Culprit Lesion Vessel Size and Risk of Reperfusion Injury in ST-Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study.

BACKGROUND: Microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) are well-established imaging biomarkers of failed myocardial tissue reperfusion in patients with ST-segment elevation-myocardial infarction treated with percutaneous coronary intervention. MVO and IMH are associated with an increased risk of adverse outcome independent of infarct size, but whether the size of the culprit lesion vessel plays a role in the occurrence and severity of reperfusion injury is currently unknown. This study aimed to evaluate the association between culprit lesion vessel size and the occurrence and severity of reperfusion injury as determined by cardiac magnetic resonance imaging. METHODS AND RESULTS: Patients (n=516) with first-time ST-segment-elevation myocardial infarction underwent evaluation with cardiac magnetic resonance at 4 (3-5) days after infarction. MVO was assessed with late gadolinium enhancement imaging and IMH with T2* mapping. Vessel dimensions were determined using catheter-based reference. Median culprit lesion vessel size was 3.1 (2.7-3.6) mm. MVO and IMH were found in 299 (58%) and 182 (35%) patients. Culprit lesion vessel size was associated with body surface area, diabetes, total ischemic time, postinterventional thrombolysis in myocardial infarction flow, and infarct size. There was no association between vessel size and MVO or IMH in univariable and multivariable analysis (P>0.05). These findings were consistent across patient subgroups with left anterior descending artery and non-left anterior descending artery infarctions and those with thrombolysis in myocardial infarction 3 flow post-percutaneous coronary intervention. CONCLUSIONS: Comprehensive characterization of myocardial tissue reperfusion injury by cardiac magnetic resonance revealed no association between culprit lesion vessel size and the occurrence of MVO and IMH in patients treated with primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction.

Evolution of REperfusion Strategies and impact on mortality in Old and Very OLD STEMI patients. The RESOVOLD-e-MUST study.

BACKGROUND: The use of myocardial reperfusion-mainly via angioplasty-has increased in our region to over 95%. We wondered whether old and very old patients have benefited from this development. METHODS: Setting: Greater Paris Area (Ile-de-France). DATA: Regional registry, prospective, including since 2003, data from 39 mobile intensive care units performing prehospital treatment of patients with ST segment elevation myocardial infarction (STEMI) (<24 h). PARAMETERS: Demographic, decision to perform reperfusion and outcome (in-hospital mortality). PRIMARY ENDPOINT: Reperfusion decision rate by decade over age 70. SECONDARY ENDPOINT: Outcome. RESULTS: We analysed the prehospital management of 27,294 patients. There were 21,311 (78%) men and 5,919 (22%) women with a median age of 61 (52-73 years). Among these patients, 8,138 (30%) were > 70 years, 3,784 (14%) > 80 years and 672 (2%) > 90 years.The reperfusion decision rate was 94%. It decreased significantly with age: 93, 90 and 76% in patients in their seventh, eighth and ninth decade, respectively. The reperfusion decision rate increased significantly over time. It increased in all age groups, especially the higher ones. Mortality was 6%. It increased significantly with age: 8, 16 and 25% in patients in their seventh, eighth and ninth decade, respectively. It significantly decreased over time in all age groups. The odds ratio of the impact of reperfusion decision on mortality reached 0.42 (0.26-0.68) in patients over 90 years. CONCLUSION: the increase in the reperfusion decision rate was the greatest in the oldest patients. It reduced mortality even in patients over 90 years of age.

Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease.

Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of ischemic heart disease. Improvements in prevention and treatment of ischemic heart disease have reduced mortality in developed countries over the last decades, but further progress is now stagnant, and morbidity and mortality from ischemic heart disease in developing countries are increasing. Significant problems remain to be resolved and require a better pathophysiological understanding. The present review attempts to briefly summarize the state of the art in myocardial ischemia/reperfusion research, with a view on both its coronary vascular and myocardial aspects, and to define the cutting edges where further mechanistic knowledge is needed to facilitate translation to clinical practice.

