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Interstitial fibrosis, common to most chronic kidney diseases, can potentially affect the speckle patterns of kidney ultrasound (US). Here we use Radiomics features derived from US images to identify kidneys with chronic kidney disease.B-mode US without speckle reduction was performed on a cohort of CKD patients (n = 75) and healthy subjects (n = 27). Images of the patients with renal cysts, agenesis and calculi were excluded. After background subtraction, regions of interest were selected from each kidney. Four hundred and sixty-five Radiomics features including first and second-order gray level statistics were calculated on the selected regions. Second-order features were also calculated on wavelet transformed images. A random forest model was used to identify the most important features that can differentiate healthy and diseased kidneys. The ten most important features, based on the Gini index, were used to train a support vector machine. Synthetic minority oversampling technique was used to remove over fitting.Wavelet transformed, Gray Level Run Length Matrix based Normalized Run Length Non-uniformity, WT (LH) (GRLN) was identified as the most significant feature in differentiating CKD and healthy kidneys (accuracy - 0.85, sensitivity - 1.0). The mean WT (LH) GRLN of healthy kidneys (0.40 ± 0.01) was significantly higher (p0.01) than that of the CKD kidneys (0.24 ± 0.01). According to the Gini Index, the differentiability of WT (LH) GRLN was highest when the long axis of the kidney was oriented perpendicular to the columns of the image matrix.Radiomics features based on wavelet transformation are sensitive to directionality of US speckle patters and can be successfully used to differentiate CKD and healthy US kidney images.

Dilated cardiomyopathy (DCM), which results from genetic disorders resulting in decreased myocardial contractility, is a leading cause of morbidity and mortality worldwide. There are several therapeutic challenges in treating DCM, which include poor understanding of the underlying mechanism of impaired myocardial contractility, and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. The long, treacherous, and expensive path to new drug development, coupled with the rarity of individual mutations underscore the difficulties of drug development for DCMs. In the current report we focused on K210del, a DCM-causing mutation, which was identified over 20 years ago. This mutation is a three-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of lysine 210. Here we present the crystal structure of the troponin complex carrying the K210del mutation. We found that K210del leads to an allosteric shift in the troponin complex resulting in distortion of activation Ca2+ binding domain of TnnC at S69, thereby resulting in calcium discoordination. Next, we adopted an in-silico approach to identify FDA approved drugs that may correct the structure of the mutant troponin complex, which led us to identify the bisphosphonate risedronate as a potential structural corrector. Co-crystallization of risedronate with the mutant troponin complex restored of the normal configuration of S69 and calcium coordination. At a phenotypic level, risedronate normalized force generation in iPSC-derived cardiomyocytes from a patient carrying the mutation, and restored calcium sensitivity in skinned papillary muscles isolated from K210del mutant mice. Importantly, systemic administration of risedronate to K210del mutant mice normalized left ventricular ejection fraction (LVEF) as determined by echocardiography and MRI. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight a path to structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

SummaryMitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans, and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I (cI) is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Metabolomic analysis suggests that the electron transfer flavoprotein complex constitutes a major route for electron entry into the hepatic ETC. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.

The robustness of a complex network measures its ability to withstand random or targeted attacks. Most network robustness measures operate under the assumption that the nodes in a network are homogeneous and abstract. However, most real-world networks consist of nodes that are heterogeneous in nature. In this work, we propose a robustness measure called fitness-incorporated average network efficiency, that attempts to capture the heterogeneity of nodes using the ‘fitness’ of nodes in measuring the robustness of a network. Further, we adopt the same measure to compare the robustness of networks with heterogeneous nodes under varying topologies, such as the scale-free topology or the Erdős–Rényi random topology. We apply the proposed robustness measure using a wireless sensor network simulator to show that it can be effectively used to measure the robustness of a network using a topological approach. We also apply the proposed robustness measure to two real-world networks, namely the CO2 exchange network and an air traffic network. We conclude that with the proposed measure, not only the topological structure, but also the fitness function and the fitness distribution among nodes, should be considered in evaluating the robustness of a complex network.

Frequency dependence of the tissue backscatters provides useful information about the tissue structure. Further, it has been found that structure of tissue changes due to different diseases and these alterations cause observable changes in acoustic scattering properties. Several parameters have been developed to identify these alterations and tissue identification. This study has introduced a new tissue characterization parameter, which is Full width at half maximum (FWHM) of the fitted Gaussian curve of the Fast furrier transformed back scattered signal and it has been used to identify two different tissue samples; bovine liver and chicken liver. The experiment was carried out for nine bovines and nine chicken livers and FWHM of the chicken liver 3.72±0.16 was greater than that of bovine liver 3.28±0.16 (p=2.91E-05). Hence, it can be concluded that the bovine liver and the chicken liver can be differentiate using the FWHM parameter.

Objectives: The aim of this study was to use ultrasound-based kidney morphological features to classify chronic kidney disease (CKD) in an agricultural community in Sri Lanka where there is a high prevalence of CKD with unknown etiology. Materials and Methods: A cohort of CKD patients (n = 50) and healthy subjects (n = 26) underwent B-mode renal ultrasound. CKD patients were further categorized as those clinically diagnosed with diabetes mellitus, hypertension, and other known causes (n = 30) and those of unknown etiology (n = 20). Following kidney morphological features were calculated: Length (LEN), width (WDTH), cortical thickness, volume (VOL), and shape index. Results: CKD kidneys of both groups were significantly smaller than the healthy kidneys (P < 0.001). Based on a random forest procedure, the top three influential features that distinguished CKD kidneys from healthy kidneys were: VOL normalized to waist circumference (CKD = 0.6 ± 0.2 cm2, healthy = 0.9 ± 0.2 cm2), VOL normalized to body surface area (CKD = 36 ± 9 cm3/m2, healthy = 52 ± 13 cm3/m2), and WDTH (CKD = 3.6 ± 0.5 cm, healthy = 4.3 ± 0.6 cm). Patients with CKD of unknown etiology had higher kidney LEN and VOL normalized to height (HGHT) (LEN/HGHT = 0.58 ± 0.05 cm/m, VOL/HGHT = 0.40 ± 0.09 cm3/m, P < 0.05) compared to those of the known etiology group (LEN/HGHT = 0.51 ± 0.09 cm/m, VOL/HGHT = 0.30 ± 0.10 cm3/m). Conclusion: The study shows that ultrasound-based kidney volume can distinguish healthy versus diseased kidneys as well as CKD of known versus unknown etiology. Normalizing for height is required when comparing diseased groups.

