Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

In Vivo MRI Tracking of Degradable Polyurethane Hydrogel Degradation In Situ Using a Manganese Porphyrin Contrast Agent.

BACKGROUND: A noninvasive method to track implanted biomaterials is desirable for real-time monitoring of material interactions with host tissues and assessment of efficacy and safety. PURPOSE: To explore quantitative in vivo tracking of polyurethane implants using a manganese porphyrin (MnP) contrast agent containing a covalent binding site for pairing to polymers. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Rodent model of dorsal subcutaneous implants (10 female Sprague Dawley rats). FIELD STRENGTH/SEQUENCE: A 3-T; two-dimensional (2D) T1-weighted spin-echo (SE), T2-weighted turbo SE, three-dimensional (3D) spoiled gradient-echo T1 mapping with variable flip angles. ASSESSMENT: A new MnP-vinyl contrast agent to covalently label polyurethane hydrogels was synthesized and chemically characterized. Stability of binding was assessed in vitro. MRI was performed in vitro on unlabeled hydrogels and hydrogels labeled at different concentrations, and in vivo on rats with unlabeled and labeled hydrogels implanted dorsally. In vivo MRI was performed at 1, 3, 5, and 7 weeks postimplantation. Implants were easily identified on T1-weighted SE, and fluid accumulation from inflammation was distinguished on T2-weighted turbo SE. Implants were segmented on contiguous T1-weighted SPGR slices using a threshold of 1.8 times the background muscle signal intensity; implant volume and mean T1 values were then calculated at each timepoint. Histopathology was performed on implants in the same plane as MRI and compared to imaging results. STATISTICAL TESTS: Unpaired t-tests and one-way analysis of variance (ANOVA) were used for comparisons. A P value <0.05 was considered to be statistically significant. RESULTS: Hydrogel labeling with MnP resulted in a significant T1 reduction in vitro (T1 = 517 ± 36 msec vs. 879 ± 147 msec unlabeled). Mean T1 values of labeled implants in rats increased significantly by 23% over time, from 1 to 7 weeks postimplantation (651 ± 49 msec to 801 ± 72 msec), indicating decreasing implant density. DATA CONCLUSION: Polymer-binding MnP enables in vivo tracking of vinyl-group coupling polymers. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 1.

A Manganese Porphyrin Platform for the Design and Synthesis of Molecular and Targeted MRI Contrast Agents.

Magnetic resonance imaging (MRI) contrast agents, in contrast to the plethora of fluorescent agents available to target disease biomarkers or exogenous implants, have remained predominantly non-specific. That is, they do not preferentially accumulate in specific locations in vivo because doing so necessitates longer contrast retention, which is contraindicated for current gadolinium (Gd) agents. This double-edge sword implies that Gd agents can offer either rapid elimination (but lack specificity) or targeted accumulation (but with toxicity risks). For this reason, MRI contrast agent innovation has been severely constrained. Gd-free alternatives based on manganese (Mn) chelates have been largely ineffective, as they are inherently unstable. In this study, we present a Mn(III) porphyrin (MnP) platform for bioconjugation, offering the highest stability and chemical versatility compared to any other T1 contrast agent. We exploit the inherent metal stability conferred by porphyrins and the absence of pendant bases (found in Gd or Mn chelates) that limit versatile functionalization. As proof-of-principle, we demonstrate labeling of human serum albumin, a model protein, and collagen hydrogels for applications in in-vivo targeted imaging and material tracking, respectively. In-vitro and in-vivo results confirm unprecedented metal stability, ease of functionalization, and high T1 relaxivity. This new platform opens the door to ex-vivo validation by fluorescent imaging and multipurpose molecular imaging in vivo.

Primer and Historical Review on Rapid Cardiac CINE MRI.

