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Background: The association between left ventricular ejection fraction (LVEF) change (ΔLVEF) following percutaneous coronary intervention (PCI) and the long-term mortality rate in patients with coronary artery disease is incompletely investigated. We aimed to assess the impact of PCI on LVEF and the association of ΔLVEF after PCI with the long-term mortality rate., Methods and Results: This observational study included 8181 patients with paired angiographic LVEF measurements performed at baseline and 6 to 8 months following the index PCI. ΔLVEF was defined as LVEF measured on the 6- to 8-month angiography minus LVEF measured on the baseline angiography. LVEF change was classified according to the following categories: reduced (ΔLVEF <0), mildly improved (ΔLVEF >0% to <10%) and largely improved (ΔLVEF ≥10%). The primary outcome was the 5-year mortality rate. In patients with baseline LVEF <40%, 40% to <50% and ≥50%, ΔLVEF (median [25th-75th percentiles]) was 6.0% [0.0% to 14.0%], 4.0% [-1.0% to 11.0%] and 0.0% [-4.0% to 3.0%], respectively ( P <0.001). In patients with reduced, mildly improved, and largely improved ΔLVEF, the 5-year mortality rate (n=712) was 29.1%, 23.1%, and 16.5%, respectively, in patients with baseline LVEF <40%; 17.0%, 12.2% and 9.8%, respectively, in patients with baseline LVEF 40% to <50%; and 7.8%, 7.1%, and 5.6%, respectively, in patients with baseline LVEF ≥50% (adjusted hazard ratio [HR], 0.91 [95% CI, 0.86-0.96]; P <0.001) for all-cause death and adjusted (HR, 0.86 [95% CI, 0.81-0.92]; P <0.001) for cardiac death, calculated for 5% higher ΔLVEF., Conclusions: In patients with coronary artery disease undergoing PCI, improvement of LVEF following PCI was associated with a reduced long-term mortality rate in patients with reduced LVEF but not in patients with preserved LVEF before intervention.

Introduction:  Platelets greatly contribute to cardiovascular diseases. We sought to explore the association of platelet counts with infarct size and outcome in patients presenting with acute ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention (PPCI)., Methods and Results:  In this retrospective study, we grouped 1,198 STEMI patients into tertiles (T) based on platelet count on admission: T1 = 102-206 [10 9 platelets/L] ( n  = 402), T2 = 207-259 [10 9 platelets/L] ( n  = 396), and T3 = 260-921 [10 9 platelets/L] ( n  = 400). Primary endpoint was 1-year all-cause mortality. Patients with highest platelet counts on admission showed the greatest area at risk and infarct size: area at risk (median) was 22.0% (interquartile range [IQR]: 12.0-39.8%) in T1, 21.0% (IQR: 11.0-37.1%) in T2, and 26.0% (IQR: 14.9-45.0%) of the left ventricle in T3 ( p  = 0.003); final infarct sizes after 7 to 14 days were as follows: 10.0% (IQR: 2.0-21.0%) in T1, 9.0% (IQR: 2.0-20.7%) in T2, and 12.0% (IQR: 3.0-27.3%) of the left ventricle in T3 ( p  = 0.015) as serial imaging revealed. At 1 year, 16 all-cause deaths occurred in T1, 5 in T2, and 22 in T3 (log-rank test, p  = 0.006). After adjustment, T1 and T3 were associated with all-cause 1-year mortality (T1: hazard ratio [HR] = 3.40, 95% confidence interval [CI] = 1.23-9.54, p  = 0.02; T3: HR = 3.55, 95% CI = 1.23-9.78, p  = 0.01) compared with T2. At 5 years, all-cause mortality remained numerically higher in the T1 and T3., Conclusions:  In patients with STEMI undergoing PPCI, low and high blood platelet levels on admission were associated with increased long-term mortality (Fig. 1)., Competing Interests: None declared., (Thieme. All rights reserved.)

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies 1 . Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events 1,2 . However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events., (© 2024. The Author(s).)

Cardiovascular diseases are the leading cause of death worldwide. Pathophysiologically, metabolic and inflammatory processes contribute substantially to the development and progression of cardiovascular diseases. Over the past decade, the role of disease-propagating inflammatory processes has been strengthened and reframed, leading to trials testing anti-inflammatory drugs for the treatment of atherosclerosis and its complications. Despite these achievements, further research in both pre-clinical and clinical studies is warranted to explore new targets, to better identify responders, and to refine therapy strategies to combat inflammation in human disease. Environmental disturbances, so-called lifestyle-associated cardiovascular risk factors, greatly alter the immune system in general and leukocytes in particular, thus affecting the progression of atherosclerosis. Epidemiological studies have shown that exposure to mental stress can be closely linked to the occurrence of cardiovascular disease. Here, we describe how acute and chronic mental stress alter the immune system via neuroimmune interactions, thereby modifying vascular inflammation. In addition, we identify gaps that still need to be addressed in the future., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The frequency and prognostic value of coronary no-reflow (CNR) was investigated in studies that have used an outdated reperfusion therapy in terms of stent technology and antithrombotic drugs. We assessed the association of CNR with adverse outcomes in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and newer antithrombotic drugs, ticagrelor or prasugrel., Methods: This study included 3100 patients with AMI who underwent PCI with current DES and third-generation P2Y 12 inhibitors. CNR was defined as Thrombolysis in Myocardial Infarction (TIMI) blood flow grade ≤ 2 at the end of PCI. The primary end point was 1-year incidence of net adverse clinical and cerebral events-a composite end point of death of any cause, myocardial infarction, stroke or major bleeding., Results: CNR was diagnosed in 130 patients (4.2%). The primary end point occurred in 28 patients in the CNR group and 354 patients in the reflow group (cumulative incidence 23.2% and 12.8%; adjusted hazard ratio = 1.53, 95% confidence interval 1.01-2.33; P = 0.049). The 1-year incidences of death or myocardial infarction (14.6% vs. 7.6%; P = 0.003), myocardial infarction (8.8% vs. 3.9%; P = 0.007) and major bleeding (10.9% vs. 5.6%; P = 0.008) were significantly higher in patients with CNR than patients with reflow. The risk of adverse events in patients with CNR was highest within the first 30 days after PCI., Conclusion: In patients with AMI undergoing PCI with current DES and third generation P2Y 12 receptor inhibitors, CNR was associated with a higher risk of adverse outcomes at 1 year., (© 2023. The Author(s).)