Scavenger Receptors in Myocardial Infarction and Ischemia/Reperfusion Injury: The Potential for Disease Evaluation and Therapy.

Scavenger receptors (SRs) are a structurally heterogeneous superfamily of evolutionarily conserved receptors that are divided into classes A to J. SRs can recognize multiple ligands, such as modified lipoproteins, damage-associated molecular patterns, and pathogen-associated molecular patterns, and regulate lipid metabolism, immunity, and homeostasis. According to the literature, SRs may play a critical role in myocardial infarction and ischemia/reperfusion injury, and the soluble types of SRs may be a series of promising biomarkers for the diagnosis and prognosis of patients with acute coronary syndrome or acute myocardial infarction. In this review, we briefly summarize the structure and function of SRs and discuss the association between each SR and ischemic cardiac injury in patients and animal models in detail. A better understanding of the effect of SRs on ischemic cardiac injury will inspire novel ideas for therapeutic drug discovery and disease evaluation in patients with myocardial infarction.

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.

Controlling Reperfusion Injury With Controlled Reperfusion: Historical Perspectives and New Paradigms.

Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.

Hypothermia for Reduction of Myocardial Reperfusion Injury in Acute Myocardial Infarction: Closing the Translational Gap.

Myocardial reperfusion injury-triggered by an inevitable inflammatory response after reperfusion-may undo a considerable part of the myocardial salvage achieved through timely percutaneous coronary intervention in patients with acute myocardial infarction. Because infarct size is strongly correlated to mortality and risk of heart failure, the importance of endeavors for cardioprotective therapies to attenuate myocardial reperfusion injury and decrease infarct size remains undisputed. Myocardial reperfusion injury is the result of several complex nonlinear phenomena, and for a therapy to be effective, it should act on multiple targets involved in this injury. In this regard, hypothermia remains a promising treatment despite a number of negative randomized controlled trials in humans with acute myocardial infarction so far. To turn the tide for hypothermia in patients with acute myocardial infarction, sophisticated solutions for important limitations of systemic hypothermia should continue to be developed. In this review, we provide a comprehensive overview of the pathophysiology and clinical expression of myocardial reperfusion injury and discuss the current status and possible future of hypothermia for cardioprotection in patients with acute myocardial infarction.

Mechanism of succinate efflux upon reperfusion of the ischaemic heart.

AIMS: Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS: To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION: Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.

Ambra1 Alleviates Hypoxia/Reoxygenation Injury in H9C2 Cells by Regulating Autophagy and Reactive Oxygen Species.

Reperfusion therapy is the most important method for treating acute myocardial infarction. However, myocardial ischemia reperfusion injury (MIRI) can offset the benefit of reperfusion therapy and worsen the outcome. In both ischemia and reperfusion, autophagy remains problematic. Activating molecule in Beclin1-regulated autophagy (Ambra1) is an important protein in autophagy regulation, and its function in MIRI remains unclear. Thus, we used H9C2 cells to investigate the function of Ambra1 in MIRI and the underlying mechanisms involved. Hypoxia and reoxygenation of H9C2 cells were used to mimic MIRI in vitro. During hypoxia, autophagy flux was blocked, then recovered in reoxygenation. Ambra1 overexpression increased autophagy in the H9C2 cells, as the LC3B II/I ratio increased, and alleviated cellular necrosis and apoptosis during hypoxia and reoxygenation. This effect was counteracted by an autophagy inhibitor. Knocking down Ambra1 can block autophagy which P62 sediment/supernatant ratio increased while the ratio of LC3B II/I decreased, and worsen outcomes. Ambra1 enhances autophagy in H9C2 cells by improving the stability and activity of the ULK1 complex. Reactive oxygen species (ROS) are an important cause of MIRI. ROS were reduced when Ambra1 was overexpressed and increased when Ambra1 was knocked down, indicating that Ambra1 can protect against hypoxia and reoxygenation injury in H9C2 cells by promoting autophagy and reducing ROS.

