t.

Figure 3. In-vivo quantification of the infarct size by late-Gadolilium enhancement (LGE) and first-pass myocardial perfusion of an untreated IRI heart ((A)-(C)) and an Intralipid®-treated IRI heart ((D)-(F)) taken prior to Gd contrast ((A), (D)), 43 sec after a single Gd bolus injection, and ((C), (F)) 16-min post-Gd bolus. The white arrowheads point to the area with IRI. The white tab in (B) points to the infarct core. LV: left-ventricle; RV: right ventricle. (G) Infarct size quantified by the percentage of LV area with LGE of the untreated IRI hearts (striped bar, n = 13) and the Intralipid®-treated IRI hearts (black bar, n = 16).

3.3. Ex-Vivo MRM

The hearts were harvested at the end-point of the study for high-resolution ex-vivo MRM (Figure 5). At this imaging resolution, single MPIO-labeled MØs can be visualized as individually resolved dark spots [16] . All hearts examined showed low-level sparse distribution of dark spots throughout the heart, which are non-specific background infiltration of MPIO-labeled MØs. This sparse background infiltration of MØs may function as a surveillance for inflammation. In addition to this background of sparse infiltration, the untreated heart (Figure 5(A)) showed concentrated hypointensity in the ischemic site, which is composed of individual dark spots, as well as dark streaks. Individual dark spots are MPIO-labeled MØs [16] infiltrated in the ischemic site, whereas the dark streaks are likely to be hemorrhage in the infarct core. On the other hand, Intralipid®-treated IRI hearts showed reduced hypointensity. In the example shown in Figure 5(B), both infiltration of MPIO-labeled MØs and hemorrhage in

Figure 4. In-vivo cellular MRI of IRI hearts 2 days after a transient ischemic injury and in-vivo MPIO labeling of the untreated animals ((A)-(C)) and the Intralipid®-treated animals ((D)-(F)). White arrowheads point to the areas with IRI injury. The -weighted images were acquired at 7-Tesla with 156-μm in-plane resolution. (G) Percentage of areas with hypointensity in myocardium for untreated IRI animals (striped bars) or Intralipid®-treated IRI animals (black bars) on the day of ischemic insult (day 0) or 1 to 5 days after IRI (<1 wk). Animal numbers included in the study were 14 for the untreated group and 7 for the Intralipid®-treated for the “day 0” groups. 19 untreated animals and 6 Intralipid®-treated animals were included for the “<1 wk” group.

Figure 5. Ex-vivo MR microscopy (MRM) of the hearts harvested 2 days after a transient ischemic injury and in-vivo MPIO labeling of an untreated animal (A) or an Intralipid®-treated animal (B). MRM is acquired with 36-μm isotropic resolution at 11.7 T.

the infarct core are reduced.

3.4. Pathological Examination

Figure 6 shows the pathology images of the untreated (Figures 6(A)-(D)) and Intralipid®-treated group (Figures 6(E)-(H)). The untreated group presents a substantial increase of the immune cells in the ischemic myocardium. Figure 6(A) shows the cell-density distribution of the tissue sections on the H&E slide. The distribution reveals a prominent increase of the cell density at the ischemic injury region in the sham group. Figure 6(B) shows the distribution of ED1+ MØs of the same animal. The distribution also reveals a prominent increase of the MØ infiltration in the ischemic tissue. Figure 6(C) illustrates a view in the H&E slide, showing the infiltration of immune cells in the myocardium. The immunohistochemistry shown in Figure 6(D) confirms that the infiltrating cells are ED1+ MØs. The Intralipid® group also presents an increase of the immune cells in the ischemic myocardium, but the cell density is substantially less than the sham group. Figure 6(E) shows the cell-density distribution of the tissue sections on the H&E slide, whereas Figure 6(F) shows the distribution of ED1+ MØs of the same animal. The density of the infiltrating cells is substantially less than the sham group. Figure 6(G) illustrates a view in the H&E slide, whereas Figure 6(H) illustrates a view in the ED1+ stain slides. The density of the immune cells is less than the sham group, suggesting that Intralipid® reduces the amount of MØs infiltrating into the ischemic myocardium.

