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Background: Investigations of very long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) according to clinical presentation are scarce. Here, we investigated the 10-year clinical outcomes of patients undergoing DES-PCI according to clinical presentation., Methods: Patient-level data from five randomized trials with 10-year follow-up after DES-PCI were pooled. Patients were dichotomized into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) groups as per clinical presentation. The primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST) and repeat revascularization involving the target lesion (TLR), target vessel (TVR) or non-target vessel (nTVR)., Results: Of the 9700 patients included in this analysis, 4557 presented with ACS and 5143 with CCS. Compared with CCS patients, ACS patients had a higher risk of all-cause death and nTVR in the first year, but comparable risk thereafter. In addition, ACS patients had a higher risk of MI [adjusted hazard ratio 1.21, 95% confidence interval (1.04-1.41)] and definite ST [adjusted hazard ratio 1.48, 95% confidence interval (1.14-1.92)], while the risk of TLR and TVR was not significantly different up to 10-year follow-up., Conclusions: Compared to CCS patients, ACS patients treated with PCI and DES implantation have an increased risk of all-cause death and repeat revascularization of remote vessels up to 1 year, with no significant differences thereafter and up to 10-year follow-up. ACS patients have a consistently higher risk of MI and definite ST. Whether these differences persist with current antithrombotic and secondary prevention therapies requires further investigation., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Cardiogenic shock complicating acute myocardial infarction (AMI-CS) remains a critical condition with high morbimortality. Despite advances, gender disparities persist in the management of this condition. Our aim was to evaluate gender differences in the utilization and outcomes of mechanical circulatory support (MCS) in AMI-CS. In addition, we addressed the management strategies for AMI-CS stratified by race/ethnicity. We performed a retrospective study using the National Inpatient Sample from 2016 to 2019, including admissions with AMI-CS. The use of MCS and outcomes were compared between genders using inverse probability of treatment weighting. Odds ratios (OR) with their 95% confidence interval (CI) were estimated. A total of 151,560 admissions for AMI-CS were analyzed, including 98,855 male and 52,705 female patients. After the inverse probability of treatment weighting adjustment, females were significantly less likely to receive MCS (OR 0.77, 95% CI 0.73 to 0.81, p <0.001) and had higher in-hospital mortality rates (OR 1.09, 95% CI 1.00 to 1.18, p = 0.045) than males. No significant gender differences were observed in major bleeding, renal replacement therapy, or mechanical ventilation. Racial disparities were also evident, with female patients across all racial groups being less likely to receive MCS compared with their male counterparts. In conclusion, significant gender disparities exist in the utilization and outcomes of MCS in patients with AMI-CS. Female patients are less likely to receive MCS and have higher in-hospital mortality rates compared with male patients. Racial minorities, including Black and Hispanic patients, experience lower utilization of MCS compared with White patients. These findings underscore the complex interplay between gender, race/ethnicity, and health care access and outcomes., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Electrophysiological characterization of ventricular tachycardia (VT) isthmus sites is complex and time-consuming. We aimed at developing and validating a global mapping strategy during programmed ventricular stimulation (PVS) to reveal the underlying electrophysiological properties of the infarct-related substrate and to enable identification of highly heterogeneous activation sites associated with protected VT isthmus sites., Methods and Results: Experimental study that included 22 pigs with established myocardial infarction undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with potential arrhythmogenicity. High-density sequential activation maps during ventricular pacing and VT were compared with single-beat maps using a 64-pole basket catheter positioned in the left ventricle. Further analyses were performed using a novel local activation time-dispersion score to identify regional activation time heterogeneities on both baseline drive pacing and each of the extrastimuli of the PVS protocol. Basket catheter splines covered a median of 81.2% of the endocardial surface of the left ventricle. Basket-catheter-derived single-beat activation maps (N=16) during pacing showed a linear relationship with high-density sequential activation maps. Induction of ventricular arrhythmias was associated with higher local activation time-dispersion score values on single-beat global maps during PVS (N=6, 46 arrhythmia induction attempts). Single-beat-derived local activation time-dispersion score maps during successive coupled extrastimuli of the PVS showed a progressive increase in the predictive performance to identify monomorphic VT isthmus sites within the scar region (area under the curve = 0.779 in S2, area under the curve = 0.859 in S4; N=7)., Conclusions: Sixty-four-pole-derived single-beat local activation time-dispersion score global maps during PVS identify infarct-related endocardial regions with highly heterogeneous activation times that are associated with protected VT isthmus sites.

Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, N = 5/site) or IPC + I/R (N = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] N = 25 pigs/group; p < 0.001; 25 ± 13 versus 14 ± 8 [%LV]; N = 10 pigs/group; p = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit., Competing Interests: Declarations. Conflict of interest: P.F. is the founder and CEO and ZG is involved in the management of Pharmahungary Group, a group of R&D companies. Pharmahungary Group has a conflict of interest as it may be organizing multicenter studies on cardioprotection on external request and potentially including the here validated sites of the current COST action (IG16225). D.J.H. has received: consultant fees from Faraday Pharmaceuticals Inc. and Boehringer Ingelheim International GmbH; honoraria from Servier; and research funding from Astra Zeneca, Merck Sharp & Dohme Corp and Novonordisk. J. L. Z. received speaker honoraria from Pfizer, Bayer, Novartis, and Amgem. All other authors declare no competing interests. Ethical statements: The experimental protocols conformed to the EU directive 2010/63EU on the protection of animals used for scientific purposes and the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines [49]. The experimental protocols were formally approved by the appropriate national or institutional ethics committees (see Suppl. Data sheet experimental design)., (© 2024. The Author(s).)

