[Long-term outcome after dialysis-dependent renal failure on the intensive care unit]. / Langzeitergebnis nach akutem dialysepflichtigem Nierenversagen auf einer internistischen Intensivstation.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of acute life-threatening diseases. OBJECTIVES: The aim of this study was to investigate the effect of acute renal failure on mortality in intensive care patients, the need for renal replacement therapy at discharge, and the effect on long-term mortality. MATERIAL AND METHODS: Evaluation of 118 patient cases with dialysis-dependent acute renal failure between November 2016 and December 2017 admitted to a medical intensive care unit (ICU) at the University Hospital Tübingen, Germany. Dialysis at discharge and 1­year mortality were defined as the primary endpoints. The secondary endpoint was need for continuous renal replacement after 18 months. RESULTS: In 118 patients, renal replacement modality by means of hemodialysis became necessary. A mortality rate of 45.8% (54/118) was found in patients requiring dialysis. Of the 64 surviving dialysis-dependent patients, 35.9% were still dependent on renal replacement therapy at the time of discharge. The 1­year mortality rate was significantly higher in patients that still required dialysis at the time of discharge (p = 0.004). At 18-month follow-up, seven patients (10.9%) were still on renal replacement therapy. At this time, dialysis was significantly more frequent in patients with dialysis at the time of discharge than in dialysis-free patients (7.1% vs. 71.4%, p = 0.001). CONCLUSION: Severe episodes of AKI requiring renal replacement therapy in the setting of an ICU are associated with increased mortality 1 year after discharge and an increased requirement for renal replacement 18 months after discharge.

[Fatigue, breathlessness and chest pain in a 31-year-old man with schizoaffective disorder]. / Müdigkeit, Kurzatmigkeit und Brustschmerz bei einem 31-jährigen Mann mit schizoaffektiver Störung.

BACKGROUND: Clozapine is an alternative antipsychotic medication used to control symptoms of schizophrenia and to reduce risks of suicidal behavior in patients who did not adequately respond to standard medication. Due to severe side effects including cardiomyopathy and myocarditis its clinical use is limited. CASE REPORT: A 31-year-old man of east European descent presented to the emergency medical department with fatigue, shortness of breath and chest pain. Due to a schizoaffective disorder he was treated with clozapine and lithium. Echocardiography revealed severely impaired left ventricular systolic function. After exclusion of coronary artery disease by coronary angiography an endomyocardial biopsy was performed according to the guidelines. This confirmed the clinically suspected toxic cardiomyopathy. Therefore, antipsychotic treatment was immediately changed and state of the art heart failure medication was started resulting in a clear improvement of left ventricular function. CONCLUSION: In patients treated with clozapine or lithium and clinical signs of heart failure, toxic cardiomyopathy should be considered.

Heart rate variability for rapid risk stratification of emergency patients with malignant disease.

INTRODUCTION: Neoplasms are the second most common diseases in western countries. Many patients with malignant diseases repeatedly present themselves in the emergency department (ED). Due to limited capacities, appropriate risk stratification strategies for cancer patients have to be developed. This study assesses if deceleration capacity (DC) of heart rate as a parameter of heart rate variability predicts mortality in emergency patients with malignant diseases. METHODS: Prospectively, 140 adults with different entities of malignant diseases who presented in the medical ED were included. Primary and secondary endpoints were intrahospital mortality and mortality within 180 days, respectively. We calculated DC from short-term ECG readings of the surveillance monitors. Additionally, the Modified Early Warning Score (MEWS) and laboratory parameters such as white blood cells (WBC), lactate dehydrogenase, serum hemoglobin, and serum creatinine were determined. RESULTS: The median age of the patients was 65 ± 14 years. 19.3% of the patients died within the hospital stay and 57.9% died within 180 days. DC and WBC were independent predictors of intrahospital death reaching a hazard ratio (HR) of 0.79 (95% confidence interval (CI) 0.63-0.993, p = 0.043) and of 1.00 (95% CI 1.00-1.00, p = 0.003), respectively. DC and serum creatinine independently predicted death within 180 days (HR 0.90, 95% CI 0.82-0.98, p = 0.023 and HR 1.41, 95% CI 1.05-1.90, p = 0.018, respectively). CONCLUSION: Deceleration capacity of heart rate is suitable for rapid risk assessment of emergency patients with malignant diseases.

