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PubMed2003

A Newtonian rheological model for the interface of microbubble contrast agents.

A quantitative model of the dynamics of an encapsulated microbubble contrast agent will be a valuable tool in contrast ultrasound (US). Such a model must have predictive ability for widely varying frequencies and pressure amplitudes. We have developed a new model for contrast agents, and successfully investigated its applicability for a wide range of operating parameters. The encapsulation is modeled as a complex interface of an infinitesimal thickness. A Newtonian rheology with surface viscosities and interfacial tension is assumed for the interface, and a modified Rayleigh-Plesset equation is derived. The rheological parameters (surface tension and surface dilatational viscosity) for a number of contrast agents (Albunex, Optison and Quantison) are determined by matching the linearized model dynamics with experimentally obtained attenuation data. The model behavior for Optison (surface tension 0.9 N/m and surface dilatational viscosity 0.08 msP) was investigated in detail. Specifically, we have carried out a detailed interrogation of the model, fitted in the linear regime, for its nonlinear prediction. In contrast to existing models, the new model is found to capture the characteristic subharmonic emission of Optison observed by. A detailed parametric study of the bubble behavior was executed using the ratio of scattering to attenuation (STAR). It shows that the encapsulation drastically reduces the influence of resonance frequency on scattering cross-section, suggesting possible means of improvement in imaging at off-resonant frequencies. The predictive capability of the present model indicates that it can be used for characterizing different agents and designing new ones.

Albumins↗

PubMed2006

Lateral phase separation in lipid-coated microbubbles.

In the design of lipid-coated microbubble ultrasound contrast agents for molecular imaging and targeted drug delivery, the surface distribution of the shell species is important because it dictates such properties as ligand location, brush coverage, and amount of drug loading. We used a combination of spectroscopy and microscopy techniques to test the prevailing notion that the main phosphatidyl choline (PC) and lipopolymer species are completely miscible within the monolayer shell. NMR spectroscopy showed that the shell composition is roughly equivalent to the bulk lipid ratio. FTIR spectroscopy showed a sharp melting peak corresponding to the main phase-transition temperature of the main PC species, with no observed pretransitions while scanning from room temperature, indicating a single PC-rich ordered phase. Electron and fluorescence microscopy showed a heterogeneous microstructure with dark (ordered) domains and bright (disordered) regions. Domain formation was thermotropic and reversible. Fluorescent labeling of the lipopolymer following shell formation showed that it partitions preferentially into the disordered interdomain regions. The ordered domains, therefore, are composed primarily of PC, and the disordered interdomain regions are enriched in lipopolymer. Phase heterogeneity was observed at all lipopolymer concentrations (0.5 to 20 mol %), and the degree of phase separation increased with lipopolymer content. The composition and temperature dependence of the microstructure indicates that phase separation is driven thermodynamically rather than being a kinetically trapped relic of the shell-formation process. The overall high variation in microstructure, including the existence of anomalous three-phase coexistence, highlights the nonequilibrium (history-dependent) nature of the monolayer shell.

Coated Materials, Biocompatible↗

PubMed2006

Sonochemical nanosynthesis at the engineered interface of a cavitation microbubble.

This work demonstrates the potential of sonochemistry to become a most valuable tool for nanotechnology if the underlying complex processes are understood and controlled. It is shown that control of cavitation requires controlling of interfaces at the microsec time scale and thus a diversity of phenomena are observed using different surfactants. By means of concrete examples it is shown that non-equilibrium nanostructures, e.g. Ru/Pt core-shell nanoparticles can be prepared. Hollow microbubbles with nanoparticles in the wall, which may contain gases over weeks, can be constructed by sonication of the corresponding colloid solutions.

Microbubbles↗

PubMed2006

Detection of microbubble formation during radiofrequency ablation using phonocardiography.

