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

Background: Percutaneous mitral valve repair (PMVR) has evolved to be a standard procedure in suitable patients with mitral regurgitation (MR) not accessible for open surgery. Here, we analyzed the influence of the number and positioning of the clips implanted during the procedure on MR reduction analyzing also sub-collectives of functional and degenerative MR (DMR)., Results: We included 410 patients with severe MR undergoing PMVR using the MitraClip® System. MR and reduction of MR were analyzed by TEE at the beginning and at the end of the PMVR procedure. To specify the clip localization, we sub-divided segment 2 into 3 sub-segments using the segmental classification of the mitral valve., Results: We found an enhanced reduction of MR predominantly in DMR patients who received more than one clip. Implantation of only one clip led to a higher MR reduction in patients with functional MR (FMR) in comparison to patients with DMR. No significant differences concerning pressure gradients could be observed in degenerative MR patients regardless of the number of clips implanted. A deterioration of half a grade of the achieved MR reduction was observed 6 months post-PMVR independent of the number of implanted clips with a better stability in FMR patients, who got 3 clips compared to patients with only one clip., Conclusions: In patients with FMR, after 6 months the reduction of MR was more stable with an increased number of implanted clips, which suggests that this specific patient collective may benefit from a higher number of clips., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: Ultrasound-facilitated and catheter-directed low-dose fibrinolysis (EKOS) has shown favorable hemodynamic and safety outcomes in intermediate- to high-risk pulmonary embolism (PE) cases. Objectives: This prospective single-arm monocentric study assessed the effects of using a delivery catheter for fibrinolysis as a novel approach for acute intermediate- to high-risk patients on pulmonary artery hemodynamics PE. Methods: Forty-five patients (41 intermediate−high and 4 high risk) with computer tomography (CT)-confirmed PE underwent EKOS therapy. By protocol, a total of 6 mg of tissue-plasminogen activator (t-PA) was administered over 6 h in the pulmonary artery (unilateral 6 mg or bilateral 12 mg). Unfractionated heparin was provided periprocedurally. The primary safety outcome was death, as well as major and minor bleeding within 48 of procedure initiation and at 90 days. The primary effectiveness outcomes were: 1. to assess the difference in pulmonary artery pressure from baseline to 6 h post-treatment as a primary precise surrogate marker, and 2. to determine the echocardiographic RV/LV ratio from baseline to 48 h and at 90 days post-delivery. Results: Pulmonary artery pressure decreased by 15/6/10 mmHg (p < 0.001). The mean RV/LV ratio decreased from 1.2 ± 0.85 at baseline to 0.85 ± 0.12 at 48 and to 0.76 ± 0.13 at 90 days (p < 0.001). Five patients (11%) died within 90 days of therapy. Conclusions and Highlights: Pulmonary artery hemodynamics were assessed using a delivery catheter for fibrinolysis, which is reproducible for identifying PE at risk of adverse outcomes. The results matched the right heart catheter results in EKOS and Heparin arm of Ultima trial, thereby confirming the validity of this potential diagnostic tool to assess therapy effectiveness and thereby reduce additional procedure-related complications, hospital residency, and economics. These results stress the importance of having an interdisciplinary team involved in the management of PE to evaluate the quality of life of these patients and this protocol shortens ICU admission to 6 h.

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1 -/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.

Aims: The aim of this meta-analysis was to compare general anaesthesia (GA) and deep sedation (DS) with regard to safety and length of intensive care unit (ICU) stay in patients undergoing percutaneous edge-to-edge mitral valve repair (PMVR)., Methods and Results: Four studies comparing GA and DS in patients undergoing PMVR were included in an individual patient data meta-analysis. Data were pooled after multiple imputation. The composite safety endpoint of all-cause death, stroke, pneumonia, or major to life-threatening bleeding occurred in 87 of 626 (13.9%) patients with no difference between patients treated with DS as compared to GA (56 and 31 events in 420 and 206 patients, respectively). In this regard, the odds ratio (OR) was 1.27 (95% confidence interval [CI]: 0.78 to 2.09; p=0.338) and 1.26 (95% CI: 0.49 to 3.22; p=0.496) following the one-stage and two-stage approach, respectively. Length of ICU stay was longer after GA as compared to DS (ratio of days 3.08, 95% CI: 2.18 to 4.36, p<0.001, and 2.88, 95% CI: 1.45 to 5.73, p=0.016, following the one-stage and two-stage approach, respectively)., Conclusions: Both DS and GA might offer a similar safety profile. However, ICU stay seems to be shorter after DS.

