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Myocardial segmentation as defined by the American Heart Association (17). Middle slice of the left ventricle is divided into six sectors: A = anterior, AL = anterolateral, IL = inferolateral, I = inferior, IS = inferoseptal, AS = anteroseptal.
Source publication
Manganese (Mn(2+)) was recognized early as an efficient intracellular MR contrast agent to assess cardiomyocyte viability. It had previously been used for the assessment of myocardial infarction in various animal models from pig to mouse. However, whether Manganese-Enhanced MRI (MEMRI) is also able to assess infarction in the acute phase of a coron...
Contexts in source publication
Context 1
... were defined by the American Heart Association (AHA) standardized guidelines for myocardial segmentation (19). Figure 1 shows this segmentation. For the Mn 2þ dose study and infarction quantification, segmentation was done by manually drawing a region of interest (ROI) in septum area, myocardial infarction (MI) or free wall. ...
Context 2
... measured before and after Mn 2þ injection. Values are mean AE SD. For the IR60 group, P indicates significant difference with the sham and control groups respectively obtained with post-hoc Bonferroni test ( Ã p < 0.05; xp < 0.01; yp < 0.001 Table 3. Wall thickening between diastolic and systolic phase in the 6 left ventricle sectors (defined in Fig. 1) for IR60, sham and control groups, before and after Mn 2þ injection. Values are mean AE SD. For the IR60 group, P indicates significant difference with the sham and control groups respectively obtained with post-hoc Bonferroni test ( Ã p < 0.05; xp < 0.01; yp < 0.001) ...
Citations
... To quantify real-time effects of Mn 2+ on myocardial contractility in vivo, studies were performed in mice using b-mode ultrasound to measure left ventricular fractional shortening prior to and after administration of 2 µL g −1 of the following man- [39][40][41] and our pilot data in which sufficient MRI contrast was generated without obvious effects on cardiac function or animal recovery, behavior, and survival. Ultrasound showed immediate and transient reduction of myocardial contractility after 0.02 mM and 0.1 mM MnCl 2 i.v., with contractility severely impaired at the higher dose (Figure 1 and Table S1, Supporting Information). ...
... This is the first study to quantify Mn 2+ uptake in the first hours of AMI using T1-mapping. Previous studies have used T1-weighted imaging to investigate Mn 2+ uptake, [37,39,41,52,53] but these approaches do not quantify R1, so are only sensitive to relative changes in contrast rather than direct measurements of Mn 2+ uptake. We had initially hypothesized that the Mn 2+ preloaded myocardium would lose contrast agent in the AAR over the time-course of cell death. ...
... Previous studies have demonstrated the accuracy of MEMRI in delineating infarct size in experimental MI [37,39,41,52,53] and its usefulness in interrogating pathophysiology, [30,54,55] but none have investigated such early changes after coronary occlusion in comparison to LGE-MRI. Our data suggest that myocytes within the AAR rapidly stop internalizing Mn 2+ under ischemic conditions, while our T1 mapping results show increased Mn 2+ uptake in the viable myocardium remote from the infarct. ...
Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn2+ dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping‐manganese‐enhanced MRI (MEMRI) reveals elevated and increasing Mn2+ uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold‐standard technique, late‐gadolinium‐enhanced MRI. These data, coupled with the re‐emergence of clinical Mn2+‐based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients. Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning. Here, the safety and efficacy of manganese‐enhanced magnetic resonance imaging (MEMRI) in vitro in cardiomyocytes and in vivo in mouse models of MI are evaluated. It is demonstrated that MEMRI offers a novel biomarker of myocardial viability in the first hours after MI.
... However, the availability of such systems is limited by their high costs, which may hinder clinical translation. Although CMR imaging in mice has been successfully performed on clinical systems at 1.5-3 T [35], only a few attempts have been made to evaluate MI in mouse as part of a clinical system [36][37][38]. Here, the proposed technique would be a supplementary alternative strategy at such kinds of clinical system and would be clinically feasible for the evaluation of MI in mice. ...
Purpose
To develop and assess a three-dimensional (3D) self-gated technique for the evaluation of myocardial infarction (MI) in mouse model without the use of external electrocardiogram (ECG) trigger and respiratory motion sensor on a 3T clinical MR system.