Aims: There is lack of agreement on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging processing for guiding ventricular tachycardia (VT) ablation. We aim at developing and validating a systematic processing approach on LGE-CMR images to identify VT corridors that contain critical VT isthmus sites., Methods and Results: This is a translational study including 18 pigs with established myocardial infarction and inducible VT undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with VT maintenance. Clinical validation was conducted in a multicentre series of 33 patients with ischaemic cardiomyopathy undergoing VT ablation. Three-dimensional LGE-CMR images were processed using systematic scanning of 15 signal intensity (SI) cut-off ranges to obtain surface visualization of all potential VT corridors. Analysis and comparisons of imaging and electrophysiological data were performed in individuals with full electrophysiological characterization of the isthmus sites of at least one VT morphology. In both the experimental pig model and patients undergoing VT ablation, all the electrophysiologically defined isthmus sites (n = 11 and n = 19, respectively) showed overlapping regions with CMR-based potential VT corridors. Such imaging-based VT corridors were less specific than electrophysiologically guided ablation lesions at critical isthmus sites. However, an optimized strategy using the 7 most relevant SI cut-off ranges among patients showed an increase in specificity compared to using 15 SI cut-off ranges (70 vs. 62%, respectively), without diminishing the capability to detect VT isthmus sites (sensitivity 100%)., Conclusion: Systematic imaging processing of LGE-CMR sequences using several SI cut-off ranges may improve and standardize procedure planning to identify VT isthmus sites., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The present analysis from the Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial aims to explore the significance of pre-admission physical activity and assess whether the benefits of physiology-guided complete revascularization apply consistently to sedentary and active older patients., Methods and Results: Patients aged 75 years or more with myocardial infarction (MI) and multivessel disease were randomized to receive physiology-guided complete revascularization or culprit-only strategy. The primary outcome was a composite of death, MI, stroke, or any revascularization within a year. Secondary endpoints included the composite of cardiovascular death or MI, as well as single components of the primary endpoint. Pre-admission physical activity was categorized into three groups: (i) absent (sedentary), (ii) light, and (iii) vigorous. Among 1445 patients, 692 (48%) were sedentary, whereas 560 (39%) and 193 (13%) performed light and vigorous physical activity, respectively. Patients engaging in light or vigorous pre-admission physical activity exhibited a reduced risk of the primary outcome compared with sedentary individuals [light hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.55-0.91 and vigorous HR 0.14, 95% CI 0.07-0.91, respectively]. These trends were also observed for death, cardiovascular death, or MI. When comparing physiology-guided complete revascularization vs. culprit-only strategy, no significant interaction was observed for primary and secondary endpoints when stratified by sedentary or active status., Conclusion: In older patients with MI, pre-admission physical activity emerges as a robust and independent prognostic determinant. Physiology-guided complete revascularization stands out an effective strategy in reducing ischaemic adverse events, irrespective of pre-admission physical activity status., Clinical Trial Registration: ClinicalTrials.gov NCT03772743., Competing Interests: Conflict of interest: G.Cam. received research grants and personal fees from ABBOTT VASCULAR, personal fees from MENARINI, personal fees from AMGEN, personal fees from SANOFI, outside the submitted work. S.B. received personal fees from ABBOTT VASCULAR, outside the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Red blood cell transfusion can cause fluid overload. We evaluated the interaction between heart failure (HF) at baseline and transfusion strategy on outcomes in acute myocardial infarction (AMI)., Methods: We used data from the randomized REALITY trial. HF was defined as history of HF or Killip class > 1 at randomization. Primary outcome was major adverse cardiovascular events (MACE): composite of all-cause death, nonrecurrent AMI, stroke, or emergency revascularization prompted by ischemia at 30 days., Results: Among 658 randomized patients, 311 (47.3%) had HF. Patients with HF had higher rates of MACE at 30 days and 1 year and higher rates of nonfatal new-onset HF. There was no interaction between HF and effect of randomized assignment on the primary outcome or nonfatal new-onset HF. A liberal transfusion strategy was associated with increased all-cause death at 30 days and at 1 year in patients with HF (P interaction  = 0.009 and P = 0.049, respectively). The main numerical difference in cause of death between restrictive and liberal strategies was death by HF at 30 days (4 vs 11)., Conclusions: HF is frequent in patients with AMI and anemia and is associated with higher risk of MACE (including all-cause death) and nonfatal new-onset HF. Although there was no interaction of HF with effect of transfusion strategy on MACE, a liberal transfusion strategy was associated with higher all-cause death that appears driven by a higher risk of early death caused by HF., Clinical Trial Registration: NCT02648113., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: The present study sought to establish the diagnostic yield of cardiovascular magnetic resonance (CMR) in a large cohort of patients admitted with myocardial infarction (MI) with nonobstructive coronary artery disease (MINOCA) based on the timing of referral to CMR., Methods: Consecutive patients referred to CMR from January 2009 to February 2022 with a working diagnosis of MINOCA were retrospectively evaluated. Cine, T 2 -weighted, early, and late gadolinium-enhanced images were acquired and analyzed. The frequency of the underlying diagnosis and the association between timing of CMR and relative frequency of each diagnosis were assessed., Results: We included 207 patients (median age 50 years, 60% men). Final diagnosis after CMR was achieved in 91% of the patients (myocarditis in 45%, MI in 20%, tako-tsubo cardiomyopathy in 19%, and other cardiomyopathies in 7%). The performance of CMR within 7 days of admission with MINOCA (median, 5 days; 117 patients) allowed a higher diagnostic yield compared with CMR performed later (median, 10 days; 88 patients) (96% vs 86%, P=.02). Although myocarditis was the most frequent diagnosis in both groups according to time to CMR, its frequency was higher among patients with a CMR performed within the first 7 days (53% vs 35%, P=.02). The frequency of other underlying diagnoses was not influenced by CMR timing., Conclusions: CMR led to an underlying diagnosis of MINOCA in 91% of patients and its diagnostic yield increased to 96% when CMR was performed within 7 days of admission. The most frequent diagnosis was myocarditis.., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Evidence on the association between subclinical atherosclerosis (SA) and cardiovascular (CV) events in low-risk populations is scant. To study the association between SA burden and an ischaemic scar (IS), identified by cardiac magnetic resonance (CMR), as a surrogate of CV endpoint, in a low-risk population., Methods and Results: A cohort of 712 asymptomatic middle-aged individuals from the Progression of Early SA (PESA-CNIC-Santander) study (median age 51 years, 84% male, median SCORE2 3.37) were evaluated on enrolment and at 3-year follow-up with 2D/3D vascular ultrasound (VUS) and coronary artery calcification scoring (CACS). A cardiac magnetic study (CMR) was subsequently performed and IS defined as the presence of subendocardial or transmural late gadolinium enhancement (LGE). On CMR, 132 (19.1%) participants had positive LGE, and IS was identified in 20 (2.9%) participants. Individuals with IS had significantly higher SCORE2 at baseline and higher CACS and peripheral SA burden (number of plaques by 2DVUS and plaque volume by 3DVUS) at both SA evaluations. High CACS and peripheral SA (number of plaques) burden were independently associated with the presence of IS, after adjusting for SCORE2 [OR for 3rd tertile, 8.31; 95% confidence interval (CI) 2.85-24.2; P < 0.001; and 2.77; 95% CI, 1.02-7.51; P = 0.045, respectively] and provided significant incremental diagnostic value over SCORE2., Conclusion: In a low-risk middle-aged population, SA burden (CAC and peripheral plaques) was independently associated with a higher prevalence of IS identified by CMR. These findings reinforce the value of SA evaluation to early implement preventive measures., Clinical Trial Registration: Progression of Early Subclinical Atherosclerosis (PESA) Study Identifier: NCT01410318., Competing Interests: Conflict of interest. J.S.