Combining existing numerical models with data assimilation using weighted least-squares finite element methods.

A new approach has been developed for combining and enhancing the results from an existing computational fluid dynamics model with experimental data using the weighted least-squares finite element method (WLSFEM). Development of the approach was motivated by the existence of both limited experimental blood velocity in the left ventricle and inexact numerical models of the same flow. Limitations of the experimental data include measurement noise and having data only along a two-dimensional plane. Most numerical modeling approaches do not provide the flexibility to assimilate noisy experimental data. We previously developed an approach that could assimilate experimental data into the process of numerically solving the Navier-Stokes equations, but the approach was limited because it required the use of specific finite element methods for solving all model equations and did not support alternative numerical approximation methods. The new approach presented here allows virtually any numerical method to be used for approximately solving the Navier-Stokes equations, and then the WLSFEM is used to combine the experimental data with the numerical solution of the model equations in a final step. The approach dynamically adjusts the influence of the experimental data on the numerical solution so that more accurate data are more closely matched by the final solution and less accurate data are not closely matched. The new approach is demonstrated on different test problems and provides significantly reduced computational costs compared with many previous methods for data assimilation. Copyright © 2016 John Wiley & Sons, Ltd.

Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Optimized administration regimen of lopinavir for a myocardial ischaemia reperfusion study in Sprague-Dawley rats.

Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague-Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4-10 µg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

[Phalloidin suppresses the force in nebulin-rich lamprey cardiac muscle].

The effect of phalloidin, an agent detaching nebulin from actin in skeletal muscle, on the isometric force in lamprey skinned cardiac muscle, which has nebulin in amounts comparable to that in skeletal muscle, has been studied. We found that, unlike mammalian cardiac muscle expressing nebulin less abundantly and responding to phalloidin by a force increase, lamprey cardiac muscle responds to phalloidin by a force decrease (approximately 50% decrease), thereby resembling the response of skeletal muscle. These results support our hypothesis that nebulin detachment from actin underlies phalloidin-induced force loss and suggest a role of actin-nebulin interaction in contractile function.

Real-time strain rate imaging: validation of peak compression and expansion rates by a tissue-mimicking phantom.

Strain rate imaging is a new modality in echocardiography intended for analysis of left ventricular function. This modality extends ultrasonographic techniques for analysis of tissue velocities by providing information about rates of local myocardial compression and expansion. Cyclic cardiac deformation is a complex process. Precision and accuracy of real-time strain rate (rtSR) measurements have not been studied under controlled laboratory conditions. Using a cyclically compressed tissue-mimicking gelatin phantom, we compared rtSR values to corresponding strain rate values calculated off line from local tissue velocities measured by Doppler echocardiography. We tested a clinically relevant range of strain rates (0.5 - 3.5 sec(-1)) and different angles of insonation. Initial tests showed high precision (r > or = 0.973, P < 0.001), but the assessment of accuracy (bias < or = 0.559 sec(-1)) suggested a trend toward systematic underestimation of the reference values. We suspected a confounding influence of a clutter filter and repeated the tests with the filter inactive. The resulting accuracy improved tenfold (bias < or = 0.045 sec(-1)), and the systematic underestimation was no longer present. We conclude that the rtSR is precise and accurate for a range of the tested values.

Intracardiac measurement of pre-ejection myocardial velocities estimates the transmural extent of viable myocardium early after reperfusion in acute myocardial infarction.

OBJECTIVES: We hypothesized that wall motion velocity during pre-ejection is proportional to the regional content of viable myocardium after reperfusion for acute myocardial infarction (AMI). BACKGROUND: Pre-ejection wall motion consists of short and fast inward and outward movement towards and away from the center of the left ventricle (LV) and is altered during regional ischemia. This short-lived event can be accurately quantified by Doppler myocardial imaging (DMI). METHODS: Fourteen open-chest pigs underwent 60 to 120 min of left anterior descending coronary artery occlusion followed by 30 min of reperfusion. The DMI data were collected using a phased-array intracardiac catheter (LV cavity) from ischemic and nonischemic myocardium encompassed within a plane passing through two epicardial bead markers. Peak tissue velocities during isovolumic contraction (IVC) (peak positive and peak negative), ejection (S) and early filling (E) were measured. The cardiac specimen was sliced through the epicardial markers in a plane approximating the ultrasound imaging plane. The transmural extent of necrosis (TEN) (%) was measured by triphenyltetrazolium chloride staining. RESULTS: During ischemia, positive IVC velocity was zero in ischemic walls with TEN >20%. At reperfusion, positive IVC velocity correlated better with TEN (r = -0.94, p < 0.0001) than it did S (r = -0.70, p < 0.01) and E (r = -0.81, p < 0.01). Differential IVC (the difference between peak positive and peak negative velocity) highly correlated with TEN, during ischemia (r = -0.78, p < 0.001) and during reperfusion (r = -0.93, p < 0.0001). CONCLUSIONS: Pre-ejection tissue velocity, as measured by intracardiac ultrasound, allows rapid estimation of the transmural extent of viable myocardium after reperfusion for AMI.