Point-of-care testing of cardiac autonomic function for risk assessment in patients with suspected acute coronary syndromes.

BACKGROUND: Impaired cardiac autonomic function has been linked to adverse outcomes in patients with acute coronary syndromes (ACS) but is not included in clinical risk models. This is the first study to investigate whether point-of-care testing of cardiac autonomic function by means of short-term deceleration capacity (DC) of heart rate improves risk assessment in patients with suspected ACS. METHODS: 1821 patients with suspected ACS were prospectively enrolled if they were older than 17 years and in sinus rhythm. Short-term DC was automatically assessed from monitor recordings at hospital admission. The Global Registry of Acute Coronary Events (GRACE) score was used as gold standard risk predictor. Primary endpoint was the composite of intrahospital and 30-day mortality. Secondary endpoint was 180-day mortality. RESULTS: Of the 1,821 patients with suspected ACS, 28 (1.5%) and 60 (3.3%) reached the primary and secondary endpoints, respectively. DC was a highly significant predictor of both endpoints, yielding areas under the curve (AUC) of 0.784 (95% CI 0.714-0.854) and 0.781 (0.727-0.832) (p < 0.001 for both), respectively. Implementing DC into the GRACE-risk model leads to a significant increase of the C-statistics from 0.788 (0.703-0.874) to 0.825 (0.750-0.900; p < 0.01 for difference) and from 0.814 (0.759-0.864) to 0.851 (0.808-0.889; p < 0.01 for difference) for the primary and secondary endpoints, respectively. Stratification by dichotomized DC was especially powerful in patients with GRACE score <140. CONCLUSIONS: In patients with suspected ACS, point-of-care testing of cardiac autonomic function by means of DC is feasible and improves risk assessment by the GRACE score. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01486589.

Insertable cardiac monitors after cryptogenic stroke--a risk factor based approach to enhance the detection rate for paroxysmal atrial fibrillation.

BACKGROUND AND PURPOSE: Recently, the CRYSTAL AF trial detected paroxysmal atrial fibrillation (AF) in 12.4% of patients after cryptogenic ischaemic stroke (IS) or cryptogenic transient ischaemic attack (TIA) by an insertable cardiac monitor (ICM) within 1 year of monitoring. Our aim was (i) to assess if an AF risk factor based pre-selection of ICM candidates would enhance the rate of AF detection and (ii) to determine AF risk factors with significant predictive value for AF detection. METHODS: Seventy-five patients with cryptogenic IS/TIA were consecutively enrolled if at least one of the following AF risk factors was present: a CHA2DS2-VASc score ≥4, atrial runs, left atrium (LA) size >45 mm, left atrial appendage (LAA) flow ≤0.2 m/s, or spontaneous echo contrast in the LAA. The electrocardiographic and echocardiographic criteria were chosen as they have been repeatedly reported to predict AF; the same applies for four of the six items of the CHA2DS2-VASc score. The study end-point was the detection of one or more episodes of AF (≥2 min). RESULTS: Seventy-four patients underwent implantation of an ICM; one patient had AF at the date of implantation. After 6 months, AF was detected in 21/75 patients (28%), after 12 months in 25/75 patients (33.3%). 92% of AF episodes were asymptomatic. LA size >45 mm and the presence of atrial runs were independently associated with AF detection [hazard ratio 3.6 (95% confidence interval 1.6-8.4), P = 0.002, and 2.7 (1.2-6.7), P = 0.023, respectively]. CONCLUSIONS: The detection rate of AF is one-third after 1 year if candidates for an ICM after cryptogenic IS/TIA are selected by AF risk factors. LA dilation and atrial runs independently predict AF.