Acceleration is an important consideration when imaging moving organs such as the heart. Not only does acceleration enable motion-free scans but, more importantly, it lies at the heart of capturing the dynamics of cardiac motion. For over three decades, various ingenious approaches have been devised and implemented for rapid CINE MRI suitable for dynamic cardiac imaging. Virtually all techniques relied on acquiring less data to reduce acquisition times. Parallel imaging was among the first of these innovations, using multiple receiver coils and mathematical algorithms for reconstruction; acceleration factors of 2 to 3 were readily achieved in clinical practice. However, in the context of imaging dynamic events, further decreases in scan time beyond those provided by parallel imaging were possible by exploiting temporal coherencies. This recognition ushered in the era of k-t accelerated MRI, which utilized predominantly statistical methods for image reconstruction from highly undersampled k-space. Despite the successes of k-t acceleration methods, however, the accuracy of reconstruction was not always guaranteed. To address this gap, MR physicists and mathematicians applied compressed sensing theory to ensure reconstruction accuracy. Reconstruction was, indeed, more robust, but it required optimizing regularization parameters and long reconstruction times. To solve the limitations of all previous methods, researchers have turned to artificial intelligence and deep neural networks for the better part of the past decade, with recent results showing rapid, robust reconstruction. This review provides a comprehensive overview of key developments in the history of CINE MRI acceleration, and offers a unique and intuitive explanation behind the techniques and underlying mathematics.Level of Evidence: 5Technical Efficacy Stage: 1.

Three-Dimensional Bioprinted MR-Trackable Regenerative Scaffold for Postimplantation Monitoring on T1-Weighted MRI.

BACKGROUND: A three-dimensional (3D) bioprinted tissue scaffold is a promising therapeutic that goes beyond providing physical support for tissue regeneration by enabling precise spatial control over scaffold geometry and integration of different materials/cells. Critically important is in vivo confirmation of correct scaffold placement and retention during the initial 24 hours postimplantation, to detect unwanted implant migration. PURPOSE: To incorporate a safe, efficient MR contrast agent into a bioprinting workflow, and to achieve bright-contrast scaffold monitoring in vivo postimplantation. STUDY TYPE: In vitro and animal in vivo longitudinal study. ANIMAL MODEL: Two female Sprague Dawley rats (~200 g) for labeled and unlabeled scaffold implantation in the subcutaneous dorsal space flanking the vertebral column. FIELD STRENGTH/SEQUENCE: A 7.0 T/T1 -weighted spin echo (SE) sequence and T1 mapping using turbo SE with variable repetition times (TRs). ASSESSMENT: Cell viability and proliferation were assessed over 2 weeks after labeling bioprinted gelatin/alginate scaffolds with MnPNH2 (0.5 mM, 24 hours). In vitro MRI was performed 0, 12, and 24 hours postlabeling in nine labeled and three unlabeled (control) scaffolds to monitor T1 evolution. In vivo MRI was performed immediately and 24 hours postimplantation to assess T1 . Acute inflammation near surgical site was monitored in one rat to 3 days. STATISTICAL TESTS: One-way analysis of variance with Tukey-Kramer post hoc analysis (P < 0.01). RESULTS: Cell viability was unaffected by bioprinting/labeling: viability exceeded 90% in all scaffolds after 1 week. In vitro T1 's were significantly lower in labeled scaffolds compared to control (207 msec vs. 2257 msec) immediately postlabeling and 24 hours later (1227 msec vs. 2257 msec). In vivo T1 's were significantly different (243.6 msec vs. 2414.6 msec) immediately postimplantation, and no differences emerged compared to respective in vitro control/labeled counterparts. The 24-hours imaging and gross pathology confirmed migration of scaffolds beyond the imaging field. DATA CONCLUSION: We report an MR-detectable, cell-compatible bioprinted scaffold, utilizing a T1 -weighting contrast agent for high-resolution, postimplantation scaffold tracking. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

MRI method for labeling and imaging decellularized extracellular matrix scaffolds for tissue engineering.