Radiofrequency spectral analysis of attenuated ultrasound signals in experiments with echo contrast microbubbles.

Conventional gray-scale myocardial contrast echocardiography cannot distinguish perfused but attenuated from nonperfused myocardium because both may appear similar at low image intensity. We hypothesized that with radiofrequency spectral analysis of attenuated ultrasound signals, the harmonic-to-fundamental frequency ratio of the peak power spectrum (HFR(P)) could determine the presence of contrast microbubbles. We measured frequency responses of Optison microbubbles at defined degrees of ultrasound signal attenuation with different formulations of silicone (55D, 80A, and 3M); gray-scale intensities of Optison plus water compared with degassed water were analyzed at different attenuation settings (-25, -32, and -44 dB, respectively). HFR(P) values of Optison plus water were significantly higher than reference values of degassed water at each attenuation setting (55D, -14 +/- 2 dB versus -30 +/- 2 dB, P <.001; 80A, -19 +/- 2 dB versus -30 +/- 3 dB, P <.01; 3M, -22 +/- 2 dB versus -30 +/- 3 dB, P <.05), even though conventional videodensitometric analysis could not distinguish them. HFR(P) analysis objectively detects microbubbles in clinically relevant conditions of attenuation.

Shape reconstruction of the left ventricle: accuracy of limited-plane three-dimensional echocardiography.

OBJECTIVE: To assess the accuracy of left ventricular cavity shape reproduction from 8 spatially related, apical two-dimensional ultrasonographic images. METHODS: We scanned 6 dog heart specimens. Left ventricular cavity casts were reconstructed from 48-tomogram (high-density), 8-tomogram (octaplane), and 2-tomogram (low-density biplane) apical data sets. The 48-plane left ventricular cast served as the reference. Spatial shape resolution of 3 mm in radial distance from the rotational axis to the interpolated endocardium was used as the criterion of shape accuracy. RESULTS: The adjusted limits of agreement for the octaplane and biplane left ventricular casts were +/-2.31 and +/-6.84 mm, respectively. CONCLUSIONS: The three-dimensional left ventricular cavity shape can be accurately reproduced by using a low-data density apical octaplane echocardiographic examination.

Rapid three-dimensional echocardiography : clinically feasible alternative for precise and accurate measurement of left ventricular volumes.

BACKGROUND: Clinical applicability of conventional ultrasonographic systems using mechanical adapters for 3D echocardiographic imaging has been limited by long acquisition and processing times. We developed a rapid (6-s) acquisition technique that collects apical tomograms using a continuously internally rotating transthoracic transducer. This study was performed to examine the clinical feasibility of rapid-acquisition 3D echocardiography to estimate left ventricular end-diastolic and end-systolic volumes using electron-beam computed tomography as the reference standard. Methods and Results-We collected a series of 6 to 11 apical echocardiographic tomograms, depending on heart rate, in 11 patients. There was good correlation, low variability, and low bias between rapid 3D echocardiography and electron-beam computed tomography for measuring left ventricular end-diastolic volume (r=0.96; standard error of the estimate, 21.34 mL; bias, -4.93 mL) and left ventricular end-systolic volume (r=0.96; standard error of the estimate, 14.78 mL; bias, -6.97 mL). CONCLUSIONS: The rapid-acquisition 3D echocardiography extends the use of a multiplane, internally rotating handheld transducer so that it becomes a precise and clinically feasible tool for assessing left ventricular volumes and function. A rapid-image acquisition time of 6 s would allow repeated image collection during the course of a clinical echocardiographic examination. Additional work must address rapid and automated data processing.

Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium.

