Christakis Constantinides - Academia.edu (original) (raw)

Papers by Christakis Constantinides

Biomedical Materials, Mar 9, 2012

This study uses standard synthetic methodologies to produce tissue-mimicking materials that match... more This study uses standard synthetic methodologies to produce tissue-mimicking materials that match the morphology and emulate the in vivo murine and human cardiac mechanical and imaging characteristics, with dynamic mechanical analysis, atomic force microscopy (AFM), scanning electron microscopy (SEM) and magnetic resonance imaging. In accordance with such aims, poly(glycerol sebacate) (PGS) elastomeric materials were synthesized (at two different glycerol (G)-sebacic (S) acid molar ratios; the first was synthesized using a G:S molar ratio of 2:2, while the second from a 2:5 G:S molar ratio, resulting in PGS2:2 and PGS2:5 elastomers, respectively). Unlike the synthesized PGS2:2 elastomers, the PGS2:5 materials were characterized by an overall mechanical instability in their loading behavior under the three successive loading conditions tested. An oscillatory response in the mechanical properties of the synthesized elastomers was observed throughout the loading cycles, with measured increased storage modulus values at the first loading cycle, stabilizing to lower values at subsequent cycles. These elastomers were characterized at 4 °C and were found to have storage modulus values of 850 and 1430 kPa at the third loading cycle, respectively, in agreement with previously reported values of the rat and human myocardium. SEM of surface topology indicated minor degradation of synthesized materials at 10 and 20 d post-immersion in the PBS buffer solution, with a noted cluster formation on the PGS2:5 elastomers. AFM nanoindentation experiments were also conducted for the measurement of the Young modulus of the sample surface (no bulk contribution). Correspondingly, the PGS2:2 elastomer indicated significantly decreased surface Young's modulus values 20 d post-PBS immersion, compared to dry conditions (Young's modulus = 1160 ± 290 kPa (dry) and 200 ± 120 kPa (20 d)). In addition to the two-dimensional (2D) elastomers, an integrative platform for accurate construction of three-dimensional tissue-mimicking models of cardiac anatomy from 2D MR images using rapid prototyping manufacturing processes was developed. For synthesized elastomers, doping strategies with two different concentrations of the MRI contrast agent Dotarem allowed independent and concurrent control of the imaging characteristics (contrast and relaxivity) during the synthetic process for increased contrast agent absorption, with tremendous potential for non-destructive in vivo use and applications to cardiovascular and cerebrovascular diseases.

Magnetic Resonance in Medicine, 2004

Computerized Medical Imaging and Graphics, Mar 1, 2012

MR imaging (MRI) has significant potential for quantifying cardiac function and dysfunction in th... more MR imaging (MRI) has significant potential for quantifying cardiac function and dysfunction in the mouse. Recent advances in high-resolution cardiac MRI techniques have contributed to developing atlas-based approaches to describe anatomic structures and their function in normal and transgenic mice. This study directly compares morphological features of the mouse heart in its end-relaxed state based on constructed morphometric maps and atlases using Principal Component Analysis in C57BL/6J (n=8) and DBA (n=5) mouse strains. Comparing the constructed probabilistic atlases, a gradient probability exists for both strains in longitudinal locations from base to apex, and also shows increased variability in apical locations of both strains. Based on the statistical atlases, differences in size (49.8%), apical direction (15.6%), basal ventricular blood pool size (13.2%), and papillary muscle shape and position (17.2%) account for the most significant modes of shape variability for the left ventricle of the C57BL/6J mice. For DBA mice, differences in left ventricular size and direction (67.4%), basal size (15.7%), and position of papillary muscles (16.8%) account for significant variability. The right ventricles compared for each mouse strain yields variability in the position and size (85.1 and 68.3%), and basal and apical size and locations (12.3 and 31.6%) for C57BL/6J and DBA/2J mice, respectively.

Journal of Cardiovascular Magnetic Resonance, Oct 16, 2014

Background: The complex cardiac fiber structural organization and spatial arrangement of cardiomy... more Background: The complex cardiac fiber structural organization and spatial arrangement of cardiomyocytes in laminar sheetlets contributes greatly to cardiac functional and contractile ejection patterns. This study presents the first comprehensive, ultra-high resolution, fully quantitative statistical tensor map of the fixed murine heart at isotropic resolution of 43 μm using diffusion tensor (DT) cardiovascular magnetic resonance (CMR). Methods: Imaging was completed in approximately 12 hours using a six-directional encoding scheme, in five ex vivo healthy C57BL/6 mouse hearts. The tensor map constructed from this data provides an average description of the murine fiber architecture visualized with fiber tractography, and its population variability, using the latest advances in image tensor analysis and statistics. Results: Results show that non-normalized cardiac tensor maps are associated with mean fractional anisotropy of 0.25 ± 0.07 and mean diffusivity of 8.9 ± 1.6 × 10 −4 mm 2 /s. Moreover, average mid-ventricular helical angle distributions ranged between-41 ± 3°and +52 ± 5°and were highly correlated with transmural depth, in agreement with prior published results in humans and canines. Calculated variabilities of local myocyte orientations were 2.0°a nd 1.4°. Laminar sheet orientation variability was found to be less stable at 2.6°. Despite such variations, the murine heart seems to be highly structured, particularly when compared to canines and humans. Conclusions: This tensor map has the potential to yield an accurate mean representation and identification of common or unique features of the cardiac myocyte architecture, to establish a baseline standard reference of DTI indices, and to improve detection of biomarkers, especially in pathological states or post-transgenetic modifications.

