ST-segment elevation myocardial infarction (STEMI) is the most severe outcome of coronary artery disease. Despite rapid reperfusion of the artery, acute irrigation of the cardiac tissue is associated with increased inflammation. While innate immune response in STEMI is well described, an in-depth characterization of adaptive immune cell dynamics and their potential role remains elusive. We performed a translational study using a controlled porcine reperfusion model of STEMI and the analysis of lymphocyte subsets in 116 STEMI patients undergoing percutaneous coronary intervention (PCI). In the animal model, a sharp drop in circulating T lymphocytes occurred within the first hours after reperfusion. Notably, increased apoptosis of circulating lymphocytes and infiltration of proinflammatory Th1 lymphocytes in the heart were observed 48 h after reperfusion. Similarly, in STEMI patients, a sharp drop in circulating T lymphocyte subsets occurred within the first 24 h post-PCI. A cardiac magnetic resonance (CMR) evaluation of these patients revealed an inverse association between 24 h circulating T lymphocyte numbers and infarction size at 1-week and 6-month post-PCI. Our translational approach revealed striking changes in the circulating and tissue-infiltrating T lymphocyte repertoire in response to ischemia-reperfusion. These findings may help in developing new diagnostic and therapeutic approaches for coronary diseases.

Background: Cardiovascular magnetic resonance (CMR) predicts combined clinical events in post-ST segment elevation myocardial infarction (STEMI) patients. However, its contribution to predicting longterm major events (ME: cardiac death and non-fatal myocardial infarction [MI]) is unknown. We aimed to assess whether CMR predicts long-term MEs when performed soon after STEMI.Methods and results: We prospectively recruited 546 STEMI patients between 2004 and 2012. The Left ventricular (LV) ejection fraction (LVEF,%), infarct size (IS), edema, hemorrhage, microvascular obstruction, and myocardial salvage were quantified by CMR at pre-discharge. During a mean follow-up of 840 days, 57 ME events (10%; 23 cardiac deaths, 34 non-fatal MIs) were documented. Patients with MEs has more depressed LVEFs (p < 0.001), larger ISs (p < 0.001), more extensive edema, hemorrhage, and microvascular obstruction, and lower myocardial salvage (p < 0.05). CMR indexes were dichotomized according to the best cutoff values for predicting ME. In a comprehensive multivariate model, a LVEF <40% (HR: 2.3; 95% CI [12, 43]; p = 0.009) and an IS > 30% of LV mass (HR: 2.4; 95% CI [13, 44]; p = 0.007) independently doubled the ME risk. The ME risk rates were 6%, 14%, and 30%, respectively (p <0.001) in patients with both the LVEF >= 40% and an IS <= 30% of LV mass (n = 393), those with only one altered value (n = 84), and in cases with both the LVEF <40% and an IS > 30% of LV mass (n= 69). Similar tendencies were observed regarding cardiac deaths (2%, 6%, 14%; p < 0.001) and MI (4%, 8%, 16%; p < 0.001).Conclusions: CMR performed soon after STEMI predicts long-term MEs. Combined analysis of CMR-derived LVEF and IS allows robust stratification of patient outcomes. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

In extensive nonreperfused myocardial infarction (MI), remote fibrosis has been documented. Early reperfusion by primary angioplasty represents the gold standard method to minimize the extension of the infarction. We aimed to ascertain whether fibrosis also affects remote regions in reperfused MI in swine and patients. Swine were subjected to a transient occlusion of the left anterior descending artery followed by 1-week or 1-month reperfusion. Collagen content in the remote area macroscopically, microscopically, by magnetic resonance microimaging, and at the molecular level was similar to controls. In patients with previous MI, samples from autopsies displayed a significant increase in collagen content only in the infarct region. In patients with previous MI submitted to cardiac magnetic resonance-T1 mapping, the extracellular volume fraction in remote segments was similar to that for controls. In all scenarios, the remote region did not show a significant increase of collagen content in comparison with controls.

La obstrucción microvascular produce efectos nocivos después del infarto de miocardio. Con objeto de esclarecer el papel de la lesión por isquemia-reperfusión en la aparición y la dinámica de la obstrucción microvascular, se llevó a cabo un estudio metodológico preliminar para definir con exactitud este proceso en un modelo in vivo. Se indujo un infarto de miocardio en cerdos mediante una oclusión de 90 min en la parte media de la arteria coronaria descendente anterior izquierda empleando balones de angioplastia. Se aplicó una infusión intracoronaria de tioflavina-S y se comparó con la instilación tradicional intraaórtica o intraventricular. Se cuantificó el área perfundida por la arteria coronaria coronaria descendente anterior izquierda y la obstrucción microvascular en los grupos sin reperfusión (administración de tioflavina-S a través de la luz de un balón hinchado montado sobre la guía) y con reperfusión de 1 min, 1 semana y 1 mes (administración de tioflavina-S mediante el catéter intracoronario después de deshinchar el balón). En comparación con la administración intraaórtica e intraventricular, la infusión intracoronaria de tioflavina-S permitió una evaluación mucho más clara del área perfundida por la arteria coronaria descendente anterior izquierda y de la obstrucción microvascular. La lesión por isquemia-reperfusión tuvo un papel decisivo en la aparición y la dinámica de la obstrucción microvascular. El grupo sin reperfusión presentó una perfusión completamente preservada. Con la misma duración de la oclusión coronaria, la obstrucción microvascular se detectó ya en el grupo de reperfusión de 1 min (14 ± 7%), alcanzó un máximo en el grupo de reperfusión de 1 semana (21 ± 7%) y se redujo significativamente en el grupo de reperfusión de 1 mes (4 ± 3%; p < 0,001). Se presenta una prueba de concepto del papel crucial que desempeña la lesión por isquemia-reperfusión en la aparición y la dinámica de la obstrucción microvascular. El modelo de cerdo descrito, que emplea inyección intracoronaria de tioflavina-S, permite una caracterización exacta de la obstrucción microvascular después del infarto de miocardio. Microvascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model. Myocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation). In comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14% ± 7%), peaked in the 1-week reperfusion group (21% ± 7%), and significantly decreased in the 1-month reperfusion group (4% ± 3%; P < .001). We present proof-of-concept evidence on the crucial role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction. Full English text available from: www.revespcardiol.org/en