Postsystolic compression (PSC) is a sensitive indicator of regional left ventricular ischemic diastolic dysfunction. Quantitative assessment of compression patterns by strain rate imaging could determine the presence and spatial extent of PSC for the detection and analysis of acute ischemic diastolic dysfunction. With the use of a segmental left ventricular model, we evaluated time to compression/expansion crossover (T-CEC) in standard apical views. Data at baseline and after acute left anterior descending coronary artery occlusion were collected from 18 open-chest pigs. We found significant mean prolongation of T-CEC, ranging from 43.9 +/- 48.6 ms to 110.8 +/- 73.8 ms, in all apical segments and in 2 midventricular (anterior and anteroseptal) segments. Analysis of variance demonstrated that the prolonged T-CEC is spatially consistent with perfusion defect. The temporal and spatial analysis of T-CEC with the use of strain rate imaging is a new noninvasive technique for identification and topographic quantitation of ischemic diastolic dysfunction expressed by PSC.

Regional asynchrony during acute myocardial ischemia quantified by ultrasound strain rate imaging.

OBJECTIVES: We propose a new method to easily quantify asynchronous wall motion due to postsystolic shortening (PSS). We also studied the relationship of the spatial and temporal extent of PSS to the extent of myocardium at ischemic risk after variable duration of ischemia. BACKGROUND: Postsystolic shortening is a sensitive marker of asynchrony during ischemia. Current techniques for detection of asynchrony are either subjective, or invasive and time-consuming. Strain rate imaging (SRI) can noninvasively depict PSS as prolonged compression/expansion crossover. METHODS: Nineteen open-chest pigs were scanned from apical views, before and after left anterior descending coronary artery occlusion. Strain rates were derived offline from tissue Doppler velocity cineloops. The time from electrocardiographic R-wave to the occurrence of compression/expansion crossover (TCEC) was calculated. Prolonged TCEC during ischemia was identified using a standardized analysis and both spatial (% of left ventricle) and temporal extent were quantified. The extent of myocardium at risk was measured in seven animals from dye-stained specimens. RESULTS: Prolonged TCEC was found in all ischemic segments. There was a good correlation (r = 0.91; p < 0.001) and good agreement between the spatial distributions of prolonged TCEC and myocardium at risk. The extent of myocardium at risk was better approximated by TCEC measurement (36 +/- 7% vs. 39 +/- 8%, respectively; p = NS) than by wall motion analysis (47 +/- 17%, p < 0.05). The duration of occlusion did not prolong TCEC. CONCLUSIONS: Prolonged TCEC consistently occurs in ischemic myocardium and is apparently not affected by the duration of ischemia. Standardized analysis of TCEC in SRI closely quantifies the extent of ischemic myocardium. This new method may be a useful tool in other cardiac conditions associated with regional diastolic asynchrony.

Vibro-acoustography: quantification of flow with highly-localized low-frequency acoustic force.

The intersection of two ultrasound beams with slightly different frequencies results in generation of a localized radiation force and stimulates emission of audio signals from targeted objects. Vibro-acoustography uses this phenomenon to probe elastic properties of objects. Vibro-acoustography of contrast microbubbles in degassed water produced quantitative flow measurements from analysis of their acoustic emission. We used a dual-beam transducer generating bursts of 40-kHz vibrations. The vibrations resulted from interference of 3.48-MHz and 3.52-MHz confocal beams intersecting at the center of a thin plastic conduit. We tested flows of 13,48, 85, and 120 mL/min of contrast microbubbles at concentrations from 1.2 x 10(5) to 6 x 10(9) bubbles/mL. The amplitude of the acoustic emission was linear with microbubble concentrations up to a value of 3.6 x 10(5) bubbles/mL. A replenishment method for microbubble contrast and flow rate analysis was used with radiation force bursts deployed at 0.05, 0.1, 0.2, (.5, 1, and 2-second pulsing intervals. The relation between the pulsing intervals and the peak amplitude was fitted by an exponential curve and a rate constant calculated for each tested flow rate. The rate constant values were linearly correlated with the tested flows. The vibro-acoustography method provides objective, quantitative, and highly-localized assessment of flow using contrast microbubbles.

Myocardial contrast echocardiography: texture analysis for identification of nonperfused versus perfused myocardium.

