Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Background In spontaneously hypertensive rats ( SHR ) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. In this study, we evaluated whether metformin improved myocardial metabolic abnormalities and simultaneously prevented contractile dysfunction and left ventricular hypertrophy in SHR . Methods and Results SHR and control Wistar–Kyoto rats were treated with metformin from 2 to 5 months of age, when SHR hearts exhibit metabolic abnormalities and develop cardiac dysfunction and left ventricular hypertrophy. We evaluated the effect of metformin on myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography. We used cardiac MRI in vivo to assess the effect of metformin on ejection fraction, left ventricular mass, and end‐diastolic wall thickness, and also analyzed metabolites, AMP ‐activated protein kinase and mammalian target‐of‐rapamycin activities, and mean arterial blood pressure. Metformin‐treated SHR had lower mean arterial blood pressure but remained hypertensive. Cardiac glucose uptake rates, left ventricular mass/tibia length, wall thickness, and circulating free fatty acid levels decreased to normal, and ejection fraction improved in treated SHR . Hearts of treated SHR exhibited increased AMP ‐activated protein kinase phosphorylation and reduced mammalian target‐of‐rapamycin activity. Cardiac metabolite profiling demonstrated that metformin decreased fatty acyl carnitines and markers of oxidative stress in SHR . Conclusions Metformin reduced blood pressure, normalized myocardial glucose uptake, prevented left ventricular hypertrophy, and improved cardiac function in SHR . Metformin may exert its effects by normalizing myocardial AMPK and mammalian target‐of‐rapamycin activities, improving fatty acid oxidation, and reducing oxidative stress. Thus, metformin may be a new treatment to prevent or ameliorate chronic hypertension–induced left ventricular hypertrophy.

Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl‐ and branched chain amino acid‐derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 month‐old SHR. Conclusions Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension‐induced left ventricular hypertrophy.

Introduction: In a chronic hypertension model [spontaneously hypertensive rats (SHR)], we observed profound myocardial metabolic changes during early hypertension, before or concomitant with cardia...

Rodent models of liver tumorigenesis have reproducibly shown that dietary sugar intake is a powerful driver of liver tumor initiation and growth. In contrast, dietary sugar restriction with ketogenic diets or calorie restriction generally prevents liver tumor formation. Ketogenic diet is viewed positively as a therapeutic adjuvant; however, most ketogenic diet studies described to date have been performed in prevention mode rather than treatment mode. Therefore, it remains unclear whether a ketogenic diet can be administered in late stages of disease to stall or reverse liver tumor growth. To model the clinically relevant treatment mode, we administered a ketogenic diet to mice after liver tumor initiation and monitored tumor growth by magnetic resonance imaging (MRI). Male C57BL/6 mice were injected with diethylnitrosamine (DEN) at 2 weeks of age and fed a chow diet until 39 weeks of age, when they underwent MRI imaging to detect liver tumors. Mice were then randomised into two groups and fed either a chow diet or switched to a ketogenic diet from 40–48 weeks of age. Serial MRIs were performed at 44 and 48 weeks of age. All mice had tumors at study completion and there were no differences in total tumor burden between diet groups. Although a ketogenic diet has marked protective effects against DEN-induced liver tumourigenesis in this mouse model, these data demonstrate that ketogenic diet cannot stop the progression of established liver tumors.