AIMS: To detect and characterize the acoustic energy generated by microbubble (MB) formation in an isolated tissue preparation. MB formation during radiofrequency (RF) ablation indicates excessive tissue heating and may precede explosive 'pops'. Currently, MB formation can only be detected with echocardiography. We hypothesized that MB formation can be detected with high-sensitivity phonocardiography. METHODS AND RESULTS: In a saline bath, RF lesions were created in sections of porcine left ventricle, using a 4 mm tip irrigated catheter. MB formation was visualized with an echocardiography probe. In 20 preparations, RF energy was begun at 25 W and increased by 5 W every 20 s until a pop occurred. A high-sensitivity computerized phonocardiography transducer with frequency bandwidth of 2 kHz and system noise -90 dB (SonoMedica, Inc., Vienna, VA, USA) was coupled to the external glass wall of the bath. In 15 of 20 (75%) preparations, a characteristic acoustic signature corresponding to MB formation was noted before the pop. These signals were within the 600-2000 Hz range and had an intensity range of 10-40 dB. The earliest MB and acoustic signals occurred 51.3+/-51.5 s before the pop. The acoustic signals continued intermittently up to 10.3+/-12.9 s before the pop. CONCLUSION: The acoustic energy created by MB formation can be detected in an isolated tissue preparation, using a computer-based phonocardiography system. Characteristic acoustic signatures are present before pops and correspond to MB formation. Acoustic monitoring for MB formation may allow for the titration of cooled RF ablation without echocardiography.

Animals↗

PubMed2006

Blood flow changes in hepatocellular carcinoma after the administration of thalidomide assessed by reperfusion kinetics during microbubble infusion: preliminary results.

OBJECTIVES: We sought to investigate whether thalidomide is able to produce tumor vascular changes in patients with untreatable hepatocellular carcinoma (HCC) that can be detected using microbubble contrast agents. MATERIALS AND METHODS: Eleven consecutive patients with untreatable HCC underwent contrast-enhanced ultrasound before and during thalidomide administration. Real-time destruction reperfusion kinetics was obtained from a representative HCC nodule and from the surrounding liver parenchyma during SonoVue infusion (Bracco, Milan, Italy) at a constant rate of 0.10 mL/s by using a syringe pump and modelized according to the mathematical function SI = A(1 - exp(-betat)) where the plateau signal intensity A reflects the percent blood volume, the time constant beta reflects the average speed of blood, and their product A*beta reflects the nutrient blood flow. RESULTS: Size of the representative nodule reduced significantly 3 to 6 months after the start of thalidomide treatment. Before thalidomide administration A, beta, and A*beta of the index lesion were 44 +/- 60 LIU, 0.31 +/- 0.40 seconds and 8.1 +/- 11.8 LIU/s, respectively). A and A*beta reduced significantly after 15 days (26 +/- 50 LIU and 2.9 +/- 4.8 LIU/s, P < 0.01), 3 months (12 +/- 18 LIU, and 4.3 +/- 7.7 LIU/s, P < 0.01), and 6 months (13 +/- 23 LIU and 2.4 +/- 3.7 LIU/s, P < 0.05) of treatment. No statistically significant changes of the exponential time constant beta were observed, nor changes of A, beta and A*beta in the liver parenchyma. CONCLUSIONS: Contrast-enhanced ultrasound can be used effectively to evaluate changes in perfusion parameters of HCC nodules during thalidomide administration.

Aged↗

PubMed2006

Optical and acoustic detection of laser-generated microbubbles in single cells.

Acoustically monitored laser-induced optical breakdown (LIOB) has potential as an important tool to diagnose and treat living cells. Laser-induced intracellular microbubbles are readily detectable using high-frequency ultrasound, and LIOB can be controlled to operate within two distinct regimes. In the nondestructive regime, a single, short-lived bubble can be generated within a cell, without affecting its immediate viability. In the destructive regime, the induced photodisruption quickly can kill a targeted cell. To generate and monitor this range of bioeffects in real time, we have developed a system integrating an ultrafast laser source with optical and acoustic microscopy. Experiments were performed on monolayers of Chinese hamster ovary (CHO) cells. A 793 nm, 100 fs laser pulsed at 3.8 kHz was tightly focused within each cell to produce the photodisruption, and a 50 MHz ultrasonic transducer monitored the resultant bubble via continuous pulse-echo recordings. Photodisruption was also observed using bright field microscopy, and cell viability was assessed following laser exposure with a trypan blue assay. By controlling laser pulse fluence and exposure duration, either nondestructive or destructive LIOB could be produced. The intracellular position of the laser focus was also varied to demonstrate that cell viability was affected by the specific location of material breakdown.

Acoustics↗

PubMed2006

Microbubble expansion in a flexible tube.