Objectives: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery., Methods: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated., Results: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS., Conclusions: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Right ventricular (RV) function is an important prognostic indicator. The acute effects of cardiac interventions or cardiac surgery on global and longitudinal RV function are not entirely understood. In this study, acute changes of RV function during mitral valve surgery (MVS), percutaneous mitral valve repair (PMVR) and off-pump coronary artery bypass surgery (OPCAB) were investigated employing 3D echocardiography., Methods: Twenty patients scheduled for MVS, 23 patients scheduled for PMVR and 25 patients scheduled for OPCAB were included retrospectively if patients had received 3D transesophageal echocardiography before and immediately after MVS, PMVR or OPCAB, respectively. RV global and longitudinal function was assessed using a 3D multiparameter set consisting of global right ventricular ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE), longitudinal contribution to RVEF (RVEF long ) and free wall longitudinal strain (FWLS)., Results: Longitudinal RV function was significantly depressed immediately after MVS, as reflected by all parameters (RVEF long : 20 ± 5% vs. 13 ± 6%, p <  0.001, TAPSE: 13.1 ± 5.1 mm vs. 11.0 ± 3.5 mm, p = 0.04 and FWLS: -20.1 ± 7.1% vs. -15.4 ± 5.1%, p <  0.001, respectively). The global RVEF was slightly impaired, but the difference did not reach significance (37 ± 13% vs. 32 ± 9%, p = 0.15). In the PMVR group, both global and longitudinal RV function parameters were unaltered, whereas the OPCAB group showed a slight reduction of RVEF long only (18 ± 7% vs. 14 ± 5%, p <  0.01). RVEF long yielded moderate case-to-case but good overall reproducibility., Conclusions: TAPSE, FWLS and RVEF long reflect the depression of longitudinal compared to global RV function initially after MVS. PMVR alone had no impact, while OPCAB had a slight impact on longitudinal RV function. The prognostic implications of these phenomena remain unclear and require further investigation.

Background: Mitral regurgitation (MR) has a severe impact on hemodynamics and induces severe structural changes in the left atrium. Atrial remodeling is known to alter excitability and conduction in the atrium facilitating atrial fibrillation and atrial flutter. PMVR is a feasible and highly effective procedure to reduce MR in high-risk patients, which are likely to suffer from atrial rhythm disturbances. So far, electroanatomical changes after PMVR have not been studied., Hypothesis: In the current study, we investigated changes in surface electrocardiograms (ECGs) of patients undergoing PMVR for reduction of MR., Methods: We evaluated 104 surface ECGs from patients in sinus rhythm undergoing PMVR. P wave duration, P wave amplitude, PR interval, QRS duration, QRS axis, and QT interval were evaluated before and after PMVR and at follow-up., Results: We found no changes in QRS duration, QRS axis, and QT interval after successful PMVR. However, P wave duration, amplitude, and PR interval were significantly decreased after reduction of MR through PMVR (P < .05, respectively)., Conclusion: The data we provide offers insight into changes in atrial conduction after reduction of MR using PMVR in patients with sinus rhythm., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Introduction: In this study, we evaluated right ventricular (RV) function before and after percutaneous mitral valve repair (PMVR) using conventional echocardiographic parameters and novel 3DE data sets acquired prior to and directly after the procedure., Patients and Methods: Observational study on 45 patients undergoing PMVR at an university hospital., Results: In the overall collective, the 3D RV-EF before and after PMVR showed no significant change (p = 0.16). While there was a significant increase of the fractional area change (FAC, from 23 [19-29] % to 28 [24-33] %, p = 0.001), no significant change of the tricuspid annular plane systolic excursion (TAPSE, from 17 ± 6 mm to 18 ± 5 mm (standard deviation), p = 0.33) was observed. Regarding patients with a reduced RV-EF (< 35%), a significant RV-EF improvement was observed (from 27 [23-34] % to 32.5 [30-39] % (p = 0.001). 71.4% of patients had an improved clinical outcome (improvement in 6-minute walk test and/or improvement in NYHA class of more than one grade), whereas clinical outcome did not improve in 28.6% of patients. Using univariate logistic regression analysis, the post-PMVR RV-EF (OR 1.15: 95% CI 1.02-1.29; p = 0.02) and the change in RV-EF (OR 1.13: 95% CI 1.02-1.25; p = 0.02) were significant predictors for improved clinical outcome at 6 months follow up., Conclusion: Thus, RV function may be an important non-invasive parameter to add to the predictive parameters indicating a potential clinical benefit from treatment of severe mitral regurgitation using PMVR., Competing Interests: Dr. H. F. Langer and Dr. P. Seizer were reimbursed for PMVR training courses by Abbott Vascular, otherwise we have no potential conflict of interest to declare.