BackgroundFamilial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.ObjectivesThe aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.MethodsFunctional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (MypnWT/Q526X) and homozygote mice harboring the human MYPN-Q529X mutation.ResultsEchocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old MypnWT/Q526X mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated MypnQ526X protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal–regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha–smooth muscle actin, osteopontin, and periostin) markers.ConclusionsHeterozygote MypnWT/Q526X knock-in mice develop RCM due to persistence of mutant MypnQ526X protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in MypnWT/Q526X hearts.

Chronic Kidney Disease of unknown aetiology (CKDu) is a prevalent disease in the North Central Province of Sri Lanka. Towards the latter stages of the disease, kidney function fails by 80%. During the initial stages of CKDu, interstitial fibrosis is formed and grows as the disease progresses. The cause of the disease remains elusive and early detection is vital to arrest the progressive decline of kidney function. The objective of this study is to construct a computer program to perform texture analysis on ultrasound kidney images and extract various features that can be used to distinguish between normal and diseased kidney patients. The computer program was developed using MATLAB and a user interface was created to perform mathematical operations such as: Fourier analysis to extract Root Mean Square and First Moment values and Grey Level Co-occurrence Matrix (GLCM) to extract Homogeneity and Sum Average values. A sample of ultrasound images were taken from 32 patients. Region of interest (ROI) selection was performed on entire kidney, cortex region and white (renal medulla or renal sinus) region separately. Among these methods Root Mean Square values over the entire kidney (p=0.03) and cortex region (p=0.0049) gave significant results in distinguishing between normal and diseased kidneys.

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln +/− ) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution. Anatomic (aortic root vs. ascending aorta) and molecular (APS vs. non-APS) regions of proximal aorta tissue were examined in adult and aged wild type (WT) and mutant (Eln +/− ) mice. CNC, VSMCs, elastic fiber architecture, proteoglycan expression, morphometrics and biomechanical properties were examined using histology, 3D reconstruction, micropipette aspiration and in vivo magnetic resonance imaging (MRI). In the APS side of Eln +/− aorta, Sonic Hedgehog (SHH) is decreased while SM22 is increased. Elastic fiber architecture abnormalities are present in the Eln +/− aortic root and APS ascending aorta, and biglycan is increased in the aortic root while aggrecan is increased in the APS aorta. The Eln +/− ascending aorta is stiffer than the aortic root, the APS side is thicker and stiffer than the non-APS side, and significant differences in the individual aortic root sinuses are observed. Asymmetric structure–function abnormalities implicate regional CNC dysregulation in the development and progression of aortopathy.

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.

Background Children with advanced chronic kidney disease (CKD) frequently develop left ventricular (LV) hypertrophy. The extent of hypertrophy that results in cardiac dysfunction is unknown. Systolic function, routinely determined by ejection fraction (EF), is usually preserved in these patients. However, a decrease in EF represents an advanced cardiac dysfunction. We used cardiac magnetic resonance (CMR) and phosphorus-31 MR spectroscopy (31P MRS) to assess markers of cardiac dysfunction in young CKD patients.

Delta-sarcoglycan (δ-sarcoglycan) null, Scgd(-/-), mice develop cardiac and skeletal muscle histopathological alterations similar to those in humans with limb-girdle muscular dystrophy. The objective of this study was to assess the feasibility of using MRI to investigate cardiac dysfunction in Scgd(-/-) mice. Cardiac MRI of 8 month old Scgd(-/-) and wild type (WT) mice was performed. Compared to WT, Scgd(-/-) mice had significantly lower LV ejection fraction (44±5% vs. 66±4%, p=0.014), lower RV ejection fraction (25±2% vs. 51±3%, p

Barth syndrome is an X-linked genetic disorder caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia. Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling. Although tafazzin function has been studied in non-mammalian model organisms, mammalian genetic loss of function approaches have not been used. We examined the consequences of tafazzin knockdown on sarcomeric mitochondria and cardiac function in mice. Tafazzin knockdown resulted in a dramatic decrease of tetralinoleoyl cardiolipin in cardiac and skeletal muscles and accumulation of monolysocardiolipins and cardiolipin molecular species with aberrant acyl groups. Electron microscopy revealed pathological changes in mitochondria, myofibrils, and mitochondrion-associated membranes in skeletal and cardiac muscles. Echocardiography and magnetic resonance imaging revealed severe cardiac abnormalities, including left ventricular dilation, left ventricular mass reduction, and depression of fractional shortening and ejection fraction in tafazzin-deficient mice. Tafazzin knockdown mice provide the first mammalian model system for Barth syndrome in which the pathophysiological relationships between altered content of mitochondrial phospholipids, ultrastructural abnormalities, myocardial and mitochondrial dysfunction, and clinical outcome can be completely investigated.

Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial. This trial was registered at http://clinicaltrials.gov as #NCT00011648.

