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Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): "Instituto de Salud Carlos III" and "Fondos Europeos de Desarrollo Regional FEDER" and Conselleria de Educación – Generalitat Valenciana. Introduction After acute myocardial infarction (AMI), the lack of oxygen and nutrients leads to cardiomyocyte necrosis and eventually to the formation of a collagen-based scar. Infarct scar characteristics, such as collagen bundle orientation, have a relevant influence on scar mechanics, the occurrence of cardiac arrhythmias, left ventricular dilation or aneurysm formation, wall stiffness, and the development of wall rupture or heart failure. However, the most adequate method for collagen bundle orientation (CBO) measurement in myocardial scar is not established. Purpose We aim to compare the measurement of collagen bundle orientation in infarct scar by Fourier analysis in three different histopathological techniques. Methods Juvenile swine (n=21) were subjected, by means of percutaneous balloon inflation, to a transient 90-min occlusion of mid left anterior descending artery followed by one month of reperfusion (chronic AMI group). Samples were obtained from the infarcted zone and stained with Masson's trichrome, Picrosirius red and Haematoxylin-Eosin (H-E) standard protocols. Five microphotographs of the myocardial scar were taken at 200x magnification with light, polarised and confocal microscopy, respectively. A single observer measured CBO by means of Fast Fourier Transform analysis using a semi-automated protocol. Comparability between techniques was studied by the Intraclass Correlation Coefficient (ICC), the coefficient of variation (CV) and the Bland-Altman (B&A) plots and limits of agreement. Results Measurement of CBO in Masson's trichrome tended to show higher (more "random-oriented") values than in Picrosirius and H-E+confocal techniques (ICC 0.79 and 0.7, p=0.001 and 0.005; B&A 0.29 to -0.02 and 0.43 to 0.01; CV 6.97% and 12.98%, respectively). However, measurement of CBO in Picrosirius and H-E+confocal techniques showed an "almost perfect" agreement (ICC 0.84, p<0.001; B&A 0.28 to -0.09; CV 17.33%). Selective staining and/or visualization of collagen in these latter techniques may underlie our findings, contrary to non-selective Masson's trichrome. Conclusion Picrosirius red staining (visualized with polarised microscopy) and Haematoxylin-Eosin (visualized with confocal microscopy) are comparable in terms of collagen bundle orientation measurement by Fourier analysis in an animal model of chronic infarct scar. Masson's trichrome (visualized with light microscopy) tends to show more "random-oriented" values, potentially due to non-specific staining and visualization of non-collagenous structures such as cells, and should not be recommended for this specific purpose. [ABSTRACT FROM AUTHOR]

Background: Left ventricular thrombus (LVTh) is a severe complication after ST-segment elevation myocardial infarction (STEMI)., Objectives: We aim to predict LVTh occurrence by cardiac magnetic resonance (CMR) using clinical, echocardiographic, and electrocardiographic (ECG) variables readily available at admission., Methods: We included 590 reperfused STEMI patients who underwent early (1-week) and/or late (6-month) CMR in our institution. Baseline clinical, echocardiographic (left ventricular ejection fraction -LVEF-) and ECG data (summatory of ST-segment elevation -sum-STE- and Q-wave and residual ST-elevation >1 mm -Q-STE-) during admission were registered. Multivariate binary logistic regression models and receiver operating characteristic curves were computed for LVTh prediction., Results: LVTh was detected by CMR in 43 (7.3 %) patients and was predicted by previous chronic coronary syndrome (CCS, HR 4.74 [1.82-12.35], p = 0.001), anterior STEMI (HR 10.93 [2.47-48.31], p = 0.002), LVEF (HR 0.96 [0.93-0.99] per %, p = 0.008), maximum sum-STE (HR 1.04 [1.01-1.07] per mm, p = 0.04), and Q-STE (HR 1.31 [1.08-1.6] per lead, p = 0.008). High-risk patients with both major (anterior STEMI and Q-STE in ≥1 leads) and 1-3 minor (CCS, maximum sum-STE >10 mm, LVEF <50%) factors showed the highest LVTh risk (19.6 % within 6 months). The model showed excellent discrimination ability (area under the curve=0.85 [0.81-0.9], p < 0.001). Simplified 4-variable (excluding sum-STE) and 3-variable (also excluding CCS) risk scores showed similar discrimination ability and were externally validated., Conclusions: LVTh within 6 months post-STEMI can be predicted using pre-discharge clinical (anterior infarction and CCS), echocardiographic (LVEF), and ECG (sum-STE and Q-STE) data. Our results can help select patients who should undergo CMR after STEMI for LVTh detection., Competing Interests: Conflict of interest disclosures Julio Núñez reports personal fees from Alleviant, Bayer, Astra Zeneca, Novartis, Boehringer-Ingelheim, Rovi, and Novo Nordisk, not related to the contents of this paper. The other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship.

We aimed to assess the correlation of cardiovascular magnetic resonance (CMR)-derived epicardial adipose tissue (EAT) with infarct size (IS) and residual systolic function in ST-segment elevation myocardial infarction (STEMI). We enrolled patients discharged for a first anterior reperfused STEMI submitted to undergo CMR. EAT, left ventricular (LV) ejection fraction (LVEF), and IS were quantified at the 1-week ( n = 221) and at 6-month CMR ( n = 167). At 1-week CMR, mean EAT was 31 ± 13 mL/m 2 . Patients with high EAT volume ( n = 72) showed larger 1-week IS. After adjustment, EAT extent was independently related to 1-week IS. In patients with large IS at 1 week (>30% of LV mass, n = 88), those with high EAT showed more preserved 6-month LVEF. This association persisted after adjustment and in a 1:1 propensity score-matched patient subset. Overall, EAT decreased at 6 months. In patients with large IS, a greater reduction of EAT was associated with more preserved 6-month LVEF. In STEMI, a higher presence of EAT was associated with a larger IS. Nevertheless, in patients with large infarctions, high EAT and greater subsequent EAT reduction were linked to more preserved LVEF in the chronic phase. This dual and paradoxical effect of EAT fuels the need for further research in this field.

Endothelial cells (ECs) are a key target for cardioprotection due to their role in preserving cardiac microvasculature and homeostasis after myocardial infarction (MI). Our goal is to identify the genes involved in post-MI EC proliferation, EC apoptosis, and angiogenesis regulation via RNA-sequencing transcriptomic datasets. Using eight studies from the Gene Expression Omnibus, RNA-sequencing data from 92 mice submitted to different times of coronary ischemia or sham were chosen. Functional enrichment analysis was performed based on gene ontology biological processes (BPs). Apoptosis-related BPs are activated up to day 3 after ischemia onset, whereas endothelial proliferation occurs from day 3 onwards, including an overrepresentation of up to 37 genes. Endothelial apoptosis post-MI is triggered via both the extrinsic and intrinsic signaling pathways, as reflected by the overrepresentation of 13 and 2 specific genes, respectively. BPs implicated in new vessel formation are upregulated soon after ischemia onset, whilst the mechanisms aiming at angiogenesis repression can be detected at day 3. Overall, 51 pro-angiogenic and 29 anti-angiogenic factors displayed altered transcriptomic expression post-MI. This is the first study using RNA sequencing datasets to evaluate the genes participating in post-MI endothelium physiology and angiogenesis regulation. These novel data could lay the groundwork to advance understanding of the implication of ECs after MI.