Background This study analyzed the effects on long-term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge-to-edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty-five patients who underwent percutaneous edge-to-edge mitral valve repair were analyzed. Kaplan-Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all-cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge-to-edge mitral valve repair, mean MVPG increased from 1.6±1.0 to 3.1±1.5 mm Hg ( P<0.001). Reduction of MR severity to ≤2+ postintervention was achieved in 98.4% of all patients. In the overall patient cohort, residual MR was predictive of the combined end point while elevated MVPG >4.4 mm Hg was not according to Kaplan-Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR , elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR . Conclusions MVPG >4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR . In the patient cohort with functional MR , MVPG >4.4 mm Hg was not associated with increased clinical events.

In recent years, various studies have increasingly explained platelet functions not only in their central role as a regulator in cellular hemostasis and coagulation. In fact, there is growing evidence that under specific conditions, platelets act as a mediator between the vascular system, hemostasis, and the immune system. Therefore, they are essential in many processes involved in tissue remodeling and tissue reorganization after injury or inflammatory responses. These processes include the promotion of inflammatory processes, the contribution to innate and adaptive immune responses during bacterial and viral infections, the modulation of angiogenesis, and the regulation of cell apoptosis in steady-state tissue homeostasis or after tissue breakdown. All in all platelets may contribute to the control of tissue homeostasis much more than generally assumed. This review summarizes the current knowledge of platelets as part of the tissue remodeling network and seeks to provide possible translational implications for clinical therapy.

Background: Patients after transcatheter aortic valve replacement (TAVR) and persistent severe mitral regurgitation (MR) are increasingly treated with percutaneous edge-to-edge mitral valve repair (PMVR). The impact of a former TAVR on PMVR procedures is not clear., Methods and Results: We retrospectively analyzed 332 patients undergoing PMVR using the MitraClip system with respect to procedural and clinical outcome. 21 of these 332 patients underwent TAVR before PMVR. Intra-procedural transthoracic (TTE) and transesophageal echocardiograms (TEE) immediately before and after clip implantation as well as invasive hemodynamic measurements were evaluated. At baseline, we found a significantly smaller mitral valve anterior-posterior diameter in the TAVR cohort (p < 0.001). A reduction of MR by at least three grades was achieved in a smaller fraction in the TAVR cohort as compared to the cohort with a native aortic valve (p = 0.02). Accordingly, we observed a smaller post-procedural cardiac output in the TAVR cohort (p = 0.02)., Conclusion: PMVR in patients who had a TAVR before, is associated with altered MR anatomy before and a reduced improvement of MR after the procedure. Future larger and prospective studies will have to determine, whether a previous TAVR influences long-term clinical outcome of patients undergoing PMVR., Competing Interests: The authors have declared that no competing interests exist.

