Potential of non-contrast stress T1 mapping for the assessment of myocardial injury in hypertrophic cardiomyopathy.

BACKGROUND: Ischemia of the hypertrophied myocardium due to microvascular dysfunction is related to a worse prognosis in hypertrophic cardiomyopathy (HCM). Stress and rest T1 mapping without contrast agents can be used to assess myocardial blood flow. Herein, we evaluated the potential of non-contrast stress T1 mapping in assessing myocardial injury in patients with HCM. METHODS: Forty-five consecutive subjects (31 HCM patients and 14 control subjects) underwent cardiac magnetic resonance (CMR) at 3T, including cine imaging, T1 mapping at rest and during adenosine triphosphate (ATP) stress, late gadolinium enhancement (LGE), and phase-contrast (PC) cine imaging of coronary sinus flow at rest and during stress to assess coronary flow reserve (CFR). PC cine imaging was performed on 25 subjects (17 patients with HCM and 8 control subjects). Native T1 values at rest and during stress were measured using the 16-segment model, and T1 reactivity was defined as the change in T1 values from rest to stress. RESULTS: ATP stress induced a significant increase in native T1 values in both the HCM and control groups (HCM: p < 0.001, control: p = 0.002). T1 reactivity in the HCM group was significantly lower than that in the control group (4.2 ± 0.3% vs. 5.6 ± 0.5%, p = 0.044). On univariate analysis, T1 reactivity correlated with native T1 values at rest, left ventricular mass index, and CFR. Multiple linear regression analysis demonstrated that only CFR was independently correlated with T1 reactivity (ß = 0.449; 95% confidence interval, 0.048-0.932; p = 0.032). Furthermore, segmental analysis showed decreased T1 reactivity in the hypertrophied myocardium and the non-hypertrophied myocardium with LGE in the HCM group. CONCLUSIONS: T1 reactivity was lower in the hypertrophied myocardium and LGE-positive myocardium compared to non-injured myocardium. Non-contrast stress T1 mapping is a promising CMR method for assessing myocardial injury in patients with HCM. Trial registration Retrospectively registered.

Detection of Carotid Artery Stenosis with Intraplaque Hemorrhage and Neovascularization Using a Scanning Interferometer.

Carotid artery stenosis (CAS) is a major cause of stroke or transient ischemic attack (TIA, mini-stroke) in the United States. Carotid endarterectomy (CEA), a surgical procedure, is used to treat CAS. According to the American Heart Association, 1 out of 5 patients underwent CEA inappropriately, which was most commonly due to apparent overestimation of stenosis severity, and half had uncertain indicators. The current imaging modalities are limited in providing critical information on carotid arterial plaque content, extent, and biology. To circumvent these limitations, we developed a sensing interferometer (SI) imaging system to assess vulnerable carotid plaques noninvasively to detect stenosis, neovascularization, and intraplaque hemorrhage (IPH). We have custom-built a SI prototype and its peripheral systems with back-mode-projection capability. We detected stenosis, neo-vessels, and IPH through SI imaging system in in vivo mice carotid atherosclerotic plaques and further verified the same plaques ex vivo through a histology scope, CRi Maestro, and histological analysis.

Ultra-selective carbon nanotubes for photoacoustic imaging of inflamed atherosclerotic plaques.

