The purpose of this study was to develop and investigate a new noninvasive approach to quantify left ventricular (LV) pressures using subharmonic emissions from microbubbles. A Sonix RP ultrasound scanner with PA4-2 phased array transducer was used in pulse inversion grayscale mode. Unprocessed radiofrequency data were obtained for 5 seconds (n=3) with pulsed wave Doppler from the aorta and/or LV of 4 canines during Sonazoid infusion. Simultaneous pressure measurements were obtained using Millar manometer. Subharmonic data (in dB) were extracted and processed. The resulting calibration factor (mmHg/dB), from the aorta, was used to estimate LV pressures. Errors ranged from 0.19 to 2.50 mmHg when estimating these pressures using the aortic calibration factor from the respective canines; but were considerably higher (0.64-8.98 mmHg) when a mean aortic calibration factor was used. In conclusion, subharmonic emissions from ultrasound contrast agents have the potential to noninvasively monitor LV pressures.

The lack of open access to the pre-beamformed data of an ultrasound scanner has limited the research of novel imaging methods to a few privileged laboratories. To address this need, we have developed a pre-beamformed data acquisition (DAQ) system that can collect data over 128 array elements in parallel from the Ultrasonix series of research-purpose ultrasound scanners. Our DAQ system comprises three system-level blocks: 1) a connector board that interfaces with the array probe and the scanner through a probe connector port; 2) a main board that triggers DAQ and controls data transfer to a computer; and 3) four receiver boards that are each responsible for acquiring 32 channels of digitized raw data and storing them to the on-board memory. This system can acquire pre-beamformed data with 12-bit resolution when using a 40-MHz sampling rate. It houses a 16 GB RAM buffer that is sufficient to store 128 channels of pre-beamformed data for 8000 to 25 000 transmit firings, depending on imaging depth; corresponding to nearly a 2-s period in typical imaging setups. Following the acquisition, the data can be transferred through a USB 2.0 link to a computer for offline processing and analysis. To evaluate the feasibility of using the DAQ system for advanced imaging research, two proof-of-concept investigations have been conducted on beamforming and plane-wave B-flow imaging. Results show that adaptive beamforming algorithms such as the minimum variance approach can generate sharper images of a wire cross-section whose diameter is equal to the imaging wavelength (150 μm in our example). Also, planewave B-flow imaging can provide more consistent visualization of blood speckle movement given the higher temporal resolution of this imaging approach (2500 fps in our example).

In this work, the development of subharmonic emission based noninvasive pressure estimation technique is presented. In vitro, ambient pressures were varied (between 0 and 120 mmHg) in a closed-loop flow system circulating 0.2 ml Sonazoid microbubbles (GE Healthcare, Oslo, Norway) suspended in 750 ml of isotonic diluent and recorded by a Millar pressure catheter as the reference standard. Simultaneously, a SonixRP ultrasound scanner (Ultrasonix Medical Corp., Richmond, BC, Canada) operating in pulse inversion mode (f transmit : 2.5 MHz) was used to acquire unprocessed RF data at five different incident acoustic pressures (from 76 kPa to 897 kPa; n=3). The subharmonic data for each pulse was extracted using band-pass filtering with averaging, and subsequently, processed to eliminate noise. The incident acoustic pressure most sensitive to ambient pressure fluctuations was determined; then the ambient pressure was tracked over 20 seconds. Regression analysis compared subharmonic and catheter pressure values. In vivo validation of this technique was performed noninvasively for tracking left ventricular (LV) pressures of two canines using similar post processing as in vitro. The subharmonic signal tracked ambient pressures with r 2 = 0.922 for 20 seconds in vitro. In vivo the subharmonic signal tracked the LV pressures with r 2 > 0.790. Maximum errors in estimating clinically relevant systolic and diastolic pressures ranged from 0.22 to 2.84 mmHg using this subharmonic technique relative to Millar catheter pressures. Clinical validation and real time implementation of this technique may ultimately lead to the first noninvasive cardiac pressure monitoring tool.

Right heart catheterization is often required to monitor intra-cardiac pressures in a number of disease states. Ultrasound contrast agents can produce pressure modulated subharmonic emissions that may be used to estimate right ventricular (RV) pressures. A technique based on subharmonic acoustic emissions from ultrasound contrast agents to track RV pressures noninvasively has been developed and its clinical potential evaluated. The subharmonic signals were obtained from the aorta, RV, and right atrium (RA) of five anesthetized closed-chest mongrel dogs using a SonixRP ultrasound scanner and PA4-2 phased array. Simultaneous pressure measurements were obtained using a 5-French solid state micromanometer tipped catheter. Initially, aortic subharmonic signals and systemic blood pressures were used to obtain a calibration factor in units of millimeters of mercury per decibel. This factor was combined with RA pressures (that can be obtained noninvasively) and the acoustic data from the RV to obtain RV pressure values. The individual calibration factors ranged from -2.0 to -4.0 mmHg/dB. The subharmonic signals tracked transient changes in the RV pressures within an error of 0.6 mmHg. Relative to the catheter pressures, the mean errors in estimating RV peak systolic and minimum diastolic pressures, and RV relaxation [isovolumic negative derivative of change in pressure over time (-dP/dt)] by use of the subharmonic signals, were -2.3 mmHg, -0.8 mmHg, and 2.9 mmHg/s, respectively. Overall, acoustic estimates of RV peak systolic and minimum diastolic pressures and RV relaxation were within 3.4 mmHg, 1.8 mmHg, and 5.9 mmHg/s, respectively, of the measured pressures. This pilot study demonstrates that subharmonic emissions from ultrasound contrast agents have the potential to noninvasively track in vivo RV pressures with errors below 3.5 mmHg.

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