We have utilized a computational model of the expansion of a microbubble in a liquid-filled flexible tube to investigate the potential for acoustic vaporization of perfluorocarbon droplets to damage blood vessels during a novel gas embolotherapy technique for the potential treatment of tumors. This model uses a fixed grid, multi-domain, interface tracking, direct numerical simulation method that treats all interfaces and boundaries as sharp discontinuities for high accuracy. In the current work, we examined effects of initial bubble size on the flows and wall stresses that result from droplet vaporization. The remaining dimensionless parameters that govern the system response (Reynolds, Weber, and Strouhal numbers, initial bubble pressure, and wall stiffness and tension) were selected to model an arteriole. The results for a flexible tube are significantly different from those for a rigid tube. Two major flow regimes occur due to the combined effect of bubble and tube deformation: in flow at the tube ends and out flow near the bubble surface. The flexibility of the tube largely dissipates the extreme pressure that develops in the rigid tube model. Both the magnitude and the overall expansion time of the rapidly changing pressure are greatly reduced in the flexible tube. Smaller initial bubble diameters, relative to the vessel diameter, result in lower wall stresses. This study indicates that wall flexibility can significantly influence the wall stresses that result from acoustic vaporization of intravascular perfluorocarbon droplets, and suggests that acoustic activation of droplets in larger, more flexible vessels may be less likely to damage or rupture vessels than activation in smaller and stiffer vessels.

Animals↗

PubMed2006

Detection of acoustic cavitation in the heart with microbubble contrast agents in vivo: a mechanism for ultrasound-induced arrhythmias.

Ultrasound fields can produce premature cardiac contractions under appropriate exposure conditions. The pressure threshold for ultrasound-induced premature contractions is significantly lowered when microbubble contrast agents are present in the vasculature. The objective of this study was to measure directly ultrasound-induced cavitation in the murine heart in vivo and correlate the occurrence of cavitation with the production of premature cardiac contractions. A passive cavitation detection technique was used to quantify cavitation activity in the heart. Experiments were performed with anesthetized, adult mice given intravenous injections of either a contrast agent (Optison) or saline. Murine hearts were exposed to ultrasound pulses (200 kHz, 1 ms, 0.1-0.25 MPa). Premature beats were produced in mice injected with Optison and the likelihood of producing a premature beat increased with increasing pressure amplitude. Similarly, cavitation was detected in mice injected with Optison and the amplitude of the passive cavitation detector signal increased with increasing exposure amplitude. Furthermore, there was a direct correlation between the extent of cavitation and the likelihood of ultrasound producing a premature beat. Neither premature beats nor cavitation activity were observed in animals injected with saline and exposed to ultrasound. These results are consistent with acoustic cavitation as a mechanism for this bioeffect.

Animals↗

PubMed2005

Microbubble destruction with ultrasound augments neovascularisation by bone marrow cell transplantation in rat hind limb ischaemia.

OBJECTIVE: To examine the effects of microbubble destruction with ultrasound (MB) combined with bone marrow derived mononuclear cell transplantation (BMT) into ischaemic tissues in rat hind limb ischaemia. METHODS AND RESULTS: Unilateral hind limb ischaemia was surgically induced in Lewis rats. At postoperative day 7, rats were randomly divided into three groups: a vehicle treated group, an ultrasound treated group, and an MB treated group. MB treatment increased vascular endothelial growth factor mRNA as assessed by real time polymerase chain reaction (3.0-fold, p < 0.05). At four weeks, the MB group had increases in laser Doppler blood flow index (LDBFI; 1.2-fold, p < 0.05), angiographically detectable collateral vessels (angiographic score: 1.4-fold, p < 0.01), and capillary to muscle fibre ratio (1.4-fold, p < 0.01) in ischaemic limbs compared with the vehicle treated group. No differences were seen between the vehicle and ultrasound treated groups. Secondly, rats were allocated to vehicle treatment, BMT (5 x 10(6) cells/rat), or a combination of MB and BMT (MB+BMT) at seven days after hind limb ischaemia. BMT treatment significantly increased LDBFI, angiographic score, and capillary to muscle fibre ratio compared with vehicle treatment. Interestingly, MB+BMT treatment produced significantly greater LDBFI (1.2-fold, p < 0.01), angiographic score (1.5-fold, p < 0.01), and capillary to muscle fibre ratio (1.5-fold, p < 0.05) than BMT treatment alone. CONCLUSIONS: MB may be a useful technique to enhance BMT induced neovascularisation.