Magnetic Resonance in Medicine, Nov 1, 1997

A method is proposed to estimate signal-to-noise ratio(SNR) values in phased array magnitude imag... more A method is proposed to estimate signal-to-noise ratio(SNR) values in phased array magnitude images, based on a region-of-interest (ROI) analysis. It is shown that the SNR can be found by correcting the measured signal intensity for the noise bias effects and by evaluating the noise variance as the mean square value of all the pixel intensities in a chosen background ROI, divided by twice the number of receivers used. Estimated SNR values are shown to vary spatially within a bound of 20% with respect to the true SNR values as a result of noise correlations between receivers.

Journal of Magnetic Resonance, Sep 1, 2012

This study proposes a method to empirically minimize mutual inductance, using passive end-ring ci... more This study proposes a method to empirically minimize mutual inductance, using passive end-ring circular paddles, with neighboring coil loops placed in a non-overlapped configuration. The proposed concepts are validated through B 1-field simulations for resonant coils at f o = 300.5 MHz, having various sizes (3-10 cm), and for paddles with sizes ranging from 16 to 30 mm, and bench tests on constructed 4 Â 4 cm 2 two-(1 Â 2) and four-coil loop (2 Â 2) planar arrays. Simulation results yield total mean percentage B 1-field differences of only 7.03% between the two nonoverlapping coil array configurations (paddles vs. no-paddles). Pair-wise comparisons of elicited mean B 1-field differences from the use of different circular and rectangular paddle sizes, yield values <5.3%. Theoretical calculation of the normalized mutual coupling coefficient in the non-overlapped coil configuration reduces to almost zero with optimally sized-paddles having a radius of approximately 28% the coil's largest dimension. In the absence of paddles, differences in the split of resonance peaks of 9.9 MHz were observed for the two coils in the 1 Â 2 array, which vanished with paddle placement. Single coil responses (unloaded/ loaded) without paddles, and responses from array coils with use of optimally-sized paddles yielded quality factor ratios that ranged between 1.1-1.86 and 1.0-1.5, respectively. Phantom and mouse loaded reflection coefficients S 11 /S 22 were À16.7/À16.2 dB and À28.2/À16.1 dB, for the two array loops, respectively. Under unloaded conditions and in the absence of paddles, split resonances were observed for the 1 Â 2 array, yielding transmission coefficients of À5.5 to À8.1 dB, reversing to single resonance responses upon paddle placements, with transmission coefficients of À14.4 to À15.6 dB.

Radiology, Aug 1, 2000

PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium ... more PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease. MATERIALS AND METHODS: Total [Na] sodium was determined from the ratio of the relaxation-corrected 23 Na signal intensities measured from short echo-time (0.4 msec) 23 Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. 23 Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis. RESULTS: 23 Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight Ϯ 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10-15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints. CONCLUSION: 23 Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodiumpotassium pump and perfusion in normal and diseased muscle.

Physiological Measurement, Jun 9, 2015

The study&#39;s objective is to quantify in vivo epicardial force and strain in the normal an... more The study&#39;s objective is to quantify in vivo epicardial force and strain in the normal and transgenic myocardium using microsensors.Male mice (n = 39), including C57BL/6 (n = 26), 129/Sv (n = 5), wild-type (WT) C57 × 129Sv (n = 5), and muscle LIM protein (MLP) knock-out (n = 3), were studied under 1.5% isoflurane anaesthesia. Microsurgery allowed the placement of two piezoelectric crystals at longitudinal epicardial loci at the basal, middle, and apical LV regions, and the independent (and/or concurrent) placement of a cantilever force sensor. The findings demonstrate longitudinal contractile and relaxation strains that ranged between 4.8-9.3% in the basal, middle, and apical regions of C57BL/6 mice, and in the mid-ventricular regions of 129/Sv, WT, and MLP mice. Measured forces ranged between 3.1-8.9 mN. The technique&#39;s feasibility is also demonstrated in normal mice following afterload, occlusion-reperfusion challenges.Furthermore, the total mid-ventricular forces developed in MLP mice were significantly reduced compared to the WT controls (5.9 ± 0.4 versus 8.9 ± 0.2 mN, p &lt; 0.0001), possibly owing to the fibrotic and stiffer myocardium. No significant strain differences were noted between WT and MLP mice.The possibility of quantifying in vivo force and strain from the normal murine heart is demonstrated with a potential usefulness in the characterisation of transgenic and diseased mice, where regional myocardial function may be significantly altered.

This study examines the effects of changing oxygen fractional inspiration ratio (FiO(2)), and nit... more This study examines the effects of changing oxygen fractional inspiration ratio (FiO(2)), and nitrous oxide (N(2)O) for the improvement of cardiovascular control of mean arterial blood pressure (MAP) and heart rate (HR) in C57BL/6 mice under isoflurane anesthesia (1.5%) for up to 90 minutes post-induction. Heart rate variability (HRV) indices are also quantified under these conditions. The results indicate that changing the FiO(2) does result in lower MAP and HR values compared to the case of N(2)O (50%) administration to the isoflurane gas mixture. HRV indices declined over the course of all anesthetic regimens, suggesting a decrease in parasympathetic tone. We conclude that the most optimal anesthetic condition is achieved when N(2)O (50%) is added to the gas mixture.