Background: The ISAR-REACT 5 trial compared the efficacy and safety of ticagrelor and prasugrel in patients with ACS managed invasively. The present study sought to investigate the impact of ticagrelor and prasugrel on the incidence and pattern of urgent revascularization in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This post-hoc analysis of the ISAR-REACT 5 trial included all ACS patients who underwent PCI. The primary endpoint for this analysis was the incidence of urgent revascularization at 12-month follow-up. Secondary outcome was the pattern of urgent revascularization procedures (namely, urgent target vessel/non-target vessel revascularization - TVR/NTVR). Among 3,377 ACS patients who underwent PCI, 1,676 were assigned to ticagrelor and 1,701 to prasugrel before PCI. After 12 months, the incidence of urgent revascularization was higher among patients assigned to ticagrelor as compared to prasugrel (6.8% vs. 5.2%; hazard ratio [HR] = 1.32, 95% confidence interval [CI] 1.00-1.75; p = 0.051), mostly attributable to significantly more urgent NTVR in the ticagrelor group (3.8% vs. 2.4%; HR = 1.62 [1.09-2.41]; p = 0.017). The risk of urgent TVR did not differ between treatment groups (3.3% vs. 3.0%; HR = 1.13 [0.77-1.65]; p = 0.546)., Conclusions: In ACS patients treated with PCI, the cumulative rate of urgent revascularizations after 12 months is higher with ticagrelor compared to prasugrel, due to a significant increase in urgent revascularizations involving remote coronary vessels., (© 2024. The Author(s).)

Background: The performance of modified balloons (namely cutting or scoring balloons) to prepare severely calcified lesions in patients undergoing percutaneous coronary intervention (PCI) remains controversial. We investigated the clinical and imaging outcomes of patients undergoing PCI assigned to modified balloon therapy to prepare severely calcified coronary lesions before stent implantation., Methods: In this meta-analysis, we aggregated the study-level data from trials enrolling invasively treated patients who were randomly assigned to modified balloon or control therapy to prepare severely calcified lesions before stenting. The primary outcome was major adverse cardiac events (MACE), including death, myocardial infarction (MI), and repeat revascularization. The secondary outcomes included the individual components of the primary outcome, coronary perforation and final minimal stent area (MSA) as measured by intracoronary imaging., Results: A total of 648 participants in six trials were allocated to modified balloon therapy (n = 335) or control therapy (semi-compliant, non-compliant, or super high-pressure balloon, n = 313). The median follow-up was 11 months. Overall, MACE occurred in 8.96% of patients assigned to a modified balloon and 12.78% of patients assigned to control therapy [risk ratio = 0.70, 95% confidence interval (CI) 0.35-1.39; P = 0.24]. There was a significant treatment effect-by-modified balloon type interaction for the outcome MACE in patients assigned to cutting balloon compared with control therapy [RR = 0.40 (0.28-0.56), P for interaction (P int ) < 0.001]. Patients treated with a modified balloon compared with control therapy showed neither a significant difference for the other clinical outcomes nor for final MSA [standardized mean difference = 0.67 (- 0.71, 2.06); P = 0.26]., Conclusions: In patients treated with PCI for severely calcific coronary artery disease a strategy of lesion preparation with a modified balloon before stenting does not improve clinical or imaging outcomes compared with control therapy. The different performance of cutting and scoring balloons warrants further investigation., (© 2023. The Author(s).)

Introduction and Objectives: Multivessel percutaneous coronary intervention (MV-PCI) is recommended in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD) without cardiogenic shock. The present network meta-analysis investigated the optimal timing of MV-PCI in this context., Methods: We pooled the aggregated data from randomized trials investigating stable STEMI patients with multivessel CAD treated with a strategy of either MV-PCI or culprit vessel-only PCI. The primary outcome was all-cause death. The main secondary outcomes were cardiovascular death, myocardial infarction, and unplanned ischemia-driven revascularization., Results: Among 11 trials, a total of 10 507 patients were randomly assigned to MV-PCI (same sitting, n=1683; staged during the index hospitalization, n=3460; staged during a subsequent hospitalization within 45 days, n=3275) or to culprit vessel-only PCI (n=2089). The median follow-up was 18.6 months. In comparison with culprit vessel-only PCI, MV-PCI staged during the index hospitalization significantly reduced all-cause death (risk ratio, 0.73; 95%CI, 0.56-0.92; P=.008) and ranked as possibly the best treatment option for this outcome compared with all other strategies. In comparison with culprit vessel-only PCI, a MV-PCI reduced cardiovascular mortality without differences dependent on the timing of revascularization. MV-PCI within the index hospitalization, either in a single procedure or staged, significantly reduced myocardial infarction and unplanned ischemia-driven revascularization, with no significant difference between each other., Conclusions: In patients with STEMI and multivessel CAD without cardiogenic shock, multivessel PCI within the index hospitalization, either in a single procedure or staged, represents the safest and most efficacious approach. The different timings of multivessel PCI did not result in any significant differences in all-cause death. This study is registered at PROSPERO (CRD42023457794)., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The association of aspirin loading with the risk of coronary no-reflow (CNR) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been investigated. We assessed the association of aspirin loading before PCI with CNR in patients with AMI., Materials and Methods: This study included 3100 patients with AMI undergoing PCI. Of them, 2812 patients received aspirin loading (a single oral [or chewed] or intravenous dose of 150-300 mg) and 288 patients did not receive aspirin loading before PCI. The primary endpoint was CNR, defined as Thrombolysis in Myocardial Infarction blood flow grade of <3 after the PCI., Results: CNR occurred in 130 patients: 127 patients in the group with aspirin loading and 3 patients in the group without aspirin loading before PCI (4.5% vs. 1.0%; odds ratio [OR] = 4.50, 95% confidence interval, [1.42-14.21], p = 0.005). After adjustment, the association between aspirin loading and CNR was significant (adjusted OR = 4.49 [1.56-12.92]; p < 0.001). There was no aspirin loading-by-P2Y 12 inhibitor (ticagrelor or prasugrel) interaction (p int  = 0.465) or aspirin loading-by-chronic aspirin therapy on admission (p int  = 0.977) interaction with respect to the occurrence of CNR after PCI. Chronic low-dose aspirin therapy on admission was not independently associated with higher risk of CNR after PCI (adjusted OR = 1.06 [0.65-1.72]; p = 0.824)., Conclusion: In patients with AMI undergoing PCI, aspirin loading before the PCI procedure at the guideline-recommended doses was associated with higher odds of developing CNR. However, due to the limited number of events, the findings should be considered as hypothesis generating., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The association between uric acid (UA) and long-term mortality in patients with coronary artery disease is poorly investigated. We assessed the association between UA and 10-year mortality after percutaneous coronary intervention (PCI) in 3,998 patients who underwent PCI. Patients were categorized in groups according to UA tertiles: tertile 1 (UA <5.80 mg/100 ml, n = 1,347), tertile 2 (UA 5.80 to 7.04 mg/100 ml, n = 1,340), and tertile 3 (UA >7.94 mg/100 ml, n = 1,311). The primary outcome was 10-year all-cause mortality. All-cause deaths occurred in 1,200 patients: 320 deaths (26.5%) in patients with UA in the first tertile, 325 deaths (26.9%) in patients with UA in the second tertile, and 555 deaths (46.0%) in patients with UA in the third tertile (adjusted hazard ratio 1.22, 95% confidence interval 1.17 to 1.27, p <0.001) for 1 mg/100 ml increment in UA level. Cardiac deaths occurred in 748 patients: 194 deaths (16.5%) in patients with UA in the first tertile, 202 deaths (17.0%) in patients with UA in the second tertile, and 352 deaths (29.7%) in patients with UA in the third tertile (adjusted hazard ratio 1.24 [1.17 to 1.32], p <0.001) for 1 mg/100 ml increment in the UA level. The 10-year rates of target lesion revascularization, target vessel revascularization, or nontarget vessel revascularization did not differ significantly according to the UA level. In conclusion, in patients with coronary artery disease treated with PCI, increased UA level was associated with higher 10-year mortality. Increased UA level was not associated with the progression of atherosclerosis in nontreated coronary vessels or progression of intimal hyperplasia in stented lesions requiring intervention., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest statement T.K. is the Principal Investigator of MATRICARD. T.K. received lecture fees from Bayer, Abbott, and Astra-Zeneca and is named inventor on a patent application for prevention of restenosis after angioplasty and stent implantation, all unrelated to this work. The other authors have nothing to disclose.

