Non-destructive classification of unlabeled cells: Combining an automated benchtop magnetic resonance scanner and artificial intelligence.

In order to treat degenerative diseases, the importance of advanced therapy medicinal products has increased in recent years. The newly developed treatment strategies require a rethinking of the appropriate analytical methods. Current standards are missing the complete and sterile analysis of the product of interest to make the drug manufacturing effort worthwhile. They only consider partial areas of the sample or product while also irreversibly damaging the investigated specimen. Two-dimensional T1 / T2 MR relaxometry meets these requirements and is therefore a promising in-process control during the manufacturing and classification process of cell-based treatments. In this study a tabletop MR scanner was used to perform two-dimensional MR relaxometry. Throughput was increased by developing an automation platform based on a low-cost robotic arm, resulting in the acquisition of a large dataset of cell-based measurements. Two-dimensional inverse Laplace transformation was used for post-processing, followed by data classification performed with support vector machines (SVM) as well as optimized artificial neural networks (ANN). The trained networks were able to distinguish non-differentiated from differentiated MSCs with a prediction accuracy of 85%. To increase versatility, an ANN was trained on 354 independent, biological replicates distributed across ten different cell lines, resulting in a prediction accuracy of up to 98% depending on data composition. The present study provides a proof of principle for the application of T1 / T2 relaxometry as a non-destructive cell classification method. It does not require labeling of cells and can perform whole mount analysis of each sample. Since all measurements can be performed under sterile conditions, it can be used as an in-process control for cellular differentiation. This distinguishes it from other characterization techniques, as most are destructive or require some type of cell labeling. These advantages highlight the technique's potential for preclinical screening of patient-specific cell-based transplants and drugs.

Determination of the mesio-distal tooth width via 3D imaging techniques with and without ionizing radiation: CBCT, MSCT, and µCT versus MRI.

Objective: The purpose of this study was to estimate the feasibility and accuracy of mesio-distal width measurements with magnetic resonance imaging (MRI) in comparison to conventional 3D imaging techniques [multi-slice CT (MSCT), cone-beam CT (CBCT), and µCT]. The measured values of the tooth widths were compared to each other to estimate the amount of radiation necessary to enable orthodontic diagnostics. Material and Methods: Two pig skulls were measured with MSCT, CBCT, µCT, and MRI. Three different judges were asked to determine the mesio-distal tooth width of 14 teeth in 2D tomographic images and in 3D segmented images via a virtual ruler in every imaging dataset. Results: Approximately 19% (27/140) of all test points in 2D tomographic slice images and 12% (17/140) of the test points in 3D segmented images showed a significant difference (P ≤ 0.05). The largest significant difference was 1.6mm (P < 0.001). There were fewer significant differences in the measurement of the tooth germs than in erupted teeth. Conclusions: Measurement of tooth width by MRI seems to be clinically equivalent to the conventional techniques (CBCT and MSCT). Tooth germs are better illustrated than erupted teeth on MRI. Three-dimensional segmented images offer only a slight advantage over 2D tomographic slice images. MRI, which avoids radiation, is particularly appealing in adolescents if these data can be corroborated in further studies.

Monitoring of monocyte recruitment in reperfused myocardial infarction with intramyocardial hemorrhage and microvascular obstruction by combined fluorine 19 and proton cardiac magnetic resonance imaging.

