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Abstract: Purpose: Platelet-derived stromal-cell-derived factor-1 (SDF-1) plays an important role in trafficking hematopoetic progenitor cells for tissue regeneration and neovascularisation. The aim was to evaluate platelet-SDF-1 and CD34+ progenitor cells in patients with acute myocardial infarction (AMI) compared with hemodynamic function and infarct size using late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging. Materials and methods: We consecutively evaluated 40 patients with AMI, who received coronary angiography for primary coronary intervention. Blood was sampled for flow cytometry to determine mean fluorescence intensity (MFI) of platelet-SDF-1 and for isolation of CD34+ progenitor cells. 48h and three months after coronary stenting, all patients underwent 1.5T CMR for volumetric assessment and LGE. Results: Patients with enhanced platelet-SDF-1 expression (median≥68.5MFI) showed a significant amelioration of left ventricular ejection fraction (LVEF) (baseline vs. follow-up mean±SD: 45±6% vs. 56±6%; P =0.018) and of stroke volume (73.1±19.1mL vs. 89.9±21.3mL; P =0.032) at three-month follow-up in contrast to patients with a decreased platelet-SDF-1 expression level (LVEF: 53±8% vs. 56±10%; P =0.267; stroke volume: 85.6±23.1mL vs. 87.4±23.2mL; P =0.803). Inversely, LGE infarct size showed significantly reduced in patients with enhanced platelet-SDF-1 expression at three months (18.9±12mL vs. 6.3±5.1mL; P =0.002) compared to patients with decreased platelet-SDF-1 (12.7±12.7mL vs. 7.6±8.4mL; P =0.156). Time-dependent autocorrelation coefficients shifted for both SV (lag 1: r =−0.368; P =0.001) and the number of CD34+ cells (lag 1: r =0.633; P =0.001) to a positive autocorrelation (SV; lag 2: r =0.295; P =0.001; CD34+ cells; lag 2: r =0.287; P =0.001). Patients with increased number of CD34+ cells (median≥420cells/hpf) showed a significant amelioration of stroke volume in three-month follow-up (83.9±5.3mL vs. 99.4±4.1mL; P =0.020) compared with patients with decreased number of CD34+ cells (69.3±4.1mL vs. 76.1±3.2mL; P =0.282). Conclusions: Platelet-SDF-1 and number of CD34+ progenitor cells are associated with CMR hemodynamic function in patients with AMI. [Copyright &y& Elsevier]

Background: Recently, a novel left atrioventricular coupling index (LACI) has been introduced providing prognostic value to predict cardiovascular events beyond common risk factors in patients without cardiovascular disease. Since data on cardiovascular magnetic resonance (CMR)-derived LACI in patients following acute myocardial infarction (AMI) are scarce, we aimed to assess the diagnostic and prognostic implications of LACI in a large AMI patient cohort., Methods: In total, 1046 patients following AMI were included. After primary percutaneous coronary intervention CMR imaging and subsequent functional analyses were performed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular (LV) end-diastolic volume. Major adverse cardiac events (MACE) including death, reinfarction or heart failure within 12 months after the index event were defined as primary clinical endpoint., Results: LACI was significantly higher in patients with MACE compared to those without MACE (p < 0.001). Youden Index identified an optimal LACI cut-off at 34.7% to classify patients at high-risk (p < 0.001 on log-rank testing). Greater LACI was associated with MACE on univariate regression modeling (HR 8.1, 95% CI 3.4-14.9, p < 0.001) and after adjusting for baseline confounders and LV ejection fraction (LVEF) on multivariate regression analyses (HR 3.1 95% CI 1.0-9, p = 0.049). Furthermore, LACI assessment enabled further risk stratification in high-risk patients with impaired LV systolic function (LVEF ≤ 35%; p < 0.001 on log-rank testing)., Conclusion: Atrial-ventricular interaction using CMR-derived LACI is a superior measure of outcome beyond LVEF especially in high-risk patients following AMI. Trial registration ClinicalTrials.gov, NCT00712101 and NCT01612312., (© 2023. The Author(s).)

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.)

Aims: Deformation imaging enables optimized risk prediction following acute myocardial infarction (AMI). However, costly and time-consuming post processing has hindered widespread clinical implementation. Since manual left-ventricular long-axis strain (LV LAS) has been successfully proposed as a simple alternative for LV deformation imaging, we aimed at the validation of left-atrial (LA) LAS., Methods and Results: The AIDA STEMI and TATORT-NSTEMI trials recruited 795 patients with ST-elevation myocardial infarction and 440 with non-ST-elevation myocardial infarction. LA LAS was assessed as the systolic distance change between the middle of a line connecting the origins of the mitral leaflets and either a perpendicular line towards the posterior atrial wall (LAS 90 ) or a line connecting to the LA posterior portion of the greatest distance irrespective of a predefined angle (LAS). Primary endpoint was major adverse cardiac event (MACE) occurrence within 12 months. There were no significant differences between LA LAS and LAS 90 , both with excellent reproducibility. LA LAS correlated significantly with LA reservoir function (Es, r  = 0.60, P  < 0.001). Impaired LA LAS resulted in higher MACE occurrence [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.82-0.88, P  < 0.001]. LA LAS (HR 0.90, 95% CI 0.83-0.97, P  = 0.005) and LV global longitudinal strain (GLS, P  = 0.025) were the only independent predictors for MACE in multivariate analyses. C-statistics demonstrated incremental value of LA LAS in addition to GLS ( P  = 0.016) and non-inferiority compared with FT Es (area under the receiver operating characteristic curve 0.74 vs. 0.69, P  = 0.256)., Conclusion: Left-atrial LAS provides fast and software-independent approximations of quantitative LA function with similar value for risk prediction compared with dedicated deformation imaging., Clinical Trial Registration: ClinicalTrials.gov: NCT00712101 and NCT01612312., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

MR imaging with an albumin-binding probe enables the visualization of endothelial permeability and damage in the arterial system. The goal of this study was to compare signal enhancement of lesions with different grades of stenosis segments on molecular CMR in combination with the albumin-binding probe gadofosveset. This prospective clinical study included patients with symptoms suggestive of coronary artery disease (CAD). Patients underwent gadofosveset-enhanced cardiovascular magnetic resonance (CMR) imaging and x-ray angiography (QCA) within 24 h. CMR imaging was performed prior to and 24 h following the administration of gadofosveset. Contrast-to-noise ratios (CNRs) between segments with different grades of stenosis were compared. Overall, n = 203 segments of 26 patients were included. Lesions with more than > 70% stenosis demonstrated significantly higher CNRs compared to lesions < 70% (7.6 ± 8.3 vs. 2.5 ± 4.9; p < 0.001). Post-stenotic segments of lesions > 70% stenosis showed significant higher signal enhancement compared to segments located upstream of these lesions (7.3 ± 8.8 vs. 2.8 ± 2.2; p = 0.02). No difference in signal enhancement between segments proximal and distal of lesions with stenosis greater than 50% was measured (3.3 ± 2.8 vs. 2.4 ± 2.7; p = 0.18). ROC analysis for the detection of lesions ≥ 70% revealed an area under the curve of 0.774 (95% CI 0.681-0.866). This study suggests that relevant coronary stenosis and their down-stream segments are associated with increased signal enhancement on Gadofosveset-enhanced CMR, suggesting a higher endothelial permeability in these lesions. An albumin-binding MR probe could represent a novel in vivo biomarker for the identification and characterization of these vulnerable coronary segments., (© 2021. The Author(s).)