Magnetic Resonance in Medicine, 2001

An intravascular iron-based contrast agent was used as a sodium (23 Na) MRI T 2 relaxant in an ef... more An intravascular iron-based contrast agent was used as a sodium (23 Na) MRI T 2 relaxant in an effort to suppress the blood signal from the ventricular cavities in normal and infarcted canine myocardium in vivo. 23 Na MRI signal decreases in blood were attributed to decreases in the fast (T 2f) and slow (T 2s) transverse relaxation components, which were quantified as a function of dose and MRI echo time (TE). In vivo 23 Na MRI signal decreases up to 65% were noted in ventricular blood when imaging under dose and TE conditions of 10 mg/kg body weight and 5 ms, respectively. Contrast injection followed by subsequent 23 Na MRI in canine myocardial infarction led to a clear delineation of the location of the injured tissue, as identified by postmortem triphenyltetrazolium chloride staining, and to an improvement in the contrast-to-noise ratio between the blood in the ventricular chamber and the infarcted tissue that was as high as 3.3-fold in the postcontrast images in comparison to the precontrast images.

Annals of Biomedical Engineering, Aug 5, 2011

This study examines (a) the temporal stability of hemodynamic indices of systolic and diastolic f... more This study examines (a) the temporal stability of hemodynamic indices of systolic and diastolic function in C57BL/6 mice under 1.5% isoflurane (ISO) (v/v) anesthesia conditions in 50:50 O(2)/N(2)O (v/v) within 90 min post-induction, and (b) the effects of Mn(2+) on the mouse hemodynamic response in male C57BL/6 mice (n = 16). Left ventricular catheterizations allowed estimation of the hemodynamic indices. Hypertonic saline infusion (10%) allowed absolute volume quantification in conjunction with a separate series of aortic flow experiments (n = 3). In a separate cohort of mice (n = 6), MnCl(2) (190 nmoles/g/bw) was infused via the left jugular for 29-39 min, following 11 min of baseline recording, to assess temporal responses. Stable temporal hemodynamic responses were achieved in control mice under ISO anesthesia. Hemodynamic indices during control, time-matched-control, baseline-Mn, and Mn-infused periods, were within normal expected ranges. No chronotropic changes were observed. Significant differences in systolic and diastolic cardiac indices of function (HR, EF, ESP, dP/dt (max), dP/dt (min), PAMP, τ(glantz), and τ(weiss)) resulted between baseline-Mn and Mn-infused time periods in Mn-treated mice at the 1% significance (p &amp;amp;lt; 0.001). Transient positive, or negative, or positive followed by negative evoked pressure-volume loop shifts were observed (exemplified through changes in the end-systolic pressure-volume relationship and dP/dt (max)) in Mn-infusion studies. It is concluded that Mn(2+) can be used safely for prolonged mouse imaging studies, however, the significant variations elicited in cardiovascular hemodynamics post-manganese infusion, necessitate further investigations for its suitability and appropriateness for quantification of global cardiac function in image-based phenotyping.

IEEE Transactions on Biomedical Engineering, Nov 1, 2011

Catheter-based measurements are extensively used nowadays in animal models to quantify global lef... more Catheter-based measurements are extensively used nowadays in animal models to quantify global left ventricular (LV) cardiac function and hemodynamics. Conductance catheter measurements yield estimates of LV volumes. Such estimates, however, are confounded by the catheter's nonhomogeneous emission field and the contribution to the total conductance of surrounding tissue or blood conductance values (other than LV blood), a term often known as parallel conductance. In practice, in most studies, volume estimates are based on the assumptions that the catheter's electric field is homogeneous and that parallel conductance is constant, despite prior results showing that these assumptions are incorrect. This study challenges the assumption for spatial homogeneity of electric field excitation of miniature catheters and investigated the electric field distribution of miniature catheters in the murine heart, based on cardiac model-driven (geometric, lump component) simulations and noninvasive imaging, at both systolic and diastolic cardiac phases. Results confirm the nonuniform catheter emission field, confined spatially within the LV cavity and myocardium, falling to 10% of its peak value at the ring electrode surface, within 1.1-2.0 mm, given a relative tissue permittivity of 33 615. Additionally, <1% of power leaks were observed into surrounding cavities or organs at end-diastole. Temporally varying parallel conductance effects are also confirmed, becoming more prominent at end-systole.

Magnetic Resonance Imaging, 2000

A new iterative extrapolation image reconstruction algorithm is presented, which enhances low res... more A new iterative extrapolation image reconstruction algorithm is presented, which enhances low resolution metabolic magnetic resonance images (MRI) with information about the bounds of signal sources obtained from a priori anatomic proton ((1)H) MRI. The algorithm ameliorates partial volume and ringing artefacts, leaving unchanged local metabolic heterogeneity that is present in the original dataset but not evident at (1)H MRI. Therefore, it is ideally suited to metabolic studies of ischemia, infarction and other diseases where the extent of the abnormality at (1)H MRI is uncertain. The performance of the algorithm is assessed by simulations, MRI of phantoms, and by surface coil 23Na MRI studies of canine myocardial infarction on a clinical scanner where the injury was not evident at (1)H MRI. The algorithm includes corrections for transverse field inhomogeneity, and for the leakage of intense signals into regions of interest such as 23Na MRI signals from ventricular blood ringing into the myocardium. The simulations showed that the algorithm reduced ringing artefacts by 15%, was stable at low SNR ( approximately 7), but is sensitive to the positioning of the (1)H MRI boundaries. The 23Na MRI showed hyperenhancement of regions identified as infarcted at post-mortem histological staining. The areas of hyperenhancement were measured by five independent observers in four 23Na images of infarction reconstructed with and without the algorithm. The infarct areas were correlated with areas determined by post-mortem histological staining with coefficient 0.85 for the enhanced images, compared to 0.58 with the conventional images. The scatter in the amplitude and in the area measurements of ischemia-associated hyper-enhancement in 23Na MRI was reduced by the algorithm by 1.6-fold and by at least 3-fold, respectively, demonstrating its ability to substantially improve quantification of the extent and intensity of metabolic changes in injured tissue that is not evident by (1)H MRI.