Efficacy and safety of zero-fluoroscopy ablation for supraventricular tachycardias. Use of optional contact force measurement for zero-fluoroscopy ablation in a clinical routine setting.

BACKGROUND: Conventional catheter ablation of cardiac arrhythmias is associated with radiation risks for patients and laboratory personnel. Widespread use of zero-fluoroscopic catheter ablation in clinical routine is limited by safety concerns. This study investigated the feasibility of zero-fluoroscopy catheter ablation using a three-dimensional mapping system and optional catheter contact force technology for an all-comers collective. PATIENTS AND METHODS: The study comprised 184 patients; 91 patients, including 29 pediatric patients, underwent a zero-fluoroscopic electrophysiology (EP) study using the EnSite NavX system with real-time visualization of all electrodes. These patients were matched to a control group, which was treated using fluoroscopy in the same period. Inclusion criteria were documented supraventricular tachycardia or a history of symptomatic paroxysmal supraventricular tachycardia. Transseptal access, if necessary, was achieved under transesophageal echocardiographic guidance for ablation of left-sided arrhythmias. Radiofrequency (using optional contact force measurement) or a cryotechnique was used for ablation. RESULTS: We observed no major acute complications. There were no significant differences between the two groups in the follow-up period. CONCLUSION: Zero-fluoroscopic catheter ablation is generally feasible in right-sided cardiac arrhythmias. Safety concerns regarding left atrial substrates or children can be overcome with optional real-time contact force measurement.

Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7.

Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4-CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4-CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1-M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4-CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163(+) macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1-M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte-macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation.

Impact of the serum- and glucocorticoid-inducible kinase 1 on platelet dense granule biogenesis and secretion.

BACKGROUND: Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood. OBJECTIVES: Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far. METHODS AND RESULTS: Electron microscopy analysis of the platelet ultrastructure revealed a significant reduction in the number and packing of dense granules in platelets lacking SGK1 (sgk1(-/-) ). In sgk1(-/-) platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3 -induced vascular injury was significantly diminished in sgk1(-/-) mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1(-/-) platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active (S422) (D) SGK1 but not with inactive (K127) (N) SGK1 significantly enhanced Rab27b mRNA levels. Sgk1(-/-) megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared with sgk1(+/+) megakaryocytes. Proteome analysis identified nine further vesicular transport proteins regulated by SGK1, which may have an impact on impaired platelet granule biogenesis in sgk1(-/-) platelets independent of Rab27b. CONCLUSIONS: The present observations identify SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective because it regulates transcription of Rab27b in megakaryocytes.

Platelet surface expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease.

BACKGROUND: Surface expression of stromal cell-derived factor-1 (SDF-1, CXCL12) on platelets is enhanced during ischemic events and plays an important role in peripheral homing of stem cells and myocardial repair mechanisms. SDF-1 effects are mediated through CXCR4 and CXCR7. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in patients with coronary artery disease (CAD) compared with healthy controls. In this study, we investigated the prognostic role of platelet CXCR4- and CXCR7 surface expression in patients with symptomatic CAD. METHODS AND RESULTS: In a cohort study, platelet surface expression of CXCR4 and CXCR7 was measured by using flow cytometry in 284 patients with symptomatic CAD at the time of percutaneous coronary intervention (PCI). The primary combined end point was defined as all-cause death and/or myocardial infarction (MI) during 12-month follow-up. Secondary end points were defined as the single events of all-cause death and MI. We found significant differences of CXCR4 values in patients who developed a combined end point compared with event-free patients (mean MFIAUTHOR: Please define MFI at first use. 3.17 vs. 3.44, 95% confidence interval [CI] 0.09-0.45) and in patients who subsequently died (mean MFI 3.10 vs. 3.42, 95% CI 0.09-0.56). In multivariate Cox regression analysis, lower platelet CXCR4 levels were independently and significantly associated with all-cause mortality (hazard ratio 0.24, 95% CI 0.07-0.87) and the primary combined end point of all-cause death and/or MI (hazard ratio 0.30, 95% CI 0.13-0.72). CONCLUSION: These findings highlight a potential prognostic value of platelet expression CXCR4 on clinical outcomes in patients with CAD.