The present study evaluated progressive cardiac dysfunction using serial circumferential strain (epsilon(cc)) measurements in patients with Duchenne muscular dystrophy (DMD). DMD is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that serial epsilon(cc) changes could be detected in individual patients with DMD during a time when the left ventricular ejection fraction (EF) changes are insignificant. Cardiac magnetic resonance imaging data from patients with DMD were evaluated. The left ventricular EF was calculated from steady-state free precession cine images and the composite epsilon(cc) measurement from tagged cine images. The serial epsilon(cc) and EF values for each patient were analyzed using the Wilcoxon sign rank test. Data from 51 patients with DMD (2 studies per patient, mean age at the initial study 11.8 +/- 3.5 years, range 7.4 to 25.4) were analyzed, with a mean interval between cardiac magnetic resonance studies of 15.6 +/- 6.0 months (range 6.2 to 28.1). In the interval between studies, the epsilon(cc) had decreased in all patients with DMD. The average decrease was 1.8 +/- 1.3 (p0.001). However, the EF had decreased in 33 of the 51 patients and had increased in 18 of the 51 patients. On average, the EF decreased by 2.9 +/- 8.57% (p = NS). In conclusion, in patients with DMD, epsilon(cc) abnormalities indicate progression within a relatively short period when the EF changes were not significant. Serial epsilon(cc) measurements might provide reliable monitoring of the progression of DMD-associated cardiac dysfunction before overt heart failure develops, because it is more sensitive than the EF.

Chronic kidney disease (CKD) of unknown etiology is recognized as a major public health challenge and a leading cause of morbidity and mortality in the dry zone in Sri Lanka. CKD is asymptomatic and are diagnosed only in late stages. Evidence points to strong correlation between progression of CKD and kidney fibrosis. Several biochemical markers of renal fibrosis have been associated with progression of CKD. However, no marker is able to predict CKD consistently and accurately before being detected with traditional clinical tests (serum creatinine, and cystatin C, urine albumin or protein, and ultrasound scanning). In this paper, we hypothesize that fibrosis in the kidney, and therefore the severity of the disease, is reflected in the frequency spectrum of the scattered ultrasound from the kidney. We present a design of a simple ultrasound system, and a set of clinical and laboratory studies to identify spectral characteristics of the scattered ultrasound wave from the kidney that correlates with CKD. We believe that spectral parameters identified in these studies can be used to detect and stratify CKD at an earlier stage than what is possible with current markers of CKD.

Objectives To compare a steady-state free precession cine sequence-based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (epsilon(cc)) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD). Background Current epsilon(cc) assessment techniques require cardiac magnetic resonance-tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences. Methods We compared mid-left ventricular whole-slice epsilon(cc) by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices. Results For the entire study population (N = 233), mean FT epsilon(cc) values (-13.3 +/- 3.8%) were highly correlated with HARP epsilon(cc) values (-13.6 +/- 3.4%), with a Pearson correlation coefficient of 0.899. The mean epsilon(cc) of DMD patients determined by HARP (-12.52 +/- 2.69%) and FT (-12.16 +/- 3.12%) was not significantly different (p = NS). Similarly, the mean epsilon(cc) of the control subjects by determined HARP (-18.85 +/- 1.86) and FT (-18.81 +/- 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis. Conclusions FT-based assessment of epsilon(cc) correlates highly with epsilon(cc) derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging.

Objectives This study sought to evaluate the natural history of occult cardiac dysfunction in Duchenne muscular dystrophy (DMD). Background Duchenne muscular dystrophy is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (ecc) would decrease in DMD before global systolic functional abnormalities regardless of age or ventricular ejection fraction (EF). Methods We evaluated cardiac magnetic resonance image (MRI) data from 70 DMD patients and 16 aged-matched control subjects. Standard imaging data included steady-state free precession short-axis cine stack images, cine myocardial tagged images, and myocardial delayed enhancement (MDE) (an indicator of myocardial fibrosis) sequences. Analysis was performed with QMASS (Medis Medical Imaging Systems, Leiden, the Netherlands) and HARP (Diagnosoft, Palo Alto, California) software. The DMD patient data were subdivided by age ( 10 years), EF (>55% or Results The DMD patients with normal EF had reduced eccat an early age ( 10 years with normal EF had further decline in ecccompared with younger DMD patients (p Conclusions Myocardial strain abnormalities are prevalent in young DMD patients despite normal EF, and these strain values continue to decline with advancing age. Strain analysis in combination with standard MRI and MDE imaging provides a means to stratify DMD cardiomyopathy.

Standard methods of longitudinal relaxation (T1) measurements in the heart produce only one T1 map of the myocardium, usually at the end diastole (ED). In this article, we investigated the feasibility of using a dual flip angle fast gradient echo technique in the steady state to generate a movie of T1 maps in the myocardium during the cardiac cycle. The effects of nonideal slice profile and transient steady state on the T1 measurements were evaluated by Bloch simulations. Based on these results, we introduce a linear correction to the measured T1 values, which was validated by phantom experiments. In vivo T1 cine maps in healthy volunteers show 70±7% drop in T1 from the ED to the end systole in the septum and a 43±13% drop in the left ventricular lateral wall. With further improvements, this technique could be used to assess the myocardial blood volume changes during the cardiac cycle.

Steady-state free precision techniques are often used in cine cardiac MRI, but are highly susceptible to off-resonance artifacts. In this article, we review the types and prevalence of off-resonance artifacts in the left ventricle on a 3 T MR scanner and describe the implementation of a technique to mitigate these artifacts. A group of 16 healthy children underwent SSFP cine imaging in the short axis. The synthesizer frequency was adjusted after scouting for the optimal frequency in a series of SSFP images with different frequency shifts. A total of 136 short-axis slices were examined for artifacts after the frequency adjustment. A significant number of slices in the apex region contained dark bands, flow artifacts and/or bright out-of-plane coherent artifacts. However, only five slices (3.6%) had artifacts that were detrimental to the accurate detection of myocardial boundaries. This technique offers a fast and easy way to suppress off-resonance artifacts in SSFP imaging at 3 T.