Background: Cardiac PET has recently found novel applications in coronary atherosclerosis imaging using [ 18 F]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 [ 18 F]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.

Background: Cardiac magnetic resonance myocardial feature tracking (CMR-FT)-derived global strain assessments provide incremental prognostic information in patients following acute myocardial infarction (AMI). Functional analyses of the remote myocardium (RM) are scarce and whether they provide an additional prognostic value in these patients is unknown., Methods: 1034 patients following acute myocardial infarction were included. CMR imaging and strain analyses as well as infarct size quantification were performed after reperfusion by primary percutaneous coronary intervention. The occurrence of major adverse cardiac events (MACE) within 12 months after the index event was defined as primary clinical endpoint., Results: Patients with MACE had significantly lower RM circumferential strain (CS) compared to those without MACE. A cutoff value for RM CS of - 25.8% best identified high-risk patients (p < 0.001 on log-rank testing) and impaired RM CS was a strong predictor of MACE (HR 1.05, 95% CI 1.07-1.14, p = 0.003). RM CS provided further risk stratification among patients considered at risk according to established CMR parameters for (1) patients with reduced left ventricular ejection fraction (LVEF) ≤ 35% (p = 0.038 on log-rank testing), (2) patients with reduced global circumferential strain (GCS) > -  18.3% (p = 0.015 on log-rank testing), and (3) patients with large microvascular obstruction ≥ 1.46% (p = 0.002 on log-rank testing)., Conclusion: CMR-FT-derived RM CS is a useful parameter to characterize the response of the remote myocardium and allows improved stratification following AMI beyond commonly used parameters, especially of high-risk patients., Trial Registration: ClinicalTrials.gov, NCT00712101 and NCT01612312 Defining remote segments (R) in the presence of infarct areas (I) for the analysis of remote circumferential strain (CS). Remote CS was significantly lower in patients who suffered major adverse cardiac events (MACE) and a cutoff value for remote CS of - 25.8% best identified high-risk patients. In addition, impaired remote CS ≥ - 25.8 % (Remote -) and preserved remote CS < - 25.8 % (Remote +) enabled further risk stratification when added to established parameters like left ventricular ejection fraction (LVEF), global circumferential strain (GCS) or microvascular obstruction (MVO).

Background Cardiovascular magnetic resonance imaging is considered the reference methodology for cardiac morphology and function but requires manual postprocessing. Whether novel artificial intelligence-based automated analyses deliver similar information for risk stratification is unknown. Therefore, this study aimed to investigate feasibility and prognostic implications of artificial intelligence-based, commercially available software analyses. Methods and Results Cardiovascular magnetic resonance data (n=1017 patients) from 2 myocardial infarction multicenter trials were included. Analyses of biventricular parameters including ejection fraction (EF) were manually and automatically assessed using conventional and artificial intelligence-based software. Obtained parameters entered regression analyses for prediction of major adverse cardiac events, defined as death, reinfarction, or congestive heart failure, within 1 year after the acute event. Both manual and uncorrected automated volumetric assessments showed similar impact on outcome in univariate analyses (left ventricular EF, manual: hazard ratio [HR], 0.93 [95% CI 0.91-0.95]; P <0.001; automated: HR, 0.94 [95% CI, 0.92-0.96]; P <0.001) and multivariable analyses (left ventricular EF, manual: HR, 0.95 [95% CI, 0.92-0.98]; P =0.001; automated: HR, 0.95 [95% CI, 0.92-0.98]; P =0.001). Manual correction of the automated contours did not lead to improved risk prediction (left ventricular EF, area under the curve: 0.67 automated versus 0.68 automated corrected; P =0.49). There was acceptable agreement (left ventricular EF: bias, 2.6%; 95% limits of agreement, -9.1% to 14.2%; intraclass correlation coefficient, 0.88 [95% CI, 0.77-0.93]) of manual and automated volumetric assessments. Conclusions User-independent volumetric analyses performed by fully automated software are feasible, and results are equally predictive of major adverse cardiac events compared with conventional analyses in patients following myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00712101 and NCT01612312.

Takotsubo syndrome (TTS) is an acute and mostly reversible cardiomyopathy that mimics an acute coronary syndrome with left ventricular (LV) systolic dysfunction without relevant obstructive coronary artery disease. Its prevalence is probably underestimated and reaches 1.2-2% in patients with acute coronary syndrome undergoing coronary catheterization. Although supraphysiological epinephrine levels have been associated with TTS, the detailed pathophysiology is incompletely understood. Chest pain is the most common clinical presentation; however, cardiac decompensation, cardiogenic shock, and sudden cardiac death due to ventricular fibrillation may also be the first clinical manifestations. Patients are mostly postmenopausal women, in whom the condition is commonly associated with emotional triggers; however, men have a higher prevalence of TTS being associated with physical triggers, which has a worse prognosis compared with TTS associated with emotional triggers. As a diagnosis of exclusion, TTS has no single definitive diagnostic test. According to the distribution of LV wall motion abnormalities, various morphological subtypes have been identified. The final diagnosis depends on cardiac imaging with left ventricular angiography during acute heart catheterization, as well as on echocardiography and cardiac magnetic resonance. Most patients recover completely, albeit several factors have been associated with worse prognosis. Management is based on observational data, while randomized multicenter studies are still lacking. This review provides a general overview of TTS and focuses on the hypothesized pathophysiology, and especially on current practices in diagnosis, prognosis, and treatment.

Background: Prognosis in acute myocardial infarction (AMI) depends on the amount of infarct-related artery (IRA)-subtended myocardium and associated damage but has not been described in great detail. Consequently, we sought to describe IRA-associated pathophysiological consequences using cardiac magnetic resonance (CMR)., Methods: 1235 AMI patients (n = 795 ST-elevation (STEMI) and 440 non-STEMI) underwent CMR following percutaneous coronary intervention. Blinded core-laboratory data were compared according to left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA) regarding major adverse clinical events (MACE) within 12 months. Left ventricular (LV) global longitudinal/circumferential/radial (GLS/GCS/GRS) as well as left atrial (LA) total (ε s ), passive (ε e ) and active (ε a ) strains were determined using CMR-feature tracking. Tissue characterisation included infarct size (IS) and microvascular obstruction., Results: LAD and LCx were associated with higher mortality compared to RCA lesions (4.6% and 4.4% vs 1.6%). LAD lesions showed largest IS (16.8%), largest ventricular [LV ejection fraction (EF) 47.4%, GLS - 13.2%, GCS - 20.8%] and atrial (ε s 20.2%) impairment. There was less impairment in LCx (IS 11.8%, LVEF 50.8%, GLS - 17.4%, GCS - 25.0%, ε s 20.7%) followed by RCA lesions (IS 11.3%, LVEF 50.8%, GLS - 19.1%, GCS - 26.6%, ε s 21.7%). In AUC analyses, ε s (LAD, RCA) and GLS (LCx) best predicted MACE (AUC > 0.69). Multivariate analyses identified ε s (p = 0.017) in LAD and GLS (p = 0.034) in LCx infarcts as independent predictors of MACE., Conclusions: CMR allows IRA-specific phenotyping and characterisation of morphologic and functional changes. These alterations carry infarct-specific prognostic implications, and may represent novel diagnostic and therapeutic targets following AMI., Trial Registration: ClinicalTrials.gov: NCT00712101 and NCT01612312.

