Effects of pioglitazone on fasting and postprandial levels of lipid and hemostatic variables in overweight non-diabetic patients with coronary artery disease.

OBJECTIVES: To evaluate the effects of pioglitazone on insulin sensitivity and levels of biomarkers associated with thrombotic risk in overweight and obese, non-diabetic subjects with coronary artery disease. BACKGROUND: Little information is available regarding the effects of thiazolidinediones in the absence of diabetes. Further, although postprandial hyperlipemia is a risk factor for cardiovascular diseases, there is limited information about the postprandial effects. METHODS: Twenty overweight and obese, non-diabetic patients with coronary artery disease were enrolled in a randomized, placebo-controlled, double-blind study. Subjects were on atorvastatin for the duration of the study and received either placebo or pioglitazone (45 mg day(-1)) for 12 weeks and then crossed over to the alternative therapy for an additional 12 weeks. Insulin sensitivity, fasting and postprandial levels of lipid, hemostatic, and inflammatory variables were measured, and endothelial function was assessed. RESULTS: Insulin sensitivity improved from 0.03 micromol kg(-1) x min pM(-1) on placebo to 0.04 on pioglitazone (P = 0.0002), and there were decreases in fasting levels of factor (F) VII:C (102 +/- 17% to 92 +/- 18%, P = 0.001), FVII:Ag (68 +/- 12% to 60 +/- 14%, P = 0.01) and in von Willebrand factor (VWF) (174 +/- 94% to 142 +/- 69%, P = 0.01). Pioglitazone lowered postprandial levels of FVII:Ag, FVII:C, plasminogen activator inhibitor-1, VWF, and triglycerides, and increased high-density lipoproteins (+9%, P = 0.02). CONCLUSIONS: Pioglitazone improves insulin sensitivity and favorably modifies fasting and postprandial lipid, hemostatic and inflammatory markers of the metabolic syndrome in overweight and obese non-diabetic patients with coronary artery disease.

Left ventricular myocardial mass determination by contrast enhanced colour Doppler compared with magnetic resonance imaging.

OBJECTIVE: To assess the feasibility of using contrast enhanced colour Doppler echocardiography to determine left ventricular (LV) mass and to compare its accuracy with LV mass obtained by magnetic resonance imaging (MRI). METHODS: Images were acquired in the short axis plane of the heart, derived from coronal and sagittal scout views and double oblique angulation. The LV mass was calculated by two methods: Simpson's rule and the area-length method. Levovist (Schering AG, Berlin, Germany) 2.5 g was given by slow intravenous bolus or infusion over about 45 seconds for contrast imaging. LV images were captured in the apical two chamber, four chamber, and three chamber views. Each contrast harmonic colour Doppler image was converted to a cavity-only image by simple image mathematics. RESULTS: 27 (77.1%) of the patients (mean (SD) age 66.2 (8.9) years) were men. There was a mean (SD) interval of 6.6 (8.6) days (range 0-27 days) between echocardiography and MRI. The mean (SD) LV mass determined by MRI Simpson's rule method was 171.0 (52.4) g (range 105.1-318.7 g). The mean LV mass (SD) determined by the echocardiographic Simpson's rule method was 178.2 (47.0) g (range 112.6-307.6 g). The mean (SD) MRI area-length LV mass was 187.3 (64.5) g (range 109.0-393.6 g). The linear regression correlation between LV mass determined by MRI Simpson's and echocardiographic Simpson's methods was excellent (y = 1.022x, R2 = 0.986) with a mean (SD) difference of 7.20 (20.9) g. The linear regression correlation between the MRI area-length LV mass and MRI Simpson's LV mass was excellent (y = 1.101x, R2 = 0.989) with a mean (SD) difference of 16.3 (22.3) g. CONCLUSIONS: LV mass may be obtained reliably by contrast enhanced colour Doppler and two dimensional echocardiography. The contrast Doppler method accurately determines LV mass with excellent agreement with the MRI technique.