Quantification of intramyocardial hemorrhage volume using magnetic resonance imaging with three-dimensional T1-weighted sequence in patients with ischemia-reperfusion injury: a semi-automated image processing technique.

Although intramyocardial hemorrhage (IMH) is a poor prognostic factor caused by ischemia reperfusion injury, little evidence is available regarding the association between IMH volume and biomarkers. In the present study, we measured IMH volume using three-dimensional (3D) T1-weighted magnetic resonance imaging (T1-MRI) and investigated its association with biomarkers. Moreover, the accuracy of semi-automatic measurement of IMH volume was validated. We retrospectively enrolled 33 consecutive patients (mean age 67 ± 11 years) who underwent cardiac MRI after reperfusion therapy for acute myocardial infarction. IMH was observed in 4 patients (12.1%). Receiver operating characteristics (ROC) analysis of creatine kinase (CK) and CK-muscle/brain (CK-MB) tests for detecting IMH were performed. IMH volume measured using semi-automatic methods by a 2 standard deviation (SD) threshold was compared to manual measurements using the Spearman's correlation coefficient (ρ) and Bland-Altman analyses. ROC analysis revealed optimal cutoff values of CK: 2460 IU/l and CK-MB: 231 IU/l (area under the curve: 0.95 and 0.91; sensitivity: 86% and 79%; specificity: 100% for both). IMH volume with the 2SD threshold correlated with that of the manual measurement [5.84 g (3.30 to 9.00) g vs. 8.07 g (5.37 to 9.33); ρ: 0.85, p < 0.01; bias (limit of agreement): - 0.01 g (- 0.51 to 0.49); intraclass correlation coefficients 0.84 (0.75 to 0.90)]. Our findings could help identify the risk of IMH after reperfusion therapy with biomarkers. 3D T1-MRI can semi-automatically provide accurate IMH volume without being time-consuming.

Residual atherothrombotic burden after primary percutaneous coronary intervention and myocardial reperfusion-An optical frequency domain imaging study.

OBJECTIVES: We aimed to assess the relationship between residual in-stent atherothrombotic burden (ATB) after primary percutaneous coronary intervention (PCI) measured by optical frequency domain imaging (OFDI) using different measurement methods and myocardial blush grade (MBG). BACKGROUND: The impact of residual ATB after primary PCI on myocardial reperfusion remains unclear. METHODS: We prospectively included 60 ST-elevation myocardial infarction patients pretreated with aspirin and ticagrelor. OFDI volumetric quantification using planimetry (with intervals every frame or every millimeter) and semiquantitative score were used to determine ATB. Patients were divided into two groups according to final MBG 3 or <3. RESULTS: The mean ATB was 10.08 ± 5.21%. ATB was lower in patients with final MBG 3 compared to those with impaired MBG, regardless of the measurement method (8.15 ± 5.58 vs. 11.77 ± 4.28%; p = .007 for quantification per frame; 7.8 ± 5.19 vs. 11.07 ± 4.07%; p = .009 for quantification per mm and 11.21 ± 11.75 vs. 22.91 ± 17.35; p = .003 for the semiquantitative thrombus score, respectively). CONCLUSION: Residual post-stenting ATB remains substantial after primary PCI in STEMI patients, even when pretreated with ticagrelor and aspirin. ATB appears as a significant correlate of suboptimal myocardial reperfusion, a known surrogate of clinical outcome.

Fragmented QRS predicts reperfusion failure and in-hospital mortality in ST-Elevation myocardial infarction: a systematic review and meta-analysis.

