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1.  In Vivo Magnetization Transfer and Diffusion-Weighted Magnetic Resonance Imaging Detects Thrombus Composition in a Mouse Model of Deep Vein Thrombosis 
Deep vein thrombosis remains a major health problem necessitating accurate diagnosis. Thrombolysis is associated with significant morbidity and is effective only for the treatment of unorganized thrombus. We tested the feasibility of in vivo magnetization transfer (MT) and diffusion-weighted magnetic resonance imaging to detect thrombus organization in a murine model of deep vein thrombosis.
Methods and Results
Deep vein thrombosis was induced in the inferior vena cava of male BALB/C mice. Magnetic resonance imaging was performed at days 1, 7, 14, 21, and 28 after thrombus induction using MT, diffusion-weighted, inversion-recovery, and T1-mapping protocols. Delayed enhancement and T1 mapping were repeated 2 hours after injection of a fibrin contrast agent. Finally, excised thrombi were used for histology. We found that MT and diffusion-weighted imaging can detect histological changes associated with thrombus aging. MT rate (MTR) maps and percentage of MT rate (%MTR) allowed visualization and quantification of the thrombus protein content, respectively. The %MTR increased with thrombus organization and was significantly higher at days 14, 21, and 28 after thrombus induction (days 1, 7, 14, 21, 28: %MTR=2483±451, 2079±1210, 7029±2490, 10 295±4356, 32 994±25 449; Panova<0.05). There was a significant positive correlation between the %MTR and the histological protein content of the thrombus (r=0.70; P<0.05). The apparent diffusion coefficient was lower in erythrocyte-rich and collagen-rich thrombus (0.72±0.10 and 0.69±0.05 [×10−3 mm2/s]). Thrombus at days 7 and 14 had the highest apparent diffusion coefficient values (0.95±0.09 and 1.10±0.18 [×10−3 mm2/s]).
MT and diffusion-weighted magnetic resonance imaging sequences are promising for the staging of thrombus composition and could be useful in guiding medical intervention.
PMCID: PMC3983477  PMID: 23564561
diffusion weighting; magnetization transfer; MRI; thrombosis; vein
2.  Perfusion Imaging With Vasodilator Stress Echocardiography 
PMCID: PMC3965690  PMID: 22086942
Editorials; echocardiography; regional blood flow; myocardium
3.  Imaging the Physiology of the Ischemic Cascade 
PMCID: PMC3954515  PMID: 19808525
4.  Detecting Myocardial Ischemia at Rest with Cardiac Phase-Resolved BOLD CMR 
Fast, noninvasive identification of ischemic territories at rest (prior to tissue-specific changes) and assessment of functional status can be valuable in the management of severe coronary artery disease. This study investigated the utility of cardiac phase-resolved Blood-Oxygen-Level-Dependent (CP-BOLD) CMR in detecting myocardial ischemia at rest secondary to severe coronary artery stenosis.
Methods and Results
CP-BOLD, standard-cine, and T2-weighted images were acquired in canines (n=11) at baseline and within 20 minutes of ischemia induction (severe LAD stenosis) at rest. Following 3-hours of ischemia, LAD stenosis was removed and T2-weighted and late-gadolinium-enhancement (LGE) images were acquired. From standard-cine and CP-BOLD images, End-Systolic (ES) and End-Diastolic (ED) myocardium were segmented. Affected and remote sections of the myocardium were identified from post-reperfusion LGE images. S/D, quotient of mean ES and ED signal intensities (on CP-BOLD and standard-cine), was computed for affected and remote segments at baseline and ischemia. Ejection fraction (EF) and segmental wall-thickening (sWT) were derived from CP-BOLD images at baseline and ischemia. On CP-BOLD images: S/D was greater than 1 (remote and affected territories) at baseline; S/D was diminished only in affected territories during ischemia and the findings were statistically significant (ANOVA, post-hoc p<0.01). The dependence of S/D on ischemia was not observed in standard-cine images. Computer simulations confirmed the experimental findings. ROC analysis showed that S/D identifies affected regions with similar performance (AUC:0.87) as EF (AUC:0.89) and sWT (AUC:0.75).