366 Objectives: The objective of this study was to evaluate the temporal relationship between metabolic, functional and structural changes in spontaneously hypertensive rat (SHR) hearts. Methods: SHR (n=8) and control Wistar Kyoto (WKY) rats (n=4-5) were serially imaged at 1, 2, 3, 5, 9 and 12 months of age. Briefly, dynamic FDG PET imaging (with Siemens microPET Focus F 120 scanner) for measuring glucose uptake in rat hearts in vivo was performed wherein a 60 minute list mode acquisition was initiated following an intravenous injection of ~1mCi FDG via a tail-vein catheter. The rats were fasted for 5-6 hours prior to the PET scan. The time-resolved cardiac PET images corrected for attenuation were used to compute rate of myocardial FDG uptake, Ki (ml/min/g), using a 3-compartment kinetic model with spill-over and partial volume corrections [1]. The same rats were also imaged using the Bruker Clinscan 7T MR scanner for measuring functional and structural changes in the rat hearts in vivo. Briefly, an ECG-triggered cine black blood pulse sequence was used to image the rat hearts with 1.5 mm slice thickness and 100 x 100 µm2 in-plane resolution [2]. The images were analyzed using SEGMENT to compute left ventricular mass (LVM), end-diastolic volume (EDV) and end-systolic volume (ESV). The LVM was normalized to body weight (BW) to compute LVM/BW ratios, and EDV and ESV were used to compute ejection fraction (EF). In addition, diastolic function of the rat hearts were assessed at 12 months of age using high temporal-resolution phase-contrast MRI [3]. Specifically, the trans-mitral and trans-aortic velocity-time curves were used to quantify isovolumetric relaxation time (IVRT) of the rat hearts. The PET and MRI serial data were analyzed by way of linear mixed models. A value of p Results: Rates of myocardial FDG uptake (Ki) in SHR was significantly higher than in WKY from 2-12 months of age with a marked difference observed at 2 months of age (p

Objective: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA).Methods: Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 mu L of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 mu L of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement.Results: Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P <.01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P <.001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% +/- 36.6%, 285.8% +/- 78.6%, and 801% +/- 160% on days 21, 28, and 100, respectively; P <.001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1 beta, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100.Conclusions: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.

Disturbances in the function of neuronal circuitry contribute to most neurologic disorders. As knowledge of the brain's connectome continues to improve, a more refined understanding of the role of specific circuits in pathologic states will also evolve. Tools capable of manipulating identified circuits in a targeted and restricted manner will be essential not only to expand our understanding of the functional roles of such circuits, but also to therapeutically disconnect critical pathways contributing to neurologic disease. This study took advantage of the ability of low-intensity focused ultrasound (FUS) to transiently disrupt the blood-brain barrier (BBB) to deliver a neurotoxin with poor BBB permeability (quinolinic acid [QA]) in a guided manner to a target region in the brain parenchyma. Ten male Sprague-Dawley rats were divided into two groups receiving the following treatments: (i) magnetic resonance-guided FUS + microbubbles + saline (n = 5), or (ii) magnetic resonance-guided FUS + microbubbles + QA (n = 5). Systemic administration of QA was well tolerated. However, when QA and microbubbles were systemically administered in conjunction with magnetic resonance-guided FUS, the BBB was disrupted and primary neurons were destroyed in the targeted subregion of the hippocampus in all QA-treated animals. Administration of vehicle (saline) together with microbubbles and FUS also disrupted the BBB but did not produce neuronal injury. These findings indicate the feasibility of non-invasively destroying a targeted region of the brain parenchyma using low-intensity FUS together with systemic administration of microbubbles and a neurotoxin. This approach could be of therapeutic value in various disorders in which disturbances of neural circuitry contribute to neurologic disease.

The goal of our study was to determine if the timing of the tissue plasminogen activator (tPA) administration influenced its effect on blood-brain barrier (BBB) permeability and the subsequent risk of hemorrhagic transformation. Thirty spontaneously hypertensive male rats were subjected to a 90-minute unilateral middle cerebral artery occlusion. Six rats did not receive tPA treatment (vehicle control: Group 0), intravenous tPA was administered immediately after reperfusion (Group 1) or 4h after reperfusion (Group 2). Dynamic contrast enhancement (DCE) and gradient-echo (GRE) MR sequences were used to assess the dynamic evolution of BBB permeability and hemorrhagic transformation changes at the following time points: during occlusion, and 3h, 6h, and 24h post reperfusion. In all groups, BBB permeability values in the ischemic tissue were low during occlusion. In Group 0, BBB permeability values increased at 3h after reperfusion (p=0.007, compared with the values during occlusion), and further at 6h after reperfusion (p=0.004, compared with those at 3h post reperfusion). At 24h post reperfusion, the values decreased to a level relative to but still higher than those during occlusion (p=0.025, compared with the values during occlusion). At 3h after reperfusion, BBB permeability values in the ischemic tissue increased, but to a greater extent in Group 1 than in Group 0 (p=0.034) and Group 2 (p=0.010). At 6h after reperfusion, BBB permeability values in the ischemic tissue increased further in Group 2 than in Group 0 (p=0.006) and Group 1 (p=0.001), while Group 1 exhibited BBB permeability that were still abnormal but less than those observed at 3h (p=0.001). Group 2 tended to have a higher hemorrhage incidence (36.4%, 4/11) than Group 1 (10.0%, 1/10, p=0.311) and Group 0 (0%), and hemorrhages occurred around 6h after reperfusion when BBB permeability values were the highest. Mortality was higher in Group 2 (63.6%, 7/11) than in Group 0 (0%) and Group 1 (10.0%, 1/10, p=0.024). The findings suggest that the timing of tPA administration is of importance for its impact on BBB permeability and subsequent risk of hemorrhagic transformation.

