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Purpose: Using cardiac imaging techniques it has been demonstrated that, after successful coronary revascularization of acute myocardial infarction (MI), microvascular obstruction (MVO) resolves spontaneously. Data on the course of this process in “in vivo” models are scarce. We aimed to characterize the dynamics of MVO in a swine model of reperfused anterior MI.Methods: Swine were subjected, by means of percutaneous balloon inflation, to a transient 90-min occlusion of mid left anterior descending artery followed by 72-h (acute MI model) or 1-month (chronic MI model) reperfusion. Area at risk (thioflavin-S staining) and the extent of MVO (% of area at risk without thioflavin-S staining) were quantified. Microvessel density (using immunohistochemistry by von Willebrand factor antibody, vessels/field) and the expression of Hypoxia Induced Factor-1α (HIF-1α mRNA) were determined in controls and in the acute and chronic MI models.Results: In the acute MI model, MVO (8.4±4.5%) was detected in all cases. MVO significantly decreased in the chronic MI model (0.14±0.09%, p <0.001 vs. acute MI model, Figure). Microvessel density was significantly reduced in the acute MI model in comparison with the chronic MI model and controls (p <0.001, Figure). The expression of HIF-1α mRNA was significantly increased in the acute MI model in the infarct area (p<0.05 vs. controls) and in the chronic MI model in the infarct, adjacent and remote areas (p <0.01 vs. controls, Figure).Conclusion: In an “in vivo” controlled model of reperfused anterior MI, MVO spontaneously improves one month after reperfusion at macroscopic and microscopic levels. HIF could play a role in the molecular control of this process. [ABSTRACT FROM AUTHOR]

Purpose: In the context of myocardial infarction (MI) the availability of metabolites is clearly restricted, therefore a fuel metabolic shifts takes place. Previous studies have indicated that peroxisome proliferator activated receptor co-activator alpha (PGC-1α) pathway is a crucial regulator of cardiac metabolism in response to cardiac stress. Here we address the role of PGC-1α in regulating metabolic changes of MI.Methods: We studied a group of 12 common swine in which anterior MI was induced by means of angioplasty balloon inflation. A series of 6 swine were sacrificed at 48h post-infarction (acute infarction group) and another series of 6 swine were sacrificed at 3 weeks (chronic infarction group). Metabolites such as: glucose, pyruvate, ketone bodies, and lipids were analyzed in serum (mmol/L) at baseline, 75 min after balloon inflation, 2 h, 48 h and 3 weeks after reperfusion by means of enzymatic analysis. Results were compared to baseline levels. Genes related to PGC-1α such as: PGC-1α, ERR-α, PPAR-α, and HIF-1α, were analysed (fold change) in infarcted, adjacent and remote areas of porcine hearts 48h or 3 weeks post-infarction by molecular biology. Results were compared to 5 control swine without infarction.Results: In all groups, after 2h of infarction, a striking increase of lactate (3.2 ± 0.6 vs. 0.8 ± 0.3) and non-esterified fatty acids (0.6 ± 0.2 vs. 1.8 ± 0.3) was observed in serum compared to baseline (p<0.001 in both cases). Conversely, a significant decrease of glucose (5.2 ± 0.3 vs. 3.8 ± 0.2) and β-Hydroxybutyrate (1.8 ± 0.5 vs. 0.6 ± 0.2) occurred at the same time (p<0.001 in both cases). All values reverted progressively to baseline after 3 weeks. In comparison with controls, molecular biology analysis of acute infarcted hearts revealed a significant decrease of expression in mRNA and protein levels of transcription factors related to lipid and mitochondrial metabolism: PGC-1α(0.3 ± 0.1 vs. 1.2 ± 0.2 fold), ERR-α(0.8 ± 0.3 vs. 1.6 ± 0.2 fold) and PPAR-α(0.9 ± 0.3 vs. 1.7 ± 0.2 fold) (p<0.01 in all cases). Values didn't change after 3 weeks. However genes related to glucose metabolism were significantly increased in acute infarcts compared to controls: GLUT-1 (3.8 ± 0.4 vs. 1.1 ± 0.3 fold), HIF-1α(4.2 ± 1.3 vs. 1.0 ± 0.2 fold) (p<0.01 in both cases). These values recovered control levels after 3 weeks.Conclusion: A metabolic deregulation mediated by PGC-1α decreased expression takes place in the context of acute MI. This is mediated by a decrease of fatty acid oxidation and an increase of glucose utilization and it reverts after 3 weeks. [ABSTRACT FROM AUTHOR]