Loss of oligophrenin1 leads to uncontrolled Rho activation and increased thrombus formation in mice.

BACKGROUND: Platelet cytoskeletal reorganization is essential for platelet adhesion and thrombus formation in hemostasis and thrombosis. The Rho GTPases RhoA, Rac1 and Cdc42 are the main players in cytoskeletal dynamics of platelets and induce filopodia and lamellipodia formation and actin polymerization to strongly increase the platelet surface upon activation. Moreover, they are important for platelet secretion, integrin activation and arterial thrombus formation. OBJECTIVES: Rho GTPases are regulated by GTPase-activating proteins (GAPs) that stimulate their GTPase activity to terminate Rho signaling. The regulation of Rho GTPase activity in platelets is not well defined. Recently, we identified oligophrenin1 (OPHN1), a RhoGAP in platelets that exhibits strong GTPase-stimulating activity towards RhoA, Cdc42 and Rac1. RESULTS: In the present study we show for the first time, that deficiency of OPHN1 led to abnormal Rho activation and increased platelet cytoskeletal reorganization, including cell adhesion and lamellipodia formation on fibrinogen. Furthermore, platelets from ophn1(-/-) mice showed enhanced susceptibility to platelet activation with alterations in actin distribution and early release of granules. Platelet activation was enhanced following GPVI and PAR4 stimulation. This translated into elevated platelet thrombus formation and promoted arterial thrombosis under low shear conditions with altered hemostasis, as detected by tail bleeding time. CONCLUSIONS: The results of the present study identified OPHN1 as an important regulator of platelet cytoskeletal reorganization and demonstrate that abnormal regulation of Rho proteins leads to increased platelet adhesion and thrombus formation under low shear conditions in vitro and in vivo, suggesting a prothrombotic phenotype of mice critical for acute thrombotic occlusions.

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death.

Tissue damage due to apoptotic or necrotic cell death typically initiates distinct cellular responses, leading either directly to tissue repair and regeneration or to immunological processes first, to clear the site, for example, of potentially damage-inducing agents. Mesenchymal stem cells (MSC) as well as immature dendritic cells (iDC) and monocytes migrate to injured tissues. MSC have regenerative capacity, whereas monocytes and iDC have a critical role in inflammation and induction of immune responses, including autoimmunity after tissue damage. Here, we investigated the influence of apoptotic and necrotic cell death on recruitment of MSC, monocytes and iDC, and identified hepatocyte growth factor (HGF) and the alarmin high mobility group box 1 (HMGB1) as key factors differentially regulating these migratory responses. MSC, but not monocytes or iDC, were attracted by apoptotic cardiomyocytic and neuronal cells, whereas necrosis induced migration of monocytes and iDC, but not of MSC. Only apoptotic cell death resulted in HGF production and HGF-mediated migration of MSC towards the apoptotic targets. In contrast, HMGB1 was predominantly released by the necrotic cells and mediated recruitment of monocytes and iDC via the receptor of advanced glycation end products. Moreover, necrotic cardiomyocytic and neuronal cells caused an HMGB1/toll-like receptor-4-dependent inhibition of MSC migration towards apoptosis or HGF, while recruitment of monocytes and iDC by necrosis or HMGB1 was not affected by apoptotic cells or HGF. Thus, the type of cell death differentially regulates recruitment of either MSC or monocytes and iDC through HGF and HMGB1, respectively, with a dominant, HMGB1-mediated role of necrosis in determining tropism after tissue injury.

Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease.