Meta-analysis on immunohistological (IHC) concepts for the detection of inflammatory cardiomyopathy (InfCM) in endomyocardial biopsies (EMB). We included 61 publications, with 10,491 patients (mean age 47.1 years; men 66%) who underwent EMB and IHC evaluation. The 460 control patients were devoid of IHC proof of InfCM. The mean IHC detection rate of InfCM was 50.8% (95% CI 47.7-53.8%; range 18.4-91.7%). A publication bias was excluded (Funnel Plot p = 0.4264). This IHC detection rate was significantly (p < 0.0001) higher compared to the histological detection of myocarditis according to the Dallas criteria (mean 8.04%; 95% CI 5.08-12.5%; subset of 3274 patients in 30 publications). However, 13 different diagnostic IHC criteria were described in the publications, with various thresholds of diverse phenotypes of quantified infiltrates, and endothelial expression of diverse cell adhesion molecules (CAM), quantified either visually or by digital image analysis (DIA). The comparison of IHC with cardiac magnetic resonance (CMR) data available in a subset of 13 publications with 1185 patients revealed a sensitivity for CMR of 69% (95% CI 58-79%), a specificity of 73% (95% CI 59-84%), and a ROC-AUC of 0.77 (95% CI 0.73-0.81). This meta-analysis encompassing 10,491 patients confirms a mean detection rate of InfCM in 50.8% of EMB, being significantly more sensitive compared to the histological Dallas criteria. IHC cannot be fully substituted by CMR. However, standardization of the diverse IHC markers and protocols seems pertinent, especially considering the published adverse prognostic impact of IHC-confirmed InfCM and its published suitability for the selection of candidates responding favorably to immunosuppression.

Background: Percutaneous closure (LAAC) of the left atrial appendage (LAA) is an efficacious preventive procedure for patients with non-valvular atrial fibrillation (NVAF) and considerable bleeding risk. We sought to systematically review the available LAAC data on the novel occluder device LAmbre™., Methods: For this systematic review, a search of the literature was conducted by 3 independent reviewers, reporting the safety and therapeutic success of LAAC in patients being treated with a LAmbre™. Publications reporting the safety and therapeutic success of LAAC using LAmbre™ in n > 5 patients were included., Results: The literature search retrieved n = 10 publications, encompassing n = 403 NVAF patients treated with a LAmbre™ LAAC, with relevant data regarding safety and therapeutic success of the procedure. The mean CHA 2 DS 2 -VASc Score was 4.0 + 0.9, and the mean HAS-BLED score was 3.4 + 0.5. The implantation success was 99.7%, with a mean procedure time of 45.4 ± 18.7 min, and a fluoroscopy time of 9.6 ± 5.9 min, and a contrast agent volume of 96.7 ± 0.7 ml. The anticoagulation regimen was switched to DAPT post procedure in the majority of the patients (96.8%). Partial and full recapture were done in 45.5% and in 25.6%, respectively. Major complications were reported in 2.9%, with 0.3% mortality, 1.7% pericardial tamponade, 0.3% stroke, and 0.6% major bleeding complications; no device embolization was observed. During follow up at 6 or 12 months, major adverse cardiovascular events were reported in 3.3%: Stroke or TIA in 1.7%, thrombus formation on the device in 0.7%, and residual flow > 5 mm in 1.0%. In some publications, the favorable implantion properties of the LAmbre™ for difficult anatomies such as shallow or multilobular LAA anatomies were described., Conclusions: This systematic review on the LAmbre™ LAA-occluder including n = 403 NVAF patients demonstrates an excellent implantion success rate, promising follow-up clinical data, and favorable properties for also challenging LAA anatomies,. While its design seems to be helpful in preventing device embolization, pericardial tamponade may not be substantially reduced by the LAmbre™ as compared with other established LAAC devices. Further larger prospective multicenter registries and randomized trials are needed to scrutinize the value of the LAmbre™ compared with established LAAC devices.

Background The role of left atrial (LA) performance in acute myocardial infarction (AMI) remains controversial. Cardiac MRI myocardial feature tracking (hereafter, MRI-FT) is a method used to quantify myocardial function that enables reliable assessment of atrial function. Purpose To assess the relationship between LA function assessed with MRI-FT and major adverse cardiovascular events (MACE) after AMI. Materials and Methods This secondary analysis of two prospective multicenter cardiac MRI studies (AIDA STEMI [NCT00712101] and TATORT NSTEMI [NCT01612312]) included 1235 study participants with ST-elevation myocardial infarction ( n = 795) or non-ST-elevation myocardial infarction ( n = 440) between July 2008 and June 2013. All study participants underwent primary percutaneous coronary intervention. MRI-FT analyses were performed in a core laboratory by researchers blinded to clinical status to determine LA performance using LA reservoir function peak systolic strain (ε s ), LA conduit strain (ε e ), and LA booster pump function active strain (ε a ). The relationship of LA performance to a MACE within 12 months after AMI was evaluated by using Cox proportional hazards models and area under the receiver operating characteristic curve (AUC). Results Study participants with MACE had worse LA performance parameters compared with study participants without MACE (ε s = 21.2% vs 16.2%, ε e = 8.8% vs 6.9%, ε a = 11.8% vs 10%; P < .001 for all). All atrial parameters were strongly associated with MACE (hazard ratio [HR], ε s = 0.9, ε e = 0.88, ε a = 0.89; P < .001 for all). For ε s , a cutoff of 18.8% was identified as the only independent atrial parameter with which to predict MACE after accounting for confounders and established prognostic markers in adjusted analysis (HR, 0.95; P = .02). The ε s yielded incremental prognostic value above left ventricular ejection fraction, global longitudinal strain, microvascular obstruction, and infarct size (AUC comparisons, P < .04 for all). Conclusion Feature tracking of cardiac MRI to derive left atrial peak reservoir strain provided incremental prognostic value for major adverse cardiovascular events prediction versus established cardiac risk factors after acute myocardial infarction. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Almeida in this issue.