Background: Extracellular matrix (ECM) suffers substantial alterations after myocardial infarction (MI), including the invasion of leukocyte subtypes. Despite a complete reopening at epicardial level, hypoperfusion within the infarcted myocardium, known as microvascular obstruction (MVO), occurs and exerts a negative impact on ventricular remodeling. In this study, ECM composition at MVO regions was described using a morphometric analysis., Methods: MI was induced in female swine (n = 10) by transitory 90-minute coronary occlusion followed by seven days of reperfusion. Prior to euthanasia, intracoronary thioflavin-S was infused. Within the infarcted myocardium, regions displaying MVO (thioflavin-S-) or no MVO (thioflavin-S+) were isolated and stained to morphometrically compare ECM composition., Results: As reflected by cell invasion through ECM, areas with MVO displayed an enlarged presence of neutrophils and lymphocytes, whilst no differences in the amount of macrophages and myofibroblasts were detected compared to infarcted myocardium without MVO. Indeed, those regions with macroscopic MVO showed lower capillary density than areas without MVO. Lastly, a significant reduction in the extension of total collagen, type I, but not type III, collagen, laminin, and fibronectin together with an augmentation of polysaccharides were noted in areas showing MVO compared to those without microvascular injury., Conclusions: ECM composition in infarcted regions with MVO isolated from female swine displays a higher presence of inflammatory infiltrate and polysaccharides as well as reduced number of microvessels and collagen content compared to those areas without microvascular hypoperfusion. These characteristics might underlie the development of adverse ventricular remodeling in MI patients with extensive MVO., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Little is known about the occurrence and implications of persistent microvascular obstruction (MVO) after reperfused ST-segment elevation myocardial infarction (STEMI)., Objectives: The authors used cardiac magnetic resonance (CMR) to characterize the impact of persistent MVO on adverse left ventricular remodeling (ALVR)., Methods: A prospective registry of 471 STEMI patients underwent CMR 7 (IQR: 5-10) days and 198 (IQR: 167-231) days after infarction. MVO (≥1 segment) and ALVR (relative increase >15% at follow-up CMR) of left ventricular end-diastolic index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were determined., Results: One-week MVO occurred in 209 patients (44%) and persisted in 30 (6%). The extent of MVO (P = 0.026) and intramyocardial hemorrhage (P = 0.001) at 1 week were independently associated with the magnitude of MVO at follow-up CMR. Compared with patients without MVO (n = 262, 56%) or with MVO only at 1 week (n = 179, 38%), those with persistent MVO at follow-up (n = 30, 6%) showed higher rates of ALVR-LVEDVI (22%, 27%, and 50%; P = 0.003) and ALVR-LVESVI (20%, 21%, and 53%; P < 0.001). After adjustment, persistent MVO at follow-up (≥1 segment) was independently associated with ΔLVEDVI (relative increase, %) (P < 0.001) and ΔLVESVI (P < 0.001). Compared with a 1:1 propensity score-matched population on CMR variables made up of 30 patients with MVO only at 1 week, patients with persistent MVO more frequently displayed ALVR-LVEDVI (12% vs 50%; P = 0.003) and ALVR-LVESVI (12% vs 53%; P = 0.001)., Conclusions: MVO persists in a small percentage of patients in chronic phase after STEMI and exerts deleterious effects in terms of LV remodeling. These findings fuel the need for further research on microvascular injury repair., Competing Interests: Funding Support and Author Disclosures This work was supported by Instituto de Salud Carlos III and Fondos Europeos de Desarrollo Regional FEDER (grant numbers PI20/00637, CIBERCV16/11/00486, CIBERCV16/11/00420, CIBERCV16/11/00479, and a postgraduate contract CM21/00175 to V.M.-G.), by Conselleria de Educación–Generalitat Valenciana (PROMETEO/2021/008) and by Sociedad Española de Cardiología (grant SEC/FEC-INV-CLI 21/024). Dr Gavara has received financial support from the Agencia Estatal de Investigación (grant FJC2020-043981-I/AEI/10.13039/501100011033). Dr Moratal has received financial support from the Conselleria d’Educació, Investigació, Cultura i Esport, Generalitat Valenciana (grants AEST/2019/037, AEST/2020/029). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Implantable cardioverter defibrillators (ICD) are effective as a primary prevention measure of ventricular tachyarrhythmias in patients with ST-segment elevation myocardial infarction (STEMI) and depressed left ventricular ejection fraction (LVEF). The implications of using cardiac magnetic resonance (CMR) instead of echocardiography (Echo) to assess LVEF prior to the indication of ICD in this setting are unknown., Materials and Methods: We evaluated 52 STEMI patients (56.6 ± 11 years, 88.5% male) treated with ICD in primary prevention who underwent echocardiography and CMR prior to ICD implantation. ICD implantation was indicated based on the presence of heart failure and depressed LVEF (≤ 35%) by echocardiography, CMR, or both. Prediction of ICD therapies (ICD-T) during follow-up by echocardiography and CMR before ICD implantation was assessed., Results: Compared to echocardiography, LVEF was lower by cardiac CMR (30.2 ± 9% vs. 37.4 ± 7.6%, p < 0.001). LVEF ≤ 35% was detected in 24 patients (46.2%) by Echo and in 42 (80.7%) by CMR. During a mean follow-up of 6.1 ± 4.2 years, 10 patients received appropriate ICD-T (3.16 ICD-T per 100 person-years): 5 direct shocks to treat very fast ventricular tachycardia or ventricular fibrillation, 3 effective antitachycardia pacing (ATP) for treatment of ventricular tachycardia, and 2 ineffective ATP followed by shock to treat ventricular tachycardia. Echo-LVEF ≤ 35% correctly predicted ICD-T in 4/10 (40%) patients and CMR-LVEF ≤ 35% in 10/10 (100%) patients. CMR-LVEF improved on Echo-LVEF for predicting ICD-T (area under the curve: 0.76 vs. 0.48, p = 0.04)., Conclusion: In STEMI patients treated with ICD, assessment of LVEF by CMR outperforms Echo-LVEF to predict the subsequent use of appropriate ICD therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marcos-Garcés, Perez, Gavara, Lopez-Lereu, Monmeneu, Rios-Navarro, de Dios, Merenciano-González, Gabaldon-Pérez, Ferrero-De-Loma-Osorio, Martínez-Brotons, Bondanza, Sánchez-Gómez, Albiach, Nunez, Bayés-Genís, Chorro, Ruiz-Granell and Bodi.)

Aims: Traditional adverse events in chronic coronary syndrome (CCS) include atherothrombotic events but usually exclude heart failure (HF). Data are scarce about how new-onset HF modifies mortality risk. We aimed to determine the incidence of HF and compare its long-term mortality risk with myocardial infarction (MI) and stroke in patients with known or suspected CCS., Methods: We prospectively evaluated 5811 consecutive HF-free patients submitted to vasodilator stress cardiac magnetic resonance (CMR) for known or suspected CCS. Ischaemic burden and left ventricular ejection fraction were assessed by CMR. HF included outpatient diagnosis or acute HF hospitalization. The mortality risk for the incident events and their cross-comparisons were evaluated using a Markov illness-death model with transition-specific survival models., Results: The mean age was 55 ± 11 years, and 38.9% were female. At a median follow-up of 5.44 (IQR = 2.53-8.55) years, 591 deaths were registered (1.79 per 100 P-Y). The rates of new-onset HF were higher compared with MI and stroke [1.02, 0.62, and 0.51, respectively (P < 0.05)]. The adjusted association between new-onset HF, MI, and stroke, and subsequent mortality was time dependent. The risk increased almost linearly for HF and became significant by the third year. By Year 10, the mortality risk attributable to new-onset HF was more than 2.5-fold (HR: 2.68, 95% CI = 1.74-4.12). For MI, there was a significant increase in mortality risk up to the second year, followed by a monotonic decrease. For stroke, the mortality risk increased for the entire follow-up but became significant by the third year. A cross-comparison among incident endpoints HF outnumbers risk for those with MI by the sixth year (HR year6.3 : 1.88, 95% CI = 1.03-3.43). There was no difference in mortality risk between incident HF and stroke., Conclusions: In patients with CCS, long-term rates of incident HF were higher than MI and stroke. Patients with new-onset HF showed a higher risk of long-term mortality., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Residual ST-segment elevation after ST-segment elevation myocardial infarction (STEMI) has traditionally been considered a predictor of left ventricular (LV) dysfunction and ventricular aneurism. However, the implications in terms of long-term prognosis and cardiac magnetic resonance (CMR)-derived structural consequences are unclear. A total of 488 reperfused STEMI patients were prospectively included. The number of Q wave leads with residual ST-segment elevation > 1 mm (Q-STE) at pre-discharge ECG was assessed. LV ejection fraction (LVEF, %) and infarct size (IS, % of LV mass) were quantified in 319 patients at 6-month CMR. Major adverse cardiac events (MACE) were defined as all-cause death and/or re-admission for acute heart failure (HF), whichever occurred first. During a mean follow-up of 6.1 years, 92 MACE (18.9%), 39 deaths and 53 HF were recorded. After adjustment for baseline characteristics, Q-STE (per lead with > 1 mm) was independently associated with a higher risk of long-term MACE (HR 1.24 [1.07-1.44] per lead, p = 0.004), reduced (< 40%) LVEF (HR 1.36 [1.02-1.82] per lead, p = 0.04) and large (> 30% of LV mass) IS (HR 1.43 [1.11-1.85] per lead, p = 0.006) at 6-month CMR. Patients with Q-STE ≥ 2 leads (n = 172, 35.2%) displayed lower MACE-free survival, more depressed LVEF, and larger IS at 6-month CMR (p < 0.001 for all comparisons). Residual ST-segment elevation after STEMI represents a universally available tool that predicts worse long-term clinical and CMR-derived structural outcomes., (© 2022. The Author(s).)