BACKGROUND: Monocytes and macrophages are indispensable in the healing process after myocardial infarction (MI); however, the spatiotemporal distribution of monocyte infiltration and its correlation to prognostic indicators of reperfused MI have not been well described. METHODS AND RESULTS: With combined fluorine 19/proton ((1)H) magnetic resonance imaging, we noninvasively visualized the spatiotemporal recruitment of monocytes in vivo in a rat model of reperfused MI. Blood monocytes were labeled by intravenous injection of (19)F-perfluorocarbon emulsion 1 day after MI. The distribution patterns of monocyte infiltration were correlated to the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage. In vivo, (19)F/(1)H magnetic resonance imaging performed in series revealed that monocyte infiltration was spatially inhomogeneous in reperfused MI areas. In the absence of MVO, monocyte infiltration was more intense in MI regions with serious ischemia-reperfusion injuries, indicated by severe intramyocardial hemorrhage; however, monocyte recruitment was significantly impaired in MVO areas accompanied by severe intramyocardial hemorrhage. Compared with MI with isolated intramyocardial hemorrhage, MI with MVO resulted in significantly worse pump function of the left ventricle 28 days after MI. CONCLUSIONS: Monocyte recruitment was inhomogeneous in reperfused MI tissue. It was highly reduced in MVO areas defined by magnetic resonance imaging. The impaired monocyte infiltration in MVO regions could be related to delayed healing and worse functional outcomes in the long term. Therefore, monocyte recruitment in MI with MVO could be a potential diagnostic and therapeutic target that could be monitored noninvasively and longitudinally by (19)F/(1)H magnetic resonance imaging in vivo.

Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach.

AIMS: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. METHODS AND RESULTS: Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14-22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. CONCLUSION: We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.

Specific identification of iron oxide-labeled stem cells using magnetic field hyperthermia and MR thermometry.

Cell-based therapies represent important novel strategies for the improved treatment of various diseases. To monitor the progress of therapy and cell migration, noninvasive imaging methods are needed. MRI represents such a modality, allowing, for example, for the tracking of cells labeled with superparamagnetic iron oxide nanoparticles. Unfortunately, the labeled cells cannot always be identified nonambiguously in the MR images. In this article, we present the combination of two different types of MR experiment to identify iron oxide-labeled cells nonambiguously. The labeled cells appear as hypointense spots on standard T(2)*-weighted MR images. Furthermore, they can be heated magnetically and subsequently identified by MR thermometry as a result of their heat dissipation. Other hypointense regions in the MR images are not heated and do not show heat dissipation. A proof-of-principle study was successfully performed in vitro and in vivo. The positive identification of the iron oxide-labeled cells was demonstrated in collagen type I hydrogel phantoms and in living mice with high spatial and temporal accuracy. The motion of the in vitro samples was corrected in order to improve the specificity of the identification of labeled cells. Therefore, this method possesses the potential for cell tracking without prior knowledge about the cells, and thus allows the noninvasive monitoring of cell-based therapies, as long as the cells contain a sufficient amount of iron oxide for detection in MR thermometry and imaging.

Contrast agent derived determination of the total circulating blood volume using magnetic resonance.

OBJECT: Knowledge of the total circulating blood volume (TCBV) is essential for the treatment of a variety of medical conditions and blood disorders. To date, blood volume analysis is rarely carried out due to the disadvantages of available methods. Our aim was to develop a widely available, simple, fast, yet accurate method for the determination of the total circulating blood volume. MATERIALS AND METHODS: Magnetic resonance (MR) is a well-established, non-invasive technique. In this article, we present a method that uses MR contrast agents for the determination of the blood volume. The dependence of MR relaxation times on the concentration of MR contrast agents allows the calculation of the volume the contrast agent has been diluted in. RESULTS: In phantom and in vivo experiments we could demonstrate that TCBV can be determined with high accuracy and precision. CONCLUSION: This work introduces a novel method for the determination of the total circulating blood volume using magnetic resonance contrast agents as tracers.

Tissue ACE inhibition improves microcirculation in remote myocardium after coronary stenosis: MR imaging study in rats.

