Artificial Intelligence for the Measurement of the Aortic Valve Annulus.

OBJECTIVE: The authors aim to evaluate an automated echocardiography software as compared with computed tomography in measurement of the aortic valve annulus in patients with aortic stenosis. The authors hypothesize that aortic annular measurements by this software and computed tomography will show acceptable correlation. DESIGN: This study is an Institutional Review Board-approved, retrospective data collection of patients with aortic stenosis who underwent implantation of a transcatheter heart valve with intraprocedural transesophageal echocardiography, multidetector computed tomography, and use of the Siemens eSie Valves automated aortic valve software. SETTING: Intraprocedural in a single hospital institution. PARTICIPANTS: The participants are 47 patients who underwent implantation of an Edwards SAPIEN 3 transcatheter heart valve. INTERVENTIONS: The authors compared aortic valve annulus measurements by two-dimensional transesophageal echocardiography, computed tomography, and the automated software. MEASUREMENTS AND MAIN RESULTS: Aortic annulus measurements by the software correlated more closely to the computed tomography measurements than two-dimensional measurements. Bland-Altman analysis showed qualitative comparability of measurements performed by the automated software to computed tomography (95% limits of agreement between -4.62 mm and 1.26 mm for area-derived and -4.51 mm and 1.45 mm for perimeter-derived methods). Similarly, there was significant linear correlation with automated software use (r = 0.84, p < 0.0001 and r = 0.85, p < 0.0001). CONCLUSIONS: Periprocedural aortic valve measurement by automated echocardiographic software correlates with computed tomography in patients with severe aortic stenosis. This technology is helpful and accurate, but has limitations.

Clinical Implications of Three-Dimensional Real-Time Color Doppler Transthoracic Echocardiography in Quantifying Mitral Regurgitation: A Comparison with Conventional Two-Dimensional Methods.

BACKGROUND: Automatic quantification of real-time three-dimensional (3D) full-volume color Doppler transthoracic echocardiography (FVCD) has been proposed as a feasible and accurate method for quantifying MR. We aimed to explore the clinical implications of real-time 3D-FVCD for mitral regurgitation (MR) with various clinical manifestations, in comparison with the conventional two-dimensional (2D) proximal isovelocity surface area (PISA) and volumetric method and cardiac magnetic resonance imaging (CMR) methods. METHODS: A total 186 patients with MR were enrolled prospectively. Based on exclusion criteria and image quality review, 152 patients were included in the final analysis for 3D-FVCD and 2D transthoracic echocardiography. Among them, 37 patients underwent subsequent CMR for the validation of 3D-FVCD. RESULTS: MR volume from 3D-FVCD demonstrated a better agreement (r = 0.94) with CMR than 2D-PISA or the 2D volumetric method (VM; r = 0.87 vs 0.56). Overall, 2D methods underestimated MR when compared with 3D-FVCD (35.4 ± 28.4 mL for 2D-VM vs 43.8 ± 24.6 mL for 2D-PISA vs 64.6 ± 35.1 mL for 3D-FVCD; P < .001). In subgroup analysis, multijet MR (odds ratio [OR], 6.30; 95% CI, 2.52-15.72) and dilated left ventricular end-systolic diameter ≥40 mm (OR, 2.90; 95% CI, 1.12-7.50) were predictors of significant difference in MR volume (>30 mL for primary MR and >15 mL for secondary MR) between 2D-PISA and 3D-FVCD. In identifying surgical candidates, patients with multijet MR (OR, 4.53, 95% CI, 1.99-10.35) demonstrated a higher risk of discrepancy between 2D-PISA and 3D-FVCD, which were consistent in both primary and secondary MR, respectively. CONCLUSIONS: MR quantification with 3D-FVCD showed better correlation and agreement than conventional 2D methods. MR was underestimated by 2D methods, especially in multijet and dilated left ventricle. Multijet MR demonstrated higher risk of discrepancy for the identification of surgical candidate, regardless of MR etiology.

