In contrast to ionising radiation ultrasound do not cause ionisation, but this is not synonymous with being biologically inert. The biological effects of ultrasound (NCRP, 1983) can be either thermal (changes within the

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Table 1 Summary of studies on genetic effects of medical ultrasounds References

Assay system

Endpoint

Exposure

Result

Miller et al., 1983

Human lymphocytes exposed in vitro

SCE

2 MHz SPPA intensity 100 W/cm2

Negative

Stella et al., 1984

Human lymphocytes exposed in vitro

SCE CA

1 W/cm2; 0.860 MHz; for 40–160 s

Positive/negative

Barnett et al., 1987

Human lymphocytes exposed in vitro

SCE

3.1 MHz SPPA intensities from 15–135 W/cm2.

Negative

Carrera et al., 1990

Chorionic villi exposed in vitro Chorionic villi from exposed pregnant women

SCE

2 MHz at 1, 2, 3 h Diagnostic ultrasound for 20 min (in vivo exposure)

Negative

Miller et al., 1991

Human lymphocytes from exposed patients

SCE

4 patients underwent therapeutic ultrasound 4 healthy persons underwent shamtherapeutic ultrasound

Negative

Martin et al., 1991

Lymphocyte and lymphoblastoid cells exposed in vitro

SCE

5 MHz for 20 s, 1, 5, and 20 min

Negative

Sahin et al., 2004

Human lymphocytes from exposed patients

MN

10 patients underwent 10 session of US therapy at 1 MHz for 10 min and 10 control subjects underwent shamtherapeutic ultrasound

Negative

Garaj-Vrhovac and Kopjar, 2000

Human lymphocytes from cardiologists working with Doppler ultrasound

CA

Unit working with colour Doppler ultrasound (transducer frequencies 2.5–7.5 MHz). SPPA intensity 60–110 W/cm2

Positive

SCE MN

SCE: sister-chromatid exchange; MN: micronuclei; CA: chromosomal aberrations; SPPA: spatial peak pulse average: modified from Andreassi, 2004.

tissues as a direct result of elevation of the tissue temperature caused by ultrasound) and non-thermal effect, also known as mechanical effect: the latter may involve cavitation or non-cavitation phenomena. Cavitation is the phenomenon of microbubble formation from gases that exist in living tissue, such as adult lung or intestine. The sound waves can cause the bubbles to expand and contract rhythmically: in other words, to pulsate, or resonate. When they pulsate, the bubbles send secondary sound waves off in all directions. These secondary sound waves can actually improve ultrasound images because the secondary waves also reflect back to the transducer, and provide more information. Thus, doctors now sometimes inject artificial bubbles known as contrast agents into the body before taking ultrasound images, for instance, of the circulatory system (Apfel, 1982, Blomley et al., 2001; Nesser et al., 2002). The microbubble compression cycles of negative and positive pressures results in secondary motions, high local shear stress in the tissue and microstreaming of surrounding fluid. These events determine fragmentation of subcellular and cellular structures in the tissue (Nesser et al., 2002). When diagnostic ultrasound is focused on the lung or intestine of laboratory animals, which contain gas bubbles, these cavitation effects can cause ruptures in very small blood vessels (Skyba et al., 1998). Ultrasound can also create other mechanical effects that do not require the presence of bubbles in order to occur. These effects include changes in pressure, force, torque (causing things to rotate) and streaming (stirring of the liquid). These changes, in turn, can cause audible sounds, electrical changes in cell membranes that make them more permeable to large molecules, movement and redistribution of cells in liquid, and cell damage. In experiments with animals, when streaming of the liquid comes near a solid object, shearing can occur, and this can damage platelets and lead to abnormal blood clotting (thrombosis). It is not clear to what extent this effect occurs in humans exposed to diagnostic ultrasound.

