Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine.

BACKGROUND: Intimal hyperplasia and subsequent in-stent restenosis remain a major limitation after stent implantation. In vitro cell culture studies show that low-frequency, noncavitational ultrasound energy may impact smooth muscle cell proliferation. Accordingly, we assessed the efficacy of intravascular sonotherapy treatment on intimal hyperplasia in a swine stent model. METHODS AND RESULTS: After balloon injury, biliary stents (Johnson & Johnson) were implanted in the femoral arteries of 14 swine. A total of 48 stented sites were randomized to sonotherapy or sham treatment using a custom-built, 8-French catheter intravascular sonotherapy system (URX, PharmaSonics Inc). After stent deployment, ultrasound energy (700 KHz) was applied to the treatment group for up to 5 minutes. Smooth muscle cell proliferation was assessed using bromodeoxyuridine histology preparation (BrdU) at 7 days in 28 stented sites. At 28 days, the neointimal thickness and the ratio of neointimal/stent area (percent stenosis) was calculated by histomorphometric quantification in 20 stented sites. At 7 days, percent of BrdU staining was significantly reduced in the sonotherapy group compared with the sham group (24.1+/-7.0% versus 31.2+/-3.0%, P<0.05). At 28 days, percent stenosis was significantly less in the sonotherapy group than in the sham group (36+/-24% versus 44+/-27%, P<0.05), and the mean neointimal thickness in the sonotherapy group was less than in the sham group (417+/-461 micrometer versus 643+/-869 micrometer, P=0.06). CONCLUSIONS: In this swine peripheral model, intravascular sonotherapy seemed to decelerate cellular proliferation and decrease in-stent hyperplasia. Therefore, intravascular sonotherapy may be an effective form of nonionizing energy to reduce in-stent restenosis.

Instantaneous and continuous cardiac output in humans obtained with a Doppler pulmonary artery catheter.

A new Doppler pulmonary artery catheter was used to measure instantaneous and continuous cardiac output in both an in vitro model and in 44 patients undergoing cardiac catheterization. Cardiac output was calculated with use of the Doppler catheter-determined instantaneous space-average velocity and the ultrasonically determined instantaneous vessel area. Doppler flow and thermodilution were compared with electromagnetic flow in the in vitro model and with Fick cardiac output in patients. Doppler catheter-determined flow was highly predictive of electro-magnetic flow in the pulsatile flow model (r = 0.99, slope [m] = 1.01 and SEE = 0.05) and appeared comparable to thermodilution measurements (r = 1.00, m = 1.03 and SEE = 0.02). In patients undergoing cardiac catheterization, Doppler catheter-determined cardiac output appeared to modestly underestimate Fick cardiac output (r = 0.82, m = 0.80 and SEE = 0.09; mean error +/- SEM = -0.26 +/- 0.14 liters/min). However, predictive accuracy was comparable to simultaneously obtained thermodilution measurements (r = 0.85, m = 1.07 and SEE = 0.10; mean error +/- SEM = 0.61 +/- 0.16 liters/min). This new Doppler catheter system utilizes multiple ultrasound transducers to provide angle-independent measurements of vessel diameter and instantaneous velocity within the main pulmonary artery, resulting in a more accurate assessment of Doppler-derived cardiac output. In addition, useful information concerning hemodynamic variables such as peak flow, acceleration, deceleration, stroke work and pulmonary impedance may be derived.

Flow determination using computed tomography: application to aortic dissection. Part I.

The CT method of flow determination evaluated in this study was based on the application of contrast enhancement dynamics. In order to characterize flow, such parameters as mean transit time, rise time, peak CT value, curve width and variance, and others were derived from the venoarterial indicator dilution curves using a perfect mixers-in-series model of curve fitting analysis and a bolus injection of contrast medium. The technique was first validated in a steady state phantom model that simulated in vivo conditions of right-sided mixing closely by the introduction of a number of mixers. A series of flows through small tubes was measured. Good correlation was obtained (r = .85). For a fixed number of mixers, the central second moment of the primary peak of the indicator dilution curve or variance decreased with increasing flow and peak CT value increased. Applied to the clinical situation, this method would allow characterization of blood flow using an intravenous bolus of contrast.

Variability of myocardial CT measurements in vivo.

Variability of myocardial CT measurements, as indicated by standard deviations of mean CT numbers from four myocardial regions, was compared in 12-second scans, 3-second scans, and gated end-diastolic and end-systolic images, all from the same 12 seconds of scan data, both without and with radiographic contrast enhancement in experimental animals. There were statistically significant differences (P less than 0.05) in standard deviations of myocardial CT measurements when comparing 3-second and 12-second scans without contrast (10.4 vs. 7.7 CT#s), and 12-second scans without and with contrast (7.7 vs. 11.2 CT#s). Standard deviations of mean myocardial CT measurements were significantly greater (P less than 0.01) in gated images (end-diastolic) when compared with 12-second scans, both without contrast (22.2 vs. 7.7 CT#s) and with contrast (20.2 vs. 11.2 CT#s). In this study variability of myocardial CT measurements increased as scan time decreased, with radiographic contrast enhancement and with gating cardiac images.

