Yiying I. Zhu

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.

Characterization of Macrolesions Induced by Myocardial Cavitation-Enabled Therapy

Intermittent high intensity ultrasound pulses with circulating contrast agent microbubbles can induce scattered cavitation caused myocardial microlesions of potential value for tissue reduction therapy. Here, computer-aided histological evaluation of the effective treated volume was implemented to optimize ultrasound pulse parameters, exposure duration, and contrast agent dose. Rats were treated with 1.5 MHz focused ultrasound bursts and Evans blue staining indicates lethal cardiomyocytic injury. Each heart was sectioned to provide samples covering the entire exposed myocardial volume. Both brightfield and fluorescence images were taken for up to 40 tissue sections. Tissue identification and microlesion detection were first done based on 2-D images to form microlesion masks containing the outline of the heart and the stained cell regions. Image registration was then performed on the microlesion masks to reconstruct a volume-based model according to the morphology of the heart. The therapeutic beam path was estimated from the 3-D stacked microlesions, and finally the total microlesion volume, here termed macrolesion, was characterized along the therapeutic beam axis. Radially symmetric fractional macrolesions were characterized via stepping disks of variable radius determined by the local distribution of microlesions. Treated groups showed significant macrolesions of a median volume of 87.3 μL, 2.7 mm radius, 4.8 mm length, and 14.0% lesion density compared to zero radius, length, and lesion density for sham. The proposed radially symmetric lesion model is a robust evaluation for myocardial cavitation-enabled therapy. Future work will include validating the proposed method with varying acoustic exposures and optimizing involved parameters to provide macrolesion characterization.

Characterization of macrolesions induced by myocardial contrast enabled therapy (MCET)

Intermittent high intensity ultrasound pulses with circulating contrast agent microbubbles can induce scattered cavitation microlesions of potential value for myocardial reduction therapy. In this study, a computer-aided evaluation scheme of the effective treated volume was implemented in order to optimize ultrasound pulse parameters, exposure duration, and contrast agent dose. Rats with Evans blue injections were treated with 1.5 MHz focused ultrasound bursts. Evans blue staining indicates lethal cardiomyocytic injury. After frozen in compound on dry ice, each heart was sectioned to provide samples covering the entire exposed myocardial volume. Both brightfield and fluorescence images of 25 tissue sections were taken. Tissue detection and microlesion detection were first done based on the 2D images to form microlesion masks containing the outline of the heart and the dead cell regions. Image registration was then performed on the microlesion masks to reconstruct a volume-based model according to the morp...

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.

Passive microlesion detection and mapping for treatment of hypertrophic cardiomyopathy

Intermittent high intensity ultrasound pulses with circulating contrast agent microbubbles can induce scattered microlesions of potential value for myocardial reduction therapy. This paper presents an in vitro setup imitating the treatment for monitoring development. A preclinical imaging system with a single element transducer, synchronization and receive-only imaging transducer array has been implemented on a research platform. Contrast agent microbubbles pumped in a dialysis tubing setup were exposed to high intensity focused ultrasound at 1.0/3.5 MHz center frequencies. Polystyrene spheres were employed as linear scatterers compared to contrast agents for system transfer function equalization. A cavitation mapping technique was employed to spatially locate and depict microbubble activity during treatment. For high acoustic pressure amplitudes a 5 dB difference between contrast agent and solid spheres was observed and spatially mapped. The in-plane resolution was 4.5 mm for axial and 1.5 mm laterally. In the future, this cavitation detection scheme will be applied to monitor in vivo microlesioning in real-time.

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 ...

Myocardial cavitation-enabled therapy modeling

A therapeutic method named Myocardial Cavitation Enabled Therapy aiming at noninvasive cardiac tissue reduction is modeled here. Sparsely distributed microlesions induced by ultrasound cavitation of contrast agents are hypothesized to cause myocardial shrinkage. The objective is to model lesion formation based on the acoustic field and plan treatments accordingly. An ultrasound field simulation was established in Field II, an acoustics toolbox. It simulates the acoustic field of a 1.5 MHz ultrasound burst of five cycles at 4.0 MPa peak rarefactional pressure amplitude (PRPA) by use of a F# 2 single element therapeutic transducer, as used in concomitant animal studies. Medium parameters, including speed of sound, density, absorption, and B/A were set to water path and heart tissue along the acoustic path. Lesions were masked as region exceeding 2 MPa PRPA, the threshold of microlesions occurrence. The lesion volume is 143 μL compared to in vivo rodent study of approximately 100 μL. To reach a larger lesion...