Quantitative assessment of mitral inflow and aortic outflow stroke volumes by 3-dimensional real-time full-volume color flow doppler transthoracic echocardiography: an in vivo study.

OBJECTIVES: Noninvasive quantification of left ventricular (LV) stroke volumes has an important clinical role in assessing circulation and monitoring therapeutic interventions for cardiac disease. This study validated the accuracy of a real-time 3-dimensional (3D) color flow Doppler method performed during transthoracic echocardiography (TTE) for quantifying volume flows through the mitral and aortic valves using a dedicated offline 3D flow computation program compared to LV sonomicrometry in an open-chest animal model. METHODS: Forty-six different hemodynamic states in 5 open-chest pigs were studied. Three-dimensional color flow Doppler TTE and 2-dimensional (2D) TTE were performed by epicardial scanning. The dedicated software was used to compute flow volumes at the mitral annulus and the left ventricular outflow tract (LVOT) with the 3D color flow Doppler method. Stroke volumes by 2D TTE were computed in the conventional manner. Stroke volumes derived from sonomicrometry were used as reference values. RESULTS: Mitral inflow and LVOT outflow derived from the 3D color flow Doppler method correlated well with stroke volumes by sonomicrometry (R = 0.96 and 0.96, respectively), whereas correlation coefficients for mitral inflow and LVOT outflow computed by 2D TTE and stroke volumes by sonomicrometry were R = 0.84 and 0.86. Compared to 2D TTE, the 3D method showed a smaller bias and narrower limits of agreement in both mitral inflow (mean ± SD: 3D, 2.36 ± 2.86 mL; 2D, 10.22 ± 8.46 mL) and LVOT outflow (3D, 1.99 ± 2.95 mL; 2D, 4.12 ± 6.32 mL). CONCLUSIONS: Real-time 3D color flow Doppler quantification is feasible and accurate for measurement of mitral inflow and LVOT outflow stroke volumes over a range of hemodynamic conditions.

Quantification of mitral regurgitation by real time three-dimensional color Doppler flow echocardiography pre- and post-percutaneous mitral valve repair.

BACKGROUND: Echocardiographic quantification of mitral regurgitation (MR) can be challenging if the valve geometry is significantly altered. Our aim was to compare the quantification of MR by the recently developed real time three-dimensional (3D) volume color flow Doppler (RT-VCFD) method to the conventional two-dimensional (2D) echocardiographic methods during the MitraClip procedure. METHODS: Twenty-seven patients (mean age 76 ± 8 years, 56% male) were prospectively enrolled and severity of MR was assessed before and after the MitraClip procedure in the operating room by 3 different methods: (1) by integrative visual approach by transesophageal echocardiography, (2) by transthoracic 2D pulsed-wave Doppler-based calculation of aortic stroke volumes (SV) and mitral inflow allowing calculation of regurgitant volume, and (3) by transthoracic 3D RT-VCFD-based calculation of regurgitant volume. RESULTS: We found moderate agreement between the integrative visual approach and the 3D RT-VCFD method for assessment of MR severity before (κ = 0.4, P < 0.05) and after MitraClip (κ = 0.5, P < 0.05). Relevant MR (3+ and 4+) was detected by visual approach in 27/27 and by 3D-VCFD method in 24/27 patients before and in 1 patient by both methods after the MitraClip procedure. In contrast, MR quantification by 2D SV method did not agree with the integrative visual approach or with the 3D RT-VCFD method. CONCLUSIONS: Quantification of MR before and after percutaneous MV repair by 3D RT-VCFD is comparable to the integrative visual assessment and more reliable than the 2D SV method in this small study population. Further automation of 3D RT-VCFD is needed to improve the accuracy of peri-interventional MR quantification.

Effects of right ventricular hemodynamic burden on intraventricular flow in tetralogy of fallot: an echocardiographic contrast particle imaging velocimetry study.