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It is well known that the bioeffects of ultrasound depend on the characteristics of the sound wave, the sensitivity and attenuation of the exposed tissue, and time duration of exposure. The intensity of ultrasound (the concentration of acoustic power of the sound wave in a given area), the frequency of the transducer, and the mode (continuous or pulsed) of application all influence the bioeffects of ultrasound (NCRP, 1983; Dalecki, 2004). But in the clinical setting, the real energy impacting on the target tissue remains uncertain, due to many technological and biological factors modulating energy. There are millions of combinations of control settings that might conceivably affect the machine output (BMUS, 2000), including the mechanical index, imaging mode, duration of insonation, optimal frequency, and need of concomitant bubble infusion, type and thickness of interposed tissues. 6. Biological effects of diagnostic cardiac ultrasound A better understanding of these effects may improve our understanding of the complex interactions between ultrasound and biological tissues and may open new avenues to therapeutic applications based on the ultrasound-modulated cell functions, such as membrane transduction, apoptosis, cell permeability and thrombolysis. There are data suggesting that ultrasound with frequency, intensity and duration fully in the diagnostic range have significant molecular, cellular and organ effects. 6.1. Molecular effect It has been shown that diagnostic ultrasound can markedly enhance the endothelial uptake of bioactive proteins in vivo (Keyhani et al., 2001). Ultrasound selectively induced activation of extracellular signalregulated kinase (ERK) in human skin fibroblasts (Zhou et al., 2004). In vitro experiments, on cultured human umbilical vein endothelial cells (HUVEC), demonstrated that caveolar internalisation without alteration of the cell membrane integrity is a novel mechanism of diagnostic ultrasound-induced protein uptake by endothelial cells, associated with the phosphorylation/activation of ERK1/2 (Lionetti et al., 2005). 6.2. Cellular effect The production of intracellular reactive oxygen species (ROS) on endothelial cells is a key modulator of atheroprotective (at low level) and atherogenic (at high level) actions (Kunsch and Medford, 1999), because large amounts of ROS are known to induce apoptotic endothelial cell death (MacLellan and Schneide, 1997), and may contribute to the initial endothelial injury which promotes atherosclerotic lesion formation (Riesz and Kondo, 1992). A number of studies have shown that endothelial cells damage occurs after ultrasound exposure to cultured cells and organs containing air, such as lungs or the heart after contrast injection (Dalecki et al., 1999; Ay et al., 2001). Our group evaluated the in vitro effects on intracellular ROS of endothelial cells monolayer after ultrasound exposure of variable duration with commercially available cardiac imaging systems (Basta et al., 2003) and concluded that diagnostic cardiac ultrasound (1.3/2.6 MHz and mechanical index 1.5) increase intracellular oxidative stress on endothelial cells in vitro (Fig. 5). This increase was accompanied by morphological evidence of endothelial damage only after longer exposure times (30 s), persists 1 h after withdrawal of ultrasound, and can be modulated over a wide range according to the duration of ultrasound exposure. Ultrasound exposure induced significant DNA laddering and lactate dehydrogenase (LDH) leakage after 15 s of exposure. Effects on endothelial cells could be reproduced by adding exposed extracellular medium to unexposed cells, and could be prevented removing exposed medium form cell culture or pretreating the medium with catalase. The hypothesized mechanism is that free radical formation, due to inertial cavitation, determine intracellular DNA and cellular damage up to death. These results were obtained in vitro and, obviously, cannot be directly transferred to the in vivo setting, where, theoretically, the several systems for maintaining antioxidant status (gluthatione, ascorbate, catalase) can rapidly inactivate Hd and OHd radicals making ultrasound-evoked reactive oxygen species production physiologically negligible.

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Fig. 5. Time course of ROS production in endothelial cells after ultrasound exposure. Upper panel: schematic representation of the experimental design, with (from left to right) sham and ultrasound irradiation of 5, 15 and 30 s. Middle panel: representative photography of intracellular ROS production (proportional to the intracellular fluorescence) and endothelial cells damage (detectable as confluent dark zone in the endothelial cells monolayer) at baseline, and following ultrasound irradiation for the indicated time periods. Lower panel: kinetics of quantified ROS production induced by ultrasound; results are mean7SD of 3 separate experiments, with each experimental field comprising 150–200 cells. *po0.001, compared with corresponding baseline values (modified from Basta et al., 2003).