PURPOSE: To develop a facile method for labeling and imaging decellularized extracellular matrix (dECM) scaffolds intended for regenerating 3D tissues. METHODS: A small molecule manganese porphyrin, MnPNH2 , was synthesized and used to label dECM scaffolds made from porcine bladder and trachea and murine whole lungs. The labeling protocol was optimized on bladder dECM, and imaging on a 3T clinical scanner was performed to assess reductions in T1 and T2 relaxation times. In vivo MRI was performed on dECM injected in the rat dorsum to verify sensitivity of detection. Toxicity assays for cell viability, metabolism, and proliferation were performed on human umbilical vein endothelial cells. The incorporation of MnPNH2 and its long-term retention in dECM were assessed on transmission electron microscopy and ultraviolet absorbance of eluted MnPNH2 over time. RESULTS: All tissues, including thick whole 3D organs, were uniformly labeled and demonstrated high signal-to-noise on MRI. A nearly 10-fold reduction in T1 was consistently obtained at a labeling dose of 0.4 mM, and even 0.2 mM provided sufficient contrast in vivo and ex vivo. No toxicity was observed up to 0.4 mM, the maximum tested. Binding studies suggested nonspecific association, and retention studies in the labeled whole decellularized lungs revealed less than 20% MnPNH2 loss over 30 days, the majority occurring in the first 3 days after labeling. CONCLUSION: The proposed labeling method is the first report for visualizing dECM on MRI and has the potential for long-term monitoring and optimization of dECM-based organ tissue engineering.

Heart failure with preserved ejection fraction: the missing pieces in diagnostic imaging.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent phenotype affecting over half of today's heart failure patients. With no proven therapy and no universally accepted diagnostic guideline, many HFpEF patients continue to be misdiagnosed or underdiagnosed at the early stages until the disease has progressed much further along. It is extremely difficult to diagnose the HFpEF patient, because they have a normal ejection fraction and present with non-specific symptoms such as dyspnea or exercise intolerance. To provide greater specificity, the current diagnostic criteria mandate the presence of diastolic dysfunction, where myocardial relaxation is impaired and ventricular filling pressure is elevated as a result of a hypertrophic and stiff heart. Unfortunately, diastolic dysfunction reflects late-stage structural and functional changes and offers a very narrow window, if at all, for successful intervention. In this article, we review the imaging modalities used in the current diagnostic workflow for assessing HFpEF. We also describe the most up-to-date insight into its pathophysiological basis, which attributes systemic inflammation driven by comorbidities as the initiator of disease. With this extramyocardial perspective, we provide our recommendation on new imaging targets that extend beyond the heart to enable early, accurate diagnosis of HFpEF and allow an opportunity for treating this fatal condition.

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane.

BACKGROUND: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. METHODS: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. RESULTS: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. CONCLUSIONS: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

Assessment of microvascular dysfunction in acute limb ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) injury involves damage to the microvessel structure (eg, increased permeability) and function (blunted vasomodulation). While microstructural damage can be detected with dynamic contrast-enhanced (DCE) MRI, there is no diagnostic to detect deficits in microvascular function. PURPOSE: To apply a novel MRI method for evaluating dynamic vasomodulation to assess microvascular dysfunction in skeletal muscle following I/R injury. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Twenty-three healthy male adult Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: Dynamic T1 fast field echo imaging at 3.0T with preinjection T1 mapping. ASSESSMENT: Injury in the left hindlimb was induced using a 3-hour I/R procedure. Longitudinal MRI scanning was performed up to 74 days, with animals completing assessment at different intervals for histological and laser Doppler perfusion validation. Pharmacokinetic parameters Ktrans and ve were determined following i.v. injection of gadovist (0.1 mmol/kg). Vasomodulatory response was probed on gadofosveset (0.3 mmol/kg) using hypercapnic gases delivered through a controlled gas-mixing circuit to induce vasoconstriction and vasodilation in ventilated rats. Heart rate and blood oxygen saturation were monitored. STATISTICAL TESTS: Two-way analysis of variance with Tukey-Kramer post-hoc analysis was used to determine significant changes in vasomodulatory response, Ktrans , and ve . RESULTS: This new MRI technique revealed impaired vasomodulation in the injured hindlimb. Vasoconstriction was maintained, but vasodilation was blunted up to 21 days postinjury (P < 0.05). However, DCE-MRI measured Ktrans and ve were significantly (P < 0.05) different from baseline only during acute inflammation (Day 3), with severe inflammation noted on histology. DATA CONCLUSION: While conventional DCE-MRI shows normalization after the acute phase, our new approach reveals sustained functional impairment in muscle microvasculature following I/R injury, with compromised response in vasomotor tone present for at least 21 days. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1174-1185.