BACKGROUND: The purpose of this investigation was to test the hypothesis that flow patterns in the right ventricle are abnormal in patients with repaired tetralogy of Fallot (TOF). High-resolution echocardiographic contrast particle imaging velocimetry was used to investigate rotation intensity and kinetic energy dissipation of right ventricular (RV) flow in patients with TOF compared with normal controls. METHODS: Forty-one subjects (16 with repaired TOF and varying degrees of RV dilation and 25 normal controls) underwent prospective contrast imaging using the lipid-encapsulated microbubble (Definity) on Sequoia systems. A mechanical index of 0.4, three-beat high-frame rate (>60 Hz) captures, and harmonic frequencies were used. Rotation intensity and kinetic energy dissipation of flow in the right and left ventricles were studied (Hyperflow). Ventricular volumes and ejection fractions in all subjects were derived from same-day cardiac magnetic resonance (CMR). RESULTS: Measurable planar maps were obtained for the left ventricle in 14 patients and the right ventricle in 10 patients among those with TOF and for the left ventricle in 23 controls and the right ventricle in 21 controls. Compared with controls, the TOF group had higher RV indexed end-diastolic volumes (117.8 ± 25.5 vs 88 ± 15.4 mL/m(2), P < .001) and lower RV ejection fractions (44.6 ± 3.6% vs 51.8 ± 3.6%, P < .001). Steady-streaming (heartbeat-averaged) flow rotation intensities were higher in patients with TOF for the left ventricle (0.4 ± 0.13 vs 0.29 ± 0.08, P = .012) and the right ventricle (0.53 ± 0.15 vs 0.26 ± 0.12, P < .001), whereas kinetic energy dissipation in TOF ventricles was lower (for the left ventricle, 0.51 ± 0.29 vs 1.52 ± 0.69, P < .001; for the right ventricle, 0.4 ± 0.24 vs 1.65 ± 0.91, P < .001). CONCLUSIONS: It is feasible to characterize RV and left ventricular flow parameters and planar maps in adolescents and adults with repaired TOF using echocardiographic contrast particle imaging velocimetry. Intraventricular flow patterns in the abnormal and/or enlarged right ventricle in patients with TOF differ from those in normal young adults. The rotation intensity and energy dissipation trends in this investigation suggest that they may be quantitative markers of RV and left ventricular compliance abnormalities in patients with repaired TOF. This hypothesis merits further investigation.

Evaluation of a new 3-dimensional color Doppler flow method to quantify flow across the mitral valve and in the left ventricular outflow tract: an in vitro study.

OBJECTIVES: The aim of this study was to assess the accuracy, feasibility, and reproducibility of determining stroke volume from a novel 3-dimensional (3D) color Doppler flow quantification method for mitral valve (MV) inflow and left ventricular outflow tract (LVOT) outflow at different stroke volumes when compared with the actual flow rate in a pumped porcine cardiac model. METHODS: Thirteen freshly harvested pig hearts were studied in a water tank. We inserted a latex balloon into each left ventricle from the MV annulus to the LVOT, which were passively pumped at different stroke volumes (30-80 mL) using a calibrated piston pump at increments of 10 mL. Four-dimensional flow volumes were obtained without electrocardiographic gating. The digital imaging data were analyzed offline using prototype software. Two hemispheric flow-sampling planes for color Doppler velocity measurements were placed at the MV annulus and LVOT. The software computed the flow volumes at the MV annulus and LVOT within the user-defined volume and cardiac cycle. RESULTS: This novel 3D Doppler flow quantification method detected incremental increases in MV inflow and LVOT outflow in close agreement with pumped stroke volumes (MV inflow, r = 0.96; LVOT outflow, r = 0.96; P < .01). Bland-Altman analysis demonstrated overestimation of both (MV inflow, 5.42 mL; LVOT outflow, 4.46 mL) with 95% of points within 95% limits of agreement. Interobserver variability values showed good agreement for all stroke volumes at both the MV annulus and LVOT. CONCLUSIONS: This study has shown that the 3D color Doppler flow quantification method we used is able to compute stroke volumes accurately at the MV annulus and LVOT in the same cardiac cycle without electrocardiographic gating. This method may be valuable for assessment of cardiac output in clinical studies.

