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Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Non-alcoholic fatty liver disease (NAFLD) with advanced liver fibrosis is associated with cardiovascular disease (CVD). To examine if markers of vascular injury mediate the link between liver fibrosis non-invasive tests (LFNITs) and CVD events, and to compare the incremental predictive value of LFNITs over established CVD risk scores., Methods: Consecutively recruited individuals (n=1,692) with or without clinically overt coronary artery disease (CAD) from the Athens Cardiometabolic Cohort, were analysed. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), and BARD score were evaluated for direct and indirect associations with indices of subclinical arterial injury including carotid maximal wall thickness (maxWT) and pulse wave velocity (PWV) and with a composite of major adverse cardiovascular events (MACE) that consisted of cardiac death, acute myocardial infarction, or coronary revascularization (39-month median follow-up)., Results: FIB-4 was the only LFNIT which consistently associated with multiple markers of vascular injury, irrespective of CAD presence and after controlling for traditional risk factors, surrogates of insulin resistance or obesity (adjusted p<0.05 for all). FIB-4 also independently associated with CAD presence (adjusted OR 6.55 (3.48-12.3), p<0.001). Increased FIB-4>2.67 was incrementally associated with increased risk for MACE (OR (95% CI) 2.00(1.12, 3.55), deltaAUC (95% CI) 0.014(0.002-0.026)). These associations were mediated by maxWT rather than PWV. Only FIB-4 (>3.25) was independently and incrementally associated with all-cause mortality (adjusted p<0.05)., Conclusions: In a cardio-metabolically diverse population, the incremental associations of LFNITs with CVD outcomes were mediated by atherosclerotic burden rather than arterial stiffening. FIB-4 consistently demonstrated associations with all study endpoints. These findings provide mechanistic insights and support the clinical applicability of FIB-4 in CVD prevention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Circulating amyloid-beta 1-40 (Αb40) has pro-atherogenic properties and could serve as a biomarker in atherosclerotic cardiovascular disease (ASCVD). However, the association of Ab40 levels with morphological characteristics reflecting atherosclerotic plaque echolucency and composition is not available. Carotid atherosclerosis was assessed in consecutively recruited individuals without ASCVD (n = 342) by ultrasonography. The primary endpoint was grey scale median (GSM) of intima-media complex (IMC) and plaques, analysed using dedicated software. Vascular markers were assessed at two time-points (median follow-up 35.5 months). In n = 56 patients undergoing carotid endarterectomy, histological plaque features were analysed. Plasma Αb40 levels were measured at baseline. Ab40 was associated with lower IMC GSM and plaque GSM and higher plaque area at baseline after multivariable adjustment. Increased Ab40 levels were also longitudinally associated with decreasing or persistently low IMC and plaque GSM after multivariable adjustment (p < 0.05). In the histological analysis, Ab40 levels were associated with lower incidence of calcified plaques and plaques without high-risk features. Ab40 levels are associated with ultrasonographic and histological markers of carotid wall composition both in the non-stenotic arterial wall and in severely stenotic plaques. These findings support experimental evidence linking Ab40 with plaque vulnerability, possibly mediating its established association with major adverse cardiovascular events., (© 2024. The Author(s).)

Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury., Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury., Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023., Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE)., Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event., Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056)., Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.

Background and Aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI., Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention., Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 T EM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 T EM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808])., Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI., Competing Interests: MM-H. reports consulting fees for Zoll CMS GmbH, research funding from Roche Diagnostics and BRAHMS Thermo Scientific. NF has received lecture fees from AstraZeneca, Boehringer Ingelheim, Bayer Vital and consulting fees for Boehringer Ingelheim, all of which not related to the subject in this manuscript. DD reports consulting and speaker fees from Bayer Healthcare, Boston Scientific, Daiichi Sankyo, AstraZeneca, and research grants from DFG, DZHK. EG has received honoraria for lectures from AstraZeneca, Daiichi Sankyo and Roche Diagnostics, consulting fees for BRAHMS Deutschland, Roche Diagnostics, AstraZeneca, Daiichi and Novo Nordisk, research funding from Daiichi and Roche Diagnostics. IS receives research grants from Kancera AB and Astra Zaneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sopova, Tual-Chalot, Mueller-Hennessen, Vlachogiannis, Georgiopoulos, Biener, Sachse, Turchinovich, Polycarpou-Schwarz, Spray, Maneta, Bennaceur, Mohammad, Richardson, Gatsiou, Langer, Frey, Stamatelopoulos, Heineke, Duerschmied, Giannitsis, Spyridopoulos and Stellos.)

