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Abstract Objectives This study sought to investigate the potential of the noninvasive albumin-binding probe gadofosveset-enhanced cardiac magnetic resonance (GE-CMR) for detection of coronary plaques that can cause acute coronary syndromes (ACS). Background ACS are frequently caused by rupture or erosion of coronary plaques that initially do not cause hemodynamically significant stenosis and are therefore not detected by invasive x-ray coronary angiography (XCA). Methods A total of 25 patients with ACS or symptoms of stable coronary artery disease underwent GE-CMR, clinically indicated XCA, and optical coherence tomography (OCT) within 24 h. GE-CMR was performed approximately 24 h following a 1-time application of gadofosveset-trisodium. Contrast-to-noise ratio (CNR) was quantified within coronary segments in comparison with blood signal. Results A total of 207 coronary segments were analyzed on GE-CMR. Segments containing a culprit lesion in ACS patients (n = 11) showed significant higher signal enhancement (CNR) following gadofosveset-trisodium application than segments without culprit lesions (n = 196; 6.1 [3.9 to 16.5] vs. 2.1 [0.5 to 3.5]; p < 0.001). GE-CMR was able to correctly identify culprit coronary lesions in 9 of 11 segments (sensitivity 82%) and correctly excluded culprit coronary lesions in 162 of 195 segments (specificity 83%). Additionally, segmented areas of thin-cap fibroatheroma (n = 22) as seen on OCT demonstrated significantly higher CNR than segments without coronary plaque or segments containing early atherosclerotic lesions (n = 185; 9.2 [3.3 to 13.7] vs. 2.1 [0.5 to 3.4]; p = 0.001). Conclusions In this study, we demonstrated for the first time the noninvasive detection of culprit coronary lesions and thin-cap fibroatheroma of the coronary arteries in vivo by using GE-CMR. This method may represent a novel approach for noninvasive cardiovascular risk prediction. Graphical abstract [ABSTRACT FROM AUTHOR]

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 1800s (NanoPET/CT scanner; Mediso, Hungary & Bioscan, USA) was carried out 24h after intravenous tail vein administration of 50µl 64Cu-CD68-Fc (~20-30µg labeled protein/mouse containing approximately 10-12MBq 64Cu-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 (23mm). Enhanced 64Cu-CD68-Fc uptake was found in the aortic arches of ApoE-/- compared to WT mice (ApoE-/- mice:10.5±1.5Bq/cm³ vs. WT mice: 2.1±0.3Bq/cm³; 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 R¹ maps (R¹=1.47±0.06 s-1 vs. 0.92±0.05 s-1; P <0.001). Radiolabeled scavenger receptor (64Cu-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. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to test the hypothesis that transmural perfusion gradients (TPG) on adenosine stress myocardial perfusion cardiac magnetic resonance (CMR) predict hemodynamically significant coronary artery disease (CAD) as defined by fractional flow reserve (FFR). Background: Myocardial ischemia affects the subendocardial layers of the left ventricular myocardium earlier and more severely than the outer layers, and the identification of TPG should be sensitive and specific for the diagnosis of CAD. Previous studies have shown that high spatial resolution myocardial perfusion CMR allows quantitation of TPG between the subendocardium and the subepicardium. Methods: Sixty-seven patients (53 men, age 61 ± 9 years) underwent coronary angiography and high-resolution (1.2 × 1.2-mm in-plane) adenosine stress perfusion CMR at 3.0-T. TPG was calculated for 3 coronary territories. Visual analysis was performed to identify myocardial ischemia. FFR was measured in all vessels with ≥50% severity stenosis. FFR <0.8 was considered hemodynamically significant. In a training group of 30 patients, the optimal threshold of TPG to detect significant CAD was determined (Group 1). This threshold was then tested prospectively in the remaining 37 patients (Group 2). Results: In Group 1, a 20% TPG provided the best diagnostic threshold on both per-segment and per-patient analysis. Applied to Group 2, this threshold yielded a sensitivity of 0.78, specificity of 0.94, and area under the curve of 0.86 for the detection of CAD in a per-segment analysis and of 0.89, 0.83, and 0.86 in a per-patient analysis, respectively. TPG had a similar diagnostic accuracy to visual assessment. Linear regression analysis showed a relationship between TPG and FFR values, with r = 0.63 (p < 0.001). Conclusions: The quantitative analysis of transmural perfusion gradients on high-resolution myocardial perfusion CMR accurately predicts hemodynamically significant CAD as defined by FFR. A TPG diagnostic threshold of 20% is as accurate as visual assessment. [Copyright &y& Elsevier]