Introduction and objectives: Microvascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model.Methods: Myocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation).Results: In comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14% +/- 7%), peaked in the 1-week reperfusion group (21% +/- 7%), and significantly decreased in the 1-month reperfusion group (4% +/- 3%; P < .001).Conclusions: We present proof-of-concept evidence on the crucial role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction. (C) 2015 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

PURPOSETo assess predictors of reverse remodeling by using cardiac magnetic resonance (MR) imaging soon after ST-segment-elevation myocardial infarction (STEMI).MATERIALS AND METHODSWritten informed consent was obtained from all patients, and the study protocol was approved by the institutional committee on human research, ensuring that it conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Five hundred seven patients (mean age, 58 years; age range, 24-89 years) with a first STEMI were prospectively studied. Infarct size and microvascular obstruction (MVO) were quantified at late gadolinium-enhanced imaging. Reverse remodeling was defined as a decrease in left ventricular (LV) end-systolic volume index (LVESVI) of more than 10% from 1 week to 6 months after STEMI. For statistical analysis, a simple (from a clinical perspective) multiple regression model preanalyzing infarct size and MVO were applied via univariate receiver operating characteristic techniques.RESULTSPatients with reverse remodeling (n = 211, 42%) had a lesser extent (percentage of LV mass) of 1-week infarct size (mean ± standard deviation: 18% ± 13 vs 23% ± 14) and MVO (median, 0% vs 0%; interquartile range, 0%-1% vs 0%-4%) than those without reverse remodeling (n = 296, 58%) (P < .001 in pairwise comparisons). The independent predictors of reverse remodeling were infarct size (odds ratio, 0.98; 95% confidence interval [CI]: 0.97, 0.99; P = .04) and MVO (odds ratio, 0.92; 95% CI: 0.86, 0.99; P = .03). Once infarct size and MVO were dichotomized by using univariate receiver operating characteristic techniques, the only independent predictor of reverse remodeling was the presence of simultaneous nonextensive infarct-size MVO (infarct size < 30% of LV mass and MVO < 2.5% of LV mass) (odds ratio, 3.2; 95% CI: 1.8, 5.7; P < .001).CONCLUSIONAssessment of infarct size and MVO with cardiac MR imaging soon after STEMI enables one to make a decision in the prediction of reverse remodeling.

We aimed to characterize the organization of collagen within a fibrotic scar in swine and human samples from patients with chronic infarctions. Swine were subjected to occlusion of the left anterior descending artery followed by reperfusion 1 week (acute myocardial infarction group) or 1 month (chronic myocardial infarction group) after infarction. The organization of the collagen fibers (Fast Fourier Transform of samples after picrosirius staining; higher values indicate more disorganization) was studied in 100 swine and 95 human samples. No differences in collagen organization were found between the acute and chronic groups in the core area of the scar in the experimental model. In the chronic group, the endocardium [0.90 (0.84-0.94); median (interquartile range)], epicardium [0.84 (0.79-0.91)] and peripheral area [0.73 (0.63-0.83)] displayed a much more disorganized pattern than the core area of the fibrotic scar [0.56 (0.45-0.64)]. Similarly, in human samples, the collagen fibers were more disorganized in all of the outer areas than in the core of the fibrotic scar (P < 0.0001). Both in a highly controlled experimental model and in patient samples, collagen fibers exhibited an organized pattern in the core of the infarction, whereas the outer areas displayed a high level of inhomogeneity. This finding contributes pathophysiological information regarding the healing process and may lead to a clearer understanding of the genesis and invasive treatment of arrhythmias after acute myocardial infarction.

Programmed death-1 (PD-1) is an activation marker of lymphocytes induced by antigen specific and non-specific stimulation that is overexpressed soon after the trigger onset in order to limit inflammation [ [1] Agata Y. Kawasaki A. Nishimura H. Ishida Y. Tsubata T. Yagita H. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996; 8: 765-772 Crossref PubMed Scopus (1120) Google Scholar ]. In turn this leads to a certain regulation of the adaptive immune response by inducing controlled death in massively activated lymphocytes [ [2] Grabie N. Gotsman I. DaCosta R. Pang H. Stavrakis G. Butte M.J. et al. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation. 2007; 116: 2062-2071 Crossref PubMed Scopus (178) Google Scholar ]. Knowledge on the PD-1 in cardiovascular diseases is scarce and its dynamics in ST-segment elevation myocardial infarction (STEMI) is unknown.