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Jessica Kristin Henes,1,* Patrick Groga-Bada,1,* Elke Schaeffeler,2,3 Stefan Winter,2,3 Luis Hack,1 Monika Zdanyte,1 Karin Mueller,1 Michal Droppa,1 Fabian Stimpfle,1 Meinrad Gawaz,1 Harald Langer,4 Matthias Schwab,2,3,5,6 Tobias Geisler,1 Dominik Rath1 1Department of Cardiology, University Hospital Tuebingen, Tuebingen, Germany; 2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; 3University of Tuebingen, Tuebingen, Germany; 4Department of Cardiology, Angiology and Intensive Care, University Hospital Luebeck, Luebeck, Germany; 5Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany; 6Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany*These authors contributed equally to this workCorrespondence: Tobias GeislerMedizinische Klinik III, Department Cardiology and Cardiovascular Research, Otfried-Müller-Strasse 10, Tübingen, 72076 Tel +49 7071/29-8 36 88Fax +49 7071/29-57 49Email tobias.geisler@med.uni-tuebingen.deBackground: Complement component 5a (C5a) is a highly potent anaphylatoxin with a variety of pro-inflammatory effects. C5a contributes to progression of atherosclerosis and inhibition of the receptor (C5aR) might offer a therapeutic strategy in this regard. Single nucleotide polymorphisms (SNPs) of the C5 gene may modify protein expression levels and therefore function of C5a and C5aR. This study aimed to examine associations between clinically relevant C5a SNPs and the prognosis of patients with symptomatic coronary artery disease (CAD). Furthermore, we sought to investigate the influence of C5 SNPs on C5aR platelet surface expression and circulating C5a levels.Methods: C5 variants (rs25681, rs17611, rs17216529, rs12237774, rs41258306, and rs10985126) were analyzed in a consecutive cohort of 833 patients suffering from symptomatic coronary artery disease (CAD). Circulating C5a levels were determined in 116 patients whereas C5aR platelet surface expression was measured in 473 CAD patients. Endpoints included all-cause mortality, myocardial infarction (MI), and ischemic stroke (IS). Homozygous carriers (HC) of the minor allele (rs10985126) showed significantly higher all-cause mortality than major allele carriers. While we could not find significant associations between rs10985126 allele frequency and C5aR platelet surfazl ce expression, significantly elevated levels of circulating C5a were found in HC of the minor allele of the respective genotype. rs17216529 allele frequency correlated with the composite combined endpoint and bleeding events. However, since the number of HC of the minor allele of this genotype was low, we cannot draw a robust conclusion about the observed associations.Conclusion: In this study, we provide evidence for the prognostic relevance of rs10985126 in CAD patients. C5 rs10985126 may serve as a prognostic biomarker for risk stratification in high-risk CAD patients and consequently promote tailored therapies.Keywords: coronary artery disease, SNPs, complement C5, prognostic factors

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. [ABSTRACT FROM AUTHOR]

Introduction: The role of cryoballoon (CB) pulmonary vein isolation (PVI) for patients with persistent atrial fibrillation (AF) is controversial, since long-term success can be poor. We performed left atrial voltage mapping before CB PVI and determined AF-free survival depending on the extent of low-voltage areas (LVAs)., Methods and Results: We consecutively enrolled 60 patients with persistent AF (average age, 60.6 ± 12.9 years; CHA 2 DS 2 VASc score, 2.3 ± 1.6; and left atrial size 46.0 ± 5.2 mm) who were planned for CB PVI. Before ablation, we performed left atrial voltage mapping (Abbott EnSite Precision or Velocity). LVAs were defined if local bipolar signal amplitudes were less than 0.5 mV during sinus rhythm. Thirty-seven patients did not show significant LVAs (<10%), while 12 patients had LVAs between 10% and 30% and 11 patients showed substantial LVAs greater than 30% of the left atrial area. CB PVI could be successfully performed in all patients. A 7-day holter monitoring was obtained 3, 6, and 12 months after ablation. After a 12-month follow-up time, 83.8% of patients without LVAs (<10%) were free of atrial fibrillation, while 50.0% of patients with 10% to 30% LVAs and 9.1% of patients with LVAs more than 30% had stable sinus rhythm. The degree of atrial fibrosis correlated with the risk of AF recurrence., Conclusion: In patients with persistent AF undergoing CB PVI, the extent of left atrial LVAs predicts an AF-free survival. CB PVI seems to be a highly effective treatment for patients with persistent AF without atrial fibrosis., (© 2019 Wiley Periodicals, Inc.)