-G. is an employee of Philips Healthcare. All other authors have reported that they have no relationships to disclose relevant to the content of this paper., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction and Objectives: Myocardial infarction (MI) incidence and case fatality trends are highly informative but relatively untested at the population level. The objective of this work was to estimate MI incidence and case fatality in the Girona population aged 35-74 years, and to determine their 30-year trends (1990-2019)., Methods: The REGICOR (Girona Heart Registry) monitored MI incidence and case fatality rates from 1990 to 2008. For the period 2008 to 2019, we linked discharges from Girona hospitals (n=4 974 977) and mortality registry (n=70 405) during this period. Our linkage algorithm selected key MI diagnostic codes and removed duplicates. Estimates from the linkage algorithm and the REGICOR registry were compared using chi-square tests for overlapping years (2008-2009). We estimated the annual percent change (APC) of standardized MI incidence and 28-day case fatality, and analyzed their trends using joinpoint regression., Results: MI incidence and case fatality estimates were similar in the linkage algorithm and the REGICOR registry. We observed significant decreasing trends in the incidence of MI. The trend was APC, -0.96% (95% confidence interval (95%CI), -1.4 to -0.53) in women from 1990 to 2019 and -4.2% (95%CI, -5.5 to -3.0) in men from 1994 to 2019. The largest decrease in case fatality was -3.8% (95%CI, -5.1 to -2.5) from 1995 to 2003 in women and -2.4% (95%CI, -2.9 to -1.9) from 1995 to 2004 in men, mainly due to prehospital case fatality declines: -1.8% (95%CI, -2.6 to -1.1) in men and -3.2% (95%CI, -4.6 to -1.8) in women., Conclusions: In Girona, MI incidence and case fatality decreased between 1990 and 2019. The incidence showed a slow but continuous decrease while case fatality only stabilized in the last decade, particularly in women., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Ventricular fibrillation (VF) in acute myocardial infarction (AMI) is the main cause of deaths occurring in the acute phase of an ischemic event. Although it is known that genetics may play an important role in this pathology, the possible role of long non-coding RNAs (lncRNA) has never been studied. Therefore, the aim of this work is to study the expression of 10 lncRNAs in patients with and without VF in AMI. For this purpose, the expression of CDKN2B-AS1, KCNQ1OT1, LIPCAR, MALAT1, MIAT, NEAT1, SLC16A1-AS1, lnc-TK2-4:2, TNFRSF14-AS1, and UCA1 were analyzed. After the analysis and Bonferroni correction, the lncRNA CDKN2B-AS showed a statistical significance lower expression (P values of 2.514 x 10-5). In silico analysis revealed that six proteins could be related to the possible effect of lncRNA CDKN2B-AS1: AGO3, PLD4, POU4F1, ZNF26, ZNF326 and ZNF431. These in silico proteins predicted to have a low cardiac expression, although there is no literature indicating a potential relationship with VF in AMI. Thus, the lncRNA CDKN2B-AS1 shows a significant lower expression in patients with VF in AMI vs patients without VF in AMI. Literature data suggest that the role of CDKN2B1-AS is related to the miR-181a/SIRT1 pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pan-Lizcano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: The ecto-nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI)., Methods: Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed., Results: Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time., Conclusions: Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion., Competing Interests: The authors declare no conflicts of interest.

Background: The impact on age on the short-term and long-term prognosis in patients with Takotsubo syndrome (TTS) is unclear. We aimed to evaluate whether age has prognostic implications during hospital stay and long-term follow-up of TTS patients., Methods: 688 consecutive patients were admitted for TTS in 7 tertiary centers from January-2008 to June-2021. We divided our cohort into two groups (patients <75 years and ≥75 years). Clinical, analytical, and hemodynamic variables as well as in-hospital management were registered and compared between groups. Mortality rates during hospital stay and follow-up were assessed. Adverse cardiovascular events (ACE) were defined as the composite of cardiovascular death, heart failure event, acute myocardial infarction, stroke and symptomatic arrhythmia., Results: Median age was 74.7 years and 49.4 % were ≥75 years. 86.9 % were women and 22.3 % were secondary forms of TTS. In-hospital mortality was 3.6 % (1.5 % cardiovascular). Median clinical follow-up was 4.3 years. Mortality during the follow-up period was 23 % (5.0 % cardiovascular) while ACE were 22.5 %, mainly due to heart failure events. Kaplan-Meier curves showed both higher rates of mortality and ACE in ≥75 years group (30.2 % vs 15.8 %; p < 0.001 and 28.3 % vs 16.7 %; p < 0.001). Age was independently associated with higher rates of overall mortality and ACE in patients with TTS. Hypertension, absence of sinus rhythm, Killip class > I and a more impaired coronary microvascular resistance were also associated to ACE in TTS patients., Conclusions: Advanced age was associated with higher rate of overall mortality and ACE during long-term follow-up in TTS patients., Competing Interests: Declaration of competing interest Dr. Hector M. Garcia-Garcia reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips and Corflow. The following is the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.carrev.2023.10.018., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

Protein glycosylation controls cell-cell and cell-extracellular matrix (ECM) communication in immune, vascular, and inflammatory processes, underlining the critical role of this process in the identification of disease biomarkers and the design of novel therapies. Emerging evidence highlights the critical role of blood cell glycosylation in the pathophysiology of atherosclerosis (ATH) and myocardial infarction (MI). Here, we review the role of glycosylation in the interplay between blood cells, particularly erythrocytes, and endothelial cells (ECs), highlighting the involvement of this critical post/cotranslational modification in settings of cardiovascular disease (CVD). Importantly, we focus on emerging preclinical studies and clinical trials based on glycan-targeted drugs to validate their therapeutic potential. These findings may help establish new trends in preventive medicine and delineate novel targeted therapies in CVD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lipoprotein(a) (Lp[a]) is an emerging risk factor for incident ischemic heart disease. However, its role in risk stratification in in-hospital survivors to an index acute myocardial infarction (AMI) is scarcer, especially for predicting the risk of long-term recurrent AMI. We aimed to assess the relation between Lp(a) and very long-term recurrent AMI after an index episode of AMI. It is a retrospective analysis