Flow determination using computed tomography: application to aortic dissection. Part II.

Dynamic CT is not only useful in imaging an aortic dissection but may provide additional information concerning the hemodynamic significance of differing flow patterns in the false channel compared with the true channel. Once validated, the computed tomographic (CT) method of flow determination (See Part I) was applied to an experimental animal model with a surgically created aortic dissection. Good correlation was obtained for the flow estimates of cardiac output derived for the true and false channel (r = .82). The shapes of the curves, however, were distinct, reflecting different flow patterns for the true and false channels. Curve parameters, such as peak CT number (P = .0001), variance (P = .006), and, in particular, the number of mixers (a parameter used to quantify the degree of mixing) (P = .0001), demonstrated significant differences between the two channels of the dissection. The curve parameters derived can therefore be used to differentiate the true and false channels and may then predict the long-term outcome of the false channel, and the aortic branches derived from it.

Regional myocardial flow estimation using computed tomography.

A novel method is presented for estimating regional myocardial blood flow (RMBF) using x-ray computed tomography (CT). Two major setbacks are removed from the existing methods; namely, the requirement for intra-arterial bolus injection of tracer, and the inability to determine regional volumes of tracer distribution when the corresponding partition coefficients are unknown. The mathematical model developed for RMBF estimation combines both the tracer dispersion process and the CT measurement process. Intravenously administered contrast media (tracer) is assumed to be perfectly mixed by the myocardium. Tracer dynamics, as measured by CT (CT#s. vs time curves) in the myocardial regions and in the left ventricular chamber, can then be used to compute cardiac output, regional volumes of tracer distribution, and absolute RMBF. These computations use the zeroth and the first moments of the measured CT#s. vs time curves. Errors due to partial volume effects, and methods for their correction, are analysed. This formulation is readily adapted to existing computed tomographic systems having the capability to produce multiple sequential CT scans.

Quantitative evaluation of left ventricular function using computed tomography.

Computed tomography (CT) provides a noninvasive technique with high resolution cross-sectional tomographic images which allow volume measurements of an object, independent of its geometric configuration. A phantom of known volume with controllable periodic motion was used to validate the CT method of volume determination. A good correlation (P less than 0.05) was achieved. Missing angle reconstruction algorithms for gating were applied to estimate left ventricular volumes and ejection fraction in an experimental animal, and the results compared with a standard angiographic method. Left ventricular volumes correlated poorly, whereas the ejection fraction obtained correlated well (r = 0.9). The discrepancies may be attributed in part to the CT method in which difficulties were recognized in defining the left ventricular borders at the base of the heart and partial volume effect, and in part to inaccuracies in the standard angiographic method. Once validated, this method has been applied to the animal model in the form of a pilot study.

In vivo stochastic ultrasonic characterisation of abdominal tissues.

Two experimental systems have been used for digitization of waveforms backscattered from normal and pathologic abdominal tissues in vivo. Initial studies were performed with a digitization system which allowed only A-mode display of areas of interest before and during waveform recording. A new interactive system allows for digitization of waveforms from areas of interest in abdominal organs, selected with the aid of real-time B-mode images of a mechanical sector scanner. Statistical parameters of these waveforms, derived in the amplitude and frequency domains, show potential utility for diagnosis of diffuse diseases of the liver and spleen.

The critical importance of convolution function (algorithm) selection in the measurement of blood flow in small blood vessels by computed tomography scanning.

In order to assess the capability for measuring blood flow in small vessels, the cardiac output was measured directly by either the microsphere reference sample technique or by obtaining blood samples simultaneously with the CT scan. The cardiac output was also measured in vivo by dynamic CT scanning and intravenous contrast as the indicator in an indicator dilution curve. Cardiac output was then calculated by two convolution back projection algorithms which optimized for either contrast or spatial resolution. The results of this study suggest that CT scanners are capable of accurately averaging intravascular changes in contrast density. Although it is good to optimize contrast resolution, the convolution back projection algorithm selected must have a pixel matrix which is much smaller than the vessel being analyzed.

Baseline subtraction in quantitative cardiovascular computed tomography.

