Arantxa Hervas

Effect of ischemic postconditioning on microvascular obstruction in reperfused myocardial infarction. Results of a randomized study in patients and of an experimental model in swine.

BACKGROUND Ischemic postconditioning (PCON) appears as a potentially beneficial tool in ST-segment elevation myocardial infarction (STEMI). We evaluated the effect of PCON on microvascular obstruction (MVO) in STEMI patients and in an experimental swine model. METHODS A prospective randomized study in patients and an experimental study in swine were carried out in two university hospitals in Spain. 101 consecutive STEMI patients were randomized to undergo primary angioplasty followed by PCON or primary angioplasty alone (non-PCON). Using late gadolinium enhancement cardiovascular magnetic resonance, infarct size and MVO were quantified (% of left ventricular mass). In swine, using an angioplasty balloon-induced anterior STEMI model, MVO was defined as the % of area at risk without thioflavin-S staining. RESULTS In patients, PCON (n=49) in comparison with non-PCON (n=52) did not significantly reduce MVO (0 [0-1.02]% vs. 0 [0-2.1]% p=0.2) or IS (18 ± 13% vs. 21 ± 14%, p=0.2). MVO (>1 segment in the 17-segment model) occurred in 12/49 (25%) PCON and in 18/52 (35%) non-PCON patients, p=0.3. No significant differences were observed between PCON and non-PCON patients in left ventricular volumes, ejection fraction or the extent of hemorrhage. In the swine model, MVO occurred in 4/6 (67%) PCON and in 4/6 (67%) non-PCON pigs, p=0.9. The extent of MVO (10 ± 7% vs. 10 ± 8%, p=0.9) and infarct size (23 ± 14% vs. 24 ± 10%, p=0.8) was not reduced in PCON compared with non-PCON pigs. CONCLUSIONS Ischemic postconditioning does not significantly reduce microvascular obstruction in ST-segment elevation myocardial infarction. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT01898546.

Prediction of Reverse Remodeling at Cardiac MR Imaging Soon after First ST-Segment–Elevation Myocardial Infarction: Results of a Large Prospective Registry

PURPOSE To assess predictors of reverse remodeling by using cardiac magnetic resonance (MR) imaging soon after ST-segment-elevation myocardial infarction (STEMI). MATERIALS AND METHODS Written 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. RESULTS Patients 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). CONCLUSION Assessment of infarct size and MVO with cardiac MR imaging soon after STEMI enables one to make a decision in the prediction of reverse remodeling.

Prediction of long-term major events soon after a first ST-segment elevation myocardial infarction by cardiovascular magnetic resonance

BACKGROUND Cardiovascular magnetic resonance (CMR) predicts combined clinical events in post-ST-segment elevation myocardial infarction (STEMI) patients. However, its contribution to predicting long-term 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.

Inhomogeneity of collagen organization within the fibrotic scar after myocardial infarction: results in a swine model and in human samples

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.

Intracoronary Infusion of Thioflavin-S to Study Microvascular Obstruction in a Model of Myocardial Infarction

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.

A Multidisciplinary Assessment of Remote Myocardial Fibrosis After Reperfused Myocardial Infarction in Swine and Patients.

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.

Apoptosis and Mobilization of Lymphocytes to Cardiac Tissue Is Associated with Myocardial Infarction in a Reperfused Porcine Model and Infarct Size in Post-PCI Patients

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.

532In vivo characterization of microvascular obstruction resolution after reperfused myocardial infarction

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. ![Figure][1] [1]: pending:yes