Background: Stress cardiac MRI permits comprehensive evaluation of patients with known or suspected chronic coronary syndromes (CCS). The impact of sex on the use of invasive cardiac angiography (ICA) after vasodilator stress cardiac MRI is unclear., Purpose: To evaluate the impact of sex on ICA use after vasodilator stress cardiac MRI., Study Type: Retrospective., Population: A total of 6229 consecutive patients (age [mean ± standard deviation] 65.2 ± 11.5 years, 38.1% women)., Field Strength/sequence: A 5-T; a steady-state free-precession cine sequence; stress first-pass perfusion imaging; late enhancement imaging., Assessment: Patients underwent vasodilator stress cardiac MRI for known or suspected CCS. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model)., Statistical Tests: Multivariate logistic regression was used to evaluate the potential differential association between ischemic burden and use of cardiac MRI-related ICA across sex., Results: A total of 1109 (17.8%) patients were referred to ICA, among which there were significantly more men (762, 19.7%) than women (347, 14.6%). Overall, after multivariate adjustment, female sex was not associated with lower use of ICA (odds ratio [OR] = 0.99; confidence interval [CI] 95%: 0.84-1.18, P = 0.934). However, significant sex differences were detected across ischemic burden. Whereas women with nonischemic vasodilator stress cardiac MRI (0 ischemic segments) were less commonly submitted to ICA (OR = 0.49; CI 95%: 0.35-0.69) in patients with ischemia (>1 ischemic segment), adjusted use of ICA was more frequent in women than men (OR = 1.27; CI 95%: 1.1-1.5)., Data Conclusions: In patients with known or suspected CCS submitted to undergo vasodilator stress cardiac MRI, cardiac MRI-related ICA may be overused in men without ischemia. Furthermore, ICA referral in patients with negative ischemia resulted in greater odds of revascularization in men., Evidence Level: 3 TECHNICAL EFFICACY: Stage 5., (© 2022 International Society for Magnetic Resonance in Medicine.)

Collagen bundle orientation (CBO) in myocardial infarct scars plays a major role in scar mechanics and complications after infarction. We aim to compare four histopathological methods for CBO measurement in myocardial scarring. Myocardial infarction was induced in 21 pigs by balloon coronary occlusion. Scar samples were obtained at 4 weeks, stained with Masson's trichrome, Picrosirius red, and Hematoxylin-Eosin (H&E), and photographed using light, polarized light microscopy, and confocal microscopy, respectively. Masson's trichrome images were also optimized to remove non-collagenous structures. Two observers measured CBO by means of a semi-automated, Fourier analysis protocol. Interrater reliability and comparability between techniques were studied by the intraclass correlation coefficient (ICC) and Bland-Altman (B&A) plots and limits of agreement. Fourier analysis showed an almost perfect interrater reliability for each technique (ICC ≥ 0.95, p < 0.001 in all cases). CBO showed more randomly oriented values in Masson's trichrome and worse comparability with other techniques (ICC vs. Picrosirius red: 0.79 [0.47-0.91], p = 0.001; vs. H&E-confocal: 0.70 [0.26-0.88], p = 0.005). However, optimized Masson's trichrome showed almost perfect agreement with Picrosirius red (ICC 0.84 [0.6-0.94], p < 0.001) and H&E-confocal (ICC 0.81 [0.54-0.92], p < 0.001), as well as these latter techniques between each other (ICC 0.84 [0.60-0.93], p < 0.001). In summary, a semi-automated, Fourier-based method can provide highly reproducible CBO measurements in four different histopathological techniques. Masson's trichrome tends to provide more randomly oriented CBO index values, probably due to non-specific visualization of non-collagenous structures. However, optimization of Masson's trichrome microphotographs to remove non-collagenous components provides an almost perfect comparability between this technique, Picrosirius red and H&E-confocal., (© 2022. The Author(s).)

Background: Magnetic resonance imaging (MRI) is the most accurate imaging technique for left ventricular ejection fraction (LVEF) quantification, but as yet the prognostic value of LVEF assessment at any time after ST-segment elevation myocardial infarction (STEMI) for subsequent major adverse cardiac event (MACE) prediction is uncertain., Purpose: To explore the prognostic impact of MRI-derived LVEF at any time post-STEMI to predict subsequent MACE (cardiovascular death or re-admission for acute heart failure)., Study Type: Prospective., Population: One thousand thirteen STEMI patients were included in a multicenter registry., Field Strength/sequence: 1.5-T. Balanced steady-state free precession (cine imaging) and segmented inversion recovery steady-state free precession (late gadolinium enhancement) sequences., Assessment: Post-infarction MRI-derived LVEF (reduced [r]: <40%; mid-range [mr]: 40%-49%; preserved [p]: ≥50%) was sequentially quantified at 1 week and after >3 months of follow-up., Statistical Tests: Multi-state Markov model to determine the prognostic value of each LVEF state (r-, mr- or p-) at any time point assessed to predict subsequent MACE. A P-value <0.05 was considered to be statistically significant., Results: During a 6.2-year median follow-up, 105 MACE (10%) were registered. Transitions toward improved LVEF predominated and only r-LVEF (at any time assessed) was significantly related to a higher incidence of subsequent MACE. The observed transitions from r-LVEF, mr-LVEF, and p-LVEF states to MACE were: 15.3%, 6%, and 6.7%, respectively. Regarding the adjusted transition intensity ratios, patients in r-LVEF state were 4.52-fold more likely than those in mr-LVEF state and 5.01-fold more likely than those in p-LVEF state to move to MACE state. Nevertheless, no significant differences were found in transitions from mr-LVEF and p-LVEF states to MACE state (P-value = 0.6)., Data Conclusion: LVEF is an important MRI index for simple and dynamic post-STEMI risk stratification. Detection of r-LVEF by MRI at any time during follow-up identifies a subset of patients at high risk of subsequent events., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