This study examined texture analysis for objective identification of nonperfused myocardial segments in myocardial contrast echocardiographic (MCE) images. Short-axis MCE images from six open chest pigs after coronary artery ligation were examined. Six of 26 features (low gray level run emphasis, high gray level run emphasis, sum mean, sum variance, coefficient of variance and diagonal variance) demonstrated a significant texture value difference (P < 0.01) between the nonperfused and perfused segments with minimal statistical distribution overlap between the two groups. This study demonstrates that texture features other than mean gray level can objectively distinguish nonperfused from perfused myocardium in MCE images and may thus augment the diagnostic accuracy of current analysis techniques.

Intracardiac echocardiography: newest technology.

Intracardiac echocardiography, defined as ultra-sonographic navigation and visualization within large blood-filled cavities or vessels of the cardio-vascular system, has recently undergone refinement as a clinical tool through technologic advances in transducer miniaturization. Intra-cardiac ultra-sound catheters image at lower frequencies than current conventional intravascular ultrasound catheters used for intracoronary imaging. The lower imaging frequency enables greater tissue penetration, permitting whole-heart evaluation from a right-sided catheter position. Newer devices are steerable, have variable imaging frequency (5.5 to 10 MHz), and full Doppler capability (pulsed, continuous wave, and tissue Doppler). These advances have made intracardiac high-resolution imaging as well as hemodynamic assessment possible. A historical perspective, current capabilities and limitations, and potential clinical and research applications of this new imaging technique are discussed.

Tissue harmonic imaging: experimental analysis of the mechanism of image improvement.

Tissue harmonic scanning visually improves echocardiographic image quality. The aim of the present study was to objectively assess the improvement in harmonic image quality under controlled laboratory conditions. A tissue-mimicking phantom that contained 8-mm-diameter cystic lesions at depths ranging from 2 to 12 cm was used. Harmonic scans (1.7 MHz transmit, 3.4 MHz receive) of the phantom were obtained and lesion detectability was compared to that in scans acquired with 2 fundamental frequencies (2.0 and 3.3 MHz). A 2 cm-thick ethanol layer was also used to simulate the nonlinear effect of human fat. Cyst detectability was quantified by measurement of the contrast-to-speckle ratio (CSR). The results indicated no significant difference in the CSR between harmonic and fundamental images obtained without the ethanol layer. With images obtained with the ethanol layer, a relative increase of the CSR during harmonic imaging was observed with respect to fundamental imaging (p<0.05). In conclusion, a fat layer, here simulated by ethanol, plays a significant role in determining the resulting image quality. Without this layer, the contribution of the second harmonic mode was not significant. Thus, in a slim patient, the harmonic mode may not be as beneficial to image improvement as in an obese patient.

Myocardial contraction maps using tissue Doppler acceleration imaging.

OBJECTIVE: To evaluate the tissue Doppler acceleration imaging (TDAI) data which can be used to determine the intramural site of origin of myocardial contraction in response to electrical stimulation. METHODS: Six open-chest pigs with left ventricle (LV) pacing were evaluated with TDAI. An epicardial surface scanning method was used to collect short-axis views of the left ventricle. The electrode was implanted from the epicardium through the anterior free wall to an intramural position. RESULTS: During pacing, the intramural onset of myocardial acceleration occurred within 33 ms after electrical stimulation and always surrounded the embedded subendocardial end of the pacing needle. The observed short-axis diameter of the area of initial myocardial acceleration ranged from 2.9 mm to 5.0 mm (4.2 +/- 0.9 mm, n = 6). The onset of myocardial acceleration allowed appreciation of the initial intramural myocardial contraction. The spatial size and acceleration magnitude of the initial myocardial acceleration distribution were irregular. CONCLUSION: Two-dimensional myocardial acceleration mapping can show the intramural site of origin of myocardial contraction in response to paced electrical stimulation. The location of myocardial acceleration conformed to the site of initial electrical stimulation. The delay to the earliest regional myocardial contraction, 33 ms after paced electrical stimulation, was related to the frame rate of image acquisition.

Evolving era of multidimensional medical imaging.

Currently, computer-assisted imaging can visualize very fast or very slow nonvisible motion events. We can create measurable geometric representations of physiology, including transformation, blood flow velocity, perfusion, pressure, contractility, image features, electricity, metabolism, and a vast number of other constantly changing parameters. The greatest attribute is the ability to present physiologic phenomena as easily understood geometric images more suited to the human's four-dimensional comprehension of reality. The key research challenges are to discover new visual metaphors for representing information, understand the analysis tasks that they support, and associate relevant information to create new information.