This study aimed at determining the optimal age group for high-intensity focused ultrasound (HIFU) experiments for producing lesions in rats. Younger rats have thinner skulls, allowing for the acoustic waves to propagate easily through the skull without causing burns of the skin and brain surface. Younger rats however, have a smaller brain that can make HIFU focusing in the brain parenchyma challenging because of the focus size. In this study, we conducted transcranial HIFU sonications in rat pups of different ages (from 9 to 43 d) with a 1.5MHz MR compatible transducer. The electric power was selected to always reach a target temperature of at least 50°C in the parenchyma. The thickness of the skull and of the brain parenchyma was measured using T2-weighted MR imaging. Results showed that the thickness of the brain parenchyma increased quickly from P9 to P12, reaching 8.5 mm at P16, and then increasing gradually along with age. The skull thickness increased gradually from P9 to P26, and then more quickly after P30. The ratio between brain parenchyma thickness and skull thickness decreased gradually with age. For the pups at 30 d, the temperature in the brain tissue adjacent to the skull increased to 48.9°C, and those from the rodents older than 33 d reached 60°C or higher, which can produce undesired irreversible damage in this location. We conclude that young rats aged 16-26 d are optimal for experiments producing transcranial HIFU lesions in rats with an intact skull.

Background Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose‐6‐phosphate levels regulate mammalian target of rapamycin ( mTOR ) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6‐phosphate (G6P) accumulation. Methods and Results We subjected the working rat heart ex vivo to a high workload in the presence of different energy‐providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum ( ER ) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin ( mTOR inhibition) or metformin ( AMPK activation). The histone deacetylase inhibitor 4‐phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2‐deoxy‐ d ‐glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro‐ PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load‐induced mTOR activation and ER stress.

Atherosclerosis is a complex disease whose spatial distribution is hypothesized to be influenced by the local hemodynamic environment. The use of transgenic mice provides a mechanism to study the relationship between hemodynamic forces, most notably wall shear stress (WSS), and the molecular factors that influence the disease process. Phase contrast MRI using rectilinear trajectories has been used to measure boundary conditions for use in computational fluid dynamic models. However, the unique flow environment of the mouse precludes use of standard imaging techniques in complex, curved flow regions such as the aortic arch. In this article, two-dimensional and three-dimensional spiral cine phase contrast sequences are presented that enable measurement of velocity profiles in curved regions of the mouse vasculature. WSS is calculated directly from the spatial velocity gradient, enabling WSS calculation with a minimal set of assumptions. In contrast to the outer radius of the aortic arch, the inner radius has a lower time-averaged longitudinal WSS (7.06 +/- 0.76 dyne/cm(2) vs. 18.86 +/- 1.27 dyne/cm(2); P < 0.01) and higher oscillatory shear index (0.14 +/- 0.01 vs. 0.08 +/- 0.01; P < 0.01). This finding is in agreement with humans, where WSS is lower and more oscillatory along the inner radius, an atheroprone region, than the outer radius, an atheroprotective region. Magn Reson Med 66: 1382-1390, 2011. (C) 2011 Wiley Periodicals, Inc.