Aim: The aim of this study is to analyse the prognostic value of complement anaphylatoxin receptors in patients with non-ischaemic cardiomyopathy undergoing endomyocardial biopsy., Methods and Results: In 102 patients (72.5% male patients, median age 54 years) with non-ischaemic cardiomyopathy, myocardial expression of C3aR was assessed among other parameters. The primary study endpoint was a composite of death, heart transplantation, heart failure-related re-hospitalization, and deterioration of left ventricular ejection fraction within a mean follow-up of 11.9 months. The number of cells, which stained positive for C3aR, was significantly increased in patients with inflammatory compared with non-inflammatory cardiomyopathy (1.75 ± 0.31 cells in inflammatory cardiomyopathy vs. 0.94 ± 0.26 in non-inflammatory cardiomyopathy, P = 0.049). Subsequently, positive expression for C3aR was judged based on a semi-quantitative scoring system. Significantly, more patients with positive MHCII and CD68 expression showed an increased number of C3aR-positive cells. C3aR expression based on this score was more pronounced in patients with human herpesvirus 6 viral genome detection. Kaplan-Meier curves illustrate that the C3aR-negative group reached the primary endpoint significantly more often (mean follow-up 11.9 months, log rank 5.963, P = 0.015). Lack of C3aR expression was a strong independent predictor for the primary endpoint in Cox regression analysis [hazard ratio 0.46 (0.26-0.82, P = 0.009)]., Conclusions: C3aR-positive cells are found more often in patients with inflammatory cardiomyopathy. The relevance of C3aR-positive cells in patients with non-ischaemic cardiomyopathy should be further evaluated as potential predictors or modulators of adverse cardiac remodelling, the substrate of progressive heart failure., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Plasma Galectin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galectin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR., Methods: Forty-four consecutive patients (median age 79 years, LV ejection fraction 39.5 ± 11.4%, 91% in NYHA functional class ≥III) with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a ≥10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years., Results: 72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 < 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p = 0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels ≥ 10 ng/ml had significantly more MACE than patients with Galectin-3 levels < 10 ng/ml (100% vs. 45.5%, p = 0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9.4, p = 0.049); Galectin-3 ≥ 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p = 0.088)., Conclusions: Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Improved mitral valve leaflet coaptation with consecutive reduction of mitral regurgitation (MR) is a central goal of percutaneous mitral valve repair (PMVR) with the MitraClip® system. As influences of PMVR on mitral valve geometry have been suggested before, we examined the effect of the procedure on mitral annular size in relation to procedural outcome., Methods and Results: Geometry of the mitral valve annulus was evaluated in 183 patients undergoing PMVR using echocardiography before and after the procedure and at follow-up. Mitral valve annular anterior-posterior (ap) diameter decreased from 34.0 ± 4.3 to 31.3 ± 4.9 mm (P < 0.001), and medio-lateral (ml) diameter from 33.2 ± 4.8 to 32.4 ± 4.9 mm (P < 0.001). Accordingly, we observed an increase in MV leaflet coaptation after PMVR. The reduction of mitral valve ap diameter showed a significant inverse correlation with residual MR. Importantly, the reduction of mitral valve ap diameter persisted at follow-up (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up)., Conclusion: This study demonstrates mechanical approximation of both mitral valve annulus edges with improved mitral valve annular coaptation by PMVR using the MitraClip® system, which correlates with residual MR in patients with MR.