Methods
A 3D T1-weighted GRE sequence with stack-of-stars sampling trajectories was developed and performed on six mice with MIs that were injected with a gadolinium-based contrast agent at a 3T clinical MR system. Respiratory and cardiac self-gating signals were derived from the Cartesian mapping of the k-space center along the partition encoding direction by bandpass filtering in image domain. The data were then realigned according to the predetermined self-gating signals for the following image reconstruction. In order to accelerate the data acquisition, image reconstruction was based on compressed sensing (CS) theory by exploiting temporal sparsity of the reconstructed images. In addition, images were also reconstructed from the same realigned data by conventional regridding method for demonstrating the advantageous of the proposed reconstruction method. Furthermore, the accuracy of detecting MI by the proposed method was assessed using histological analysis as the standard reference. Linear regression and Bland-Altman analysis were used to assess the agreement between the proposed method and the histological analysis.
Results
Compared to the conventional regridding method, the proposed CS method reconstructed images with much less streaking artifact, as well as a better contrast-to-noise ratio (CNR) between the blood and myocardium (4.1 ± 2.1 vs. 2.9 ± 1.1, p = 0.031). Linear regression and Bland-Altman analysis demonstrated that excellent correlation was obtained between infarct sizes derived from the proposed method and histology analysis.
Conclusion
A 3D T1-weighted self-gating technique for mouse cardiac imaging was developed, which has potential for accurately evaluating MIs in mice at 3T clinical MR system without the use of external ECG trigger and respiratory motion sensor.
... The phantoms in that previous study were prepared using agarose, gadolinium chloride (GdCl 3 ), and sodium chloride (NaCl). Although Gd-based agents are gaining popularity [19][20][21][22][23], CuSO 4 , MnCl 2 , and NiCl 2 remain the most commonly used paramagnetic agents for making imaging phantoms [24][25][26][27]. However, except for a few studies on MnCl 2 , the relaxivities for these agents have not yet been reported at 3 T. ...
... Comparing these values with the ones listed in Table 2, gadolinium-based agents have significantly higher relaxivites than CuSO 4 and NiCl 2 . On the other hand, relaxivities of MnCl 2 are comparable or higher than these clinical contrast agents, which is one of the reasons for the popularity of manganese-based contrast agents in preclinical research at 3 T and at higher field strengths [23,26,27]. It should be emphasized that the dosage of the manganese utilized in preclinical/clinical settings should be carefully adjusted to minimize the toxic side effects [49]. ...
Phantoms with known T1 and T2 values that are prepared using solutions of easily accessible paramagnetic agents are commonly used in MRI imaging centers, especially with the goal of validating the accuracy of quantitative imaging protocols. The relaxivity parameters of several agents were comprehensively examined at lower B0 field strengths, but studies at 3 T remain limited. The main goal of this study is to measure r1 and r2 relaxivities of three common paramagnetic agents (CuSO4, MnCl2, and NiCl2) at room temperature at 3 T. Separate phantoms were prepared at various concentrations of 0.05-0.5 mM for MnCl2 and 1-6 mM for CuSO4 and NiCl2. For assessment of T1 relaxation times, inversion recovery turbo spin echo images were acquired at 15 inversion times ranging between 24 and 2500 ms. For assessment of T2 relaxation times, spin-echo images were acquired at 15 echo times ranging between 8.5 and 255 ms. Voxel-wise T1 and T2 relaxation times at each concentration were separately determined from the respective signal recovery curves (inversion recovery for T1 and spin echo decay for T2). Relaxivities r 1 and r2 for all three agents that were derived from these relaxation time measurements are reported: r1 = 0.602 mM⁻¹ s⁻¹ and r2 = 0.730 mM⁻¹ s⁻¹ for CuSO4, r1 = 6.397 mM⁻¹ s⁻¹ and r2 = 108.266 mM⁻¹ s⁻¹ for MnCl2, r1 = 0.620 mM⁻¹ s⁻¹ and r2 = 0.848 mM⁻¹ s⁻¹ for NiCl2. These results will serve as a practical reference to design phantoms of target T1 and T2 values at 3 T, in particular phantoms with relaxation times equivalent to specific human tissues.
... Thus, a precise characterization of cell viability and injury in this vulnerable region is imperative. Since the non-specific distribution of gadolinium in DEMRI overestimates the scar area, MEMRI is used to delineate the live cells within the scar, which was previously deemed infarcted by DEMRI [13][14]16,[23][24]. The dual contrast MEMRI-DEMRI defines the peri-infarct region at the leading edge of the DEMRI scar signal where viable but injured myocardium is present. ...
Background:
Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model.
Methods:
51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5μg/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9.
Results:
A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9±3.2% to 23.1±1.7%* vs. 23.5±1.7% to 16.9±2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri-infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri-infarct region (16.5±3.1% vs. 8.1±1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found.
Conclusions:
A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium.
