Myocardial Healing Research Articles

The Kinetics of Circulating Monocyte Subsets and Monocyte-Platelet Aggregates in the Acute Phase of ST-Elevation Myocardial Infarction: Associations with 2-Year Cardiovascular Events.

In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; P = 0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; P = 0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; P = 0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; P = 0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.

Role of T-cells in myocardial infarction.

Innate immunity has been studied for several decades in the context of ischaemia-reperfusion injury, myocardial remodelling, and healing. In the last years, a number of experimental and clinical studies focused on adaptive immunity in these processes. Meanwhile, there is considerable evidence especially on the role of CD4(+) T-cells in myocardial injury and healing, whereas their role in remodelling is less clear. Innate leukocytes are able to recognize a wide array of self and foreign molecular patterns, whereas the activation of adaptive immunity requires the highly specific cooperation of antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. Relevant autoantigens have not yet been definitely identified but experimental evidence indicates that autoantigen recognition is necessary for T-cell activation after myocardial infarction. Non-antigen-specific modes of activation might also play a role especially during acute ischaemia and reperfusion of the myocardium. This review summarizes the current evidence from experimental studies and presents side-by-side recent clinical data on the role of T cells in the pathophysiology of myocardial reperfusion injury and post myocardial infarction healing.

Complementary, Selective PET Imaging of Integrin Subtypes α5β1 and αvβ3 Using 68Ga-Aquibeprin and 68Ga-Avebetrin.

Despite in vivo mapping of integrin αvβ3 expression being thoroughly investigated in recent years, its clinical value is still not well defined. For imaging of angiogenesis, the integrin subtype α5β1 appears to be a promising target, for which purpose we designed the PET radiopharmaceutical (68)Ga-aquibeprin. (68)Ga-aquibeprin was obtained by click-chemistry (CuAAC) trimerization of a α5β1 integrin-binding pseudopeptide on the triazacyclononane-triphosphinate (TRAP) chelator, followed by automated (68)Ga labeling. Integrin α5β1 and αvβ3 affinities were determined in enzyme linked immune sorbent assay on immobilized integrins, using fibronectin and vitronectin, respectively, as competitors. M21 (human melanoma)-bearing severe combined immunodeficient mice were used for biodistribution, PET imaging, and determination of in vivo metabolization. The expression of α5 and β3 subunits was determined by immunohistochemistry on paraffin sections of M21 tumors. (68)Ga-aquibeprin shows high selectivity for integrin α5β1 (50% inhibition concentration [IC50] = 0.088 nM) over αvβ3 (IC50 = 620 nM) and a pronounced hydrophilicity (log D = -4.2). Severe combined immunodeficient mice xenografted with M21 human melanoma were found suitable for in vivo evaluation, as M21 immunohistochemistry showed not only an endothelial and strong cytoplasmatic expression of the β3 integrin subunit but also an intense expression of the α5 integrin subunit particularly in the endothelial cells of intratumoral small vessels. Ex vivo biodistribution (90 min after injection) showed high uptake in M21 tumor (2.42 ± 0.21 percentage injected dose per gram), fast renal excretion, and low background; tumor-to-blood and tumor-to-muscle ratios were 10.6 ± 2.5 and 20.9 ± 2.4, respectively. (68)Ga-aquibeprin is stable in vivo; no metabolites were detected in mouse urine, blood serum, kidney, and liver homogenates 30 min after injection. PET imaging was performed for (68)Ga-aquibeprin and the previously described, structurally related c(RGDfK) trimer (68)Ga-avebetrin, which shows an inverse selectivity for integrin αvβ3 (IC50 = 0.22 nM) over α5β1 (IC50 = 39 nM). In vivo target specificity was proven by cross-competition studies; tumor uptake of either tracer was not affected by the coadministration of 40 nmol (∼5 mg/kg) of the respective other compound. (68)Ga-aquibeprin and (68)Ga-avebetrin are recommendable for complementary mapping of integrins α5β1 and αvβ3 by PET, allowing for future studies on the role of these integrins in angiogenesis, tumor progression, metastasis, and myocardial infarct healing.