T2* and T1 assessment of abdominal tissue response to graded hypoxia and hypercapnia using a controlled gas mixing circuit for small animals.

PURPOSE: To characterize T2* and T1 relaxation time response to a wide spectrum of gas challenges in extracranial tissues of healthy rats. MATERIALS AND METHODS: A range of graded gas mixtures (hyperoxia, hypercapnia, hypoxia, and hypercapnic hypoxia) were delivered through a controlled gas-mixing circuit to mechanically ventilated and intubated rats. Quantitative magnetic resonance imaging (MRI) was performed on a 3T clinical scanner; T2* and T1 maps were computed to determine tissue response in the liver, kidney cortex, and paraspinal muscles. Heart rate and blood oxygen saturation (SaO2 ) were measured through a rodent oximeter and physiological monitor. RESULTS: T2* decreases consistent with lowered SaO2 measurements were observed for hypercapnia and hypoxia, but decreases were significant only in liver and kidney cortex (P < 0.05) for >10% CO2 and <15% O2 , with the new gas stimulus, hypercapnic hypoxia, producing the greatest T2* decrease. Hyperoxia-related T2* increases were accompanied by negligible increases in SaO2 . T1 generally increased, if at all, in the liver and decreased in the kidney. Significance was observed (P < 0.05) only in kidney for >90% O2 and >5% CO2 . CONCLUSION: T2* and T1 provide complementary roles for evaluating extracranial tissue response to a broad range of gas challenges. Based on both measured and known physiological responses, our results are consistent with T2* as a sensitive marker of blood oxygen saturation and T1 as a weak marker of blood volume changes. J. Magn. Reson. Imaging 2016;44:305-316.

Positive-contrast cellular MRI of embryonic stem cells for tissue regeneration using a highly efficient T1 MRI contrast agent.

PURPOSE: To investigate the feasibility of high-sensitivity cellular MRI of embryonic stem (ES) cells using a novel cell permeable and cell retentive T1 contrast agent. MATERIALS AND METHODS: Mouse ES cells were labeled with a novel manganese porphyrin contrast agent, MnAMP, at 0.1 mM over 2 to 24 h and retained in contrast-free medium for up to 24 h postlabeling. MRI was performed on a 3 Tesla clinical scanner; T1 and T2 relaxation times were measured. Quantification of manganese content was performed using atomic absorption spectroscopy. Viability and proliferation assays were done for the longest labeling interval. Differentiation capacity was assessed using the hanging drop method to direct differentiation toward cardiomyocytes. RESULTS: MnAMP-labeled ES cells exhibited over a fourfold decrease in T1 compared with unlabeled cells, and maintained up to a threefold decrease 24 h postlabeling. Viability and proliferation were not affected. Most importantly, labeled ES cells differentiated into functional cardiomyocytes that exhibited normal contractility patterns. CONCLUSION: MnAMP-based cellular MRI is a very high sensitivity T1 approach for cellular imaging. It has the potential for noninvasive in vivo monitoring of stem cell therapy in cardiac regeneration and other tissue engineering and regenerative medicine applications. J. Magn. Reson. Imaging 2016;44:1456-1463.

Manganese-enhanced MRI of minimally gadolinium-enhancing breast tumors.