Aims: Cardiovascular magnetic resonance feature tracking (CMR-FT) global longitudinal strain (GLS) provides incremental prognostic value following acute myocardial infarction (AMI) but requires substantial post-processing. Alternatively, manual global long-axis strain (LAS) can be easily assessed from standard steady state free precession images. We aimed to define the prognostic value of LAS in a large multicentre study in patients following AMI., Methods and Results: A total of 1235 patients with myocardial infarction [n = 795 with ST-elevation myocardial infarction (STEMI) and 440 with non-ST-elevation myocardial infarction (NSTEMI)] underwent cardiovascular magnetic resonance imaging after primary percutaneous coronary intervention in eight centres across Germany. Assessment of LAS was performed in a blinded core-laboratory measuring the systolic shortening between the epicardial apical border and the middle of a line connecting the origins of the mitral leaflets. Primary clinical endpoint was the occurrence of major adverse clinical events (MACE) including death, reinfarction, and congestive heart failure within 1 year after AMI. During 1-year follow-up, 76 patients suffered from MACE. Impaired LAS was associated with higher MACE occurrence both in STEMI (P < 0.001) and NSTEMI (P = 0.001) patients. Association of LAS remained significant (P = 0.017) after correction for univariate significant parameters for MACE prediction. C-statistics revealed incremental value of additional LAS assessment for optimized event prediction compared with left ventricular ejection fraction (MACE P = 0.044; mortality P = 0.013) and a combination of established clinical and imaging parameters (MACE P = 0.084; mortality P = 0.027), but not CMR-FT GLS (MACE P = 0.075; mortality P = 0.380)., Conclusion: LAS provides software independent, widely available, easy and fast approximation of longitudinal left ventricular shortening early after reperfused AMI with incremental prognostic value beyond established risk stratification parameters., Clinical Trials.gov: NCT00712101 and NCT01612312., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: The exact pathophysiology of Takotsubo syndrome (TTS) remains not fully understood with most studies focussing on ventricular pathology. Since atrial involvement may have a significant role, we assessed the diagnostic and prognostic potential of atrial cardiovascular magnetic resonance feature tracking (CMR-FT) in TTS., Methods and Results: This multicentre study recruited 152 TTS patients who underwent CMR on average within 3 days after hospitalization. Reservoir [total strain εs and peak positive strain rate (SR) SRs], conduit (passive strain εe and peak early negative SRe), and booster pump function (active strain εa and peak late negative SRa) were assessed in a core laboratory. Results were compared with 21 control patients with normal biventricular function. A total of 20 patients underwent follow-up CMR (median 3.5 months, interquartile range 3-5). All patients were approached for general follow-up. Left atrial (LA) but not right atrial (RA) reservoir and conduit function were impaired during the acute phase (εs: P = 0.043, εe: P < 0.001, SRe: P = 0.047 vs. controls) and recovered until follow-up (εs: P < 0.001, SRs: P = 0.04, εe: P = 0.001, SRe: P = 0.04). LA and RA booster pump function were increased in the acute setting (LA-εa: P = 0.045, SRa: P = 0.002 and RA-εa: P = 0.004, SRa: P = 0.002 vs. controls). LA-εs predicted mortality [hazard ratio 1.10, 95% confidence interval (CI) 1.01-1.20; P = 0.037] irrespectively of established cardiovascular risk factors (P = 0.019, multivariate analysis) including left ventricular ejection fraction (LVEF) (area under the curve 0.71, 95% CI 0.55-0.86, P = 0.048)., Conclusion: TTS pathophysiology comprises transient impairments in LA reservoir and conduit functions and enhanced bi-atrial active booster pump functions. Atrial CMR-FT may evolve as a superior marker of adverse events over and above established parameters such as LVEF and atrial volume., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils constituted by misfolded proteins, which can modify tissue anatomy and hinder the function of multiple organs including the heart. Amyloidosis that can affect the heart includes mostly systemic amyloidosis (amyloid light chain, AL) and transthyretin amyloidosis (ATTR). The latter can be acquired in elderly patients (ATTRwt), or be inherited in younger individuals (ATTRm). The diagnosis is demanding given the high phenotypic heterogeneity of the disease. Therefore, "red flags," which are suggestive features giving support to diagnostic suspicion, are extremely valuable. However, the lack of broad awareness among clinicians represents a major obstacle for early diagnosis and treatment of ATTR. Furthermore, recent implementation of noninvasive diagnostic techniques has revisited the need for endomyocardial biopsy (EMB). In fact, unlike AL amyloidosis, which requires tissue confirmation and typing for diagnosis, ATTR can now be diagnosed noninvasively with the combination of bone scintigraphy and the absence of a monoclonal protein. Securing the correct diagnosis is pivotal for the newly available therapeutic options targeting both ATTRm and ATTRwt, and are directed to either stabilization of the abnormal protein or the reduction of the production of transthyretin. The purpose of this article is to review the contemporary aspects of diagnosis and management of transthyretin amyloidosis with cardiac involvement, summarizing also the recent therapeutic advances with tafamidis, patisiran, and inotersen.

Treatment of left ventricular outflow tract (LVOT) obstruction in hypertrophic obstructive cardiomyopathy (HOCM) with septal reduction, either with myectomy or alcohol septal ablation, is aiming to reduce the LVOT gradient and improve symptoms in patients who are refractory to or do not tolerate medical treatment. Apart from contributing to the evolution to heart failure, LVOT obstruction is considered a risk factor for sudden cardiac death (SCD). Both septal reduction treatments have been proven effective in reducing symptoms and seem to improve survival, which has been shown equal to the expected in the normal population. SCD is probably reduced after septal reduction, implying that LVOT obstruction is a major factor predisposing to ventricular tachyarrhythmias. Although available algorithms for SCD stratification have not been tested in patients after septal reduction treatments, effective treatment improves SCD risk profile substantially. Furthermore, high-risk patients with already implanted implantable cardioverter defibrillators (ICDs) before septal reduction show very low appropriate ICD shock rate after effective treatment. It should be noted, however, that the best outcomes for septal myectomy or ablation have been reported in HOCM patients treated in high-volume centres, which substantiates the need to refer patients to centres with high procedural expertise.

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.)

In iron overload diseases (thalassemia, sickle cell, and myelodysplastic syndrome), iron is deposited in all internal organs, leading to functional abnormalities. Hematopoietic stem cell transplantation (HSCT) is the only treatment offering a potential cure in these diseases. Our aim was to describe the experience in the field and the role of magnetic resonance imaging in the evaluation of iron overload before and after HSCT. Magnetic resonance imaging (MRI), using T2*, is the most commonly used tool to diagnose myocardial-liver iron overload and guide tailored treatment. Currently, HSCT offers complete cure in thalassemia major, after overcoming the immunologic barrier, and should be considered for all patients who have a suitable donor. The overall thalassemia-free survival of low-risk, HLA-matched sibling stem cell transplantation patients is 85-90%, with a 95% overall survival. The problems of rejection and engraftment are improving with the use of adequate immunosuppression. However, a detailed iron assessment of both heart and liver is necessary for pre- and post-transplant evaluation. In iron overload diseases, heart and liver iron evaluation is indispensable not only for the patients' survival, but also for evaluation before and after HSCT.

Cardiomyopathies are complex diseases of multifactorial pathogenesis and have a high morbidity and mortality. Over the past decades, several revisions of classifications and definitions of cardiomyopathies have been proposed, primarily focusing on the phenotypic characterization of cardiomyopathies. The MOGE(S) classification system published in 2013 encompasses the classification of rapidly growing knowledge on genetic mutations, acquired causes (i.e., intramyocardial inflammation, viral infections), and further conditions involved in the induction of cardiomyopathies (e.g., storage diseases, toxicity). It is based on five attributes, including morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological annotation (E), and optional information about the heart failure functional status (S). This review summarizes the development, the cornerstones of the MOGE(S) classification, and the published data on the clinical relevance of the MOGE(S) classification. We furthermore discuss new issues which might be considered for future updates of the MOGE(S) classification of cardiomyopathies.

A 74-year-old female patient was referred to our department in 2015 with dyspnea, cough and dysphagia. She had been diagnosed with adenocarcinoma of the right breast in 1986 and underwent mastectomy. When she presented with a local recurrence in 1988, she was receiving high-voltage radiation therapy. Transthoracic echocardiography and magnetic resonance imaging revealed tricuspid regurgitation grade III and unclear right heart failure with a massively dilated right atrium. Coronary heart disease could be ruled out. In summary, the patient's findings represented right ventricular myocardial restriction which we attributed to irradiation of the right anterior chest 17 years previously.

