Background— Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the makeup and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored. Methods and Results— Patients (n=15; 3 women), recruited after successful percutaneous coronary intervention for first segment–elevation myocardial infarction, underwent cardiovascular magnetic resonance imaging on day 3 and month 6 after percutaneous coronary intervention. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* cardiovascular magnetic resonance on day 3 (n=11), showed persistent T2* losses colocalized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than nonhemorrhagic (Hemo−) and remote territories ( P <0.001); however, T2* values of nonhemorrhagic (Hemo−) and remote territories were not different ( P =0.51). Canines (n=20) subjected to ischemia-reperfusion injury (n=14) underwent cardiovascular magnetic resonance on days 3 and 56 after ischemia-reperfusion injury. Similarly, sham-operated animals (Shams; n=3) were imaged using cardiovascular magnetic resonance at similar time points. Subsequently, hearts were explanted and imaged ex vivo, and samples of Hemo+, Hemo−, remote, and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared with the other (control) groups ( P <0.001), and Perls stain confirmed localized iron deposition. Mean [Fe] of Hemo+ was nearly an order of magnitude greater than that of the control groups ( P <0.001), but no significant differences were observed among the control groups. A strong linear relationship was observed between log(T2*) and −log([Fe]); R 2 =0.7 and P <0.001. The monoclonal antibody Mac387 stains, along with Perls stains, showed preferential localization of newly recruited macrophages at the site of chronic iron deposition. Conclusions— Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in the chronic phase of myocardial infarction.

Background We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and anti-oxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe) deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis but the potential effects of IGF-1 on their function are unknown. Methods and Results To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/ macrophage specific IGF1R knockout (MΦ-IGF1R-KO) mice on Apoe−/− background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil-red-O staining of en face aortae and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses upon stimulation by IFNγ and oxidized LDL and elevated antioxidant gene expression levels. Moreover, IGF1R deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux. Conclusions Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts anti-atherogenic effects.

Purpose:To evaluate T2 and T2* changes in acute reperfused hemorrhagic and nonhemorrhagic myocardial infarctions and to determine which technique is more suitable in the detection of intramyocardial hemorrhage at 1.5 T. Materials and Methods:Patient studies were approved by the institutional review board and were HIPAA compliant. Patients (n = 14, three women) with first ST-elevation myocardial infarction underwent cardiac magnetic resonance (MR) imaging 3 days after angioplasty. T2* maps, T2 short inversion time inversion-recovery (STIR) images, and late gadolinium enhancement (LGE) images were acquired. Animal studies were approved by the institutional animal care and use committee. Canines (n = 20) were subjected to ischemia-reperfusion injury, and cardiac MR imaging was performed 5 days after reperfusion. T2* and T2 maps and T2 STIR and LGE images were acquired. Repeated-measures analysis of variance or the Friedman test was used to compare T2 and T2* changes in patients with hemorrhagic infarctions and those with nonhemorrhagic infarctions. Results:Relative to remote myocardium, mean T2* of hemorrhagic infarctions was 54% 6 13 (standard deviation) lower in patients (15.9 msec 6 4.5 vs 35.2 msec 6 2.1, P , .001) and 40% 6 10 lower in canines (23.0 msec 6 4.0 vs 39.3 msec 6 2.5, P , .001). Mean T2* of nonhemorrhagic infarctions was marginally elevated by 6% 6 2.5 (37.8 msec 6 2.5, P = .021) in patients and by 8% 6 5 (44.6 msec 6 4.8, P = .012) in canines. In contrast, mean T2 STIR signal intensity (SI) of both hemorrhagic infarctions and nonhemorrhagic infarctions was higher than that in remote myocardium both in patients (hemorrhagic: 37% 6 19, P , .001; nonhemorrhagic: 78% 6 27, P , .001) and in canines (hemorrhagic: 42% 6 22, P , .001; nonhemorrhagic: 65% 6 22, P , .001). Consistent with STIR SI findings, mean T2 of both hemorrhagic (62.0 msec 6 4.9) and nonhemorrhagic (71.7 msec 6 7.3) infarctions in canines was elevated relative to mean T2 of remote myocardium (52.1 msec 6 4.8) by 18% 6 9 and 38% 6 13, respectively (P , .001 for both). Conclusion