Abstract 11695: The Kinetics of Circulating Monocyte Subsets and Microbial Translocation in the Acute Phase of ST-Elevation Myocardial Infarction Reveals Prognostic Values for Cardiovascular Outcomes

Introduction: In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing, and to atherosclerotic plaque destabilization.The underlying pathophysiological mechanisms for the post-MI monocytosis and the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) are still unclear. Hypothesis: The kinetics of the three monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes) and gut microbial translocation are associated with cardiovascular outcomes after STEMI. Methods: In 100 STEMI patients treated with primary percutaneous coronary intervention (PCI), monocyte subsets and microbial translocation markers (lipopolysaccharide [LPS] and D-lactate) were measured on Days 1, 2, 3, 5 and 7 of STEMI onset, compared with 35 stable coronary heart disease patients and 35 healthy volunteers. All STEMI patients were prospectively followed for the first occurrence of an adverse cardiovascular event. Results: From Day 1 to Day 7, a parallel increase in CD14++CD16- cell counts, CD14++CD16+ cell counts, and gut permeability markers was observed, with peak levels on Day 2. During a median follow-up of 1.5 years, 25 events were recorded. Univariate Kaplan-Meier analysis revealed that Day 2 CD14++CD16- cell counts ( P =0.022), CD14++CD16+ cell counts ( P =0.024) and Δ LPS (Day 2 – Day 1; P =0.027) each predicted the primary endpoint when stratified by median values. After adjustment for confounders, Day 2 CD14++CD16+ monocyte counts showed the strongest predictive value (per SD increase: hazard ratio [HR]: 2.127; 95% CI 1.313 to 3.446; P =0.002) for cardiovascular events. Conclusions: The expansion of the CD14++CD16+ monocyte subset on Day 2, which is associated a transient increase in microbial translocation, independently predicts adverse cardiovascular outcome in STEMI patients treated with primary PCI.

Abstract 16031: The Apolipoprotein A1 Mimetic 4F Attenuates Cardiac Remodeling After Reperfused Infarction by Modulating Monocyte Polarity and Attenuating Immune Cell Activation

Heart failure (HF) is characterized by exaggerated systemic and myocardial pro-inflammatory responses, which impede myocardial healing and promote pathological remodeling and dysfunction. Currently, there are no strategies available to restrain and/or modulate immune cell responses triggered by myocardial injury. 4F, an apolipoprotein A-I mimetic, exhibits anti-inflammatory properties and influences macrophage polarity. We hypothesized that 4F treatment following reperfused myocardial infarction (MI) in mice would attenuate post-MI cardiac remodeling by inducing an anti-inflammatory and tissue healing monocyte polarity. C57BL/6 mice (6-8/group) were intravenously injected with either PBS or L-4F (100 μg/day) for 5 d starting at day 3 after reperfused MI (60 min ischemia). Flow cytometry revealed that compared to PBS injected MI mice, 4F significantly (p < 0.05) decreased levels of pro-inflammatory monocytes (CD45+Cd11b+Ly6Chigh) in blood (20.4 ± 4.6 vs 9.4 ± 1.7%), spleen (25.5 ± 7.4 vs 8.0 ± 6.0%), and heart (0.9 ± 0.4 vs 0.2 ± 0.1%); and decreased myocardial macrophage (CD45+CD11b+F4/80+) infiltration (1.6 ± 0.8 vs 0.28 ± 0.2%). The levels of anti-inflammatory monocytes, however, were unchanged. Echocardiography revealed that these changes in immune cell profiles in 4F-injected mice were also accompanied by improvements in cardiac function. Compared to PBS injected MI mice, 4F treatment attenuated post-MI LV chamber dilatation (84.1 ± 16 vs 65.0 ± 8.5 uL and 59.15 ± 16.6 vs 38.4 ± 11.8 uL; end-diastolic and systolic volumes, respectively), and improved LV ejection fraction (28.4 ± 10.8 vs 41.7 ± 12.8%). In addition, in vitro studies using mouse peritoneal macrophages indicated that 4F promotes an anti-inflammatory macrophage phenotype potentially by inhibiting the glycolytic metabolic profile typical of pro-inflammatory macrophages. These effects on macrophage polarity by 4F were associated with parallel alterations in the expression of hypoxia inducible factor isoforms 1 and 2α, known markers of macrophage polarity. We conclude that 4F could be used therapeutically after MI to augment reparative immune responses and thereby limit the long-term maladaptive effects of exaggerated inflammation on adverse post-MI cardiac remodeling.