ACE inhibition has been shown to improve left ventricular (LV) and myocardial blood flow. Previous data regarding changes in capillary density and angiogenesis during ACE inhibition are controversial. The aim of the following study was to determine myocardial microcirculation and heart function in the rat after coronary stenosis using non invasive MR imaging techniques. MR spin labeling and cine techniques have been performed in female Wistar rats 2weeks after coronary artery stenosis. In one group, animals were treated with quinapril in a dose of 6mg/kg/day. Perfusion, relative blood volume (RBV), LV mass and function were determined non-invasively 2weeks after treatment. Finally, fibrosis and capillary density were analyzed histologically. Additionally, hemodynamic measurements were realized in a further group in order to calculate systemic vascular resistance (SVR). Quinapril resulted in a significant increase in perfusion at rest in the remote and the poststenotic myocardium with improved systolic function and a decrease in SVR compared to the non treated control group. Additionally, maximum perfusion and RBV were slightly elevated whereas capillary density was unchanged among the groups. MRI allows for non-invasive quantification of functional microcirculation and heart function. In addition to the well known effect of ACE inhibition on systolic function, treatment with the tissue specific ACE inhibitor quinapril revealed an important microvascular improvement, especially at arteriolar level. These findings may support the use of tissue ACE inhibitors to improve cardiac microcirculation after ischemia.

In vivo comparison of atherosclerotic plaque progression with vessel wall strain and blood flow velocity in apoE(-/-) mice with MR microscopy at 17.6 T.

OBJECT: At present, in vivo plaque characterization in mice by MRI is typically limited to the visualization of vascular lesions with no accompanying analysis of vessel wall function. The aim of this study was to analyze the influence of atherosclerotic plaque development on the morphological and mechanical characteristics of the aortic vessel wall in a pre-clinical murine model of atherosclerosis. MATERIALS AND METHODS: Groups of apolipoprotein E-deficient (apoE(-/-)) and C57BL/6J control mice fed a high-fat diet were monitored over a 12-week time period by high-field MRI. Multi-Slice-Multi-Spin-Echo and Phase-Contrast MRI sequences were employed to track changes to aortic vessel wall area, blood flow velocity and distensibility. RESULTS: After 6- and 12-weeks, significant changes in vessel wall area and circumferential strain were detected in the apoE(-/-) mice relative to the control animals. Blood flow velocity and intravascular lumen remained unchanged in both groups, findings that are in agreement with the theory of positive remodeling of the ascending aorta during plaque progression. CONCLUSION: This study has demonstrated the application of high-field MRI for characterizing the temporal progression of morphological and mechanical changes to murine aortic vasculature associated with atherosclerotic lesion development.

Ex vivo expanded hematopoietic progenitor cells improve cardiac function after myocardial infarction: role of beta-catenin transduction and cell dose.

Cell-based therapy after myocardial infarction (MI) is a promising therapeutic option but the relevant cell subsets and dosage requirements are poorly defined. We hypothesized that cell therapy for myocardial infarction is improved by ex vivo expansion and high-dose transplantation of defined hematopoietic progenitor cells (HPCs). Since beta-catenin promotes self-renewal of stem cells we evaluated the therapeutic efficacy of beta-catenin-mediated ex vivo expansion of mouse HPCs in a mouse model of myocardial ischemia/reperfusion followed by intraarterial cell delivery. The impact of cell dose was determined by comparing a low-dose (LD, 5 x 10(5) cells) vs. a high-dose (HD, 1 x 10(7) cells) cell transplantation regimen of beta-catenin-HPCs. The impact of beta-catenin modification of HPCs was determined by comparing control-transduced HPCs (GFP-HPCs) vs. transgenic beta-catenin-HPCs. HD beta-catenin-HPCs significantly improved LV function and end-systolic and end-diastolic dimensions as compared to saline and LD beta-catenin-HPCs. Furthermore, while treatment with HD GFP-HPC resulted in a modest cardiac improvement the application of beta-catenin-HPCs was superior, resulting in a significant improvement in EF, FS and LVESD over saline and control GFP-HPC treatment. Although myocardial engraftment of HPCs was only transient, as determined by cell quantification after dye labeling, beta-catenin-HPC treatment significantly decreased infarct size, reduced cardiomyocyte apoptosis and increased capillary angiogenesis in vitro and in vivo. Ex vivo expanded HPCs improve cardiac function and remodeling post MI in a cell number- and beta-catenin-dependent manner.