Preclinical studies and computer simulations showed that CP-BOLD CMR could be useful in detecting myocardial ischemia at rest. Patient studies are needed for clinical translation.
PMCID: PMC3684209  PMID: 23258476
coronary artery disease; acute coronary syndrome; ischemia; BOLD; MRI
5.  99mTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses 
Differentiating immunoglobulin light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of 99mTc-pyrophosphate scintigraphy (99mTc-PYP) in AL vs. TTR-related cardiac amyloidoses.
Methods and Results
45 subjects (12 AL, 16 ATTR wild-type, and 17 ATTR mutants) underwent 99mTc-PYP planar and single-photon positive emission computed tomography (SPECT) cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects’ cohort assignment. Cardiac retention was assessed with both a semi-quantitative visual score (range 0, no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest (ROI) over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio (H/CL).
Subjects with ATTR cardiac amyloid had a significantly higher semi-quantitative cardiac visual score than the AL cohort (2.9±0.06 vs. 0.8±0.27, p<0.0001) as well as a higher quantitative score (1.80±0.04 vs.1.21±0.04, p<0.0001). Using aH/CL ratio ≥ 1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, p<0.0001 for identifying ATTR cardiac amyloidosis.
99mTc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis which should be studied in a larger prospective manner.
PMCID: PMC3727049  PMID: 23400849
AL amyloid; ATTR transthyretin cardiomyopathy; technetium; 99m-TcPYP scintigraphy
6.  Dual-Energy Computed Tomography Imaging of Atherosclerotic Plaques in a Mouse Model Using a Liposomal-Iodine Nanoparticle Contrast Agent 
The accumulation of macrophages in inflamed atherosclerotic plaques has been long recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography (CT) imaging of macrophage-rich atherosclerotic plaques in a mouse model.
Methods and Results
Liposomal-iodine formulations varying in particle size and polyethylene glycol coating were fabricated, and shown to stably encapsulate the iodine compound. In vitro uptake studies using optical and CT imaging in the RAW264.7 macrophage cell line identified the formulation that promoted maximal uptake. Dual-energy CT imaging using this formulation in Apolipoprotein E deficient (ApoE−/−) mice (n=8) and control C57BL/6 mice (n=6) followed by spectral decomposition of the dual-energy images enabled imaging of the liposomes localized in the plaque. Imaging cytometry confirmed the presence of liposomes in the plaque and their co-localization with a small fraction (~2%) of the macrophages in the plaque.
The results demonstrate the feasibility of imaging macrophage-rich atherosclerotic plaques using a liposomal-iodine nanoparticle contrast agent and dual-energy CT.
PMCID: PMC3760185  PMID: 23349231
liposome; contrast media; atherosclerosis; computed tomography; macrophage
7.  Identification of Nodal Tissue in the Living Heart Using Rapid Scanning Fiber-optics Confocal Microscopy and Extracellular Fluorophores 
Risks associated with pediatric reconstructive heart surgery include injury of the sinoatrial node (SAN) and atrioventricular node (AVN), requiring cardiac rhythm management using implantable pacemakers. These injuries are result of difficulties in identifying nodal tissues intraoperatively. Here, we describe an approach based on confocal microscopy and extracellular fluorophores to quantify tissue microstructure and identify nodal tissue.
Methods and Results
Using conventional three-dimensional confocal microscopy we investigated the microstructural arrangement of SAN, AVN, and atrial working myocardium (AWM) in fixed rat heart. AWM exhibited a regular striated arrangement of the extracellular space. In contrast, SAN and AVN had an irregular, reticulated arrangement. AWM, SAN and AVN tissue were beneath a thin surface layer of tissue that did not obstruct confocal microscopic imaging. Subsequently, we imaged tissues in living rat hearts with real-time fiber-optics confocal microscopy (FCM). FCM images resembled images acquired with conventional confocal microscopy. We investigated spatial regularity of tissue microstructure from Fourier analysis and 2nd order image moments. Fourier analysis of FCM images showed that the spatial regularity of AWM was greater than that of nodal tissues (37.5±5.0% versus 24.3±3.9% for SAN and 23.8±3.7% for AVN, P<0.05). Similar differences of spatial regularities were revealed from 2nd order image moments (50.0±7.3% for AWM versus 29.3±6.7% for SAN and 27.3±5.5% for AVN; P<0.05).