Cryoablation is one of several minimally invasive treatments that may be suitable for a targeted treatment of prostate cancer. Because efficacy is improved when a sufficiently cold end temperature is reached, the purpose of this work was to demonstrate an image-based thermometry method that could provide temperature maps throughout the frozen tissue. In five in vivo canine prostate cryoablation experiments performed under magnetic resonance imaging guidance, two MR parameters were measured and correlated to temperature: R2* and changes in signal intensity. R2* is elevated approximately linearly as tissue temperature decreases below the freezing point, while the signal intensity decreases exponentially. In vivo temperature maps with isotherms at −5°C, −15°C, and −30°C are demonstrated.

Purpose To evaluate the acute lesion created by cryosurgery with diffusion-weighted magnetic resonance imaging (DWI). Materials and Methods The appearance of the acute cryolesion was evaluated in four canine prostates DWI after they were warmed to original body temperature. The prostates were excised, stained with triphenyl tetrazolium chloride (TTC), photographed, prepared for hematoxylin and eosin (H&E) staining, and examined under a light microscope. Results A marked decrease in apparent diffusion coefficient of 38% was evident in the center of the previously frozen tissue, but not in all of the previously frozen tissue. Histologic results confirm differences between the iceball core and the periphery of the iceball, which have markedly different imaging characteristics on DWI. Conclusion The core of the previously frozen tissue has a reduced apparent diffusion coefficient (ADC) compared to the periphery of the previously frozen tissue and previously unfrozen tissue. J. Magn. Reson. Imaging 2003;17:131–135. © 2002 Wiley-Liss, Inc.

Purpose To investigate the peak temperature and thermal dose (T43) as tissue damage indicators for thermal therapy. Materials and Methods The proton resonant frequency (PRF) shift thermal coefficient was calibrated on six in vivo rabbit brains during interstitial laser ablation. The peak temperature and T43 were correlated with the lesion boundary observed on T2-weighted spin-echo (SE) MRI at 4 hours post-heating in seven thermal lesions using direct MR measurement and analysis based on a binary discriminate model. Results The peak temperature and T43 were 48.3 ± 1.7°C and 191 ± 219 minutes, respectively, from the direct MR measurement. The values derived by the binary discriminate analysis were 47.8 ± 2.2°C and 28 ± 41 minutes, respectively. Conclusion Our results suggest that tissue damage in rabbit brain 4 hours after thermal ablation can be predicted reliably from a threshold temperature of approximately 48°C. J. Magn. Reson. Imaging 2002;16:147–152. © 2002 Wiley-Liss, Inc.

High intensity focused ultrasound (HIFU) is a noninvasive medical procedure during which a large amount of energy is deposited in a short duration, which causes sudden localized rise in tissue temperature, and ultimately, cell necrosis. In the preclinical characterization of thermal fields generated by HIFU systems, the temperature rise in an ex vivo or an in vivo tissue must be accurately measured. The temperature rise can be measured using thin wire thermocouples or magnetic resonance (MR) thermometry. Among the two methods, thermocouples can be embedded invasively in the animal tissue, and HIFU induced temperature rise can be measured by focusing the beam on the thermocouple junction for the desired sonication time. However, the temperature rise measured using thermocouples is subject to several significant sources of error. One source of error associated with direct HIFU sonication of thermocouples is viscous-heating artifact [1]. Positioning errors represent another challenge in measuring temperature by locating beam atop a thermocouple [2]. Consequently, it has been difficult to accept that the temperature recorded by the thermocouple is the actual temperature at the focus of the HIFU beam. Therefore, there is a need for a method that can address these limitations. Unlike the measurement of temperature using thermocouples, the MR thermometry is a noninvasive method that does not suffer from the problems of positioning error and thermal artifacts. The magnetic resonance imaging (MRI) scanner is capable of assessing the transient temperature rise across the treatment volume, as well as measuring the volume of the thermal lesion [3]. Although the MR temperature monitoring was used to evaluate the feasibility of MR-guided HIFU ablation in the liver and kidney [4], the effect of higher acoustic powers on initiation of cavitation and possible maximum temperature rise in these organs were not assessed using MR thermometry. In this study, MR thermometry was used to monitor HIFU ablations performed on in vivo porcine livers, at elevated acoustic powers of 10 W, 30 W, and 40 W to assess the temperature field where initiation of cavitation is known to occur. Temperature rise during the heating phase as well as the temperature decay during the cooling phase was acquired. The transient temperature profiles measured during the heating and cooling phases for the three powers were compared, in order to check the HIFU induced maximum temperature rise.

Cryosurgery has been shown to be an effective therapy for prostate cancer. Temperature monitoring throughout the cryosurgical iceball could dramatically improve efficacy, since end temperatures of at least –40°C are required. The results of this study indicate that MR thermometry based on tissue R has the potential to provide this information. Frozen tissue appears as a complete signal void on conventional MRI. Ultrashort echo times (TEs), achievable with half pulse excitation and a short spiral readout, allow frozen tissue to be imaged and MR characteristics to be measured. However, half pulse excitation is highly sensitive to eddy current distortions of the slice-select gradient. In this work, the effects of eddy currents on the half pulse technique are characterized and methods to overcome these effects are developed. The methods include: 1) eddy current compensated slice-select gradients, and 2) a correction for the phase shift between the first and second half excitations at the center of the slice. The effectiveness of these methods is demonstrated in R maps calculated within the frozen region during cryoablation. Magn Reson Med 46:985–992, 2001. © 2001 Wiley-Liss, Inc.