Automated quantification of mitral regurgitation by three dimensional real time full volume color Doppler transthoracic echocardiography: a validation with cardiac magnetic resonance imaging and comparison with two dimensional quantitative methods.

BACKGROUND: Accurate assessment of mitral regurgitation (MR) severity is crucial for clinical decision-making and optimizing patient outcomes. Recent advances in real-time three dimensional (3D) echocardiography provide the option of real-time full volume color Doppler echocardiography (FVCD) measurements. This makes it practical to quantify MR by subtracting aortic stroke volume from the volume of mitral inflow in an automated manner. METHODS: Thirty-two patients with more than a moderate degree of MR assessed by transthoracic echocardiography (TTE) were consecutively enrolled during this study. MR volume was measured by 1) two dimensional (2D) Doppler TTE, using the proximal isovelocity surface area (PISA) and the volumetric quantification methods (VM). Then, 2) real time 3D-FVCD was subsequently obtained, and dedicated software was used to quantify the MR volume. MR volume was also measured using 3) phase contrast cardiac magnetic resonance imaging (PC-CMR). In each patient, all these measurements were obtained within the same day. Automated MR quantification was feasible in 30 of 32 patients. RESULTS: The mean regurgitant volume quantified by 2D-PISA, 2D-VM, 3D-FVCD, and PC-CMR was 72.1 ± 27.7, 79.9 ± 36.9, 69.9 ± 31.5, and 64.2 ± 30.7 mL, respectively (p = 0.304). There was an excellent correlation between the MR volume measured by PC-CMR and 3D-FVCD (r = 0.85, 95% CI 0.70-0.93, p < 0.001). Compared with PC-CMR, Bland-Altman analysis for 3D-FVCD showed a good agreement (2 standard deviations: 34.3 mL) than did 2D-PISA or 2D-VM (60.0 and 62.8 mL, respectively). CONCLUSION: Automated quantification of MR with 3D-FVCD is feasible and accurate. It is a promising tool for the real-time 3D echocardiographic assessment of patients with MR.

Quantification of chronic functional mitral regurgitation by automated 3-dimensional peak and integrated proximal isovelocity surface area and stroke volume techniques using real-time 3-dimensional volume color Doppler echocardiography: in vitro and clinical validation.

BACKGROUND: The aim of this study was to test the accuracy of an automated 3-dimensional (3D) proximal isovelocity surface area (PISA) (in vitro and patients) and stroke volume technique (patients) to assess mitral regurgitation (MR) severity using real-time volume color flow Doppler transthoracic echocardiography. METHODS AND RESULTS: Using an in vitro model of MR, the effective regurgitant orifice area and regurgitant volume (RVol) were measured by the PISA technique using 2-dimensional (2D) and 3D (automated true 3D PISA) transthoracic echocardiography. The mean anatomic regurgitant orifice area (0.35±0.10 cm(2)) was underestimated to a greater degree by the 2D (0.12±0.05 cm(2)) than the 3D method (0.25±0.10 cm(2); P<0.001 for both). Compared with the flowmeter (40±14 mL), the RVol by 2D PISA (20±19 mL) was underestimated (P<0.001), but the 3D peak (43±16 mL) and integrated PISA-based (38±14 mL) RVol were comparable (P>0.05 for both). In patients (n=30, functional MR), 3D effective regurgitant orifice area correlated well with cardiac magnetic resonance imaging RVol r=0.84 and regurgitant fraction r=0.80. Compared with cardiac magnetic resonance imaging RVol (33±22 mL), the integrated PISA RVol (34±26 mL; P=0.42) was not significantly different; however, the peak PISA RVol was higher (48±27 mL; P<0.001). In addition, RVol calculated as the difference in automated mitral and aortic stroke volumes by real-time 3D volume color flow Doppler echocardiography was not significantly different from cardiac magnetic resonance imaging (34±21 versus 33±22 mL; P=0.33). CONCLUSIONS: Automated real-time 3D volume color flow Doppler based 3D PISA is more accurate than the 2D PISA method to quantify MR. In patients with functional MR, the 3D RVol by integrated PISA is more accurate than a peak PISA technique. Automated 3D stroke volume measurement can also be used as an adjunctive method to quantify MR severity.