Animals↗

PubMed2004

Improved characterization of liver lesions with liver-phase uptake of liver-specific microbubbles: prospective multicenter study.

PURPOSE: To evaluate in a prospective multicenter study whether conventional ultrasonographic (US) characterization of liver lesions can be improved by imaging during the liver-specific phase of SH U 508A uptake in the microbubble-specific agent detection imaging mode. MATERIALS AND METHODS: One hundred forty-two patients with liver lesions underwent conventional gray-scale and color Doppler US and SH U 508A-enhanced US. Two radiologists blindly read digital cine clips and assigned scores for confidence in diagnosis of benignancy or malignancy, diagnosis of specific lesion types, and relative difference in SH U 508A uptake between the lesion and the liver parenchyma (ie, subjective conspicuity score [SCS]). Comparisons were made to see whether the addition of agent detection imaging led to improved diagnostic performance. RESULTS: Receiver operating characteristic analysis revealed improved discrimination of benign and malignant lesions for readers 1 (P =.049) and 2 (P <.001). The number of patients with a correct diagnosis of benignancy or malignancy assigned by readers 1 and 2, respectively, improved from 114 and 113 to 125 and 128 with agent detection imaging (reader 1: P =.027; reader 2: P =.008; McNemar test). Specific diagnoses were made more accurately with agent detection imaging: At McNemar testing, the number of correct lesion type determinations increased from 83 to 92 (P =.022) for reader 1 and from 85 to 99 (P <.001) for reader 2. Both readers assigned high scores for differences in SH U 508A uptake between the liver parenchyma and the lesion for metastases and cholangiocarcinomas and low scores for uptake differences in most of the benign lesions. Hepatocellular carcinomas (HCCs), hemangiomas, and adenomas had more variable uptake differences. Fourteen of 22 hemangiomas were assigned an SCS of less than 50%, and 22 (reader 1) and 15 (reader 2) of 31 HCCs were assigned an SCS of greater than 50%. CONCLUSION: With use of SH U 508A-enhanced agent detection imaging, liver lesion characterization and diagnostic performance are significantly improved.

Adult↗

PubMed2006

Prospective evaluation of vascular complications after liver transplantation: comparison of conventional and microbubble contrast-enhanced US.

PURPOSE: To prospectively compare diagnostic performance of conventional Doppler ultrasonography (US) and microbubble contrast material-enhanced US for assessment of vascular complications after liver transplantation, with clinical follow-up or angiography as reference standard. MATERIALS AND METHODS: This study was approved by institutional review board and was HIPAA compliant. Written informed consent was obtained. Seventy-two patients (49 men, 23 women; average age, 52.3 years) were included in this study. Patients who had undergone liver transplantation underwent conventional color Doppler and contrast-enhanced US of the liver. Quality of hepatic artery (HA) and portal vein (PV) visualization, contrast material arrival time, and time for complete evaluation of vasculature were compared for both techniques. McNemar test was used to compare vascular flow visualization scores; Student t test was used to compare mean study times with both techniques. Patients without HA flow at Doppler US underwent angiography; those with flow were followed up clinically. McNemar test was used to compare sensitivity of both techniques. RESULTS: Contrast-enhanced US helped significantly improve flow visualization in hepatic vessels (P < .001). Mean contrast material arrival time was 13.7 seconds +/- 3.8 (standard deviation) in proper HA and 20.7 seconds +/- 6.3 in PV. Mean study time decreased from 27.4 minutes +/- 13.9 to 9.3 minutes +/- 4.5 (P < .01). Doppler US failed to depict HA flow in eight patients; contrast-enhanced US showed flow in six and no flow in two of these patients. Follow-up results confirmed contrast-enhanced US findings. Sensitivity, specificity, and accuracy for Doppler US were 91.3%, 100%, and 91.5%, respectively. Sensitivity, specificity, and accuracy of contrast-enhanced US were all 100%. Sensitivity and accuracy values of the two techniques were significantly different (P < .014); there was no significant difference in specificity (P > .99) CONCLUSION: Contrast-enhanced US helped improve flow visualization in the HA and PV, decrease scanning time, and correctly differentiate between thrombosis and a patent artery in patients without HA flow at conventional Doppler US.

Adult↗

PubMed2005

Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator.

BACKGROUND AND PURPOSE: We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring. METHODS: We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded. RESULTS: Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score. CONCLUSIONS: Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Adult↗

PubMed2006

Gene transfer to corneal epithelium and keratocytes mediated by ultrasound with microbubbles.