Concepts in Magnetic Resonance Part A, Sep 1, 2011

Multi-turn spiral surface coils are constructed in flat and cylindrical arrangements and used for... more Multi-turn spiral surface coils are constructed in flat and cylindrical arrangements and used for high field (7.1 T) mouse cardiac MRI. Their electrical and imaging performances, based on experimental measurements, simulations, and MRI experiments in free space, and under phantom, and animal loading conditions, are compared with a commercially available birdcage coil. Results show that the four-turn cylindrical spiral coil exhibits improved relative SNR (rSNR) performance to the flat coil counterpart, and compares fairly well with a commercially available birdcage coil. Phantom experiments indicate a 50% improvement in the SNR for penetration depths ≤ 6.1 mm from the coil surface compared to the birdcage coil, and an increased penetration depth at the halfmaximum field response of 8 mm in the 4-spiral cylindrical coil case, in contrast to 2.9 mm in the flat 4-turn spiral case. Quantitative comparison of the performance of the two spiral coil geometries in anterior, lateral, inferior, and septal regions of the murine heart yield maximum mean percentage rSNR increases of the order of 27-167% in vivo post-mortem (cylindrical compared to flat coil). The commercially available birdcage outperforms the cylindrical spiral coil in rSNR by a factor of 3-5 times. The comprehensive approach and methodology adopted to accurately design, simulate, implement, and test radiofrequency coils of any geometry and type, under any loading conditions, can be generalized for any application of high field mouse cardiac MRI.

Practical Applications in Biomedical Engineering, 2013

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging: The Current Sta... more Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging: The Current Status, Challenges, and Future Perspectives 345 (RF), and gradient technologies) based on recent work and advances in miniature RF coils for imaging, state-of-the-art imaging techniques and pulse sequences based on rectilinear and non-cartesian sampling schemes, including functional MRI, atlas-based approaches for morphology assessment and four-dimensional (4D) motional variability, as well as regional cardiac functional characterization and quantification methods, Displacement Encoding with Stimulated Echoes (DENSE) [Aletras 1999], Harmonic Phase (HARP) [Osman 1999, Kuijer 2001], tagging and advanced imaging techniques. MRI-based, accurate threedimensional (3D) and 4D surface and finite element mesh model extractions, in association with advanced segmentation-seed-based or semi-automatic-and registration techniquesdiffeomorphic or landmark-based, are shown to facilitate efficient mouse inter-strain cardiac hemodynamical comparisons of both right and left-ventricular chambers. Based on recently published DENSE human-mouse comparative studies, and findings from image-based regional functional quantifications, similar transmural motional patterns are observed in both species, lending additional support to long-standing hypotheses for the existence of allometric scaling in metabolism, energetics [Dobson 1995, Nielsen 1958, Phillips 2012], and mechanical function in mouse and man. Practical Applications in Biomedical Engineering 346 Todate, multiple thousands of different knockout mice have been constructed (by individual Institutions, Laboratories, or National or International Consortia), most of which affect cardiovascular function. As attempts to match genotype to phenotype continue, an increasing number of knockout or loss-of-function mice is expected to be generated. However, despite the usefulness, practicality, and low costs associated with the study of the mouse, important genetic, developmental, morphological, and physiological differences exist between mouse and man [Doevendans 1998, Schaper 1998]. The section that follows addresses succinctly common and distinctly differing features and functional differences in mouse and man and discusses the mechanisms of anesthesia effects on the mouse physiology and cardiac contractile machinery.

Magnetic Resonance in Medicine, 2004

Radiology, 2000

To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human ... more To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease. Total [Na] sodium was determined from the ratio of the relaxation-corrected (23)Na signal intensities measured from short echo-time (0.4 msec) (23)Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. (23)Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis. (23)Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight +/- 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10-15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints. (23)Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodium-potassium pump and perfusion in normal and diseased muscle.

The transport of sodium and potassium between the intra-and extracellular pools and the maintenan... more The transport of sodium and potassium between the intra-and extracellular pools and the maintenance of the transmembrane concentration gradients are important to cell function and integrity. The early disruption of the sodium pump in myocardial infarction in response to the exhaustion of energy reserves following ischemia and reperfusion results in increased intracellular (and thus total) sodium levels. In this study a method for noninvasively quantifying myocardial sodium levels directly from sodium (23 Na) MRI is presented. It was used to measure total myocardial sodium on a clinical 1.5T system in six normal dogs and five dogs with experimentally-induced myocardial infarction (MI). The technique was validated by comparing total sodium content measured by 23 Na MRI with that measured by atomic absorption spectrophotometry (AAS) in biopsied tissue. Total sodium measured by 23 Na MRI was significantly elevated in regions of infarction (81.3 ؎ 14.3 mmol/kg wet wt, mean ؎ SD) compared to noninfarcted myocardial tissue from both infarcted dogs (36.2 ؎ 1.1, P < 0.001) and from normal controls (34.4 ؎ 2.8, P < 0.0001). Myocardial tissue sodium content as measured by 23 Na MRI did not vary regionally in the lateral, anterior, or inferior regions in normal hearts (ANOVA, P ‫؍‬ NS). Sodium content measured by 23 Na MRI agreed with the mean AAS estimates of 31.3 ؎ 5.6 mmol/kg wet wt (P ‫؍‬ NS) in normal hearts, and did not differ significantly from AAS measurements in MI (P ‫؍‬ NS). Thus, local tissue sodium levels can be accurately quantified noninvasively using 23 Na MRI in normal and acutely reperfused MI. The detection of regional myocardial sodium elevations may help differentiate viable from nonviable, infarcted tissue.