Beam-hardening (BH) effect was evaluated to determine its potential significance in quantitative blood flow measurements using computed tomography (CT). CT scans of a water bath containing a range of concentrations of iodine (0-15 mg/ml) placed outside and within the chest of a dead dog were obtained at different kVp levels (100, 120, and 130 kVp). The mean CT number and standard deviation were measured over a small region of interest for each concentration. The CT numbers measured outside the chest were significantly higher (p less than 0.01) than those measured inside, suggesting a BH effect. However, this BH error was almost eliminated (p greater than 0.01) when water values (CTw) were subtracted from the CT numbers of the iodine solutions (delta CT = CT1 - CTW). Water subtraction was used to simulate baseline tissue CT numbers prior to contrast enhancement so that the delta CT values were analogous to those generally used to analyze blood flow. The BH effect was therefore not found to be significant for blood flow measurement accuracy in cardiovascular CT.

Validation of a CT method for flow determination. Work in progress.

The dynamic computed tomographic (DCT) method of flow determination is based on the application of venoarterial indicator dilution curves as they reflect flow. Using a simple model consisting of a tube and a single mixing chamber, experimental parameters were optimized in a controlled manner to achieve ideal mixing for flow determination. Under these ideal conditions, and using 16 consecutive 3-second scans of an 8-mm thick section, tube diameters of 8 mm and 20 mm, and flow range of 0.7-2.7 liters per minute, the accuracy of the CT method of flow determination was good (17% error). There was a correlation coefficient of 0.85 between measured flow (FM) and calculated flow (FC), and the paired t-test for FM and FC indicated that there was no statistically significant difference (P = .25). The DCT method of flow determination has been validated in this experiment preliminary to its application to flow characterization in blood vessels in the animal model.

Dynamics of myocardial contrast enhancement: an in vivo computed-tomographic study.

Enhancement of normal functioning myocardium was quantitated in 15 dogs by serial computed transmission tomographic (CT) images during the bolus (10 ml/sec.) or slow (1 ml/sec.) intravenous injection of diatrizoate contrast media (1 ml/kg body weight) in concentrations of 37, 18.5, or 9.25 g iodine (I)/dl. Homogenous images of myocardial enhancement were obtained. However, major streak artifacts were observed frequently when contrast material was injected as a bolus, and myocardial edges were not defined clearly when contrast material with a concentration of 9.25 g I/dl was injected slowly. Time-attenuation curves of normal myocardial enhancement constructed from serial CT images demonstrated a peak in contrast enhancement (delta Hounsfield units, 22-45) followed by a period of deterioration that lasted two to three minutes. These results can be applied to make optimal use of both single (static) and serial (dynamic) myocardial CT images.

Estimation of the slope of the acoustic attenuation coefficient.

In this paper, a theoretical framework is developed which removes the Gaussian assumption commonly used in ultrasonic attenuation estimation based on mean frequency shift. The theory is developed for general non-Gaussian spectra and for media whose attenuation coefficient is nonlinear with frequency. Then, a linear approximation in the estimation of the attenuation coefficient's slope is examined. It is shown that the error due to the linear approximation is negligibly small.

Ultrasound attenuation measurements of the liver in vivo using a commercial sector scanner.

Attenuation measurements of various tissue mimicking phantoms and three different groups of patients were obtained using a modified commercial sector scanner. Estimates of attenuation were made using the spectral shift method with mean frequencies at different depths of a region of interest being obtained by both zero crossing and fast Fourier transform techniques. The accuracy and precision of both techniques was compared in phantoms and it was found that the FFT technique yielded less day-to-day variation (SD=3 percent) than the zero crossing technique (5 percent). For larger regions of interest, the range of variation in both techniques was more similar. Day-to-day variation in livers of normal patients was much larger than that seen in phantoms (10 to 15 percent) suggesting that in vivo measurements may be less precise due to actual daily changes in patients' livers. Attenuation estimates of phantoms were high by approximately 0.16 dB/MHz/cm compared to values obtained by transmission techniques. The attenuation values of livers in a group of 31 normal patients ranged from 0.214 dB/cm/MHz to 0.849 dB/cm/MHz with a mean of 0.627 +/- 0.126 dB/cm/MHz for the zero crossing technique while the mean value using the FFT technique was 0.86 +/- 0.168 dB/cm/MHz. A group of 26 Gauchers disease patients also showed wide variation with a mean attenuation value of 0.768 +/- 0.21 dB/cm/MHz using the FFT technique. This was significantly different than that of the normal group (p less than .05). Also, a group of 22 chronic B hepatitis patients was examined, having a mean attenuation value of 0.823 +/- 0.21 dB/cm/MHz, not significantly different from those of normal patients. Highly significant differences were found between the three groups when the power spectrum bandwidths of signals received were compared. These differences may be due to differences in the dependence of attenuation as a function of frequency between the groups and may represent a useful tissue characterization parameter.