Early Mortality and Long-term Survival after Repair of Post-infarction Ventricular Septal Rupture: An Institutional Report of Experience

To determine predictors of mortality after surgical management of post-infarction ventricular septal rupture repair. A total of 63 patients (73.2%, mean age 67.22±7.71 years, male:female ratio; 35:28) underwent open heart surgery for post-infarction ventricular septal rupture repair. Patient demographics, operative data and postoperative parameters were analysed to reveal predictors of early mortality and long-term survival. In-hospital mortality was 54.0% (34/63). Time from myocardial infarction to operation ≤ 14 days (OR: 4.10, 95% CI 1.16-14.46, p=0.02), systolic pulmonary artery pressure > 45 mmHg (OR: 4.14, 95% CI 1.110-15.496, p=0.03) and age (years) (OR: 1.09, 95% CI 1.002-1.194, p=0.04) were found to be independent predictors of in-hospital mortality. In multivariate Cox regression analysis, presence of pulmonary oedema on admission (HR: 4.95, 95% CI 1.58-15.54, p=0.006), age (years) (HR: 1.09, 95% CI 1.009-1.180, p= 0.02) and cross-clamp time <60 min (HR: 3.93, 95% CI 1.13-13.64, p=0.03) were found to be independent predictors of long-term survival. Within a follow-up of a median of 60.0 months, five-year survival rate was 67±9.0%. In line with the previous studies, our study demonstrated the benefits of delaying the repair for post-infarction ventricular septal rupture to allow adequate myocardial healing if haemodynamic status of the patient allows.

Stimulating endogenous cardiac repair.

The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players.

Oxidative stress contributes to the impaired sonic hedgehog pathway in type 1 diabetic mice with myocardial infarction.

Our previous study demonstrated that an impaired sonic hedgehog (Shh) pathway contributed to cardiac dysfunction in type 1 diabetic mice with myocardial infarction (MI). The present study aimed to test the hypothesis that oxidative stress may contribute to the impaired Shh pathway and cardiac dysfunction in type 1 diabetic mice with MI. Streptozotocin-induced type 1 diabetic mice (C57/Bl6, male) and rat neonatal cardiomyocytes were used in the present study. Mice were randomly assigned to undergo ligation of the coronary artery or pseudosurgery. A potent antioxidant Tempol was administered in vivo and in vitro. Cardiac function was assessed by echocardiography, capillary density by immunohistochemisty, percentage of myocardial infarct using Massons trichrome staining, reactive oxygen species detection using dihydroethidium dye or 2,7-dichlorofluorescein diacetate probe and protein expression levels of the Shh pathway by western blot analysis. The antioxidant Tempol was shown to significantly increase myocardial protein expression levels of Shh and patched-1 (Ptc1) at 7–18 weeks and improved cardiac function at 18 weeks in type 1 diabetic mice, as compared with mice receiving no drug treatment. Furthermore, myocardial protein expression levels of Shh and Ptc1 were significantly upregulated on day 7 after MI, and capillary density was enhanced. In addition, the percentage area of myocardial infarct was reduced, and the cardiac dysfunction and survival rate were improved on day 21 in diabetic mice treated with Tempol. In vitro, treatment of rat neonatal cardiomyocytes with a mixture of xanthine oxidase and xanthine decreased protein expression levels of Shh and Ptc1 in a concentration-dependent manner, and Tempol attenuated this effect. These results indicate that oxidative stress may contribute to an impaired Shh pathway in type 1 diabetic mice, leading to diminished myocardial healing and cardiac dysfunction. Antioxidative strategies aimed at restoring the endogenous Shh pathway may offer a useful means for improving diabetic cardiac function.

