A Quick Introduction to Subharmonic Imaging and Pressure Estimation

Our imaging field has had access to commercial microbubble-based ultrasound contrast agents for well over twenty years by now. It is well established that these agents—combined with nonlinear contrast-specific imaging techniques—improve both the sensitivity and specificity of ultrasound diagnoses across a wide range of clinical applications.

There are currently 3 ultrasound contrast agents approved by the United States’ Food and Drug Administration (FDA) for cardiology and/or radiology applications: Optison (GE Healthcare, Princeton, NJ); Definity (Lantheus Medical Imaging, N Billerica, MA); and Lumason (marketed for more than a decade in Europe and elsewhere as SonoVue; Bracco Imaging, Milan, Italy). There are other contrast agents in commercial development around the world; in particular Sonazoid (GE Healthcare) and BR55 (Bracco Imaging). Very importantly, the safety profiles of all of these agents are also well established with a severe reaction rate of less than 0.01% (based on studies of millions of dosages injected worldwide), making them the safest of all contrast media used for imaging.

Flemming Forsberg, PhD

Ultrasound agents consist of billions of gas microbubbles (typically < 8 mm in diameter) that are each encapsulated by an outer shell for stability. Following an intravenous injection, the microbubbles can traverse the lung capillaries and circulate in the blood for 3–6 minutes (under continuous imaging—longer if intermittent imaging is employed), due to their size and the higher molecular weight gasses used as filling gasses (rather than just air as was used in earlier microbubble designs), which reduces diffusion back into solution.

The acoustic properties of the bubble filing gasses (specifically the compressibility) are very different from those of the surrounding blood (by six orders of magnitude). Hence, microbubble-based ultrasound contrast agents can enhance ultrasound signals markedly with echo signals being increased by up to 30 dB. This in turn enables signals from breast tumor neovascularity corresponding mainly to vessels 20–39 mm in diameter to be imaged.

Ultrasound contrast agents not only enhance the backscattered ultrasound signals, but at sufficient acoustic pressures (typically above 0.3 MPa) they also act as nonlinear oscillators. These oscillations generate significant energy components in the received echo signals, which span the range of possible frequency emissions from subharmonics through ultra-harmonic frequency components. These nonlinear bubble echoes can be separated from tissue echoes and used to create contrast-sensitive imaging modalities such as harmonic imaging (HI), which is commercially available on most state-of-the-art ultrasound scanners.

Multi-pulse imaging strategies, such as pulse-inversion imaging or pulse-amplitude modulation, can further improve the depiction of microvascularity compared to color Doppler imaging modes. However, HI suffers from reduced blood-to-tissue contrast resulting from second harmonic generation and accumulation in tissue. Hence, subharmonic imaging (SHI), transmitting at the fundamental frequency (f0) and receiving at the subharmonic (f0/2), becomes an attractive alternative because of the weaker subharmonic generation in tissue and the significant subharmonic scattering produced by some new contrast agents. Several ultrasound scanners (from GE Healthcare and Mindray) have now been released with commercial SHI software packages. A recent multi-center study of 3D SHI for characterizing suspicious breast lesions indicates that diagnostic accuracies up to 97% can be achieved.

Ultrasound contrast agents can be used not only as vascular tracers but also as sensors for noninvasive pressure estimation by monitoring subharmonic contrast bubble amplitude variations. This innovative technique, called subharmonic-aided pressure estimation (SHAPE), relies on the inverse linear correlation (r2 > 0.90) between the amplitude of the subharmonic signals and hydrostatic pressure (up to 186 mmHg) measured in vitro for most (but not all) commercial contrast agents. SHAPE offers the possibility of allowing pressure gradients in the heart and throughout the cardiovascular system as well as interstitial fluid pressure in tumors to be obtained noninvasively. Studies indicate that SHAPE can provide in vivo pressure estimates with errors of less than 5 mmHg in the left and right ventricles of patients. Moreover, a large multi-center clinical trial of using SHAPE to diagnose clinically significant portal hypertension in 178 subjects resulted in a sensitivity of 91% and a specificity of 82% and these subjects had a higher SHAPE gradient than participants with lower pressures (0.27 ± 2.13 dB vs -5.34 ± 3.29 dB; p<0.001) indicating SHAPE may indeed be a useful tool for the diagnosis of portal hypertension.

Flemming Forsberg, PhD, FAIUM, FAIMBE, is a Professor of Radiology at Thomas Jefferson University in Philadelphia, Pennsylvania. He also serves as a Deputy Editor of the Journal of Ultrasound in Medicine and as the Vice Chair of the American Institute of Ultrasound in Medicine’s (AIUM’s) Contrast-Enhanced Ultrasound Community (2021–2023).

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