Background:  Phenotype-guided de-escalation (PGDE) of P2Y 12 -inhibitor treatment with an early switch from prasugrel to clopidogrel was identified as an effective alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). The Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Genotyping Substudy aimed to investigate whether CYP2C19 genotypes correlate with on-treatment platelet reactivity (PR) in ACS patients treated with clopidogrel or prasugrel and thus might be useful for guidance of early de-escalation of anti-platelet treatment., Methods and Results:  A total of 603 ACS consecutive patients were enrolled in four centres (23.1% of the overall TROPICAL-ACS population). Rapid genotyping (Spartan RX) for CYP2C19*2 , *3 and *17 alleles was performed. Associations between PR and the primary and secondary endpoints of the TROPICAL-ACS trial and CYP2C19*2 and CYP2C19*17 carrier status were evaluated.For the PGDE group, the on-clopidogrel PR significantly differed across CYP2C19*2 ( p  < 0.001) and CYP2C19*17 genotypes ( p  = 0.05). Control group patients were not related ( p  = 0.90, p  = 0.74) to on-prasugrel PR. For high PR versus non-high PR patients within the PGDE group, significant differences were observed for the rate of CYP2C19*2 allele carriers (43% vs. 28%, p  = 0.007)., Conclusion:   CYP2C19*2 and CYP2C19*17 carrier status correlates with PR in ACS patients treated with clopidogrel and thus might be useful for pre-selecting patients who will and who may not be suitable for PGDE of anti-platelet treatment. Regarding phenotype-guided treatment, we did not observe added benefit of genotyping to predict ischaemic and bleeding risk in patients who underwent a PGDE approach., Clinical Trial Registration:  URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451., Competing Interests: Dr. Trenk reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Otsuka, Sanofi, outside the submitted work; Dr. Aradi reports personal fees from Roche Diagnostics, DSI/Lilly, AstraZeneca, Pfizer, Bayer AG, MSD Pharma, outside the submitted work; Dr. Sibbing reports grants from Roche Diagnostics and Daiichi Sankyo, during the conduct of the study; personal fees from Bayer AG, Daiichi Sankyo Eli Lilly, Roche Diagnostics, MSD, Pfizer, Astra Zeneca, outside the submitted work; Dr. Geisler reports personal fees from Astra Zeneca, Boehringer Ingelheim, Pfizer and MSD, grants and personal fees from Bayer Healthcare, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Medcines Company, Siemens Healthcare, grants from Spartan Bioscience, outside the submitted work. The other authors have nothing to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: During invasive electrophysiological studies (EPS), atrial fibrillation (AF) can be induced in patients without a history of AF. However, the prognostic value is not well evaluated in this population. Our aim was to investigate whether AF inducibility in those patients is associated with future clinical episodes of AF; whether non-inducibility is predictive of freedom from new-onset AF and finally, to examine clinical factors associated with inducibility., Methods: Medical records from patients undergoing EPS between the years 2011 and 2014 were analysed retrospectively with 62 patients matching our inclusion criteria. Patients were divided into subgroups according to their inducibility status and underwent follow-up. Patients were assessed by a structured telephone interview, data from the further treating physicians and ECG recordings., Results: AF was inducible in 19 patients ("induction group") and not inducible in the remaining 43 ("control group"). Inducibility was associated with a higher age (p=0.002), lower GFR (p=0.002), higher CHAD2S2-VASc score (p=0.004) and diagnosis of mitral (p=0.014), tricuspid (p=0.017) and pulmonary (p=0.026) valve insufficiency. Three months after EPS, 89.5% of all inducible patients were free of diagnosed AF, in contrast to 100% of those without inducibility (p=0.031). At three years, no significant difference was left (p=0.162)., Conclusion: AF inducibility was found more often in an older population with cardiac comorbidities. While inducibility was associated with an increased rate of diagnosed new-onset clinical AF in the months after testing, non-inducibility seemed to be associated with freedom from AF at least in the short to medium term. However, there was no significant difference in the long term follow-up.