The study demonstrates feasibility of identifying nodal tissue in living heart using extracellular fluorophores and FCM. Application of the approach in pediatric reconstructive heart surgery may reduce risks of injuring nodal tissues.
PMCID: PMC3928358  PMID: 23811748
Confocal imaging; two-dimensional; sinoatrial node; atrioventricular node; congenital cardiac defect
8.  Patterns of Stress Testing and Diagnostic Catheterization after Coronary Stenting in 250,350 Medicare Beneficiaries 
Patterns of non-invasive stress test (ST) and invasive coronary angiography (CA) utilization after percutaneous coronary intervention (PCI) are not well described in older populations.
Methods and Results
We linked National Cardiovascular Data Registry® CathPCI Registry® data with longitudinal Medicare claims data for 250,350 patients undergoing PCI from 2005 to 2007 and described subsequent testing and outcomes. Between 60 days post-PCI and end of follow-up (median 24 months), 49% (n=122,894) received stress testing first, 10% (n=25,512) underwent invasive CA first, and 41% (n=101,944) had no testing (NT). A number of clinical risk factors at time of index PCI were associated with decreased likelihood of downstream testing (ST or CA, p<0.05 for all), including older age (HR 0.784 per 10 year increase), male sex (HR 0.946), heart failure (HR 0.925), diabetes (HR 0.954), smoking (HR 0.804), and renal failure (HR 0.880). Fifteen percent of patients with ST first proceeded to subsequent CA within 90 days of testing (n=18,472/101,884); of these, 48% (n=8831) underwent revascularization within 90 days, compared to 53% (n=13,316) of CA first patients (p<0.0001).
In this descriptive analysis, stress testing and invasive CA were common in older patients after PCI. Paradoxically, patients with higher-risk features at baseline were less likely to undergo post-PCI testing. The revascularization yield was low on patients referred for ST after PCI, with only 9% undergoing revascularization within 90 days.
PMCID: PMC3915772  PMID: 23074343
non-invasive stress test; coronary angiography; percutaneous coronary intervention; clinical outcomes
9.  Myocardial Imaging Should Not Exclude Ischemic Heart Failure Patients From Coronary Revascularization 
Circulation. Cardiovascular imaging  2012;5(2):10.1161/CIRCIMAGING.111.964650.
PMCID: PMC3878903  PMID: 22438425
10.  Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis: Effects of Antioxidant Therapy with NADPH Oxidase Inhibition 
In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype.
Methods and Results
Mice deficient for both the LDL receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg/day orally). In vivo molecular imaging of VCAM-1, P-selectin and platelet GPIbα in the thoracic aorta was performed with targeted contrast-enhanced ultrasound (CEU) molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultra-high frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in non-treated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 wks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group.
Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion; which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.
PMCID: PMC3575135  PMID: 23239832
contrast ultrasound; microbubbles; oxidative stress; platelets
11.  The Role of Transcytolemmal Water Exchange in Magnetic Resonance Measurements of Diffuse Myocardial Fibrosis in Hypertensive Heart Disease 
The myocardial extracellular volume fraction (MECVF) has been used to detect diffuse fibrosis. Estimation of MECVF relies quantification of the T1 relaxation time after contrast enhancement, which can be sensitive to equilibrium transcytolemmal water exchange. We hypothesized that MECVF, quantified with a parsimonious 2-space water-exchange model, correlates positively with the connective tissue volume fraction (CTVF) in a rodent model of hypertensive heart disease, while the widely used analysis based on assuming fast transcytolemmal water exchange could result in a significant underestimate of MECVF.