Biomedical Materials, Mar 9, 2012

This study uses standard synthetic methodologies to produce tissue-mimicking materials that match... more This study uses standard synthetic methodologies to produce tissue-mimicking materials that match the morphology and emulate the in vivo murine and human cardiac mechanical and imaging characteristics, with dynamic mechanical analysis, atomic force microscopy (AFM), scanning electron microscopy (SEM) and magnetic resonance imaging. In accordance with such aims, poly(glycerol sebacate) (PGS) elastomeric materials were synthesized (at two different glycerol (G)-sebacic (S) acid molar ratios; the first was synthesized using a G:S molar ratio of 2:2, while the second from a 2:5 G:S molar ratio, resulting in PGS2:2 and PGS2:5 elastomers, respectively). Unlike the synthesized PGS2:2 elastomers, the PGS2:5 materials were characterized by an overall mechanical instability in their loading behavior under the three successive loading conditions tested. An oscillatory response in the mechanical properties of the synthesized elastomers was observed throughout the loading cycles, with measured increased storage modulus values at the first loading cycle, stabilizing to lower values at subsequent cycles. These elastomers were characterized at 4 °C and were found to have storage modulus values of 850 and 1430 kPa at the third loading cycle, respectively, in agreement with previously reported values of the rat and human myocardium. SEM of surface topology indicated minor degradation of synthesized materials at 10 and 20 d post-immersion in the PBS buffer solution, with a noted cluster formation on the PGS2:5 elastomers. AFM nanoindentation experiments were also conducted for the measurement of the Young modulus of the sample surface (no bulk contribution). Correspondingly, the PGS2:2 elastomer indicated significantly decreased surface Young&amp;amp;#39;s modulus values 20 d post-PBS immersion, compared to dry conditions (Young&amp;amp;#39;s modulus = 1160 ± 290 kPa (dry) and 200 ± 120 kPa (20 d)). In addition to the two-dimensional (2D) elastomers, an integrative platform for accurate construction of three-dimensional tissue-mimicking models of cardiac anatomy from 2D MR images using rapid prototyping manufacturing processes was developed. For synthesized elastomers, doping strategies with two different concentrations of the MRI contrast agent Dotarem allowed independent and concurrent control of the imaging characteristics (contrast and relaxivity) during the synthetic process for increased contrast agent absorption, with tremendous potential for non-destructive in vivo use and applications to cardiovascular and cerebrovascular diseases.

Magnetic Resonance in Medicine, 2004

Computerized Medical Imaging and Graphics, Mar 1, 2012

MR imaging (MRI) has significant potential for quantifying cardiac function and dysfunction in th... more MR imaging (MRI) has significant potential for quantifying cardiac function and dysfunction in the mouse. Recent advances in high-resolution cardiac MRI techniques have contributed to developing atlas-based approaches to describe anatomic structures and their function in normal and transgenic mice. This study directly compares morphological features of the mouse heart in its end-relaxed state based on constructed morphometric maps and atlases using Principal Component Analysis in C57BL/6J (n=8) and DBA (n=5) mouse strains. Comparing the constructed probabilistic atlases, a gradient probability exists for both strains in longitudinal locations from base to apex, and also shows increased variability in apical locations of both strains. Based on the statistical atlases, differences in size (49.8%), apical direction (15.6%), basal ventricular blood pool size (13.2%), and papillary muscle shape and position (17.2%) account for the most significant modes of shape variability for the left ventricle of the C57BL/6J mice. For DBA mice, differences in left ventricular size and direction (67.4%), basal size (15.7%), and position of papillary muscles (16.8%) account for significant variability. The right ventricles compared for each mouse strain yields variability in the position and size (85.1 and 68.3%), and basal and apical size and locations (12.3 and 31.6%) for C57BL/6J and DBA/2J mice, respectively.

Journal of Cardiovascular Magnetic Resonance, Oct 16, 2014

Background: The complex cardiac fiber structural organization and spatial arrangement of cardiomy... more Background: The complex cardiac fiber structural organization and spatial arrangement of cardiomyocytes in laminar sheetlets contributes greatly to cardiac functional and contractile ejection patterns. This study presents the first comprehensive, ultra-high resolution, fully quantitative statistical tensor map of the fixed murine heart at isotropic resolution of 43 μm using diffusion tensor (DT) cardiovascular magnetic resonance (CMR). Methods: Imaging was completed in approximately 12 hours using a six-directional encoding scheme, in five ex vivo healthy C57BL/6 mouse hearts. The tensor map constructed from this data provides an average description of the murine fiber architecture visualized with fiber tractography, and its population variability, using the latest advances in image tensor analysis and statistics. Results: Results show that non-normalized cardiac tensor maps are associated with mean fractional anisotropy of 0.25 ± 0.07 and mean diffusivity of 8.9 ± 1.6 × 10 −4 mm 2 /s. Moreover, average mid-ventricular helical angle distributions ranged between-41 ± 3°and +52 ± 5°and were highly correlated with transmural depth, in agreement with prior published results in humans and canines. Calculated variabilities of local myocyte orientations were 2.0°a nd 1.4°. Laminar sheet orientation variability was found to be less stable at 2.6°. Despite such variations, the murine heart seems to be highly structured, particularly when compared to canines and humans. Conclusions: This tensor map has the potential to yield an accurate mean representation and identification of common or unique features of the cardiac myocyte architecture, to establish a baseline standard reference of DTI indices, and to improve detection of biomarkers, especially in pathological states or post-transgenetic modifications.