Abstract: 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 mm3. 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

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 μmol/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 ≥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 ≥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. [Copyright &y& Elsevier]

Abstract: Purpose: To assess endothelial injury and repair using fluorescence-labeled glycoprotein VI (GPVI)-Fc in a murine model. Materials and methods: Three 4-week-old male ApoE-deficient (ApoE−/−)-mice were fed with a 1.25% cholesterol diet over 16 weeks and compared to three wild type (WT) C57BL/6J-mice in a wire-induced vascular injury model. Another group of WT mice (n =10) were mechanically injured by carotid ligation. Fluorescence-labeled GPVI-Fc (150μg/mouse) was administered and assessed by optical imaging 24h after injury and compared to another group (n =3) which was injected two days after injury and sacrificed another day later. Results: After denudation, all injured carotids of WT mice showed a higher mean fluorescence signal than the corresponding intact carotids of the same animals (48.4±18.9 vs. 10.4±1.0; P =0.028). Injection of unlabeled GPVI-Fc 20h and 3h before injecting GPVI-Fc-FITC significantly reduced the fluorescence signal in injured carotids to 14.6±4.6, while intact carotids showed a signal of 9.2±1.1; P =0.046. Ligation injury resulted with an increased GPVI-Fc-binding to injured carotids compared to intact carotids (31.53±6.18 vs. 16.48±5.15; P =0.039). Three days after injury and 24h after GPVI-Fc-FITC injection, differences between intact and injured carotids have vanished (12.51±2.76 vs. 14.76±1.59; P =0.519). Conclusions: A GPVI-based plaque imaging system could help to identify vascular lesions and to take a precautionary measure as necessary. [Copyright &y& Elsevier]

Abstract: Background: Platelet glycoprotein VI (GPVI) is elevated in patients with acute coronary syndrome (ACS), stroke and associated with acute coronary events. GPVI may be helpful to distinguish an imminent ACS from non-coronary (NC) causes in patients with chest pain who were transferred to chest pain unit, before the myocardial necrosis is evident with classical biomarkers. Methods: Based on the findings of our previous studies, we consecutively examined 1004 patients with chest pain in a prospective study design. ACS was found in 416 (41.4%), stable angina pectoris (SAP) in 233 (23.2%), and NC causes of chest pain (hypertension, musculoskeletal disease, pulmonary embolism, myocarditis, cardiophobia) in 355 patients (35.4%). Platelet surface expression of GPVI was measured by flow cytometry. Results: Patients with ACS showed significantly enhanced GPVI expression levels compared to patients with SAP or NC causes of chest pain (ACSvs.SAP(mean fluorescence intensity (MFI)±SD):18.9±7.4vs.17.9±9.5;P=0.028;ACSvs.NC:15.4±6.9;P=0.002). Elevated GPVI expression was associated with ACS independent of markers of myocardial necrosis like troponin and creatine kinase-MB. Patients with an elevated GPVI expression (MFI≥18.6) had a poorer clinical outcome than patients with baseline GPVI expression in regard to composite cumulative survival that included myocardial infarction, stroke, and cardiovascular death at three months (Log rank;P=0.025). Discussion: Platelet GPVI surface expression is enhanced in patients at risk for an ACS and is an early marker for imminent acute coronary events in patients with chest pain. [Copyright &y& Elsevier]