Image enhancement by noncontrast harmonic echocardiography. Part I. Qualitative assessment of endocardial visualization.

OBJECTIVE: To determine whether harmonic imaging--use of signals with frequencies twice that of the transmitted ultrasound to produce ultrasound images--can improve endocardial border definition in patients who have technically difficult echocardiograms. METHODS: We studied 29 patients with technically difficult echocardiograms (nonvisualization of 2 or more endocardial segments in a 16-segment model). Apical long-axis, four-chamber, and two-chamber images were acquired during fundamental imaging (at 2.0 and 3.5 MHz) and second harmonic imaging (3.5-MHz receive mode) in random order. Images were digitally stored and subsequently reviewed blindly for endocardial segment score (0 = not visualized; 1 = adequate; or 2 = excellent) and overall ranking of image quality (1 [best] to 3 [worst]). RESULTS: Mean endocardial segment score was significantly better (P < 0.0001) for harmonic imaging (1.02 +/- 0.36) than for either fundamental mode (0.49 +/- 0.21 and 0.57 +/- 0.27 for the 2.0- and 3.5-MHz images, respectively). The harmonic images were ranked as better (P < 0.0001) than those of either fundamental mode: harmonic mean rank was 1.07 in comparison with 2.67 and 2.26 for the 2.0- and 3.5-MHz fundamental images, respectively. CONCLUSION: Noncontrast harmonic imaging appreciably enhances endocardial definition in patients with technically difficult echocardiographic studies and significantly improves overall image quality.

Image enhancement by noncontrast harmonic echocardiography. Part II. Quantitative assessment with use of contrast-to-speckle ratio.

OBJECTIVE: To ascertain whether "harmonic imaging"--use of ultrasound signals with the frequency twice that of the transmitted signal for ultrasound image generation--can improve image contrast while reducing noise. METHODS: Technically difficult echocardiograms (nonvisualization of 2 or more endocardial segments in a 16-segment model) from 25 patients were analyzed. Corresponding fundamental and harmonic images of the left ventricle in the apical four-chamber, two-chamber, and long-axis views were divided into basal, mid, and apical regions. The difference in image quality between fundamental and harmonic scans was assessed by using the muscle-to-cavity contrast-to-speckle ratio (CSRmc). RESULTS: The mean CSRmc values of pooled data revealed significant image enhancement by harmonic scanning (CSRmc increased from 0.84 to 1.06; P < 0.0001). Regression analysis showed that harmonic imaging improved the CSRmc values in 68% of all scans. Regional analysis indicated the most enhancement in basal regions (CSRmc increased from 0.96 to 1.34; P < 0.0001), followed by the mid (CSRmc increased from 0.84 to 1.04; P < 0.0001) and apical (CSRmc increased from 0.68 to 0.74; P = 0.0138) left ventricular regions. CONCLUSION: Noncontrast harmonic imaging significantly enhances suboptimal echocardiographic images, particularly in the regions distant from the transducer.

Toroidal geometry: novel three-dimensional intracardiac imaging with a phased-array transducer.

Recent advances in small, linear-array transducers have opened new avenues for three-dimensional image acquisition from an intracardiac approach. The purpose of this study was to introduce a novel method of image acquisition using toroidal geometry, explore its fidelity of reproduction of three-dimensional cardiac anatomy, and determine whether a whole-heart scan is achievable. Acquisition was accomplished through 360-degree incremental rotation of a rigid endoscope with a side-mounted ultrasound transducer. The procedure was first tested with the use of a gelatin model to define far-field slice resolution with 1.8-degree rotational increments. Comparison of three-dimensional scans of cardiac specimens with corresponding photographs confirmed that toroidal geometry can provide a high-quality display of structures from all sides. We conclude that whole-heart three-dimensional scanning from within the cardiac chambers is possible with toroidal geometry. The quality of depicted anatomy depends on transducer location within the heart, distance from the transducer, density of slices, and image resolution. The potential of intracardiac three-dimensional ultrasound imaging includes detailed spatial evaluation of cardiac morphology, determination of appropriate placement of investigative or therapeutic devices (catheters, closure devices, etc.), and assessment of cardiac function.