Disruption of vulnerable atherosclerotic plaques often leads to myocardial infarction and stroke, the leading causes of morbidity and mortality in the United States. A diagnostic method that detects high-risk atherosclerotic plaques at early stages could prevent these sequelae. The abundance of immune cells in the arterial wall, especially inflammatory Ly-6Chi monocytes and foamy macrophages, is indicative of plaque inflammation, and may be associated with plaque vulnerability. Hence, we sought to develop a new method that specifically targets these immune cells to offer clinically-relevant diagnostic information about cardiovascular disease. We combine ultra-selective nanoparticle targeting of Ly-6Chi monocytes and foamy macrophages with clinically-viable photoacoustic imaging (PAI) in order to precisely and specifically image inflamed plaques ex vivo in a mouse model that mimics human vulnerable plaques histopathologically. Within the plaques, high-dimensional single-cell flow cytometry (13-parameter) showed that our nanoparticles were almost-exclusively taken up by the Ly-6Chi monocytes and foamy macrophages that heavily infiltrate plaques. PAI identified inflamed atherosclerotic plaques that display ~6-fold greater signal compared to controls (P<0.001) six hours after intravenous injection of ultra-selective carbon nanotubes, with in vivo corroboration via optical imaging. Our highly selective strategy may provide a targeted, non-invasive imaging strategy to accurately identify and diagnose inflamed atherosclerotic lesions.

In vivostudy of iron oxide-calcium phosphate composite nanoparticles for delivery to atherosclerosis.

Atherosclerosis is a macrophage-related inflammatory disease that remains a leading cause of death worldwide. Magnetic iron oxide (IO) nanocrystals are clinically used as magnetic resonance imaging contrast agents and their application as a detection agent for macrophages in arterial lesions has been studied extensively. We recently fabricated heparin-modified calcium phosphate (CaP) nanoparticles loaded with a large number of IO nanocrystals via coprecipitation from a supersaturated CaP solution supplemented with heparin and ferucarbotran (IO nanocrystals coated with carboxydextran). In this study, we further increased the content of IO nanocrystals in the heparin-modified IO-CaP composite nanoparticles by increasing the ferucarbotran concentration in the supersaturated CaP solution. The increase in nanoparticle IO content caused a decrease in particle diameter without impairing its dispersibility; the nanoparticles remained dispersed in water for up to 2 h due to electrostatic repulsion between particles due to the surface modification with heparin. The nanoparticles were more effectively taken up by murine RAW264.7 macrophages compared to free ferucarbotran without showing significant cytotoxicity. A preliminaryin vivostudy showed that the nanoparticles injected intravenously into mice delivered more IO nanocrystals to macrophage-rich carotid arterial lesions than free ferucarbotran. Our nanoparticles have potential as a delivery agent of IO nanocrystals to macrophages in arterial lesions.

Myocardial perfusion reserve quantified by cardiac magnetic resonance imaging is associated with late gadolinium enhancement in hypertrophic cardiomyopathy.

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging has demonstrated the capability of stratifying hypertrophic cardiomyopathy (HCM). Stress perfusion test of CMR can quantify myocardial perfusion reserve (MPR), but its clinical role is not determined. The purpose of this study was to investigate the relationship between MPR and LGE in patients with HCM. A total of 61 consecutive cases underwent complete evaluation with electrocardiography and CMR [cine imaging, coronary MR angiography (MRA), and stress perfusion testing with LGE]. HCM cases were diagnosed by the Japanese conventional guideline prior to this CMR study. Mild LVH was defined as more than 13 mm in maximum LV wall thickness at end diastole on the cine imaging of the CMR. MPR was calculated as the ratio of stress/rest myocardial blood flow using an intensity curve on the stress perfusion test. Cases with ischemic heart disease were excluded from the study based on clinical history and coronary MRA. There were 37 HCM and 24 mild LVH cases (average age: 60.5 ± 10.9 vs. 64.8 ± 10.8; male: 62.2 vs. 75.0%, respectively, non-significant). MPR in HCM was lower than in LVH (1.5 ± 0.5 vs. 2.2 ± 0.9, p < 0.001) and normal subjects (2.4 ± 0.9, p < 0.001). MPR in HCM with LGE (N = 34) was lower than in HCM without LGE (N = 3) (1.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.014). Multiple regression analysis verified that LGE was the strongest predictor of MPR among multiple clinical parameters, including LVH, LV dysfunction (ejection fraction < 50%), and the presence of negative T wave (p < 0.001). MPR was impaired in HCM with LGE compared with HCM without LGE. The clinical role of MPR on CMR needs to be clarified by further research.

RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm.

PURPOSE: To evaluate Arg-Gly-Asp (RGD)-conjugated human ferritin (HFn) iron oxide nanoparticles for in vivo magnetic resonance imaging (MRI) of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: HFn was genetically engineered to express the RGD peptide and Fe3 O4 nanoparticles were chemically synthesized inside the engineered HFn (RGD-HFn). Macrophage-rich left carotid lesions were induced by ligation in FVB mice made hyperlipidemic and diabetic (n = 14), with the contralateral right carotid serving as control. Murine AAAs were created by continuous angiotensin II infusion in ApoE-deficient mice (n = 12), while control mice underwent saline infusion (n = 8). All mice were imaged before and after intravenous injection with either RGD-HFn-Fe3 O4 or HFn-Fe3 O4 using a gradient-echo sequence on a whole-body 3T clinical scanner, followed by histological analysis. The nanoparticle accumulation was assessed by the extent of T2*-induced carotid lumen reduction (% lumen loss) or aortic T2*-weighted signal intensity reduction (% SI [signal intensity] loss). RESULTS: RGD-HFn-Fe3 O4 was taken up more than HFn-Fe3 O4 in both the ligated left carotid arteries (% lumen loss; 69 ± 9% vs. 36 ± 7%, P = 0.01) and AAAs (% SI loss; 47 ± 6% vs. 20 ± 5%, P = 0.01). The AAA % SI loss correlated positively with AAA size (r = 0.89, P < 0.001). Histology confirmed the greater accumulation and colocalization of RGD-HFn-Fe3 O4 to both vascular macrophages and endothelial cells. CONCLUSION: RGD-HFn-Fe3 O4 enhances in vivo MRI by targeting both vascular inflammation and angiogenesis, and provides a promising translatable MRI approach to detect high-risk atherosclerotic and aneurysmal vascular diseases. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1144-1153.

Characterizing Cathepsin Activity and Macrophage Subtypes in Excised Human Carotid Plaques.

BACKGROUND AND PURPOSE: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo. METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes. RESULTS: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU). CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction.

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging.

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant.

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Bioluminescence and magnetic resonance imaging of macrophage homing to experimental abdominal aortic aneurysms.

Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n  =  32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n  =  13) at day 14 demonstrated T2* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.

Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma.

Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+)) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+). Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+).

Performance of Hybrid Imaging in the Diagnosis of Coronary Artery Disease.

Single-photon emission computed tomography (SPECT) and computed tomography coronary angiography (CTCA) are usually performed independently in patients with suspected coronary artery disease. We assessed the hypothesis that hybrid SPECT/CTCA imaging results in higher diagnostic accuracy than either method alone, particularly in cases presenting with high levels of coronary calcification. A total of 243 major coronary vessels in 81 patients with known or suspected coronary artery disease were screened using SPECT with semiconductor detectors and CTCA with 256-detector row computed tomography. Patients who were diagnosed with myocardial ischemia underwent coronary angiography. Coronary angiography results were defined as positive for stenosis when the stenosis diameter was >70% or fractional flow reserve was <0.8. These data were then compared with a fused image of the SPECT and CTCA datasets generated using a dedicated workstation. To detect significant coronary artery stenosis, the respective sensitivity, specificity, and accuracy were 73%, 61%, and 67% with SPECT alone, 96%, 44%, and 67% with CTCA alone, and 95%, 75%, and 84% with hybrid imaging. Moreover, hybrid imaging allowed the accurate diagnosis of 47 vessels with severe calcification that CTCA alone could not evaluate correctly. Hybrid imaging shows greater diagnostic accuracy than single-modality evaluation through more comprehensive information on potential coronary stenosis and its hemodynamic significance.

Pathogenic variant of RBM20 in a multiplex family with hypertrophic cardiomyopathy.