A method was developed for quantitating the temperature within frozen tissue with the magnetic resonance (MR) parameter R2*. The pulse sequence uses half-pulse excitation and a short spiral readout to achieve echo times as short as 0.2 msec. Fiber-optic temperature sensors were inserted into bovine liver tissue. The tissue was frozen at one end while being held warm at the other end. Once steady state was reached, the parameter R2* was measured. A linear dependence of R2* on temperature was demonstrated. R2* is independent of freeze number and of the orientation of the temperature gradient with respect to the main magnetic field. Feasibility in a canine prostate during cryosurgery is demonstrated. J. Magn. Reson. Imaging 2001;13:99–104. © 2001 Wiley-Liss, Inc.

Relaxation time measurements at 3.0 T are reported for both gray and white matter in normal human brain. Measurements were made using a 3.0 T Bruker Biospec magnetic resonance imaging (MRI) scanner in normal adults with no clinical evidence of neurological disease. Nineteen subjects, 8 female and 11 male, were studied for T1 and T2 measurements, and 7 males were studied for T2. Measurements were made using a saturation recovery method for T1, a multiple spin-echo experiment for T2, and a fast low-angle shot (FLASH) sequence with 14 different echo times for T2. Results of the measurements are summarized as follows. Average T1 values measured for gray matter and white matter were 1331 and 832 msec, respectively. Average T2 values measured for gray matter and white matter were 80 and 110 msec, respectively. The average T2 values for occipital and frontal gray matter were 41.6 and 51.8 msec, respectively. Average T2 values for occipital and frontal white matter were 48.4 and 44.7 msec, respectively. ANOVA tests of the measurements revealed that for both gray and white matter there were no significant differences in T1 from one location in the brain to another. T2 in occipital gray matter was significantly higher (0.0001 < P < .0375) than the rest of the gray matter, while T2 in frontal white matter was significantly lower (P < 0.0001). Statistical analysis of cerebral hemispheric differences in relaxation time measurements showed no significant differences in T1 values from the left hemisphere compared with the right, except in insular gray matter, where this difference was significant at P = 0.0320. No significant difference in T2 values existed between the left and right cerebral hemispheres. Significant differences were apparent between male and female relaxation time measurements in brain.

Pulmonary insufficiency (PI) can render the right ventricle dysfunctional due to volume overloading and hypertrophy. The treatment requires a pulmonary valve replacement surgery. However, determining the right time for the valve replacement surgery has been difficult with currently employed clinical techniques such as, echocardiography and cardiac MRI. Therefore, there is a clinical need to improve the diagnosis of PI by using patient-specific (PS) hemodynamic endpoints. While there are many reported studies on the use of PS geometry with time varying boundary conditions (BC) for hemodynamic computation, few use spatially varying PS velocity measurement at each time point of the cardiac cycle. In other words, the gap is that, there are limited number of studies which implement both spatially- and time-varying physiologic BC directly with patient specific geometry. The uniqueness of this research is in the incorporation of spatially varying PS velocity data obtained from phase-contrast MRI (PC-MRI) at each time point of the cardiac cycle with PS geometry obtained from angiographic MRI. This methodology was applied to model the complex developing flow in human pulmonary artery (PA) distal to pulmonary valve, in a normal and a subject with PI. To validate the methodology, the flow rates from the proposed method were compared with those obtained using QFlow software, which is a standard of care clinical technique. For the normal subject, the computed time average flow rates from this study differed from those obtained using the standard of care technique (QFlow) by 0.8 ml/s (0.9%) at the main PA, by 2 ml/s (3.4%) at the left PA and by 1.4 ml/s (3.8%) at the right PA. For the subject with PI, the difference was 7 ml/s (12.4%) at the main PA, 5.5 ml/s (22.6%) at the left PA and 4.9 ml/s (18.0%) at the right PA. The higher percentage differences for the subject with PI, was the result of overall lower values of the forward mean flow rate caused by excessive flow regurgitation. This methodology is expected to provide improved computational results when PS geometry from angiographic MRI is used in conjunction with PS PC-MRI data for solving the flow field.

Nebulette (NEBL) is a sarcomeric Z-disk protein involved in mechanosensing and force generation via its interaction with actin and tropomyosin-troponin complex. Genetic abnormalities in NEBL lead to dilated cardiomyopathy (DCM) in humans and animal models. The objectives of this study are to determine the earliest preclinical mechanical changes in the myocardium and define underlying molecular mechanisms by which NEBL mutations lead to cardiac dysfunction. We examined cardiac function in 3-month-old non-transgenic (non-Tg) and transgenic (Tg) mice (WT-Tg, G202R-Tg, A592E-Tg) by cardiac magnetic resonance (CMR) imaging. Contractility and calcium transients were measured in isolated cardiomyocytes. A592E-Tg mice exhibited enhanced in vivo twist and untwisting rate compared to control groups. Ex vivo analysis of A592E-Tg cardiomyocytes showed blunted calcium decay response to isoproterenol. CMR imaging of G202R-Tg mice demonstrated reduced torsion compared to non-Tg and WT-Tg, but conserved twist and untwisting rate after correcting for geometric changes. Ex vivo analysis of G202R-Tg cardiomyocytes showed elevated calcium decay at baseline and a conserved contractile response to isoproterenol stress. Protein analysis showed decreased α-actinin and connexin43, and increased cardiac troponin I phosphorylation at baseline in G202R-Tg, providing a molecular mechanism for enhanced ex vivo calcium decay. Ultrastructurally, G202R-Tg cardiomyocytes exhibited increased I-band and sarcomere length, desmosomal separation, and enlarged t-tubules. A592E-Tg cardiomyocytes also showed abnormal ultrastructural changes and desmin downregulation. This study showed distinct effects of NEBL mutations on sarcomere ultrastructure, cellular contractile function, and calcium homeostasis in preclinical DCM in vivo. We suggest that these abnormalities correlate with detectable myocardial wall motion patterns.