Background: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis., Methods: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe -/- and Apoe -/- Adamts7 -/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques., Results: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe -/- mice, atherosclerotic aortas of Apoe -/- mice lacking Adamts-7 (Apoe -/- Adamts7 -/- ) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe -/- and Apoe -/- Adamts7 -/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe -/- as compared to Apoe -/- Adamts7 -/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site., Conclusions: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events., Competing Interests: Disclosures Dr Schunkert has received personal fees from MSD SHARP & DOHME, AMGEN, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol-Myers-Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, and Vifor T as well as grants and personal fees from Astra-Zeneca outside the submitted work. Drs Schunkert and Kessler are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. Dr Kessler received lecture fees from Bayer, Bristol-Myers Squibb, Abbott, and Astra-Zeneca, which are unrelated to this work. Dr Bernhagen is an inventor on patents related to anti-MIF and antichemokine strategies in inflammation and CVD (cardiovascular diseases) outside the submitted work. The other authors report no conflicts.

Objectives: To assess the efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome (ACS) presenting during off- and on-hours., Background: The efficacy and safety of ticagrelor versus prasugrel in patients with ACS according to time of hospital presentation remain unknown., Methods: This post hoc analysis of the ISAR-REACT 5 trial included 1565 patients with ACS presenting off-hours and 2453 patients presenting on-hours, randomized to ticagrelor or prasugrel. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium (BARC) type 3-5 bleeding, both at 12 months., Results: The primary endpoint occurred in 80 patients (10.4%) in the ticagrelor group and 57 patients (7.3%) in the prasugrel group in patients presenting off-hours (hazard ratio [HR] = 1.45; 95% confidence interval [CI] 1.03-2.03; P = 0.033), and 104 patients (8.5%) in the ticagrelor group and 80 patients (6.7%) in the prasugrel group in patients presenting on-hours (HR = 1.29 [0.97-1.73]; P = 0.085), without significant treatment arm-by-presentation time interaction (P int  = 0.62). BARC type 3 to 5 bleeding occurred in 35 patients (5.1%) in the ticagrelor group and 37 patients (5.3%) in the prasugrel group (P = 0.84) in patients presenting off-hours, and 60 patients (5.9%) in the ticagrelor group and 43 patients (4.6%) in the prasugrel group in patients presenting on-hours (P = 0.17)., Conclusions: In patients with ACS planned to undergo an invasive treatment strategy, time of presentation (off-hours vs. on-hours) does not interact significantly with the relative efficacy and safety of ticagrelor vs. prasugrel., Clinical Trial Registration: NCT01944800., (© 2022. The Author(s).)

Physical exercise represents an effective preventive and therapeutic strategy beneficially modifying the course of multiple diseases. The protective mechanisms of exercise are manifold; primarily, they are elicited by alterations in metabolic and inflammatory pathways. Exercise intensity and duration strongly influence the provoked response. This narrative review aims to provide comprehensive up-to-date insights into the beneficial effects of physical exercise by illustrating the impact of moderate and vigorous exercise on innate and adaptive immunity. Specifically, we describe qualitative and quantitative changes in different leukocyte subsets while distinguishing between acute and chronic exercise effects. Further, we elaborate on how exercise modifies the progression of atherosclerosis, the leading cause of death worldwide, representing a prime example of a disease triggered by metabolic and inflammatory pathways. Here, we describe how exercise counteracts causal contributors and thereby improves outcomes. In addition, we identify gaps that still need to be addressed in the future.

Background The efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome and prior myocardial infarction (MI) remain unstudied. We aimed to assess the treatment effect of ticagrelor versus prasugrel according to prior MI status in patients with ACS. Methods and Results Patients with acute coronary syndrome planned for an invasive strategy and randomized to ticagrelor or prasugrel in the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial were included. The primary end point was the composite of 1-year all-cause death, MI, or stroke; the secondary safety end point was the composite of 1-year Bleeding Academic Research Consortium type 3 to 5 bleeding. The study included 4015 patients (prior MI=631 patients; no prior MI=3384 patients). As compared with patients without prior MI, the primary end point occurred more frequently in patients with prior MI (12.6% versus 7.2%; hazard ratio [HR], 1.78 [95% CI, 1.38-2.29]); the secondary safety end point appears to differ little between patients with and without prior MI (5.8% versus 5.7%, respectively; HR, 1.02 [95% CI, 0.71-1.45]). With regard to the primary end point, ticagrelor versus prasugrel was associated with an HR of 1.62 (95% CI, 1.03-2.55) in patients with prior MI and an HR of 1.28 (95% CI, 0.99-1.65) in patients without prior MI ( P int =0.37). With regard to the secondary safety end point, ticagrelor versus prasugrel was associated with an HR of 1.28 (95% CI, 0.56-2.91) in patients with prior MI and an HR of 1.13 (95% CI, 0.82-1.55) in patients without prior MI ( P int =0.79). Conclusions Patients with acute coronary syndrome and prior MI are at higher risk for recurrent ischemic but not bleeding events. Prasugrel is superior to ticagrelor in reducing the risk of ischemic events without a tradeoff in bleeding regardless of prior MI status. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Myocardial infarction (MI), a major contributor to worldwide morbidity and mortality, is caused by a lack of blood flow to the heart. Affected heart tissue becomes ischemic due to deficiency of blood perfusion and oxygen delivery. In case sufficient blood flow cannot be timely restored, cardiac injury with necrosis occurs. The ischemic/necrotic area induces a systemic inflammatory response and hundreds of thousands of leukocytes are recruited from the blood to the injured heart. The blood pool of leukocytes is rapidly depleted and urgent re-supply of these cells is needed. Myeloid cells are generated in the bone marrow (BM) and spleen, released into the blood, travel to sites of need, extravasate and accumulate inside tissues to accomplish various functions. In this review we focus on the "leukocyte supply chain" and will separately evaluate different myeloid cell compartments (BM, spleen, blood, heart) in steady state and after MI. Moreover, we highlight the local and systemic kinetics of extracellular factors, chemokines and danger signals involved in the regulation of production/generation, release, transportation, uptake, and activation of myeloid cells during the inflammatory phase of MI.

Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr -/- mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. I mp or ta ntly, p ha rm ac ol ogical sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr -/- mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD., Competing Interests: Competing interests H.S. has received personal fees from MSD Sharp & Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer and Vifor T as well as grants and personal fees from AstraZeneca that are unrelated to the submitted work. H.S. and T.K. are named inventors on a patent application for the prevention of restenosis after angioplasty and stent implantation (patent applicants: Klinikum rechts der Isar, German Heart Centre Munich; inventors: T. Kessler, A. Kastrati, H. Schunkert; application no. PCT/EP2021/053116; status: pending), which is unrelated to the submitted work. T.K. received lecture fees from Bayer HealthCare Pharmaceuticals. L.D., F.W. and P.S. are full-time employees of Bayer HealthCare Pharmaceuticals. The other authors declare no competing interests.

Aims: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies., Methods and Results: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for 6 weeks), we found that 3 weeks of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3)-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3-inflammasome inhibitor which blocks production and release of active IL-1β, or a murine analogue of canakinumab) dampened accumulation of leucocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leucocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leucocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leucocyte supply by decreasing proliferation of bone marrow haematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leucocytes. Using bone marrow reconstitution experiments, we observed that haematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leucocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leucocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers., Conclusions: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leucocyte (i) supply and (ii) uptake into atherosclerotic aortas providing additional mechanistic insights into links between haematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies., Competing Interests: Conflict of interest: H.G. is a full time Novartis employee. H.S. reports personal fees from MSD Sharp & Dohme, AMGEN, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol-Myers Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, grants and personal fees from Astra-Zeneca, and personal fees from Vifor outside the submitted work. H.S. and T.K. are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. T.K. received lecture fees from Bayer AG, Pharmaceuticals. H.B.S. reports grants from the European Research Council, the ‘Else-Kröner-Fresenius-Stiftung’, the ‘Deutsche Herzstiftung’, and the ‘Deutsche Forschungsgemeinschaft’ during the conduct of the study. A.A.B.R. is inventor on several licensed patents on novel NLRP3 inhibitors. P.L. is an unpaid consultant to, or involved in, clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, Inc. He is a member of the scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc and also serves on the Board of XBiotech, Inc. P.L.’s laboratory has received research funding in the last 2 years from Novartis, and he has a financial interest in Xbiotech, a company developing therapeutic human antibodies. P.L.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare, Boston, USA, in accordance with their conflict of interest policies. W.K. reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin-Chemie, Sanofi, Bristol-Myers Squibb, and grants and non-financial support from Singulex, Abbott, Roche Diagnostics, and Beckmann, all outside the submitted work. P.R. has received research grant support from Novartis, Kowa, Amarin, Pfizer, and the NHLBI; and has served as a consultant to Corvidia, Novartis, Flame, Agepha, Inflazome, AstraZeneca, Janssen, Civi Biopharm, SOCAR, Novo Nordisk, Uptton, Omeicos, Health Outlook, and Boehringer-Ingelheim. All other authors have nothing to disclose., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The relative efficacy and safety of more potent P2Y 12 inhibitors in patients with acute coronary syndrome and high bleeding risk (HBR) undergoing percutaneous coronary intervention remains unclear. We aimed to study the treatment effect of ticagrelor and prasugrel in percutaneous coronary intervention patients presenting with acute coronary syndrome and HBR., Methods: This post hoc analysis of the ISAR-REACT 5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) included patients with acute coronary syndrome undergoing percutaneous coronary intervention, randomized to ticagrelor or prasugrel, in whom HBR was defined as per Academic Research Consortium criteria. The primary (efficacy) end point was the composite of all-cause death, myocardial infarction, or stroke. The secondary (safety) end point was Bleeding Academic Research Consortium type 3 to 5 bleeding. Outcomes were assessed 12 months after randomization., Results: Out of the 3239 patients included in this analysis, 486 fulfilled the criteria for Academic Research Consortium-HBR definition (HBR group; ticagrelor, n=230 and prasugrel, n=256), while 2753 did not (non-HBR group; ticagrelor, n=1375 and prasugrel, n=1378). Compared with the non-HBR group, the HBR group had a higher risk for the primary (hazard ratio [HR]=3.57 [95% CI, 2.79-4.57]; P <0.001) and secondary end point (HR=2.94 [2.17-3.99]; P <0.001). In the HBR group, the primary (HR=1.09 [0.73-1.62]) and secondary (HR=1.18 [0.67-2.08]) end points were not significantly different between patients assigned to ticagrelor and prasugrel. In the non-HBR group, the primary end point (HR=1.62 [1.19-2.20]) occurred more frequently in patients assigned to ticagrelor as compared to patients assigned to prasugrel, without difference in safety (HR=1.08 [0.74-1.58]). There was no significant treatment allocation-by-HBR status interaction with respect to the primary ( P for interaction=0.12) or secondary ( P for interaction=0.80) end points., Conclusions: In patients with acute coronary syndrome undergoing percutaneous coronary intervention, HBR status increased both ischemic and bleeding risk without significant impact on the relative efficacy and safety of either ticagrelor or prasugrel. These results warrant confirmation in larger cohorts., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01944800.

Aims: To assess whether the efficacy and safety of ticagrelor vs. prasugrel in patients with acute coronary syndromes (ACSs) are influenced by pre-admission treatment with aspirin and/or clopidogrel., Methods and Results: Patients (n = 4018) were categorized into two groups: pre-admission aspirin and/or clopidogrel group (n = 1455) and no pre-admission aspirin or clopidogrel group (n = 2563). The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke; the secondary safety endpoint was Bleeding Academic Research Consortium (BARC) type 3-5 bleeding, both at 1 year. Patients in the pre-admission aspirin and/or clopidogrel group had a higher risk of ischaemic events, but a similar risk of bleeding to patients in the no pre-admission aspirin or clopidogrel group (cumulative incidences 10.5% vs. 6.7%, and 5.7% vs. 5.7%, respectively). The primary endpoint occurred in 81/717 patients assigned to ticagrelor and 69/738 patients assigned to prasugrel in the pre-admission aspirin and/or clopidogrel group [11.5% vs. 9.5%; hazard ratio (HR) = 1.23; 95% confidence interval (CI) 0.89-1.69], and in 103/1295 patients assigned to ticagrelor and 68/1268 patients assigned to prasugrel in the no pre-admission aspirin or clopidogrel group [8.0% vs. 5.4%; HR = 1.50 (1.10-2.03); Pint = 0.38]. BARC type 3-5 bleeding events did not differ between ticagrelor and prasugrel in patients in the pre-admission aspirin and/or clopidogrel (6.2% vs. 4.5%) or no pre-admission aspirin or clopidogrel (5.3% vs. 5.1%) group (Pint = 0.54)., Conclusion: In patients with ACS, pre-admission therapy with aspirin and/or clopidogrel has no influence on the relative efficacy and safety of ticagrelor and prasugrel., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background Anemia and blood loss occur often in patients with ST-segment-elevation myocardial infarction (STEMI). In-hospital hemoglobin drop is associated with 1-year mortality in patients with acute coronary syndrome. However, data on the effect of hemoglobin reduction on myocardial salvage and long-term outcomes are scarce. We investigated the impact of in-hospital hemoglobin drop on myocardial salvage and 5-year mortality in patients with STEMI treated with primary percutaneous coronary intervention. Methods and Results In-hospital hemoglobin drop was defined as a decrease in hemoglobin levels from admission and nadir hemoglobin values. Patients were categorized as having the following: no drop, minimal drop (<3 g/dL), minor drop (≥3 to <5 g/dL), and major drop (≥5 g/dL). Myocardial area at risk and infarct size were measured using serial single-photon emission computerized tomography imaging. The co-primary outcomes were myocardial salvage and 5-year all-cause mortality. Of 1204 patients, 1169 (97.1%) showed a hemoglobin drop during hospitalization: minimal, minor, and major drop occurred in 894 (74.3%), 214 (17.8%), and 61 (5.1%) patients, respectively. Myocardial salvage was reduced in patients with minimal (median, 0.53 [interquartile range, 0.27-0.83]), minor (median, 0.40 [interquartile range, 0.18-0.62]), and major (median, 0.40 [interquartile range, 0.14-0.77]) drop compared with patients without drop (median, 0.70 [interquartile range, 0.44-1.0], P <0.001). After adjusting for covariates, hemoglobin drop remained an independent correlate of poor myocardial salvage. A drop of ≥3 g/dL was associated with reduced left ventricular function at 6 months and with increased mortality at 5-year follow-up after STEMI. Conclusions In patients with STEMI undergoing primary percutaneous coronary intervention, in-hospital hemoglobin drop was associated with reduced myocardial salvage, left ventricular function, and increased long-term mortality.