Abstract: Background: During inflammatory cardiomyopathy matrix metalloproteinases are crucially involved in cardiac remodeling. The aim of the present study was to investigate whether the “extracellular matrix metalloproteinase inducer” EMMPRIN (CD147) and its ligand Cyclophilin A (CyPA) are upregulated in inflammatory cardiomyopathy and may serve as diagnostic markers. Therefore, a series of 102 human endomyocardial biopsies were analyzed for the expression of EMMPRIN and CyPA and correlated with histological and immunohistological findings. Methods and results: Endomyocardial biopsies were stained for EMMPRIN and CyPA in addition to standard histology (HE, Trichrom) and immunohistological stainings (MHC-II, CD68, CD3). 39 (38.2%) biopsies met the immunohistological criteria of an inflammatory cardiomyopathy. EMMPRIN, which was predominantly expressed on cardiomyocytes, was slightly (but significantly) upregulated in non inflammatory cardiomyopathies compared to normal histopathological findings and highly upregulated in inflammatory cardiomyopathy compared to both non inflammatory cardiomyopathy and normal histopathology. In contrast, CyPA reveals no enhanced expression in non inflammatory cardiomyopathies and a highly enhanced expression in inflammatory cardiomyopathy, where it is closely associated with leucocytes infiltrates. We found a strong correlation between both EMMPRIN and CyPA with the expression of MHC-II molecules (correlation coefficient 0.475 and 0.527, p<0.05). Moreover, we found a correlation for both EMMPRIN and CyPA with CD68 (correlation coefficient 0.393 and 0.387, p<0.05) and CD3 (correlation coefficient 0.360 and 0.235, p<0.05). Conclusion: EMMPRIN is enhanced in both inflammatory and non inflammatory cardiomyopathies and can serve as a marker of myocardial remodeling. CyPA may represent a novel and specific marker for cardiac inflammation. [Copyright &y& Elsevier]

Sex-specific outcome data following myocardial infarction (MI) are inconclusive with some evidence suggesting association of female sex and increased major adverse cardiac events (MACE). Since mechanistic principles remain elusive, we aimed to quantify the underlying phenotype using cardiovascular magnetic resonance (CMR) quantitative deformation imaging and tissue characterisation. In total, 795 ST-elevation MI patients underwent post-interventional CMR imaging. Feature-tracking (CMR-FT) was performed in a blinded core-laboratory. Left ventricular function was quantified using ejection fraction (LVEF) and global longitudinal/circumferential/radial strains (GLS/GCS/GRS). Left atrial function was assessed by reservoir (εs), conduit (εe) and booster-pump strains (εa). Tissue characterisation included infarct size, microvascular obstruction and area at risk. Primary endpoint was the occurrence of MACE within 1 year. Female sex was associated with increased MACE (HR 1.96, 95% CI 1.13–3.42, p = 0.017) but not independently of baseline confounders (p = 0.526) with women being older, more often diabetic and hypertensive (p < 0.001) and of higher Killip-class (p = 0.010). Tissue characterisation was similar between sexes. Women showed impaired atrial (εs p = 0.011, εe p < 0.001) but increased systolic ventricular mechanics (GLS p = 0.001, LVEF p = 0.048). While atrial and ventricular function predicted MACE in men only LV GLS and GCS were associated with MACE in women irrespective of confounders (GLS p = 0.036, GCS p = 0.04). In men ventricular systolic contractility is impaired and volume assessments precisely stratify elevated risks. In contrast, women experience reduced atrial but increased ventricular systolic strain. This may reflect ventricular diastolic failure with systolic compensation, which is independently associated with MACE adding incremental value to sex-specific prognosis evaluation. • Atrial function is reduced in women after AMI, while ventricular systolic function is increased. • In women, ventricular systolic compensation is independently associated with MACE. • In women, deformation assessments but not volumetric analyses identify elevated risks. [ABSTRACT FROM AUTHOR]