Background:  The noncoding antisense transcript for β-secretase-1 ( BACE1-AS ) is a long noncoding RNA with a pivotal role in the regulation of amyloid-β (Aβ). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD)., Methods:  Expression of BACE1-AS and its target, β-secretase 1 ( BACE1 ) mRNA, was measured in peripheral blood mononuclear cells derived from 434 individuals (259 without established ASCVD [non-CVD], 90 with stable coronary artery disease [CAD], and 85 with acute coronary syndrome). Intima-media thickness and atheromatous plaques evaluated by ultrasonography, as well as arterial wave reflections and pulse wave velocity, were measured as markers of subclinical ASCVD. Patients were followed for a median of 52 months for major adverse cardiovascular events (MACE)., Results:  In the cross-sectional arm, BACE1-AS expression correlated with BACE1 expression ( r  = 0.396, p  < 0.001) and marginally with Aβ1-40 levels in plasma ( r  = 0.141, p  = 0.008). Higher BACE1-AS was associated with higher estimated CVD risk assessed by HeartScore for non-CVD subjects and by European Society of Cardiology clinical criteria for the total population ( p  < 0.05 for both). BACE1-AS was associated with higher prevalence of CAD (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.37-2.5), multivessel CAD (OR = 1.36, 95% CI: 1.06-1.75), and with higher number of diseased vascular beds (OR = 1.31, 95% CI: 1.07-1.61, for multiple diseased vascular beds) after multivariable adjustment for traditional cardiovascular risk factors. In the prospective arm, BACE1-AS was an independent predictor of MACE in high cardiovascular risk patients (adjusted hazard ratio = 1.86 per ascending tertile, 95% CI: 1.011-3.43, p  = 0.046)., Conclusion:   BACE1-AS is associated with the incidence and severity of ASCVD., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture., Objectives: The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score., Methods: This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint., Results: In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction., Conclusions: Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score., Competing Interests: Funding Support and Author Disclosures This research was funded by the German Research Foundation DFG (SFB834 project number 75732319) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 759248) (to Dr Stellos). Dr Sopova was supported with a scholarship from the German Heart Foundation (Deutsche Herzstiftung). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is associated with excess mortality after hospital discharge. Identification of patients at increased risk of death following hospital discharge is needed to guide clinical monitoring and early intervention. Herein, we aimed to identify predictors of early vs. late mortality in COVID-19 patients., Methods: A total of 471 patients with polymerase chain reaction-confirmed COVID-19 were followed up for 9 months [median (inter-quartile range) of follow-up time: 271 (14) days] after hospital admission. COVID-19-related signs and symptoms, laboratory features, co-morbidities, Coronavirus Clinical Characterisation Consortium (4C) mortality and Clinical Frailty Scale (CFS) scores were analysed by logistic regression for association with early (28 day) vs. late mortality. Receiver operating characteristic (ROC) analysis was used to determine the discriminative value of 4C and CFS scores for early vs. late mortality., Results: A total of 120 patients died within 28 days from hospital admission. Of the remaining 351 patients, 41 died within the next 8 months. Respiratory failure, systemic inflammation, and renal impairment were associated with early mortality, while active cancer and dementia were associated with late mortality, after adjustment for age and sex. 4C mortality score and CFS were associated with both early [odds ratio (OR) (95% confidence interval-CI): 4C: 1.34 (1.25-1.45); CFS: 1.49 (1.33-1.66)] and late [OR (95% CI): 4C: 1.23 (1.12-1.36); CFS: 2.04 (1.62-2.56)] mortality. After adjustment for CFS, the association between 4C and late mortality was lost. By ROC analysis, 4C mortality score was superior to CFS for 28 day mortality [area under the curve (AUC) (95% CI): 0.779 (0.732-0.825) vs. 0.723 (0.673-0.773), respectively; P = 0.039]. In contrast, CFS had higher predictive value for late mortality compared with 4C mortality score [AUC (95% CI): 0.830 (0.776-0.883) vs. 0.724 (0.650-0.798), respectively; P = 0.007]., Conclusions: In our cohort, late mortality in COVID-19 patients is more strongly associated with premorbid clinical frailty than with severity of the acute infection phase., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background and Aim: Although the diagnostic usefulness of high-sensitivity cardiac troponin T (hs-cTnT) is well established in ST-segment elevation myocardial infarction (STEMI), its prognostic relevance in risk stratification of patients with STEMI remains obscure. This study sought to determine the prognostic value of pre-reperfusion (admission) and post-reperfusion (12-hour) hs-cTnT in patients with STEMI treated with primary percutaneous coronary intervention (PPCI)., Methods: Retrospective observational longitudinal study including consecutive patients with STEMI treated with PPCI at a university hospital in the northeast of England. hs-cTnT was measured at admission to the catheterisation laboratory and 12 hours after PPCI. Clinical, procedural and laboratory data were prospectively collected during patient hospitalisation (June 2010-December 2014). Mortality data were obtained from the UK Office of National Statistics. The study endpoints were in-hospital and overall mortality., Results: A total of 3113 patients were included. Median follow-up was 53 months. Admission hs-cTnT >515 ng/L (fourth quartile) was independently associated with in-hospital mortality (HR=2.53 per highest to lower quartiles; 95% CI: 1.32 to 4.85; p=0.005) after multivariable adjustment for a clinical model of mortality prediction. Likewise, admission hs-cTnT >515 ng/L independently predicted overall mortality (HR=1.27 per highest to lower quartiles; 95% CI: 1.02 to 1.59; p=0.029). Admission hs-cTnT correctly reclassified risk for in-hospital death (net reclassification index (NRI)=0.588, p<0.001) and overall mortality (NRI=0.178, p=0.001). Conversely, 12-hour hs-cTnT was not independently associated with mortality., Conclusion: Admission, but not 12-hour post-reperfusion, hs-cTnT predicts mortality and improves risk stratification in the PPCI era. These results support a prognostic role for admission hs-cTnT while challenge the cost-effectiveness of routine 12-hour hs-cTnT measurements in patients with STEMI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P < 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p < 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P < 0.001) and reclassification value (NRI = 0.381, P < 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores., (© 2021. The Author(s).)