Purpose:To examine the dependence of steady-state freeprecession (SSFP) -based myocardial blood-oxygen-leveldependent (BOLD) contrast on field strength using theoretical and experimental models. Materials and Methods:Numerical simulations using a two-pool exchange model and a surgically prepared dog model were used to assess the SSFP-based myocardial BOLD signal changes at 1.5T and 3.0T. Experimental studies were performed in eight canines with pharmacological vasodilation under various levels of left circumflex coronary artery stenosis. Experimentally obtained BOLD signal changes were correlated against microsphere-based true flow changes. Results:Theoretical results showed that, at 3.0T, relative to 1.5T, a threefold increase in oxygen sensitivity can be expected. Experimental studies in canines showed near similar results-a 2.5 Ϯ 0.2-fold increase in BOLD sensitivity at 3.0T relative to 1.5T (P Ͻ 0.05). Based on the scatter gram of BOLD data and microsphere data, it was found that the minimum regional flow difference that can be detected with SSFP-based myocardial BOLD imaging at 1.5T and 3.0T were 2.9 and 1.6, respectively (P Ͻ 0.05). Conclusion:This study demonstrated that SSFP-based myocardial BOLD sensitivity is substantially greater at 3.0T compared with 1.5T. The findings here suggest that SSFP-based myocardial BOLD imaging at 3.0T may have the necessary sensitivity to detect the clinically required minimum flow difference of 2.0.

Background LGE CMR is a powerful method for characterizing MI, but the requisite gadolinium infusion is estimated to be contraindicated in nearly 20% of MI patients due to end-stage chronic kidney disease. The purpose of this study is to investigate whether T1 Cardiovascular-Magnetic-Resonance Imaging (CMR) obtained without contrast agents at 3T could be an alternative to Late-Gadolinium-Enhanced (LGE) CMR for characterizing chronic myocardial infarctions (MIs) using a canine model of MI. Methods and Results Canines (n=29) underwent CMR at 7 days (acute, AMI) and 4 months (chronic, CMI) post-MI. Infarct location, size and transmurality measured using native T1 maps and LGE images at 1.5T and 3T were compared. Resolution of edema between AMI and CMI was examined with T2 maps. T1 maps overestimated infarct size and transmurality relative to LGE images in AMI (p=0.016 and p=0.007, respectively), which was not observed in CMI (p=0.49 and p=0.81, respectively), at 3T. T1 maps underestimated infarct size and transmurality relative to LGE images in AMI and CMI (p<0.001), at 1.5T. Relative to the remote territories, T1 of the infarcted myocardium was increased in CMI and AMI (p<0.05); and T2 of the infarcted myocardium was increased in AMI (p<0.001), but not in CMI (p >0.20) at both field strengths. Histology showed extensive replacement fibrosis within the CMI territories. CMI detection sensitivity and specificity of T1 CMR at 3T were 95% and 97%, respectively. Conclusions Native T1 maps at 3T can determine the location, size and transmurality of CMI with high diagnostic accuracy. Patient studies are necessary for clinical translation.

Background 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). Conclusions 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.

Therapeutics based on transcription factors have the potential to revolutionize medicine but have had limited clinical success due to delivery problems1–4. The delivery of transcription factors is challenging because it requires developing a delivery vehicle that can complex transcription factors, target cells, and stimulate endosomal disruption, with minimal toxicity5,6. In this report we present a novel multifunctional oligonucleotide, termed DARTs (DNA Assembled Recombinant Transcription factors), which can deliver transcription factors with high efficiency in vivo. DARTs are composed of an oligonucleotide that contains a transcription factor binding sequence and hydrophobic membrane disruptive chains that are masked by acid cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to bind transcription factors, trigger endocytosis in hepatocytes, and stimulate endosomal disruption. The DARTs target hepatocytes as a result of the galactose residues and can disrupt endosomes efficiently with minimal toxicity, because unmasking of their hydrophobic domains selectively occurs in the acidic environment of the endosome. We show here that DARTs can deliver the transcription factor Nuclear erythroid 2-related factor 2 (Nrf2) to the liver, catalyze the transcription of Nrf2 downstream genes, and rescue mice from acetaminophen induced liver injury.

Magnetic resonance (MR) images of coronary arteries were acquired with an inversion recovery-prepared technique after intraarterial injection of contrast material in five dogs. Real-time two-dimensional projection images were obtained with a temporal resolution of 3 frames per second. Three-dimensional electrocardiographically triggered high-spatial-resolution images were obtained with a fraction of the contrast agent required for intravenous injections. Background tissues were adequately suppressed in all images. On the basis of this experimental data, the optimal contrast agent concentration for two-dimensional real-time projection imaging was 6%. This preliminary work shows that contrast material-enhanced MR angiography with intraarterial injections is feasible with the proposed techniques.