Figure 6. MR pathology images comparing the cell distribution of the myocardium in the sham and Intralipid®-treated group: (A) the cell density in the H&E-slide of a sham animal shows a prominent increase of cell density due to ischemic injury by WSI; (B) the ED1+ MØ distribution of the same sham animal shows the spatial distribution of the infiltrating MØ in the ischemic myocardium by WSI; (C) the H&E image of the myocardium of the sham animal illustrates the infiltrating cells; (D) the immune-stain image confirms that the infiltrating cells are ED1+ MØ; (E) the cell density in the H&E-slide of an Intralipid®-treated animal shows less density than the sham animal by WSI; (F) the ED1+ MØ distribution of the same animal also shows fewer MØs in the ischemic myocardium by WSI; (G) the H&E image of the Intralipid®-treated animal shows fewer cells than the shame group; and (H) the immuno-staining image shows less ED1+ MØs of the Intralipid®-treated animal.

One limitation of the cellular MRI is that both hemorrhage and MPIO-labeled MØs show hypointensity in -weighted MRI. We cannot distinguish the blood clots from the infiltrated labeled MØs in the heart in vivo. Ex-vivo high-resolution -weighted MRM (Figure 5) revealed that the hypointensed area detected in the in-vivo - weighted MRI are composed of a “core” with continuous dark area, probably the hemorrhage of the infarct core, and the individual dark “dots”, are probably MPIO-la- beled MØs. One single dot is likely to be one labeled MØ [16] . Pathological examinations (Figure 6) have confirmed that these are ED1+ MØs and blood. Although in-vivo -weighted MRI cannot distinguish labeled MØs and hemorrhage, both are reduced with Intralipid® treatment after IRI.

3.5. Flow Cytometry Study

On day 1 after IRI, we have found that Intralipid® can decrease the circulating ED1+ MØs dramatically in the peripheral blood (Figure 7(A) and Figure 7(B)). On day 2, although the in-situ MØ infiltration is greatly reduced by the Intralipid® treatment (Figure 4 and Figure 6), the composition of MØ and other types of immune cells, including helper T-lymphocytes (CD4), cytotoxic T-cells (CD8), TL-2α receptor containing cells (CD25), Class II antigen-presenting cells (RT1B), NK cells (CD 161), in the peripheral blood show no different with or without Intralipid® treatment (Figure 7(C) and Figure 7(D)). No statistically significant differences in CD4 (p = 0.4162, pa = 1.000), CD8 (p = 0.3024, pa = 1.000), CD25 (p = 0.3024, pa = 1.000), RT1B (p = 0.1234, pa = 1.000), CD161 (p = 0.5557, pa = 1.000), and ED1 (p = 0.8119, pa = 1.000) were found between the two groups.

4. Discussions

As survival from acute myocardial infarction has improved due to the implementation of prompt revascularization therapy, improving the long-term outcomes has arisen as an important goal. Patients who survive the initial event could suffer significant morbidity and mortality due to adverse ventricular remodeling resulting in the long-term heart failure. Acute myocardial IRI is the major cause of the adverse effects of CHD on the myocardium [2] . Our results demonstrate that Intralipid® indeed can protect the resulting injury in hearts due to IRI as shown by our in-vivo non-invasive multi-parameter CMRI in a rat model of acute myocardial infaction. With a single intravenous Intralipid® administration after LAD occlusion, rats treated with Intralipid® show a marked improvement of cardiac function, both global systolic function, such as EF, stroke volumes, and cardiac output, as well as regional ventricular wall motion and strain in vivo. Our results show that the Intralipid® treatment also greatly reduces the size of infarcted and “at risk” myocardium after IRI.

Previously, conflicting results were reported regarding whether Intralipid® could protect the heart against ischemic insult or not [21] [22] [25] [26] . It is known that the pressure and the volume loading of the heart are important for the response to IRI [34] . Although important conclusions were drawn, some of the previous functional mea-

Figure 7. Flow cytometry analysis of the changes of immune cells in peripheral blood upon Intralipid® treatment after LAD occlusion: (A) representative flow cytometry dot plots showing the changes of ED1+ MØ population on day 1, with or without Intralipid® treatment; (B) a summary bar figure of the data shown in (A); (C) representative flow cytometry dot plots of CD4, CD8, CD25, RT1B, CD 161, and ED1 positive cells in peripheral blood on day 2, with or without Intralipid® treatment; and (D) a summary chart of the data shown in (C). *p < 0.01. No statistically significant differences in any of the markers tested (CD4, CD8, CD25, RT1B, CD161 and ED1) on day 2 were found between the two groups.

surements for Intralipid®’s cardio-protective effects were done in isolated Langendorff- perfused heart preparation or by an invasive pressure measurement of hemodynamics. Here, we have measured the ventricular function in the intact physiological context with a multi-parameter in-vivo CMR approach, which provides reliable evaluation of the functional outcomes.