Platelets comprise a highly interactive immune cell subset of the circulatory system traditionally known for their unique haemostatic properties. Although platelets are considered as a vault of growth factors, cytokines and chemokines with pivotal role in vascular regeneration and angiogenesis, the exact mechanisms by which they influence vascular endothelial cells (ECs) function remain underappreciated. In the present study, we examined the role of human IL-17A/IL-17RA axis in platelet-mediated pro-angiogenic responses. We reveal that IL-17A receptor (IL-17RA) mRNA is present in platelets transcriptome and a profound increase is documented on the surface of activated platelets. By quantifying the protein levels of several factors, involved in angiogenesis, we identified that IL-17A/IL17RA axis selectively induces the release of vascular endothelial growth factor, interleukin -2 and -4, as well as monocyte chemoattractant protein -1 from treated platelets. However, IL-17A exerted no effect on the release of IL-10, an anti-inflammatory factor with potentially anti-angiogenic properties, from platelets. Treatment of human endothelial cell two-dimensional tubule networks or three-dimensional spheroid and mouse aortic ring structures with IL-17A-induced platelet releasate evoked pro-angiogenic responses of ECs. Our findings suggest that IL-17A may critically affect platelet release of pro-angiogenic factors driving ECs towards a pro-angiogenic state.

Aims: Latent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CX 3 CR1 + effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CX 3 CR1 (fractalkine receptor) in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI)., Methods and Results: We retrospectively analysed lymphocyte count, troponin, and survival in 4874 STEMI/pPCI patients, evaluated lymphocyte kinetics during reperfusion in a prospective cohort, and obtained sequential cardiac MRI (cMRI) to assess remodeling. Pre-reperfusion lymphopenia independently predicted mortality at 7.5 years. Prior to reperfusion, CCR7 + T-lymphocytes appeared to be depleted. After reperfusion, T-lymphocytes expressing CX 3 CR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CX 3 CR1 + T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction. At 12 weeks, CMV+ patients displayed adverse LV remodeling., Conclusion: We show that lymphopenia occurs before and after reperfusion in STEMI by different mechanisms and predicts long-term outcome. In CMV+ patients, increased fractalkine induction and sequestration of CX 3 CR1 + T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Spray, Park, Cormack, Mohammed, Panahi, Boag, Bennaceur, Sopova, Richardson, Stangl, Rech, Rainer, Ramos, Hofmann, Stellos and Spyridopoulos.)