Background: Atrial fibrosis is a hallmark of arrhythmogenic structural remodeling in patients with persistent atrial fibrillation (AF) and is negatively correlated with procedure outcome in patients undergoing ablation. However, noninvasive methods to determine the extent of atrial fibrosis are limited. Here, we used microRNA (miRNA) expression analysis to detect markers of left atrial low-voltage areas (LVAs) in patients with persistent AF undergoing catheter ablation., Methods: We performed 3-dimensional voltage mapping in 102 patients (average age 62.1±13.1 years, CHA 2 DS 2 -VASc score of 2.3±1.6, LA size 41.5±5.7 mm) undergoing ablation for persistent AF and determined the extent of left atrial low-voltage. LVAs were defined if bipolar electrogram amplitudes were <0.5 mV during sinus rhythm. Before ablation, we obtained a blood sample, isolated miRNAs, and profiled them on a miRCURY LNA Universal RT microRNA PCR Human panel., Results: Sixty-nine miRNAs were identified in all samples, with an average of 123 miRNAs detectable per sample. We found that the serum concentration of miR-21, a miRNA that has been previously linked to cardiac fibrosis development, was strongly associated with the extent of LVAs determined by voltage mapping. We could confirm that LVAs were negatively correlated with ablation success in a 1-year follow-up. In addition, miR-21 serum levels were associated with AF-free survival after catheter ablation., Conclusions: Circulating miR-21 correlates with left atrial LVAs and is associated with procedure outcome in patients with persistent AF undergoing ablation., (© 2018 The Authors.)

Introduction: Platelet endothelial aggregation receptor 1 (PEAR1) triggers platelet aggregation and is expressed in platelets and endothelial cells. Genome-wide association studies (GWAS) showed an association between platelet function and single-nucleotide polymorphisms (SNPs) in PEAR1 . Methods: In 582 consecutive patients with stable coronary artery disease (CAD) or acute coronary syndrome (ACS) scheduled for PCI and treated with ASA and Clopidogrel, Prasugrel, or Ticagrelor, SNP analysis for rs12566888, rs2768759, rs41273215, rs3737224, and rs822442 was performed. During a follow-up period of 365 days after initial PCI, all patients were tracked for a primary endpoint, defined as a combined endpoint consisting of either time to death, myocardial infarction (MI) or ischemic stroke. All cause mortality, MI and ischemic stroke were defined as secondary endpoints. Results: Multivariable Cox model analysis for the primary endpoint revealed a significantly increased risk in homozygous PEAR1 rs2768759 minor allele carriers (hazard ratio, 3.16; 95% confidence interval, 1.4-7.13, p = 0.006). Moreover, PEAR1 rs12566888 minor allele carriers also showed an increased risk in all patients (hazard ratio, 1.69; 95% confidence interval, 0.87-3.27, p = 0.122), which was marginally significant in male patients (hazard ratio, 2.12; 95% confidence interval, 1.02-4.43, p = 0.045; n = 425). Conclusions: To the best of our knowledge, this is the first study showing that distinct genetic variants of PEAR1 are associated with cardiovascular prognosis in high risk patients undergoing PCI and treated with dual anti platelet therapy.

Background: Platelet membrane glycoprotein receptors mediate thrombus formation. GP Ia/IIa is an essential platelet integrin receptor. Single-nucleotide polymorphisms (SNPs) of the GP Ia/IIa gene alter GP Ia/IIa expression; however, their influence on cardiovascular disease remains unclear. This study aimed to investigate the effect of the GP Ia/IIa SNPs rs1126643 and rs1062535 on clinical outcomes in a large collective including high-risk patients with cardiovascular disease., Methods and Results: GP Ia SNP analysis was performed in 943 patients with symptomatic coronary artery disease. All patients were tracked for all-cause death, myocardial infarction, and ischemic stroke for 360 days. Homozygous carriers of the minor allele showed significantly worse event-free survival when compared with major allele carriers in the complete collective as well as in the subset of high-risk patients (carrying all of the following three risk factors: diabetes type II, hypertension, and hyperlipidemia). There was no significant difference in the subset of low-risk patients (carrying none of the three risk factors)., Conclusions: GPla SNPs are associated with cardiovascular prognosis especially in high-risk patients. Identification of GPIa SNPs is of importance to tailor therapies in patients at already high cardiovascular risk.