Background Identification of new risk markers in aortic valve stenosis (AS) is of great interest. Here, we hypothesized that the presence of severe autonomic failure (SAF) is an important prognostic marker in both, symptomatic patients undergoing invasive treatment for severe AS, and in asymptomatic patients with severe AS who were primarily treated conservatively. Methods We prospectively enrolled 300 patients with severe AS (aortic valve area < 1.0 cm² or mean aortic gradient > 40 mm Hg) in sinus rhythm. All patients underwent a 24-h Holter recording for assessment of heart rate turbulence (HRT) and deceleration capacity (DC). Patients with both, abnormal DC and HRT were considered to suffer from SAF. Results The first hypothesis was tested in 216 symptomatic patients who underwent successful aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI). During follow-up of 2 years, 29 of these patients died. SAF was the strongest independent predictor of mortality (hazard ratio 5.6, 95% confidence interval 2.6-12.0; p < 0.001) with 2-year mortality rates of 50.0% and 10.7% in SAF-positive and SAF-negative patients, respectively (p < 0.001). The second hypothesis was tested in 71 patients, who were asymptomatic at study entry and for whom a primarily conservative treatment strategy was proposed. During follow-up, 10 of these patients died. SAF also predicted death in asymptomatic patients with 2-year mortality rates of 52.4% and 8.7% in SAF-positive and SAF-negative patients, respectively (p = 0.010). Conclusions SAF is a strong and independent predictor of mortality in symptomatic and asymptomatic patients with severe AS. [ABSTRACT FROM AUTHOR]

Background Cardiac inflammation has been suggested to play a critical role in the pathogenesis of inflammatory cardiomyopathy as well as in progressive heart failure (HF). CXC motif ligand 16 (CXCL16) is a recently discovered chemokine produced by several inflammatory cells and representing an important pathogenic mediator in the development of HF. The present study evaluates the diagnostic and prognostic relevance of CXCL16 expression in endomyocardial biopsies of consecutive patients with congestive HF. Methods and results 174 patients (age 54.4 ± 14.6 years) with congestive HF undergoing endomyocardial biopsy for diagnostic reasons were prospectively enrolled. Biopsies were analyzed using established histopathological and immunohistological criteria together with CXCL16 staining. CXCL16 was significantly enhanced in patients with inflammatory cardiomyopathy (78/127, 61.4%) as compared to patients with non-inflammatory cardiomyopathy (17/47, 36.2%, p = 0.003). During a mean follow-up of 27.5 months, 20 patients (11.5%) reached the primary endpoint (death of all causes). Of all clinical (age, gender, NYHA functional class, systolic pulmonary artery pressure, left ventricular ejection fraction), laboratory (brain natriuretic peptide) and immunohistological (CXCL16) parameters tested, CXCL16 was the only independent predictor of death (hazard ratio 5.4; 95% confidence interval 1.2 to 24.0; p = 0.027). Subgroup analysis revealed CXCL16 as a predictor of death in both patients with inflammatory and with non-inflammatory cardiomyopathy. Conclusion According to the present observations CXCL16 is enhanced in inflammatory cardiomyopathy and turned out as an independent predictor of death in patients with HF undergoing endomyocardial biopsy. [ABSTRACT FROM AUTHOR]

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) >25kg/m2, and had evidence of metabolic syndrome. The primary endpoint was change in body weight and BMI at 6months follow-up. Secondary endpoints included blood pressure, heart rate, intima media thickness, lipids, fasting glucose, glycated hemoglobin, fibrinogen, C-reactive protein (CRP) at 6months follow-up and change in body weight and BMI at 12months. Results: Both groups of patients showed significantly reduced body weight and BMI compared to baseline (6months, usual care weight change: −3.2±3.0kg; BMI change: −1.1±1.0kg/m2; Tibetan diet weight change: −6.2±4.4kg/m2; BMI change: −2.1±1.5kg/m2), 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 12months 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±47.8mg/dL; p=0.024; LDL: 111.6±37.8 vs. 119.4±40.9mg/dL; p=0.026; fibrinogen: 318.3±90.4 vs. 334.1±87.9mg/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 6months significantly better than Western diet and may induce lipid-modifying and anti-inflammatory effects (ClinicalTrials.gov identifier: NCT00810992). [ABSTRACT FROM AUTHOR]