Contrast harmonic color Doppler left ventriculography: machine-interpreted left ventricular ejection fraction compared with equilibrium-gated radionuclide ventriculography.

BACKGROUND: Multi-gated acquisition (equilibrium-gated radionuclide ventriculography) (MUGA) is considered the gold standard for measuring left ventricular ejection fraction (LVEF) because it is accurate, machine interpreted, and reproducible. Echocardiographic LVEF measurements are subject to variability in image acquisition and interpretation and to the limitations of 2-dimensional (2D) versus 3-dimensional imaging. GOAL: The shortcomings of traditional echocardiography may be addressed by combining multiplane 2D harmonic imaging, echocardiographic contrast, color Doppler ultrasonography, and digital image processing to create a new imaging modality: contrast harmonic color Doppler left ventriculography. METHODS: We compared the accuracy of a new method for measuring LVEF that allows for machine interpretation and uses contrast-enhanced intermittent harmonic color Doppler ultrasonography (CHCD). Quantitative LVEF measurements by hand-traced harmonic 2D echocardiography, contrast-enhanced harmonic 2D echocardiography, CHCD, and machine-interpreted CHCD were compared with MUGA in 35 patients. RESULTS: Contrast-enhanced intermittent harmonic color Doppler provided images with vivid endocardial definition in all patients, but hand-traced harmonic 2D echocardiography and contrast-enhanced harmonic 2D echocardiography had inadequate images in 9% of patients. The MUGA LVEF range was 0. 09 to 0.70. All echocardiographic methods showed excellent correlation with the MUGA LVEF (R (2) > 0.96), but the CHCD method had the best limits of agreement. CONCLUSIONS: Contrast-enhanced intermittent harmonic color Doppler LVEF correlates with MUGA at least as well as traditional noncontrasted echocardiography, but it provides diagnostic images in a greater proportion of patients. The CHCD images have vivid endocardial delineation and can be machine interpreted.

A mathematical model for the assessment of hemodynamic parameters using quantitative contrast echocardiography.

A mathematical model for the assessment of hemodynamic parameters using quantitative echocardiography is presented. The method involves the intravenous injection of an ultrasonic echo contrast agent. The relative enhancement of the backscattered ultrasound intensity is measured as a function of time (the time-intensity curve). From this measurement, the volume flow rate (cardiac output) and the mixing volume are calculated. Relevant acoustic properties of the ultrasound contrast agent are discussed. An in vitro experiment is performed to corroborate the theory presented.

Methods for quantifying ultrasound backscatter and two-dimensional video intensity: implications for contrast-enhanced sonography.

Quantification of acoustic backscatter energy is believed to be useful for assessing "tissue character" and for quantifying the regional concentration of echo contrast. Measurement of ultrasonic video intensity has been the traditional means of quantifying backscatter energy, with "integrated backscatter" considered the gold standard. The purpose of this work is to review the commonly used methods for quantifying ultrasonic backscatter and to describe the difference between detected backscatter energy and the intrinsic tissue backscatter coefficient. Many of the quantification pitfalls that can lead to erroneous conclusions will also be discussed. A set of eight rubber phantoms with backscatter coefficient from -6 dB to +15 dB relative to liver were imaged at 2.5, 3.5, and 5.0 MHz. Methods for calculating the acoustic backscatter intensity from calibrated video intensity measurements and for calculating the tissue backscatter coefficient are described and tested using equipment from two different manufacturers. A commercially available automatic "acoustic densitometry" system with on-board quantitative integrated backscatter is also evaluated. Ultrasound attenuation and ultrasound system factors were found to strongly influence the detected backscatter intensity using either calibrated video intensity or on-board integrated backscatter. Special system transfer functions and attenuation correction were found to be useful in converting video intensity and integrated backscatter to a measure of the intrinsic tissue backscatter coefficient. With these correction factors, the correlation between the measured tissue backscatter coefficient and the phantom backscatter coefficient was excellent (r = 0.99, intercept 0.0, regression slope essentially 1.0) at all three imaging frequencies with traditional video intensity or on-board integrated backscatter. Uncalibrated video intensity and on-board integrated backscatter have limitations when used in isolation for tissue characterization. Rigorous attention to the imaging parameters and the use of calibration functions are necessary before video intensity measurement or integrated backscatter can be used reliably to measure the tissue backscatter coefficient.