Methods and Results
Nω–nitro-L-arginine-metyl-ester (L-NAME) or placebo was administered to 22 and 15 wild-type mice, respectively. MECVF was measured at baseline and 7-week follow-up by pre- and post-contrast T1 CMR imaging at 4.7 T, using a 2-space water-exchange model. CTVF was quantified, using Masson’s trichrome stain. L-NAME induced hypertrophy (weight-indexed LV mass 2.2±0.3 vs. 4.1±0.4 µg/g, p<0.001), and increased CTVF (8.6%±1.5 vs. 2.58%±0.6, p<0.001), compared to controls. MECVF was higher in L-NAME-treated animals (0.43±0.09 vs, 0.26±0.03, p<0.001), and correlated with CTVF and weight-indexed LV mass (r=0.842 and r=0.737 respectively, both P<0.0001). Neglecting transcytolemmal water-exchange caused a significant underestimate of MECVF changes. Ten patients with history of hypertension had significantly higher MECVF (0.446±0.063) compared to healthy controls 0.307±0.030, p<0.001).
CMR allowed detection of myocardial extracellular matrix expansion in a mouse model, and in patients with a history of hypertension. Accounting for the effects of transcytolemmal water exchange can result in a substantial difference of MECVF, compared to assuming fast transcytolemmal water exchange.
PMCID: PMC3587170  PMID: 23159497
cardiac magnetic resonance; gadolinium-DTPA; myocardial fibrosis; extracellular volume fraction; transcytolemmal; water-exchange; Nω–nitro-L-arginine-metyl-ester; mice
12.  Nanoparticle PET-CT detects rejection and immunomodulation in cardiac allografts 
Macrophages (MΦ) predominate among the inflammatory cells in rejecting allografts. These innate immune cells, in addition to allospecific T cells, can damage cardiomyocytes directly.
Methods and Results
We explored if sensitive PET/CT imaging of MΦ-avid nanoparticles detects rejection of heart allografts in mice. In addition, we employed the imaging method to follow the immunomodulatory impact of angiotensin converting enzyme inhibititor therapy (ACEi) on myeloid cells in allografts. Dextran nanoparticles were derivatized with the PET isotope copper-64 and imaged seven days after transplantation. C57/BL6 recipients of BALB/c allografts displayed robust PET signal (standard uptake value allograft, 2.8±0.3; isograft control, 1.7±0.2; p<0.05). Autoradiography and scintillation counting confirmed the in vivo findings. We then imaged the effects of ACEi (5mg/kg Enalapril). ACEi significantly decreased nanoparticle signal (p<0.05). Histology and flow cytometry showed a reduced number of myeloid cells in the graft, blood and lymph nodes, as well as diminished antigen presentation (p<0.05 versus untreated allografts). ACEi also significantly prolonged allograft survival (12 versus 7 days, p<0.0001).
Nanoparticle MΦ PET-CT detects heart transplant rejection and predicts organ survival by reporting on myeloid cells.
PMCID: PMC3734553  PMID: 23771986
heart transplantation; macrophages; imaging; PET/CT
13.  Subclinical Left Ventricular Dysfunction in Preeclamptic Women with Preserved Left Ventricular Ejection Fraction: A 2D Speckle Tracking Imaging Study 
Circulation. Cardiovascular imaging  2012;5(6):10.1161/CIRCIMAGING.112.973818.
Patients with preeclampsia are at risk for cardiovascular disease. Changes in cardiac function are subtle in preeclampsia and are difficult to quantify with conventional imaging. Strain measurements using speckle-tracking echocardiography have been used to sensitively quantify abnormalities in other disease settings.
Methods and Results
We evaluated the feasibility and sensitivity of strain imaging using speckle-tracking echocardiography in women with preeclampsia. Forty-seven women were enrolled in this pilot study and 39 were analyzed: 11 with preeclampsia, 17 without a hypertensive disorder and 11 with nonproteinuric hypertension. Echocardiographic ejection fraction and global peak longitudinal, radial and circumferential strain were measured.
Longitudinal strain was significantly worsened in women with preeclampsia compared to women without a hypertensive disorder (P=0.0009). Similar results were observed for radial strain (P=0.007) and circumferential strain (P=0.04). Women with preeclampsia also had significantly worsened longitudinal (P=0.04), radial (P=0.01) and circumferential (P=0.002) strain compared with women with nonproteinuric hypertension. Women with preeclampsia did not have a significantly different ejection fraction compared with women without a hypertensive disorder (P=0.52) and women with nonproteinuric hypertension (P=0.44).