PURPOSE:To prospectively evaluate a gadolinium-based collagen-targeting contrast agent, EP-3533, for in vivo magnetic resonance (MR) imaging of myocardial fibrosis in a mouse model of healed myocardial infarction (MI).MATERIALS AND METHODS:All procedures were performed in accordance with protocols approved by the animal care and use committee. MI was induced in eight mice by means of occlusion of the left anterior descending coronary artery followed by reperfusion. Four MR examinations were performed in each animal: one examination before, one examination 1 day after, and two examinations 6 weeks after the MI. For the latter two examinations, electrocardiographically gated inversion-recovery gradient-echo MR images were acquired before and serially (every 5 minutes) after the intravenous injection of either gadopentetate dimeglumine or EP-3533. The image enhancement kinetic properties of the postinfarction scar, normal myocardium, and blood were compared.RESULTS:Dynamic T1-weighted MR imaging revealed the washout time constants for EP-3533 to be significantly longer than those for gadopentetate dimeglumine in regions of postinfarction scarring (mean, 194.8 minutes +/-116.8 [standard deviation] vs 25.5 minutes +/- 4.2; P < .05) and in normal myocardium (mean, 45.4 minutes +/- 16.7 vs 25.1 minutes +/- 9.7; P < .05). Findings on postmortem histologic sections stained for collagen correlated well with EP-3533-enhanced areas seen on inversion-recovery MR images. Fifty minutes after EP-3533 injection, the postinfarction scar tissue samples, as compared with the normal myocardium, had a twofold higher concentration of gadolinium.CONCLUSION:Use of the gadolinium-based collagen-targeting contrast agent, EP-3533, enabled in vivo molecular MR imaging of fibrosis in a mouse model of healed postinfarction myocardial scarring.