Platelet surface expression levels of stromal cell derived factor 1 (SDF-1) are elevated in acute coronary syndrome and associated with LVEF% improvement after myocardial infarction (MI). Platelet SDF-1 might facilitate thrombus formation and endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy and positively correlates with myocardial fibrosis. The influence of platelet SDF-1 on outcome in the patients with symptomatic coronary artery disease (CAD) is to the best of our knowledge unknown. Blood samples of 608 consecutive CAD patients were collected during the percutaneous coronary intervention and analyzed for surface expression of SDF-1 by flow cytometry. The primary combined endpoint was defined as the composite of either MI, or ischemic stroke, or all-cause death. Secondary endpoints were defined as the aforementioned single events. The patients with baseline platelet SDF-1 levels above the third quartile showed a significantly worse cumulative event-free survival when compared to the patients with lower baseline SDF-1 levels (first to third quartile) (log rank 0.009 for primary combined endpoint and log rank 0.016 for secondary endpoint all-cause death). Multivariate Cox regression analysis showed that SDF-1 levels above the third quartile were independently associated with the primary combined endpoint and the secondary endpoint all-cause death. We provide first clinical evidence that high platelet expression levels of SDF-1 influence clinical outcomes in CAD patients in a negative way.

Background: SDF1 and its cognate receptors CXCR4 and CXCR7 are involved in myocardial repair and are associated with outcome in cardiovascular patients. Hence, we aimed to investigate clinically significant SDF1 SNPs for their prognostic impact in patients with cardiovascular disease., Methods and Results: Genotyping for selected SDF1 variants (rs1065297, rs2839693, rs1801157, rs266087, rs266085 and rs266089 was performed in patients (n = 872) who underwent percutaneous coronary intervention. Carriers of variant rs2839693 and rs266089 showed significantly higher cumulative event-free survival compared with non-carriers. All other polymorphisms had no relevant influence on outcome. Multivariate Cox regression analysis showed a significant correlation of these SNPs with cardiovascular outcome after inclusion of clinical and prognostic relevant variables (hazard ratio (HR) 0.51 (95% CI 0.30-0.88), p = 0.015 and [HR 0.51 (95% CI 0.30-0.88), p = 0.016, respectively). In addition, multivariate Cox regression with SDF1 haplotypes revealed a significantly reduced risk for the haplotype carrying the minor alleles of rs2839693 and rs266089 (HR 0.47 (95% CI 0.27-0.84), p = 0.011)., Conclusion: Distinct SDF1 polymorphisms are associated with improved cardiovascular prognosis in CAD patients. Further studies are warranted to validate these results and to better describe the endogenous regeneration potential in carriers of these SNPs. Targeted, genotype guided therapeutic approaches to foster myocardial regeneration and thus cardiovascular prognosis should be evaluated in future., Competing Interests: The authors have declared that no competing interests exist.

Objectives: This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI)., Methods: 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort., Results: Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort., Conclusions: Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients.

Acute coronary syndromes are a major disease burden and the prognosis has improved over the last decades due to improvement of medical and interventional treatments. Novel P2Y12-ADP-receptor antagonists have been introduced into clinical treatment offering more potent and rapid onset of action with the downside of increased bleeding risk. This special report will focus on interindividual variability of antiplatelet drugs in the setting of acute coronary syndromes and the current impact and potential future of point-of-care testing to personalize therapy aiming to improve prognosis in acute coronary syndrome patients.