Purpose: Fibrosis plays a key role in the pathophysiology of left ventricular (LV) remodelling after myocardial infarction (MI). The dynamics of this process and whether it is a localized or diffuse phenomenon has not been totally clarified. We aimed to characterize these issues in a swine model of reperfused anterior MI.Methods: Swine were subjected by means of percutaneous balloon inflation to a transient 90-min occlusion of mid left anterior descending artery followed by 72-h (acute MI model) or 1-month (chronic MI model) reperfusion. The extent of fibrosis was macroscopically (triphenyltetrazolium staining, % of LV volume) and microscopically (Sirius red staining, % of field) quantified in the infarct, adjacent and remote areas as well as in controls. TGF-β1, collagen1-A1, A2 and 3A1 gene expression was determined.Results: Macroscopically, necrosis (16±5% in the acute MI model) and fibrosis (16±4% in the chronic MI model) were detected in all cases. Macroscopic fibrosis occurred in the infarct but not in the adjacent or remote areas (Figure). At microscopic level, in comparison with controls, fibrosis was only significantly increased in the chronic MI model at the infarct area (35±4%, p<0.001) but not in the acute MI model or in the adjacent and remote areas in the chronic MI model (<4% in all cases, p=ns, Figure). TGF-β1 (p<0.05, acute and chronic MI models, Figure) and collagen1-A1, A2 and 3A1 (p<0.001, chronic MI model) gene expression were significantly increased in the infarct but not in the adjacent or remote areas (p=ns).Conclusion: In a model of anterior MI, 1-month after reperfusion, at macroscopic, microscopic and molecular levels, myocardial fibrosis appears as a localized process which mainly affects the infarct area but not the adjacent or remote regions. [ABSTRACT FROM PUBLISHER]

Programmed death-1 (PD-1) and Programmed death-1 ligand (PD-L1) regulate immune response. Previous studies associate an immune deregulation in ST-elevation myocardial infarction STEMI.We recruited 100 patients with a first STEMI treated with reperfusion. In all patients PD-1 and PD-L1 expression was studied 24 h post-reperfusion in peripheral blood mononuclear cells (PBMCs), by means of flow cytometry and molecular biology. PD-1 and PD-L1 expression was serially analyzed in the first 20 patients before reperfusion and 24h, 96h and 30 days afterwards. Results were compared with 30 age- and sex-matched controls. Cardiac Magnetic Resonance was used to quantify infarct size 1-week after infarction. In a series of 8 swine with induced STEMI, PD-1 and PD-L1 expression was analyzed at baseline, 90 min after balloon inflation, 2 h and 24 h after reperfusion in PBMCs, and in swine hearts. Results were compared to 5 controls.In patients, in comparison with controls, a significant decrease of PD-1 expression [mRNA fold change 0.8 ± 0.3 vs. 1.2 ± 0.6] and an increase of PD-L1+ expression [mRNA fold change 2.7 ± 2.1 vs. 0.9 ± 0.5] was observed 24h after infarction in PBMCs (p <0.05). STEMI patients with large infarct size showed decreased PD-1 expression, PD-L1 did not changed (Figure 1). Both in patients and swine, showed a significant increase of PD-1 and PD-L1 expression before reperfusion. Swine hearts revealed a marked infiltration of PMBCs and a significant increase of PD-1 and PD-L1 expression in the infarcted area compared to controls (Figure 2)Acute changes in the PD-1 pathway take place in acute STEMI. A lesser expresion of PD-1 in peripheral blood, which could be due to myocardial infiltration in the infarcted area of PBMCs, associates with a larger infarct size. [ABSTRACT FROM PUBLISHER]