Toward multiple catheters detection in fluoroscopic image guided interventions.

Catheters are routinely inserted via vessels to cavities of the heart during fluoroscopic image guided interventions for electrophysiology (EP) procedures such as ablation. During such interventions, the catheter undergoes nonrigid deformation due to physician interaction, patient's breathing, and cardiac motions. EP clinical applications can benefit from fast and accurate automatic catheter tracking in the fluoroscopic images. The typical low quality in fluoroscopic images and the presence of other medical instruments in the scene make the automatic detection and tracking of catheters in clinical environments very challenging. Toward the development of such an application, a robust and efficient method for detecting and tracking the catheter sheath is developed. The proposed approach exploits the clinical setup knowledge to constrain the search space while boosting both tracking speed and accuracy, and is based on a computationally efficient framework to trace the sheath and simultaneously detect one or multiple catheter tips. The algorithm is based on a modification of the fast marching weighted distance computation that efficiently calculates, on the fly, important geodesic properties in relevant regions of the image. This is followed by a cascade classifier for detecting the catheter tips. The proposed technique is validated on 1107 fluoroscopic images acquired on multiple patients across four different clinics, achieving multiple catheter tracking at a rate of 10 images/s with a very low false positive rate of 1.06.

Automated quantification of mitral inflow and aortic outflow stroke volumes by three-dimensional real-time volume color-flow Doppler transthoracic echocardiography: comparison with pulsed-wave Doppler and cardiac magnetic resonance imaging.

BACKGROUND: The aim of this study was to compare the feasibility, accuracy, and reproducibility of automated quantification of mitral inflow and aortic stroke volumes (SVs) using real-time three-dimensional volume color-flow Doppler transthoracic echocardiography (RT-VCFD), with cardiac magnetic resonance (CMR) imaging as the reference method. METHODS: In 44 patients (86% of the screened patients) without valvular disease, RT-VCFD, CMR left ventricular short-axis cines and aortic phase-contrast flow measurement and two-dimensional (2D) transthoracic echocardiography (TTE) were performed. Dedicated software was used to automatically measure mitral inflow and aortic SVs with RT-VCFD. CMR total SV was calculated using planimetry of short-axis slices and aortic SV by phase-contrast imaging. SVs by 2D TTE were computed in the conventional manner. RESULTS: The mean age of the included patients was 40 ± 16 years, and the mean left ventricular ejection fraction was 61 ± 9%. Automated flow measurements were feasible in all study patients. Mitral inflow SV by 2D TTE and RT-VCFD were 85.0 ± 21.5 and 94.5 ± 22.0 mL, respectively, while total SV by CMR was 95.6 ± 22.7 mL (P < .001, analysis of variance). On post hoc analysis, mitral inflow SV by RT-VCFD was not different from the CMR value (P = .99), while SV on 2D TTE was underestimated (P = .001). The respective aortic SVs were 82.8 ± 22.3, 94.2 ± 22.3, and 93.4 ± 24.6 mL (P < .001). On post hoc analysis, aortic SV by RT-VCFD was not different from the CMR value (P = .99), while SV on 2D TTE was underestimated (P = .006). The interobserver variability for SV measurements was significantly worse for 2D TTE compared with RT-VCFD. CONCLUSIONS: RT-VCFD imaging with an automated quantification algorithm is feasible, accurate, and reproducible for the measurement of mitral inflow and aortic SVs and is superior to manual 2D TTE-based measurements. The rapid and automated measurements make this technique practical in the clinical setting to measure and report SVs routinely where the acoustic window will allow it, which was 86% in our study.