PURPOSE: To investigate the potential of manganese (Mn)-enhanced MRI for sensitive detection and delineation of tumors that demonstrate little enhancement on Gd-DTPA. MATERIALS AND METHODS: Eighteen nude rats bearing 1 to 2 cm in diameter orthotopic breast tumors (ZR75 and LM2) were imaged on a 3 Tesla (T) clinical scanner. Gd-DTPA was administered intravenously and MnCl2 subcutaneously, both at 0.05 mmol/kg. T1 -weighted imaging and T1 measurements were performed precontrast, 10 min post-Gd-DTPA, and 24 h post-MnCl2 . Tumors were excised and histologically assessed using H&E (composition and necrosis) and CD34 (vascularity). RESULTS: Most tumors (78%) demonstrated little enhancement (< 20% change in R1 ) on Gd-DTPA. MnCl2 administration achieved greater and more uniform enhancement throughout the tumor mass (i.e., not restricted to the tumor periphery), with R1 changing over 20% in 72% of tumors. MnCl2 -induced R1 changes compared with Gd-induced changes were significantly greater in both ZR75 (P < 0.01) and LM2 tumors (P < 0.05). Histology confirmed very low vascularity in both tumor models, and necrotic areas were well delineated only on Mn-enhanced MRI. CONCLUSION: Mn-enhanced MRI is a promising approach for detection of low-Gd-enhancing tumors.

Gadolinium-free extracellular MR contrast agent for tumor imaging.

PURPOSE: To evaluate a new formulation of manganese porphyrin as a potential gadolinium (Gd)-free extracellular magnetic resonance imaging (MRI) contrast agent for dynamic contrast-enhanced (DCE) MRI of tumors. MATERIALS AND METHODS: A previously reported new contrast agent, MnTCP, was evaluated in six female tumor-bearing nude rats. MRI was performed on a 3 T clinical scanner 3 to 4 weeks after inoculation of breast tumor cells in the mammary fat pads. Gd-DTPA was injected intravenously, followed by injection of MnTCP at least 2 hours later (both at 0.05 mmol/kg). T1 relaxation time measurements and DCE-MRI were performed. RESULTS: Enhancement and clearance patterns were visually similar between MnTCP and Gd-DTPA. However, relative R1 increases in all 11 tumors were larger for MnTCP over 60 minutes postcontrast, the difference being significant as late as 20 minutes (R1post /R1pre = 1.42 ± 0.15 for MnTCP vs. 1.20 ± 0.08 for Gd-DTPA, P < 0.05). R1 -related effects for MnTCP were largely reduced after 60 minutes (R1post /R1pre = 1.13 ± 0.07) and completely gone within 24 hours (R1post /R1pre = 0.97 ± 0.06). DCE-MRI revealed a consistently larger (1.5 to over 2-fold) peak enhancement and higher values of the steepest slope, time-to-peak, and AUC60 in all tumors with MnTCP (P < 0.01). CONCLUSION: MnTCP is an alternative to extracellular Gd agents for tumor imaging, offering sensitive detection and rapid renal clearance.

Noninvasive manganese-enhanced magnetic resonance imaging for early detection of breast cancer metastatic potential.

Cancer cells with a high metastatic potential will more likely escape and form distant tumors. Once the cancer has spread, a cure is rarely possible. Unfortunately, metastasis often proceeds unnoticed until a secondary tumor has formed. The culprit is that current imaging-based cancer screening and diagnosis are limited to assessing gross physical changes, not the earliest cellular changes that drive cancer progression. The purpose of this study is to develop a novel noninvasive magnetic resonance (MR) cellular imaging capability for characterizing the metastatic potential of breast cancer and enable early cancer detection. This MR method relies on imaging cell uptake of manganese, an endogenous calcium analogue and an MR contrast agent, to detect aggressive cancer cells. Studies on normal breast epithelial cells and three breast cancer cell lines, from nonmetastatic to highly metastatic, demonstrated that aggressive cancer cells appeared significantly brighter on MR as a result of altered cell uptake of manganese. In vivo results in nude rats showed that aggressive tumors that are otherwise unseen on conventional gadolinium-enhanced MR imaging are detected after manganese injection. This cellular MR imaging technology brings a critically needed, unique dimension to cancer imaging by enabling us to identify and characterize metastatic cancer cells at their earliest appearance.

Ultrashort echo time magnetic resonance imaging of the lung using a high-relaxivity t1 blood-pool contrast agent.