OBJECTIVE: Inhibition of components of the complement system or of its receptors has been postulated as a concept for primary and secondary prevention in atherosclerosis and was applied in clinical trials. Although the anaphylatoxin-receptors C3aR and C5aR are commonly associated with inflammatory cells, in vitro studies suggested their expression also on platelets. METHODS AND RESULTS: Expression levels of C3aR and C5aR were measured by flow cytometry in a collective of 302 patients with documented coronary artery disease (CAD) including patients with stable CAD (n = 152), unstable angina (n = 54), acute myocardial infarction (AMI; Non-ST elevation myocardial infarction, n = 70, ST elevation MI, n = 26) or healthy controls (n = 21). Patients with stable CAD, unstable angina or AMI had significantly higher expression of C5aR on platelets in comparison to healthy controls (MFI 14.68 (5.2), 14.56 (5.18) and 13.34 (4.52) versus 10.68 (3.1)); p < 0.001). In contrast, the expression of C3aR on platelets was significantly enhanced in patients with stable and unstable CAD but not in patients with AMI compared to controls. While there was a strong correlation between the soluble ligands of these receptors C3a and C5a, we observed only a weak correlation with their receptors on platelets. Similarly, agonist induced aggregation (MEA, ADP, and TRAP) showed only a weak correlation with the expression level of anaphylatoxin - receptors on platelets. Of note, the expression of both anaphylatoxin-receptors on platelets strongly correlated with platelet activation as assessed with the surface activation marker P-selectin (r = 0.47, p > 0.001 for C3aR, r = 0.76 for C5aR, p < 0.001). Likewise, we observed a positive correlation of C3aR with other molecules associated with platelet activation such as SDF-1. CONCLUSION: In summary, we observed a positive correlation between the expression of anaphylatoxin-receptors C3aR and C5aR with platelet activation in patients with CAD. Further investigations are needed to study the clinical and mechanistic relevance of these findings.

Is the diagnostic yield of myocardial stress perfusion MRI impaired by three-vessel coronary artery disease?

BACKGROUND: Three-vessel coronary artery disease (CAD) comes along with globally reduced myocardial perfusion potentially restricting the demarcation of regional hypoperfusion in stress perfusion cardiac magnetic resonance imaging (MRI). PURPOSE: To evaluate whether stress perfusion cardiac MRI is capable of detecting myocardial hypoperfusion in patients with 3-vessel CAD reliably. MATERIAL AND METHODS: Two hundred and five patients with symptoms of CAD were included. The examination protocol comprised imaging of myocardial perfusion at stress (0.14 mg/kg/min adenosine for 4 min) using a 2D saturation recovery gradient echo sequence after administration of gadobutrol (0.1 mmol/kg body weight). Perfusion sequences were assessed qualitatively by two experienced observers. Coronary angiography served as standard of reference. RESULTS: Sensitivity and specificity for hemodynamically relevant stenoses in patients with 0-, 1-, 2-, 3-vessel coronary artery disease were 100%/91%, 91%/73%, 90%/71%, 92%/64%; positive/negative predictive value, 67%/100%, 91%/73%, 83%/81%, 93%/58%; diagnostic accuracy, 93%/87%/83%/87%, respectively. The negative predictive value in patients with 3-vessel CAD was lower than in patients with 0- and 2-vessel CAD and the specificity lower than in patients with no CAD whereas the positive predictive value was higher than in patients with no CAD. The other proportions did not differ significantly between the groups. CONCLUSION: The diagnostic value of stress perfusion cardiac MRI in patients with 3-vessel CAD is comparable to results in patients with 1- or 2-vessel CAD. In the rare event that stress perfusion images do not depict regional hypoperfusion in patients with severe 3-vessel CAD, myocardial ischemia could be identified by reduced semi-quantitative perfusion parameters.

Differential MMP-9 activity in CD34⁺progenitor cell-derived foam cells from diabetic and normoglycemic patients.