Abstract: Background: Low dose dobutamine stress magnetic resonance imaging is valuable to assess viability in patients with ischemic cardiomyopathy. Analysis is usually qualitative with considerable operator dependency. The aim of the current study was to investigate the feasibility of cine images derived quantitative cardiac magnetic resonance (CMR) myocardial feature tracking (FT) strain parameters to assess viability in patients with ischemic cardiomyopathy. Methods: 15 consecutive patients with ischemic cardiomyopathy referred for viability assessment were studied at 3T at rest and during low dose dobutamine stress (5 and 10μg/kg/min of dobutamine). Subendocardial and subepicardial circumferential (Eccendo and Eccepi) and radial (Err) strains were assessed using steady state free precession (SSFP) cine images orientated in 3 short axis slices covering 16 myocardial segments. Results: Dysfunctional segments without scar (n=75) improved in all three strain parameters: Eccendo (Rest: −10.5±6.9; 5μg: −12.1±6.9; 10μg: −14.1±9.2; p<0.05), Eccepi (Rest: −7±4.8; 5μg: −8.2±5.5; 10μg: −9.1±5.9; p<0.05) and Err (Rest: 11.7±8.3; 5μg: 16±10.9; 10μg: 16.5±12.8; p<0.05). There was no response to dobutamine in dysfunctional segments with scar transmurality above 75% (n=6): Eccendo (Rest: −4.7±3.0; 5μg: −2.9±2.5; 10μg: −6.6±3.3; p=ns), Eccepi (Rest: −2.9±2.9; 5μg: −5.4±3.9; 10μg: −4.5±4.2; p=ns) and Err (Rest:9.5±5; 5μg:5.4±6.2; 10μg:4.9±3.3; p=ns). Circumferential strain (Eccendo, Eccepi) improved in all segments up to a transmurality of 75% (n=60; p<0.05). Err improved in segments <50% transmurality (n=45; p<0.05) and remained unchanged above 50% transmurality (n=21; p=ns). Conclusions: CMR-FT is a novel technique, which detects quantitative wall motion derived from SSFP cine imaging at rest and with low dose dobutamine stress. CMR-FT holds promise of quantitative assessment of viability in patients with ischemic cardiomyopathy. [Copyright &y& Elsevier]

Abstract: Background: Acute coronary syndrome (ACS) along with myocardial ischemic injury are the leading causes for chest pain. Platelet surface expression of stromal-cell-derived factor-1 (SDF-1) is enhanced during ischemic events and may play an important role in trafficking hematopoietic progenitor cells for tissue regeneration and neovascularization. This study examined the platelet surface expression of SDF-1 in patients with chest pain. Methods: We consecutively evaluated 1000 patients, who were admitted to the emergency department with chest pain. Platelet surface expression of GPIb and SDF-1 was determined by two-color whole blood flow cytometry. Results: Patients with ACS showed significantly enhanced SDF-1 expression on admission compared to patients with other causes such as stable angina pectoris (SAP) and other origin of chest pain (CPO) (ACS vs. SAP/CPO (mean fluorescence intensity (MFI)±SD): 39.7±26.3 vs. SAP: 37.6±31.5;P=0.045; arterial hypertension: 27.3±12.7;P=0.003; orthopedic disease: 22.1±6.5;P=0.014; pulmonary embolism: 26.6±19.1;P=0.003; Da Costa''s syndrome: 22.1±12.5;P=0.021; inflammatory cardiomyopathy: 19.8±11.5;P=0.025). Logistic regression analysis showed that surface expression of platelet SDF-1 was significantly associated with ACS (P=0.026), however, the superiority of troponin-I in predicting ACS remains on a high level (P=0.001). Areas under the curve of receiver operating characteristic analysis revealed 0.718 (95% confidence interval (CI):0.680-0.757) using SDF-1, and 0.795 (95%CI:0.760-0.829) applying troponin-I baseline serum levels. Patients with enhanced SDF-1 levels (cutoff:MFI≥27.7) had a 1.4-fold relative risk (95%CI:1.17-1.52) for ACS. Conclusions: Platelet SDF-1 surface expression was significantly enhanced in patients with ACS compared to SAP or CPO. Determination of platelet SDF-1 may be useful as an early additional biomarker for cardiovascular risk stratification. [Copyright &y& Elsevier]