Myocardial strain imaging using speckle tracking is more sensitive than left ventricular ejection fraction to detect differences in left ventricular systolic function in women with and without preeclampsia.
PMCID: PMC3871635  PMID: 22891044
preeclampsia; echocardiography; speckle tracking
14.  Comparison of Velocity Vector Imaging Echocardiography with Magnetic Resonance Imaging in Mouse Models of Cardiomyopathy 
Myocardial strain imaging using echocardiography can be a cost-effective method to objectively quantify ventricular wall motion but few studies have compared strain measured with echocardiography against MRI in small animals.
Methods and Results
We compared circumferential (CS) and radial strain (RS) measured with echocardiography (vector velocity imaging [VVI]) to displacement encoding with stimulated-echo (DENSE) MRI in two mouse models of cardiomyopathy. In 3 month old mice with gene targeted deficiency of cardiac myosin binding protein-C (cMyBP-C−/−, n=6) or muscle LIM protein (MLP−/−, n=6), and wild-type (WT) mice (n=8), myocardial strains were measured at three cross-sectional levels and averaged to obtain global strains. There was modest correlation between VVI and MRI measured strains, with global CS yielding stronger correlation compared to global RS (CS R2 = 0.4452 vs. RS R2 = 0.2794, both p<0.05). Overall, strain measured by VVI was more variable than MRI (p<0.05) and the limits of agreement were slightly, but not significantly (p=0.14) closer for global CS than RS. Both VVI and MRI strain measurements showed significantly lower global CS strain in the knockout groups compared to the wild-type. The VVI (but not MRI) CS strain measurements were different between the two knockout groups (−14.5 ± 3.8% vs. −6.6 ± 4.0%, cMyBP-C−/− vs. MLP−/− respectively, p<0.05).
Measurements of LV circumferential and radial strains are feasible in small animals using 2D echocardiography. VVI and MRI strain measurements correlated modestly and the agreement between the modalities tended to be greater for circumferential than radial strain. Although VVI and MRI strains were able to differentiate between wild-type and knockout mice, only global circumferential VVI strain differentiated between the two models of cardiomyopathy.
PMCID: PMC3504170  PMID: 22977126
strain; speckle-tracking echocardiography; magnetic resonance imaging
15.  Multimodality Imaging of Lower Extremity Peripheral Arterial Disease: Current Role and Future Directions 
PMCID: PMC3504350  PMID: 23169982
Peripheral arterial disease; Computed tomographic angiography; Magnetic resonance angiography; Duplex ultrasonography
16.  A Simple Echocardiographic Prediction Rule for Hemodynamics in Pulmonary Hypertension 
Pulmonary hypertension (PH) has diverse causes with heterogeneous physiology compelling distinct management. Differentiating patients with primarily elevated pulmonary vascular resistance (PVR) from those with PH predominantly due to elevated left sided filling pressure is critical.
Methods and Results
We reviewed hemodynamics, echocardiography, and clinical data for 108 patients seen at a referral PH clinic with transthoracic echocardiogram and right heart catheterization within 1 year. We derived a simple echocardiographic prediction rule to allow hemodynamic differentiation of PH due to pulmonary vascular disease (PHPVD, defined as pulmonary artery wedge pressure (PAWP) ≤ 15mmHg and PVR >3WU). Age averaged 61.3±14.8 years, μPAWP and PVR were 16.4±7.1mmHg and 6.3±4.0WU respectively, and 52 (48.1%) patients fulfilled PHPVD hemodynamic criteria. The derived prediction rule ranged from −2 to +2 with higher scores suggesting higher probability of PHPVD: +1 point for left atrial AP dimension<3.2cm; +1 for presence of a mid-systolic notch or acceleration time<80msec; −1 for lateral mitral E:e′>10; −1 for left atrial AP dimension>4.2cm. PVR increased stepwise with score (for −2, 0 and +2, μPVR were 2.5, 4.5, and 8.1WU) while the inverse was true for PAWP (corresponding μPAWP were 21.5, 16.5 and 10.4mmHg). Among subjects with complete data, the score had an AUC of 0.921 for PHPVD. A score ≥ 0 had 100% sensitivity and 69.3% positive predictive value for PHPVD, with 62.3% specificity. No patients with a negative score had PHPVD. Patients with a negative score and acceleration time >100msec had normal PVR (μPVR=1.8WU, range=0.7–3.2WU).
