Xiaofang Lu

Use of Theranostic Strategies in Myocardial Cavitation-Enabled Therapy.

The accumulation of microlesions induced by ultrasound interaction with contrast microbubbles in the myocardium potentially represents a new method of tissue reduction therapy. Anesthetized rats were treated in a heated water bath with 1.5-MHz focused ultrasound pulses triggered once every four heartbeats from the electrocardiogram during infusion of microbubble contrast agent. Treatment was guided by an 8-MHz B-mode imaging transducer, which also was used to provide estimates of left ventricular echogenicity as a possible predictor of efficacy during treatment. Strategies to reduce prospective clinical treatment durations were tested, including pulse modulation to simulate a theranostic scanning strategy and an increased agent infusion rate over shorter durations. Sources of variability, including ultrasound path variation and venous catheter placement, also were investigated. Electrocardiographic premature complexes were monitored, and Evans-blue stained cardiomyocyte scores were obtained from frozen sections. Left ventricular echogenicity reflected variations in the infused microbubble concentration, but failed to predict efficacy. Comparison of suspensions of varied microbubble size revealed that left ventricular echogenicity was dominated by larger bubbles, whereas efficacy appeared to be dependent on smaller sizes. Simulated scanning was as effective as the normal fixed-beam treatment, and high agent infusion allowed reduced treatment duration. The success of these theranostic strategies may increase the prospects for realistic clinical translation of myocardial cavitation-enabled therapy.

Do Anesthetic Techniques Influence the Threshold for Glomerular Capillary Hemorrhage Induced in Rats by Contrast-Enhanced Diagnostic Ultrasound?

Glomerular capillary hemorrhage can be induced by ultrasonic cavitation during contrast‐enhanced diagnostic ultrasound (US) exposure, an important nonthermal US bioeffect. Recent studies of pulmonary US exposure have shown that thresholds for another nonthermal bioeffect of US, pulmonary capillary hemorrhage, is strongly influenced by whether xylazine is included in the specific anesthetic technique. The objective of this study was to determine the influence of xylazine on contrast‐enhanced diagnostic US‐induced glomerular capillary hemorrhage.

Ultrasonic Cavitation-Enabled Treatment for Therapy of Hypertrophic Cardiomyopathy: Proof of Principle

Ultrasound myocardial cavitation-enabled treatment was applied to the SS-16BN rat model of hypertrophic cardiomyopathy for proof of the principle underlying myocardial reduction therapy. A focused ultrasound transducer was targeted using 10-MHz imaging (10 S, GE Vivid 7) to the left ventricular wall of anesthetized rats in a warmed water bath. Pulse bursts of 4-MPa peak rarefactional pressure amplitude were intermittently triggered 1:8 heartbeats during a 10-min infusion of a microbubble suspension. Methylprednisolone was given to reduce initial inflammation, and Losartan was given to reduce fibrosis in the healing tissue. At 28 d post therapy, myocardial cavitation-enabled treatment significantly reduced the targeted wall thickness by 16.2% (p <0.01) relative to shams, with myocardial strain rate and endocardial displacement reduced by 34% and 29%, respectively, which are sufficient for therapeutic treatment. Premature electrocardiogram complexes and plasma troponin measurements were found to identify optimal and suboptimal treatment cohorts and would aid in achieving the desired impact. With clinical translation, myocardial cavitation-enabled treatment should fill the need for a new non-invasive hypertrophic cardiomyopathy therapy option.

Influence of Microbubble Size and Pulse Amplitude on Hepatocyte Injury Induced by Contrast-Enhanced Diagnostic Ultrasound