Objective: Recent studies have shown that fragmented QRS (fQRS) is associated with unfavourable outcomes in STEMI patients. However, there is controversy amongst studies. We performed a systematic review and meta-analysis to explore the effect of fQRS on reperfusion failure and in-hospital mortality among this population.Methods: We searched the databases of MEDLINE and EMBASE from inception to October 2018. Included studies were published cohort studies of STEMI patients that underwent primary percutaneous coronary intervention (pPCI) and thrombolysis. Data from each study were combined using the random-effects model.Results: Ten studies from January 2011 to October 2018 (2753 patients, 1075 patients with fQRS), were included. The fQRS was associated with higher risk of reperfusion failure in pPCI when defined by ST-segment resolution (OR = 3.08, 95% CI = 1.27-7.46, p-value = .013) but not when defined by TIMI flow grade (pooled OR = 1.45, 95% CI = 0.83-2.54, p-value = .192). In thrombolysis, fQRS was associated with higher risk of reperfusion failure when defined by both ST-segment resolution (pooled OR = 4.35, 95% CI = 1.80-10.49, p-value = .001) and TIMI flow grade (OR = 3.70, 95% CI = 2.10-6.53, p-value < .001). The fQRS was also associated with an increased risk of in-hospital mortality in both pPCI (pooled OR = 4.41, 95% CI = 1.60-12.16, p-value = .004) and thrombolysis (pooled OR = 2.38, 95% CI = 1.06-5.35, p-value = .036).Conclusions: Our meta-analysis demonstrated that fQRS in STEMI patients was associated with reperfusion failure as well as in-hospital mortality.

Can WeChat group-based intervention reduce reperfusion time in patients with ST-segment myocardial infarction? A controlled before and after study.

BACKGROUND: Pre-hospital identification of acute ST-elevation myocardial infarction and activation of the catheterization laboratory can reduce first medical contact to wire-crossing times. We conducted a study on providing 24-hour tele-electrocardiography services via the WeChat group application, aiming to reduce the time taken for diagnosis and treatment of ST-elevation myocardial infarction. METHODS: A controlled before and after study was conducted on 140 ST-elevation myocardial infarction patients who were initially seen in non-percutaneous coronary intervention-capable hospital and transferred for primary percutaneous coronary intervention at our percutaneous coronary intervention centre from 1 February to 31 October 2018. The WeChat group had 70 patients with pre-hospital electrocardiography transmission via WeChat and the control group had 70 patients who did not transfer pre-hospital electrocardiography. The reperfusion time of the two groups was compared to evaluate the effect of the WeChat group intervention. RESULTS: In the WeChat group versus the control group, the median symptom onset to first medical contact time was similar (129 vs 150 min, p > 0.05), but the median first medical contact to wire, door to wire and first medical contact to catheterization laboratory activity were significantly shorter (132 vs 171 minutes, p < 0.001; 60 vs 95 minutes, p < 0.001; 29 vs 74 minutes, p < 0.001, respectively). CONCLUSIONS: Pre-hospital electrocardiography transfer via a WeChat group resulted in earlier reperfusion of ST-elevation myocardial infarction patients who were transferred from the non-percutaneous coronary intervention centre.

Hype or hope: Vagus nerve stimulation against acute myocardial ischemia-reperfusion injury.

Acute myocardial infarction (MI) is a major cause of death worldwide. Although timely and successful reperfusion could reduce myocardial ischemia injury, limit infarct size, and improve ventricular dysfunction and reduce acute mortality, restoring blood flow might also lead to unwanted myocardial ischemic-reperfusion (I/R) injury. Pre-clinical studies have demonstrated that multiple approaches are capable of attenuating the myocardial I/R injury. However, there is still no effective therapy for preventing myocardial I/R injury for the clinical setting. It is known that myocardial I/R injury could induce cardiac autonomic imbalance with over-activated sympathetic tone and reduced vagal activity, in turn, contributing to pathogenesis of myocardial I/R injury. Cumulative evidence shows that the enhancement of vagal activity, so called vagus nerve stimulation (VNS), is able to reduce injury and promote recovery of injured myocardium. Therefore, VNS might be a potentially novel strategy choice for preventing/attenuating myocardial I/R injury. In this review, we describe the protective role of VNS in myocardial I/R injury and related potential mechanisms. Then, we discuss the challenge and the opportunity of VNS in the treatment of acute myocardial I/R injury.