Aims: The role of revascularization in chronic coronary syndrome (CCS) and the value of ischaemia vs. anatomy to guide decision-making are in constant debate. We explored the potential of a combined assessment of ischaemic burden by vasodilator stress cardiovascular magnetic resonance (CMR) and presence of multivessel disease by angiography to predict the effect of revascularization on all-cause mortality in CCS., Methods and Results: The study group comprised 1066 CCS patients submitted to vasodilator stress CMR pre-cardiac catheterization (mean age 66 ± 11 years, 69% male). Stress CMR-derived ischaemic burden (extensive if >5 ischaemic segments) and presence of multivessel disease in angiography (two- or three-vessel or left main stem disease) were computed. The influence of revascularization on all-cause mortality was explored and adjusted hazard ratios (HRs) with the corresponding 95% confidence intervals were obtained. During a median 7.51-year follow-up, 557 (52%) CMR-related revascularizations and 308 (29%) deaths were documented. Revascularization exerted a neutral effect on all-cause mortality in the whole study group [HR 0.94 (0.74-1.19), P = 0.6], in patients without multivessel disease [n = 598, 56%, HR 1.12 (0.77-1.62), P = 0.6], and in those with multivessel disease without extensive ischaemic burden [n = 181, 17%, HR 1.66 (0.91-3.04), P = 0.1]. However, compared to non-revascularized patients, revascularization significantly reduced all-cause mortality in patients with simultaneous multivessel disease and extensive ischaemic burden (n = 287, 27%): 3.77 vs. 7.37 deaths per 100 person-years, HR 0.60 (0.40-0.90), P = 0.01., Conclusions: In patients with CCS submitted to catheterization, evidence of simultaneous extensive CMR-related ischaemic burden and multivessel disease identifies the subset in whom revascularization can reduce all-cause mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Cardiac magnetic resonance (CMR) performed early after ST-segment elevation myocardial infarction (STEMI) can improve major adverse cardiac event (MACE) risk prediction. We aimed to create a simple clinical-CMR risk score for early MACE risk stratification in STEMI patients., Methods: We performed a multicenter prospective registry of reperfused STEMI patients (n = 1118) in whom early (1-week) CMR-derived left ventricular ejection fraction (LVEF), infarct size and microvascular obstruction (MVO) were quantified. MACE was defined as a combined clinical endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (NF-MI) or re-admission for acute decompensated heart failure (HF)., Results: During a median follow-up of 5.52 [2.63-7.44] years, 216 first MACE (58 CV deaths, 71 NF-MI and 87 HF) were registered. Mean age was 59.3 ± 12.3 years and most patients (82.8%) were male. Based on the four variables independently associated with MACE, we computed an 8-point risk score: time to reperfusion >4.15 h (1 point), GRACE risk score > 155 (3 points), CMR-LVEF <40% (3 points), and MVO >1.5 segments (1 point). This score permitted MACE risk stratification: MACE per 100 person-years was 1.96 in the low-risk category (0-2 points), 5.44 in the intermediate-risk category (3-5 points), and 19.7 in the high-risk category (6-8 points): p < 0.001 in multivariable Cox survival analysis., Conclusions: A novel risk score including clinical (time to reperfusion >4.15 h and GRACE risk score > 155) and CMR (LVEF <40% and MVO >1.5 segments) variables allows for simple and straightforward MACE risk stratification early after STEMI. External validation should confirm the applicability of the risk score., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Vasodilator stress cardiac magnetic resonance (VS-CMR) has become crucial in the workup of patients with known or suspected chronic coronary syndrome (CCS). Whether traditional exercise ECG testing (ExECG) contributes prognostic information beyond VS-CMR is unclear., Methods: We retrospectively included 288 patients with known or suspected CCS who had undergone ExECG and subsequent VS-CMR in our institution. Clinical, ExECG, and VS-CMR variables were recorded. We defined the serious adverse events (SAE) as a combined endpoint of acute coronary syndrome, admission for heart failure, or all-cause death., Results: During a mean follow-up of 4.2 ± 2.15 yr, we registered 27 SAE (15 admissions for acute coronary syndrome, eight admissions for heart failure, and four all-cause deaths). Once adjusted for clinical, ExECG, and VS-CMR parameters associated with SAE, the only independent predictors were HRmax in ExECG (HR = 0.98: 95% CI, 0.96-0.99; P = .01) and more extensive stress-induced perfusion defects (PDs, number of segments) in VS-CMR (HR = 1.19: 95% CI, 1.07-1.34; P < .01). Adding HRmax significantly improved the predictive power of the multivariable model for SAE, including PDs (continuous reclassification improvement index: 0.47: 95% CI, 0.10-0.81; P < .05). The annualized SAE rate was 1% (if PD < 2 segments and HRmax > 130 bpm), 2% (if PD < 2 segments and HRmax ≤ 130 bpm), 3.2% (if PD ≥ 2 segments and HRmax > 130 bpm), and 6.3% (if PD ≥ 2 segments and HRmax ≤ 130 bpm), P < .01, for the trend. In patients on β-blocker therapy, however, only PDs in VS-CMR, but not HRmax, predicted SAE., Conclusions: We conclude that ExECG contributes significantly to prognostic information beyond VS-CMR in patients with known or suspected CCS., Competing Interests: Conflicts of Interest: None., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In acute ST-segment elevation myocardial infarction (STEMI) late gadolinium enhancement (LGE) may underestimate segmental functional recovery. We evaluated the predictive value of cardiac magnetic resonance (CMR) feature-tracking (FT) for functional recovery and whether it incremented the value of LGE compared to low-dose dobutamine stress echocardiography (LDDSE) and speckle-tracking echocardiography (STE). Eighty patients underwent LDDSE and CMR within 5-7 days after STEMI and segmental functional recovery was defined as improvement in wall-motion at 6-months CMR. Optimal conventional and FT parameters were analyzed and then also applied to an external validation cohort of 222 STEMI patients. Circumferential strain (CS) was the strongest CMR-FT predictor and addition to LGE increased the overall accuracy to 74% and was especially relevant in segments with 50-74% LGE (AUC 0.60 vs. 0.75, p = 0.001). LDDSE increased the overall accuracy to 71%, and in the 50-74% LGE subgroup improved the AUC from 0.60 to 0.69 ( p = 0.039). LGE + CS showed similar value as LGE + LDDSE. In the validation cohort, CS was also the strongest CMR-FT predictor of recovery and addition of CS to LGE improved overall accuracy to 73% although this difference was not significant (AUC 0.69, p = 0.44). Conclusion: CS is the strongest CMR-FT predictor of segmental functional recovery after STEMI. Its incremental value to LGE is comparable to that of LDDSE whilst avoiding an inotropic stress agent. CS is especially relevant in segments with 50-74% LGE where accuracy is lower and further testing is frequently required to clarify the potential for recovery.