We present a simple echocardiographic prediction rule that accurately defines PH hemodynamics facilitates improved screening and focused clinical investigation for PH diagnosis and management.
PMCID: PMC3505751  PMID: 22914595
pulmonary heart disease; echocardiography; heart failure; hemodynamics
17.  3.0T Whole-Heart Coronary Magnetic Resonance Angiography Performed with 32-Channal Cardiac Coils: A Single Center Experience 
Whole-heart coronary MR angiography (MRA) is a promising method for non-invasive, radiation-free detection and exclusion of obstructive coronary artery disease (CAD); however, the required imaging time and robustness of the technique are not yet satisfactory. We evaluated the value of whole-heart coronary MRA at 3.0T using a 32-channal cardiac coil, which reduces image acquisition times and hence allows to increase the clinical throughput.
Methods and Results
A total of 110 consecutive patients with suspected CAD referred for clinically indicated conventional coronary angiography were included in this prospective study. 32-channel receiver coils were used for 3.0T coronary MRA data acquisition. An ECG-triggered, navigator-gated, inversion-recovery prepared, segmented gradient-echo sequence was used for image acquisition with an acceleration factor of three in the phase-encoding direction using GRAPPA reconstruction. Acquisition of coronary MRA was successfully completed in 101 of 110 (92%) patients with average imaging time of 7.0 ± 1.8 min. The sensitivity, specificity, positive and negative predictive value of coronary MRA on a patient-based analysis were 95.9% (47/49, 95% CI: 86.0% to 99.4%), 86.5% (45/52, 95% CI, 74.2% to 94.4%), 87.0% (47/54, 95% CI, 75.1% to 94.6%) and 95.7% (45/47, 95% CI, 85.4% to 99.4%), respectively.
Whole-heart coronary MRA at 3.0 T using a 32-channal cardiac coil allows high overall accuracy for detecting significant CAD with reduced imaging time. It has potential to be a robust and alternative technique for ruling out significant CAD.
Clinical Trial Registration
URL: Unique identifier: ChiCTR-DDT-07000121.
PMCID: PMC3465076  PMID: 22887689
magnetic resonance angiography; coronary arteries; 3.0 T
18.  In Vivo Noninvasive Characterization of Brown Adipose Tissue Blood Flow by Contrast Ultrasound in Mice 
Interventions to increase brown adipose tissue (BAT) volume and activation are being extensively investigated as therapies to decrease the body weight in obese subjects. Noninvasive methods to monitor these therapies in animal models and humans are rare. We investigated whether contrast ultrasound (CU) performed in mice could detect BAT and measure its activation by monitoring BAT blood flow. After validation, CU was used to study the role of uncoupling protein 1 (UCP1) and nitric oxide synthases in the acute regulation of BAT blood flow.
Methods and Results
Blood flow of interscapular BAT was assessed in mice (n=64) with CU by measuring the signal intensity of continuously infused contrast microbubbles. Blood flow of BAT estimated by CU was 0.5±0.1 (mean±SEM) dB/s at baseline and increased 15-fold during BAT stimulation by norepinephrine (NE, 1 μg·kg−1·min−1). Assessment of BAT blood flow using CU was correlated to that performed with fluorescent microspheres (R2=0.86, p<0.001). To evaluate whether intact BAT activation is required to increase BAT blood flow, CU was performed in UCP1-deficient (UCP1−/−) mice with impaired BAT activation. Norepinephrine infusion induced a smaller increase in BAT blood flow in UCP1−/− mice than in wild-type mice. Finally, we investigated whether NOS played a role in acute NE-induced changes of BAT blood flow. Genetic and pharmacologic inhibition of NOS3 attenuated the NE-induced increase in BAT blood flow.