Harmonic imaging with Levovist.

Our purpose was to test the hypothesis that second harmonic imaging preferentially detects backscatter from microbubbles compared with tissue structural components. A prototype second harmonic scanner was used to image a flow channel in a tissue-mimicking rubber phantom (liver density). Video time-intensity curves were calculated from repeated bolus injections of microbubble echocardiographic contrast material under the same fluid dynamic conditions but with three different imaging modes: (1) fundamental imaging at 2.5 MHz (transmit and receive at 2.5 MHz), (2) fun damental imaging at 5.0 MHz (transmit and receive at 5.0 MHz), and (3) second harmonic imaging (transmit at 2.5 MHz and receive at 5.0 MHz). Each video time-intensity curve was calibrated-such that quantitative backscatter intensity was measured relative to the tissue phantom (0 dB). The peak increase in backscatter from the contrast material in the channel relative to the tissue phantom and the intensity in the channel before the contrast effect (the noise floor) was measured along with the area under the calibrated time-intensity curve relative to the phantom. When referenced to the noise floor in the flow channel, all imaging modes produced approximately 25 dB of enhancement. However, when referenced to the tissue phantom, second harmonic imaging produced a 22.3 +/- 1.8 dB peak enhancement, which was greater than either fundamental imaging at 2.5 MHz (15.5 +/- 0.8 dB; p < 0.001) or fundamental imaging at 5.0 MHz (15.3 +/- 1.5 dB; p < 0.001). The area under the time-intensity curves confirmed that harmonic imaging has approximately 7 dB of relative enhancement to the phantom compared with fundamental imaging at either frequency. Second harmonic imaging specifically enhances backscatter from microbubbles compared with a tissue-mimicking phantom. This specificity for microbubbles is due to a decrease in backscatter for the tissue phantom, rather than an increase in backscatter for the microbubbles. These data support the hypothesis that second harmonic imaging may be able to detect microbubbles in the tissue vascular space by preferentially decreasing the backscatter from tissue structural components.

The measurement of backscatter coefficient from a broadband pulse-echo system: a new formulation.

A new formulation for obtaining the absolute backscatter coefficient from pulse-echo measurements is presented. Using this formulation, performing the diffraction correction and system calibration is straightforward. The diffraction correction function for the measurement of backscatter coefficient and the acoustic coupling function for a pulse-echo system are defined. Details of these functions for two very useful cases are presented: a flat disk transducer and a spherically focused transducer. Approximations of these functions are also provided. For a flat disk transducer, the final formulation appears as a modification to the established Sigelmann-Reid formulation. For a focused transducer, the final correction is a weak function of frequency when the scattering volume is near the focal area, rather than the frequency squared dependence proposed by earlier investigators.

Transcranial duplex ultrasound: experience with contrast enhancing agents.