HomeCirculationVol. 115, No. 17Serial Multimodality Assessment of Myocardial Infarction in Mice Using Magnetic Resonance Imaging and Micro–Positron Emission Tomography Provides Complementary Information on the Progression of Scar Formation Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBSerial Multimodality Assessment of Myocardial Infarction in Mice Using Magnetic Resonance Imaging and Micro–Positron Emission Tomography Provides Complementary Information on the Progression of Scar Formation Stuart S. Berr, Yaqin Xu, R. Jack Roy, Bijoy Kundu, Mark B. Williams and Brent A. French Stuart S. BerrStuart S. Berr From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. , Yaqin XuYaqin Xu From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. , R. Jack RoyR. Jack Roy From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. , Bijoy KunduBijoy Kundu From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. , Mark B. WilliamsMark B. Williams From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. and Brent A. FrenchBrent A. French From the Departments of Radiology (S.S.B., J.R., B.K., M.B.W., B.A.F.) and Biomedical Engineering (S.S.B., Y.X., M.B.W., B.A.F.), University of Virginia, Health System, Charlottesville, Va. Originally published1 May 2007https://doi.org/10.1161/CIRCULATIONAHA.106.673749Circulation. 2007;115:e428–e429Recent technological advances have made imaging the mouse heart possible using both 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI),1–4 thus facilitating the investigation of mechanisms underlying the progression toward heart failure after myocardial infarction (MI). These imaging modalities provide complementary information regarding cellular metabolism and infarct location, respectively. To demonstrate this, we used FDG PET and MRI in a serial study of male C57Bl/6 mice that were subjected to a 1-hour coronary occlusion and then 30 days of reperfusion. Imaging was performed 1, 7, and 28 days after coronary occlusion. Gd-enhanced ECG-gated cardiac MRI was performed using a 4.7-T MRI scanner (Varian, Inc, Palo Alto, Calif) with a physiological monitoring/gating system (Model 1025, SA Instruments, Inc, Stony Brook, NY). ECG-gated PET was completed within 2 hours after the intravenous injection of 1.0-mCi FDG using a Focus 120 micro-PET system (Siemens Medical Solutions USA, Inc, Malvern, Pa) with a Model 1025L monitoring/gating system (SA Instruments, Stony Brook, NY). Midventricular, short-axis image planes were compared over time between the 2 modalities. Hearts from parallel mice were used in immunohistochemistry studies of neutrophil and macrophage infiltration. Gd-enhanced MRI revealed MI expansion and left ventricular wall thinning between post-MI days 1 (Figure, D) and 7 (Figure, E). FDG PET revealed a signal void in the infarcted anterior left ventricle when imaged on post-MI day 1 (Figure, A). Interestingly, this signal void became hyperintense relative to normal myocardium when imaged 7 days after MI (Figure, B). By 28 days after MI, the signal void in the infarcted anterior left ventricle had largely returned (Figure, C). Immunohistochemistry using an anti-Mac2 antibody revealed few macrophages in the infarcted anterior wall on post-MI days 1 or 28 but abundant macrophages in the infarct zone on post-MI day 7 (Figure, F). This study shows that macrophage uptake of FDG outstrips that of either cardiomyocytes or neutrophils in mice after MI. The use of MRI for infarct sizing (via Gd-DTPA–delayed hyperenhancement) and volumetrics (via end diastolic and end systolic volumes, ejection fraction, and cardiac output), combined with FDG PET for glucose metabolism, provides considerable information regarding the progression of wound healing and scar formation in the left ventricle after MI. Download figureDownload PowerPointFDG PET images of a mouse heart are shown on post–MI days 1 (A), 7 (B), and 28 (C). Gd-DTPA–enhanced MR images from the same mouse are shown for post-MI days 1 (D) and 7 (E). The hyperenhanced, infarcted region is indicated by the red arrows on the MR images. F, Histological slice from a parallel mouse 7 days after MI, stained for neutrophils and macrophages. Areas of infarction are hyperintense on the MR images and correspond to hypointense regions in the FDG PET scans on days 1 and 28. Seven days after MI, macrophages infiltrate the infarcted region of the heart and account for the increase in FDG uptake shown in the day 7 PET image (B).The online-only Data Supplement, consisting of a movie, is available with this article at http://circ.ahajournals.org/cgi/content/full/115/17/e428/DC1.Sources of FundingThis work was carried out in the University of Virginia Molecular Imaging Core Laboratory and was supported by the UVA Pratt Fund and by National Institutes of Health R01 grants HL 058582 and HL 069494 to Dr French.DisclosuresNone.FootnotesCorrespondence to Stuart S. Berr, PhD, University of Virginia, PO Box 801332, 409 Lane Road, MR4 Building, Room 1192, Charlottesville, VA 22908. E-mail [email protected]References1 Ross AJ, Yang Z, Berr SS, Gilson WD, Petersen WC, Oshinski JN, French BA. Serial MRI evaluation of cardiac structure and function in mice after reperfused myocardial infarction. Magn Reson Med. 2002; 47: 1158–1168.CrossrefMedlineGoogle Scholar2 Epstein FH, Yang Z, Gilson WD, Berr SS, Kramer CM, French BA. MR tagging early after myocardial infarction in mice demonstrates contractile dysfunction in adjacent and remote zones. Magn Reson Med. 2002; 48: 399–403.CrossrefMedlineGoogle Scholar3 Berr SS, Roy RJ, French BA, Yang Z, Gilson W, Kramer CM, Epstein FH. Black-blood gradient-echo cine magnetic resonance imaging of the mouse heart. Magn Reson Med. 2005; 53: 1074–1079.CrossrefMedlineGoogle Scholar4 Young AA, French BA, Yang Z, Cowan BR, Gilson WD, Berr SS, Kramer CM, Epstein FH. Reperfused myocardial infarction in mice: 3D mapping of late gadolinium enhancement and strain. J Cardiovasc Magn Reson. 2006; 8: 685–692.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By St. John Sutton M, Morrison A, Sinusas A and Ferrari V (2020) Cardiac Imaging in Heart Failure Heart Failure: a Companion to Braunwald's Heart Disease, 10.1016/B978-0-323-60987-6.00032-6, (418-448.e5), . Boutagy N, Feher A, Sikanderkhel S and Sinusas A (2019) Molecular Imaging Targets in Heart Failure and Left Ventricular Remodeling Cardiac CT, PET & MR, 10.1002/9781118754467.ch13, (405-435) Boutagy N, Feher A, Alkhalil I, Umoh N and Sinusas A (2019) Molecular Imaging of the Heart Comprehensive Physiology, 10.1002/cphy.c180007, (477-533) Sager H, Hulsmans M, Lavine K, Moreira M, Heidt T, Courties G, Sun Y, Iwamoto Y, Tricot B, Khan O, Dahlman J, Borodovsky A, Fitzgerald K, Anderson D, Weissleder R, Libby P, Swirski F and Nahrendorf M (2016) Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure, Circulation Research, 119:7, (853-864), Online publication date: 16-Sep-2016.Nahrendorf M and Swirski F (2014) Imaging Systemic Inflammation in Patients With Acute Myocardial Infarction, Circulation: Cardiovascular Imaging, 7:5, (762-764), Online publication date: 1-Sep-2014.Wollenweber T, Roentgen P, Schäfer A, Schatka I, Zwadlo C, Brunkhorst T, Berding G, Bauersachs J and Bengel F (2014) Characterizing the Inflammatory Tissue Response to Acute Myocardial Infarction by Clinical Multimodality Noninvasive Imaging, Circulation: Cardiovascular Imaging, 7:5, (811-818), Online publication date: 1-Sep-2014. Jivraj N, Phinikaridou A, Shah A and Botnar R (2013) Molecular imaging of myocardial infarction, Basic Research in Cardiology, 10.1007/s00395-013-0397-2, 109:1, Online publication date: 1-Jan-2014. Phinikaridou A, Andia M, Shah A and Botnar R (2012) Advances in molecular imaging of atherosclerosis and myocardial infarction: shedding new light on in vivo cardiovascular biology, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00583.2012, 303:12, (H1397-H1410), Online publication date: 15-Dec-2012. Geelen T, Paulis L, Coolen B, Nicolay K and Strijkers G (2012) Contrast-enhanced MRI of murine myocardial infarction - Part I, NMR in Biomedicine, 10.1002/nbm.2768, 25:8, (953-968), Online publication date: 1-Aug-2012. Majmudar M and Nahrendorf M (2012) Cardiovascular Molecular Imaging: The Road Ahead, Journal of Nuclear Medicine, 10.2967/jnumed.111.099838, 53:5, (673-676), Online publication date: 1-May-2012. Leuschner F and Nahrendorf M (2011) Molecular Imaging of Coronary Atherosclerosis and Myocardial Infarction, Circulation Research, 108:5, (593-606), Online publication date: 4-Mar-2011. Makowski M, Jansen C, Webb I, Chiribiri A, Nagel E, Botnar R, Kozerke S and Plein S (2010) First-pass contrast-enhanced myocardial perfusion MRI in mice on a 3-T clinical MR scanner, Magnetic Resonance in Medicine, 10.1002/mrm.22470, 64:6, (1592-1598), Online publication date: 1-Dec-2010. French B, Epstein F, Hossack J, Berr S and Kramer C (2007) Multimodal Imaging of Myocardial Infarction in Mice 2007 41st Asilomar conference on Signals, Systems and Computers (ACSSC), 10.1109/ACSSC.2007.4487314, 978-1-4244-2109-1, (741-745) May 1, 2007Vol 115, Issue 17 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.106.673749PMID: 17470701 Originally publishedMay 1, 2007 PDF download Advertisement SubjectsAnimal Models of Human DiseaseComputerized Tomography (CT)ImagingMyocardial InfarctionNuclear Cardiology and PET