Fetuin-A is related to infarct size, left ventricular function and remodelling after acute STEMI

ObjectiveTo investigate the relationship between plasma fetuin-A, an anti-inflammatory glycoprotein which might be involved in myocardial healing after acute infarction, and infarct size, left ventricular (LV) function and dimensions as...

Cardiomyocytes, endothelial cells and cardiac fibroblasts: S100A1's triple action in cardiovascular pathophysiology.

Over the past decade, basic and translational research delivered comprehensive evidence for the relevance of the Ca(2+)-binding protein S100A1 in cardiovascular diseases. Aberrant expression levels of S100A1 surfaced as molecular key defects, driving the pathogenesis of chronic heart failure, arterial and pulmonary hypertension, peripheral artery disease and disturbed myocardial infarction healing. Loss of intracellular S100A1 renders entire Ca(2+)-controlled networks dysfunctional, thereby leading to cardiomyocyte failure and endothelial dysfunction. Lack of S100A1 release in ischemic myocardium compromises cardiac fibroblast function, entailing impaired damage healing. This review focuses on molecular pathways and signaling cascades regulated by S100A1 in cardiomyocytes, endothelial cells and cardiac fibroblasts in order to provide an overview of our current mechanistic understanding of S100A1's action in cardiovascular pathophysiology.

Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse.

Myocardial ischaemia-reperfusion (MIR) triggers a sterile inflammatory response important for myocardial healing, but which may also contribute to adverse ventricular remodelling. Such inflammation is initiated by molecular danger signals released by damaged myocardium, which induce innate immune responses by activating toll-like receptors (TLRs). Detrimental roles have been recently reported for TLR2, TLR3 and TLR4. The role of other TLRs is unknown. We therefore evaluated the role of TLR5, expressed at high level in the heart, in the development of myocardial damage and inflammation acutely triggered by MIR. TLR5(-/-) and wild-type (WT) mice were exposed to MIR (30 min ischaemia, 2 h reperfusion). We measured infarct size, markers of cardiac oxidative stress, myocardial phosphorylation state of mitogen-activated protein (MAP) kinases and AKT, expression levels of chemokines and cytokines in the heart and plasma, as well as cardiac function by echography and conductance volumetry. TLR5-deficient mice had normal cardiac morphology and function under physiological conditions. After MIR, the absence of TLR5 promoted an increase in infarct size and myocardial oxidative stress. Lack of TLR5 fostered p38 phosphorylation, reduced AKT phosphorylation and markedly increased the expression of inflammatory cytokines, whereas it precipitated acute LV (left ventricle) dysfunction. Therefore, contrary to the detrimental roles of TLR2, TLR3 and TLR4 in the infarcted heart, TLR5 is important to limit myocardial damage, inflammation and functional compromise after MIR.

Myocardial infarction: a critical role of macrophages in cardiac remodeling.

Ischemic heart disease is a common condition and a leading cause of mortality and morbidity. Macrophages, besides their role in host defense and tissue homeostasis, are critical players in the pathophysiological processes induced by myocardial infarction. In this article we will summarize the current understanding of the role of monocytes and macrophages in myocardial damage and cardiac remodeling in relation to their origin and developmental paths. Furthermore, we describe their potential implications in therapeutic strategies to modulate myocardial healing and regeneration.

Myocardial healing requires Reg3β-dependent accumulation of macrophages in the ischemic heart

Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry-based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.

The p66ShcA adaptor protein regulates healing after myocardial infarction.