Transcranial duplex real time sonography (TCCS) is a non-invasive imaging modality that allows repetitive examinations of central nervous system vascular and parenchymal anatomy; a broad spectrum of cerebral pathology may be disclosed: vascular changes include ischemic and hemorrhagic stroke, arteriosclerotic vascular degeneration, arteno-venous malformations and aneurysms, as well as neoplastic and degenerative parenchymal disorders. Imaging was performed with a duplex ultrasound system, employing a 2.25 resp. 2.0 MHz phased-array transducer. Imaging was achieved through the acoustic bone window of the temporal bone and through the foramen magnum. For three-dimensional image reconstruction a mechanical position sensor and online video grabbing was applied. To evaluate the potential of a transpulmonary stable ultrasound contrast enhancing agent we used galactose-based SH U 508 A (Levovist, Schering, Berlin) with 1 to 6 i.v. injections per patient in a phase 2/3 clinical protocol. The signal to noise ratio is significantly improved; the Doppler signal intensity is increased by approx. 25 dB. Levovist was well tolerated and no adverse events occurred, approx. 30% of patients had a sensation of heat and slight pain at the injection site during and shortly after the injection. With the increase in signal intensity, the complete circle of Willis, the peripheral arterial branches, the vertebro-basilar system and the basal venous system may be depicted. In addition, tumour parenchyma vascularisation may be detected, as well as improved delineation of arteriovenous malformations and aneurysms. Three dimensional image reconstruction may represent a novel option in contrast enhanced transcranial duplex imaging including additional information about 3D structure and continuity.

Hemodynamic effects of microbubble echo contrast.

The dose-related hemodynamic effects of an active (bubble-rich) echo contrast agent were compared with those of a bubble-free contrast agent and saline solution to determine whether the microbubbles contained in the echo contrast agent are truly passive indicators in the circulation or whether they actively alter the hemodynamic state independent of the volume and osmotic loading associated with such injections. The study population consisted of 13 fully instrumented open-chest mongrel dogs. Four hundred ninety-two bolus injections were made of three different types: active contrast agent (Levovist, Schering AG, Berlin) (n = 333), saline solution (n = 112), and bubble-free contrast agent (n = 47). Levovist was administered in five dose ranges spanning 0.013 to 0.341 gm/kg and, like the saline solution, was administered in bolus volumes of 0.053 to 1.136 ml/kg. For each injection type, the percent change in hemodynamic parameters after administration of the bolus were calculated on the basis of the dose or volume of the injectate. Audio Doppler signal intensity was used to document the presence of bubbles in the injectate. Statistical significance was defined at the p = 0.05 level; clinical significance was defined as a greater than 15% change in a hemodynamic parameter. Statistically, but not clinically, significant changes were noted in almost all hemodynamic parameters regardless of injection type, and at all dose and volume ranges. Although statistically significant, injection of an active contrast agent in the human dose range resulted in a < 5% change in hemodynamic parameters. High doses of a contrast agent (active or bubble-free) increased the left atrial pressure and had associated changes in peripheral vascular hemodynamics because of the osmotic load. Clinically significant increases (> 15%) in pulmonary artery pressure and pulmonary vascular resistance were unique to the active contrast agent at high dose ranges. Standard doses of the active contrast agent changed the hemodynamics by less than 5% in healthy dogs. Transient clinically significant increases in pulmonary artery pressure and pulmonary vascular resistance are a unique side effect to high dose bolus injections of microbubble echo contrast agent.

The Doppler kinetics of microbubble echo contrast.

The right and left heart kinetics of a saccharide-based microbubble echo contrast agent were measured in 11 anesthetized dogs using Doppler intensity as a measure of microbubble concentration while controlling for the dose administered, weight of the subject and cardiac output. A two-phase Doppler time-intensity curve was noted in all vascular regions. A brief first pass effect (phase 1) was found to depend on the contrast dose, cardiac output and subject size. This was followed by a much longer nearly steady-state elevation in the Doppler intensity compared with baseline (phase 2). The kinetics of phase 2 were found to be the same in all vascular distributions and independent of cardiac output. The phase 2 kinetics depend on the contrast dose, subject size and elimination characteristics of the contrast agent. The clinically important conclusions are: (1) the magnitude of Doppler enhancement and duration of the contrast effect can be predicted using the simple formulas presented; (2) the flow-dependent portion of the arterial contrast effect is effectively over only a few seconds after intravenous injection; and (3) the kinetics of phase 2 are the same throughout the body.

When can Doppler be used in place of integrated backscatter as a measure of scattered ultrasound intensity?