BACKGROUND: Upon coincubation with platelet aggregates, CD34(+) progenitor cells have the potential to differentiate into foam cells. There is evidence that progenitor cells from diabetic and nondiabetic patients have different properties, which may affect the patients' prognosis. In this study we investigated an in vitro model of foam cell formation based on patient-derived CD34(+) progenitor cells. We analyzed the growth characteristics as well as the M-CSF-release and matrix metalloproteinase (MMP) synthesis from CD34(+) progenitor cell-derived foam cells originating from diabetic and nondiabetic patients. METHODS AND RESULTS: Bone marrow samples were obtained from 38 patients who were elected for thoracic surgery. CD34(+) progenitor cells from diabetic and nondiabetic patients were isolated and incubated with platelets from healthy volunteers. Foam cell formation was confirmed by immunostaining (CD68) and quantified by light microscopy. Whereas the absolute number of foam cells was not affected, the negative slope in the growth curve was seen significantly later in the diabetic group. In supernatants derived from"diabetic" CD34(+) progenitor cells, MMP-9 was significantly enhanced, whereas MMP-2 activity or M-CSF-release was not affected significantly. CONCLUSION: In a coculture model of CD34(+) progenitor cells with platelets, we show for the first time that"diabetic" CD34(+) progenitor cells exhibit functional differences in their differentiation to foam cells concerning growth characteristics and release of MMP-9.

The serum- & glucocorticoid-inducible kinase in the regulation of platelet function.

The serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed in megakaryocytes and circulating platelets. In megakaryocytes, SGK1 activates transcription factor nuclear factor kappa-B (NF-κB), which in turn stimulates expression of Orai1, a Ca(2+) channel protein accomplishing store-operated Ca(2+) enrty (SOCE). SGK1 enhances SOCE and several Ca(2+) -sensitive platelet functions, including degranulation, integrin αII b ß3 activation, phosphatidylserine exposure, aggregation and thrombus formation. As shown in other cell types, stimulators of SGK1 expression include ischaemia, oxidative stress, hyperglycaemia, advanced glycation end products (AGEs) and a variety of hormones such as glucocorticoids, mineralocorticoids, transforming growth factor beta (TGFß), interleukin 6 (IL-6), platelet-derived growth factor (PDGF), thrombin and endothelin. Thus, SGK1-sensitive Ca(2+) signalling may contribute to altered platelet function in several clinical conditions including inflammation, metabolic syndrome, diabetes mellitus and chronic renal failure. Nevertheless, further studies are needed defining the contribution of altered SGK1 expression and activity to physiology and pathophysiology of platelets.

Nadrin GAP activity is isoform- and target-specific regulated by tyrosine phosphorylation.

Cytoskeletal reorganization is crucial for platelet adhesion and thrombus formation to avoid excessive bleeding. Major regulators of cytoskeletal dynamics are small GTPases of the Rho family. Rho GTPases become activated by G-protein coupled receptor activation, downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors and by outside-in signaling of integrins. They act as molecular switches and cycle between active and inactive states. GTPase activating proteins (GAPs) stimulate the hydrolysis of GTP to GDP to terminate Rho signaling. Nadrin is a RhoGAP that was recently identified in platelets. Five Nadrin isoforms are known consisting of a unique GAP and an N-terminal BAR domain responsible for the selective regulation of RhoA, Cdc42 and Rac1. Besides BAR domain mediated regulation of Nadrin GAP activity nothing is known about the regulation of Nadrin and the impact on cytoskeletal reorganization. Here we show that Nadrin becomes tyrosine phosphorylated upon platelet activation. We found Src family proteins (Src, Lyn, Fyn) to be responsible to control Nadrin GAP activity by phosphorylation. Interestingly, phosphorylation of Nadrin leads to tightly regulated Rho activation that was found to be Nadrin isoform- and (Rho) target-specific. Src-phosphorylation of Nadrin5 mediated inactivation of Cdc42 while RhoA and Rac1 became activated upon Src-mediated phosphorylation of Nadrin2. Our results suggest a critical role for spatial and temporal regulation of Nadrin and thus for the control of Rho GTPases in platelets.