Heart rupture and heart failure are deleterious complications of myocardial infarction. The ShcA gene encodes for three protein isoforms, p46-, p52- and p66ShcA. p66ShcA induces oxidative stress. We studied the role of p66ShcA post-infarction. Expression of p66ShcA was analyzed in myocardium of patients with stable angina (n=11), in explanted hearts with end-stage ischemic heart failure (n=9) and compared to non-failing hearts not suitable for donation (n=7). p66ShcA was increased in the patients with stable angina, but not in the patients with end-stage heart failure. Mice (n=105) were subjected to coronary artery ligation. p66ShcA expression and phosphorylation were evaluated over a 6-week period. p66ShcA expression increased transiently during the first weeks post-infarction. p66ShcA knockout mice (KO) were compared to wild type (n=82 in total). KO had improved survival and reduced occurrence of heart rupture post-infarction. Expression of cardiac matrix metalloproteinase 2 (MMP-2) was reduced; fibroblast activation and collagen accumulation were facilitated, while oxidative stress was attenuated in KO early post-infarction. 6weeks post-infarction, reactive fibrosis and left ventricular dilatation were diminished in KO. p66ShcA regulation of MMP-2 was demonstrated in cultured fibroblasts: lack or overexpression of p66ShcA in vitro altered expression of MMP-2. Myocardial infarction induced cardiac p66ShcA. Deletion of p66ShcA improved early survival, myocardial healing and reduced cardiac fibrosis. Upon myocardial infarction p66ShcA regulates MMP-2 activation. The role of p66ShcA in human cardiac disease deserves further study as a potential target for reducing adverse cardiac remodeling post-infarction.

Role of lymphocytes in myocardial injury, healing, and remodeling after myocardial infarction.

A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes' central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation's relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4(+) T-cells contribute to ischemia-reperfusion injury. Several studies have shown that CD4(+) T-cells, especially CD4(+) T-regulatory cells, improve wound healing after MI, whereas depleting B-cells is beneficial post MI. That T-cell activation after MI is induced by T-cell receptor signaling implicates autoantigens that have not yet been identified in this context. Also, the significance of lymphocytes in humans post MI remains unclear, primarily as a result of methodology. This review summarizes current experimental evidence of lymphocytes' activation, functional role, and crosstalk with innate leukocytes in myocardial ischemia-reperfusion injury, wound healing, and remodeling after myocardial infarction.

Intramyocardial hemorrhage: an enigma for cardiac MRI?

Cardiovascular magnetic resonance (CMR) is a useful noninvasive technique for determining the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH), frequently occurring in patients after reperfused myocardial infarction (MI). MVO, or the so-called no-reflow phenomenon, is associated with adverse ventricular remodeling and a poor prognosis during follow-up. Similarly, IMH is considered a severe damage after revascularization by percutaneous primary coronary intervention (PPCI) or fibrinolysis, which represents a worse prognosis. However, the pathophysiology of IMH is not fully understood and imaging modalities might help to better understand that phenomenon. While, during the past decade, several studies examined the distribution patterns of late gadolinium enhancement with different CMR sequences, the standardized CMR protocol for assessment of IMH is not yet well established. The aim of this review is to evaluate the available literature on this issue, with particular regard to CMR sequences. New techniques, such as positron emission tomography/magnetic resonance imaging (PET/MRI), could be useful tools to explore molecular mechanisms of the myocardial infarction healing process.

