Background 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.

ZUSAMMENFASSUNGDie korrekte Behandlung der Lungenarterienembolie beginnt mit einer frühzeitigen multimodalen Einschätzung des Risikos unter Berücksichtigung der klinischen Vorhersagekraft, Laborparametern und bildmorphologischen Risikomerkmalen. Während die Lysetherapie hauptsächlich Patienten mit Schocksituation vorbehalten ist, kann sie bei ausgewählten stabilen Patienten mit intermediär hohem Risiko und vertretbarem Blutungsrisiko ebenfalls in Betracht gezogen werden. Im Niedrigrisikobereich ist eine ambulante Behandlung vertretbar. Neue Aspekte umfassen auch den Einsatz von kathetergestützen Reperfusionsmaßnahmen, sowie Algorithmen, um das Langzeitrezidivrisiko als auch die Entwicklung einer chronisch thrombembolischen pulmonalen Hypertonie frühzeitig zu erkennen. Der Vorteil der verlängerten Sekundärprophylaxe nach Lungenarterienembolie ist bei bestimmten Patienten durch Anwendung von klinischen Vorhersagemodellen und auch im Bereich der Tumorerkrankungen durch aktuelle Studiendaten belegt worden. Dieser Übersichtsartikel dient als Update unter Berücksichtigung der aktuellen Entwicklung und liefert Perspektiven über derzeit laufende Studien zur Klärung von offenen Fragen in der Behandlung der Lungenarterienembolie.

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).We consecutively enrolled 60 patients with persistent AF (average age, 60.6 ± 12.9 years; CHA2 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.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.

Abstract Background Short duration 50 Watt radiofrequency (RF) ablation has been shown to be feasible for atrial fibrillation (AF) ablation with short procedure times. Purpose We evaluated 50 Watt RF power with a different fixed short application duration at the anterior and posterior left atrial wall using contact force (CF) sensing catheters for circumferential pulmonary vein isolation (PVI). Methods Consecutive patients (pts) with indication for de novo AF ablation (n=40, age 64±12 years) with paroxysmal (n=23) or persistent (n=17) AF underwent high density 3D mapping of the left atrium. Low voltage areas of more than 5% of the left atrium were only found in 20% of pts. Thereafter, circumferential PVI using CF sensing catheters was performed. For each RF application (50 Watt, RF duration 11–13s at the anterior wall, 9–11s at the posterior wall) a stable catheter tip position with minimal mean CF of 3g was required and application was stopped in case of CF more than 30g. Esophageal temperature measurement was performed with temperature cut off 39.0°C. In case of temperature rise, ablation protocol was switched to conventional 20 Watt RF applications for ablation adjacent to the esophagus. Results Complete PVI was achieved in all pts with 81±29 short RF applications resulting in cumulative RF applications duration of 13.1±4.2min and an ablation duration of 59±17min for complete PVI. Even RF application with low CF (3–5g) were effective. Due to esophageal temperature rise, switch to conventional RF application with 20 Watt was performed in 43% of pts at least at one posterior PV entrance. After a waiting period of 20 min only in 33% of pts any PV conduction recurs, in 28% of pts only at a single spot and reconnected fibers were not associated with low CF application at that spot, but clearly associated with low energy application at the posterior wall. All PV were successfully re-isolated in most of pts with a single spot high energy RF application. No serious complications occurred in association with PVI. Follow up will be available at presentation time. Conclusion RF ablation with 50 Watt fixed short duration is efficient and safe for circumferential PVI. Ablation procedure durations are shorter and early recurrence rates are lower compared to reported conventional ablation procedures. The importance of CF titration seems to be diminished by 50 Watt RF applications in the left atrium. Further follow up have to be waited.

Abstract Background Matrix Metalloproteinase-2 (MMP-2) is involved in regulation and proliferation of vascular and endothelial cells and is therefore an important component of atherosclerotic vessels. Inhibition of MMP-2 activity is associated with improvement of cardiac function in animal models after myocardial infarction. MMP-2 single nucleotide polymorphisms (SNPs) might alter MMP-2 expression and therefore influence prognosis in patients with symptomatic coronary artery disease (CAD). Methods and results Genotyping for selected MMP-2 SNPs variants (rs2241145, rs2285053, rs2287076, rs243865, rs7201) was performed in 943 consecutive patients with symptomatic CAD. All patients were followed-up for all-cause death (ACD), myocardial infarction (MI) and ischemic stroke (IS) for 360 days. The primary combined endpoint (CE) consisted of either first occurrence of ACD, and/or MI, and/or IS. Secondary endpoints were defined as the single events of ACD or MI. Homozygous carriers of major allele (rs2241145, rs2287076) showed significantly better event-free survival than carriers of the minor allele for CE (Log rank = 0.022 and Log rank= 0.015, respectively). Furthermore, homozygous carriers of major allele (rs2241145, rs2285053, rs2287076) showed significantly better event-free survival for ACD (Log rank= 0.047, Log rank= 0.006 and Log rank= 0.023, respectively). In multivariate analysis, MMP-2 rs2241145, rs2287076 and rs2285053 were significantly and independently associated with CE and ACD. Figure 1 Conclusions MMP-2 rs2241145, rs2287076 and rs2285053 are associated with prognosis and might be valuable for further risk stratification in CAD patients. Acknowledgement/Funding DFG, KFO 274, CRC TR 240

Background Phenotype-guided de-escalation (PGDE) of P2Y12-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.

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.

In TROPICAL-ACS, phenotype-guided de-escalation (PGDE) of P2Y12 inhibition was non-inferior to standard treatment with prasugrel in terms of net clinical benefit. CYP2C19*2 and 3 alleles are established risk factors for ischemic events with clopidogrel, whereas CYP2C19*17 carriers are exposed to

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.

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.

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.

We report the case of a 73-year-old male patient who first presented for cardiology consultation after transient ischemic attack. No pre-existing conditions, other than hypertension, were known. Long-term electrocardiography did not reveal atrial fibrillation. Transesophageal echocardiography (TEE)

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.

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.

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.