Magnetic resonance of mouse models of cardiac disease.

In recent years magnetic resonance imaging (MRI) has become the noninvasive standard for the quantitative evaluation of cardiac function, masses, and infarct size. Wall motion analysis is used to display myocardial dysfunction and microcirculatory deficits can be displayed by perfusion imaging and quantification of the myocardial regional blood volume. Magnetic resonance spectroscopy (MRS) also provides quantitative information on cardiac energetics and, in combination with MRI, insights into cardiac structure and function. The use of both techniques permits complementary data collection within the same experimental setup.Nevertheless, it should be mentioned that MR does not directly visualize genes or gene product expression but morphological or bioenergetical outcomes of gene expression instead. In conclusion, cardiac MR is a valuable tool applicable to mouse phenotyping and, also, can be applied to assess the effects of therapeutic agents. Thus, MR of mouse models of cardiac disease has great potential to substantially contribute to the understanding of the underlying pathomechanisms and can help to evaluate new therapy options.

Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. METHODS AND RESULTS: Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin+/-) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P<0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin+/- hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin+/- mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. CONCLUSIONS: Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.

Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction.

BACKGROUND: Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data. METHODS AND RESULTS: To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII(-/-) and FXIII(-)(/+) (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII(-/-) mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII(-/-) mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII(-/-) mice receiving supplemental FXIII than in FXIII(-/-) mice (P<0.05). In FXIII(-/-) but not in reconstituted FXIII(-/-) mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII(-/-) mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII(-/-) mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII(-/-) mice. CONCLUSIONS: These data suggest that FXIII has an important role in murine myocardial healing after infarction.

In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis.

OBJECTIVE: Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis. RESULTS: Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast. CONCLUSION: This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of tissue damage free of MR contrast agents.

Creatine kinase knockout mice show left ventricular hypertrophy and dilatation, but unaltered remodeling post-myocardial infarction.

OBJECTIVE: Creatine kinase (CK) is responsible for the transport of high-energy phosphates in excitable tissue and is of central importance in myocardial energy homeostasis. Significant changes in myocardial energetics have been reported in mice lacking the various CK isoenzymes. Our hypothesis was that ablation of CK isoenzymes leads to cardiac hypertrophy, impaired function, and aggravation of left ventricular remodeling post-myocardial infarction. METHODS: CK-deficient mice (CK KO) were examined by cardiac magnetic resonance imaging (MRI) to determine left ventricular volumes, ejection fraction, and mass: ten wild-type (WT), 6 mitochondrial CK KO (Mito-CK-/-), 10 cytosolic CK KO (M-CK-/-), and 10 mice with combined KO (M/Mito-CK-/-). RESULTS: While ejection fraction was similar in all groups, there was significant LV dilatation with a approximately 30% increase in LV end-diastolic volumes in Mito-CK-/- and in M/Mito-CK-/-. Compared to WT, there was a striking 73% and 64% increase of LV mass in Mito-CK-/- and in M/Mito-CK-/- mice, respectively, but no significant increase of LV mass (+33%; p=n.s.) in M-CK-/-. Furthermore, significant re-expression of beta-MHC, a marker of myocardial hypertrophy, was found in all CK-deficient hearts. LV remodeling was investigated by MRI in hearts of 7 WT and 10 M/Mito-CK-/- mice 4 weeks postmyocardial infarction (MI). Four weeks post-LAD ligation (MI size approximately 32%), WT and M/Mito-CK-/- showed a similar degree of cardiac dysfunction, dilatation, and hypertrophy. CONCLUSION: Mito-CK-/- and M/Mito-CK-/- mice show significant LV dilatation and marked LV hypertrophy, but LV remodeling post-MI is not aggravated. CK ablation leads to substantial adaptational changes in heart.