6.3. Organ effect The microcirculation is sensitive to the exposure of ultrasound of frequency, intensity and duration fully within the range used for cardiac diagnostics. Bertuglia et al. (2004) demonstrated that in the hamster cheek punch, both during baseline and reperfusion, ultrasound exposure increases endothelial permeability, which is an early and reversible sign of morphologic change of the membrane, likely due to loosening of cell-to-cell tight junctions for mechanical low-amplitude vibration. This low-level endothelial damage in baseline conditions is likely to cause some kind of preconditioning, thus, leading to a state of increased resistance during reperfusion. Ultrasound may enhance wall shear stress on the endothelium increasing its antioxidant activity, as suggested by the reduction of ROS formation during postischemic reperfusion after ultrasound exposure, thus increasing capillary perfusion. Therefore, ultrasound has a beneficial effect in the treatment of reperfusion tissue injury (Bertuglia et al., 2004). This intriguing finding opens a novel therapeutic window to the application of diagnostic ultrasound microvascular damage, which occurs in a variety of pathological conditions including acute myocardial infarction. 7. Clinical effects of diagnostic ultrasound The knowledge of ultrasound bioeffects have opened up powerful applications of cardiac sonography in therapy. In experimental models, ultrasound energy enhances the activity of thrombolytic agents possibly by increasing contact between the thrombus and the fibrinolytic drug (Blinc et al., 1993; Nilsson et al., 1995;

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Ultrasound

407

Popped microbubbles

Cationic microbubbles

DNA entering cell

Fig. 6. Ultrasound-targeted microbubble destruction is a highly promising approach for gene or drug delivery to specific tissues and cells.

Pfaffenberger et al., 2003). Even in the absence of fibrinolytic drug, ultrasound can enhance spontaneous thrombolysis, possibly through a thermal and/or a cavitation effect (Trubestein et al., 1976; Tachibana and Tachibana, 1997; Behrens et al., 2001). Recently, clinical trials revealed encouraging results in recanalization and clinical outcome in acute stroke patients when 2-MHz transcranial Doppler monitoring was applied. In particular, diagnostic ultrasound energy facilitates somewhat the activity of fibrinolytic agents (Cintas et al., 2002), but preliminary reports also indicate a possible beneficial effect of ultrasound alone in enhancing spontaneous thrombolysis (Eggers et al., 2003). The initial clinical interest focused on middle cerebral artery, which is a relatively easy target of diagnostic ultrasound—although temporal bone may critically attenuate the intensity and therefore the thrombolytic efficacy of ultrasound (Alexandrov, 2004). Contrast agents, widely used in ultrasound imaging (Blomley et al., 2001) to improve accuracy of conventional ultrasonographic assessment, recently are also used as tools for delivery of drugs or genes to specific site and for non-invasive clot lysis (Miller, 2000). They are like a Troyan horse-bringing drugs (or genes) within the target organ. The horse is opened from the outside through diagnostic ultrasound, which break the bubble, so their content can be delivered in the target tissue (Fig. 6). For instance, a recent report demonstrated that an ultrasound transfection method with echo-contrast microbubble agent enhanced transfection efficiency of an anti-oncogene (p53) plasmid into carotid artery after balloon injury as a model of gene therapy for restenosis (Taniyama et al., 2002). Therefore, the transfection of naked plasmid DNA by the ultrasound- echo-contrast microbubble method could be a useful approach for the clinical treatment of restenosis after coronary intervention and other cardiovascular disease (Fig. 7). 8. Conclusion Medical imaging is an essential part of contemporary medicine, often providing essential and life-saving information. At the moment, there are no consistent adverse biological effects caused by exposures to diagnostic ultrasound. However, several bioeffects of diagnostic ultrasound have been described. A better understanding of these effects may open new avenues to therapeutic applications of ultrasound in medicine. Furthermore, it is clearly necessary to continually monitor both the potential risks and safety of diagnostic ultrasound exposure. According to recommendations of British Medical Ultrasound Society (BMUS), European Committee for Medical Ultrasound Safety (ECMUS) and the World Federation for Ultrasound in Medicine (WFUMB), the ultrasound operators should know the safety indices—Thermal Index (TI) and Mechanical Index (MI)—to avoid the excessive scanning at higher acoustic output, when possible. TI and MI are an estimate of risk from heat and non-thermal effect of ultrasound, respectively. The education in evaluating risks and benefits should be part of the process of ultrasound training. When the MI is above 0.5 or the TI is above 1.0, the NCRP

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Fig. 7. Effect of transfection of naked p53 plasmid DNA on neointimal formation in rat balloon injury model. Two weeks after transfection, the intimal to medial area ratio was significantly decreased by means of ultrasound+contrast microbubble agent (Optison). (modified from Taniyama et al., 2002).

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