Abstract: Background: Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a promising novel method for quantification of myocardial wall mechanics from standard steady-state free precession (SSFP) images. We sought to determine whether magnetic field strength affects the intra-observer reproducibility of CMR-FT strain analysis. Methods: We studied 2 groups, each consisting of 10 healthy subjects, at 1.5T or 3T Analysis was performed at baseline and after 4 weeks using dedicated CMR-FT prototype software (Tomtec, Germany) to analyze standard SSFP cine images. Right ventricular (RV) and left ventricular (LV) longitudinal strain (EllRV and EllLV) and LV long-axis radial strain (ErrLAX) were derived from the 4-chamber cine, and LV short-axis circumferential and radial strains (EccSAX, ErrSAX) from the short-axis orientation. Strain parameters were assessed together with LV ejection fraction (EF) and volumes. Intra-observer reproducibility was determined by comparing the first and the second analysis in both groups. Results: In all volunteers resting strain parameters were successfully derived from the SSFP images. There was no difference in strain parameters, volumes and EF between field strengths (p >0.05). In general EccSAX was the most reproducible strain parameter as determined by the coefficient of variation (CV) at 1.5T (CV 13.3% and 46% global and segmental respectively) and 3T (CV 17.2% and 31.1% global and segmental respectively). The least reproducible parameter was EllRV (CV 1.5T 28.7% and 53.2%; 3T 43.5% and 63.3% global and segmental respectively). Conclusions: CMR-FT results are similar with reasonable intra-observer reproducibility in different groups of volunteers at 1.5T and 3T. CMR-FT is a promising novel technique and our data indicate that results might be transferable between field strengths. However there is a considerable amount of segmental variability indicating that further refinements are needed before CMR-FT can be fully established in clinical routine for quantitative assessment of wall mechanics and strain. [Copyright &y& Elsevier]

Abstract: 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 21.6pmol/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 &y& Elsevier]

Objectives: The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease. Background: The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders. Methods: In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale). Results: PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05). Conclusions: PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events. [Copyright &y& Elsevier]

Abstract: 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 &y& Elsevier]

Abstract: 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 &y& Elsevier]

Abstract: Upon coincubation with platelets, CD34+ progenitor cells have the potential to differentiate into foam cells, and thereby may promote the progression of atherosclerosis. The exact mechanism of MMP-regulation during the cellular differentiation process to foam cells is still unclear. Thus, we investigated the role of EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) during foam cell formation originating from both monocytes/macrophages and CD34+ progenitor cells. Methods and results: Differentiation of CD34+ progenitor to foam cells was analyzed in a coculture model of progenitor cells and platelets. While CD34+ cells did not express EMMPRIN or MT1-MMP, mature foam cells strongly expressed EMMPRIN, which was associated with MT1-MMP expression as well as MMP-9. Gene silencing of EMMPRIN by siRNA during the cell differentiation process hindered not only the upregulation of MMPs (MT1-MMP, MMP-9), but also the secretion of the cytokine M-CSF. During the differentiation process CyPA was substantially released into the supernatant. The presence of the CyPA inhibitor NIM811 significantly reduced MMP-9 secretion during the differentiation process. Similar results were obtained using the classical pathway of foam cell formation by coincubating human macrophages with AcLDL. Additionally, the presence of soluble EMMPRIN ligands (CyPA, recombinant EMMPRIN) further enhanced MMP-9 secretion by mature foam cells. Consistently, CyPA and EMMPRIN were found in atherosclerotic plaques of ApoE-deficient mice by immunohistochemistry. Conclusion: EMMPRIN is upregulated during the differentiation process from CD34+ progenitor cells to foam cells, whereas its ligand, CyPA, is released. The CyPA/EMMPRIN activation pathway may play a relevant role in promoting the vulnerability of atherosclerotic plaques. [Copyright &y& Elsevier]

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]