Regurgitation quantification using 3D PISA in volume echocardiography.

We present the first system for measurement of proximal isovelocity surface area (PISA) on a 3D ultrasound acquisition using modified ultrasound hardware, volumetric image segmentation and a simple efficient workflow. Accurate measurement of the PISA in 3D flow through a valve is an emerging method for quantitatively assessing cardiac valve regurgitation and function. Current state of the art protocols for assessing regurgitant flow require laborious and time consuming user interaction with the data, where a precise execution is crucial for an accurate diagnosis. We propose a new improved 3D PISA workflow that is initialized interactively with two points, followed by fully automatic segmentation of the valve annulus and isovelocity surface area computation. Our system is first validated against several in vitro phantoms to verify the calculations of surface area, orifice area and regurgitant flow. Finally, we use our system to compare orifice area calculations obtained from in vivo patient imaging measurements to an independent measurement and then use our system to successfully classify patients into mild-moderate regurgitation and moderate-severe regurgitation categories.

Esophagus silhouette extraction and reconstruction from fluoroscopic views for cardiac ablation procedure guidance.

Cardiac ablation involves the risk of serious complications when thermal injury to the esophagus occurs. This paper proposes to reduce the risk of such injuries by a proactive visualization technique, improving physician awareness of the esophagus location in the absence of or in addition to a reactive monitoring device such as a thermal probe. This is achieved by combining a graphical representation of the esophagus with live fluoroscopy. Toward this goal, we present an automated method to reconstruct and visualize a 3-D esophagus model from fluoroscopy image sequences acquired using different C-arm viewing directions. In order to visualize the esophagus under fluoroscopy, it is first biomarked by swallowing a contrast agent such as barium. Images obtained in this procedure are then used to automatically extract the 2-D esophagus silhouette and reconstruct a 3-D surface of the esophagus internal wall. Once the 3-D representation has been computed, it can be visualized using fluoroscopy overlay techniques. Compared to 3-D esophagus imaging using CT or C-arm CT, our proposed fluoroscopy method requires low radiation dose and enables a simpler workflow on geometry-calibrated standard C-arm systems.

Passive cavitation imaging with ultrasound arrays.

A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh-Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed.

Ultrasound-enhanced thrombolysis using Definity as a cavitation nucleation agent.

Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 microm) and plasminogen (241 microm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment.

Acoustic emissions during 3.1 MHz ultrasound bulk ablation in vitro.

Acoustic emissions associated with cavitation and other bubble activity have previously been observed during ultrasound (US) ablation experiments. Because detectable bubble activity may be related to temperature, tissue state and sonication characteristics, these acoustic emissions are potentially useful for monitoring and control of US ablation. To investigate these relationships, US ablation experiments were performed with simultaneous measurements of acoustic emissions, tissue echogenicity and tissue temperature on fresh bovine liver. Ex vivo tissue was exposed to 0.9-3.3-s bursts of unfocused, continuous-wave, 3.10-MHz US from a miniaturized 32-element array, which performed B-scan imaging with the same piezoelectric elements during brief quiescent periods. Exposures used pressure amplitudes of 0.8-1.4 MPa for exposure times of 6-20 min, sufficient to achieve significant thermal coagulation in all cases. Acoustic emissions received by a 1-MHz, unfocused passive cavitation detector, beamformed A-line signals acquired by the array, and tissue temperature detected by a needle thermocouple were sampled 0.3-1.1 times per second. Tissue echogenicity was quantified by the backscattered echo energy from a fixed region-of-interest within the treated zone. Acoustic emission levels were quantified from the spectra of signals measured by the passive cavitation detector, including subharmonic signal components at 1.55 MHz, broadband signal components within the band 0.3-1.1 MHz and low-frequency components within the band 10-30 kHz. Tissue ablation rates, defined as the thermally ablated volumes per unit time, were assessed by quantitative analysis of digitally imaged, macroscopic tissue sections. Correlation analysis was performed among the averaged and time-dependent acoustic emissions in each band considered, B-mode tissue echogenicity, tissue temperature and ablation rate. Ablation rate correlated significantly with broadband and low-frequency emissions, but was uncorrelated with subharmonic emissions. Subharmonic emissions were found to depend strongly on temperature in a nonlinear manner, with significant emissions occurring within different temperature ranges for each sonication amplitude. These results suggest potential roles for passive detection of acoustic emissions in guidance and control of bulk US ablation treatments.

Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model.

INTRODUCTION: Thrombolytics such as recombinant tissue plasminogen activator (rt-PA) have advanced the treatment of ischemic stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism. OBJECTIVE: To improve the efficacy of this thrombolytic therapy, the synergistic effect of rt-PA and 120 kHz or 1.0 MHz ultrasound was assessed in vitro using a porcine clot model. MATERIALS AND METHODS: Fully retracted whole blood clots prepared from fresh porcine blood were employed to compare rt-PA thrombolytic treatment with and without exposure to 120-kHz or 1-MHz ultrasound. For sham studies (without ultrasound), clot mass loss was measured as a function of rt-PA concentration from 0.003 to 0.107 mg/ml. For combined ultrasound and rt-PA treatments, peak-to-peak pressure amplitudes of 0.35, 0.70 or 1.0 MPa were employed. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was fixed at 1.7 KHz. RESULTS: For rt-PA alone, the mass loss increased monotonically as a function of rt-PA concentration up to approximately 0.050 mg/ml. With ultrasound and rt-PA exposure, clot mass loss increased by as much as 104% over rt-PA alone. Ultrasound without the presence of rt-PA did not significantly enhance thrombolysis compared to control treatment. The ultrasound-mediated clot mass loss enhancement increased with the square root of the overall treatment duration. CONCLUSIONS: Both 120-kHz and 1-MHz pulsed and CW ultrasound enhanced rt-PA thrombolysis in a porcine whole blood clot model in vitro. No clear dependence of the observed thrombolytic enhancement on ultrasound duty cycle was evident. The lack of duty cycle dependence suggests a more complex mechanism that could not be sustained by merely increasing the pulse duration.

Correlation of cavitation with ultrasound enhancement of thrombolysis.

Pulsed ultrasound, when used as an adjuvant to recombinant tissue plasminogen activator (rt-PA), has been shown to enhance thrombolysis in the laboratory as well as in clinical trials for the treatment of ischemic stroke. The exact mechanism of this enhancement has not yet been elucidated. In this work, stable and inertial cavitation (SC and IC) are investigated as possible mechanisms for this enhancement. A passive cavitation detection scheme was utilized to measure cavitation thresholds at 120 kHz (80% duty cycle, 1667 Hz pulse repetition frequency) for four host fluid and sample combinations: plasma, plasma with rt-PA, plasma with clot and plasma with clot and rt-PA. Following cavitation threshold determination, clots were exposed to pulsed ultrasound for 30 min in vitro using three separate ultrasound treatment regimes: (1) no cavitation (0.15 MPa), (2) SC alone (0.24 MPa) or (3) SC + IC combined (0.36 MPa) in the presence of rt-PA. Percent clot mass loss after each treatment was used to determine thrombolysis efficacy. The highest percent mass loss was observed in the stable cavitation regime (26%), followed by the combined stable and inertial cavitation regime (20.7%). Interestingly, the percent mass loss in clots exposed to ultrasound without cavitation (13.7%) was not statistically significantly different from rt-PA alone (13%) [p > 0.05]. Significant enhancement of thrombolysis correlates with presence of cavitation and stable cavitation appears to play a more important role in the enhancement of thrombolysis. (E-mail: ).