Implications of glycoprotein VI for theranostics.

Glycoprotein VI (GPVI), a membrane glycoprotein solely expressed in platelets and megakaryocytes, plays a critical role in thrombus formation due to collagen/GPVI-mediated platelet activation and adhesion. Recent studies have shown that surface expression of GPVI on circulating platelets is enhanced in acute cardiovascular diseases such as myocardial infarction and ischaemic stroke. Increased GPVI levels are associated with poor clinical outcome and are an early indicator for imminent myocardial infarction in patients with chest pain. The soluble form of the dimeric GPVI fusion protein (sGPVI-Fc) binds with high affinity to collagen and atherosclerotic plaque tissue. Non-invasive imaging studies with radiolabelled sGPVI-Fc show specific binding activity to vascular lesions in vivo. Further, sGPVI-Fc has been developed as a new therapeutic platelet-based strategy for lesion-directed antithrombotic therapy. This review summarises the potential of GPVI for diagnostic and therapeutic options based on novel non-invasive molecular imaging modalities to ameliorate care of patients with cardiovascular diseases.

Combination of high on-treatment platelet aggregation and low deaggregation better predicts long-term cardiovascular events in PCI patients under dual antiplatelet therapy.

High on-treatment platelet reactivity is associated with short-term major cardiovascular (CV) events in patients undergoing percutaneous coronary intervention (PCI). Maximum and final aggregation assessed by light transmission aggregometry (LTA) have both been used to predict short-term outcome after PCI, however their long-term prognostic impact remains controversial. There is currently no information regarding the prognostic role of deaggregation and its added value in combination with established aggregation parameters. About 1279 patients with symptomatic coronary artery disease (CAD) undergoing PCI were enrolled in this monocentric study. On-treatment platelet aggregation under clopidogrel maintenance therapy, as well as deaggregation was determined by maximum and final aggregation (5 min after adding of the agonist). Deaggregation was defined as slope of the tangent between Aggmax +0.5 min. Primary endpoints were the composite of myocardial infarction, stroke, and CV death or stent thrombosis according to the ARC criteria. Low deaggregation, defined as values in the lowest tertile (<1.5), was more frequent in patients with acute coronary syndromes (ACS) compared to patients with stable angina pectoris (SAP), ACS: 29.6% vs. SAP: 22.0%, p = 0.001. The combination of high on-treatment platelet reactivity, defined by the upper tertile of Aggmax and low deaggregation, was associated with significantly increased risk for combined long-term CV events. The combination of low deaggregation and high on-treatment platelet reactivity is associated with higher risk for recurrent events in patients with CAD undergoing PCI. Thus, deaggregation might be a more sensitive parameter providing added value in terms of risk prediction for long-term recurrent CV events in relation with established aggregation parameters.

Platelet-derived CXCL12 (SDF-1α): basic mechanisms and clinical implications.

Platelets are a major source of CXCL12 (stromal cell-derived factor -1α, SDF-1α) and store CXCL12 as part of their α-granule secretome. Platelet activation enhances surface expression and release of CXCL12. Platelets and megakaryocytes express CXCR4, the major receptor for CXCL12, and interaction of CXCL12 with CXCR4 regulates megakaryopoiesis and the function of circulating platelets. Platelet-derived CXCL12 also modulates paracrine mechanisms such as chemotaxis, adhesion, proliferation and differentiation of nucleated cells, including progenitor cells. Platelet-derived CXCL12 enhances peripheral recruitment of progenitor cells to the sites of vascular and tissue injury both in vitro and in vivo and thereby promotes repair mechanisms. CXCL12 expression on platelets is elevated in patients with acute myocardial infarction, correlates with the number of circulating progenitor cells, is associated with preservation of myocardial function and is an independent predictor of clinical outcome. Administration of recombinant CXCL12 reduces infarct size following transient ischemia in mice. The present review summarizes the role of platelet-derived CXCL12 in cardiovascular biology and its diagnostic and therapeutic implications.