The lung remains one of the most challenging organs to image using magnetic resonance imaging (MRI) due to intrinsic rapid signal decay. However, unlike conventional modalities such as computed tomography, MRI does not involve radiation and can provide functional and morphologic information on a regional basis. Here we demonstrate proof of concept for a new MRI approach to achieve substantial gains in a signal to noise ratio (SNR) in the lung parenchyma: contrast-enhanced ultrashort echo time (UTE) imaging following intravenous injection of a high-relaxivity blood-pool manganese porphyrin T1 contrast agent. The new contrast agent increased relative enhancement of the lung parenchyma by over 10-fold compared to gadolinium diethylene triamine pentaacetic acid (Gd-DTPA), and the use of UTE boosted the SNR by a factor of 4 over conventional T1-weighted gradient echo acquisitions. The new agent also maintains steady enhancement over at least 60 minutes, thus providing a long time window for obtaining high-resolution, high-quality images and the ability to measure a number of physiologic parameters.

Manganese-enhanced magnetic resonance imaging for early detection and characterization of breast cancers.

Very early cancer detection is the key to improving cure. Our objective was to investigate manganese (Mn)-enhanced magnetic resonance imaging (MRI) for very early detection and characterization of breast cancers. Eighteen NOD scid gamma mice were inoculated with MCF7, MDA, and LM2 breast cancer cells and imaged periodically on a 3 T scanner beginning on day 6. T1-weighted imaging and T1 measurements were performed before and 24 hours after administering MnCl2. At the last imaging session, Gd-DTPA was administered and tumors were excised for histology (hematoxylin-eosin and CD34 staining). All mice, except for two inoculated with MCF7 cells, developed tumors. Tumors enhanced uniformly on Mn and showed clear borders. Early small tumors (≤ 5 mm3) demonstrated the greatest enhancement with a relative R1 (1/T1) change of 1.57 ± 0.13. R1 increases correlated with tumor size (r  =  -.34, p  =  .04). Differences in R1 increases among the three tumor subtypes were most evident in early tumors. Histology confirmed uniform cancer cell distribution within tumor masses and vasculature in the periphery, which was consistent with rim-like enhancement on Gd-DTPA. Mn-enhanced MRI is a promising approach for detecting very small breast cancers in vivo and may be valuable for very early cancer detection.

3D myocardial T1 mapping at 3T using variable flip angle method: pilot study.

PURPOSE: Myocardial T1 mapping is an emerging technique that could improve cardiovascular magnetic resonance diagnostic accuracy. In this study, a variable flip angle approach with B1 correction is proposed at 3T on the myocardium, employing standard 3D spoiled fast gradient echo and echo planar imaging sequences. METHODS: The method was tested on phantoms to determine the set of standard 3D spoiled fast gradient echo angles adapted to myocardial T1 measurements and was compared to the inversion-recovery spin-echo reference T1 method. Seven volunteers underwent magnetic imaging resonance to acquire myocardial T1 maps and T1 values of the human heart. RESULTS: This original method demonstrated good reproducibility in phantoms and a significant correlation between variable flip angle T1 values and reference inversion-recovery spin-echo T1 values. It yielded myocardial T1 values consistent with expected T1 and an increasing homogenization of myocardial segments owing to B1 correction. The mean myocardial T1 value was 1341 ± 42 ms. CONCLUSION: Myocardial 3D T1 mapping using the variable flip angle approach can potentially be useful for evaluating fibrosis on the entire myocardium using a standard clinical sequence.

Binding of a dimeric manganese porphyrin to serum albumin: towards a gadolinium-free blood-pool T1 MRI contrast agent.

As the first clinically approved gadolinium-based blood-pool MRI contrast agent, gadofosveset was designed to bind to human serum albumin (HSA) reversibly, extending the circulation time in the bloodstream. This valuable pharmacokinetic property required for vasculature imaging, however, raises the risk of release and accumulation of gadolinium in vivo. The binding of gadofosveset to HSA significantly increases the relaxivity at low field, which decreases drastically when the magnetic field increases, limiting the applications of gadofosveset at fields of 3 T and higher. To address those challenges, we evaluated a novel dimeric manganese(III) porphyrin (MnP2) in vitro and in vivo as a potential gadolinium-free blood-pool agent. Through multiple spectroscopic studies, we demonstrated that MnP2 binds to HSA tightly. MnP2 exhibits a moderate relaxivity decrease on HSA binding. Nevertheless, owing to the unique field-dependent relaxation behaviors and the dimeric construct (two Mn(III) ions per complex), MnP2-HSA has a molar relaxivity twice that of the gadofosveset-HSA complex at 3 T. Through intravenous injection in rats, MnP2 exhibits long retention and significant contrast enhancement in the vascular compartment, as tested in a 3-T high-field clinical MRI scanner. Taken together, these data demonstrate that MnP2 represents a new class of gadolinium-free blood-pool agents suitable for both regular and high-field applications.