PURPOSE: The cornea is an ideal organ for evaluating gene transfer because it can be treated noninvasively and monitored easily. The present study was performed to investigate the practical efficacy and safety of ultrasound (US) plus microbubble (MB)-mediated gene transfer to cornea. METHODS: Cultured rabbit corneal epithelial (RC-1) cells were incubated in 24-well dishes with plasmid DNA having a green fluorescent protein (GFP) gene under a cytomegalovirus promoter. The cells were exposed to US under different intensities (1 MHz; power, 0.5 approximately 2 W/cm2; duration, 15-120 seconds; duty cycle, 20%-100%). The effect of simultaneous stimulation with MBs was also examined. Gene transfer was quantified by counting the number of GFP-positive cells under microscopy. Furthermore, in vivo gene transfer was examined by GFP plasmid injection into rabbit cornea and US exposure with MBs. RESULTS: In the in vitro study, DNA exposure alone could not transfer gene into cultured RC-1 cells; US enhanced gene transfer slightly. Coexposure with MBs significantly increased gene transfer efficiency. In the in vivo study, DNA injection alone could transfer the gene to a limited degree, but plasmid injection plus US with MBs strongly increased gene transfer efficiency without apparent tissue damage, and gene transfer was achieved two dimensionally. CONCLUSIONS: US with MBs greatly increases gene transfer to in vivo and in vitro corneal cells. This noninvasive gene transfer method may be a useful tool for clinical gene therapy.

Animals↗

PubMed2005

Comparison of conventional extracorporeal circulation and minimal extracorporeal circulation with respect to microbubbles and microembolic signals.

The intention of minimal extracorporeal circulation (MECC) is to reduce priming volume and minimize contact of blood with polymers and air in a closed system. In contrast to conventional extracorporeal circulation (ECC), a venous reservoir is missing. Thus, air trapping is limited and avoidance of bubble embolism is a major concern. This study investigates microbubbles (MBB) number and size in the venous and arterial lines of ECC and MECC compared to the number of microembolic signals (MES) in the right and left middle cerebral artery (MCA). Twenty patients undergoing coronary surgery were operated either with conventional ECC (cardiotomy reservoir, Rotaflow pump, Quadrox oxygenator, Quart filter) or MECC (Quart filter, Rotaflow pump, Quadrox oxygenator). Number and size of MBB were monitored in the venous and arterial lines with an ultrasound Doppler system. MES in right and left MCAs were measured by transcranial Doppler (TCD) monitoring. Patients undergoing MECC had additional sealing of the venous cannula by a ligature at the site of its insertion into the right atrium. There were no significant differences between groups with respect to age, X-clamping, bypass time and number of distal anastomoses. The number of MES and MBB in the arterial line was comparable between the groups. On the venous side, MECC-perfusion shows a significantly lower number of MBB. This could be explained with the additional sealing of the venous cannula. Furthermore, our data indicate that the MBB-volume reaching the pump will also appear in the arterial outflow and into the patient's MCA. For this reason, the avoidance of air contamination is a major concern for surgeons, anaesthesiologists and perfusionists.

Aged↗

PubMed2003

Microbubble ultrasound contrast agents: a review.

The superior scattering properties of gas bubbles compared with blood cells have made microbubble ultrasound contrast agents important tools in ultrasound diagnosis. Over the past 2 years they have become the focus of a wide and rapidly expanding field of research, with their benefits being repeatedly demonstrated, both in ultrasound image enhancement, and more recently in drug and gene delivery applications. However, despite considerable investigation, their behaviour is by no means fully understood and, while no definite evidence of harmful effects has been obtained, there remain some concerns as to their safety. In this review the existing theoretical and experimental evidence is examined in order to clarify the extent to which contrast agents are currently understood and to identify areas for future research. In particular the disparity between the conditions considered in theoretical models and those encountered both in vitro, and more importantly in vivo is discussed, together with the controversy regarding the risk of harmful bio-effects.

Coated Materials, Biocompatible↗

PubMed2003

Stable microbubble test and click test to predict respiratory distress syndrome in preterm infants not requiring ventilation at birth.