Continued uptake of modified low-density lipoproteins (LDL) by the scavenger receptor, CD68, of activated macrophages is a crucial process in the development of atherosclerotic plaques and leads to the formation of foam cells. Eight-weeks-old male Apolipoprotein E-deficient (ApoE(-/-)) mice (n = 6) were fed a high-fat diet for 12 weeks. C57BL/6J wildtype (WT) mice served as controls (n = 6). Positron emission tomography (PET) with an acquisition time of 1800 s (NanoPET/CT scanner; Mediso, Hungary & Bioscan, USA) was carried out 24h after intravenous tail vein administration of 50 µl (64)Cu-CD68-Fc (~20-30 µg labeled protein/mouse containing approximately 10-12 MBq (64)Cu-CD68-Fc per mouse). Three days after PET/CT, all mice received an intravenous administration of 0.2 mmol/kg body weight of a gadolinium-based elastin-binding contrast agent to assess plaque burden and vessel wall remodeling. Two hours after injection, mice were imaged in a 3T clinical MR scanner (Philips Healthcare, Best, NL) using a dedicated single loop surface coil (23 mm). Enhanced (64)Cu-CD68-Fc uptake was found in the aortic arches of ApoE(-/-) compared to WT mice (ApoE(-/-) mice:10.5 ± 1.5 Bq/cm(3) vs. WT mice: 2.1 ± 0.3 Bq/cm(3); P = 0.002). Higher gadolinium-based elastin-binding contrast agent uptake was also detected in the aortic arch of ApoE(-/-) compared to WT mice using R(1) maps (R(1) = 1.47 ± 0.06 s(-1) vs. 0.92 ± 0.05 s(-1); P <0.001). Radiolabeled scavenger receptor ((64)Cu-CD68-Fc) may help to target foam cell rich plaques with high content of oxidized LDL. This novel imaging biomarker tool may have potential to identify unstable plaques and for risk stratification., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

History and Admission Findings: We report on a case of a 31-year-old patient who was admitted to hospital with acute cardiac failure. At physical examination we found peripheral edema and wet rales., Investigations: Cardiac ultrasound revealed severely impaired left and right ventricular function and prominent trabeculation in the right ventricle, but also in the apex of the left ventricle. This was confirmed by cardiac magnetic resonance imaging. Both pulmonary embolism and coronary heart disease were excluded by thoracic computed tomography and coronary angiography., Diagnosis, Treatment and Course: These findings were in line with the diagnosis of non-compaction cardiomyopathy resulting in cardiac failure. We introduced diuretic therapy which leads to weight loss and release of dyspnoea. Due to prevention of embolic events an anticoagulative therapy was started. In light of rhythmogenic vulnerability, a subcutaneous implantable cardioverter defibrillator (ICD) system was implanted. Afterwards the patient was discharged in good general health., Conclusion: Non-compaction cardiomyopathy (NCCM) is a hereditary non-ischaemic cardiac disease which occurs due to the failure of myocardial compaction during embryogenesis. Common manifestation is the triad of heart failure, rhythmogenic vulnerability and systemic embolic events. First-line imaging technique for diagnosing NCCM is cardiac ultrasound. The prognosis depends on severity of heart failure, ventricular arrhythmia and the incidence of embolic events., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.

Platelet-bound stromal cell-derived factor-1 (SDF-1) plays a crucial role in attachment of circulating CD34(+) progenitor cells to the vascular wall, facilitating tissue healing after injury. However there is no evidence about expression of platelet-bound SDF-1 in patients with congestive heart failure (CHF). The aim of our study was to evaluate expression of platelet-bound SDF-1 and number of CD34(+) progenitor cells in patients with CHF. Forty-eight patients with idiopathic dilated cardiomyopathy (DCM) and 61 patients with ischaemic cardiomyopathy (ICM) were consecutively enrolled into the study. Blood taken from 109 consecutive patients was studied for surface expression of platelet-bound SDF-1 and number of CD34(+) progenitor cells by flow cytometry. The highest expression of platelet-bound SDF-1 was observed in patients with severe impairment of left ventricular systolic function compared with patients with mild or moderate impairment of left ventricular systolic function (mild vs. moderate vs. severe impairment of left ventricular systolic function: MFI ± SD: 35.6 ± 34 vs. 101.45 ± 73 vs. 124.86 ± 86.7, Kruskal-Wallis p < 0.001). Similar to platelet-bound SDF-1 number of CD34(+) progenitor cells was the highest in severe impairment of left ventricular systolic function (mild vs. moderate vs. severe impairment of left ventricular systolic function: mean ± SD: 260.4 ± 177.5 vs. 580.7 ± 340.5 vs. 640.82 ± 370.6, Kruskal-Wallis p < 0.001). Platelet-bound SDF-1 expression was associated with number of circulating CD34(+) progenitor cells (r = 0.454, p < 0.001) in patients with CHF. Expression of platelet-bound SDF-1 and number of CD34(+) cells were higher in patients with DCM compared with patients with ICM (p < 0.001 for both) and inversely correlated with age and aspirin therapy. Platelet-bound SDF-1 and CD34(+) progenitor cells are especially increased in patients with severe impairment of left ventricular systolic function in CHF.

Aims: The aim of the present study was to evaluate the levels of platelet interaction with circulating CD34+ cells in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS) and to study the functional consequence of coaggregates formation in vitro and in vivo., Methods and Results: Platelet binding to circulating progenitor cells was defined by the presence of the platelet-specific marker glycoprotein Ib (CD42b) on the surface of CD34+ cells using flow cytometry. The percentage of CD34+/CD42b+ cell coaggregates was increased in patients with ACS (n = 162), and especially in patients with ST-elevation myocardial infarction (STEMI) (n = 44), compared with patients with SAP (n = 116; P < 0.001). In the ANCOVA analysis, platelet/CD34+ cell coaggregates were independently increased in ACS after adjustment for possible confounders. In a subgroup of our cohort, we also evaluated the levels of CD34+/CD133+/CD42b+ cell coaggregates, which were also significantly increased in ACS, and especially in STEMI (P < 0.05). Platelet/CD34+ cell coaggregates formation correlated with platelet activation (P = 0.001). In a prospective pilot study of patients with AMI (n = 40) using cardiac MRI, patients with increased baseline platelet/CD34+ cell coaggregates presented with a less myocardial infarct size and better left ventricular function at a 3-month follow-up compared with patients with lower coaggregates (P < 0.05 for all). The adhesion of platelet/CD34+ cell coaggregates onto the extracellular matrix and to endothelial monolayer was enhanced compared with CD34+ under high shear rates in vitro (P < 0.05) and within the microcirculation in mice after ischaemia/reperfusion injury as assessed by intravital microscopy (P < 0.05)., Conclusions: These findings imply that circulating platelet/CD34+ cell coaggregate levels are increased in ACS, especially in STEMI, which may be a novel mechanism of domiciliation of CD34+ progenitor cells to the injured microvasculature after acute myocardial infarction.