Magnetic Resonance in Medicine, Nov 1, 1997

A method is proposed to estimate signal-to-noise ratio(SNR) values in phased array magnitude imag... more A method is proposed to estimate signal-to-noise ratio(SNR) values in phased array magnitude images, based on a region-of-interest (ROI) analysis. It is shown that the SNR can be found by correcting the measured signal intensity for the noise bias effects and by evaluating the noise variance as the mean square value of all the pixel intensities in a chosen background ROI, divided by twice the number of receivers used. Estimated SNR values are shown to vary spatially within a bound of 20% with respect to the true SNR values as a result of noise correlations between receivers.

Journal of Magnetic Resonance, Sep 1, 2012

This study proposes a method to empirically minimize mutual inductance, using passive end-ring ci... more This study proposes a method to empirically minimize mutual inductance, using passive end-ring circular paddles, with neighboring coil loops placed in a non-overlapped configuration. The proposed concepts are validated through B 1-field simulations for resonant coils at f o = 300.5 MHz, having various sizes (3-10 cm), and for paddles with sizes ranging from 16 to 30 mm, and bench tests on constructed 4 Â 4 cm 2 two-(1 Â 2) and four-coil loop (2 Â 2) planar arrays. Simulation results yield total mean percentage B 1-field differences of only 7.03% between the two nonoverlapping coil array configurations (paddles vs. no-paddles). Pair-wise comparisons of elicited mean B 1-field differences from the use of different circular and rectangular paddle sizes, yield values <5.3%. Theoretical calculation of the normalized mutual coupling coefficient in the non-overlapped coil configuration reduces to almost zero with optimally sized-paddles having a radius of approximately 28% the coil's largest dimension. In the absence of paddles, differences in the split of resonance peaks of 9.9 MHz were observed for the two coils in the 1 Â 2 array, which vanished with paddle placement. Single coil responses (unloaded/ loaded) without paddles, and responses from array coils with use of optimally-sized paddles yielded quality factor ratios that ranged between 1.1-1.86 and 1.0-1.5, respectively. Phantom and mouse loaded reflection coefficients S 11 /S 22 were À16.7/À16.2 dB and À28.2/À16.1 dB, for the two array loops, respectively. Under unloaded conditions and in the absence of paddles, split resonances were observed for the 1 Â 2 array, yielding transmission coefficients of À5.5 to À8.1 dB, reversing to single resonance responses upon paddle placements, with transmission coefficients of À14.4 to À15.6 dB.

Radiology, Aug 1, 2000

PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium ... more PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease. MATERIALS AND METHODS: Total [Na] sodium was determined from the ratio of the relaxation-corrected 23 Na signal intensities measured from short echo-time (0.4 msec) 23 Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. 23 Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis. RESULTS: 23 Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight Ϯ 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10-15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints. CONCLUSION: 23 Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodiumpotassium pump and perfusion in normal and diseased muscle.

Physiological Measurement, Jun 9, 2015

The study&#39;s objective is to quantify in vivo epicardial force and strain in the normal an... more The study&#39;s objective is to quantify in vivo epicardial force and strain in the normal and transgenic myocardium using microsensors.Male mice (n = 39), including C57BL/6 (n = 26), 129/Sv (n = 5), wild-type (WT) C57 × 129Sv (n = 5), and muscle LIM protein (MLP) knock-out (n = 3), were studied under 1.5% isoflurane anaesthesia. Microsurgery allowed the placement of two piezoelectric crystals at longitudinal epicardial loci at the basal, middle, and apical LV regions, and the independent (and/or concurrent) placement of a cantilever force sensor. The findings demonstrate longitudinal contractile and relaxation strains that ranged between 4.8-9.3% in the basal, middle, and apical regions of C57BL/6 mice, and in the mid-ventricular regions of 129/Sv, WT, and MLP mice. Measured forces ranged between 3.1-8.9 mN. The technique&#39;s feasibility is also demonstrated in normal mice following afterload, occlusion-reperfusion challenges.Furthermore, the total mid-ventricular forces developed in MLP mice were significantly reduced compared to the WT controls (5.9 ± 0.4 versus 8.9 ± 0.2 mN, p &lt; 0.0001), possibly owing to the fibrotic and stiffer myocardium. No significant strain differences were noted between WT and MLP mice.The possibility of quantifying in vivo force and strain from the normal murine heart is demonstrated with a potential usefulness in the characterisation of transgenic and diseased mice, where regional myocardial function may be significantly altered.

This study examines the effects of changing oxygen fractional inspiration ratio (FiO(2)), and nit... more This study examines the effects of changing oxygen fractional inspiration ratio (FiO(2)), and nitrous oxide (N(2)O) for the improvement of cardiovascular control of mean arterial blood pressure (MAP) and heart rate (HR) in C57BL/6 mice under isoflurane anesthesia (1.5%) for up to 90 minutes post-induction. Heart rate variability (HRV) indices are also quantified under these conditions. The results indicate that changing the FiO(2) does result in lower MAP and HR values compared to the case of N(2)O (50%) administration to the isoflurane gas mixture. HRV indices declined over the course of all anesthetic regimens, suggesting a decrease in parasympathetic tone. We conclude that the most optimal anesthetic condition is achieved when N(2)O (50%) is added to the gas mixture.