The purpose of this work was to determine under what circumstances the intensity of Doppler audio signals can be used as a substitute for the more direct and complex measure of ultrasonic backscatter (integrated backscatter) which requires radio-frequency ultrasound signals. Using a rotating rubber disk phantom and a microbubble echo-contrast flow phantom, we have shown that the intensity of audio Doppler signals is independent of the constraints typically associated with Doppler ultrasound (velocity and angle), but like integrated backscatter depends on the transmit intensity, gain of the ultrasound receiver, attenuation and the nature of the scatterers. Using Doppler ultrasound for backscatter measurements is ideally suited for the expected application of the technique: the assessment of echo contrast in cardiac chambers, blood vessels and tissue perfusion (i.e., any flow system). Compared to integrated backscatter, the Doppler audio method has the advantage of using standard clinical ultrasound machines, requires less sophisticated data storage and processing equipment and the positioning system for the region of interest (the Doppler sample volume) is built into all pulsed-wave Doppler machines. Further, the low-velocity filter removes all nonmoving scatterers (like the intense echoes from heart valves and the walls of blood vessels), thus allowing study of only those echoes originating from the blood pool. This combination of features is what attracted us to the Doppler method for quantitating ultrasonic backscatter in flow systems.

Doppler enhancement with SH U 508A in multiple vascular regions.

PURPOSE: To determine the magnitude and duration of peripheral vascular and cardiac Doppler signal enhancement after intravenous administration of contrast agent SH U 508A. MATERIALS AND METHODS: Suboptimal cardiac or peripheral vascular Doppler examinations were evaluated. A total of 75 intravenous bolus injections were made in 30 patients. Spectral audio Doppler intensity was measured throughout the duration of contrast effect. RESULTS: No clinically relevant adverse effects were noted, and Doppler enhancement was apparent in all cases. The diagnostic confidence of the investigators when scored before and after Doppler enhancement improved from 35% to 91% (P < .05). Doppler intensity increased more than 16 dB in all vascular regions investigated (P < .05). The contrast effect lasted for more than 120 seconds in the peripheral vascular and cardiac groups at equivalent doses. CONCLUSION: Intravenously administered SH U 508A is effective in markedly increasing cardiac, femoral arterial, and transcranial (cerebral arterial) Doppler signal intensity. The effect improves the clinical diagnostic confidence in cases of suboptimal unenhanced Doppler examinations.

Acoustic coupling from a focused transducer to a flat plate and back to the transducer.

An approximate solution for the acoustic coupling factor (the diffraction correction function) from a focused transducer to a flat plate and back to the transducer is provided. This function is useful for system calibrations where a pulse-echo system or transmit-receive system is used. Numerical solutions are provided for the important case where the flat plate is placed near the focal plane of the transducer. The solution for a flat disk transducer is obtained as a limiting case. Experimental evidence for a focused transducer is provided.

Efficacy SH U 508 A (Levovist) as blood pool enhancer in the Doppler evaluation of multiple vascular regions.

SH U 508 A (Levovist) as a blood pool enhancer to investigate multiple vascular regions with Doppler ultrasonography. Thirty patients with sub-optimal cardiac or peripheral vascular Doppler exams received 75 intravenous contrast bolus injections in all to investigate the intensity and the duration of Doppler signal enhancement after the i.v. administration of an echo contrast agent - i.e., SH U 508 A (Levovist) by Schering AG, Berlin, Germany. All cases exhibited Doppler enhancement and the investigator's "diagnostic confidence" increased from 35% (precontrast) to 91% (post-contrast) (p < 0.05). Audio Doppler intensity was measured quantitatively and more than 16 dB enhancement was demonstrated in all the vascular regions under investigation (p < 0.05). Enhancement lasted more than 60 seconds in the peripheral vessels and 120 seconds in the heart vessels. No clinically relevant adverse reactions were ever observed. To conclude, i.v., -administered SH U 508 A (Levovist) is a valuable means of increasing cardiac, femoral arterial and transcranial (cerebral arterial) Doppler signal intensity. Enhancement is durable and improves the clinical diagnostic confidence in the patients with suboptimal Doppler findings.