Background: Coronary arteries supply oxygen and nutrients to the heart. We evaluated the dynamics of microscopic damage throughout the ischemia-reperfusion process in the wall of coronary arteries following myocardial infarction (MI)., Methods: In a swine model of reperfused MI, animals were divided into one control and four MI groups: 90-min ischemia without reperfusion, or followed by one minute, one week or one month reperfusion. Left anterior descending (LAD; infarct-related artery) and control right coronary arteries (RCA) were isolated. Taking the balloon inflation region as a reference, we isolated the proximal and distal LAD areas, performing histological staining and immunohistochemistry., Results: Although mild changes in tunica intima were observed during ischemia, an almost complete absence of endothelium, and abnormal breaks in the internal elastic layer were found post-revascularization. In tunica media, increased thickness was observed soon after reperfusion, whereas larger thickness, disorganized muscle cell distribution and edema were found one week after reperfusion. This damage was more pronounced in distal rather than proximal LAD, whereas no changes were detected in RCA. In the tunica adventitia, vasa vasorum density decayed during ischemia in both LAD regions, but was restored after one month. Leukocyte adhesion to the artery was observed post-revascularization, developing into a massive presence in the three layers one week post-reperfusion., Conclusions: Ischemia-reperfusion can itself induce damage in the wall of the epicardial coronary artery, becoming more pronounced in the region distal to balloon inflation. Exploring these abnormalities will provide insight into the pathophysiology of coronary circulation and MI., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Aims: In this study, we evaluated the association between symptoms-guided revascularization occurred within three months following a negative vasodilator stress cardiovascular magnetic resonance (negative stress-CMR) and long-term adverse events in patients with known or suspected chronic coronary syndrome (CCS)., Methods: We retrospectively evaluated 3517 patients in which the stress first-pass perfusion imaging revealed no ischemia. The primary endpoint was the composite of death, spontaneous myocardial infarction, heart failure (HF), or stroke. The association between symptoms-guided revascularization after a negative stress-CMR and the endpoint was assessed using the multivariable Cox proportional hazard regression model., Results: The mean age was 64.7 ± 11.9 years and 45.4% were females. Coronary angiography and revascularization following a negative stress-CMR were performed in 176 (5%) and 59 (1.7%) patients. At a median follow-up of 4.8 years (2.0-8.2), 529 (15%) patients experienced the primary endpoint (2.0 per 100 person-years). Revascularization following a negative CMR was associated with a higher incidence of the composite (4.85 vs. 1.96 per 100 person-years, p < 0.001) and each of the isolated components of the endpoint, except for the HF endpoint, in which differences were borderline significant. After multivariate adjustment, revascularization remained associated with an excess of risk (HR = 2.01, 95% CI:1.21-3.30; p = 0.007)., Conclusions: In CCS patients with persistent symptoms but without evidence of ischemia in vasodilator stress CMR, revascularization was associated with a higher risk of adverse clinical events., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The outbreak of severe acute respiratory syndrome coronavirus 2 that first emerged in Wuhan in December 2019 has resulted in the devastating pandemic of coronavirus disease 2019, creating an emerging need for knowledge sharing. Meanwhile, myocardial infarction is and will probably remain the foremost cause of death in the Western world throughout the coming decades. Severe deregulation of the immune system can unnecessarily expand the inflammatory response and participate in target and multiple organ failure, in infection but also in critical illness. Indeed, the course and fate of inflammatory cells observed in severe ST-elevation myocardial infarction (neutrophilia, monocytosis, and lymphopenia) almost perfectly mirror those recently reported in severe coronavirus disease 2019. A pleiotropic proinflammatory imbalance hampers adaptive immunity in favor of uncontrolled innate immunity and is associated with poorer structural and clinical outcomes. The goal of the present review is to gain greater insight into the cellular and molecular mechanisms underlying this canonical activation and downregulation of the two arms of the immune response in both entities, to better understand their pathophysiology and to open the door to innovative therapeutic options. Knowledge sharing can pave the way for therapies with the potential to significantly reduce mortality in both infectious and noninfectious scenarios.

Aims: Lymphopenia after ST-segment elevation myocardial infarction (STEMI) correlates with deleterious cardiac consequences and worse prognosis. An in-depth examination of genes implicated in lymphocyte proliferation, activation and regulation and their association with short- and long-term cardiac structure and function is therefore of great interest., Methods: Peripheral blood mononuclear cells were isolated from 10 control subjects and 64 patients with a first STEMI treated with primary percutaneous coronary intervention and submitted to cardiac magnetic resonance after 1 week and 6 months. mRNA expression of genes implicated in lymphocyte activation (CD25 and CD69) and regulation [programmed death (PD)-1 and cytotoxic T-lymphocyte antigen (CTLA)-4] were determined by qRT-PCR., Results: In comparison to controls, STEMI patients showed heightened mRNA expression of CD25 and lower PD-1 and CTLA-4 96 h after coronary reperfusion. Patients with extensive infarctions (>30% of left ventricular mass) at 1 week displayed a notable reduction in CD25, CD69, PD-1, and CTLA-4 expression (p < 0.05). However, CD25 was the only predictor of 1-week extensive infarct size in multivariate logistic regression analysis (odds ratio 0.019; 95% confidence interval [0.001-0.505]; p = 0.018). Regarding long-term ventricular function, mRNA expression of CD25 under the mean value was associated with worse ventricular function and more adverse remodelling., Conclusions: Following STEMI, heightened expression of genes expressed in regulatory T cells (CD25 and CD69) and immune checkpoints (PD-1 and CTLA-4) correlates with a better short- and long-term cardiac structure and function. Advancing understanding of the pathophysiology of lymphopenia and evaluating novel immunomodulatory therapies will help translate these results into future clinical trials., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ischemic heart disease (IHD) persists as the leading cause of death in the Western world. In recent decades, great headway has been made in reducing mortality due to IHD, based around secondary prevention. The advent of coronary revascularization techniques, first coronary artery bypass grafting (CABG) surgery in the 1960s and then percutaneous coronary intervention (PCI) in the 1970s, has represented one of the major breakthroughs in medicine during the last century. The benefit provided by these techniques, especially PCI, has been crucial in lowering mortality rates in acute coronary syndrome (ACS). However, in the setting where IHD is most prevalent, namely chronic coronary syndrome (CCS), the increase in life expectancy provided by coronary revascularization is controversial. Over more than 40 years, several clinical trials have been carried out comparing optimal medical treatment (OMT) alone with a strategy of routine coronary revascularization on top of OMT. Beyond a certain degree of symptomatic improvement and lower incidence of minor events, routine invasive management has not demonstrated a convincing effect in terms of reducing mortality in CCS. Based on the accumulated evidence more than half a century after the first revascularization procedures were used, invasive management should be considered in those patients with uncontrolled symptoms despite OMT or high-risk features related to left ventricular function, coronary anatomy, or functional assessment, taking into account the patient expectations and preferences.

Purpose: In ST-segment elevation myocardial infarction (STEMI) patients, longitudinal strain (LS) in remote non-infarcted myocardium (RNM) has not yet been characterized by tissue tracking (TT) cardiovascular magnetic resonance (CMR). In STEMI patients, we aimed to characterize RNM-LS by TT-CMR and to assess both its dynamics and its structural and prognostic implications., Methods: We recruited 271 patients with a first STEMI studied with TT-CMR 1 week after infarction. Of these patients, 145 underwent 1-week and 6-month TT-CMR and were used to characterize both the dynamics and the short-term and long-term structural implications of RNM-LS. Based on previously validated data, RNM areas were defined depending on the culprit coronary artery., Results: Reduced RNM-LS at 1 week (n = 70, 48%) was associated with larger infarct size and more depressed left ventricular ejection fraction (LVEF) at both the 1-week and 6-month TT-CMR (p value < 0.001). Late normalization of RNM-LS was frequent (28/70, 40%) and independently related to late recovery of LVEF (p value = 0.002). Patients with reduced RNM-LS at 1-week TT-CMR had more major adverse cardiac events (death, heart failure or re-infarction) in both the 271 patients included in the study group (26% vs. 11%, p value = 0.002) and in an external validation cohort made up of 177 STEMI patients (57% vs. 13%, p value < 0.001)., Conclusion: After STEMI, reduced RNM-LS by TT-CMR is common and is associated with more severe short- and long-term structural damage. There is a beneficial tendency towards recovery of RNM-LS that parallels late recovery of LVEF. More events occur in patients with reduced RNM-LS.