that included 1,223 consecutive patients with an AMI discharged from October 2000 to June 2003 in a single-teaching center. Lp(a) was assessed during index admission in all cases. The relation between Lp(a) at discharge and total recurrent AMI was evaluated through negative binomial regression. The mean age of the patients was 67.0 ± 12.3 years, 379 (31.0%) were women, and 394 (32.2%) were diabetic. The index event was more frequently non-ST-segment elevation myocardial infarction (66.0%). The median Lp(a) was 28.8 (11.8 to 63.4) mg/100 ml. During a median follow-up of 9.9 (4.6 to 15.5) years, 813 (66.6%) deaths and 1,205 AMI in 532 patients (43.5%) occurred. Lp(a) values were not associated with an increased risk of long-term all-cause mortality (p = 0.934). However, they were positively and nonlinearly associated with an increased risk of total long-term reinfarction (p = 0.016). In the subgroup analysis, there was no evidence of a differential effect for the most prevalent subgroups. In conclusion, after an AMI, elevated Lp(a) values assessed during hospitalization were associated with an increased risk of recurrent reinfarction in the very long term. Further prospective studies are warranted to evaluate their clinical implications., Competing Interests: Declaration of Competing Interest Dr. Miñana received honoraria for lectures from Abbott and Teleflex. Alberto Cordero received lecture honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim (Ingelheim, Germany), Merck Sharp & Dohme, Daiichi Sankyo, Novartis (Eli Lilly), Novo Nordisk, Sanofi, and Amarin and consulting fees from AstraZeneca, Ferrer, Sanofi, Amgen (Bristol), Novartis, Novo Nordisk, and Amarin. Dr. Fernández-Cisnal received honoraria for lectures from Abbott. Dr. Valero received honoraria for lectures from Abbott. Dr. Llergo received lecture honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer-BMS, Rovi, Eli Lilly, Novartis, and Vifor and consulting fees from AstraZeneca, Boehringer Ingelheim, and Novartis. Rosa Fernández-Olmo received honoraria for lectures from AstraZeneca, Sanofi, Novartis, Rovi, Amarin, and Amgen, and consulting fees from AstraZeneca, Sanofi, Organón, and Novartis. Dr. Castro received honoraria for lectures and consulting from Novartis, Amgen, Boehringer Ingelheim, Astra Zeneca, Novonordisk, Servier, Organón, and Daychii-Sankyo. Dr. Sanchis received honoraria for lectures from Abbott. Dr. Núñez received honoraria for lectures and consulting from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Cytokinetics, Pfizer (New York, New York), Novartis, NovoNordisk, Rovi, and Vifor Pharma. The remaining authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The sequelae of myocardial infarction (MI) require specific pharmacological therapy to minimise the post-MI remodelling, which in many cases evolves into cardiovascular complications. The aim of this study was to analyse the effect of edoxaban, an oral anticoagulant, on cardiac recovery in a rat model of permanent coronary artery ligation., Methods: An experimental method to assess the post-MI remodelling in rats for 4 weeks, based on cardiac magnetic resonance imaging (MRI) and final histological analysis of the hearts was performed. The influence of daily oral treatment with edoxaban (20 mg/kg/day) for 28 days post-MI was analysed in comparison to vehicle., Results: In our model, edoxaban was shown to be safe and bleeding was observed in 1 of 10 animals. General physical recovery of the treated animals was shown by higher body weight recovery compared with non-treated animals (38.6 ± 2.9 vs. 29.9 ± 3.1 g, respectively, after 28 days). There was not a pronounced effect of edoxaban in post-MI cardiac remodelling, but mitigated fibrosis was observed by the reduced expression of vascular endothelial growth factor and tumour growth factor β1 in the peri-infarct zone., Conclusions: Our analysis provided the experimental basis to support the feasibility of MRI to study cardiac function and characterise myocardial scarring in a rat model. Overall data suggested the safety of edoxaban in the model, and compared to placebo, it showed a better post-MI recovery, probably by reducing fibrosis of the heart. Further research on mid-term cardiac recovery with edoxaban after MI is justified., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors declare that this work was supported by Daiichi-Sankyo España, but this did not influence the results or interpretation of this manuscript for any of the authors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) is the main cause of death worldwide, with myocardial infarction (MI) being the most prevalent pathology involved in CVD. MI is characterized by a deficiency in oxygen supply to the myocardium, thereby promoting ventricular remodeling of the ischemic and remote zone of the heart. Cardiac remodeling associated with MI could promote the development of heart failure and finally death. For these reasons, it is important to develop animal models that mimic human cardiac disease which could help to identify new mechanisms involved in the pathology and, consequently, develop new therapeutic strategies. We herein describe in detail a protocol for MI induction with low mortality rate (<15%) in rats by ligation of the left anterior descending artery. In addition, we also describe two imaging techniques which allow to evaluate cardiac structure and function-including deformation parameters in rats such as transthoracic echocardiography and cardiac magnetic resonance. This animal model could be useful for acute and chronic studies and for evaluating the potential usefulness of different treatments., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training and similar technologies.)

Introduction and Objectives: Meteorin-like protein (Metrnl) is a cytokine involved in the attenuation of inflammation. In patients with heart failure, high levels of this biomarker are associated with a worse outcome. In this study, we evaluated the circulating levels and prognostic value of Metrnl in patients with ST-segment elevation myocardial infarction (STEMI)., Methods: We enrolled STEMI patients undergoing primary percutaneous coronary intervention. Circulating Metrnl levels were measured in peripheral blood 12hours after symptom onset. The primary endpoint was a composite of all-cause mortality or nonfatal myocardial infarction (MI) at 3 years., Results: We studied 381 patients (mean age 61 years, 21% female, 8% Killip class III/IV). Metrnl levels were associated with age, cardiovascular risk factors and the extent of coronary artery disease, as well as with STEMI complications, particularly heart failure and cardiogenic shock. Multivariable Cox regression analysis revealed that Metrnl independently predicted all-cause death or nonfatal MI at 3 years (HR, 1.86; 95%CI, 1.23-2.81; P=.003). Moreover, patients in the highest tertile (> 491.6 pg/mL) were at higher risk for the composite endpoint than those in the lowest tertiles (HR, 3.24; 95%CI, 1.92-5.44; P <.001), even after adjustment by age, diabetes mellitus, cardiac arrest, Killip-Kimball III/IV class, left ventricular ejection fraction, and creatinine clearance (HR, 1.90; 95%CI, 1.10-3.29; P=.021)., Conclusions: Circulating Metrnl levels are associated with complications during the acute phase of STEMI and independently predict a worse outcome in these patients., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Data on the clinical profile and outcomes of younger patients with ST-elevation myocardial infarction (STEMI) is scarce. This study compared clinical characteristics and outcomes between patients aged<45 years and those aged ≥ 45 years with STEMI managed by the acute myocardial infarction code (AMI Code) network. Sex-based differences in the younger cohort were also analyzed., Methods: This multicenter study collected individual data from the Catalonian AMI Code network. Between 2015 and 2020, we enrolled patients with an admission diagnosis of STEMI. Primary endpoints were all-cause mortality within 30 days, 1 year, and 2 years., Results: Overall, 18 933 patients (23% female) were