These results indicate that CU can detect BAT in mice, and estimate BAT blood flow in mice with functional differences in BAT.
PMCID: PMC3471995  PMID: 22776888
brown adipose tissue; imaging; contrast ultrasound; uncoupling protein; nitric oxide synthase
19.  Quantifying Pulmonary Regurgitation and Right Ventricular Function in Surgically Repaired Tetralogy of Fallot: A Comparative Analysis of Echocardiography and Magnetic Resonance Imaging 
Patients with repaired tetralogy of Fallot (TOF) are monitored for pulmonary regurgitation (PR), and right ventricular (RV) function. We sought to compare measures of PR and RV function on echocardiogram to those on cardiac magnetic resonance (CMR), and to develop a new tool for assessing PR by echocardiogram.
Methods and Results
Patients with repaired TOF (N=143, 12.5± 3.2 years) had an echocardiogram and CMR within three months of each other. On echocardiogram, RV function was assessed by (1) Doppler tissue imaging of the RV free wall, and (2) myocardial performance index (MPI). The ratio of diastolic and systolic time-velocity integrals (DSTVI) measured by Doppler of the main pulmonary artery was calculated. CMR variables included RV ejection fraction (EF), RV volumes, and pulmonary regurgitant fraction (RF). Pulmonary regurgitation was graded as mild (RF <20%), moderate (RF=20–40%), and severe (RF>40%). On CMR, RF was 34±17% and RV EF was 61±8%. Echocardiography had good sensitivity identifying cases with RF>20% (sensitivity 97%, 95% CI: 92–99%) but overestimated the amount of PR when RF<20% (false positive rate 36%, 95% CI: 18–57%). The DSTVI on echocardiogram showed moderate correlation with RF on CMR (R=0.60, P<0.0001). On CMR, RF of 20% and 40% corresponded with a DSTVI of 0.49 (95% CI: 0.44–0.56), and 0.72 (95% CI: 0.68–0.76), respectively. RV MPI correlated modestly with RV EF (r=−0.33, P<0.001).
This study suggests that the DSTVI ratio may make a modest contribution to the overall assessment of PR in patients with repaired TOF and warrants further investigation. However, echocardiography continues to have a limited ability to quantify PR and RV function as compared to CMR.
PMCID: PMC3476467  PMID: 22869820
echocardiography; regurgitation; tetralogy of Fallot
20.  Cells and Iron Oxide Nanoparticles on the Move: MRI of Monocyte Homing and Myocardial Inflammation in Patients with ST Elevation Myocardial Infarction 
PMCID: PMC3529959  PMID: 22991284
MRI; molecular imaging; myocardial infarction; inflammation; iron oxide nanoparticles
22.  Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients Treated With Anthracyclines, Taxanes, and Trastuzumab 
Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab.
Methods and Results
Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure.
In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.
PMCID: PMC3703313  PMID: 22744937
chemotherapy; echocardiography; biomarkers; left ventricular function; heart failure; trastuzumab
23.  Myocardial Alterations in Senescent Mice and Effect of Exercise Training A Strain Rate Imaging Study 
Aging is accompanied by an alteration in myocardial contractility. However, its noninvasive detection is difficult. The effect of chronic exercise on this decrease is unknown. Murine models of senescence are increasingly used to test therapies in aging. We tested whether strain rate imaging detected left ventricular (LV) systolic dysfunction in aging mice and was able to assess a potential improvement after exercise.
Methods and Results
Young (3 weeks), adult (2 to 3 months), and old (6 to 18 months) C57BL6 male mice underwent echocardiograms with strain rate imaging, either in sedentary conditions or before, 2 weeks and 4 weeks after chronic swimming. Hemodynamic parameters of LV function including maximal and end-systolic elastance were obtained before euthanizing. LV fibrosis was measured using Sirius red staining. Conventional echocardiography was unable to detect LV systolic dysfunction in old mice, whereas both systolic strain rate and load-independent hemodynamic parameters such as preload recruitable stroke work and end-systolic elastance were significantly decreased. Both strain rate and load-independent hemodynamic parameters normalized after 4 weeks of exercise. Both endocardial and epicardial fibrosis were increased in the LV of aging mice. Endocardial fibrosis decreased in exercised aged mice.