Aims: Fibroblast growth factor 23 (FGF-23) is known to be elevated in patients with congestive heart failure (CHF). As FGF-23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF-23 in CHF remains unclear. It is also unclear if FGF-23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF-23 levels measured in bone marrow plasma (FGF-23-BM) and in peripheral blood (FGF-23-P) in CHF patients to gain further insights into the heart-bone axis of FGF-23 expression. We also investigated possible associations between FGF-23-BM as well as FGF-23-P and outcome in CHF patients., Methods and Results: We determined FGF-23-P and FGF-23-BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF-23-BM and FGF-23-P with all-cause mortality in CHF patients, 32 events, median follow-up 1673 days, interquartile range [923, 1828]. FGF-23-P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF-23-BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF-23-BM levels were significantly higher than FGF-23-P levels in both CHF patients and in healthy controls (P < 0.001). FGF-23-P and FGF-23-BM correlated significantly with LVEF (r = -0.37 and r = -0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = -0.43 and r = -0.41, respectively) (P for all <0.001) and were independently associated with all-cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18-6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19-6.57], P = 0.018, respectively., Conclusions: In CHF patients, FGF-23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all-cause mortality. The failing heart seems to interact via FGF-23 within a heart-bone axis., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aflibercept appears to accumulate in systemic circulation following intravitreal injections in therapy of neovascular age-related macular degeneration. This gives raise to the question of whether aflibercept affects platelets and their function such as activation and aggregation, which are substantial in the pathogenesis of an arterial thromboembolic event (ATE). In order to determine the effect of aflibercept in platelet activation, platelets from healthy volunteers were treated with aflibercept and its solvents at equal concentrations (0.04 μg/mL - 4 μg/mL - 40 μg/mL - 400 μg/mL - 4 mg/mL) for 10 and 30 min before addition of agonists. IgG1 antibody was used as a control. The surface expression of GPIIb/IIIa, P-selectin, and platelet-bound stromal-cell-derived factor-1, which are potential blood biomarkers for ATEs, was determined on resting and activated platelets by the multispectral imaging flow cytometry, combining the features of flow cytometry with fluorescence microscopy. Platelet aggregation was assessed with light transmission aggregometry. To determine whether aflibercept directly interacts with platelets, aflibercept was labeled with the fluorescence FITC. Co-treatment of platelets with thrombin or PAR-4-AP and aflibercept resulted in increased activation of the fibrinogen receptor GPIIb/IIIa in comparison to controls (P < 0.05). Interestingly, the expression of platelet-derived P-selectin and SDF-1 was not affected by aflibercept, except thrombin-activated CD62P with 0.04 μg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.54, IC = 1.201-1.879 vs. MSI = 1.37, IC = 1.136-1.604 [P = 0.031]) and SDF-1 with 4 mg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.971, IC = 1.206-2.737 vs. MSI = 1.200, IC = 0.738-1.662 [P = 0.041]). Although the levels of platelet-bound aflibercept-FITC were significantly increased in all activated platelets, no effect was observed in platelet aggregation. Albeit no impact of aflibercept was found on platelet aggregation under the studied experimental conditions, the increased activation of the fibrinogen receptor GPIIb/IIIa and the presence of a direct interaction between aflibercept and platelets may partially explain the risk of ATE in patients under aflibercept treatment due to FcγRIIa mediated αIIbβ3 outside-in integrin signaling and transport of aflibercept into platelets. Therefore, the Fc domain seems to be involved in interactions between aflibercept and platelets. Further research is needed to explain the role of Fc containing aflibercept in the pathogenesis of drug-associated vascular events involving platelets, coagulation cascade, extracellular matrix proteins and other cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Amyloid-β (1-40) (Aβ40) is implicated in mechanisms related to plaque destabilization and correlates with adverse outcomes in stable coronary artery disease., Objective: To determine the prognostic and reclassification value of baseline circulating levels of Aβ40 after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS)., Design: Retrospective cohort study using data from 2 independent prospective cohorts, the Heidelberg study (n = 1145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) study (n = 734)., Setting: Academic hospitals in 7 European countries., Participants: Patients with adjudicated NSTE-ACS followed for a median of 21.9 and 24.9 months in the Heidelberg and APACE studies, respectively., Measurements: All-cause mortality was the primary end point., Results: Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio [HR] for 80th vs. 20th percentiles, 1.66 [95% CI, 1.06 to 2.61; P = 0.026]; APACE cohort HR, 1.50 [CI, 1.15 to 1.96; P = 0.003]). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 [CI, 1.04 to 1.18; P = 0.001]; APACE cohort HR, 1.39 [CI, 1.02 to 1.88; P = 0.036]). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P < 0.05)., Limitation: At low concentrations of Aβ40, dose-response associations with mortality differed between cohorts, possibly because of varying blood preparations used to measure Aβ40., Conclusion: Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated., Primary Funding Source: German Cardiac Society.