Magnetic Resonance in Medicine, 2001

An intravascular iron-based contrast agent was used as a sodium (23 Na) MRI T 2 relaxant in an ef... more An intravascular iron-based contrast agent was used as a sodium (23 Na) MRI T 2 relaxant in an effort to suppress the blood signal from the ventricular cavities in normal and infarcted canine myocardium in vivo. 23 Na MRI signal decreases in blood were attributed to decreases in the fast (T 2f) and slow (T 2s) transverse relaxation components, which were quantified as a function of dose and MRI echo time (TE). In vivo 23 Na MRI signal decreases up to 65% were noted in ventricular blood when imaging under dose and TE conditions of 10 mg/kg body weight and 5 ms, respectively. Contrast injection followed by subsequent 23 Na MRI in canine myocardial infarction led to a clear delineation of the location of the injured tissue, as identified by postmortem triphenyltetrazolium chloride staining, and to an improvement in the contrast-to-noise ratio between the blood in the ventricular chamber and the infarcted tissue that was as high as 3.3-fold in the postcontrast images in comparison to the precontrast images.

Annals of Biomedical Engineering, Aug 5, 2011

This study examines (a) the temporal stability of hemodynamic indices of systolic and diastolic f... more This study examines (a) the temporal stability of hemodynamic indices of systolic and diastolic function in C57BL/6 mice under 1.5% isoflurane (ISO) (v/v) anesthesia conditions in 50:50 O(2)/N(2)O (v/v) within 90 min post-induction, and (b) the effects of Mn(2+) on the mouse hemodynamic response in male C57BL/6 mice (n = 16). Left ventricular catheterizations allowed estimation of the hemodynamic indices. Hypertonic saline infusion (10%) allowed absolute volume quantification in conjunction with a separate series of aortic flow experiments (n = 3). In a separate cohort of mice (n = 6), MnCl(2) (190 nmoles/g/bw) was infused via the left jugular for 29-39 min, following 11 min of baseline recording, to assess temporal responses. Stable temporal hemodynamic responses were achieved in control mice under ISO anesthesia. Hemodynamic indices during control, time-matched-control, baseline-Mn, and Mn-infused periods, were within normal expected ranges. No chronotropic changes were observed. Significant differences in systolic and diastolic cardiac indices of function (HR, EF, ESP, dP/dt (max), dP/dt (min), PAMP, τ(glantz), and τ(weiss)) resulted between baseline-Mn and Mn-infused time periods in Mn-treated mice at the 1% significance (p &amp;amp;lt; 0.001). Transient positive, or negative, or positive followed by negative evoked pressure-volume loop shifts were observed (exemplified through changes in the end-systolic pressure-volume relationship and dP/dt (max)) in Mn-infusion studies. It is concluded that Mn(2+) can be used safely for prolonged mouse imaging studies, however, the significant variations elicited in cardiovascular hemodynamics post-manganese infusion, necessitate further investigations for its suitability and appropriateness for quantification of global cardiac function in image-based phenotyping.

IEEE Transactions on Biomedical Engineering, Nov 1, 2011

Catheter-based measurements are extensively used nowadays in animal models to quantify global lef... more Catheter-based measurements are extensively used nowadays in animal models to quantify global left ventricular (LV) cardiac function and hemodynamics. Conductance catheter measurements yield estimates of LV volumes. Such estimates, however, are confounded by the catheter's nonhomogeneous emission field and the contribution to the total conductance of surrounding tissue or blood conductance values (other than LV blood), a term often known as parallel conductance. In practice, in most studies, volume estimates are based on the assumptions that the catheter's electric field is homogeneous and that parallel conductance is constant, despite prior results showing that these assumptions are incorrect. This study challenges the assumption for spatial homogeneity of electric field excitation of miniature catheters and investigated the electric field distribution of miniature catheters in the murine heart, based on cardiac model-driven (geometric, lump component) simulations and noninvasive imaging, at both systolic and diastolic cardiac phases. Results confirm the nonuniform catheter emission field, confined spatially within the LV cavity and myocardium, falling to 10% of its peak value at the ring electrode surface, within 1.1-2.0 mm, given a relative tissue permittivity of 33 615. Additionally, <1% of power leaks were observed into surrounding cavities or organs at end-diastole. Temporally varying parallel conductance effects are also confirmed, becoming more prominent at end-systole.

Magnetic Resonance Imaging, 2000

A new iterative extrapolation image reconstruction algorithm is presented, which enhances low res... more A new iterative extrapolation image reconstruction algorithm is presented, which enhances low resolution metabolic magnetic resonance images (MRI) with information about the bounds of signal sources obtained from a priori anatomic proton ((1)H) MRI. The algorithm ameliorates partial volume and ringing artefacts, leaving unchanged local metabolic heterogeneity that is present in the original dataset but not evident at (1)H MRI. Therefore, it is ideally suited to metabolic studies of ischemia, infarction and other diseases where the extent of the abnormality at (1)H MRI is uncertain. The performance of the algorithm is assessed by simulations, MRI of phantoms, and by surface coil 23Na MRI studies of canine myocardial infarction on a clinical scanner where the injury was not evident at (1)H MRI. The algorithm includes corrections for transverse field inhomogeneity, and for the leakage of intense signals into regions of interest such as 23Na MRI signals from ventricular blood ringing into the myocardium. The simulations showed that the algorithm reduced ringing artefacts by 15%, was stable at low SNR ( approximately 7), but is sensitive to the positioning of the (1)H MRI boundaries. The 23Na MRI showed hyperenhancement of regions identified as infarcted at post-mortem histological staining. The areas of hyperenhancement were measured by five independent observers in four 23Na images of infarction reconstructed with and without the algorithm. The infarct areas were correlated with areas determined by post-mortem histological staining with coefficient 0.85 for the enhanced images, compared to 0.58 with the conventional images. The scatter in the amplitude and in the area measurements of ischemia-associated hyper-enhancement in 23Na MRI was reduced by the algorithm by 1.6-fold and by at least 3-fold, respectively, demonstrating its ability to substantially improve quantification of the extent and intensity of metabolic changes in injured tissue that is not evident by (1)H MRI.