MRI vs. CT for orthodontic applications: comparison of two MRI protocols and three CT (multislice, cone-beam, industrial) technologies.

OBJECTIVES: To examine the relative usefulness and suitability of magnetic resonance imaging (MRI) in daily clinical practice as compared to various technologies of computed tomography (CT) in addressing questions of orthodontic interest. METHODS: Three blinded raters evaluated 2D slices and 3D reconstructions created from scans of two pig heads. Five imaging modalities were used, including three CT technologies-multislice (MSCT), cone-beam CT (CBCT), and industrial (µCT)-and two MRI protocols with different scan durations. Defined orthodontic parameters were rated one by one on the 2D slices and the 3D reconstructions, followed by final overall ratings for each modality. A mixed linear model was used for statistical analysis. RESULTS: Based on the 2D slices, the parameter of visualizing tooth-germ topography did not yield any significantly different ratings for MRI versus any of the CT scans. While some ratings for the other parameters did involve significant differences, how these should be interpreted depends greatly on the relevance of each parameter. Based on the 3D reconstructions, the only significant difference between technologies was noted for the parameter of visualizing root-surface morphology. Based on the final overall ratings, the imaging performance of the standard MRI protocol was noninferior to the performance of the three CT technologies. CONCLUSIONS: On comparing the imaging performance of MRI and CT scans, it becomes clear that MRI has a huge potential for applications in daily clinical practice. Given its additional benefits of a good contrast ratio and complete absence of ionizing radiation, further studies are needed to explore this clinical potential in greater detail.

Sphingosine-1-Phosphate Receptor 1 Regulates Cardiac Function by Modulating Ca2+ Sensitivity and Na+/H+ Exchange and Mediates Protection by Ischemic Preconditioning.

BACKGROUND: Sphingosine-1-phosphate plays vital roles in cardiomyocyte physiology, myocardial ischemia-reperfusion injury, and ischemic preconditioning. The function of the cardiomyocyte sphingosine-1-phosphate receptor 1 (S1P1) in vivo is unknown. METHODS AND RESULTS: Cardiomyocyte-restricted deletion of S1P1 in mice (S1P1 (α) (MHCC) (re)) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P1 (α) (MHCC) (re) mice revealed reduced diastolic and systolic Ca(2+) concentrations that were secondary to reduced intracellular Na(+) and caused by suppressed activity of the sarcolemmal Na(+)/H(+) exchanger NHE-1 in the absence of S1P1. This scenario was successfully reproduced in wild-type cardiomyocytes by pharmacological inhibition of S1P1 or sphingosine kinases. Furthermore, Sarcomere shortening of S1P1 (α) (MHCC) (re) cardiomyocytes was intact, but sarcomere relaxation was attenuated and Ca(2+) sensitivity increased, respectively. This went along with reduced phosphorylation of regulatory myofilament proteins such as myosin light chain 2, myosin-binding protein C, and troponin I. In addition, S1P1 mediated the inhibitory effect of exogenous sphingosine-1-phosphate on ß-adrenergic-induced cardiomyocyte contractility by inhibiting the adenylate cyclase. Furthermore, ischemic precondtioning was abolished in S1P1 (α) (MHCC) (re) mice and was accompanied by defective Akt activation during preconditioning. CONCLUSIONS: Tonic S1P1 signaling by endogenous sphingosine-1-phosphate contributes to intracellular Ca(2+) homeostasis by maintaining basal NHE-1 activity and controls simultaneously myofibril Ca(2+) sensitivity through its inhibitory effect on adenylate cyclase. Cardioprotection by ischemic precondtioning depends on intact S1P1 signaling. These key findings on S1P1 functions in cardiac physiology may offer novel therapeutic approaches to cardiac diseases.

Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction: an experimental serial cardiac magnetic resonance imaging study.