Background: Percutaneous edge-to-edge mitral valve repair (PMVR) has become an established treatment option for mitral regurgitation in patients not eligible for surgical repair. Currently, most procedures are performed under general anesthesia (GA). An increasing number of centers, however, are performing the procedure under deep sedation (DS). Here, we compared patients undergoing PMVR with GA or DS., Methods and Results: A total of 271 consecutive patients underwent PMVR at our institution between May 2014 and December 2016. Seventy-two procedures were performed under GA and 199 procedures under DS. We observed that in the DS group, doses of propofol (743±228 mg for GA versus 369±230 mg for DS, P <0.001) and norepinephrine (1.1±1.6 mg for GA versus 0.2±0.3 mg for DS, P <0.001) were significantly lower. Procedure time, fluoroscopy time, and dose area product were significantly higher in the GA group. There was no significant difference between GA and DS with respect to overall bleeding complications, postinterventional pneumonia (4% for GA versus 5% for DS), or C-reactive protein levels (361±351 nmol/L for GA versus 278±239 nmol/L for DS). Significantly fewer patients with DS needed a postinterventional stay in the intensive care unit (96% for GA versus 19% for DS, P <0.001). Importantly, there was no significant difference between DS and GA regarding intrahospital or 6-month mortality., Conclusions: DS for PMVR is safe and feasible. No disadvantages with respect to procedural outcome or complications in comparison to GA were observed. Applying DS may simplify the PMVR procedure., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Successful percutaneous mitral valve repair (PMVR) in patients with severe mitral regurgitation (MR) causes changes in hemodynamics. Echocardiographic calculation of cardiac output (CO) has not been evaluated in the setting of PMVR, so far. Here we evaluated hemodynamics before and after PMVR with the MitraClip system using pulmonary artery catheterization, transthoracic (TTE) and transesophageal (TEE) echocardiography., Methods: 101 patients with severe MR not eligible for conventional surgery underwent PMVR. Hemodynamic parameters were determined during and after the intervention. We evaluated changes in CO and pulmonary artery systolic pressure before and after PMVR. CO was determined with invasive parameters using the Fick method (COi) and by a combination of TTE and TEE (COe)., Results: All patients had successful clip implantation, which was associated with increased COi (from 4.6±1.4l/min to 5.4±1.6l/min, p<0.001). Furthermore, pulmonary artery systolic pressure (PASP) showed a significant decrease after PMVR (47.6±16.1 before, 44.7±15.5mmHg after, p=0.01). In accordance with invasive measurements, COe increased significantly (COe from 4.3±1.7l/min to 4.8±1.7l/min, p=0.003). Comparing both methods to calculate CO, we observed good agreement between COi and COe using Bland Altman plots., Conclusions: CO increased significantly after PMVR as determined by echocardiography based and invasive calculation of hemodynamics during PMVR. COe shows good agreement with COi before and after the intervention and, thus, represents a potential non-invasive method to determine CO in patients with MR not accessible by conventional surgery., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Both oxidized lipids as well as the complement system contribute to atherothrombosis. The expression of complement receptors correlates with the expression of platelet activation markers, and platelet bound oxidized low-density lipoprotein (oxLDL) modulates platelet function. In the present study, we investigated the relationship of markers of complement activation, the anaphylatoxins C5a and C3a, and oxidized low-density lipoprotein. Two hundred and seven patients with coronary artery disease (CAD) were analyzed in this study. Using enzyme-linked immunosorbent assays, plasma levels of oxLDL, C3a, and C5a were measured. Moreover, we assessed platelet bound oxLDL by flow cytometry. The overall level of C5a in the troponin negative group (stable angina (SA) and unstable angina (UA)) compared to the troponin positive group (non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI)) did not differ significantly (62.7 ± 32.4 ng/ml versus 65.8 ± 40.3 ng/ml). While C5a and C3a showed a significant correlation with each other (r = 0.25, p < 0.001), there was no statistically significant relationship between C3a and platelet bound oxLDL (r = 0.06, p = 0.37). Furthermore, plasma oxLDL did not correlate with either C3a or C5a. However, we observed a moderate, yet significant negative correlation between plasma C5a and platelet bound oxLDL (r = -0.15, p = 0.04). Partial correlation analysis correcting for the presence of acute coronary syndrome (ACS), troponin status or the subgroups SA, UA, NSTEMI, or STEMI did not alter this correlation substantially. Interestingly, flow cytometric analysis of human platelets showed increased expression of C5aR and P-selectin after in vitro stimulation with oxLDL. In conclusion, the complement anaphylatoxin C5a shows an inverse correlation with platelet bound oxLDL. The relationship of oxidized lipids to particular complement components may add to the platelet-lipid interplay in atherogenesis and trigger future clinical and mechanistic studies.