Introduction and Objectives: The efficacy and safety of ticagrelor vs prasugrel in patients with acute coronary syndromes (ACS) according to body mass index (BMI) remain unstudied. We assessed the efficacy and safety of ticagrelor vs prasugrel in patients with ACS according to BMI., Methods: Patients (n=3987) were grouped into 3 categories: normal weight (BMI <25kg/m 2 ; n=1084), overweight (BMI ≥ 25 to <30kg/m 2 ; n=1890), and obesity (BMI ≥ 30kg/m 2 ; n=1013). The primary efficacy endpoint was the 1 year incidence of all-cause death, myocardial infarction, or stroke. The secondary safety endpoint was the 1 year incidence of Bleeding Academic Research Consortium type 3 to 5 bleeding., Results: The primary endpoint occurred in 63 patients assigned to ticagrelor and 39 patients assigned to prasugrel in the normal weight group (11.7% vs 7.5%; HR, 1.62; 95%CI, 1.09-2.42; P=.018), 78 patients assigned to ticagrelor and 58 patients assigned to prasugrel in the overweight group (8.3% vs 6.2%; HR, 1.36; 95%CI, 0.97-1.91; P=.076), and 43 patients assigned to ticagrelor and 37 patients assigned to prasugrel in the obesity group (8.6% vs 7.3%; HR, 1.18; 95%CI, 0.76-1.84; P=.451). The 1-year incidence of bleeding events did not differ between ticagrelor and prasugrel in patients with normal weight (6.5% vs 6.6%; P=.990), overweight (5.6% vs 5.0%; P=.566) or obesity (4.4% vs 2.8%; P=.219). There was no significant treatment arm-by-BMI interaction regarding the primary endpoint (P int =.578) or secondary endpoint (P int =.596)., Conclusions: In patients with ACS, BMI did not significantly impact the treatment effect of ticagrelor vs prasugrel in terms of efficacy or safety., Clinical Trial Registration: NCT01944800., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Whether the access site influences the comparative efficacy and safety of ticagrelor and prasugrel in patients with acute coronary syndrome (ACS) undergoing invasive treatment strategy remains unstudied., Methods: This post-hoc analysis included ACS patients undergoing invasive treatment via radial or femoral access and randomized to either ticagrelor or prasugrel in the ISAR-REACT 5 trial. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke, safety endpoint was BARC 3 to 5 bleeding. Outcomes were assessed out to 12 months after randomization., Results: Out of 4018 patients, 3984 underwent invasive treatment via radial or femoral access. 1479 had coronary angiography via radial access (ticagrelor, N = 748; prasugrel, N = 731) and 2505 via femoral access (ticagrelor, N = 1245; prasugrel, N = 1260). There was no interaction between access route and assignment to either ticagrelor or prasugrel regarding the primary efficacy or safety endpoints (P for interaction≥0.616). In the radial group, the primary efficacy endpoint (7.6% versus 5.8%, HR: 1.32 [0.88-1.97], P = 0.151) and the safety endpoint (4.3% versus 3.0%, HR: 1.36, [0.73-1.31], P = 0.300) were not statistically different in patients receiving either ticagrelor or prasugrel. In the femoral group, the primary efficacy endpoint occurred more frequently in patients assigned to ticagrelor as compared to prasugrel (10.3% versus 7.3%, HR: 1.44 [1.10-1.88], P = 0.006) without significant difference in terms of safety endpoint (6.4% versus 5.8%, HR: 1.14, [0.81-1.60], P = 0.470)., Conclusions: In patients with ACS undergoing an invasive treatment strategy, the access route does not influence the comparative efficacy and safety of ticagrelor and prasugrel., Clinical Trial Registration: NCT01944800., (Copyright © 2021. Published by Elsevier Inc.)

Background: Inflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis., Methods and Results: In mice with early atherosclerosis ( Apoe -/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages., Conclusions: Our data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk., Competing Interests: HSa reports grants from the European Research Council, the “Else-Kröner-Fresenius-Stiftung”, the “Deutsche Herzstiftung” and the “Deutsche Forschungsgemeinschaft” during the conduct of the study. HSa received lecture fees from Novo Nordisk. HSc reports personal fees from MSD Sharp & Dohme, personal fees from AMGEN, personal fees from Bayer Vital GmbH, personal fees from Boehringer Ingelheim, personal fees from Daiichi-Sankyo, personal fees from Novartis, personal fees from Servier, personal fees from Brahms, personal fees from Bristol-Myers Squibb, personal fees from Medtronic, personal fees from Sanofi Aventis, personal fees from Synlab, personal fees from Pfizer, grants and personal fees from Astra-Zeneca and personal fees from Vifor, outside the submitted work. HSc and TK are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. TK received lecture fees from Bayer AG, Pharmaceuticals. The remaining 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 © 2022 Meyer-Lindemann, Mauersberger, Schmidt, Moggio, Hinterdobler, Li, Khangholi, Hettwer, Gräßer, Dutsch, Schunkert, Kessler and Sager.)