Abstract 17166: Myeloid-specific Deletion of the Glucocorticoid Receptor Increases Mitochondrial Oxidative Stress and Impairs Wound Healing After Myocardial Infarction

Background: Glucocorticoid administration impairs ischemic wound healing by inhibiting inflammation and angiogenesis via a glucocorticoid receptor (GR)-mediated transcriptional response. However, there are also apparently contradictory reports claiming protective effects of glucorticoid administration after myocardial infarction (MI). We investigated the role of the GR in myeloid cells for infarct wound healing, using GR deficient mice (GRLysMCre). Methods and Results: MI was induced by permanent left coronary artery ligation in GRflox (wild-type [WT] controls) and GRLysMCre mice. The 7-day mortality was significantly lower in WT compared with GRLysMCre mice. At 7 days post MI, GRLysMCre mice exhibited significantly enhanced thinning and dilatation of the infarcted wall, LV chamber enlargement and functional deterioration. This was associated with altered granulation tissue formation and impaired neoangiogenesis at the site of ischemic injury. Multicolor flow cytometric analysis and immunohistochemical studies revealed at the 2nd day post infarction less infiltrating mononuclear cells [CD11bhigh and (CD49b, NK1.1, B220, CD90, Ly6G)low] in the healing myocardium of GRLysMCre mice. Mononuclear cells were identified as monocytes (F4/80, I-Ab, CD11c)low and as macrophages/dendritic cells (F4/80, I-Ab, CD11c)high. Monocytes lacking GR, isolated from peripheral blood and spleen by magnetic-activated cell sorting 1 day after MI, displayed reduced migration capacity and increased superoxide anion production in mitochondria, which was detected by HPLC-electrochemical analysis of Mito-2-hydroxy-E+. Moreover, at day 2 and 3 we found enhanced cellular and mitochondrial oxidative stress in the healing myocardium of GRLysMCre mice. Conclusions: Myeloid-specific deletion of the GR increasing mitochondrial oxidative stress alters wound healing and promotes infarct expansion. Our results suggest that the GR in myeloid cells play a crucial role during cardiac repair after myocardial infarction.

Multifunctional MR monitoring of the healing process after myocardial infarction.

Healing of the myocardium after infarction comprises a variety of local adaptive processes which contribute to the functional outcome after the insult. Therefore, we aimed to establish a setting for concomitant assessment of regional alterations in contractile function, morphology, and immunological state to gain prognostic information on cardiac recovery after infarction. For this, mice were subjected to myocardial ischemia/reperfusion (I/R) and monitored for 28 days by cine MRI, T2 mapping, late gadolinium enhancement (LGE), and (19)F MRI. T2 values were calculated from gated multi-echo sequences. (19)F-loaded nanoparticles were injected intravenously for labelling circulating monocytes and making them detectable by (19)F MRI. In-house developed software was used for regional analysis of cine loops, T2 maps, LGE, and (19)F images to correlate local wall movement, tissue damage as well as monocyte recruitment over up to 200 sectors covering the left ventricle. This enabled us to evaluate simultaneously zonal cardiac necrosis, oedema, and inflammation patterns together with sectional fractional shortening (FS) and global myocardial function. Oedema, indicated by a rise in T2, showed a slightly better correlation with FS than LGE. Regional T2 values increased from 19 ms to above 30 ms after I/R. In the course of the healing process oedema resolved within 28 days, while myocardial function recovered. Infiltrating monocytes could be quantitatively tracked by (19)F MRI, as validated by flow cytometry. Furthermore, (19)F MRI proved to yield valuable insight on the outcome of myocardial infarction in a transgenic mouse model. In conclusion, our approach permits a comprehensive surveillance of key processes involved in myocardial healing providing independent and complementary information for individual prognosis.

36 Monocyte Subpopulations Counts and Associations with Global Longitudinal Strain in St-Elevation Myocardial Infarction Patients with Normal Ejection Fraction

IntroductionMonocytes, with 3 different subsets, are implicated in the initiation and progression of the atherosclerotic plaque contributing to plaque instability and rupture. Mon1 are the “classical” monocytes with inflammatory action,...

180 Can Neutrophil Apoptosis Be Targeted Therapeutically to Modify Inflammation During Myocardial Infarct Healing?

Neutrophils are rapidly recruited to infarct site in response to cardiomyocyte death. Apoptosis and phagocytosis by macrophages prevents further damage to host tissues, but can also polarise macrophages towards an...