Background Cardiac magnetic resonance (CMR) permits robust risk stratification of discharged ST-segment-elevation myocardial infarction patients, but its indiscriminate use in all cases is not feasible. We evaluated the utility of left ventricular ejection fraction (LVEF) by echocardiography for a selective use of CMR after ST-segment-elevation myocardial infarction. Methods Echocardiography and CMR were performed in 1119 patients discharged for ST-segment-elevation myocardial infarction included in a multicenter registry. The prognostic power of CMR beyond echocardiography-LVEF was assessed using adjusted C statistic, net reclassification improvement index, and integrated discrimination improvement index. Results During a 4.8-year median follow-up, 136 (12%) first major adverse cardiac events (MACE) occurred (47 cardiovascular deaths and 89 readmissions for acute heart failure). In the entire group, CMR-LVEF (but not echocardiography-LVEF) independently predicted MACE occurrence. The MACE rate significantly increased only in patients with CMR-LVEF<40% (≥50%: 7%, 40%-49%: 9%, <40%: 27%, P <0.001). Most patients displayed echocardiography-LVEF≥50% (629, 56%), and they had a low MACE rate (57/629, 9%). In patients with echocardiography-LVEF<50% (n=490, 44%), the MACE rate was also low in those with CMR-LVEF≥40% (24/278, 9%) but significantly increased in patients with CMR-LVEF<40% (55/212, 26%; P <0.001). Compared with echocardiography-LVEF, CMR-LVEF significantly improved MACE prediction in the group of patients with echocardiography-LVEF<50% (C statistic, 0.80 versus 0.72; net reclassification improvement index, 0.73; integrated discrimination improvement index, 0.10) but not in those with echocardiography-LVEF≥50% (C statistic 0.66 versus 0.66; net reclassification improvement index, 0.17; integrated discrimination improvement index, 0.01). Conclusions A straightforward strategy based on a selective use of CMR for risk prediction in ST-segment-elevation myocardial infarction patients with echocardiography-LVEF<50% can provide insights into patient care. The cost-effectiveness of this approach, as well as the direct implications in clinical management, should be further explored.

This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies., Competing Interests: The authors declare no conflict of interest.

Objectives: This study explored the association of ischemic burden, as measured by vasodilator stress cardiovascular magnetic resonance (CMR), with all-cause mortality and the effect of revascularization on all-cause mortality in patients with stable ischemic heart disease (SIHD)., Background: In patients with SIHD, the association of ischemic burden, derived from vasodilator stress CMR, with all-cause mortality and its role for decision-making is unclear., Methods: The registry consisted of 6,389 consecutive patients (mean age: 65 ± 12 years; 38% women) who underwent vasodilator stress CMR for known or suspected SIHD. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model). The effect of CMR-related revascularization (within the following 3 months) on all-cause mortality was retrospectively explored using the electronic regional health system registry., Results: During a 5.75-year median follow-up, 717 (11%) deaths were documented. In multivariable analyses, more extensive ischemic burden (per 1-segment increase) was independently related to all-cause mortality (hazard ratio: 1.04; 95% confidence interval: 1.02 to 1.07; p < 0.001). In 1,032 1:1 matched patients using a limited number of variables (516 revascularized, 516 non-revascularized), revascularization within the following 3 months was associated with less all-cause mortality only in patients with extensive CMR-related ischemia (>5 segments, n = 432; 10% vs. 24%; p = 0.01)., Conclusions: In a large retrospective registry of unselected patients with known or suspected SIHD who underwent vasodilator stress CMR, extensive ischemic burden was related to a higher risk of long-term, all-cause mortality. Revascularization was associated with a protective effect only in the restricted subset of patients with extensive CMR-related ischemia. Further research will be needed to confirm this hypothesis-generating finding., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Following myocardial infarction (MI), we aimed to characterize morphometric and genetic changes in extracellular matrix (ECM) components from ischemia onset until late phases after coronary reperfusion in necrotic and salvaged myocardium., Results: Swine were divided into one control (n = 5) and three MI groups: 90-min of ischemia without reperfusion, or followed by 1-week or 1-month reperfusion (n = 5 per group). In samples from the necrotic and salvaged areas, ECM components were morphometrically quantified and mRNA levels of factors involved in ECM remodeling were evaluated. After 90-min of ischemia, fibronectin, laminin, and elastic fibers content as well as upregulated mRNA expression of tissue inhibitors of metalloproteinases (TIMP)1, TIMP2, TIMP3 and connective tissue growth factor increased in the necrotic and salvaged myocardium. In both reperfused MI groups, collagen-I, collagen-III, elastic fibers, glycosaminoglycans, laminin, and fibronectin levels heightened in the necrotic but not the salvaged myocardium. Moreover, mRNA expression of TIMP1, TIMP2 and TIMP3, as well as metalloproteinase-2 and metalloproteinase-9 heightened in the necrotic but not in the salvaged myocardium., Conclusions: Matrix remodeling starts after ischemia onset in both necrotic and salvaged myocardium. Even if ECM composition from the salvaged myocardium was altered after severe ischemia, ECM makes a full recovery to normal composition after reperfusion. Therefore, rapid coronary reperfusion is essential not only to save cardiomyocytes but also to preserve matrix, thus avoiding impaired left ventricular remodeling.

Vasodilator stress cardiac magnetic resonance (stressCMR) has shown robust diagnostic and prognostic value in patients with known or suspected chronic coronary syndrome (CCS). However, it is unknown whether integration of stressCMR with clinical variables in a simple clinical-imaging score can straightforwardly predict all-cause mortality in this population. We included 6187 patients in a large registry that underwent stressCMR for known or suspected CCS. Several clinical and stressCMR variables were collected, such as left ventricular ejection fraction (LVEF) and ischemic burden (number of segments with stress-induced perfusion defects (PD)). During a median follow-up of 5.56 years, we registered 682 (11%) all-cause deaths. The only independent predictors of all-cause mortality in multivariable analysis were age, male sex, diabetes mellitus (DM), LVEF and ischemic burden. Based on the weight of the chi-square increase at each step of the multivariable analysis, we created a simple clinical-stressCMR (C-CMR-10) score that included these variables (age ≥ 65 years = 3 points, LVEF ≤ 50% = 3 points, DM = 2 points, male sex = 1 point, and ischemic burden > 5 segments = 1 point). This 0 to 10 points C-CMR-10 score showed good performance to predict all-cause annualized mortality rate ranging from 0.29%/year (score = 0) to >4.6%/year (score ≥ 7). The goodness of the model and of the C-CMR-10 score was separately confirmed in 2 internal cohorts ( n > 3000 each). We conclude that a novel and simple clinical-stressCMR score, which includes clinical and stressCMR variables, can provide robust prediction of the risk of long-term all-cause mortality in a population of patients with known or suspected CCS.

Reductive stress is defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. It represents a disturbance in the redox state that is harmful to biological systems. Our aim was to study the occurrence of reductive stress in the early phases of experimental myocardial infarction and to determine the mechanisms leading to such stress using a swine model. During the ischemic period, we found a decrease in the oxidized to reduced glutathione ratio (GSSG/GSH) (0.7-0.3), in the lactate to pyruvate ratio (42.7-132.4), in protein glutathionylation (111.8-96.1), and in p38 phosphorylation (0.9-0.4). This was accompanied by a significant increase in the expression of Thioredoxin (TXN) (0.6-1.9) and peroxiredoxin (PRDX6) (0.6-1.6) in different left ventricle areas. After reperfusion, there was a massive increase in oxidative damage markers including lipid peroxidation (0.2-0.4), protein carbonylation (144.9-462.8), and glutathionylation (111.8-176.8). Concomitantly, we found an activation of nuclear factor erythroid 2-related factor 2 (Nrf2) (1.2-6.1) and of a set of antioxidant enzymes including TXN, PRDX6, glutathione peroxidase (GPX1), glutathione reductase (GSR), and glucose 6 phosphate dehydrogenase (G6PD). We describe an early reductive, followed by a late onset oxidative stress (1 week and 1 month after reperfusion) in a swine myocardial infarction model. The occurrence of an early reductive phase may explain the lack of effectiveness of antioxidant therapies when administered in the early phases after reperfusion of ischemic hearts.