The prevalence and public health burden of chronic heart failure (CHF) in Europe is steadily increasing mainly caused by the ageing population and prolonged survival of patients with CHF. Frequent hospitalizations, high morbidity and mortality rates, and enormous healthcare costs contribute to the health-related burden. However, multidisciplinary frameworks that emphasize effective long-term management and the psychological needs of the patients are sparse. The present position paper endorsed by the European Association of Preventive Cardiology (EAPC) provides a comprehensive overview on the scientific evidence of psychosocial aspects of heart failure (HF). In order to synthesize newly available information and reinforce best medical practice, information was gathered via literature reviews and consultations of experts. It covers the evidence for aetiological and prospective psychosocial risk factors and major underlying psycho-biological mechanisms. The paper elucidates the need to include psychosocial aspects in self-care concepts and critically reviews the current shortcomings of psychotherapeutic and psycho-pharmacological interventions. It also highlights the need for involvement of psychological support in device therapy for patients with HF and finally calls for better palliative care in the final stage of HF progression., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Whether bleeding and myocardial infarction (MI) improve the performance of risk prediction models for mortality in patients with acute coronary syndromes (ACS) treated with percutaneous coronary intervention (PCI) remains unknown., Methods: This study included 3377 patients with ACS who underwent PCI in the setting of the ISAR-REACT 5 trial. Patients with bleeding, MI or those dying at 1 year after PCI were characterized in terms of baseline characteristics, risk estimates and C-statistic of the risk prediction models for these outcomes., Results: Major bleeding (Bleeding Academic Research Consortium types 3-5), MI and mortality occurred in 195 patients (5.8%), 143 patients (4.3%) and 143 patients (4.3%), respectively. After adjustment, bleeding [hazard ratio = 5.08; 95% confidence interval (CI), 3.03-8.53; P < 0.001] and MI [hazard ratio = 5.90; 95% CI, (3.00-11.65); P < 0.001) remained independently associated with the risk for 1-year mortality. The C-statistic (with 95% CI) of the model for bleeding, MI and mortality was, 0.755 (0.722-0.786), 0.752 (0.717-0.789) and 0.868 (0.837-0.896), respectively. The inclusion of bleeding [C-statistic: 0.892 (0.867-0.913); delta C-statistic 0.024 (-0.014 to 0.065); P = 0.200] or MI [C-statistic: 0.878 (0.851-0.903); delta C-statistic 0.011 (-0.030 to 0.053); P = 0.635] in the risk prediction models for mortality alongside baseline demographical and clinical variables did not improve prediction for mortality., Conclusions: In patients with ACS treated with PCI, mortality is the most accurately predicted outcome. Bleeding and MI did not improve risk discrimination for mortality when added in the risk prediction models for mortality suggesting that these outcomes do not provide incremental prognostic information on top of baseline demographical and clinical data., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction and Objectives: Wound healing after myocardial infarction (MI) is a dynamic and complex multiple phase process, and a coordinated cellular response is required for proper scar formation. The current paradigm suggests that pro-inflammatory monocytes infiltrate the MI zone during the initial pro-inflammatory phase and differentiate into inflammatory macrophages, and then switch their phenotypes to anti-inflammatory during the reparative phase. Visualization of the reparative phase post-MI is of great interest because it may reveal delayed resolution of inflammation, which in turn predicts adverse cardiac remodeling. Imaging of anti-inflammatory macrophages may also be used to assess therapy approaches aiming to modulate the inflammatory response in order to limit MI size. Reparative macrophages can be distinguished from inflammatory macrophages by the surface marker mannose receptor (MR, CD206). In this study we evaluated the feasibility of 68 Ga-NOTA-anti-MMR Nb for imaging of MR on alternatively activated macrophages in murine MI models., Methods: Wildtype and MR-knockout mice and Wistar rats were subjected to MI via permanent ligation of the left coronary artery. Non-operated or sham-operated animals were used as controls. MR expression kinetics on cardiac macrophages was measured in mice using flow cytometry. PET/CT scans were performed 1 h after intravenous injection of 68 Ga-NOTA-anti-MMR Nb. Mice and rats were euthanized and hearts harvested for ex vivo PET/MRI, autoradiography, and staining. As a non-targeting negative control, 68 Ga-NOTA-BCII10 was used., Results: In vivo -PET/CT scans showed focal radioactivity signals in the infarcted myocardium for 68 Ga-NOTA-anti-MMR Nb which were confirmed by ex vivo -PET/MRI scans. In autoradiography images, augmented uptake of the tracer was observed in infarcts, as verified by the histochemistry analysis. Immunofluorescence staining demonstrated the presence and co-localization of CD206- and CD68-positive cells, in accordance to infarct zone. No in vivo or ex vivo signal was observed in the animals injected with control Nb or in the sham-operated animals. 68 Ga-NOTA-anti-MMR Nb uptake in the infarcts of MR-knockout mice was negligibly low, confirming the specificity of 68 Ga-NOTA-anti-MMR Nb to MR., Conclusion: This exploratory study highlights the potential of 68 Ga-NOTA-anti-MMR Nb to image MR-positive macrophages that are known to play a pivotal role in wound healing that follows acute MI., 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 © 2022 Varasteh, Braeuer, Mohanta, Steinsiek, Habenicht, Omidvari, Topping, Rischpler, Weber, Sager, Raes, Hernot and Schwaiger.)

Atherosclerosis is the leading cause of death worldwide and leukocyte recruitment is a key element of this phenomenon, thus allowing immune cells to enter the arterial wall. There, in concert with accumulating lipids, the invading leukocytes trigger a plethora of inflammatory responses which promote the influx of additional leukocytes and lead to the continued growth of atherosclerotic plaques. The recruitment process follows a precise scheme of tethering, rolling, firm arrest, crawling and transmigration and involves multiple cellular and subcellular players. This review aims to provide a comprehensive up-to-date insight into the process of leukocyte recruitment relevant to atherosclerosis, each from the perspective of endothelial cells, monocytes and macrophages, neutrophils, T lymphocytes and platelets. In addition, therapeutic options targeting leukocyte recruitment into atherosclerotic lesions-or potentially arising from the growing body of insights into its precise mechanisms-are highlighted., 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 © 2022 Mauersberger, Hinterdobler, Schunkert, Kessler and Sager.)

Significance: Atherosclerosis and its complications, such as acute coronary syndromes, are the leading causes of death worldwide. A wide range of inflammatory processes substantially contribute to the initiation and progression of cardiovascular disease (CVD). In addition, epidemiological studies strongly associate both chronic stress and acute psychosocial stress with the occurrence of CVDs. Recent Advances: Extensive research during recent decades has not only identified major pathways in cardiovascular inflammation but also revealed a link between psychosocial factors and the immune system in the context of atherosclerosis. Both chronic and acute psychosocial stress drive systemic inflammation via neuroimmune interactions and promote atherosclerosis progression. Critical Issues: The associations human epidemiological studies found between psychosocial stress and cardiovascular inflammation have been substantiated by additional experimental studies in mice and humans. However, we do not yet fully understand the mechanisms through which psychosocial stress drives cardiovascular inflammation; consequently, specific treatment, although urgently needed, is lacking. Future Directions: Psychosocial factors are increasingly acknowledged as risk factors for CVD and are currently treated via behavioral interventions. Additional mechanistic insights might provide novel pharmacological treatment options to reduce stress-related morbidity and mortality. Antioxid. Redox Signal. 35, 1531-1550.