Background: Direct comparison of CT and magnetic resonance (MR) perfusion techniques has been limited and in vivo assessment is affected by physiological variability, timing of image acquisition, and parameter selection., Objective: We precisely compared high-resolution k-t SENSE MR cardiac perfusion at 3 T with single-phase CT perfusion (CTP) under identical imaging conditions., Methods: We used a customized MR imaging and CT compatible dynamic myocardial perfusion phantom to represent the human circulation. CT perfusion studies were performed with a Philips iCT (256 slice) CT, with isotropic resolution of 0.6 mm(3). MR perfusion was performed with k-t SENSE acceleration at 3 T and spatial resolution of 1.2 × 1.2 × 10 mm. The image contrast between normal and underperfused myocardial compartments was quantified at various perfusion and photon energy settings. Noise estimates were based on published clinical data., Results: Contrast by CTP highly depends on photon energy and also timing of imaging within the myocardial perfusion upslope. For an identical myocardial perfusion deficit, the native image contrast-to-noise ratio (CNR) generated by CT and MR are similar. If slice averaging is used, the CNR of a perfusion deficit is expected to be greater for CTP than MR perfusion (MRP). Perfect timing during single time point CTP imaging is difficult to achieve, and CNR by CT decreases by 24%-31% two seconds from the optimal imaging time point. Although single-phase CT perfusion offers higher spatial resolution, MRP allows multiple time point sampling and quantitative analysis., Conclusion: The ability of CTP and current optimal MRP techniques to detect simulated myocardial perfusion deficits is similar., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Late gadolinium enhancement (LGE) is widely used to precisely localize and determine the extent and transmurality of myocardial scarring. Performing LGE imaging at end-systole may reduce motion artefacts. It is therefore important to know whether end-systolic imaging influences infarct transmurality in patients with ischemic scar. 107 dysfunctional segments were studied in 20 consecutive patients with established coronary artery disease. Patient specific trigger delays were used to obtain end-diastolic and end-systolic LGE images (LGE(ed), LGE(es)). Wall thickness (WT(ed), WT(es)), thickness of the remaining viable rim (RIM(ed), RIM(es)) and end-diastolic scar thickness were measured manually. There was LGE in 84% of all dysfunctional segments with a mean scar of 3.4 ± 2.5 mm. Total wall thickness and the thickness of the remaining viable rim increased from diastole to systole (WT(ed) 7.8 ± 1.9 vs. WT(es) 8.4 ± 2.2; P < 0.001; RIM(ed) 4.4 ± 3.1 vs. RIM(es) 5 ± 3.4; P < 0.001). Transmurality of scar decreased from end-diastole to end-systole (LGE(ed) 46 ± 33% vs. LGE(es) 44 ± 33%; P < 0.001). This was most pronounced in a subgroup of segments (n = 15) with visual scar transmurality between 50 and 75% (LGE(ed) 75 ± 15% vs. LGE(es) 70 ± 16%; P < 0.001). The change in transmurality was inversely correlated with the change of the thickness of the remaining viable rim between diastole and systole (r = -0.7; P < 0.001). Scar transmurality was reduced by up to 12% in the individual patient. Scar transmurality changes due to thickening of the remaining viable rim. Whereas these differences might not impact on clinical decision-making in most patients, there will be an occasional misclassification if cut-off values are used (e.g. scar <50 or >50%) or if exact data is required for research studies.

Background: The purpose of the study was to test whether an elevated surface expression of platelet collagen receptor glycoprotein VI (GPVI) is an appropriate marker for the diagnosis of the acute coronary syndrome (ACS), especially when the electrocardiogram (ECG) is ambiguous., Methods: Between 2007 to 2008, we consecutively evaluated 378 patients with ACS and ambiguous ECG on hospital admission. In all patients, GPVI surface expression was determined by flow cytometry. In addition, the myocardial necrosis markers troponin-I (Tn-I) and creatine kinase-MB (CKMB) were measured., Results: We found that in patients with ACS and unclear ECG in whom GPVI levels (mean fluorescence intensity (MFI) ≥ 18.6) were elevated, the relative risk for ACS was 2.6-fold enhanced. Binary logistic regression analysis revealed that an elevated platelet GPVI level is indicating an ACS independent of biomarkers of myocardial necrosis including Tn-I, creatine kinase (CK), CKMB (GPVI: p=0.011; Tn-I: p=0.180; CKMB: p=0.250; CK: p=0.127). Patients with evident T-wave inversion and/or ST-depression showed a strong association between ACS and GPVI expression., Conclusions: Platelet GPVI surface expression is enhanced in patients with ACS with unclear ECG findings and is strongly associated with myocardial ischemia. Additional to the classical markers of myocardial necrosis Tn-I and CK, GPVI is an early biomarker for the diagnosis of ACS, especially when the ECG is ambiguous., (Copyright © 2009 Elsevier B.V. All rights reserved.)

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)

Thrombocytopenia, fever, and acute renal failure are characteristic features of nephropathia epidemica, the predominant hantavirus infection in Europe. However, clinical presentation and blood cell counts may point to other disorders, such as a hematologic disease, particularly when impairment of renal function is not evident. This differential diagnosis often results in further extensive and unnecessary testing. We describe 3 patients with hantavirus infection with no renal failure, in whom a hematologic disorder was initially suspected. Serologic testing of hantavirus finally unraveled the mystery, and outcome of the patients was excellent. It is conceivable that similar cases often remain undiagnosed. Thus, testing for hantavirus should always be considered in cases of thrombocytopenia and fever of unknown origin, especially in areas endemic for the infection.

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.

Growing evidence supports a major role of chronic inflammation and platelet activation in the development of atherosclerosis and cardiovascular (CV) disease. Because CV dysfunction is, at least in part, reversible, identifying these early stages may enhance the development of new therapeutic and preventive interventions. Technological advances have led to appreciation of underlying pathophysiology in vivo via targeted clinical readouts by soluble markers and noninvasive imaging. Integration of these readouts in early phases of development of novel drug candidates may provide a key addition to translational steps toward robust evidence. New paradigms of drug discovery may lead to earlier and more targeted interventions at reversible stage of disease., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To investigate the role of junctional adhesion molecule A (JAM-A) on adhesion and differentiation of human CD34(+) cells into endothelial progenitor cells., Methods and Results: Tissue healing and vascular regeneration is a multistep process requiring firm adhesion of circulating progenitor cells to the vascular wall and their further differentiation into endothelial cells. The role of JAM-A in platelet-mediated adhesion of progenitor cells was investigated by adhesion assays in vitro and with the help of intravital fluorescence microscopy in mice. Preincubation of human CD34(+) progenitor cells with soluble JAM-A-Fc (sJAM-A-Fc) resulted in significantly decreased adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Human CD34(+) cells express JAM-A, as defined by flow cytometry and Western blot analysis. JAM-A mediates differentiation of CD34(+) cells to endothelial progenitor cells and facilitates CD34(+) cell-induced reendothelialization in vitro. Pretreatment of human CD34(+) cells with sJAM-A-Fc resulted in increased neointima formation 3 weeks after endothelial denudation in the carotid arteries of nonobese diabetic/severe combined immunodeficient mice., Conclusions: These results indicate that the expression of JAM-A on CD34(+) cells mediates adhesion to the vascular wall after injury and differentiation into endothelial progenitor cells, a mechanism potentially involved in vascular regeneration. Human CD34(+) cells express JAM-A, mediating their interaction with platelets and endothelial cells. Specifically, JAM-A expressed on human CD34(+) progenitor cells regulates their adhesion over immobilized platelets or inflammatory endothelium under high shear stress in vitro and after carotid ligation in vivo or ischemia/reperfusion injury in the microcirculation of mice. Moreover, it mediates differentiation of CD34(+) cells to endothelial progenitor cells and facilitates reendothelialization.