A relatively recent and non invasive method for characterizing thermal fields generated by high intensity focused ultrasound (HIFU) transducers is Magnetic Resonance (MR) Thermometry method. However, noise signals generated by external RF sources infiltrate the scanner orifice and limit its ability to measure temperature rise during the heating or ablation phase. In this study, MRI monitored HIFU ablations are performed on freshly excised porcine liver samples, at varying sonication times, 20, 30 and 40 s at a constant acoustic intensity level of 1244 W/cm2. Temperature rise during the procedure is measured using Proton Resonant Frequency MR thermometry. Preliminary experiments without an adequate noise filter, failed to record temperature rise during the heating phase. A low pass R-C filter circuit is subsequently incorporated into the experimental set up to prevent infiltration of noise signals in the MRI orifice. This modified RC filter enables measurement of temperature rise during the heating phase followed by temperature decay during cooling. The measured data is within 12% agreement with the temperature rise computed by solving the acoustic and heat equations.

Development of non-invasive diagnostic indices often requires accurate blood-flow calculation using physiologically realistic velocity profiles as boundary conditions. In this research, a methodology is being developed and validated that can directly use phase-contrast MR imaging (PC-MRI) based velocity measurement to perform blood-flow computation with patient-specific geometry. Using this methodology, the pressure drop can also be calculated non-invasively. Although the main focus of our research has been pulmonary insufficiency (PI) in tetralogy patients, our method can be employed in many other pathophysiologies. As a pilot study, the methodology is tested using a simple model of blood-flow through a straight artery of uniform cross-section.Copyright © 2011 by ASME

Magnetic resonance (MR) thermometry is a valuable method for characterizing thermal fields generated by high intensity focused ultrasound (HIFU) transducers in tissue phantoms and excised tissues. However, infiltration of noise signals generated by external rf sources into the scanner orifice limits the ability of the scanner to measure temperature rise during the heating or ablation phase. In this study, magnetic resonance interferometry (MRI) monitored HIFU ablations are performed on freshly excised porcine liver samples, at varying sonication times, 20 s, 30 s, and 40 s at a constant acoustic intensity level of 1244 W/cm2. Temperature throughout the procedure was measured using proton resonant frequency MR thermometry. Without filtering, reliable temperature measurements during the heating phase could not be obtained since temperature maps appeared blurred and analysis was impossible. Also, measurements acquired during the cooling phase decayed manifested an unrealistically slow rate of temperature decay. This abnormally slow rate was confirmed with computational results. A low-pass RC filter circuit was subsequently incorporated into the experimental setup to prevent infiltration of noise signals in the MRI orifice. This modified RC filter circuit allowed noninvasive measurement of the HIFU induced temperature rise during the heating phase followed by temperature decay during cooling. The measured data were within 13% agreement with the temperature rise computed by solving the acoustic and heat equations.

Background: Cardiac dysfunction in boys with Duchenne muscular dystrophy (DMD) is a leading cause of death. Cardiac resynchronization therapy (CRT) has been shown to dramatically decrease mortality in eligible adult population with congestive heart failure. We hypothesized that mechanical dyssynchrony is present in DMD patients and that cardiovascular magnetic resonance (CMR) may predict CRT efficacy. Methods: DMD patients (n = 236) were stratified into 4 groups based on age, diagnosis of DMD, left ventricular (LV) ejection fraction (EF), and presence of myocardial fibrosis defined as positive late gadolinum enhancement (LGE) compared to normal controls (n = 77). Dyssynchrony indices were calculated based on timing of CMR derived circumferential strain (ecc). The calculated indices included cross-correlation delay (XCD), uniformity of strain (US), regional vector of variance (RVV), time to maximum strain (TTMS) and standard deviation (SD) of TTMS. Abnormal XCD value was defined as > normal + 2SD. US, RVV, TTMS and SD were calculated for patients with abnormal XCD. Results: There was overall low prevalence of circumferential dyssynchrony in the entire DMD population; it increased to 17.1% for patients with abnormal EF and to 31.2% in the most advanced stage (abnormal EF with fibrosis). All but one DMD patient with mechanical dyssynchrony exhibited normal QRS duration suggesting absence of electrical dyssynchrony. The calculated US and RVV values (0.91 ± 0.09, 1.34 ± 0.48) indicate disperse rather than clustered dyssynchrony. Conclusion: Mechanical dyssynchrony is frequent in boys with end stage DMD-associated cardiac dysfunction. It is associated with normal QRS complex as well as extensive lateral fibrosis. Based on these findings, it is unlikely that this patient population will benefit from CRT. Background In patients with New York Heart Association (NYHA) class III, ambulatory class IV systolic heart failure (HF) and recently class I and II, with electrocardiographic evidence of ventricular dyssynchrony, cardiac resynchronization therapy (CRT) improves quality of life and functional status, reduces heart failure-related hospitalizations, and prolongs survival [1-4]. While current indications are based on QRS duration > 120 ms, HF patients with narrow QRS complexes have been investigated for the presence of mechanical dyssynchrony. In