Delayed enhancement cardiovascular magnetic resonance (MR) is the gold-standard for non-invasive assessment after myocardial infarction (MI). MR microscopy (MRM) provides a level of detail comparable to the macro objective of light microscopy. We used MRM and correlative histopathology to identify infarct and remote tissue in contrast agent-free multi-sequence MRM in swine MI hearts. One control group (n = 3 swine) and two experimental MI groups were formed: 90 min of ischemia followed by 1 week (acute MI = 6 swine) or 1 month (chronic MI = 5 swine) reperfusion. Representative samples of each heart were analysed by contrast agent-free multi-sequence (T1-weighting, T2-weighting, T2*-weighting, T2-mapping, and T2*-mapping). MRM was performed in a 14-Tesla vertical axis imager (Bruker-AVANCE 600 system). Images from MRM and the corresponding histopathological stained samples revealed differences in signal intensities between infarct and remote areas in both MI groups (p-value < 0.001). The multivariable models allowed us to precisely classify regions of interest (acute MI: specificity 92% and sensitivity 80%; chronic MI: specificity 100% and sensitivity 98%). Probabilistic maps based on MRM images clearly delineated the infarcted regions. As a proof of concept, these results illustrate the potential of MRM with correlative histopathology as a platform for exploring novel contrast agent-free MR biomarkers after MI.

Currently, chronic wounds and microbial resistance to antibiotics have led to search new healing agents. Combinations of natural products are widely practiced in traditional medicine and exhibited synergistic activity with increased efficacy in treating several pathologies. This study assays the antioxidant, synergistic antimicrobial and burn wound healing activities of Euphorbia honey and Allium sativum (garlic). The minimal inhibitory concentration (MIC) of each natural product was determined against microorganisms commonly found in wound infections. The synergistic antimicrobial effect was assessed by mixing different concentrations of honey and garlic extract below their relative MICs. Subsequently, the antioxidant activity, total phenolic (TPC) and flavonoid (TFC) contents of both natural products and a selected mixture of them were evaluated. Efficacy of that mixture was also evaluated as topical application on male and female Wistar rats skin burn wound, compared to Euphorbia honey and two conventional treatments. Results showed that the mixture honey-A. sativum has synergistic antimicrobial effect against all tested strains. Besides, A. sativum presented higher antioxidant activity along with higher TPC and TFC compared to honey and their mixture. However, the mixture showed higher wound healing activity reflected by shorter epithelialization and wound contraction time, as well as, better histological recovery of the treated tissues. Our results also showed that burn wound healing is not affected by gender. Our findings support the idea of combining natural products as an effective therapy., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

After a myocardial infarction (MI), despite the resolution of the coronary occlusion, the deterioration of myocardial perfusion persists in a considerable number of patients. This phenomenon is known as microvascular obstruction (MVO). Initially, the focus was placed on re-establishing blood flow in the epicardial artery. Then, the observation that MVO has profound negative structural and prognostic repercussions revived interest in microcirculation. In the near future, the availability of co-adjuvant therapies (beyond timely coronary reperfusion) aimed at preventing, minimizing, and repairing MVOs and finding convincing answers to questions regarding what, when, how, and where to administer these therapies will be of utmost importance. The objective of this work is to review the state-of-the-art concepts on pathophysiology, diagnostic methods, and structural and clinical implications of MVOs in patients with ST-segment elevation MIs. Based on this knowledge we discuss previously-tested and future opportunities for the prevention and repair of MVO.

Purkinje cells (PCs) are more resistant to ischemia than myocardial cells, and are suspected to participate in ventricular arrhythmias following myocardial infarction (MI). Histological studies afford little evidence on the behavior and adaptation of PCs in the different stages of MI, especially in the chronic stage, and no quantitative data have been reported to date beyond subjective qualitative depictions. The present study uses a porcine model to present the first quantitative analysis of the distal cardiac conduction system and the first reported change in the spatial distribution of PCs in three representative stages of MI: an acute model both with and without reperfusion; a subacute model one week after reperfusion; and a chronic model one month after reperfusion. Purkinje cells are able to survive after 90 minutes of ischemia and subsequent reperfusion to a greater extent than cardiomyocytes. A decrease is observed in the number of PCs, which suffer reversible subcellular alterations such as cytoplasm vacuolization, together with redistribution from the mesocardium-the main localization of PCs in the heart of ungulate species-towards the endocardium and perivascular epicardial areas. However, these changes mainly occur during the first week after ischemia and reperfusion, and are maintained in the chronic stages. This anatomical substrate can explain the effectiveness of endo-epicardial catheter ablation of monomorphic ventricular tachycardias in the chronic scar after infarction, and sets a basis for further electrophysiological and molecular studies, and future therapeutic strategies., Competing Interests: The authors have declared that no competing interests exist.

Objective: We characterized the dynamics of eosinophils in blood and in the infarcted myocardium in patients and in a swine model of reperfused myocardial infarction (MI). The association of eosinophil dynamics with various outcomes was assessed., Methods: Serial eosinophil count and pre-discharge cardiac magnetic resonance were carried out in a prospective series of 620 patients with a first ST-elevation MI. In a swine model of reperfused MI, the dynamics of circulating eosinophils and their presence in the infarcted myocardium were determined. In autopsies from chronic MI patients, eosinophils were quantified., Results: Patient eosinophil count sharply decreased 12h post-reperfusion compared to arrival. A lower minimum eosinophil count was associated with more extensive edema, microvascular obstruction, and infarct size as measured by cardiac magnetic resonance, and also with a higher rate of cardiac events (death, re-infarction, or heart failure) during follow-up. In the experimental model, eosinophil count boosted during ischemia and dropped back immediately post-reperfusion. Myocardial samples revealed progressive eosinophil migration into the infarcted myocardium, especially areas with microvascular obstruction. Markers of eosinophil maturation and survival (interleukin-5), degranulation (eosinophil cationic protein) and migration (eotoxin-1) were detected in the blood of patients, and in porcine myocardium. Eosinophil infiltration was detected in autopsies from chronic MI patients., Conclusion: Eosinopenia post-MI was associated with an impaired cardiac structure and adverse events. The decay in circulating eosinophils soon after reperfusion mirrors their migration into the infarcted myocardium, as reflected by their presence in heart samples from swine and patients. Further studies are needed to understanding this unexplored pathway and its therapeutic implications., Competing Interests: The authors have declared no competing interests exist.

Objectives: The aim of this study was to evaluate the prognostic value of strain as assessed by tissue tracking (TT) cardiac magnetic resonance (CMR) soon after ST-segment elevation myocardial infarction (STEMI)., Background: The prognostic value of myocardial strain as assessed post-STEMI by TT-CMR is unknown., Methods: The authors studied the prognostic value of TT-CMR in 323 patients who underwent CMR 1 week post-STEMI. Global (average of peak segmental values [%]) and segmental (number of altered segments) longitudinal (LS), circumferential, and radial strain were assessed using TT-CMR. Global and segmental strain cutoff values were derived from 32 control patients. CMR-derived left ventricular ejection fraction, microvascular obstruction, and infarct size were determined. Results were validated in an external cohort of 190 STEMI patients., Results: During a median follow-up of 1,085 days, 54 first major adverse cardiac events (MACE), which included 10 cardiac deaths, 25 readmissions for heart failure, and 19 readmissions for reinfarction were documented. MACE was associated with more severe abnormalities in all strain indexes (p < 0.001), although only global LS was an independent predictor (p < 0.001). The MACE rate was higher in patients with a global LS of ≥-11% (22% vs. 9%; p = 0.001). After adjustment for baseline and CMR variables, global LS (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.11 to 1.32; p < 0.001) was associated with MACE. In the external validation cohort, a global LS ≥-11% was seen in a higher proportion of patients with MACE (34% vs. 9%; p < 0.001). Global LS predicted MACE after adjustment for baseline and CMR variables (HR: 1.18; 95% CI: 1.04 to 1.33; p = 0.008). The addition of global LS to the multivariate models, including baseline and CMR variables, did not significantly improve the categorical net reclassification improvement index in either the study group (-0.015; p = 0.7) or in the external validation cohort (-0.019; p = 0.9)., Conclusions: TT-CMR provided prognostic information soon after STEMI. However, it did not substantially improve risk reclassification beyond traditional CMR indexes., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