Radiation pattern of a focused transducer: a numerically convergent solution.

The radiation pattern of a focused transducer is reexamined. The radiation field is divided into an illuminated zone and a shadow zone. A numerically convergent solution of the pressure distribution in terms summations of Bessel functions is provided. This solution is computationally more advantageous than earlier results where a double or single integral in the complex plane is required. The pressure amplitude differs from earlier reports slightly for off-axis locations at low frequency. This difference may have significance for backscatter coefficient determination where scatterers are assumed present over a time-gated volume. The solution for a flat disk radiator is obtained as a limiting case.

Predictive value of dobutamine echocardiography just before noncardiac vascular surgery.

This study prospectively evaluated 75 consecutive patients (mean age 69 +/- 9 years) undergoing major vascular surgery to test the hypothesis that dobutamine stress echocardiography can be used to predict perioperative cardiac events. A positive test was defined as a new or worsening wall motion abnormality in at least 2 of 18 wall segments. Up to 40 micrograms/kg/min of dobutamine was administered. All readings were done by physicians unaware of the patients' symptoms and electrocardiographic response. In addition, physicians caring for the patients were unaware of the test result. End points of the study were unstable angina with documented electrocardiographic changes, nonfatal myocardial infarction or cardiac death. The perioperative ischemic event rate was 7% (5 of 75 patients). Three patients developed unstable angina and 2 sustained nonfatal myocardial infarctions. All of these patients had positive results on dobutamine stress echocardiography (sensitivity 100%). However, 22 patients who also had positive results on dobutamine stress echocardiography did not have perioperative events (specificity 69%). The corresponding positive predictive value was 19%. None of the 48 patients who had negative results on dobutamine stress echocardiography had events (negative predictive value 100%). In conclusion, dobutamine stress echocardiography can be used to predict perioperative events with great sensitivity, but its positive predictive value in this patient population in low, likely due to the low incidence of perioperative events in patients with known coronary artery disease and the imperfect specificity of dobutamine stress echocardiography in identifying significant coronary stenosis. Dobutamine stress echocardiography is most useful in this setting when negative, because it predicts safety from complications with confidence.

Volumetric arterial flow quantification using echo contrast. An in vitro comparison of three ultrasonic intensity methods: radio frequency, video and Doppler.

The two hypotheses presented in this paper are: (1) absolute and relative volumetric flow rates in vessels can be measured by echo contrast time-intensity curves; and (2) echo contrast time-intensity curves generated by different ultrasound backscatter intensity techniques have equivalent capability for flow measurements. A nonpulsatile flow system was built for quantitative ultrasound backscatter measurements from bolus echo contrast injections using two different volumes of mixing. A total of 49 echo contrast bolus injections were made at various flow rates (0.44-2.59 L/min). Ultrasound backscatter time-intensity curves were generated by ultrasound radio frequency, video and Doppler techniques. The rate of backscattered ultrasound intensity washout for each technique (WASHOUT RATE), and relative change in WASHOUT RATE (delta WASHOUT RATE) were compared to the volumetric flow rate (FLOW) and changes in flow rate (delta FLOW), respectively. The relationship between WASHOUT RATE, FLOW and the volume of contrast mixing was studied. A linear relationship was demonstrated between WASHOUT RATE and delta WASHOUT RATE and the corresponding FLOW and delta FLOW by all three methods (r > 0.90 for all comparisons). The WASHOUT RATE was found to depend on the FLOW and the volume of contrast mixing, but the delta WASHOUT RATE was equal to the delta FLOW and independent of the volume of mixing. Time-intensity curves can be generated from different ultrasound backscatter intensity techniques and the WASHOUT RATE correlates well with FLOW. delta FLOW can be determined directly from the corresponding delta WASHOUT RATE. Doppler ultrasound, because of its natural association with the assessment of flow in chambers and vessels, is uniquely suited to assessment of arterial volumetric blood flow in vitro.