The cardiac disease ubiquitously associated in Duchenne Muscular Dystrophy (DMD) has traditionally been considered a progressive dilated cardiomyopathy (DCM). However, left ventricular (LV) dilatation as measured with cardiac MRI has not been a consistent finding in this population, even as circumferential strain (e(cc)) declines with advancing disease. We hypothesized that a distinct pattern of changes in LV geometry, during the course of e(cc) decline, distinguishes DMD associated heart disease from DCM. Using CMR, LV end-diastolic volume (EDV), mass (LVM), ejection fraction, e(cc) and myocardial delayed enhancement (MDE) were determined in DMD patients and normal control subjects. The LV Remodeling Index (LVRI) was calculated as the ratio of LV Mass to Volume (LVM/EDV). Statistical comparisons between all LV parameters and genotype were also performed. Median LVRI in DMD (n = 127) and control subjects (n = 41) were different (0.75 vs. 0.65, P = 0.0150) but within normal range. Furthermore, the median LVRI in DMD boys with reduced LV systolic function was significantly reduced compared to those with normal LV systolic function (0.64 vs. 0.75, P = 0.0974). However, the presence of MDE was associated with a lower median LVRI (0.57 vs. 0.76, P = 0.0471). Regression analysis showed no significant correlation between e(cc) and LVRI (r = -0.03). The LVRI of DMD patients is unexpectedly normal and not correlated with e(cc.) Based on these findings, DMD-associated heart disease exhibits a unique remodeling pattern distinct from DCM.

Background Although previous studies have helped define the natural history of Duchenne Muscular Dystrophy (DMD)-associated cardiomyopathy, the myocardial pathobiology associated with functional impairment in DMD is not yet known. The objective of this study was to assess the distribution of transverse relaxation time (T2) in the left ventricle (LV) of DMD patients, and to determine the association of myocardial T2 heterogeneity to the severity of cardiac dysfunction. DMD patients (n = 26) and normal control subjects (n = 13) were studied by Cardiovascular Magnetic Resonance (CMR). DMD subject data was stratified based on subject age and LV Ejection Fraction (EF) into the following groups: A (12 years, n = 5). LV mid-slice circumferential myocardial strain (εcc) was calculated using tagged CMR imaging. T2 maps of the LV were generated for all subjects using a black blood dual spin echo method at two echo times. The Full Width at Half Maximum (FWHM) was calculated from a histogram of LV T2 distribution constructed for each subject. Results In DMD subject groups, FWHM of the T2 histogram rose progressively with age and decreasing EF (Group A FWHM= 25.3 ± 3.8 ms; Group B FWHM= 30.9 ± 5.3 ms; Group C FWHM= 33.0 ± 6.4 ms). Further, FWHM was significantly higher in those with reduced circumferential strain (|εcc| ≤ 12%) (Group B, and C) than those with |εcc| > 12% (Group A). Group A FWHM was not different from the two normal groups (N1 FWHM = 25.3 ± 3.5 ms; N2 FWHM= 24.0 ± 7.3 ms). Conclusion Reduced EF and εcc correlates well with increased T2 heterogeneity quantified by FWHM, indicating that subclinical functional impairments could be associated with pre-existing abnormalities in tissue structure in young DMD patients.

Purpose To investigate the feasibility of radial phase contrast MR imaging to measure in vivo pulse wave velocity (PWV) and wall shear stress (WSS) in small animals on a 7 Tesla scanner. Materials and Methods The aortic compliance of 9-month-old ApoE deficient (ApoE-KO) mice (n = 10) on a normal diet was studied in comparison to that of wild-type (WT) mice (n = 10). An undersampled, asymmetric echo radial phase contrast MR technique was developed to measure through plane blood flow velocity at axial slices along the descending aorta. The PWV and the time averaged WSS was calculated from the spatiotemporal flow data. The reproducibility of PWV and WSS was evaluated by taking multiple measures on a separate cohort of WT (n = 4) mice. Results The mean percentage standard deviation among repeated measures was 10.1% for PWV and 24.8% for WSS. The PWV of ApoE-KO mice (5.84 ± 2.15 m/s) was significantly higher (p = 0.02) than that of WT (3.55 ± 0.97 m/s), whereas WSS was lower in ApoE-KO mice (1.44 ± 0.31Pa) compared with WT (1.55 ± 0.36Pa). Conclusion This study demonstrates that in vivo PWV derived from radial phase contrast MR imaging can be potentially used as a surrogate marker for impaired vascular function in mice. J. Magn. Reson. Imaging 2009;30:286–291. © 2009 Wiley-Liss, Inc.

The purpose of this study is to determine the dependence of the size of the thermal lesion on sonication time in an ex-vivo porcine liver sample during simulated High Intensity Focused Ultrasound (HIFU) tissue ablation. MRI guided HIFU ablations were performed on a freshly excised porcine liver sample at 70 W acoustic power. The size of the lesion (ablated zone) was measured at sonication times, 20 s, 30 s and 40 s. Numerical calculations were performed to validate the experimental lesion size. Also, a histology study of the ablated liver sample was performed to confirm cell necrosis within the ablated zones. It was found that the HIFU induced lesion size is strongly dependant on sonication time and lesion size almost doubles (increases from 0.368 to 0.715 cm2) as sonication time increases from 20s to 40s. The area of lesions, determined experimentally, agreed within 5% with results of numerical calculations.

Recent cardiac MRI (CMR) studies have demonstrated decline in left ventricular peak circumferential strain (ecc) despite normal ejection fraction in Duchenne muscular dystrophy (DMD) patients. However, these analyses used CMR tagging, a technique limited by tag fading and complicated analysis requirements. Feature tracking software has recently been developed for analysis of ecc from non-tagged standard steady-state free precession (SSFP) cine CMR images.