Aims: Complex percutaneous coronary intervention (PCI) is associated with a higher risk of ischaemic events. However, no study has analysed the effect of PCI complexity on outcomes in a contemporary cohort of acute coronary syndrome (ACS) patients treated with a dual anti-platelet therapy regimen based on potent P2Y12-inhibitors. Therefore, we performed the current analysis., Methods and Results: This analysis included all ACS patients treated with PCI in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. Complex PCI was defined as at least one of: multi-vessel PCI, ≥3 stents implanted, ≥3 lesions treated, and total stented length >60 mm. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months; the safety endpoint was Bleeding Academic Research Consortium types 3-5 bleeding at 12 months. Overall, 3377 patients were included in this analysis (complex PCI, n = 1429; non-complex PCI, n = 1948). The primary endpoint occurred more frequently in the complex PCI group than the non-complex PCI group [10.1% vs. 7.2%, hazard ratio (HR): 1.44, 95% confidence interval (CI) (1.14-1.82), P = 0.002], driven primarily by a higher risk of MI [HR: 1.62, (1.17-2.26), P = 0.004]. The safety endpoint was not statistically different between patients undergoing complex vs. non-complex PCI, although it was numerically higher in the complex PCI group [6.7% vs. 5.3%, HR: 1.28, (0.97-1.70), P = 0.08]., Conclusions: Acute coronary syndrome patients undergoing complex PCI have an increased incidence of ischaemic events compared with ACS patients undergoing non-complex PCI., Clinical Trial Registration: NCT01944800, Prospective, Randomized Trial of Ticagrelor Vs. Prasugrel in Patients With Acute Coronary Syndrome-Full-Text View-ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01944800., (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 Whether there are differences in the risk profile and treatment effect in patients recruited in a low recruitment center (LRC) versus patients recruited in a high recruitment center (HRC) in a randomized multicenter trial remains unknown. METHODS AND RESULTS This study included 4018 patients with acute coronary syndrome recruited in the ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial. The primary end point was a composite of all-cause death, myocardial infarction, or stroke. Overall, 3011 patients (75%) were recruited in the HRCs (7 centers recruiting 258 to 628 patients; median, 413 patients) and 1007 patients (25%) were recruited in the LRCs (16 centers recruiting 5 to 201 patients; median, 52 patients). Patients recruited in the LRCs had more favorable cardiovascular risk profiles than patients recruited in the HRCs. The primary end point occurred in 72 patients in the LRCs and 249 patients in the HRCs (cumulative incidence, 7.3% and 8.4%; P =0.267). All-cause mortality was lower among patients recruited in the LRCs (n=29) than among patients recruited in the HRCs (n=134; cumulative incidence 2.9% versus 4.5%; P =0.031). There was no significant interaction between the treatment effect of ticagrelor versus prasugrel and patient recruitment category (LRC versus HRC) regarding the primary efficacy end point (LRC: hazard ratio [HR], 1.42 [95% CI, 0.89-2.28]; HRC: HR, 1.33 [95% CI, 1.04-1.72]; P for interaction=0.800). CONCLUSIONS Patients with acute coronary syndrome recruited in a LRC appear to have more favorable cardiovascular risk profiles and lower 1-year mortality rates compared with patients recruited in a HRC. The recruitment volume did not interact with the treatment effect of ticagrelor versus prasugrel. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Aims: Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear., Methods and Results: Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques., Conclusion: Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI)., Objective: To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI., Design, Setting, and Participants: A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle., Interventions: Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization., Main Outcomes and Measures: The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding., Results: The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78; P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34; P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50; P = .54)., Conclusions and Relevance: Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT01944800.

Objectives: The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs)., Background: The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined., Methods: Patients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m 2 ), intermediate eGFR (≥60 and <90 mL/min/1.73 m 2 ), and high eGFR (≥90 mL/min/1.73 m 2 ). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year., Results: Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding., Conclusions: These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)., Competing Interests: Funding Support and Author Disclosures This research was supported by a grant (FKZ 81X1600501) from the German Center for Cardiovascular Research and Deutsches Herzzentrum München. Dr Angiolillo has received grants and personal fees from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, Sanofi, and CeloNova; has received personal fees from Haemonetics, PhaseBio, PLx Pharma, Pfizer, The Medicines Company, and St. Jude Medical; and has received grants from CSL Behring, Eisai, Gilead, Idorsia Pharmaceuticals, Matsutani Chemical Industry, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Hochholzer has received personal fees from Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Novartis, AstraZeneca, and The Medicines Company. Dr Kufner has received personal fees from Bristol Myers Squibb, AstraZeneca, and Translumina. Dr Sager has received grants from the European Research Council, Else-Kröner-Fresenius-Stiftung, Deutsche Herzstiftung, and Deutsche Forschungsgemeinschaft. Dr Neumann has received personal fees from Amgen, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, and Ferrer; has received grants and personal fees from Pfizer, Biotronik, Edwards Lifesciences, Bayer Healthcare, and Boston Scientific; and has received grants from Medtronic and GlaxoSmithKline outside the submitted work. Dr Schüpke has received the Else Kröner memorial grant from Else Kröner-Fresenius Stiftung; has received financial support from the German Center for Cardiovascular Research; has received consulting fees from Bayer Vital; and has received lecture fees from Daiichi-Sankyo and Biopas Laboratories. Dr Sibbing has received personal fees from Daichi-Sankyo, Sanofi, AstraZeneca, Bayer, Pfizer, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with acute coronary syndromes (ACS) are not known. We assessed the efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with ACS undergoing invasive management., Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 1349 smokers and 2652 nonsmokers randomized to receive ticagrelor or prasugrel. The primary endpoint was the incidence of death, myocardial infarction, or stroke; the secondary endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding (both endpoints assessed at 12 months)., Results: There was no significant treatment arm-by-smoking status interaction regarding the efficacy outcome. The primary endpoint occurred in 47 patients (7.0%) in the ticagrelor group and 41 patients (6.2%) in the prasugrel group in smokers (hazard ratio [HR] = 1.15; 95% confidence interval [CI] 0.76-1.75; P = 0.510) and in 133 patients (10.2%) in the ticagrelor group and 94 patients (7.2%) in the prasugrel group in nonsmokers (HR = 1.44 [1.10-1.87]; P = 0.007; P for interaction = 0.378). The secondary endpoint occurred in 27 patients (4.6%) in the ticagrelor group and 33 patients (5.6%) in the prasugrel group in smokers (HR = 0.81 [0.49-1.35]; P = 0.412) and in 66 patients (6.0%) in the ticagrelor group and 46 patients (4.4%) in the prasugrel group in nonsmokers (HR = 1.38 [0.94-2.01]; P = 0.097)., Conclusions: In patients with ACS undergoing an invasive management strategy, the smoking status did not significantly interact with the relative treatment effect of ticagrelor vs. prasugrel., Clinical Trial Registration: NCT01944800., (Copyright © 2021 Elsevier B.V. All rights reserved.)

[Figure: see text].

Aims: In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets., Methods and Results: Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01)., Conclusions: Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Although the importance of inflammation in atherosclerosis is now well established, the exact molecular processes linking inflammation to the development and course of the disease are not sufficiently understood. In this context, modern genetics-as applied by genome-wide association studies (GWAS)-can serve as a comprehensive and unbiased tool for the screening of potentially involved pathways. Indeed, a considerable proportion of loci discovered by GWAS is assumed to affect inflammatory processes. Despite many well-replicated association findings, however, translating genomic hits to specific molecular mechanisms remains challenging. This review provides an overview of the currently most relevant inflammation-related GWAS findings in coronary artery disease and explores their potential clinical perspectives.