Concepts in Magnetic Resonance Part A, Sep 1, 2011

Multi-turn spiral surface coils are constructed in flat and cylindrical arrangements and used for... more Multi-turn spiral surface coils are constructed in flat and cylindrical arrangements and used for high field (7.1 T) mouse cardiac MRI. Their electrical and imaging performances, based on experimental measurements, simulations, and MRI experiments in free space, and under phantom, and animal loading conditions, are compared with a commercially available birdcage coil. Results show that the four-turn cylindrical spiral coil exhibits improved relative SNR (rSNR) performance to the flat coil counterpart, and compares fairly well with a commercially available birdcage coil. Phantom experiments indicate a 50% improvement in the SNR for penetration depths ≤ 6.1 mm from the coil surface compared to the birdcage coil, and an increased penetration depth at the halfmaximum field response of 8 mm in the 4-spiral cylindrical coil case, in contrast to 2.9 mm in the flat 4-turn spiral case. Quantitative comparison of the performance of the two spiral coil geometries in anterior, lateral, inferior, and septal regions of the murine heart yield maximum mean percentage rSNR increases of the order of 27-167% in vivo post-mortem (cylindrical compared to flat coil). The commercially available birdcage outperforms the cylindrical spiral coil in rSNR by a factor of 3-5 times. The comprehensive approach and methodology adopted to accurately design, simulate, implement, and test radiofrequency coils of any geometry and type, under any loading conditions, can be generalized for any application of high field mouse cardiac MRI.

Practical Applications in Biomedical Engineering, 2013

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging: The Current Sta... more Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging: The Current Status, Challenges, and Future Perspectives 345 (RF), and gradient technologies) based on recent work and advances in miniature RF coils for imaging, state-of-the-art imaging techniques and pulse sequences based on rectilinear and non-cartesian sampling schemes, including functional MRI, atlas-based approaches for morphology assessment and four-dimensional (4D) motional variability, as well as regional cardiac functional characterization and quantification methods, Displacement Encoding with Stimulated Echoes (DENSE) [Aletras 1999], Harmonic Phase (HARP) [Osman 1999, Kuijer 2001], tagging and advanced imaging techniques. MRI-based, accurate threedimensional (3D) and 4D surface and finite element mesh model extractions, in association with advanced segmentation-seed-based or semi-automatic-and registration techniquesdiffeomorphic or landmark-based, are shown to facilitate efficient mouse inter-strain cardiac hemodynamical comparisons of both right and left-ventricular chambers. Based on recently published DENSE human-mouse comparative studies, and findings from image-based regional functional quantifications, similar transmural motional patterns are observed in both species, lending additional support to long-standing hypotheses for the existence of allometric scaling in metabolism, energetics [Dobson 1995, Nielsen 1958, Phillips 2012], and mechanical function in mouse and man. Practical Applications in Biomedical Engineering 346 Todate, multiple thousands of different knockout mice have been constructed (by individual Institutions, Laboratories, or National or International Consortia), most of which affect cardiovascular function. As attempts to match genotype to phenotype continue, an increasing number of knockout or loss-of-function mice is expected to be generated. However, despite the usefulness, practicality, and low costs associated with the study of the mouse, important genetic, developmental, morphological, and physiological differences exist between mouse and man [Doevendans 1998, Schaper 1998]. The section that follows addresses succinctly common and distinctly differing features and functional differences in mouse and man and discusses the mechanisms of anesthesia effects on the mouse physiology and cardiac contractile machinery.

Magnetic Resonance in Medicine, 2004

Radiology, 2000

To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human ... more To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease. Total [Na] sodium was determined from the ratio of the relaxation-corrected (23)Na signal intensities measured from short echo-time (0.4 msec) (23)Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. (23)Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis. (23)Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight +/- 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10-15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints. (23)Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodium-potassium pump and perfusion in normal and diseased muscle.

The transport of sodium and potassium between the intra-and extracellular pools and the maintenan... more The transport of sodium and potassium between the intra-and extracellular pools and the maintenance of the transmembrane concentration gradients are important to cell function and integrity. The early disruption of the sodium pump in myocardial infarction in response to the exhaustion of energy reserves following ischemia and reperfusion results in increased intracellular (and thus total) sodium levels. In this study a method for noninvasively quantifying myocardial sodium levels directly from sodium (23 Na) MRI is presented. It was used to measure total myocardial sodium on a clinical 1.5T system in six normal dogs and five dogs with experimentally-induced myocardial infarction (MI). The technique was validated by comparing total sodium content measured by 23 Na MRI with that measured by atomic absorption spectrophotometry (AAS) in biopsied tissue. Total sodium measured by 23 Na MRI was significantly elevated in regions of infarction (81.3 ؎ 14.3 mmol/kg wet wt, mean ؎ SD) compared to noninfarcted myocardial tissue from both infarcted dogs (36.2 ؎ 1.1, P < 0.001) and from normal controls (34.4 ؎ 2.8, P < 0.0001). Myocardial tissue sodium content as measured by 23 Na MRI did not vary regionally in the lateral, anterior, or inferior regions in normal hearts (ANOVA, P ‫؍‬ NS). Sodium content measured by 23 Na MRI agreed with the mean AAS estimates of 31.3 ؎ 5.6 mmol/kg wet wt (P ‫؍‬ NS) in normal hearts, and did not differ significantly from AAS measurements in MI (P ‫؍‬ NS). Thus, local tissue sodium levels can be accurately quantified noninvasively using 23 Na MRI in normal and acutely reperfused MI. The detection of regional myocardial sodium elevations may help differentiate viable from nonviable, infarcted tissue.