enrolled. Of them, 1403 participants (7.4%) were aged<45 years. Younger patients with STEMI were more frequently smokers (P<.001) and presented with cardiac arrest and TIMI flow 0 before pPCI (P<.05), but the time from first medical contact to wire crossing was shorter than in the older group (P<.05). All-cause mortality rates were lower in patients aged<45 years (P<.001). Among younger patients, cardiogenic shock was most prevalent in women than in their male counterparts (P=.002), with the time from symptom onset to reperfusion being longer (P<.05). Compared with men aged<45 years, younger women were less likely to undergo pPCI (P=.004)., Conclusions: Despite showing high-risk features on admission, young patients exhibit better outcomes than older patients. Differences in ischemia times and treatment were observed between men and women., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling., Methods: Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged)., Results: In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups., Conclusion: Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca 2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal., Competing Interests: Declaration of competing interest PF is the founder and CEO of Pharmahungary Group, a group of R&D companies. AMS is an adviser to Forcefield Therapeutics and CYTE – Global Network for Clinical Research and sits on the Board of Heqet Therapeutics. CM served as an advisor to Amgen, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk and Servier and received speaker honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Berlin Chemie, Novartis and NovoNordisk. No other author had an interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Bempedoic acid is a selective inhibitor of the adenosine triphosphate citrate lyase that reduces low-density lipoprotein cholesterol (LDLc) levels by 17% to 28%. Although the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (CLEAR-OUTCOMES) trials demonstrated the efficacy on cardiovascular outcomes there is a controversy related to the possible net clinical benefit. Thereafter, we performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6 months. The mean baseline LDLc was 129.4 (22.8) mg/100 ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6) mg/100 ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm., Competing Interests: Declaration of Competing Interest Dr. Cordero reports honoraria for lectures from AstraZeneca, AMGEN, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim, Merck Sharp & Dohme, Daiichy Sankio, Novartis, Novo Nordisk, Sanofi and Amarin; and consulting fees from AstraZeneca, Ferrer, Sanofi, AMGEN, Novartis, Lilly, Novo Nordisk and Amarin. Dr. Fernández reports honoraria for lectures from AstraZeneca, AMGEN, Ferrer, Merck Sharp & Dohme, Daiichi Sankio, Novartis, Novo Nordisk, Sanofi, and Amarin; and consulting fees from AstraZeneca, Sanofi, AMGEN, Novartis, Novo Nordisk, and Amarin. Dr. Castellano reports honoraria from Ferrer, Servier, Daiichi Sankyo, and Pfizer. Dr. Fácila reports honoraria for lectures from Eli Lilly Co, Daiichi Sankyo, Inc., Bayer, Pfizer, Novartis Boehringer Ingelheim, and consulting fees from AstraZeneca, Boehringer, Bayer. Dr. Rodriguez-Mañero reports research grants from Fundación Mutua Madrileña, Biosense Webster, Medtronic, and the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain). Dr. Bonanad has received fees from AstraZeneca; Amgen, Bayer; Boehringer; Bristol-Myers Squibb; Daiichi Sankyo; Ferrer; Novartis AG; Pfizer; Roche Pharma; Sanofi Pharma. Dr. González Juanatey reports honoraria for lectures from Eli Lilly Co, Daiichi Sankyo, Inc., Bayer, Pfizer, Abbott, Boehringer Ingelheim, Merck Sharp & Dohme, Ferrer, and Bristol-Myers Squibb; consulting fees from AstraZeneca, Ferrer, Bayer, Boehringer Ingelheim; and research grants from AstraZeneca, Boehringer Ingelheim and Daichi-Sankyo. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Though associations between obstructive sleep apnea (OSA) and cardiovascular outcomes are well described, limited data exist regarding the impact of OSA on sex-specific outcomes after acute myocardial infarction (AMI). Methods and Results The VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study enrolled 3572 adults aged 18 to 55 years with AMI from the United States and Spain during 2008 to 2012. We included patients for whom the Berlin Questionnaire for OSA was scored at the time of AMI admission (3141; 2105 women, 1036 men). We examined the sex-specific association between baseline OSA risk with functional outcomes including health status and depressive symptoms at 1 and 12 months after AMI. Among both groups, 49% of patients were at high risk for OSA (1040 women; 509 men), but only 4.7% (148) of patients had a diagnosed history of OSA. Though patients with a high OSA risk reported worse physical and mental health status and depression than low-risk patients in both sexes, the difference in these functional outcomes was wider in women than men. Moreover, women with a high OSA risk had worse health status, depression, and quality of life than high-risk men, both at baseline and at 1 and 12 months after AMI. Conclusions Young women with a high OSA risk have poorer health status and more depressive symptoms than men at the time of AMI, which may place them at higher risk of poorer health outcomes over the year following the AMI. Further, the majority of patients at high risk of OSA are undiagnosed at the time of presentation of AMI.

Background: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown., Aims: We sought to compare different PCI timing strategies in TAVI patients., Methods: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method., Results: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (17.4% vs 30.4% vs 30.0%; p=0.003). Results were confirmed at landmark analyses considering events from 0 to 30 days and from 31 to 720 days., Conclusions: In patients with severe aortic stenosis and stable coronary artery disease scheduled for TAVI, performance of PCI after TAVI seems to be associated with improved 2-year clinical outcomes compared with other revascularisation timing strategies. These results need to be confirmed in randomised clinical trials.

Renal impairment confers worse prognosis in patients with atrial fibrillation (AF) but there is scarce evidence about the influence of direct-acting oral anticoagulants in routine clinical practice. Herein, we compared clinical outcomes between patients with AF with and without renal impairment on rivaroxaban and investigated predictors for clinical outcomes in patients with AF with renal impairment. This was a multicenter study including patients with AF on rivaroxaban for at least 6 months. During 2.5 years follow-up, ischemic strokes (IS)/transient ischemic attacks (TIA)/systemic embolisms (SE)/myocardial infarctions (MI), major bleeding, and major adverse cardiovascular events (MACE) were recorded. Creatinine clearance (CrCl) was estimated using the Cockroft-Gault equation, renal impairment was defined as a CrCl <60 ml/min, and 1,433 patients (34.8% with CrCl <60 ml/min) were included. Patients with CrCl <60 ml/min showed higher event rates for major bleeding (1.87%/year vs 0.62%/year; p = 0.003) and MACE (1.97%/year vs 0.62%/year; p = 0.002) but similar event rates for IS/TIA/SE/MI (0.66%/year vs 0.67%/year; p = 0.955). In patients with renal impairment, CHA 2 DS 2 -VASc was associated with higher risk of IS/TIA/SE/MI; HAS-BLED and any dependency level were associated with higher risk of major bleeding; and male gender and heart failure were associated with higher risk of MACE. Antiplatelets were independently associated with increased risk of IS/TIA/SE/MI and MACE. In conclusion, in patients with AF on rivaroxaban, the incidence of IS/TIA/SE/MI did not increase in those with renal impairment, suggesting that rivaroxaban may be an effective option in this subgroup. In patients with AF, male gender, heart failure, dependency, antiplatelets, CHA 2 DS 2 -VASc, and HAS-BLED were associated with increased risk of adverse