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.

Platelets respond immediately to vascular injury by adhesion, aggregation, and thrombus formation. Disruption of the endothelial cell layer exposes extracellular matrix to the bloodstream. Collagen binding to platelet glycoprotein VI (GPVI) mediates the initial adhesion of the rolling platelet to the vascular wound. Signaling by GPVI leads to the onset of the platelet activation cascade that is finally crowned by a firm and shear-resistant integrin-based adhesive clot. Blockade of collagen binding to GPVI would prevent initial adhesion and further activation of the platelet and would have an enormous impact in antithrombotic therapy. Besides the therapeutical implication, radiolabeled GPVI gives us a valuable diagnostic means that may be used clinically for plaque imaging in the near future., (Thieme Medical Publishers.)

The chemokine stromal cell derived factor 1 (SDF-1) regulates chemotactic recruitment (homing) and differentiation of CD34 (+) stem cells. Platelets express substantial amounts of SDF-1 upon activation. The aim of the present study was to evaluate the role of SDF-1 in platelet-induced proliferation and differentiation of human CD34 (+) cells to macrophages and foam cells, as well as in regulation of matrix metalloproteinase (MMP)-9 secretion. Co-culture experiments of platelet thrombi (2 x 10(8)/mL) with human CD34 (+) progenitor cells resulted in platelet phagocytosis by the latter, causing their differentiation into CD68-positive macrophages and subsequent Sudan red III-positive foam cells. Platelet aggregates-induced foam cell generation and MMP-9 secretion were attenuated by a neutralizing monoclonal antibody against platelet-derived SDF-1, as evaluated by immunofluorescence microscopy and gelatin zymography. Co-culture experiments of human arterial endothelial cells and human CD34 (+) progenitor cells resulted in a fourfold increased proliferation of CD34 (+) cells in the presence of platelets being mainly regulated by platelet-derived SDF-1 in vitro. These findings imply that in the presence of platelet thrombi, CD34 (+) progenitor cells phagocytize platelets in an SDF-1 dependent manner, causing their differentiation into macrophages and then foam cells, a mechanism most likely contributing to atherogenesis and atheroprogression., (Thieme Medical Publishers.)

Platelets are involved in the initiation of atherosclerosis by adherence to inflamed endothelium. Monocytes bind to these platelets and transmigrate into the vessel wall, transforming into macrophages and foam cells. We have previously shown that lipid-laden platelets are phagocytosed by macrophages. In this study we investigated the functional consequences of oxidized low-density lipoprotein (oxLDL) uptake on platelet function and interaction with the endothelium. Human platelets were isolated from healthy donors and activated by adenosine diphosphate. Immunofluorescence microscopy and flow cytometry revealed that oxLDL is located intracellularly in vesicles. With mepacrine costaining and confocal microtomography, we were able to identify dense granules as the vesicles that contain oxLDL. OxLDL-laden platelets induced intercellular adhesion molecule 1 expression in endothelial cells more than exogenous native LDL, oxLDL, and oxLDL-negative platelets. Furthermore, oxLDL-laden platelets induced foam cell development from CD34(+) progenitor cells. On endothelial regeneration, oxLDL-laden platelets had the opposite effect: The number of CD34(+) progenitor cells (colony-forming units) able to transform into endothelial cells was significantly reduced in the presence of oxLDL-platelets, whereas native LDL had no effect. Our results demonstrate that activated platelets internalize oxLDL and that oxLDL-laden platelets activate endothelium, inhibit endothelial regeneration, and promote foam cell development. Platelet oxLDL contributes significantly to vascular inflammation and is able to promote atherosclerosis., (Thieme Medical Publishers.)

CD34 (+) progenitor cells are a promising source of regeneration in atherosclerosis or ischemic heart disease. However, as recently published, CD34(+) progenitor cells have the potential to differentiate not only into endothelial cells but also into foam cells upon interaction with platelets. The mechanism of platelet-induced differentiation of progenitor cells into foam cells is as yet unclear. In the present study we investigated the role of scavenger receptor (SR)-A and CD36 in platelet-induced foam cell formation. Human CD34(+) progenitor cells were freshly derived from human umbilical veins and were co-incubated with platelets (2 x 10(8)/mL) up to 14 days resulting in large lipid-laden foam cells. Developing macrophages expressed SR-A, CD36, and Lox-1 as measured by fluorescent-activated cell sorting analysis. The presence of a blocking anti-CD36 or anti-SR-A antibody nearly abrogated foam cell formation, whereas anti-Lox-1 did not affect foam cell formation. Consistently blocking either anti-CD36 or anti-SR-A antibody significantly reduced the phagocytosis of lipid-laden platelets by macrophages. We conclude that CD36 and SR-A play an important role in platelet-induced foam cell formation from CD34(+) progenitor cells and thus represent a promising target to inhibit platelet-induced foam cell formation., (Thieme Medical Publishers.)

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.)

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.

Objective: Cytokines have an important role in both the initiation and perpetuation of viral myocarditis. Because a causative therapy of myocarditis is not yet well established and immunomodulation is a promising approach, the influence of interleukin (IL)-15, a proinflammatory cytokine, on the course of experimental myocarditis in Coxsackievirus B3 (CVB3)-infected mice was examined., Methods: Hearts from CVB3-infected (n=14), sham-infected (n=14) and CVB3-infected BALB/c mice treated with IL-15 (n=6) or a competitive IL-15 fusion protein (n=6) were analyzed for hemodynamic function, cellular infiltrates and myocardial collagen content., Results: Induction of myocarditis was associated with significant loss of body and heart weight, decreased left ventricular function, and increased collagen content and cellular infiltrates in the myocardium. Treatment of infected animals with IL-15 resulted in normalization of body and heart weight, and significantly improved systolic and diastolic left ventricular function, comparable with that of uninfected animals. This was paralleled by a significant reduction of myocardial collagen content to levels observed in animals without disease and by markedly reduced cellular infiltration of lymphocytes and macrophages in the myocardium. Inhibition of intrinsic IL-15 with IL-15 fusion protein tended to aggravate the disease., Conclusions: Treatment with IL-15 has a positive effect on CVB3- induced murine myocarditis and seems to be a promising approach to modifying clinical course, hemodynamics and histopathology of virus-induced myocarditis. Further studies are needed to identify the underlying mechanisms.

Background: The platelet collagen receptor glycoprotein VI (GPVI) mediates platelet adhesion to subendothelial matrix and thrombus formation in acute coronary syndrome (ACS). This study examined patients with both ACS and stable coronary artery disease (CAD), which presented with atrial fibrillation (AF) and sinus rhythm (SR)., Methods and Results: We evaluated 992 patients with acute or stable CAD, and determined platelet surface expression of GPVI using flow cytometry. Seventy-eight patients presented with nonvalvular persistent AF. After 1:1 propensity score matching 156 matched cases with 78 pairs were obtained. Patients with AF and ACS showed a significantly decreased GPVI expression compared to patients with ACS and SR, whereas patients with stable angina pectoris (SA) presented with low level activation and no significant difference between SR and AF [mean fluorescence intensity (MFI) for ACS (SR Vs. AF): 20 +/- 6.3 Vs. 17.7 +/- 4.4; P = 0.023; SA (SR Vs. AF): 18.8 +/- 9.4 Vs. 18.1 +/- 6.1; P = 0.649]. In contrast, soluble GPVI was increased in ACS and AF accordingly [plasma GPVI (ng/ml) for ACS (SR Vs. AF): 1.4 +/- 0.8 Vs. 1.9 +/- 1.1; P = 0.038; SA (SR Vs. AF): 0.9 +/- 0.4 Vs. 1.1 +/- 0.5; P = 0.127]., Conclusion: Platelet GPVI surface expression is decreased in patients with AF and ACS compared to patients with SR and ACS. Nonvalvular AF is related to indices of chronic platelet activation and might be responsible for a down-regulation of GPVI receptor density on platelets, while soluble GPVI was increased in ACS and AF accordingly.