Redox signaling in ischemic postconditioning protection involves PKCε and Erk1/2 pathways and converges indirectly in Nrf2 activation.

Ischemic-postconditioning (iPostC) exerts cardioprotection by preserving redox homeostasis in the reperfused heart. This protective effect has been associated with the activation of endogenous antioxidant response driven by transcription factor Nrf2 and with the activation of 'reperfusion injury salvage kinases' (RISK) as PI3K, PKC and Erk1/2. Redox homeostasis is essential for normal cell physiology since reactive oxygen species (ROS) are crucial for processes that involve protein signaling. Thus, it has become clear that not only the perturbation of redox balance to oxidative state is deleterious but also towards a reductive state contributing to pathogenesis of diseases. However, there is still a scarce knowledge about the role of ROS in the cardioprotective signals mediated by RISK in postconditioned hearts. Therefore, we studied the role of ROS as initiator of RISK signaling molecules in iPostC-conferred cardioprotection. With the aim to study the relationship between redox-dependent RISK activation and the downstream activation of the transcription factor Nrf2, we evaluated the effect of redox signaling disruption by the effect of ascorbic acid in iPostC hearts. Our results showed that PKCε and Erk1/2 activation is redox-dependent and that concurs downstream with Nrf2 deficient activation. Besides, using inhibitors we found that neither PI3K nor Erk1/2 are directly related with Nrf2 activation, indicating that these kinases have other targets. We conclude that redox signaling participates in cardioprotection triggered by iPostC through the action of kinase-dependent and -independent mechanisms and concurred with the downstream regulation of Nrf2-mediated antioxidant response to prolonged redox balance during long reperfusion.

Cardiac magnetic resonance-tissue tracking for the early prediction of adverse left ventricular remodeling after ST-segment elevation myocardial infarction.

Cardiac magnetic resonance-tissue tracking (CMR-TT)-derived myocardial strain after ST-elevation myocardial infarction (STEMI) is related to adverse cardiac events. We aimed to investigate the feasibility of CMR-TT for the early prediction of adverse left ventricular (LV) remodeling after STEMI. We retrospectively searched our institution's STEMI registry for patients who underwent reperfusion therapy, post-reperfusion CMR within 1 week after STEMI, and follow-up CMR. CMR-TT analysis was performed using cine imaging of post-reperfusion CMR. Adverse LV remodeling was defined as an increase in end-diastolic LV volume by 20% or more on follow-up CMR (median interval between serial CMR exams, 197 days; interquartile, 174-241 days). A total of 82 patients (age, 59.2 ± 11.1 years; male:female = 73:9) were included and divided into two groups: STEMI without (n = 62) and with (n = 20) adverse LV remodeling. Patients with LV remodeling showed significantly higher peak creatine kinase-MB and troponin I levels and a larger infarct size compared with those without LV remodeling (p = 0.001, p = 0.001, and p = 0.010, respectively). Global circumferential, radial, and longitudinal strain (GLS) also differed significantly between the groups (p = 0.001, p = 0.004, and p < 0.001, respectively). Logistic regression and receiver operating characteristic curve analyses demonstrated that GLS was an independent predictor of LV remodeling [odds ratio (OR) = 1.282, 95% confidence interval (CI) = 1.060-1.55 p = 0.011] with an optimal cut-off of - 12.84 (AUC = 0.756, 95% CI = 0.636-0.887, p < 0.001). CMR-TT-derived GLS may aid the early prediction of adverse LV remodeling after reperfusion, within 1 week after STEMI.