... However, DEMRI does not provide direct cell viability information due to its non-specific distribution into the extracellular space and may overestimate the infarct region [11]. Thus dual-contrast MRI has been used to provide complementary information [12] and for the purpose of directly evaluating cell viability, DEMRI can be complemented by MEMRI [13,14]. MEMRI employs Mn 2+ , an essential heavy metal ion that enters cells via voltage-gated calcium channels [15]. ...
A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI–DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.
Methods and results
Dual contrast MEMRI–DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).
The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI–DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.
... They have similar properties to calcium ions (Ca 2+ ) and provide useful information about cell viability. Manganese enhanced MRI (MEMRI) has already been used in mice for accurate detection of infarct size (2)(3)(4). Combined with T 1 mapping, MEMRI has also been used to monitor the dynamic alterations of calcium homeostasis (5,6). ...
... Bland-Altman plots to assess the pre-contrast repeatability of the 3D spiral Look-Locker method. The dotted lines indicate the means and the 95% confidence intervals for ∆R 1 between successive measurement days(1,2,3). ...
Mapping longitudinal relaxation times in 3D is a promising quantitative and non-invasive imaging tool to assess cardiac remodeling. Few methods are proposed in the literature allowing us to perform 3D T1 mapping. These methods often require long scan times and use a low number of 3D images to calculate T1 . In this project, a fast 3D T1 mapping method using a stack-of-spirals sampling scheme and regular RF pulse excitation at 7 T is presented. This sequence, combined with a newly developed fitting procedure, allowed us to quantify T1 of the whole mouse heart with a high spatial resolution of 208 × 208 × 315 µm(3) in 10-12 min acquisition time. The sensitivity of this method for measuring T1 variations was demonstrated on mouse hearts after several injections of manganese chloride (doses from 25 to 150 µmol kg(-1) ). T1 values were measured in vivo in both pre- and post-contrast experiments. This protocol was also validated on ischemic mice to demonstrate its efficiency to visualize tissue damage induced by a myocardial infarction. This study showed that combining spiral gradient shape and steady RF excitation enabled fast and robust 3D T1 mapping of the entire heart with a high spatial resolution. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
... Although advanced morphological changes due to hypertrophy can be easily detected using MRI and echocardiography, early detection requires sensitivity to cellular changes in gene expression and calcium homeostasis, which precede morphological changes. Unfortunately, these early cellular changes are undetectable using standard imaging techniques but can be exploited using new functional imaging techniques such as manganese-enhanced MRI (MEMRI) (18)(19)(20)(21)(22). ...
The aim of this study was to use manganese (Mn)-enhanced MRI (MEMRI) to detect changes in calcium handling associated with cardiac hypertrophy in a mouse model, and to determine whether the impact of creatine kinase ablation is detectable using this method. Male C57BL/6 (C57, n = 11) and male creatine kinase double-knockout (CK-M/Mito(-/-) , DBKO, n = 12) mice were imaged using the saturation recovery Look-Locker T1 mapping sequence before and after the development of cardiac hypertrophy. Hypertrophy was induced via subcutaneous continuous 3-day infusion of isoproterenol, and sham mice not subjected to cardiac hypertrophy were also imaged. During each scan, the contrast agent Mn was administered and the resulting change in R1 (=1/T1 ) was calculated. Two anatomical regions of interest (ROIs) were considered, the left-ventricular free wall (LVFW) and the septum, and one ROI in an Mn-containing standard placed next to the mouse. We found statistically significant (p < 0.05) decreases in the uptake of Mn in both the LVFW and septum following the induction of cardiac hypertrophy. No statistically significant decreases were detected in the standard, and no statistically significant differences were found among the sham mice. Using a murine model, we successfully demonstrated that changes in Mn uptake as a result of cardiac hypertrophy are detectable using the functional contrast agent and calcium mimetic Mn. Our measurements showed a decrease in the relaxivity (R1 ) of the myocardium following cardiac hypertrophy compared with normal control mice. Copyright © 2014 John Wiley & Sons, Ltd.
Copyright © 2014 John Wiley & Sons, Ltd.
... However, our temporal resolution (7.7 ms) was higher than previously reported values with clinical and non-clinical scanners [26,282930 . This resolution resulted in large number of frames per cardiac cycle which enabled us to obtain accurately ED and ES frames without the need of multiple acquisitions, resulting in reduction in scan time, and accurate global and regional functional analyses [20]. ...
... The contrast between LV blood pool and myocardium was large enough to effectively use SASS for segmentation to evaluate cardiac parameters. We compared our EF values, a major determinant of cardiac function, with reported values in the manner explained by Riegler et al. [23] and Delattre at al. [28]. In our study, EF in healthy animals (71.8±1.3%) was equivalent to reported values [4, 33]. ...