Background: Functional recovery and prognosis after acute coronary syndromes (ACS) are mainly driven by the extent of reperfusion injury and myocardial repair mechanisms. Transforming growth factor-beta 1 (TGF-β1) is critically involved in cardiac injury, repair and remodeling. In this study, we investigated the prognostic role of platelet TGF-β1 surface expression and circulating TGF-β1 levels in patients with coronary artery disease (CAD)., Methods and Results: Expression of TGF-β1 in platelets and circulating TGF-β1 levels were investigated by flow cytometry and ELISA, respectively, among patients with ACS and stable CAD undergoing percutaneous coronary intervention (PCI). In a cohort study, platelet and circulating TGF-β1 was measured in 299 patients with symptomatic CAD (stable CAD = 145, ACS = 154) at the time of PCI. The primary combined endpoint was defined as death and/or STEMI during 12-month follow-up. Platelets expressed TGF-β1 and circulating TGF-β1 showed a weak, but significant negative correlation. TGF-β1 surface expression was significantly elevated on platelets in ACS patients compared to patients with stable CAD (median MFI 13.4 vs. median MFI 11.7, p = 0.003). During follow-up, lower platelet expression of TGF-β1 was associated with all-cause mortality (median MFI 11.0 vs. median MFI 13.9, p = 0.011) as well as for the combined endpoint of death and/or STEMI, (median MFI 10.8 vs. median MFI 13.9, p = 0.006). In multivariate analysis platelet TGF-β1 expression was independently associated with the combined primary endpoint in the overall cohort (Hazard Ratio 0.31, 95% Confidence Interval 0.11-0.89, p = 0.029) and was strongly associated with prognosis in ACS patients. There was no significant association of circulating TGF-β1 levels neither with the presence of ACS nor the occurrence of the primary endpoint., Conclusion: These findings highlight a potential role of platelet expressed TGF-β1 in ACS and indicate a prognostic value of TGF-β1 on clinical outcomes in patients with acute coronary syndromes. Large scale studies are warranted to further evaluate the regulatory mechanisms of platelet TGF-β1 expression- and its prognostic impact in CAD., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of-function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting., Methods and Results: 137 subjects with ACS scheduled for percutaneous coronary intervention were consecutively enrolled. Pre- and on-treatment platelet aggregation was assessed by multiple electrode aggregometry (MEA) after stimulation with adenosine diphosphate (ADP). Patients were loaded according to current guideline adherent indications and contraindications for use of P2Y12 inhibitors in ACS. POC genotyping for CYP2C19*2 was performed in the emergency room after obtaining a buccal swab using the Spartan RX CYP2C19 system and obtaining patient's informed consent. Prasugrel and ticagrelor treated patients had significantly lower PR compared to clopidogrel-treated patients. The benefits of prasugrel and ticagrelor compared to clopidogrel treated patients in terms of platelet inhibition were more pronounced in CYP2C19*2 carriers. Non-carriers showed similar inhibition regardless of particular P2Y12 inhibitor treatment. Statistical analyses adjusting for factors associated with response (e.g. smoking) revealed that CYP2C19*2 allele carrier status and loading with different type of P2Y12 receptor blockers were significant predictors of on-treatment platelet reactivity in the early phase of ACS., Conclusion: The results of this pilot study of treatment of patients in the early phase of ACS indicate that CYP2C19*2 POC genotyping might help to identify patients at risk with poor response to clopidogrel treatment, thereby benefiting from reloading and switching to alternative P2Y12 receptor inhibition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The proliferation, migration and differentiation of dentate gyrus stem and precursor cells have aroused keen interest. Neogenin and RGMb are expressed in non-overlapping compartments of the developing dentate gyrus. While Neogenin is expressed in migrating and proliferating dentate precursors, RGMb is localized in structures bordering the developing dentate, such as cornus ammonis cells and Cajal-Retzius cells in the marginal zone including the hippocampal fissure. Co-immunoprecipitation and binding assays indicate a strong physical interaction. In vitro and in vivo migration of dentate neuroepithelial cells is abolished by RGMb, and cell adhesion is reduced when cells expressing Neogenin comes into contact with cells expressing RGMb. Ectopic expression of RGMb in organotypic slice cultures and after in utero electroporation in the hippocampus modifies precursor cell migration. Our results imply that Neogenin-RGMb interaction might be involved in neuronal migration in the dentate gyrus., (Copyright 2009 Elsevier Inc. All rights reserved.)