Angiogenesis is crucial to restore microvascular perfusion in the jeopardized myocardium in the weeks following reperfused ST-segment elevation myocardial infarction (STEMI). (VEGF)-A 165 b, an anti-angiogenic factor, has been identified as a regulator of vascularization; however, it has not been previously implicated in acute myocardial infarction. We sought to investigate the dynamics of circulating VEGF-A 165 b and its association with cardiac magnetic resonance-derived infarct size and left ventricular ejection fraction (LVEF). 50 STEMI patients and 23 controls were included. Compared with control individuals, serum VEGF-A 165 b was elevated in STEMI patients prior to primary percutaneous coronary intervention (PCI). Following PCI, serum VEGF-A 165 b increased further, reaching a maximum level at 24 h and decreased one month after reperfusion. VEGF-A 165 b levels at 24 h were associated with a large infarct size and inversely related to LVEF. VEGF-A 165 b expression was increased in myocardial infarct areas from patients with previous history of AMI. An ex vivo assay using serum from STEMI patients showed that neutralization of VEGF-A 165 b increased tubulogenesis. Overall, the study suggests that VEGF-A 165 b might play a deleterious role after AMI as an inhibitor of angiogenesis in the myocardium. Accordingly, neutralization of VEGF-A 165 b could represent a novel pro-angiogenic therapy for reperfusion of myocardium in STEMI.

The controversy connecting Abacavir (ABC) with cardiovascular disease has been fuelled by the lack of a credible mechanism of action. ABC shares structural similarities with endogenous purines, signalling molecules capable of triggering prothrombotic/proinflammatory programmes. Platelets are leading actors in the process of thrombosis. Our study addresses the effects of ABC on interactions between platelets and other vascular cells, while exploring the adhesion molecules implicated and the potential interference with the purinergic signalling pathway. The effects of ABC on platelet aggregation and platelet-endothelium interactions were evaluated, respectively, with an aggregometer and a flow chamber system that reproduced conditions in vivo. The role of adhesion molecules and purinergic receptors in endothelial and platelet populations was assessed by selective pre-incubation with specific antagonists and antibodies. ABC and carbovir triphosphate (CBT) levels were evaluated by HPLC. The results showed that ABC promoted the adherence of platelets to endothelial cells, a crucial step for the formation of thrombi. This was not a consequence of a direct effect of ABC on platelets, but resulted from activation of the endothelium via purinergic ATP-P2X 7 receptors, which subsequently triggered an interplay between P-selectin and ICAM-1 on endothelial cells with constitutively expressed GPIIb/IIIa and GPIbα on platelets. ABC did not induce platelet activation (P-selectin expression or Ca 2+ mobilization) or aggregation, even at high concentrations. CBT levels in endothelial cells were lower than those required to induce platelet-endothelium interactions. Thus, ABC interference with endothelial purinergic signalling leads to platelet recruitment. This highlights the endothelium as the main cell target of ABC in this interaction, which is in line with previous experimental evidence that ABC induces manifestations of vascular inflammation., (Copyright © 2017 Elsevier B.V. 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.

Cardiovascular diseases and oxidative stress are related to polycystic ovary syndrome (PCOS) and insulin resistance (IR). We have evaluated the relationship between myeloperoxidase (MPO) and leukocyte activation in PCOS patients according to homeostatic model assessment of IR (HOMA-IR), and have explored a possible correlation between these factors and endocrine and inflammatory parameters. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 101 PCOS subjects and 105 control subjects. We divided PCOS subjects into PCOS non-IR (HOMA-IR<2.5) and PCOS IR (HOMA-IR>2.5). Metabolic and anthropometric parameters, total and mitochondrial reactive oxygen species (ROS) production, MPO levels, interactions between human umbilical vein endothelial cells and leukocytes, adhesion molecules (E-selectin, ICAM-1 and VCAM-1) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. Oxidative stress was observed in PCOS patients, in whom there was an increase in total and mitochondrial ROS production and MPO levels. Enhanced rolling flux and adhesion, and a decrease in polymorphonuclear cell rolling velocity were also detected in PCOS subjects. Increases in IL-6 and TNF-α and adhesion molecules (E-selectin, ICAM-1 and VCAM-1) were also observed, particularly in the PCOS IR group, providing evidence that inflammation and oxidative stress are related in PCOS patients. HOMA-IR was positively correlated with hsCRP (p<0.001, r = 0.304), ROS production (p<0.01, r = 0.593), leukocyte rolling flux (p<0.05, r = 0.446), E-selectin (p<0.01, r = 0.436) and IL-6 (p<0.001, r = 0.443). The results show an increase in the rate of ROS and MPO levels in PCOS patients in general, and particularly in those with IR. Inflammation in PCOS induces leukocyte-endothelium interactions and a simultaneous increase in IL-6, TNF-α, E-selectin, ICAM-1 and VCAM-1. These conditions are aggravated by the presence of IR.

Objective: We aim to assess the effect of metformin treatment on metabolic parameters, endothelial function and inflammatory markers in polycystic ovary syndrome (PCOS) subjects., Methods: The study population consisted of 40 reproductive-age women with PCOS, who underwent treatment with metformin during a 12-week period, and their corresponding matched controls (n = 44). We evaluated endocrinological parameters, adhesion molecules (vascular cell adhesion molecule 1 (VCAM-1), intercellular cell adhesion molecule 1 (ICAM-1) and E-selectin) and proinflammatory cytokines (interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα)) in serum. In addition, interactions between human umbilical vein endothelial cells and polymorphonuclear (PMN) cells were assessed by flow chamber microscopy. In addition, a group of type 2 diabetes patients who underwent treatment with metformin during a 12-week period was incorporated into the study., Results: Metformin produced beneficial effects on PCOS patients by decreasing polymorphonuclear (PMN) rolling flux and adhesion. It also decreased levels of ICAM-1, E-selectin, IL-6 and ΤΝFα. In addition, metformin induced an improvement of endocrine and anthropometric parameters in PCOS subjects by reducing glucose, follicle-stimulating hormone (FSH) and androstendione, and by increasing dehydroepiandrosterone-sulfate (DHEA-S). Metformin also had beneficial effects in type 2 diabetic subjects by reducing body weight, waist circumference and PMN adhesion, and by increasing PMN rolling velocity., Conclusion: Our results highlight the modulating effect of metformin on leukocyte/endothelium interactions. These findings may explain the potential beneficial effect of metformin in reducing the risk of vascular events in PCOS patients and in insulin resistance conditions., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The potential cardiovascular (CV) toxicity associated with combined antiretroviral therapy (cART) has been attributed mainly to the nucleoside reverse transcriptase inhibitors abacavir and didanosine. However, the other two components of cART--non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)--may also be implicated, either directly or by influencing the action of the other drugs. This study evaluates the acute direct effects of the NNRTIs efavirenz and nevirapine and one of the most widely employed PIs, lopinavir, on leucocyte-endothelium interactions, a hallmark of CV disease., Methods: Drugs were analysed in vitro in human cells (interactions of peripheral blood polymorphonuclear or mononuclear cells with human umbilical vein endothelial cells) using a flow chamber system, and in vivo in rat mesenteric vessels by means of intravital microscopy. The expression of adhesion molecules in leucocytes and endothelial cells was studied by flow cytometry, and the role of these molecules in white cell recruitment was evaluated by pre-treating human cells or rats with blocking antibodies., Results: Efavirenz and nevirapine, but not lopinavir, increased the rolling flux and adhesion of leucocytes in vitro and in vivo while inducing emigration in rat venules. Efavirenz, but not nevirapine, augmented the levels of CD11b, CD11c and CD18 in neutrophils and monocytes. The actions of efavirenz, but not of nevirapine, were reversed by antibodies against Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18) or ICAM-1 (CD54)., Conclusions: NNRTIs, but not PIs, interfere with leucocyte-endothelial interactions. However, differences between efavirenz and nevirapine suggest a specific CV profile for each compound.