Rationale: The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity in vivo . Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice via PET imaging. Methods: Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed in vitro using a Gal3-F(ab') 2 mAb labeled with AlexaFluor®488 and 89 Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO). To visualize plaques in vivo , ApoE-KO mice were injected i.v. with 89 Zr-DFO-Gal3-F(ab') 2 mAb and imaged via PET/CT 48 h post injection. Whole length aortas harvested from euthanized mice were processed for Sudan-IV staining, autoradiography, and immunostaining for Gal3, CD68 and α-SMA expression. To confirm accumulation of the tracer in plaques, ApoE-KO mice were injected i.v. with Cy5.5-Gal3-F(ab') 2 mAb, euthanized 48 h post injection, followed by cryosections of the body and acquisition of fluorescent images. To explore the clinical potential of this imaging modality, immunostaining for Gal3, CD68 and α-SMA expression were carried out in human plaques. Single cell RNA sequencing (scRNA-Seq) analyses were performed to measure LGALS3 (i.e. a synonym for Gal3) gene expression in each macrophage of several subtypes present in murine or human plaques. Results: Preferential binding to M2 macrophages was observed with both AlexaFluor®488-Gal3-F(ab') 2 and 89 Zr-DFO-Gal3-F(ab') 2 mAbs. Focal and specific 89 Zr-DFO-Gal3-F(ab') 2 mAb uptake was detected in plaques of ApoE-KO mice by PET/CT. Autoradiography and immunohistochemical analyses of aortas confirmed the expression of Gal3 within plaques mainly in macrophages. Moreover, a specific fluorescent signal was visualized within the lesions of vascular structures burdened by plaques in mice. Gal3 expression in human plaques showed similar Gal3 expression patterns when compared to their murine counterparts. Conclusions: Our data reveal that 89 Zr-DFO-Gal3-F(ab') 2 mAb PET/CT is a potentially novel tool to image atherosclerotic plaques at different stages of development, allowing knowledge-based tailored individual intervention in clinically significant disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The coronavirus disease (COVID-19) pandemic imposed diverse challenges on the health care system. Morbidity and mortality of non-COVID-19 emergencies might also have changed because hospitals may not be able to provide optimal care due to restructured resources and uncertainties how to deal with potentially infected patients. It has been recommended to stratify treatment of cardiovascular emergencies according to cardiovascular risk. However, data on the prevalence of asymptomatic SARS-CoV-2 infection in patients presenting with cardiac emergencies remain scarce. Methods: We retrospectively analyzed patients' data from a tertiary cardiology department between April 15 and May 31, 2020. All patients were screened on admission for COVID-19 symptoms using a questionnaire and body temperature measurements. All hospitalized patients were routinely screened using nasopharyngeal swab testing. Results: In total, we counted 710 urgent and emergency admissions. Nasopharyngeal swab tests were available in 689 (97%) patients, 409 and 280 of which presented as urgent and emergency admissions, respectively. Among 280 emergency admissions, none tested positive for SARS-CoV-2. Conclusion: In cardiac emergency patients which were screened negative for COVID-19 symptoms, the prevalence of SARS-CoV-2 infection in regions with a modest overall prevalence is low. This finding might be helpful to better determine timing of emergency procedures and reasonable usage of protective equipment during the COVID-19 crisis and the future., 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 © 2020 Kessler, Wiebe, Graf, Schunkert, Kastrati and Sager.)

Background: Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention., Methods: In this prespecified subgroup analysis, we included 1653 patients with ST-segment-elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization., Results: The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95-1.82]; P =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; P =0.83), stroke (1.3% versus 1.0%; P =0.46), and definite stent thrombosis (1.8% versus 1.0%; P =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18-3.23]; P =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80-1.87]; P =0.36)., Conclusions: In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Background: Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI)., Objectives: This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management., Methods: This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3-5., Results: The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month., Conclusions: In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800)., Competing Interests: Author Relationship With Industry Dr. Neumann has received lecture fees, paid to his institution, from Amgen, Daiichi-Sankyo, Novartis, and Ferrer; has received lecture fees, paid to his institution, and consulting fees, paid to his institution, from AstraZeneca and Boehringer Ingelheim; has received grant support and lecture fees, paid to his institution, from Pfizer, Biotronic, Edwards Lifesciences, Bayer HealthCare, and GlaxoSmithKline; and has received grant support from Medtronic, Abbott Vascular, and Boston Scientific. Dr. Sibbing has received personal fees from Bayer AG, Sanofi, AstraZeneca, Pfizer, Ferrer, and Daiichi-Sankyo; and has received grants and personal fees from Roche Diagnostics. Dr. Angiolillo has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payments for participation in review activities from CeloNova and St. Jude Medical; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr. Liebetrau has received consulting fees or honoraria from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, and Thermo Fisher; and has received research grants from Deutsche Herzstiftung, Kerckhoff-Stiftung, and Kühl-Stiftung outside the submitted work. Dr. Liebetrau’s institution has received payments for participation in clinical study programs from Abbott, AstraZeneca, Bayer, Biosensors, Boston Scientific, Daiichi-Sankyo, and Neovasc. Dr. Hamm has received Advisory Board and speaker fees from AstraZeneca and Daiichi-Sankyo. Dr. Sager has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (STRATO), the Else-Kröner-Fresenius-Stiftung, the Deutsche Herzstiftung, and the Deutsche Forschungsgemeinschaft. Dr. Joner has received personal fees from Biotronik, Orbus Neich, Boston Scientific, Edwards, AstraZeneca, and Recor; and has received grants from Boston Scientific, Edwards, and Amgen. Dr. Trenk has received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ferrer, Pfizer, and Sanofi; and has received research grants from Deutsche Herzstiftung and PharmCompNet Baden-Wuerttemberg: Kompetenznetzwerk Pharmakologie Baden-Wuerttemberg outside the submitted work. Dr. Trenk’s institution has received payments for participation in clinical study programs from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Doasense, Esperion, Idorsia, and Otsuka. Dr. Schunkert has received personal fees from Merck Sharp & Dohme, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol Myers Squibb, Medtronic, Sanofi, Synlab, Pfizer, and Vifor; and has received grants and personal fees from AstraZeneca. Dr. Schüpke has received grants from the DZHK (German Center for Cardiovascular Research) and the Else Kröner-Fresenius-Stiftung; has received consulting fees from Bayer Vital GmbH; and has received lecture fees from Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (ApoE -/- Svep1 +/- ) compared to Svep1 wild-type mice (ApoE -/- Svep1 +/+ ) and ApoE -/- Svep1 +/- mice displayed elevated plaque neutrophil, Ly6C high monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE -/- Svep1 +/- mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (CXCL1) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in ApoE -/- Svep1 +/- mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial CXCL1 expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency.

Aim: A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention., Methods and Results: The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered., Conclusion: We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)