Strain rate noninvasively detects LV systolic dysfunction associated with aging in mice, whereas conventional echocardiography does not. Chronic exercise normalizes LV systolic function and decreases fibrosis in old mice. Strain rate imaging in mice may be a useful tool to monitor the effect of new therapeutic strategies preventing the myocardial dysfunction associated with aging.
PMCID: PMC3754845  PMID: 19808547
aging; echocardiography; exercise
24.  A Prospective Pilot Study to Evaluate the Relationship Between Acute Change in Left Ventricular Synchrony After Cardiac Resynchronization Therapy and Patient Outcome Using a Single-Injection Gated SPECT Protocol 
There are ongoing efforts to optimize patient selection criteria for cardiac resynchronization therapy (CRT). In this regard, the relationship between acute change in left ventricular synchrony (LV) after CRT and patient outcome remains undefined.
Methods and Results
A novel protocol was designed to evaluate acute change in left LV synchrony after CRT using phase analysis of standard gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging with a single injection of radiotracer and prospectively applied to 44 patients undergoing CRT. Immediately after CRT, 18 (41%), 11 (25%), and 15 (34%) patients had an improvement, no change, or a worsening in LV synchrony. An algorithm incorporating the presence of baseline dyssynchrony, myocardial scar burden, and lead concordance predicted acute improvement or no change in LV synchrony with 72% sensitivity, 93% specificity, 96% positive predictive value, and 64% negative predictive value and had 96% negative predictive value for acute deterioration in synchrony. Over a follow-up period of 9.6±6.8 months, patients who had an acute deterioration in synchrony after CRT had a higher composite event rate of death, heart failure hospitalizations, appropriate defibrillator discharges, and CRT device deactivation for worsening heart failure symptoms, compared with patients who had an improvement or no change [hazard ratio, 4.6 (1.3 to 16.0); log rank test; P=0.003].
In this single-center pilot study, phase analysis of gated SPECT was successfully used to predict acute change in LV synchrony and patient outcome after CRT.
PMCID: PMC3717147  PMID: 21772007
cardiac resynchronization therapy; dyssynchrony; phase analysis; single-photon emission computed tomography
25.  Early Stem Cell Engraftment Predicts Late Cardiac Functional Recovery: Pre-Clinical Insights from Molecular Imaging 
Human cardiac progenitor cells have demonstrated great potential for myocardial repair in small and large animals, but robust methods for longitudinal assessment of their engraftment in humans is not yet readily available. In this study, we sought to optimize and evaluate the use of positron emission tomography (PET) reporter gene imaging for monitoring human cardiac progenitor cell (hCPC) transplantation in a mouse model of myocardial infarction.
Methods & Results
hCPCs were isolated and expanded from human myocardial samples and stably transduced with variations of the thymidine kinase (TK) PET reporter gene. TK-expressing hCPCs were characterized in vitro and transplanted into murine myocardial infarction models (n=60). Cardiac echocardiographic, magnetic resonance imaging (MRI), and pressure-volume (PV) loop analyses revealed improvement in left ventricular contractile function two weeks after transplant (hCPC vs. PBS, P<0.03). Noninvasive PET imaging was used to track hCPC fate over a four week time period, demonstrating a substantial decline in surviving cells. Importantly, early cell engraftment as assessed by PET was found to predict subsequent functional improvement, implying a “dose-effect” relationship. We isolated the transplanted cells from recipient myocardium by laser capture microdissection for in vivo transcriptome analysis. Our results provide direct evidence that hCPCs augment cardiac function after their transplantation into ischemic myocardium through paracrine secretion of growth factors.
PET reporter gene imaging can provide important diagnostic and prognostic information regarding the ultimate success of human cardiac progenitor cell treatment for myocardial infarction.
PMCID: PMC3400712  PMID: 22565608
cell therapy; stem cells; imaging; positron emission tomography

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