Inflammation plays a central role in IRI and inflammatory MØs are one of the key players [4] [6] . The amplitude of inflammation and the timely resolution affect the post-MI repair and remodeling [35] [36] . Post-inschemic myocardial inflammation is a complex process. Neutrophils arrive early peaking within 24 hr post-injury, followed by monocytes/macrophages. Macrophages are key modulator and effector cells in immune response [37] . Different macrophage classes, M1, M2, and Mreg, play different roles in IRI at different time [37] - [41] . Initial macrophage involvement and inflammation are harmful, peaking around 3 to 5 days post-ischemia, triggering necrotic myocardium loss and subsequent adverse myocardial remodeling. On the other hand, later macrophage involvement after 7 days is essential for wound healing and recovery from IRI [42] [43] . We have previously shown that myocardial inflammation and macrophage infiltration can be correctly and specifically detected in vivo with cellular MRI by iron-oxide particle labeling of macrophages [13] - [17] . The hypointensity detected by -weighted MRI arises from ED1+ macrophages. The extent of hypointensity correctly reflected the degree of myocardial inflammation [13] . In this study, we have used in-vivo cellular MRI for macrophages as a reporter index to reflect the myocardial inflammation status; in particular, the pro-inflammatory harmful macrophages within the initial 5 days post-ischemic insult [4] .

The mechanisms of how Intralipid® mediates cardio-protection in IRI are not well understood. Intralipid®’s cardio-protective effect is likely to be multi-facets, which could include Salvage kinase or other receptor-mediated pathways [22] , inhibiting mitochondrial permeability transition pore opening [24] , reducing mitochondrial superoxide production, increasing pro-survival kinases such as Akt and GSK-3 [23] , reducing calcium overload, as well as a metabolic switch [44] from glucose to fatty acid fuels for the ischemic heart. The effect of Intralipid® on myocardial inflammatory MØ has not been investigated. Our results show that, in addition to these intra-myocyte cascades, Intralipid® can also reduce in-situ myocardial inflammation after IRI. In this study, we have found that negatively charged microparticle, Intralipid®, can significantly reduce the infiltration of CD68+ or ED1+ MØs. MØ infiltration into the injured myocardium is evaluated by in-vivo and ex-vivo T2*-MRI, and validated by immuno- histochemistry. It is consistent with the findings of Getts et al. [4] that, 24 hr after the treatment of negatively charged microparticles, the number of ED1+ MØs in peripheral blood decreased. To our best knowledge, this is the very first demonstration of Intralipid®’s ability to reduce in-situ inflammation in the intact heart.

Interestingly, on day 2, even though the in-situ inflammation in the heart is reduced, there are no significant changes in the leukocyte composition in circulation with the common markers used for MØs, T-cells, and antigen-presenting cells (CD4, CD8, CD25, RT1B, CD161 and ED1). Our results show the dis-association of the in-situ inflammation status in the heart from the systemic blood marker in circulation. Therefore, in-vivo cellular MRI provides an invaluable tool to non-invasively access the in-situ inflammation status in its intact physiological context that cannot be accurately determined by a general blood-panel evaluation.

After the ischemic cardiac injury, a robust inflammation response is activated to remove necrotic heart tissue and to promote healing. This immune response after IRI is highly coordinated and dynamic [45] . If this indicates that the interaction between the immune system and the heart is perturbed, negative consequences can result. Early pre-clinical findings indicated that anti-inflammatory corticosteroids treatment could decrease infarct size [46] and led to clinical trials using anti-inflammatory agents, such as methylprednisolone, to treat MI patients [47] , but resulted in a catastrophic outcome. It is now known that inflammation can play dual roles after IRI. Myocardial inflammation is both detrimental and reparative. A general non-specific abolishing of inflammation may be harmful to the injured cardiac tissue. It is now known that there are heterogenic phenotypes of MØ sub-classes that mediate different functions at different times. Inflammatory monocytes or classically activated M1 MØs accumulate early, in the first hours of reperfusion, and are thought to be harmful to the tissue. On the other hand, “resident” or “reparative” monocytes are also known as alternatively activated M2 MØs that appear later, after 5 to 7 days after IRI, and are thought to be important for cardiac repair. Our data indicate that Intralipid® could reduce the initial phase of “harmful” inflammation after IRI. Whether Intralipid® exhibits the effects on the later “reparative” phase of inflammation needs further investigation.