Recent research has found that contrast-enhanced diagnostic ultrasound (CEDUS) has the potential to induce localized injury in the liver, with clearly observable effects for contrast agent doses higher than the recommended dose and maximal mechanical index values. This study was undertaken to assess effects with intermittent exposure at lower contrast doses of infusion and at reduced output to determine thresholds. In addition, microbubble (MB) suspensions with enhanced content of larger MBs were tested. Exposure from a phased array probe (GE Vivid 7 Dimension, GE Vingmed Ultrasound, Horten, Norway) was applied at 1.6 MHz and 1-s intermittent frame trigger for 10 min with infusion of MB suspension with normal (1.8 µm), medium (3.1 µm) and large (5.3 µm) mean MB diameters. The bio-effect endpoint was the count of hepatocytes stained with Evans blue dye in frozen sections. For the normal MBs, the count increased for clinically relevant infusion dosages, but leveled off above 20 µL/kg/min. The evidence of injury declined with time from 30 min to 4 h and was lacking at 24 h. The exposure thresholds in terms of peak rarefactional pressure amplitude, divided by the square root of frequency (in situ mechanical index) were 1.7, 1.3 and 1.2 for the normal-, medium- and large-sized MB suspensions. The enhanced efficacy for larger MBs lends support to the two-criterion model for cavitational microvascular injury during CEDUS. Overall, CEDUS in liver appears to have markedly less potential for induction of tissue injury than has been reported in other tissues, which indicates a satisfactory safety profile for CEDUS using recommended parameters in normal liver.

The Dependence of Glomerular Capillary Hemorrhage Induced by Contrast Enhanced Diagnostic Ultrasound on Microbubble Diameter

A recently proposed two-criterion model for cavitational bioeffects in tissue with microbubbles (MBs) was tested. The glomerular capillary hemorrhage bioeffect was observed in rat kidney for contrast agent MB suspensions with mean diameters of 1.6, 3.1 and 5.5 µm. A diagnostic ultrasound machine was used at 3.6 MHz and 5.5 MHz for intermittent scans at power settings 2 dB apart. Petechial hemorrhage counts scored on the surface of the kidneys, and glomeruli were scored in histology. Thresholds for the petechial hemorrhage measurements were the same for the large and medium MB suspensions but substantially higher for the small MBs. For the histology, the medium MBs gave a higher threshold than the large MBs at 5.5 MHz. The pressure amplitude thresholds are in approximate agreement with theory, and the optimum MB size counterintuitively increased for increasing ultrasound frequency, as predicted. The two-criterion model of MB-associated capillary hemorrhage is supported.

Ultrasonic cavitation-enabled treatment for therapy of hypertrophic cardiomyopathy: Proof-of-principle

Ultrasound myocardial cavitation enabled treatment (MCET) creates scattered microlesions in the myocardium, which can be accumulated to produce a desired macrolesion. MCET was applied to the SS-16BN rat model of hypertrophic cardiomyopathy (HCM) for proof-of-principle as a means for myocardial reduction. A focused ultrasound transducer was targeted using 10 MHz imaging (10S, GE Vivid 7) to the left ventricular wall of anesthetized rats in a warmed water bath. Pulse bursts of 4 MPa peak rarefactional pressure amplitude were intermittently triggered 1:8 heartbeats during 10 min infusion of a microbubble suspension. Methylprednisolone was given to reduce initial inflammation and Losartan was given to improve healing. MCET significantly reduced the targeted wall thickness (n = 11) at 28 d post treatment by 16.2% (P<0.01) relative to shams (n = 8), with myocardial strain rate and endocardial border displacement reduced by 34% and 29%, respectively. This demonstrates sufficient effect for a therapeutic outcome ...

Frequency dependence of thresholds for lethal cardiomyocyte injury in myocardial contrast echocardiography

Contrast enhanced diagnostic ultrasound employs microbubble activation for microvascular imaging; however, the on-screen Mechanical Index is a poor parameter for safety guidance. More research is needed on microvascular bioeffects, particularly their variation with frequency. A GE Vivid 7 with an S3 probe operated at 1.6 MHz, and an S5 probe operated at 2.5 and 3.5 MHz was used for myocardial contrast echocardiography of rats mounted in a water bath. Power settings were varied in 2 dB steps for determination of the thresholds for cardiomyocyte injury. The contrast agent was made to duplicate the properties of the clinical agent Definity. The scans were intermittently triggered each 4 heartbeats from the ECG signal. The cardiomyocyte death was assessed using Evans blue vital staining. Thresholds were defined as the mean of the lowest exposure with a statistically significant cardiomyocyte death and the next lower exposure level. Thresholds were 1.2 MPa, 1.7 MPa, and 2.7 MPa peak rarefactional pressure ampl...