RBM20 is a disease-causing gene associated with dilated cardiomyopathy (DCM). The proband presented with the dilated phase of hypertrophic cardiomyopathy (HCM), and the mother also suffered from HCM. A missense variant of RBM20, p.Arg636His, previously reported as pathogenic in several families with DCM, was found in both the proband and the mother. Therefore, RBM20 p.Arg636His could be the causative variant for this familial HCM, and RBM20 might be a novel causative gene for HCM.

Potential of Gold Nanoparticles for Noninvasive Imaging and Therapy for Vascular Inflammation.

PURPOSE: Macrophages contribute to the progression of vascular inflammation, making them useful targets for imaging and treatment of vascular diseases. Gold nanoparticles (GNPs) are useful as computed tomography (CT) contrast agents and light absorbers in photothermal therapy. In this study, we aimed to assess the viability of macrophages incubated with GNPs after near-infrared (NIR) laser light exposure and to evaluate the utility of intravenously injected GNPs for in vivo imaging of vascular inflammation in mice using micro-CT. PROCEDURES: Mouse macrophage cells (RAW 264.7) were incubated with GNPs and assessed for GNP cellular uptake and cell viability before and after exposure to NIR laser light. For in vivo imaging, macrophage-rich atherosclerotic lesions were induced by carotid ligation in hyperlipidemic and diabetic FVB mice (n = 9). Abdominal aortic aneurysms (AAAs) were created by angiotensin II infusion in ApoE-deficient mice (n = 9). These mice were scanned with a micro-CT imaging system before and after the intravenous injection of GNPs. RESULTS: The CT attenuation values of macrophages incubated with GNPs were significantly higher than those of cells incubated without GNPs (p < 0.04). Macrophages incubated with and without GNPs showed similar viability. The viability of macrophages incubated with GNPs (100 µg/ml or 200 µg/ml) was decreased by high-intensity NIR laser exposure but not by low-intensity NIR laser exposure. In vivo CT images showed higher CT attenuation values in diseased carotid arteries than in non-diseased contralateral arteries, although the difference was not statistically significant. The CT attenuation values of the perivascular area in AAAs of mice injected with GNPs were significantly higher than those of mice without injection (p = 0.0001). CONCLUSIONS: Macrophages with GNPs had reduced viability upon NIR laser exposure. GNPs intravenously injected into mice accumulated in sites of vascular inflammation, allowing detection of carotid atherosclerosis and AAAs in CT imaging. Thus, GNPs have potential as multifunctional biologically compatible particles for the detection and therapy of vascular inflammation.

Expert Consensus on the Clinical Use of Pulse Wave Velocity in Asia.

Arterial stiffness is a progressive aging process that predicts cardiovascular disease. Pulse wave velocity (PWV) has emerged as a noninvasive, valid, and reliable measure of arterial stiffness and an independent risk predictor for adverse outcomes. However, up to now, PWV measurement has mostly been used as a tool for risk prediction and has not been widely used in clinical practice. This consensus paper aims to discuss multiple PWV measurements currently available in Asia and to provide evidence-based assessment together with recommendations on the clinical use of PWV. For the methodology, PWV measurement including the central elastic artery is essential and measurements including both the central elastic and peripheral muscular arteries, such as brachial-ankle PWV and cardio-ankle vascular index, can be a good alternative. As Asian populations are rapidly aging, timely detection and intervention of "early vascular aging" in terms of abnormally high PWV values are recommended. More evidence is needed to determine if a PWV-guided therapeutic approach will be beneficial to the prevention of cardiovascular diseases beyond current strategies. Large-scale randomized controlled intervention studies are needed to guide clinicians.

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma.

Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-γ agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-γ antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor ß-1 (TGF-ß1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-γ and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-γ and TIMP-1, and inhibition of TGF-ß1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-γ activation were suggested to be important in addition to suppression of Ang II activity.

In vivo molecular MRI of cell survival and teratoma formation following embryonic stem cell transplantation into the injured murine myocardium.

Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO-conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO-MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium.