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Aims: 18F-sodium fluoride ([18F]fluoride) and gadobutrol are promising probes for positron emission tomography (PET) and magnetic resonance imaging (MRI) characterizing coronary artery disease (CAD) activity. Unlike [18F]fluoride-PET/computed tomography (CT), the potential of PET/MR using [18F]fluoride and gadobutrol simultaneously, has so far not been evaluated. This study assessed feasibility and diagnostic potential of [18F]fluoride and gadobutrol enhanced dual-probe PET/MR in patients with CAD., Methods and Results: Twenty-one patients (age, 66.7 ± 6.7 years) with CAD scheduled for invasive coronary angiography (XCA) underwent simultaneous [18F]fluoride (mean activity/effective dose: 157.2 ± 29.7 MBq/3.77 ± 0.72 mSv) and gadobutrol enhanced PET/MR on an integrated PET/MRI (3 T) scanner. Optical coherence tomography (OCT) was used as reference. Target-to-background ratio (TBR, [18F]fluoride-PET) and contrast-to-noise ratio (CNR) values (MRI, gadobutrol) were calculated for each coronary segment. Previously suggested PET/CT-TBR thresholds for adverse coronary events were evaluated. High-risk plaques, i.e. calcified and non-calcified thin-cap fibroatheromas (TCFAs) were predominantly located in segments with a TBR >1.28 (P = 0.012). Plaques containing a lipid core on OCT, were more frequently detected in segments with a TBR >1.25 (P < 0.001). TBR values significantly correlated with maximum calcification thickness (P = 0.009), while fibrous cap thickness was significantly less in segments with a TBR >1.28 (P = 0.044). Above a TBR threshold of >1.28, CNR values significantly correlated with the presence of calcified TCFAs (P = 0.032)., Conclusion: Simultaneous [18F]fluoride and gadobutrol dual-probe PET/MRI is feasible in clinical practice and may facilitate the identification of high-risk patients. The combination of coronary MR-derived CNR values post gadobutrol and [18F]fluoride based TBR values may improve identification of high-risk plaque features., Competing Interests: Conflict of interest: none declared., (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: There is limited knowledge about morphological molecular-imaging-derived parameters to further characterize hemodynamically relevant coronary lesions., Objective: The aim of this study was to describe and differentiate specific parameters between hemodynamically significant and non-significant coronary lesions using various invasive and non-invasive measures., Methods: This clinical study analyzed patients with symptoms suggestive of coronary artery disease (CAD) who underwent native T1-weighted CMR and gadofosveset-enhanced CMR as well as invasive coronary angiography. OCT of the culprit vessel to determine the plaque type was performed in a subset of patients. Functional relevance of all lesions was examined using quantitative flow reserve (QFR-angiography). Hemodynamically significant lesions were defined as lesions with a QFR <0.8. Signal intensity (contrast-to-noise ratios; CNRs) on native T1-weighted CMR and gadofosveset-enhanced CMR was defined as a measure for intraplaque hemorrhage and endothelial permeability, respectively., Results: Overall 29 coronary segments from 14 patients were examined. Segments containing lesions with a QFR <0.8 (n = 9) were associated with significantly higher signal enhancement on Gadofosveset-enhanced CMR as compared to segments containing a lesions without significant stenosis (lesion-QFR>0.8; n = 19) (5.32 (4.47-7.02) vs. 2.42 (1.04-5.11); p = 0.042). No differences in signal enhancement were seen on native T1-weighted CMR (2.2 (0.68-6.75) vs. 2.09 (0.91-6.57), p = 0.412). 66.7% (4 out of 6) of all vulnerable plaque and 33.3% (2 out of 6) of all non-vulnerable plaque (fibroatheroma) as assessed by OCT were hemodynamically significant lesions., Conclusion: The findings of this pilot study suggest that signal enhancement on albumin-binding probe-enhanced CMR but not on T1-weighted CMR is associated with hemodynamically relevant coronary lesions., Competing Interests: The authors have declared that no competing interests exist.

The aim of this study was to compare endothelial permeability, which is considered a hallmark of coronary artery disease, between patients with different HbA 1c levels using an albumin-binding magnetic resonance (MR) probe. This cross-sectional study included 26 patients with clinical indication for X-ray angiography who were classified into three groups according to HbA 1c level (<5.7% [<39 mmol/mol], 5.7-6.4% [39-47 mmol/mol], and ≥6.5% [48 mmol/mol]). Subjects underwent gadofosveset-enhanced coronary magnetic resonance and X-ray angiography including optical coherence within 24 h. Contrast-to-noise ratios (CNRs) were assessed to measure the probe uptake in the coronary wall by coronary segment, excluding those with culprit lesions in X-ray angiography. In the group of patients with HbA 1c levels between 5.7 and 6.4%, 0.30 increased normalized CNR values were measured, compared with patients with HbA 1c levels <5.7% (0.30 [95% CI 0.04, 0.57]). In patients with HbA 1c levels ≥6.5%, we found 0.57 higher normalized CNR values compared with patients with normal HbA 1c levels (0.57 [95% CI 0.28, 0.85]) and 0.26 higher CNR values for patients with HbA 1c level ≥6.5% compared with patients with HbA 1c levels between 5.7 and 6.4% (0.26 [95% CI -0.04, 0.57]). Additionally, late atherosclerotic lesions were more common in patients with high HbA 1c levels (HbA 1c ≥6.5%, n = 14 [74%]; HbA 1c 5.7-6.4%, n = 6 [60%]; and HbA 1c <5.7%, n = 10 [53%]). In conclusion, coronary MRI in combination with an albumin-binding MR probe suggests that both patients with intermediate and patients with high HbA 1c levels are associated with a higher extent of endothelial damage of the coronary arteries compared with patients with HbA 1c levels <5.7%., (© 2018 by the American Diabetes Association.)

Background: Surface expression of stromal cell-derived factor-1 (SDF-1) on platelets is enhanced during ischaemic events and might play an important role in peripheral homing and myocardial repair. As SDF-1 effects are mediated through CXCR4/CXCR7, we investigated platelet expression of SDF-1/CXCR4/CXCR7 in patients with coronary artery disease (CAD)., Methods and Results: Expression of SDF-1, CXCR4, and CXCR7 in platelets was investigated by western blot analysis, immunofluorescence confocal microscopy, and flow cytometry among healthy subjects and patients with acute coronary syndrome (ACS) and stable CAD. In a cohort study, platelet surface expression of CXCR4, CXCR7, and SDF-1 was measured in 215 patients with symptomatic CAD (stable CAD = 112, ACS = 103) at the time of percutaneous coronary intervention. Course of left ventricular ejection fraction (LVEF) was followed up during intrahospital stay and at 3 months. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in CAD patients when compared with healthy controls. Platelet surface expression of CXCR7 but not CXCR4 was enhanced in patients with ACS when compared with patients with stable CAD (mean fluorescence intensity 17.8 vs. 15.3, P = 0.004 and 29.0 vs. 26.3, P = 0.122, respectively). CXCR4 and CXCR7 significantly correlated with their ligand SDF-1 on platelets (ρ = 0.273, P < 0.001 and ρ = 0.454, P < 0.001, respectively). Additionally, high CXCR7 expression above the median correlated with the absolute improvement of LVEF% after 5 days and 3 months (46.2, 49.8, 53.7; P = 0.003)., Conclusion: These findings indicate that platelet surface expression of CXCR4 and CXCR7 might differentially contribute to SDF-1-mediated effects on regenerative mechanisms following ACS. Studies are warranted to further evaluate the regulatory mechanisms of CXCR4/-7 expression and its prognostic impact on CAD.

Cardiovascular risk factors are associated with coronary artery disease (CAD) and with cognitive dysfunction. However, the precise pathogenic mechanisms responsible for this association remain elusive. In the present study, CAD patients with cognitive impairment showed significantly higher platelet activation compared with CAD patients without cognitive impairment. In addition, we identified platelet activity to be a significant independent predictor for the severity of cognitive impairment in these patients. We discuss the link between platelet hyperactivity and dementia (including Alzheimer`s disease) based on the literature and our findings. We also discuss the potential mechanisms involved. This link may become a therapeutic option.

Background: To test alternative medicine approaches with a specifically designed Tibetan dietary and behavioral program in patients with established coronary artery disease (CAD) and manifest metabolic syndrome., Methods: This was a randomized, controlled, double-blinded, parallel group dietary and behavioral intervention study. Between December 2008 and November 2010, patients were randomly adjudicated either to evidence-based Western diet (usual care), or to Tibetan diet. We evaluated 524 patients undergoing coronary angiography. All patients were white Caucasian, presented with a body mass index (BMI) >25 kg/m(2), and had evidence of metabolic syndrome. The primary endpoint was change in body weight and BMI at 6 months follow-up. Secondary endpoints included blood pressure, heart rate, intima media thickness, lipids, fasting glucose, glycated hemoglobin, fibrinogen, C-reactive protein (CRP) at 6 months follow-up and change in body weight and BMI at 12 months., Results: Both groups of patients showed significantly reduced body weight and BMI compared to baseline (6 months, usual care weight change: -3.2 ± 3.0 kg; BMI change: -1.1 ± 1.0 kg/m(2); Tibetan diet weight change: -6.2 ± 4.4 kg/m(2); BMI change: -2.1 ± 1.5 kg/m(2)), but these changes were more pronounced in Tibetan diet compared to usual care (all, p<0.001). Beneficial effects on weight and BMI were maintained after 12 months of follow-up (p<0.0001). Levels of total and LDL cholesterols, fibrinogen and CRP were decreased in both groups, but more pronounced in Tibetan diet (Tibetan diet vs. usual care (total cholesterol): 176.2 ± 43.7 vs. 185.1 ± 47.8 mg/dL; p=0.024; LDL: 111.6 ± 37.8 vs. 119.4 ± 40.9 mg/dL; p=0.026; fibrinogen: 318.3 ± 90.4 vs. 334.1 ± 87.9 mg/dL; p=0.040; CRP: 1.2 ± 3.0 vs. 2.2 ± 4.5mg/dL; p=0.036)., Conclusions: Tibetan diet reduces body weight and BMI in patients with CAD and metabolic syndrome after 6 months significantly better than Western diet and may induce lipid-modifying and anti-inflammatory effects (ClinicalTrials.gov identifier: NCT00810992)., (© 2013.)

Background: C-terminal portion of provasopressin (copeptin) has recently been discussed as a novel biomarker for the early rule-out of acute myocardial infarction (AMI). The aim is to investigate the prognostic value of copeptin with regard to mortality and morbidity in patients with symptomatic coronary artery disease (CAD)., Methods: We consecutively recruited a cath lab cohort of 2,700 patients (74.1% male; AMI, n=1316; stable angina pectoris, n=1384) presenting to the emergency department of a large primary care hospital. All patients received coronary angiography. Copeptin and other laboratory markers were sampled at the time of presentation or in the cath lab. Clinical outcomes were assessed by hospital chart analysis and telephone interviews. 2621 patients (97.1%) have been successfully followed-up at three months. The primary endpoint was a combined endpoint of rehospitalization for cardiovascular events, stroke, and all-cause death., Results: Using receiver operating characteristic curves, we calculated areas under the curve of 0.703 (95%confidence interval(CI):0.681-0.725) for the composite endpoint after three months (myocardial reinfarction, stroke, all-cause death;n=183), and 0.770 (95%CI:0.736-0.803) for all-cause death (n=76) for copeptin. A cutoff value of 21.6 pmol/L for the composite endpoint yielded a sensitivity of 56.3% and a specificity of 78.6%. The predictive performance of copeptin was independent of other clinical variables or cardiovascular risk factors, and superior to that of troponin I or other cardiac biomarkers (all:P<0.0001)., Conclusions: Copeptin may help in the prediction of major adverse cardiovascular events in patients with symptomatic CAD. Further studies should substantiate the findings and support the suggested cutoff value of the present study., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In the present study, we investigated the prognostic value of MR-proANP (mid-regional pro-atrial natriuretic peptide). We consecutively evaluated a catheterization laboratory cohort of 2700 patients with symptomatic CAD (coronary artery disease) [74.1% male; ACS (acute coronary syndrome), n=1316; SAP (stable angina pectoris), n=1384] presenting to the Cardiology Department of a large primary care hospital, all of whom underwent coronary angiography. Serum MR-proANP and other laboratory markers were sampled at the time of presentation or in the catheterization laboratory. Clinical outcome was assessed by hospital chart analysis and telephone interviews. The primary end point was all-cause death at 3 months after enrolment. Follow-up data were complete in 2621 patients (97.1%). Using ROC (receiver operating characteristic) curves, the AUC (area under the curve) of 0.73 [95% CI (confidence interval), 0.67-0.79] for MR-proANP was significantly higher compared with 0.58 (95% CI, 0.55-0.62) for Tn-I (troponin-I; DeLong test, P=0.0024). According to ROC analysis, the optimal cut-off value of MR-proANP was at 236 pmol/l for all-cause death, which helped to find a significantly increased rate of all-cause death (n=76) at 3 months in patients with elevated baseline concentrations (≥236 pmol/l) compared with patients with a lower concentration level in Kaplan-Meier survival analysis (log rank, P<0.001). The predictive performance of MR-proANP was independent of other clinical variables or cardiovascular risk factors, and superior to that of Tn-I or other cardiac biomarkers (all: P<0.0001). MR-proANP may help in the prediction of all-cause death in patients with symptomatic CAD. Further studies should verify its prognostic value and confirm the appropriate cut-off value.

Coronary artery disease remains a major hazard within the western world despite early revascularisation and advanced medical therapy strategies. One of its major substrates is platelet activation and thrombus formation, triggering acute events such as myocardial infarction and ischemic strokes. There are a variety of non-invasive imaging strategies being translated from bench to bedside into clinical practice that tackle specific aspects of the pathophysiology of thrombus formation. Some of those techniques are able to visualize native contrast differences between thrombus and surrounding tissue, others focus on the use of specific contrast agents targeting thrombotic components such as fibrin or activated platelets. Some of those techniques are still in the pre-clinical stage; others have already entered the clinical arena. The current review article will introduce different techniques and their stage of development on their way from bench to bedside with a specific focus on cardiac magnetic resonance imaging, that has evolved over the last years providing high quality information on anatomy, perfusion and myocardial tissue characteristics such as scarring in clinical practice. Finally, we will give an outlook on how this exciting field might evolve in the future.

Objective: To investigate the possible association of plasma levels of stromal cell-derived factor-1 (SDF-1; CXCL12) with clinical presentation of symptomatic coronary artery disease (CAD) and with cardiovascular risk factors., Methods: A cath lab cohort of 492 consecutive patients with symptomatic CAD were recruited. Blood for plasma-SDF-1 determination was taken at the time of heart catheterization before percutaneous coronary intervention., Results: Plasma-SDF-1 was significantly decreased in ST-elevation myocardial infarction (STEMI) compared to stable angina pectoris (SAP) or to non-ST-elevation myocardial infarction (NSTEMI) (SAP vs. NSTEMI vs. STEMI: [pg/ml]: mean ± SD: 2110 ± 562 vs. 2127 ± 467 vs. 1834 ± 377; P < 0.001) independent of cardiovascular therapy. A weak correlation was observed between cholesterol levels and plasma SDF-1 in the whole study population. Left ventricular function and diabetes mellitus associated with plasma SDF-1 levels in patients with NSTEMI, while among STEMI patients, those with hyperlipidemia presented with even further decreased SDF-1 levels., Conclusion: Plasma SDF-1 is significantly decreased in patients with STEMI, a fact which may reflect the importance of SDF-1 regulation in patients with acute myocardial infarction., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Long acquisition times and complex breathing motion patterns lead to suboptimal image quality in whole heart coronary magnetic resonance angiography (WHCMRA). To overcome this problem, an abdominal belt (BELT) has been suggested by a Japanese group. However, its applicability in a Western population has not been previously demonstrated. The purpose of this study was to investigate 1) how the application of a BELT alters breathing patterns during MR scanning and 2) whether the BELT has a similar impact on breathing patterns in UK and Japanese patient populations., Methods: 30 patients (15 in the UK and 15 in Japan) were studied at 1.5 Tesla (Achieva, Philips Healthcare). Real time navigator positioned through the right diaphragm in cranio-caudal direction was evaluated. Measurements were performed in the supine position with free breathing for one minute before and after a tight-fitting BELT was positioned around the patient's abdomen. End expiratory position (EEP), end inspiratory position (EIP), end expiratory duration (EED) for the right diaphragm and respiratory rate (RR) were obtained. Scan efficiency (SE) was calculated as follows; SE = [the duration within 5 mm gating window per minutes]/[RR interval]/[heart rate]., Results: Height and weight of UK patients were significantly larger than in the Japanese population (171.2 ± 10.8 cm vs 160.8 ± 8.5 cm, p = 0.007; 80.5 ± 22.5 kg vs 59.9 ± 7.7 kg, p = 0.004). After fitting the BELT, EEP-EIP decreased (all patients, 14.9 ± 6.2 mm to 9.4 ± 3.8 mm, p < 0.001; UK patients, 15.9 ± 6.0 mm to 9.7 ± 3.1 mm, p = 0.001; Japanese patients, 14.0 ± 6.4 mm to 9.1 ± 4.6 mm, p = 0.001), RR increased (all patients, 10.0 ± 3.1 min(-1) to 11.2 ± 3.0 min(-1), p = 0.003; UK patients, 9.5 ± 2.8 min(-1) to 10.7 ± 2.8 min(-1), p = 0.038; Japanese patients, 10.4 ± 3.5 min(-1) to 11.8 ± 3.1 min(-1), p = 0.036), and calculated scan efficiency increased (all patients, 45.3 ± 11.4% to 58.6 ± 17.0%, p < 0.001; UK patients, 44.2 ± 10.8% to 55.7 ± 16.7%, p = 0.004; Japanese patients, 46.3 ± 32.2% to 61.0 ± 17.6%, p = 0.001). No significant differences were found between UK and Japanese patients before and after administration of the BELT., Conclusion: Using a BELT significantly increases whole-heart coronary MR angiography scan efficiency in both UK and Japanese patients.

Background: Platelet glycoprotein VI (pGPVI) expression is increased in acute coronary syndrome (ACS), reflecting platelet activation. There is no reliable method available to measure pGPVI. Our aim was to develop a bead-based sandwich immunoassay to measure soluble GPVI (sGPVI)., Methods: Based on antibodies for sGPVI developed earlier, we established and validated a bead-based sandwich immunoassay in 2438 consecutive patients with stable angina pectoris (SAP; n = 1371), non-ST-elevation myocardial infarction (NSTEMI; n = 724), and ST-elevation MI (STEMI; n = 343). In a subgroup (n = 1011), we measured surface expression of pGPVI using flow cytometry., Results: The assay revealed a working range of 8-500 ng/L. Intra- and interassay imprecision was <7% and <14%, respectively. Patients with NSTEMI and STEMI showed significantly lower mean sGPVI concentrations than patients with SAP [mean (SD), 8.4 (3.6) μg/L and 8.6 (4.1) μg/L vs 9.8 (4.8) μg/L; P = 0.002], whereas subgroup analysis revealed significantly enhanced pGPVI in NSTEMI (n = 276) and STEMI (n = 80) patients compared with SAP (n = 655) [mean fluorescence intensity (SD), 21.2 (8.1) and 19.8 (6.8) vs 18.5 (7.7); P = 0.002 and P = 0.018]. pGPVI and sGPVI were inversely correlated (r = -0.076; P = 0.023). Area under the ROC curve was 0.716, 95% CI 0.681-0.751, for sGPVI, distinguishing patients with SAP from those with ACS, and was superior (P = 0.044) to the curve of subgroup analysis for pGPVI (0.624, 95% CI 0.586-0.662). sGPVI (P = 0.023) and pGPVI (P = 0.028) had better association with the development of ACS than troponin I (P = 0.055) in the very early stage of disease, based on logistic regression analysis., Conclusions: This sandwich immunoassay reliably measures sGPVI and may help to identify patients with ACS earlier than other laboratory markers.

Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function., (Copyright © 2011 by the American Society of Nephrology)

Background: There is cumulative evidence that the degree of inflammation correlates with prognosis after percutaneous coronary interventions (PCI). Additionally, there is a cross-link between platelet activation and inflammatory pathways. The aim of the present analysis was to evaluate the association of inflammatory markers and effects of dual antiplatelet therapy on platelet function and outcome in patients undergoing PCI., Methods and Results: In a pilot study, 157 patients with symptomatic coronary artery disease (CAD) undergoing PCI were consecutively evaluated. Platelet response to clopidogrel and acetylsalicylic acid was assessed using whole blood multiple electrode aggregometry (MEA). Baseline levels of IL-6, RANTES and MCP-1 were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Levels of IL-6, RANTES, and CRP correlated well with ADP and arachidonic acid (AA)-induced MEA. In a second step, a retrospective analysis of a cohort of 903 PCI-patients was performed to evaluate the association of on-treatment residual platelet aggregation (RPA) and baseline CRP levels on the incidence of myocardial infarction (MI), death and stent thrombosis (ST). Patients suffering a subsequent event had a significantly higher level of baseline CRP and higher RPA compared to patients without events. After multivariate adjustment high baseline CRP and high RPA were independent predictors for combined major events and ST after PCI., Conclusion: To our knowledge this is the first study linking inflammation, antiplatelet drug responsiveness and outcome in a large CAD-patient cohort. The results suggest a relevant interaction of these parameters and encourage multimodal therapeutic approaches to treat cardiovascular risk after PCI., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Type-2 diabetes is accompanied by a prothrombotic state influenced by endothelial dysfunction, inflammatory condition and platelet hyperreagibility. We aimed to characterize the relationship of inflammation and residual platelet aggregability (RPA) under antiplatelet therapy with regard to prognosis in an unselected PCI-cohort of diabetics., Methods: In a first step, a consecutive collective of 75 type 2 diabetics compared to 153 non-diabetic controls was evaluated at the time of PCI. Inflammatory markers, Interleukin 6 and C-reactive protein were measured by immunoassays. ADP and Aspirin assays were performed by multiple electrode aggregometry. Then, we consecutively evaluated ADP-induced RPA in 542 diabetics and 1,161 non-diabetics undergoing PCI and treated by standard antiplatelet therapy. Major CV-events were assessed at 30 days after PCI., Results: Inflammatory markers were significantly increased in diabetics with peri-interventional hyperglycemic state and inversely correlated with responsiveness to clopidogrel and aspirin. In a large scale cohort, diabetics showed a higher RPA compared to non-diabetics (median 38.1 vs. 28.8%; p < 0.001). After adjustment for relevant co-factors, diabetes remained a strong predictor for increased RPA (OR 4.39; 95% CI 1.95-6.83; p < 0.001). Furthermore, diabetics with high RPA had an increased risk for 30-day MI and CV-death than diabetics with low RPA (adjusted HR 1.05; 95% CI 1.02-1.07; p < 0.001)., Conclusions: We demonstrate that peri-interventional inflammatory degree and glycaemic control correlate with decreased antiplatelet drug responsiveness in diabetics. In addition, we identified high RPA as strong predictor for short-term CV-events in this group. Therefore, approaches to treat these entities are needed to improve outcome in diabetics undergoing PCI.

Background: Platelets play a critical role in arterial thrombosis, acute coronary syndrome (ACS) and stroke. Platelet collagen receptor glycoprotein VI (GPVI) is associated with acute coronary events and a poor clinical outcome., Methods: Between January 2006 and March 2009, we evaluated 2,213 consecutive patients in a prospective study design, who presented with chest pain. Among 1,819 patients (82.2%) who underwent coronary angiography, 1,652 patients (90.8%) showed a coronary and 167 patients (9.2%) a non-coronary origin of chest pain. 901 patients (54.5%) presented with an ACS, 751 (45.5%) with a stable angina pectoris. Clinical outcome was performed by a predefined structured telephone interview after a 3-month follow-up (92.8%:1,533 of 1,652 patients)., Results: Kaplan-Meier analysis for cumulative event-free survival revealed that patients with a elevated baseline GPVI expression had a poorer clinical outcome for cardiovascular death than patients with decreased GPVI levels (log rank; P = 0.040). These results were paralleled in composite cumulative survival that included myocardial infarction, stroke, and cardiovascular death (log rank; P = 0.002). Relative risk of cardiovascular death was found at 1.41 (95% CI 1.08-1.85) for platelet GPVI, 1.64 (95% CI 1.31-2.05) for brain natriuretic peptide, 1.16 (95% CI 0.81-1.64) for troponin-I and 1.33 (95% CI 0.97-1.82) for C-reactive protein., Conclusions: Patients with CAD presenting increased levels of platelet GPVI had a poorer outcome and may profit from a dual antiplatelet therapy. Thus, GPVI may be a useful prognostic tool for adverse cardiovascular events. Future studies should substantiate GPVI for its potential role of risk prediction and consider its prognostic value to improve risk stratification.

An expanding body of evidence emphasizes the role of platelets as initial actors in inflammatory diseases such as atherosclerosis. Platelets interact with leukocytes and endothelial cells and enforce monocyte transformation into macrophages. Platelets not only mediate the recruitment of leukocytes. They also bind oxidized phospholipids and may promote foam cell formation. Platelets furthermore recruit progenitor cells to the scene, which are able to differentiate into foam cells or endothelial cells, presumably depending on the local microenvironment. Furthermore, platelets are capable of promoting the recruitment of circulating dendritic cells and influencing their functions, thereby presumably modulating immune reactions in atherogenesis. Taken together, platelets may participate in the initiation, development, and total extent of atherosclerotic lesions., (Thieme Medical Publishers.)

Previous studies suggested that the adipocytokines, adiponectin and leptin, are associated with the progression and prognosis of coronary artery disease (CAD). The aim of this study was to differentially evaluate plasma levels of adiponectin and leptin in patients with CAD and their association with conventional laboratory parameters and markers of platelet activation. We consecutively evaluated 220 patients, who presented with a symptomatic CAD. Among these 83 (37.7%) presented with an acute coronary syndrome (ACS) and 137 (62.3%) with a stable angina pectoris (SAP). All patients have received coronary angiography. Baseline concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Lower detection limits of the assay were 0.079 ng/mL for total adiponectin and 15.6 pg/mL for leptin. Patients with ACS showed significantly enhanced plasma levels of adiponectin and leptin compared with SAP (ACS vs. SAP (mean +/- SD): adiponectin: 9.9 +/- 7.6 microg/mL vs. 7.2 +/- 5.7 microg/mL; P = 0.008; leptin: 20.9 +/- 16.4 ng/mL vs. 15.2 +/- 10.9 ng/mL; P = 0.012). However, a correlation between plasma total adiponectin and leptin levels has not been observed (r = 0.038; P = 0.706). Plasma levels of total adiponectin and leptin positively correlated with C-reactive protein (adiponectin: r = 0.277; P = 0.001; leptin: r = 0.248; P = 0.007) and troponin-I (adiponectin: r = 0.219; P = 0.001; leptin: r = 0.190; P = 0.025). Plasma levels of both adipocytokines have shown an inverse correlation with markers of platelet activation such as platelet glycoprotein VI (adiponectin: r = -0.120; P = 0.048; leptin:r = -0.205; P = 0.036), and in a negative trend with P-selectin (adiponectin: r = -0.116; P = 0.073; leptin: r = -0.172; P = 0.078). To support our findings, we determined high-molecular-weight adiponectin in a subgroup of 37 patients, which showed similar results. Increased concentrations of total adiponectin and leptin were associated with ACS. Intriguingly, high plasma levels of both adipocytokines seem to modulate platelet activation. Further studies should elucidate the adipocytokine regulation in CAD.

Aims: Recent studies suggest a relevant association of post-interventional residual platelet aggregation (RPA) under therapy with oral platelet inhibitors and the occurrence of atherothrombotic events. The influence of post-interventional RPA on the incidence of stent thrombosis (ST) has not been sufficiently evaluated in consecutive unselected cohorts of percutaneous coronary intervention (PCI) patients. The aim of this observational study was to investigate the impact of RPA on the incidence of ST within 3 months in patients treated with dual antiplatelet therapy., Methods and Results: The study population included a consecutive cohort of 1019 patients treated with PCI [n = 741 bare-metal stent (BMS) and n = 278 drug-eluting stent (DES)] due to symptomatic coronary artery disease. Residual platelet activity was assessed by adenosine disphosphate (20 micromol/L)-induced PA after 600 mg clopidogrel loading dose. Maximum RPA was measured as peak of aggregation, final RPA was measured 5 min after addition of agonist. The primary endpoint was the occurrence of ST within 3 months defined according to academic research consortium (ARC) criteria. Final and maximum RPA were independent predictors of ST after 3 months. In secondary analysis, the observed effects were independently associated with early ST (HR 1.05, 95% CI 1.01-1.08 and HR 1.05, 95% CI 1.01-1.09, P < 0.01, respectively). However, incidence of 3-month late stent thrombosis (LAT) was not influenced by post-interventional RPA in multivariable analysis., Conclusion: Post-interventional RPA is associated with the occurrence of early ST in patients treated with either BMS or DES; however, there is no predictive value of RPA for the incidence of 3-month LAT, suggesting the involvement of other possible mechanisms like discontinuation of antiplatelet therapy.

Platelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) +/- standard deviation): 1(st) vs. 4(th): 20.44 +/- 6.1 vs. 18.62 +/- 3.7; p=0.012; 2(nd)vs.3(rd):21.2+/-8.5vs.18.76+/-3.7;P=0.03; 2(nd)vs.4(th): 21.2+/-8.5vs.18.62+/-3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1(st) vs. 4(th): 11.2 +/- 6.8 vs. 12.3 +/- 9; p=0.057; 2(nd) vs. 3(rd): 16.3 +/- 16 vs.12.7 +/- 5.3; p=0.138; 2(nd) vs. 4(th): 16.3 +/- 16 vs.11 +/- 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1(st)vs.4(th): 1.6 +/- 0.6 vs. 1.2 +/- 0.4; p=0.046; 1(st) vs. 3(rd): 1.6 +/- 0.6 vs. 1.1 +/- 0.5; p=0.038; 2(nd) vs. 3(rd): 1.9 +/- 0.8 vs. 1.1 +/- 0.5; p=0.04; 2(nd) vs. 4(th): 1.9 +/- 0.8 vs. 1.2 +/- 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.

Aims: To assess whether low response to clopidogrel influences cardiovascular outcome after coronary stent implantation in a consecutively measured cohort of patients with coronary stent implantation., Methods and Results: A total of 379 consecutive patients with symptomatic coronary artery disease (CAD), (stable angina n = 206 and acute coronary syndrome, n = 173) treated with percutaneous coronary stenting were enrolled in this trial. Responsiveness to clopidogrel was assessed by ADP (20 micromol/L)-induced aggregometry at least 6 h (mean 34.8+/-25.9 h) after administration of a loading dose of 600 mg clopidogrel. Platelet inhibition < 30% was defined as low response to clopidogrel. At 3-month follow-up, the primary outcome of a combined major cardiovascular event including non-fatal myocardial infarction, non-fatal ischaemic stroke, or cardiovascular death was evaluated. Twenty-two patients (5.8%) were classified as low responders. Compared with patients who adequately responded to clopidogrel, a low responder had a significantly higher risk of major cardiovascular events [22.7 vs. 5.6%; odds ratio, 4.9; 95% confidence interval (CI), 1.66-14.96; P = 0.004]. After adjustment for other factors influencing cardiovascular outcome, low response to clopidogrel and severe left ventricular dysfunction were independently associated with a major cardiovascular event within 3 months (hazard ratio for low response to clopidogrel, 3.71; 95% CI, 1.08-12.69; P = 0.037)., Conclusion: Low response to clopidogrel in patients with symptomatic CAD treated by stenting significantly enhances the occurrence of cardiovascular events and death. The evaluation of low response to clopidogrel may help to identify patients at increased risk who may benefit from intensified antiplatelet strategy.

Aims: Platelet collagen receptor glycoprotein VI (GPVI) is critical for the formation of arterial thrombosis. In this observational study, we examined the platelet surface expression of GPVI in patients with symptomatic coronary artery disease (CAD)., Methods and Results: We evaluated a consecutive cohort of 367 patients with symptomatic CAD, who underwent coronary angiography. The surface expression of platelet activation markers (GPVI, CD62P, and CD42b) was determined by flow cytometry. Patients with acute coronary syndrome (ACS) showed a significantly enhanced GPVI expression on admission when compared with patients with stable angina pectoris (SAP) (ACS: 21.4+/-9.7; SAP: 18.6+/-7.1 mean fluorescence intensity+/-SD; P=0.004). The expression of GPVI correlated with CD62P (r=0.702; P=0.001). Logistic regression analysis demonstrated that on admission, elevated platelet GPVI expression was associated with ACS, independent of markers of myocardial necrosis such as troponin and creatine kinase., Conclusion: Platelet GPVI surface expression is elevated in patients with ACS and is associated with imminent acute coronary events. The determination of the platelet-specific thrombotic marker GPVI may help to identify patients at risk before myocardial ischaemia is evident.

Aims 18F-sodium fluoride ([18F]fluoride) and gadobutrol are promising probes for positron emission tomography (PET) and magnetic resonance imaging (MRI) characterizing coronary artery disease (CAD) activity. Unlike [18F]fluoride-PET/computed tomography (CT), the potential of PET/MR using [18F]fluoride and gadobutrol simultaneously, has so far not been evaluated. This study assessed feasibility and diagnostic potential of [18F]fluoride and gadobutrol enhanced dual-probe PET/MR in patients with CAD. Methods and results Twenty-one patients (age, 66.7 ± 6.7 years) with CAD scheduled for invasive coronary angiography (XCA) underwent simultaneous [18F]fluoride (mean activity/effective dose: 157.2 ± 29.7 MBq/3.77 ± 0.72 mSv) and gadobutrol enhanced PET/MR on an integrated PET/MRI (3 T) scanner. Optical coherence tomography (OCT) was used as reference. Target-to-background ratio (TBR, [18F]fluoride-PET) and contrast-to-noise ratio (CNR) values (MRI, gadobutrol) were calculated for each coronary segment. Previously suggested PET/CT-TBR thresholds for adverse coronary events were evaluated. High-risk plaques, i.e. calcified and non-calcified thin-cap fibroatheromas (TCFAs) were predominantly located in segments with a TBR >1.28 (P = 0.012). Plaques containing a lipid core on OCT, were more frequently detected in segments with a TBR >1.25 (P < 0.001). TBR values significantly correlated with maximum calcification thickness (P = 0.009), while fibrous cap thickness was significantly less in segments with a TBR >1.28 (P = 0.044). Above a TBR threshold of >1.28, CNR values significantly correlated with the presence of calcified TCFAs (P = 0.032). Conclusion Simultaneous [18F]fluoride and gadobutrol dual-probe PET/MRI is feasible in clinical practice and may facilitate the identification of high-risk patients. The combination of coronary MR-derived CNR values post gadobutrol and [18F]fluoride based TBR values may improve identification of high-risk plaque features. [ABSTRACT FROM AUTHOR]

Background: Cardiac PET has recently found novel applications in coronary atherosclerosis imaging using [18F]NaF as a radiotracer, highlighting vulnerable plaques. However, the resulting uptakes are relatively small, and cardiac motion and respiration-induced movement of the heart can impair the reconstructed images due to motion blurring and attenuation correction mismatches. This study aimed to apply an MR-based motion compensation framework to [18F]NaF data yielding high-resolution motion-compensated PET and MR images. Methods: Free-breathing 3-dimensional Dixon MR data were acquired, retrospectively binned into multiple respiratory and cardiac motion states, and split into fat and water fraction using a model-based reconstruction framework. From the dynamic MR reconstructions, both a non-rigid cardiorespiratory motion model and a motion-resolved attenuation map were generated and applied to the PET data to improve image quality. The approach was tested in 10 patients and focal tracer hotspots were evaluated concerning their target-to-background ratio, contrast-to-background ratio, and their diameter. Results: MR-based motion models were successfully applied to compensate for physiological motion in both PET and MR. Target-to-background ratios of identified plaques improved by 7 ± 7%, contrast-to-background ratios by 26 ± 38%, and the plaque diameter decreased by −22 ± 18%. MR-based dynamic attenuation correction strongly reduced attenuation correction artefacts and was not affected by stent-related signal voids in the underlying MR reconstructions. Conclusions: The MR-based motion correction framework presented here can improve the target-to-background, contrast-to-background, and width of focal tracer hotspots in the coronary system. The dynamic attenuation correction could effectively mitigate the risk of attenuation correction artefacts in the coronaries at the lung-soft tissue boundary. In combination, this could enable a more reproducible and reliable plaque localisation. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare endothelial permeability, which is considered a hallmark of coronary artery disease, between patients with different HbA1c levels using an albumin-binding magnetic resonance (MR) probe. This cross-sectional study included 26 patients with clinical indication for X-ray angiography who were classified into three groups according to HbA1c level (<5.7% [<39 mmol/mol], 5.7-6.4% [39-47 mmol/mol], and ≥6.5% [48 mmol/mol]). Subjects underwent gadofosveset-enhanced coronary magnetic resonance and X-ray angiography including optical coherence within 24 h. Contrast-to-noise ratios (CNRs) were assessed to measure the probe uptake in the coronary wall by coronary segment, excluding those with culprit lesions in X-ray angiography. In the group of patients with HbA1c levels between 5.7 and 6.4%, 0.30 increased normalized CNR values were measured, compared with patients with HbA1c levels <5.7% (0.30 [95% CI 0.04, 0.57]). In patients with HbA1c levels ≥6.5%, we found 0.57 higher normalized CNR values compared with patients with normal HbA1c levels (0.57 [95% CI 0.28, 0.85]) and 0.26 higher CNR values for patients with HbA1c level ≥6.5% compared with patients with HbA1c levels between 5.7 and 6.4% (0.26 [95% CI -0.04, 0.57]). Additionally, late atherosclerotic lesions were more common in patients with high HbA1c levels (HbA1c ≥6.5%, n = 14 [74%]; HbA1c 5.7-6.4%, n = 6 [60%]; and HbA1c <5.7%, n = 10 [53%]). In conclusion, coronary MRI in combination with an albumin-binding MR probe suggests that both patients with intermediate and patients with high HbA1c levels are associated with a higher extent of endothelial damage of the coronary arteries compared with patients with HbA1c levels <5.7%. [ABSTRACT FROM AUTHOR]

Introduction: There is evidence for the impact of gender with higher rates of major adverse clinical events (MACE) being reported in women following myocardial infarction (MI). Since the mechanisms behind these observations are not fully understood we aimed to quantify the underlying pathophysiology on ventricular and atrial level using cardiovascular magnetic resonance (CMR) quantitative deformation imaging. Methods: In total 795 patients with ST-elevation MI (STEMI) treated by primary percutaneous coronary intervention (PCI) underwent CMR imaging amongst 8 centres across Germany. CMR feature tracking (FT) analyses were performed in a blinded core-laboratory evaluating cardiac function by the means of left ventricular global longitudinal strain (GLS) as well as left atrial (LA) reservoir (total strain εs), conduit (passive strain εe) and booster pump function (active strain εa). Primary clinical endpoint was the occurrence of major adverse clinical events (MACE) within 30 days and 1 year after MI. Results: Female gender was associated with increased short- (HR 2.96, 95% CI 1.39-6.30, p=0.005) and long-term events (HR 1.96, 95% CI 1.13-3.42, p=0.017). However, when correcting for baseline confounders with women being older (p<0.001), more often diabetic and hypertensive (p<0.001) but less frequently smokers (p=0.002) female gender was not independently associated with MACE after 30 days (HR 1.78, 95% CI 0.725-4.379, p=0.208) and 1 year (HR 1.23, 95% CI 0.65-2.36, p=0.527). Notwithstanding, compared to male patients, atrial mechanics were distinctly lower (εs p=0.011 and εe p<0.001) and systolic ventricular function was higher (LV GLS p=0.001 and LVEF p=0.048) in women. Impaired atrial function independently predicted MACE occurrence after 30 days (εs HR 1.14, 95% CI 1.01-1.30, p=0.041) and 1 year (εs HR 1.10, 95% CI 1.01-1.21, p=0.027). Conclusions: Atrial reservoir and conduit functions are distinctly worse in female patients following STEMI with impaired atrial conduit strain indicating ventricular diastolic failure, potentially compensated by increased systolic contractility. Over time complete atrial mechanical failure may occur and explain worse outcomes in the female population with total atrial strain representing an independent risk factor for short- and long-term event rate. [ABSTRACT FROM AUTHOR]