Purpose. To evaluate whether 3T clinical MRI with a small-animal coil and gradient-echo (GE) sequence could be used to characterize long-term left ventricular remodelling (LVR) following nonreperfused myocardial infarction (MI) using semi-automatic segmentation software (SASS) in a rat model. Materials and Methods. 5 healthy rats were used to validate left ventricular mass (LVM) measured by MRI with postmortem values. 5 sham and 7 infarcted rats were scanned at 2 and 4 weeks after surgery to allow for functional and structural analysis of the heart. Measurements included ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and LVM. Changes in different regions of the heart were quantified using wall thickness analyses. Results. LVM validation in healthy rats demonstrated high correlation between MR and postmortem values. Functional assessment at 4 weeks after MI revealed considerable reduction in EF, increases in ESV, EDV, and LVM, and contractile dysfunction in infarcted and noninfarcted regions. Conclusion. Clinical 3T MRI with a small animal coil and GE sequence generated images in a rat heart with adequate signal-to-noise ratio (SNR) for successful semiautomatic segmentation to accurately and rapidly evaluate long-term LVR after MI.
... MEMRI has already been used to accurately quantify myocardial infarction (11,16,17), area at risk (18) and stunned myocardium (19), or to observe cell activity changes under positive or negative inotropic challenges (dobutamine and diltiazem tests, respectively) (20). In mice, viability measurements were performed in different models of infarction, either in the chronic phase of complete ligation infarction (21) or in the acute phase of reperfused ischemia (22). Measurements of Mn 2+ washout with a T1-mapping sequence during the hours following injection provided information concerning Ca 2+ efflux, which has an important role in cardiomyocytes viability (23). ...
... The model chosen was an occlusion reperfusion because it is closer to the clinical situation in which the patient's coronary is ultimately reperfused. Even though this model is quite common, there are few studies that used Mn 2+ to investigate cell viability (16,22,25,26) and none compared acute versus chronic infarction encountered eight days after coronary occlusion-reperfusion. In mice, myocardial infarction eight days after an occlusionreperfusion protocol is characterized by scar tissue composed of collagen fibers and the presence of numerous fibroblasts cells and macrophages (27). ...
... Manganese was injected following a previously described technique (22). Briefly, MnCl 2 was diluted in NaCl 0.9% to obtain a stock solution of 15mM. ...
Manganese (Mn(2+)) is considered as a specific MRI contrast agent that enters viable cardiomyocytes through calcium pathways. Compared to extracellular gadolinium based contrast agents, it has the potential to assess cell viability. To date, only information from the washout phase after recirculation has been used for the detection and characterization of myocardial infarct. This study showed for the first time that in a mouse model of coronary occlusion-reperfusion, Mn(2+) wash-in kinetics are different at 24 h after surgery (acute infarction) than at eight days after surgery (chronic infarction). A fast but transient entry of Mn(2+) into the acute infarct area led to a double contrast between infarct and remote areas, whereas entry of Mn(2+) into the chronic infarct area remained reduced compared to remote regions during both wash-in and washout phases. The main hypothesis is that extracellular space is largely enhanced in acute infarction due to cell membrane rupture and interstitial edema, whereas scar tissue is densely composed of collagen fibers that reduce the distribution volume of free Mn(2+) ions. In addition to its ability to accurately depict the infarct area during the redistribution phase, Mn(2+) is also able to discriminate acute versus chronic injury by the observation of double-contrast kinetics in a mouse model of ischemia reperfusion.
Myocardial infarction (MI) is a major cause of death worldwide. Early and precise diagnosis of myocardial viability after MI is extremely important for effective treatment and prognosis evaluation. Herein, we developed the BSA-templated manganese carbonate (MnCO3@BSA) nanoparticles as an MR imaging contrast agent for accurate detection of the infarcted regions. The chemophysical features, targeting capability toward the infarct, and biocompatibility were evaluated. The nanoparticles showed superior chemical stability. In vitro study suggested that the MnCO3@BSA nanoparticles do not enter normal cardiomyocytes. MR imaging indicated that the MnCO3@BSA with a high longitudinal (r1) relaxivity of 5.84 mM-1s-1 at physiological condition specifically accumulated into the infarcted regions of myocardial ischemia/reperfusion (I/R) mice. In addition, the MnCO3@BSA nanoparticles exhibited low cytotoxicity to cardiomyocytes, no damage to organs and good hemocompatibility. Thereby, the MnCO3@BSA nanoparticles manifested great potential as an extracellular contrast agent of MR imaging for sensitive and specific detection of the infarcted regions during acute myocardial I/R injury.