AIMS: To determine the usefulness of the stable microbubble test (SMT) and of the click test (CT) on gastric aspirates obtained soon after birth to predict respiratory distress syndrome (RDS) in preterm babies not requiring ventilation at birth. PATIENTS AND METHODS: The study was carried out with a cohort between 24 and 34 weeks of gestational age. Gastric secretions were collected before 1 hour of life and frozen for further analysis. RESULTS: 110 neonates were studied. For a cut-off value 10 microbubbles/mm2 (mb/mm2) the sensitivity and specificity to predict RDS were 73.9 % and 92%, respectively, in the SMT. The best SMT cut-off point to predict RDS was < or = 15 mb/mm2 (sensitivity = 82.6% specificity = 85.1%) if equal weight was given to false-positive and false-negative results. CT (104 samples) showed a sensitivity of 100% and a specificity of 45.1% to predict RDS. The overall accuracy of the SMT was better than the overall accuracy of the CT (87.5% vs. 64.4%; p < 0.001) to predict RDS. CONCLUSIONS: The SMT is more accurate than the CT to predict RDS in infants below 35 weeks of gestational age and may be helpful to select patients to receive surfactant.

Cohort Studies↗

PubMed2006

Bioeffects of albumin-encapsulated microbubbles and real-time myocardial contrast echocardiography in an experimental canine model.

Myocardial contrast echocardiography has been used for assessing myocardial perfusion. Some concerns regarding its safety still remain, mainly regarding the induction of microvascular alterations. We sought to determine the bioeffects of microbubbles and real-time myocardial contrast echocardiography (RTMCE) in a closed-chest canine model. Eighteen mongrel dogs were randomly assigned to two groups. Nine were submitted to continuous intravenous infusion of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) plus continuous imaging using power pulse inversion RTMCE for 180 min, associated with manually deflagrated high-mechanical index impulses. The control group consisted of 3 dogs submitted to continuous imaging using RTMCE without PESDA, 3 dogs received PESDA alone, and 3 dogs were sham-operated. Hemodynamics and cardiac rhythm were monitored continuously. Histological analysis was performed on cardiac and pulmonary tissues. No hemodynamic changes or cardiac arrhythmias were observed in any group. Normal left ventricular ejection fraction and myocardial perfusion were maintained throughout the protocol. Frequency of mild and focal microhemorrhage areas in myocardial and pulmonary tissue was similar in PESDA plus RTMCE and control groups. The percentages of positive microscopical fields in the myocardium were 0.4 and 0.7% (P = NS) in the PESDA plus RTMCE and control groups, respectively, and in the lungs they were 2.1 and 1.1%, respectively (P = NS). In this canine model, myocardial perfusion imaging obtained with PESDA and RTMCE was safe, with no alteration in cardiac rhythm or left ventricular function. Mild and focal myocardial and pulmonary microhemorrhages were observed in both groups, and may be attributed to surgical tissue manipulation.

Animals↗

PubMed2005

Hepatocyte growth factor delivered by ultrasound-mediated destruction of microbubbles induces proliferation of cardiomyocytes and amelioration of left ventricular contractile function in Doxorubicin-induced cardiomyopathy.

At present, there is no curative strategy for advanced cardiomyopathy except for cardiac transplantation, which is not easily performed, mainly due to a shortage of donors. It has been reported that myocardial progenitor cells exist even in the postnatal heart, suggesting that myocardial progenitor cells could proliferate under some situations and might improve cardiac function in cardiomyopathy-induced hearts. In this study, recombinant human hepatocyte growth factor (rhHGF) was delivered using ultrasound-mediated destruction of microbubbles (UMDM) into the cardiomyopathy-induced heart by doxorubicin (20 mg/kg). Intravenous injection of rhHGF (IV-rhHGF) alone or UMDM alone failed to improve the morphology or the function of the cardiomyopathy-induced heart, but (IV-rhHGF + UMDM) treatment significantly improved the heart morphologically and functionally, and repetitive treatments of (IV-rhHGF + UMDM) enhanced the effects. The number of bromodeoxy-uridine-positive cardiomyocytes significantly increased in the (IV-rhHGF + UMDM)-treated hearts compared with the untreated hearts. Moreover, Sca-1+ myocardial progenitor cells express c-Met, a receptor for HGF. These results suggest that (IV-rhHGF + UMDM) treatment could morphologically and functionally improve the heart in the case of doxorubicin-induced cardiomyopathy through the proliferation of the myocardial progenitor cells.

Animals↗