Gadolinium-free T1 contrast agents for MRI: tunable pharmacokinetics of a new class of manganese porphyrins.

PURPOSE: To evaluate a new class of manganese porphyrins with tunable pharmacokinetics as potential gadolinium (Gd)-free T1 agents for contrast-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: Two new contrast agents, MnTCP and MnP2, were evaluated in four female rats. MRI was performed daily up to 3 days postinjection (0.05 mmol/kg) on a 3 T clinical scanner. T1 relaxation times and dynamic contrast-enhanced MRI were performed to assess contrast enhancement and clearance in blood, heart, liver, kidney, and muscle. RESULTS: Relative T1 decreases were similar for MnTCP and Gd-DTPA in all tissues but were significantly larger (P < 0.05) for MnP2 in blood, heart, kidney, and liver (2-6-fold larger). Clearance of MnTCP was similar to Gd-DTPA, with T1 returning to baseline by 40 minutes and complete elimination in 1 day. MnP2 was cleared from blood after 2 days and sustained a lowered T1 in other tissues for at least 1 hour (P < 0.05). The maximum enhancement, slope, and time-to-peak were similar between contrast agents. Only the parameter AUC60 differed, with MnP2 yielding the largest AUC60 values primarily through longer retention in tissue. CONCLUSION: MnTCP and MnP2 offer distinct applications as Gd-free T1 contrast agents. MnTCP behaves like a Gd-DTPA analog, while MnP2 provides significantly greater and longer positive signal enhancement.

Physiologic characterization of inflammatory arthritis in a rabbit model with BOLD and DCE MRI at 1.5 Tesla.

OBJECTIVE: Our aim was to test the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD MRI) and dynamic contrast-enhanced (DCE) MRI to monitor periarticular hypoxic/inflammatory changes over time in a juvenile rabbit model of arthritis. METHODS: We examined arthritic and contralateral nonarthritic knees of 21 juvenile rabbits at baseline and days 1,14, and 28 after induction of arthritis by unilateral intra-articular injection of carrageenin with BOLD and DCE MRI at 1.5 Tesla (T). Nine noninjected rabbits served as controls. Associations between BOLD and DCE-MRI and corresponding intra-articular oxygen pressure (PO2) and blood flow [blood perfusion units (BPU)] (polarographic probes, reference standards) or clinical-histological data were measured by correlation coefficients. RESULTS: Percentage BOLD MRI change obtained in contralateral knees correlated moderately with BPU on day 0 (r = -0.51, p = 0.02) and excellently on day 28 (r = -0.84, p = 0.03). A moderate correlation was observed between peak enhancement DCE MRI (day 1) and BPU measurements in arthritic knees (r = 0.49, p = 0.04). In acute arthritis, BOLD and DCE MRI highly correlated (r = 0.89, p = 0.04; r = 1.0, p < 0.0001) with histological scores in arthritic knees. CONCLUSION: The proposed techniques are feasible to perform at 1.5 T, and they hold potential as surrogate measures to monitor hypoxic and inflammatory changes over time in arthritis at higher-strength MRI fields. KEY POINTS: • BOLD and DCE MRI detect interval perisynovial changes in a rabbit knee • BOLD and DCE MRI act as surrogate markers of physiologic changes in arthritis • BOLD MRI signal represents oxygen extraction compared with intra-articular PO 2 • DCE MRI measurements estimate physiologic periarticular vascular properties • In rabbit knees with acute arthritis, BOLD/DCE MRI highly correlated with histological scores.