Introduction: Post-MI LV remodeling is greatly reduced in iNOS knock-out mice. This study tests the hypothesis that selective inhibition of iNOS protects against post-MI LV remodeling similar to conventional therapy. Methods: A total of 19 male C57BL/6 mice (8–10 wks) received 1h coronary occlusion and 28d of reperfusion. Seven of these were left untreated, 5 were treated with 1400W (a highly selective iNOS inhibitor) and 7 with ACE inhibition + β-blockade. Mice were studied by CMR at 4.7T before and at 1, 7 & 28 days post-MI. Alzet minipumps (Durect Corp) were used to deliver 1400W (30 mg/kg-d) from 1h post-reperfusion until Day 14. Captopril & metoprolol were mixed and 50 mg/kg-d of each were similarly applied to 7 mice (AI+BB) from 1h post-reperfusion until Day 28. CMR studies included short-axis black-blood cines covering the entire heart. On Day 1, Gd-DTPA was infused for Gd-enhanced inversion recovery imaging. Myocardial volumes and EF were measured from cine images. Day 1 infarct size was measured ...

coverage of the LV was achieved using an imaging FOV from 18–20 cm. This approach combined with higher field systems may provide close to optimal imaging of the left ventricle. Conclusions: The flexible surface coil provided sufficient RF penetration for CMR imaging at 3 Tesla. An unaliased FOV of 18–20 cm was easily acquired in three moderate sized subjects. Further studies are needed to establish FOV, penetration, and SNR tradeoffs compared with other available coils.