outcomes., Competing Interests: Declaration of Competing Interest JM Rivera-Caravaca is a consultant for Idorsia Pharmaceuticals LTD. M. Anguita Sanchez has received financial compensation from Bayer for participating in the EMIR registry. M. Sanmartín Fernández has received speaker and advisory fees from the following companies in the past 3 years: Bayer, Boehringer-Ingelheim, BMS, and Pfizer. C. Rafols is an employee of the Medical Department, Bayer Hispania S.L, which is the sponsor of the EMIR study. G. Barón-Esquivias has received lecture fees from Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Pfizer-BMS, Sanofi, Novartis, and Rovi; and financial compensation from Bayer for participating in the EMIR study and an institutional grant from Novartis. J. Cosín-Sales has received financial compensation from Bayer for participating in the EMIR registry. R. Freixa-Pamias has received consultancy/lecturing fees from Bayer, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi Sankyo; and financial compensation from Bayer for participating in the EMIR study. I. Lekuona Goya has received financial compensation from Bayer for participating in the EMIR study. JM Vázquez Rodríguez has received lecture fees from Bayer, Boehringer-Ingelheim, Pfizer, Bristol Myers Squibb, and Daiichi Sankyo; and financial compensation from Bayer for participating in the EMIR study. AI Pérez-Cabeza has received consultancy/lecturing fees from Bayer, Boehringer-Ingelheim, Pfizer, Bristol Myers Squibb, and Daiichi Sankyo. I. Ureña Montilla has received financial compensation from Bayer for participating in The EMIR study; speaker and advisory fees from the following companies: Bayer, Novartis, Daiichi Sankyo, Vifor, Boehringer-Ingelheim, and Amgen. A. Alvarez-Vieitez Blanco has received financial compensation from Bayer for participating in the EMIR study. F. Arribas Ynsaurriaga has received consultancy/lecture fees and research funding from Daiichi Sankyo, Pulse Dynamics, Medtronic, Boston Scientific, Bayer, Bristol Myers Squibb, Arrhythmia Network Technology SL/BAROSTIM, Abbott, Novartis, Janssen-Cilag, Biosensors, and Edwards Lifesciences; and received financial compensation from Bayer for participating in the EMIR registry. F Marín has received consultancy/lecturing fees from Bayer, Boehringer-Ingelheim, Pfizer, Bristol Myers Squibb, and Daiichi Sankyo., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The benefit of complete revascularization in older patients (≥75 years of age) with myocardial infarction and multivessel disease remains unclear., Methods: In this multicenter, randomized trial, we assigned older patients with myocardial infarction and multivessel disease who were undergoing percutaneous coronary intervention (PCI) of the culprit lesion to receive either physiology-guided complete revascularization of nonculprit lesions or to receive no further revascularization. Functionally significant nonculprit lesions were identified either by pressure wire or angiography. The primary outcome was a composite of death, myocardial infarction, stroke, or any revascularization at 1 year. The key secondary outcome was a composite of cardiovascular death or myocardial infarction. Safety was assessed as a composite of contrast-associated acute kidney injury, stroke, or bleeding., Results: A total of 1445 patients underwent randomization (720 to receive complete revascularization and 725 to receive culprit-only revascularization). The median age of the patients was 80 years (interquartile range, 77 to 84); 528 patients (36.5%) were women, and 509 (35.2%) were admitted for ST-segment elevation myocardial infarction. A primary-outcome event occurred in 113 patients (15.7%) in the complete-revascularization group and in 152 patients (21.0%) in the culprit-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.57 to 0.93; P = 0.01). Cardiovascular death or myocardial infarction occurred in 64 patients (8.9%) in the complete-revascularization group and in 98 patients (13.5%) in the culprit-only group (hazard ratio, 0.64; 95% CI, 0.47 to 0.88). The safety outcome did not appear to differ between the groups (22.5% vs. 20.4%; P = 0.37)., Conclusions: Among patients who were 75 years of age or older with myocardial infarction and multivessel disease, those who underwent physiology-guided complete revascularization had a lower risk of a composite of death, myocardial infarction, stroke, or ischemia-driven revascularization at 1 year than those who received culprit-lesion-only PCI. (Funded by Consorzio Futuro in Ricerca and others; FIRE ClinicalTrials.gov number, NCT03772743.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction and Objectives: Prognosis in ST-elevation myocardial infarction (STEMI) is determined by delay in primary percutaneous coronary intervention (PPCI). The impact of first medical contact (FMC) facility type on reperfusion delays and mortality remains controversial., Methods: We performed a prospective registry of primary coronary intervention (PCI)-treated STEMI patients (2010-2020) in the Codi Infart STEMI network. We analyzed 1-year all-cause mortality depending on the FMC facility type: emergency medical service (EMS), community hospital (CH), PCI hospital (PCI-H), or primary care center (PCC)., Results: We included 18 332 patients (EMS 34.3%; CH 33.5%; PCI-H 12.3%; PCC 20.0%). Patients with Killip-Kimball classes III-IV were: EMS 8.43%, CH 5.54%, PCI-H 7.51%, PCC 3.76% (P <.001). All comorbidities and first medical assistance complications were more frequent in the EMS and PCI-H groups (P <.05) and were less frequent in the PCC group (P <.05 for most variables). The PCI-H group had the shortest FMC-to-PCI delay (median 82 minutes); the EMS group achieved the shortest total ischemic time (median 151 minutes); CH had the longest reperfusion delays (P <.001). In an adjusted logistic regression model, the PCI-H and CH groups were associated with higher 1-year mortality, OR, 1.22 (95%CI, 1.00-1.48; P=.048), and OR, 1.17 (95%CI 1.02-1.36; P=.030), respectively, while the PCC group was associated with lower 1-year mortality than the EMS group, OR, 0.71 (95%CI 0.58-0.86; P <.001)., Conclusions: FMC with PCI-H and CH was associated with higher adjusted 1-year mortality than FMC with EMS. The PCC group had a much lower intrinsic risk and was associated with better outcomes despite longer revascularization delays., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Statins are the cornerstone of lipid-lowering therapy (LLT) for reduction of low-density lipoprotein cholesterol (LDLc) levels and high percentage of patients require LLT combinations or alternative treatments for adequate LDLc control., Methods: We performed an intention-to-treat meta-analysis of published data of phase III trials evaluating LLT efficacy on major adverse cardiovascular events (MACE). The primary endpoint was MACE incidence, as reported in each trial, and secondary analyses included myocardial infarction, stroke and mortality., Results: Eleven clinical trials and 135,688 patients were included; seven trials tested high intensity LLT and 4 LLT combinations. Intensive LLT reduced MACE risk by 15% (12.03% vs. 13.79%, HR: 0.85 95% CI 0.80-0.90; p<0.001). The number needed to treat was 56 patients. Meta-regression analyses showed a linear correlation between absolute LDLc reductions and the risk of MACE. Significant reductions in myocardial infarction (HR: 0.83, 95% CI 0.80-0.86) and stroke (HR: 0.81, 95% CI 0.75-0.87) were observed. Cardiovascular death rate was 3.32% in LLT treatment arm vs. 3.56% in controls, resulting in a HR: 0.94 (95% CI 0.88-0.99; p = 0.03); no effect on all-cause mortality was observed (HR: 0.97 95% CI 0.93-1.01; p = 0.09). The sensitivity analyses verified the lack of heterogeneity, except for MACE that was mainly driven by the divergent results of the 2 trials. Small study effect was detected for the assessment of mortality., Conclusions: Current evidence consistently supports the efficacy of available intensity LLT for LDLc decrease on MACE and cardiovascular mortality reduction., (Copyright © 2023. Published by Elsevier Inc.)