Patients with Duchenne Muscular Dystrophy (DMD), a dystrophinopathy, universally develop dilated cardiomyopathy, which is associated with abnormal myocardial strain, as well as heterogeneous development of fibrosis as demonstrated by pathology and more recently by cardiac MRI methods. We sought to determine the presence of systolic dyssynchrony in this population using cardiac MRI tagging methods. We analyzed tagged MRI images for the presence of dyssynchrony in 61 males (age 12.5 ± 4.4 y) with a dystrophin mutation undergoing clinical cardiac MRI. Tagged MRI images were analyzed using HARP® analysis of regional strain and strain-time curves. The mid-myocardial slice was specifically analyzed, by dividing it into 6 coronary perfusion regions. Dyssynchrony was defined by the presence of either of 2 previously published indexes modified for use with MRI data: 1) time difference of 1 st to last regional peak strain > 100 ms; 2) standard deviation of time differences to peak strain for each of the six regions > 33 ms. Additional indexes evaluated included heart rate, LV ejection fraction, mid-myocardial composite circumferential strain, and presence of delayed myocardial hyperenhancement (MDE). Among the 61 subjects analyzed, 28 (46%) exhibited dyssynchrony indexes 1 and 2, while 8 additional subjects met dyssynchrony index 2 but not index 1. Only 4 subjects, all of whom met both dyssynchrony criteria, had positive MDE and abnormal EF

Methods Retrospective cross-sectional study of 40 DMD subjects evaluated from 2004–2006. Each patient underwent standard pulmonary function testing and CMR for clinical indications (mean = 9 months between studies). Collected data included FVC% predicted (FVC%, a marker of ventilatory capacity) and FEV1%; Ejection fraction (LVEF, RVEF), end-diastolic volume (LVEDV, RVEDV), and enddiastolic mass (LVEDM, RVEDM). Spearman rank correlations were performed between pulmonary and cardiac parameters.

Background— Pathological cardiac hypertrophy inevitably remodels, leading to functional decompensation. Although modulation of apoptosis-regulating genes occurs in cardiac hypertrophy, a causal role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established. Methods and Results— We targeted the gene for proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gq-dependent hypertrophies, in the mouse germ line or specifically in cardiomyocytes (knockout [KO]) and conditionally overexpressed it in the heart (transgenic [TG]). Conditional forced Nix expression acted synergistically with the prohypertrophic Gq transgene to increase cardiomyocyte apoptosis (0.8±0.1% in GqTG versus 7.8±0.6% in GqTG+NixTG; P P =0.042). In the reciprocal experiment, germ-line Nix ablation significantly reduced cardiomyocyte apoptosis (4.8±0.2% in GqTG+ Nix KO versus 8.4±0.5% in GqTG; P =0.001), which improved percent fractional shortening (43±3% versus 27±3%; P =0.017), attenuated LV remodeling, and largely prevented lethality in the Gq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice subjected to transverse aortic constriction developed significantly less LV dilation by echocardiography and magnetic resonance imaging, maintained concentric remodeling, and exhibited preserved LV ejection fraction (61±2% in transverse aortic constriction cardiac Nix KO versus 36±6% in transverse aortic constriction wild-type mice; P =0.003) at 9 weeks, with reduced cardiomyocyte apoptosis at day 4 (1.70±0.21% versus 2.73±0.35%; P =0.032). Conclusions— Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, a finding that suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.

Background : Compensated pathological hypertrophy will inevitably remodel, leading to functional decompensation. Postulated mechanisms include cardiomyocyte dropout, changes in myocardial matrix, and altered cardiac metabolism. Transcriptional modulation of apoptosis-regulating Bcl2 family members is associated with myocardial hypertrophy, but a role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established. Methods and Results : Proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gαq-dependent hypertrophies, was subjected to germ-line or cardiac-specific gene targeting (KO) using Cre-lox technology and conditional cardiac-specific overexpression (TG) using tetracycline suppressible bitransgenic system in mice. Conditional forced Nix expression in neonatal and adult hearts was well tolerated, but acted synergistically with the pro-hypertrophic Gαq transgene to increase cardiomyocyte apoptosis (TUNEL %: 0.8±0.1 in Gαq TG vs 7.8±0.6 in Gαq+Nix TG) and caused lethal cardiomyopathy with LV dilation (LVEDD mm: 3.7±0.2 vs 4.6±0.2) and depressed systolic function (% fractional shortening (%FS): 39±4 vs 23±4). Nix KO combined with Gαq TG significantly reduced cardiomyocyte apoptosis (TUNEL %: 4.8±0.2 in GαqTG+ Nix KO vs 8.4±0.5 in GαqTG), improved systolic function (LV%FS: 43±3 vs 27±3), attenuated LV remodeling (r/h:2.4±0.1 vs 4.0±0.6), and largely prevented lethality of the Gαq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice were subjected to transverse aortic constriction (TAC) (gradients: 89±4 vs 83±5 mmHg in controls, n=12 each, P =NS). In cardiac Nix KO, serial echocardiograms and terminal invasive hemodynamic studies at 9 weeks after TAC revealed significantly less LV dilation (LVEDD mm: 3.3±0.1 vs 3.8±0.2), maintained concentric remodeling (r/h:1.8±0.1 vs 2.3±0.3), and preserved function (%FS: 63±3 vs 51±4; +dP/dt40 mmHg/s: 11519±1211 vs 8499±399) as compared with controls. Conclusions : Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, and suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.

Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3(-/-) and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3(-/-) mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target.

The ability of the phase-sensitive steady-state free precession (SSFP) technique to distinguish subcutaneous and visceral adipose tissue in the abdomen at 3 T was evaluated. A phased array receiver radiofrequency coil and a commercially available SSFP sequence were used for imaging. The raw image data were postprocessed to generate fat-only and water-only images. A postprocessing algorithm that is computationally efficient and robust is presented. The postprocessing technique separates the fat and water pixels automatically without any user interference. The feasibility of the technique is demonstrated in vivo with breath-hold abdomen images. The short scan time and the ease of use of this technique are well suited to the quantification of body fat distribution in children.