Immune cells, particularly macrophages and monocytes, are emerging therapeutic targets, however, the non-invasive clinical tools for assessing their presence in the myocardium are lacking [48] [49] . The systemic biomarkers in peripheral blood might not reflect the inflammation status in the myocardium. Diagnostic imaging tools that can access myocardial inflammation will be very beneficial in this endeavor [48] [50] [51] . In-vivo cellular MRI provides a valuable tool to investigate the intricate interplays of innate immune system and the heart, which is important for developing suitable therapeutic strategies for ischemic heart diseases, and other pathological conditions.

One major difference in the animal IRI models and human patients with coronary artery syndromes is that CHD patients are often having chronically elevated inflammation prior to the ischemic event, whereas the experimental animals do not have elevated in-situ inflammation until the contrary artery occlusion occurs. The immune system status could be different. Whether Intralipid® can reduce in-situ myocardial inflammation in the human CHD patients need further clinical studies. Interestingly, it has been reported that Intralipid® infusion might inhibit foam cell formation [52] and block the activity of lysophosphatidylcholine [53] , which is a major lipid component of the oxidized low density lipoproteins, thus benefit CHD patients.

We have investigated if a pre-treatment of Intralipid® prior to the ischemic insult can improve the cardio-protective effects of Intralipid®, but the result is negative. There is no statistically significant difference between the underlying distributions of Ecc for the pre-IRI treatment (n = 8) receiving Intralipid® one hour prior to the ischemic insult and that for the post-IRI groups (n = 6) receiving Intralipid® at the onset of reperfusion (Wilcoxon statistic = 48, n1 = 8, n2 = 6, p = 0.7520). Pre-treatment of Intralipid® does not show detectable functional or cellular differences, compared to the IRI hearts that were treated with Intralipid® after the ischemic insult.

Iron-oxide-nano-particles are cleared quickly by the reticuloendothelial system. In general, Iron-oxide-particles have short blood half-life, depending on their size and surface coating materials [17] . We have shown [54] that the pre-treatment of Intralipid® prior to iron-oxide particle administration can temporarily inhibit Kupper cells in the liver, increase its blood half-life, thus, improve labeling efficiency. For the present study, MPIO was given 1-to-3 days prior to the ischemic surgery. MPIO’s in-vivo blood half-life in rodents only lasts a few minutes [16] [54] , so MPIO particles are cleared from the circulation at the time of ischemic surgery, Intralipid® treatment, and the subsequent in-vivo CMRI measurements. Therefore, the changes in the in-situ MØ infiltration after the Intralipid® treatment observed with MRI are not due to changes in the labeling efficiency of MPIO. Pathological evaluation confirmed that ED1+ staining of all MØs in the heart did decrease with Intralipid® treatment.

Pathology and immune-histochemical evaluations of the tissue are essential in validating the cellular and functional MRI results. However, the conventional pathology examination limits the view to a very small area on the target tissue. Selection and grading of the field-of-interest can be subjective and biased. The WSI method that we have developed provides an overall and quantitative evaluation of the whole pathology slide without pre-selecting field-of-interest [28] . The computational detection algorithm provides an objective and quantitative evaluation of the true pathological evaluation of the tissue. Our WSI results (Figure 6) indicate that Intralipid® did indeed decrease ED1+ MØ infiltration in the IRI heart, confirming our cellular MRI finding.

Although it has generally been presumed that the infarct size and the efficacy of the initial treatment are key determinants of the down-stream heart failure and the adverse remodeling, the role of ischemia reperfusion injury is less well characterized. It is possible that the initial IRI may set forth a pathologic cascade that impacts the long-term outcomes. Further study is needed to assess whether the treatments designed to limit IRI may also reduce future development of heart failure. Intralipid® is a safe and broadly used nutritional supplement, and therefore an excellent model treatment to test this approach. Insights gained may set the stage for translational trials to determine if Intralipid® may be an effective treatment for IRI in the clinical setting, and whether this therapy can improve the outcomes by reducing pathological remodeling and progression of heart failure following myocardial infarction.

Acknowledgements

We thank Mr. Brent Barbe for carrying surgical procedures as well as Mr. Yehuda Creeger, Ms. Wendy F. Li, and Ms. Lanya Tseng for their assistance in flow cytometry experiments. We thank Dr. Anil V. Parwani of the Department of Pathology of University of Pittsburgh Medical Center for providing the whole slide scanner for our work. The work was supported by grants from the National Institutes of Health (P41EB- 001977 and UL1TR000005).

Conflicts of Interest

The authors declare no conflicts of interest.

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