Background: Cardiogenic shock (CGS) occurs in 10% of patients presenting with acute myocardial infarction (MI), with in-hospital mortality rates of 40-50% despite revascularisation., Aims: The EURO SHOCK trial aimed to determine if early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) could improve outcomes in patients with persistent CGS following primary percutaneous coronary intervention (PPCI)., Methods: This multicentre, pan-European trial randomised patients with persistent CGS 30 minutes after PPCI of the culprit lesion to receive either VA-ECMO or continue with standard therapy. The primary outcome measure was 30-day all-cause mortality in an intention-to-treat analysis. Secondary endpoints included 12-month all-cause mortality and 12-month composite of all-cause mortality or rehospitalisation due to heart failure., Results: Due to the impact of the COVID-19 pandemic, the trial was stopped before completion of recruitment, after randomisation of 35 patients (standard therapy n=18, VA-ECMO n=17). Thirty-day all-cause mortality occurred in 43.8% of patients randomised to VA-ECMO and in 61.1% of patients randomised to standard therapy (hazard ratio [HR] 0.56, 95% confidence interval [CI]: 0.21-1.45; p=0.22). One-year all-cause mortality was 51.8% in the VA-ECMO group and 81.5% in the standard therapy arm (HR 0.52, 95% CI: 0.21-1.26; p=0.14). Vascular and bleeding complications occurred more often in the VA-ECMO arm (21.4% vs 0% and 35.7% vs 5.6%, respectively)., Conclusions: Due to the limited number of patients recruited to the trial, no definite conclusions could be drawn from the available data. Our study demonstrates the feasibility of randomising patients with CGS complicating acute MI but also illustrates the challenges. We hope these data will inspire and inform the design of future large-scale trials.

Takotsubo syndrome (TTS) is a cardiac syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant obstructive coronary artery disease. At the autopsy, its diagnosis is often challenging, since it is generally thought that it relates to no characteristic macroscopic or microscopic findings. In order to verify this last statement, we performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. To the best of our knowledge, it is the first systematic review addressing this issue. We identified recurring but not pathognomonic (microscopic) features of TTS: contraction band necrosis and non-specific inflammatory changes (e.g., interstitial infiltrates of mononuclear lymphocytes and macrophages) typically in the absence of microscopic findings typical of acute myocardial infarction. In cases of TTS-related sudden death, careful evaluation of anamnesis, autopsy data and post-mortem genetic results (to exclude other causes) should be considered to overcome the complexity of these cases., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mechanical complications following a myocardial infarction are uncommon, but with dramatic consequences and high mortality. The left ventricle is the most often affected cardiac chamber and complications can be classified according to the timing in early (from days to first weeks) or late complications (from weeks to years). Despite the decrease in the incidence of these complications thank to primary percutaneous coronary intervention programs -wherever this option is available-, the mortality is still significant and these infrequent complications are an emergent scenario and one of the most important causes of mortality at short term in patients with myocardial infarction. Mechanical circulatory support devices, especially if minimally invasive implantation is used avoiding thoracotomy, have improved the prognosis of these patients by providing stability until definitive treatment can be applied. On the other hand, the growing experience in transcatheter interventions for the treatment of ventricular septal rupture or acute mitral regurgitation has been associated to an improvement in their results, even though prospective clinical evidence is still missing., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Importance: To our knowledge, no randomized clinical trial has compared the invasive and conservative strategies in frail, older patients with non-ST-segment elevation acute myocardial infarction (NSTEMI)., Objective: To compare outcomes of invasive and conservative strategies in frail, older patients with NSTEMI at 1 year., Design, Setting, and Participants: This multicenter randomized clinical trial was conducted at 13 Spanish hospitals between July 7, 2017, and January 9, 2021, and included 167 older adult (≥70 years) patients with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. Data analysis was performed from April 2022 to June 2022., Interventions: Patients were randomized to routine invasive (coronary angiography and revascularization if feasible; n = 84) or conservative (medical treatment with coronary angiography for recurrent ischemia; n = 83) strategy., Main Outcomes and Measures: The primary end point was the number of days alive and out of the hospital (DAOH) from discharge to 1 year. The coprimary end point was the composite of cardiac death, reinfarction, or postdischarge revascularization., Results: The study was prematurely stopped due to the COVID-19 pandemic when 95% of the calculated sample size had been enrolled. Among the 167 patients included, the mean (SD) age was 86 (5) years, and mean (SD) Clinical Frailty Scale score was 5 (1). While not statistically different, DAOH were about 1 month (28 days; 95% CI, -7 to 62) greater for patients managed conservatively (312 days; 95% CI, 289 to 335) vs patients managed invasively (284 days; 95% CI, 255 to 311; P = .12). A sensitivity analysis stratified by sex did not show differences. In addition, we found no differences in all-cause mortality (hazard ratio, 1.45; 95% CI, 0.74-2.85; P = .28). There was a 28-day shorter survival in the invasive vs conservatively managed group (95% CI, -63 to 7 days; restricted mean survival time analysis). Noncardiac reasons accounted for 56% of the readmissions. There were no differences in the number of readmissions or days spent in the hospital after discharge between groups. Neither were there differences in the coprimary end point of ischemic cardiac events (subdistribution hazard ratio, 0.92; 95% CI, 0.54-1.57; P = .78)., Conclusions and Relevance: In this randomized clinical trial of NSTEMI in frail older patients, there was no benefit to a routine invasive strategy in DAOH during the first year. Based on these findings, a policy of medical management and watchful observation is recommended for older patients with frailty and NSTEMI., Trial Registration: ClinicalTrials.gov Identifier: NCT03208153.

Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1 H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p < 0.05). However, regression analysis did not detect any significant correlation between most metabolite concentrations and infarct size, extent of edema or other cardiac magnetic resonance (CMR) variables. In conclusion, spontaneous reperfusion in TIMI 2 patients associates with enhanced succinate levels in peripheral blood, suggesting that succinate release increases overtime following reperfusion. However, early plasma levels of succinate and other metabolites obtained from peripheral blood does not correlate with the degree of irreversible injury or area at risk in STEMI patients, and cannot be considered as predictors of CMR variables.Trial registration: Registered at www.clinicaltrials.gov (NCT02404376) on 31/03/2015. EudraCT number: 2015-001000-58., (© 2023. The Author(s).)