Background: The amyloid beta peptide is the major protein constituent of neuritic plaques in Alzheimer disease and appears to play a central role in vascular inflammation pathophysiology., Objectives: This study sought to determine the clinical value of amyloid-beta 1-40 (Abeta40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects., Methods: Abeta40 was retrospectively measured in blood samples collected from 3 independent prospective cohorts and 2 case-control cohorts (total N = 1,464). Major adverse cardiac events (MACE) were assessed in the 2 prospective cohorts (n = 877) followed for a median of 4.4 years. To look at effects on subclinical disease, arterial stiffness was evaluated at baseline and after 5-year follow-up (n = 107) in young healthy subjects. The primary endpoint was the predictive value of Abeta40 for CV mortality and outcomes in patients with CHD., Results: In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein, and high-sensitivity troponin T, Abeta40 independently predicted CV death and MACE in patients with CHD (p < 0.05 for all). After multivariate adjustment, Abeta40 levels conferred a substantial enhancement of net reclassification index and integrated discrimination improvement of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Abeta40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis, and incident CHD., Conclusions: Measuring blood levels of Abeta40 identified patients at high risk for CV death., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to evaluate the potential influence of ranibizumab and bevacizumab on platelet activation and aggregation, which are critical processes in the pathogenesis of arterial thromboembolic events (ATEs)., Methods: For the assessment of platelet function, flow cytometry and aggregometry were employed. Platelets were isolated from healthy volunteers and exposed to ranibizumab (1 mg/ml and 150 ng/ml) and bevacizumab (2.5 mg/ml and 3 μg/ml) or their solvents for 10 and 30 min prior to the addition of TRAP (25 μM), PAR-4-AP (25 μM) or thrombin (0.02 U/ml). The surface expression of activated GP IIb/IIIa, P-selectin (CD62P) and platelet-bound stromal cell-derived factor-1 (SDF-1) was measured on resting (nonactivated) and activated platelets by flow cytometry. The platelet aggregation capacity was examined using light transmission aggregometry., Results: The expression of surface activation markers did not differ significantly between nonstimulated and TRAP-, PAR-4-AP- or thrombin-activated platelets after incubating with ranibizumab. However, GP IIb/IIIa, CD62P and SDF-1 were significantly downregulated in PAR-4-AP- and thrombin-activated platelets after exposure to bevacizumab 2.5 mg/ml. In addition, ranibizumab- and bevacizumab-FITC were significantly increased in all activated platelets. No significant differences were observed in the aggregation of activated platelets after incubation with ranibizumab or bevacizumab., Conclusion: All ranibizumab concentrations as well as the bevacizumab concentration of 3 μg/ml had no influence on platelet activation and aggregation. Therefore, this in vitro study did not show any relationship between the exposition of activated platelets to ranibizumab or bevacizumab and the development of ATEs. However, the highest level of bevacizumab interfered with platelet activation, leading to downregulation of platelet activation markers. This observation might explain why the systemic treatment with high-dose bevacizumab could be associated with an increased risk of bleeding. Regarding the use of lower intravitreal dosages, further research should focus on the complex interactions between platelets and other cells, such as endothelial cells, which might stronger relate to a potentially increased risk of ATEs and depend on systemic vascular endothelial growth factor levels. Facing the different activation profiles, the diverse effects of the drugs on the cellular level have to be critically scrutinized for their clinical relevance., (© 2015 S. Karger AG, Basel.)