Aims: Previous experimental studies have suggested that platelet stromal-cell-derived factor-1 (SDF-1) regulates mobilization and recruitment of haematopoietic progenitor cells supporting revascularization in mice. However, there are no clinical data available regarding platelet-bound SDF-1 in patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the platelet-surface expression of SDF-1 in patients with ACS., Methods and Results: Patients with ACS (n = 418) showed a significantly enhanced SDF-1 expression on admission compared with those with stable angina pectoris (SAP, n = 486) [SAP (mean fluorescence intensity (MFI) +/- SD): 13.48 +/- 5.27; ACS: 18.45 +/- 12.85; P < 0.001) independent of cardiovascular risk factors and medication. Enhanced platelet-bound SDF-1 expression was found in patients with reduced left ventricular ejection fraction (LVEF <55%) in comparison to patients with normal LVEF (P = 0.005). Platelet-bound SDF-1 expression positively correlated with the degree of platelet activation [CD62P: r = 0.325; glycoprotein VI (GPVI): r = 0.277; PAC-1: r = 0.501; P < 0.001 for all] and showed a significant, but slight association with plasma levels of SDF-1 (r = 0.084; P = 0.045). In a subgroup of patients with coronary artery disease, platelet-bound SDF-1, but not other platelet activation markers, significantly correlated with the number of circulating CD34(+) progenitor cells (r = 0.252; P = 0.002) or CD34(+)/CD133(+) endothelial progenitor cells (r = 0.352; P = 0.008)., Conclusion: Platelet-bound SDF-1 may play an important role in peripheral homing of circulating progenitor cells thus in tissue regeneration.

Background: Platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in acute coronary thrombosis. This prospective study examined the predictive value of GPVI for acute coronary syndromes (ACS) in a large consecutive group of patients with symptomatic coronary artery disease to identify the high-risk cohort with imminent coronary events., Methods: We evaluated 1,003 patients with symptomatic coronary artery disease, verified by coronary angiography, and determined the surface expression of GPVI using flow cytometry. In a subgroup of 471 patients, who were treated with aspirin plus clopidogrel for coronary stenting, adenosine disphosphate (20 micromol/L)-induced platelet aggregation was evaluated., Results: Patients with ACS (n = 485) showed a significantly enhanced GPVI expression compared to patients with stable angina pectoris (SAP; n = 518) (mean fluorescence intensity for ACS 19.8 +/- 5.9; SAP 18.7 +/- 8.5, P = .01). Patients with elevated GPVI levels on admission (GPVI cutoff value > or =18.6 mean fluorescence intensity) had a 1.4-fold relative risk for ACS. Logistic regression analysis showed that an elevated platelet GPVI level may indicate ACS independent of biomarkers of myocardial necrosis including troponin, creatine kinase, and creatine kinase-MB. Patients with increased platelet activation (GPVI expression level > or =18.6) showed significant enhanced residual platelet aggregation despite dual antiplatelet therapy compared to patients with low GPVI levels (P = .028)., Conclusions: Surface expression of GPVI is enhanced in patients with ACS and indicates an imminent acute coronary event before irreversible myocardial necrosis is evident. High GPVI levels are associated with increased residual platelet aggregation despite antiplatelet therapy. Therefore, GPVI is useful to identify the subgroup of patients with a high risk for coronary stent thrombosis and thromboischemic events.

Aims: There are growing data suggesting a clinical relevance of residual platelet aggregation (RPA) in patients undergoing PCI. Drug-drug interaction of statins and clopidogrel has been controversially discussed in ex vivo studies and clinical trials. The aim of the present study was to investigate the effects of peri-procedural statin medication on the metabolization of aspirin and clopidogrel with regard to platelet aggregation and clinical outcome in patients undergoing coronary intervention., Methods and Results: Patients with coronary stenting for symptomatic coronary artery disease are routinely evaluated by platelet function analysis in a monocentre registry, and for the present study, a consecutive cohort of 1155 patients were analysed. About 87.7% of the patients were treated with statins at the time of platelet function analysis. Residual platelet activity assessed by adenosine diphosphate (20 micromol/L)-induced platelet aggregation was not significantly influenced by statin treatment. Nor the significant effects of CYP3A4-metabolization pathway on post-treatment aggregation were recorded, although there was even a trend to lower RPA values in patients treated with CYP3A4-metabolized statins. Further, in an inter-individual analysis comparing patients treated with CYP3A4- and non-CYP3A4-metabolized statins, no time-dependent difference of clopidogreĺs anti-aggregatory effects was observed. Clinical follow-up of major adverse events (myocardial infarction, ischaemic stroke, death) in 991 patients within 3 months revealed no significant adverse effects of statin treatment on clinical outcome. Instead, statin treatment was independently associated with lower incidence of composite events (HR 0.44, 95% confidence interval 0.23-0.83, P = 0.01)., Conclusion: Peri-procedural co-administration of statins does not increase the post-interventional RPA in cardiovascular patients treated with dual antiplatelet therapy and does not worsen the clinical prognosis of these patients.

Background: Peripheral homing of progenitor cells in areas of diseased organs is critical for tissue regeneration. The chemokine stromal cell-derived factor-1 (SDF-1) regulates homing of CD34+ stem cells. We evaluated the role of platelet-derived SDF-1 in adhesion and differentiation of human CD34+ cells into endothelial progenitor cells., Methods and Results: Adherent platelets express substantial amounts of SDF-1 and recruit CD34+ cells in vitro and in vivo. A monoclonal antibody to SDF-1 or to its counterreceptor, CXCR4, inhibits stem cell adhesion on adherent platelets under high arterial shear in vitro and after carotid ligation in mice, as determined by intravital fluorescence microscopy. Platelets that adhere to human arterial endothelial cells enhance the adhesion of CD34+ cells on endothelium under flow conditions, a process that is inhibited by anti-SDF-1. During intestinal ischemia/reperfusion in mice, anti-SDF-1 and anti-CXCR4, but not isotype control antibodies, abolish the recruitment of CD34+ cells in microcirculation. Moreover, platelet-derived SDF-1 binding to CXCR4 receptor promotes platelet-induced differentiation of CD34+ cells into endothelial progenitor cells, as verified by colony-forming assays in vitro., Conclusions: These findings imply that platelet-derived SDF-1 regulates adhesion of stem cells in vitro and in vivo and promotes differentiation of CD34+ cells to endothelial progenitor cells. Because tissue regeneration depends on recruitment of progenitor cells to peripheral vasculature and their subsequent differentiation, platelet-derived SDF-1 may contribute to vascular and myocardial regeneration.