Background: SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI)., Methods: We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected., Results: The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group., Conclusions: One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

Extracellular vesicles (EVs) are nanosized vesicles with a lipid bilayer that are released from cells of the cardiovascular system, and are considered important mediators of intercellular and extracellular communications. Two types of EVs of particular interest are exosomes and microvesicles, which have been identified in all tissue and body fluids and carry a variety of molecules including RNAs, proteins, and lipids. EVs have potential for use in the diagnosis and prognosis of cardiovascular diseases and as new therapeutic agents, particularly in the setting of myocardial infarction and heart failure. Despite their promise, technical challenges related to their small size make it challenging to accurately identify and characterize them, and to study EV-mediated processes. Here, we aim to provide the reader with an overview of the techniques and technologies available for the separation and characterization of EVs from different sources. Methods for determining the protein, RNA, and lipid content of EVs are discussed. The aim of this document is to provide guidance on critical methodological issues and highlight key points for consideration for the investigation of EVs in cardiovascular studies., Competing Interests: Conflicts of interest: L.B. has performed advisory board work and received speaker fees from Sanofi and Novartis, and is founder and shareholder of Glycardial Diagnosis SL and Ivestatin Therapeutics, SL (all outside of this work); C.J.B. is a board member of Technoclone. A.B. is the founder and CEO of Exo-Analysis. T.T. has filed and licensed patents in the field of non-coding RNAs and targeted delivery strategies and is the founder and shareholder of Cardior Pharmaceuticals GmbH (outside of the topic of this review). R.L. discloses grants from Stago and a patent on microvesicle fibrinolytic activity licensed to Stago. E.I.B. is a member of the Advisory Board of Sphere Gene Therapeutics Inc. (Boston, USA). M.H.M.W. discloses a collaborative research agreement with BD Biosciences Europe, Erembodegem, Belgium to optimize flow cytometric analysis of EVs. “This manuscript was handled by Reviews Deputy Editor Dr Ali J. Marian”., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as the most important cell types involved in the fibrotic process. Some drugs, such as inhibitors of the renin-angiotensin-aldosterone system, have been shown to be effective in reducing cardiac fibrosis. There are currently no drugs with primarily anti-fibrotic action approved for clinical use, as well as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of CAR-T cells engineered in vivo using lipid nanoparticles containing mRNA coding for a receptor directed against the FAP protein, expressed by cardiac myofibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans., (© 2022. The Author(s).)

Aims: To estimate the cost-effectiveness and cost-utility ratios of a restrictive vs. liberal transfusion strategy in acute myocardial infarction (AMI) patients with anaemia., Methods and Results: Patients (n = 666) with AMI and haemoglobin between 7-8 and 10 g/dL recruited in 35 hospitals in France and Spain were randomly assigned to a restrictive (n = 342) or a liberal (n = 324) transfusion strategy with 1-year prospective collection of resource utilization and quality of life using the EQ5D3L questionnaire. The economic evaluation was based on 648 patients from the per-protocol population. The outcomes were 30-day and 1-year cost-effectiveness, with major adverse cardiovascular events (MACEs) averted as the effectiveness outcome. and a 1-year cost-utility ratio.The 30-day incremental cost-effectiveness ratio was €33 065 saved per additional MACE averted with the restrictive vs. liberal strategy, with an 84% probability for the restrictive strategy to be cost-saving and MACE-reducing (i.e. dominant). At 1 year, the point estimate of the cost-utility ratio was €191 500 saved per quality-adjusted life year gained; however, the cumulated MACE was outside the pre-specified non-inferiority margin, resulting in a decremental cost-effectiveness ratio with a point estimate of €72 000 saved per additional MACE with the restrictive strategy., Conclusion: In patients with AMI and anaemia, the restrictive transfusion strategy was dominant (cost-saving and outcome-improving) at 30 days. At 1 year, the restrictive strategy remained cost-saving, but clinical non-inferiority on MACE was no longer maintained., Trial Registration: ClinicalTrials.gov Identifier: NCT02648113., One Sentence Summary: The use of a restrictive transfusion strategy in patients with acute myocardial infarction is associated with lower healthcare costs, but more evidence is needed to ascertain its long-term clinical impact., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although some studies have investigated sex-related outcomes up to 5 years after percutaneous coronary intervention (PCI), analyses at longer follow-up (ie, to 10 years) in large cohorts treated exclusively with drug-eluting stent (DES) platforms are lacking. Therefore, this study aimed to define whether sex-related differences in long-term outcomes after PCI persist both in the DES era and at longer-term follow-up., Methods: Individual data of patients treated with DES in 5 randomized controlled trials with 10-year follow-up were pooled. Patients were divided into 2 groups by sex. The analysis of individual participant data was performed using a 1-stage approach by entering a clustering effect by parent study in all univariable and multivariable models focusing on sex. The main outcomes of interest for this analysis included cardiovascular death, myocardial infarction, repeat revascularization, and definite stent thrombosis to 10 years after PCI. Survival was analyzed by the Kaplan-Meier method to estimate the time to first event, and differences between the 2 groups were tested with the log-rank test. Hazard ratios (HRs) and 95% CIs were calculated with a Cox proportional hazards model. Conventional multivariable analyses with adjustment for relevant variables were performed., Results: Among 9700 patients undergoing PCI with DES implantation included in the present analysis, 2296 were women and 7404 were men. Through to 10 years, cardiovascular death occurred in 407 of the 2296 female patients and 1012 of the 7404 male patients (adjusted HR [HR adj ], 0.94 [95% CI, 0.80-1.11]). Female sex was associated with a lower risk of repeat revascularization of the target lesion (HR adj , 0.80 [95% CI, 0.74-0.87]), target vessel (HR adj , 0.81 [95% CI, 0.76-0.87]), and nontarget vessels (HR adj , 0.69 [95% CI, 0.62-0.77]). Compared with male patients, female patients displayed an increased risk of myocardial infarction in the first 30 days after PCI with DES (HR adj , 1.65 [95% CI, 1.24-2.19]) but a comparable risk of myocardial infarction thereafter. The risk of definite stent thrombosis was not significantly different between female and male patients (HR adj , 1.14 [95% CI, 0.89-1.47])., Conclusions: Through to 10-year follow-up after PCI with DES, female patients are at increased risk of early myocardial infarction, receive fewer repeat revascularizations, and have no difference in cardiovascular mortality compared with male patients.

Experimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: We performed a comprehensive assessment of the effect of myocardial ischemia duration on cardiac structural and functional parameters by serial cardiac magnetic resonance (CMR) and characterized the evolving scar., Background: CMR follow-up on the cardiac impact of time of ischemia in a closed-chest animal model of myocardial infarction with human resemblance is missing., Methods: Pigs underwent MI induction by occlusion of the left anterior descending (LAD) coronary artery for 30, 60, 90 or 120 min and then revascularized. Serial CMR was performed on day 3 and day 42 post-MI. CMR measurements were also run in a sham-operated group. Cellular and molecular changes were investigated., Results: On day 3, cardiac damage and function were similar in sham and pigs subjected to 30 min of ischemia. Cardiac damage (oedema and necrosis) significantly increased from 60 min onwards. Microvascular obstruction was extensively seen in animals with ≥90 min of ischemia and correlated with cardiac damage. A drop in global systolic function and wall motion of the jeopardized segments was seen in pigs subjected to ≥60 min of ischemia. On day 42, scar size and cardiac dysfunction followed the same pattern in the animals subjected to ≥60 min of ischemia. Adverse left ventricular remodelling (worsening of both LV volumes) was only present in animals subjected to 120 min of ischemia. Cardiac fibrosis, myocyte hypertrophy and vessel rarefaction were similar in the infarcted myocardium of pigs subjected to ≥60 min of ischemia. No changes were observed in the remote myocardium., Conclusion: Sixty-minute LAD coronary occlusion already induces cardiac structural and functional alterations with longer ischemic time (120 min) causing adverse LV remodelling., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aims: THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry., Methods and Results: The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy., Conclusions: In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.', Clinical Trial Registration: http://www., Clinicaltrials: gov identifier: NCT01991795., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)