OBJECTIVES: We sought to assess the influence of long-term hydroxymethylglutaryl coenzyme A reductase inhibition (statin) therapy on left ventricular (LV) remodeling after myocardial infarction (MI) by use of serial cardiac magnetic resonance imaging (CMRI) studies. BACKGROUND: Statin therapy has been shown to reduce cardiac hypertrophy in vitro and in vivo, but the influence on LV post-MI remodeling is largely unknown. METHODS: The CMRI measurements were taken four and 12 weeks after left coronary artery ligation in a 7.05-tesla Biospec. The MI size, LV mass and volumes, cardiac output (CO), and ejection fraction were determined. Rats were treated for 12 weeks with either placebo (P), cerivastatin (C; 0.6 mg/kg body weight per day) as a dietary supplement, or cerivastatin plus the nitric oxide synthase (NOS) inhibitor N-methyl-L-arginine methyl ester (L-NAME, 76 mg/100 ml) and hydralazine (8 mg/100 ml) in drinking water (CLH) to assess the contribution of endogenous nitric oxide formation. RESULTS: Administration of cerivastatin attenuated hypertrophy after MI, and this effect was completely abolished by NOS inhibition (increase of LV mass from 4 to 12 weeks after MI: 235.3 +/- 33.7 mg with P vs. 59.8 +/- 20.5 mg with C vs. 239.5 +/- 16.0 mg with CLH; p < 0.05 vs. P and CLH). Left ventricular dilation was not changed (increase of end-diastolic volume from 4 to 12 weeks after MI: 108.7 +/- 28.8 with P vs. 126.6 +/- 20.5 with C vs. 173.7 +/- 25.1 with CLH; p = NS). The CO was higher in the cerivastatin group (12 weeks: 76.1 +/- 2.9 ml/min with P vs. 95.8 +/- 4.8 ml/min with C; p < 0.05). The effects of cerivastatin were abolished by NOS inhibition in the CLH group (CO at 12 weeks: 69.3 +/- 2.8 ml/min, p < 0.05 vs. C). CONCLUSIONS: Left ventricular remodeling was profoundly changed by statin treatment. Hypertrophy was attenuated, and global function was improved. These positive effects were abolished by NOS inhibition.

[Magnetic resonance tomography: potentials of molecular imaging]. / Magnet-Resonanz-Tomographie: Möglichkeiten der molekularen Bildgebung.

Molecular imaging is "the in-vivo characterization and measurement of biological processes at the cellular and molecular level" and allows the imaging of molecular abnormalities associated with diseases long before morphological changes can be detected. At present, the use of magnetic resonance imaging (MRI) for molecular and cellular imaging is rapidly increasing. MRI is a very attractive candidate, since current MRI protocols already provide anatomic, functional, and biochemical information of excellent image quality and with high spatial resolution. Combining this high spatial resolution/high contrast imaging modality with specific MRI contrast imaging agents for molecular imaging is currently the focus of research in many laboratories worldwide. This paper summarizes the rationale for molecular MRI imaging and describes the basic features of modern molecular imaging strategies with MRI. Finally, a special focus is given to the growing field of applications, e.g., stem cell imaging, imaging of apoptosis, plaques, and other biological targets of interest.

NMR-microscopy with TrueFISP at 11.75T.

The purpose of this paper is to demonstrate that a fully balanced gradient echo technique (TrueFISP) can be used for microscopic experiments at high static magnetic field strengths. TrueFISP experiments were successfully performed on homogeneous and inhomogeneous objects at 11.75T. High-resolution TrueFISP images were obtained from phantoms, plants, formalin-fixed samples, and from an isolated beating rat heart with an in-plane resolution of 78 micro m and a slice thickness of 500 micro m. The signal-to-noise ratio (SNR) gain of TrueFISP compared to conventional gradient echo or spin echo sequences will allow faster acquisition times or an improvement in spatial resolution for microscopic experiments.