Elena de Dios

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 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.

Microvascular obstruction in the right ventricle in reperfused anterior myocardial infarction. Macroscopic and pathologic evidence in a swine model

INTRODUCTION Data on right ventricular (RV) involvement in anterior myocardial infarction are scarce. The presence of RV microvascular obstruction (MVO) in this context has not been analyzed yet. The aim of the present study was to characterize the presence of MVO in the RV in a controlled experimental swine model of reperfused anterior myocardial infarction. MATERIALS AND METHODS Left anterior descending (LAD) artery-perfused area (thioflavin-S staining after selective infusion in LAD artery), infarct size (lack of triphenyltetrazolium-chloride staining) and MVO (lack of thioflavin-S staining in the core of the infarcted area) in the RV were studied. A quantitative (% of the ventricular volume) and semiquantitative (number of segments involved) analysis was carried out both in the RV and LV in a 90-min left anterior descending balloon occlusion and 3-day reperfusion model in swine (n=15). RESULTS RV infarction and RV MVO (>1 segment) were detected in 9 (60%) and 6 (40%) cases respectively. Mean LAD-perfused area, infarct size and MVO in the RV were 33.8 ± 13%, 13.53 ± 11.7% and 3.4 ± 4.5%. Haematoxylin and eosin stains and electron microscopy of the RV-MVO areas demonstrated generalized cardiomyocyte necrosis and inflammatory infiltration along with patched hemorrhagic areas. Ex-vivo nuclear magnetic resonance (T2 sequences) microimaging of RV-MVO showed, in comparison with remote non-infarcted territories, marked hypointense zones (corresponding to necrosis, inflammation and hemorrhage) in the core of hyperintense regions (corresponding to edema). CONCLUSIONS In reperfused anterior myocardial infarction, MVO is frequently present in the RV. It is associated with severe histologic repercussion on the RV wall. Nuclear magnetic resonance appears as a promising technique for the noninvasive detection of this phenomenon. Further studies are warranted to evaluate the pathophysiological and clinical implications.

Incidence, Outcomes, and Predictors of Ventricular Thrombus after Reperfused ST-Segment–Elevation Myocardial Infarction by Using Sequential Cardiac MR Imaging

Purpose To characterize the incidence, outcomes, and predictors of left ventricular (LV) thrombus by using sequential cardiac magnetic resonance (MR) imaging 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 committee on human research. In a cohort of 772 patients with STEMI, 392 (mean age, 58 years; range, 24-89 years) were retrospectively selected who were studied with cardiac MR imaging at 1 week and 6 months. Cardiac MR imaging guided the initiation and withdrawal of anticoagulants. Patients with LV thrombus at 6 months were restudied at 1 year. For predicting the occurrence of LV thrombus, a multiple regression model was applied. Results LV thrombus was detected in 27 of 392 patients (7%): 18 (5%) at 1 week and nine (2%) at 6 months. LV thrombus resolved in 22 of 25 patients (88%) restudied within the first year. During a mean follow-up of 181 weeks ± 168, patients with LV thrombus displayed a very low rate of stroke (0%), peripheral embolism (0%), and severe hemorrhage (n = 1, 3.7%). LV ejection fraction (LVEF) less than 50% (P < .001) and anterior infarction (P = .008) independently helped predict LV thrombus. The incidence of LV thrombus was as follows: (a) nonanterior infarction, LVEF 50% or greater (one of 135, 1%); (b) nonanterior infarction, LVEF less than 50% (one of 50, 2%); (c) anterior infarction, LVEF 50% or greater (two of 92, 2%); and (d) anterior infarction, LVEF less than 50% (23 of 115, 20%) (P < .001 for the trend). Conclusion Cardiac MR imaging contributes information for the diagnosis and therapy of LV thrombus after STEMI. Patients with simultaneous anterior infarction and LVEF less than 50% are at highest risk.

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.