Background: Increasing evidence supports the role of cardiovascular risk factors in the development of Alzheimer's disease (AD)., Objective: In the present pilot study, we investigated plasma concentrations of myeloperoxidase (MPO) and its possible association with plasma amyloid-β (Aβ)1-42/1-40 ratio in AD patients and elderly healthy controls., Methods: The study sample included 28 AD patients and 27 elderly individuals with a normal cognitive status as a control group. The Mini-Mental Status Examination was used to determine the global cognition. MPO, Aβ1-40, and Aβ1-42 plasma concentrations were measured by enzyme linked immunoabsorbent assays., Results: AD patients showed significantly higher plasma concentrations of MPO in comparison to healthy elderly controls (AD versus healthy elderly controls (mean ± SD): 132.8 ± 114.8 ng/mL versus 55.0 ± 42.6 ng/mL; p = 0.002). MPO plasma concentrations showed a significant positive correlation in the whole sample with the presence of AD (ρ = 0.428, p < 0.001) and its stage (ρ = 0.331; p = 0.013) as well as with plasma concentrations of Aβ1-42 (ρ = 0.406; p = 0.004) and Aβ1-42/1-40 ratio (ρ = 0.354; p = 0.013). In a binary logistic regression model, plasma MPO concentrations were independently associated with the presence of AD (p = 0.014)., Conclusion: AD patients showed significantly increased plasma levels of MPO, which could be an important molecular link between atherosclerosis and AD. Further studies should evaluate whether MPO may also be a useful biomarker and potential new treatment target in AD.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Growth factors have been demonstrated to act in a synergistic way in angiogenesis and neurogenesis contributing to self-healing powers of the adult human brain. A growing body of evidence demonstrates that levels of many growth factors (neurotrophins and hematopoietins) are altered in cerebrospinal fluid and peripheral blood from AD patients and in animal models of AD. The present review summarizes the role of several neurotrophic growth factors (e.g., BDNF, SCF, NGF, GDNF) and haematopoietic growth factors (e.g., G-CSF, VEGF, SDF-1) in AD. Moreover, we summarize recent studies evaluating the diagnostic and prognostic value of growth factor levels in blood and cerebrospinal fluid in patients with AD and discuss the potential role of these growth factors as a promising new therapeutic approach in AD.

Diabetes is a well-known risk factor for Alzheimer`s disease (AD) development in the elderly. The molecular link between diabetes and AD is still not completely understood. Recent evidence suggests that platelet activation observed in diabetes may contribute to AD development. The present review summarizes the common molecular mechanisms involved in the pathophysiology of diabetes and AD and suggests novel therapeutic targets for prevention of the onset or slowing the progression of this disease.

Platelet adhesion on vascular wall is the first step following vascular injury. Differential platelet secretion supports angiogenesis and vascular homeostasis. Progenitor cells are pluripotent cells responsible for tissue regeneration and wound healing. Upon ischemia bone marrow-derived progenitor cells are mobilized into peripheral circulation and domiciliate into peripheral organ vasculature and either give birth to a series of cardiovascular cells, including endothelial cells, macrophages, smooth muscle cells, or support in a paracrinic way the angiogenic capacity of local tissue cells. Mobilization, chemotaxis, adhesion, differentiation and interaction with vascular cells are essential steps of progenitor cell-mediated tissue repair. This review summarizes the recent advances in our understanding of platelet function with focus on interaction with progenitor cells and its role in cardiovascular homeostasis. Moreover, the role of platelet microparticles in progenitor cell function is separately addressed. Understanding the mechanisms of platelet interaction with progenitor cells provides us with new insights in the mechanisms of vascular homeostasis and possible new therapeutical targets supporting vascular repair.

Vascular risk factors and atherosclerosis are critically involved in dementia development of both vascular and Alzheimer's type. However, the exact mechanisms linking atherosclerosis and the development of Alzheimer's disease (AD) are still unknown. As platelet activation and adhesion on vascular wall is the first step of vascular inflammation and atherosclerosis, it appears tempting to hypothesize that platelets could be the link between vascular risk factors/ atherosclerosis and AD. In recent years, much work has been accomplished to elucidate the role of platelets in AD. The present review will summarize and highlight the latest findings of this research area and provide novel insight and understanding in the association between platelet activation and AD.

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept©, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.

Aims: Blood cell infiltration and inflammation are involved in atrial remodelling during atrial fibrillation (AF) although the exact mechanisms of inflammatory cell recruitment remain poorly understood. Platelet-bound stromal cell-derived factor-1 (SDF-1) is increased in cases of ischemic myocardium and regulates recruitment of CXCR4(+) cells on the vascular wall. Whether platelet-bound SDF-1 expression is differentially influenced by non-valvular paroxysmal or permanent atrial fibrillation (AF) in patients with stable angina pectoris (SAP) or acute coronary syndrome (ACS) has not been reported so far., Methods and Results: A total of 1291 consecutive patients with coronary artery disease (CAD) undergoing coronary angiography were recruited. Among the patients with SAP, platelet-bound-SDF-1 is increased in patients with paroxysmal AF compared with SR or to persistent/permanent AF (P < 0.05 for both). Platelet-bound SDF-1 correlated with plasma SDF-1 (r = 0.488, P = 0.013) in patients with AF and ACS, which was more pronounced among patients with persistent AF (r = 0.842, P = 0.009). Plasma SDF-1 was increased in persistent/permanent AF compared with SR. Patients with ACS presented with enhanced platelet-bound-SDF-1 compared with SAP. Interestingly, among patients with ACS, patients with paroxysmal or persistent/permanent AF presented with an impaired platelet-bound SDF-1 expression compared with patients with SR., Conclusions: Differential expression of platelet-bound and plasma SDF-1 was observed in patients with AF compared with SR which may be involved in progenitor cell mobilization and inflammatory cell recruitment in patients with AF and ischemic heart disease. Further in vivo studies are required to elucidate the role of SDF-1 in atrial remodeling and the atrial fibrillation course.

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

Background: Alzheimer's disease (AD) and atherosclerosis share common vascular risk factors such as arterial hypertension and hypercholesterolemia. Adipocytokines and CD34(+) progenitor cells are associated with the progression and prognosis of atherosclerotic diseases. Their role in AD is not adequately elucidated., Methods and Findings: In the present study, we measured in 41 patients with early AD and 37 age- and weight-matched healthy controls blood concentrations of adiponectin and leptin by enzyme linked immunoabsorbent assay and of CD34(+) progenitor cells using flow cytometry. We found significantly lower plasma levels of leptin in AD patients compared with the controls, whereas plasma levels of adiponectin did not show any significant differences (AD vs. control (mean ± SD): leptin:8.9 ± 5.6 ng/mL vs.16.3 ± 15.5 ng/mL;P = 0.038; adiponectin:18.5 ± 18.1 µg/mL vs.16.7 ± 8.9 µg/mL;P = 0.641). In contrast, circulating CD34(+) cells were significantly upregulated in AD patients (mean absolute cell count ± SD:253 ± 51 vs. 203 ± 37; P = 0.02) and showed an inverse correlation with plasma levels of leptin (r =  -0.248; P = 0.037). In logistic regression analysis, decreased leptin concentration (P = 0.021) and increased number of CD34(+) cells (P = 0.036) were both significantly associated with the presence of AD. According to multifactorial analysis of covariance, leptin serum levels were a significant independent predictor for the number of CD34(+) cells (P = 0.002)., Conclusions: Our findings suggest that low plasma levels of leptin and increased numbers of CD34(+) progenitor cells are both associated with AD. In addition, the results of our study provide first evidence that increased leptin plasma levels are associated with a reduced number of CD34(+) progenitor cells in AD patients. These findings point towards a combined involvement of leptin and CD34(+) progenitor cells in the pathogenesis of AD. Thus, plasma levels of leptin and circulating CD34(+) progenitor cells could represent an important molecular link between atherosclerotic diseases and AD. Further studies should clarify the pathophysiological role of both adipocytokines and progenitor cells in AD and possible diagnostic and therapeutic applications.

Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination [MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score ≤ 4 after one year; n = 28) (fast versus slow cognitive decline: mean ± SD: 1051.1 ± 178.7 versus 1237.9 ± 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis.

Plasma levels of amyloid-β (Aβ) peptides are potential biomarkers of early cognitive impairment and of Alzheimer's disease (AD) risk. However, the association of Aβ peptides with the rate of cognitive decline in AD patients is still unclear. In the present study we demonstrate that Aβ₁₋₄₂ plasma levels show a significant correlation with the rate of cognitive decline and are significantly increased in AD patients with fast cognitive decline (decrease of Mini-Mental Status Examination (MMSE) score ≥ 5/year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score ≤ 4/year; n = 28), independent of baseline MMSE scores, age and cholinesterase inhibitor intake, but dependent on history of myocardial infarction and history of stroke in a multivariate analysis. These results suggest that Aβ₁₋₄₂ plasma levels are associated with the rate of cognitive decline in AD patients and may be influenced by atherosclerotic vasculopathies such as stroke and myocardial infarction.