Background: Factors causing resistance to renal denervation (RDN) for treatment of arterial hypertension are not known. In the current study, we sought to determine mechanisms involved in responsiveness to renal denervation therapy in patients with difficult-to-control and resistant hypertension., Methods and Results: We evaluated the differential CpG methylation of genes in blood samples isolated from patients of a recently described cohort of responders or non-responders to renal denervation using microarray technique and measured protein levels of identified downstream effectors in blood samples of these patients by ELISA. Our analysis revealed up to 6103 methylation sites differing significantly between non-responders and responders to renal denervation therapy. Software based analysis showed several of these loci to be relevant for arterial hypertension and sympathetic nervous activity. Particularly, genes involved in glutamate synthesis, degradation and glutamate signaling pathways were differently methylated between both groups. For instance, genes for glutamate dehydrogenase 1 and 2 central to glutamate metabolism, genes for ionotropic (AMPA, NMDA) and metabotropic glutamate receptors as well as glutamate transporters revealed significant differences in methylation correlating with responsiveness to RDN. To underline their potential relevance for responsiveness to RDN, we measured plasma protein levels of norepinephrine, a downstream effector of the glutamate receptor pathway, which were significantly lower in non-responders to RDN., Conclusions: The present study describes novel molecular targets potentially contributing to reduction of blood pressure after RDN in some patients. Identifying patients with a high responsiveness to RDN could contribute to an individualized therapy in drug resistant hypertension.

Objectives: This study sought to evaluate a ventilation maneuver to facilitate percutaneous edge-to-edge mitral valve repair (PMVR) and its effects on heart geometry., Background: In patients with challenging anatomy, the application of PMVR is limited, potentially resulting in insufficient reduction of mitral regurgitation (MR) or clip detachment. Under general anesthesia, however, ventilation maneuvers can be used to facilitate PMVR., Methods: A total of 50 consecutive patients undergoing PMVR were included. During mechanical ventilation, different levels of positive end-expiratory pressure (PEEP) were applied, and parameters of heart geometry were assessed using transesophageal echocardiography., Results: We found that increased PEEP results in elevated central venous pressure. Specifically, central venous pressure increased from 14.0 ± 6.5 mm Hg (PEEP 3 mm Hg) to 19.3 ± 5.9 mm Hg (PEEP 20 mm Hg; p < 0.001). As a consequence, the reduced pre-load resulted in reduction of the left ventricular end-systolic diameter from 43.8 ± 10.7 mm (PEEP 3 mm Hg) to 39.9 ± 11.0 mm (PEEP 20 mm Hg; p < 0.001), mitral valve annulus anterior-posterior diameter from 32.4 ± 4.3 mm (PEEP 3 mm Hg) to 30.5 ± 4.4 mm (PEEP 20 mm Hg; p < 0.001), and the medio-lateral diameter from 35.4 ± 4.2 mm to 34.1 ± 3.9 mm (p = 0.002). In parallel, we observed a significant increase in leaflet coaptation length from 3.0 ± 0.8 mm (PEEP 3 mm Hg) to 5.4 ± 1.1 mm (PEEP 20 mm Hg; p < 0.001). The increase in coaptation length was more pronounced in MR with functional or mixed genesis. Importantly, a coaptation length >4.9 mm at PEEP of 10 mm Hg resulted in a significant reduction of PMVR procedure time (152 ± 49 min to 116 ± 26 min; p = 0.05)., Conclusions: In this study, we describe a novel ventilation maneuver improving mitral valve coaptation length during the PMVR procedure, which facilitates clip positioning. Our observations could help to improve PMVR therapy and could make nonsurgical candidates accessible to PMVR therapy, particularly in challenging cases with functional MR., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atherosclerosis and its late sequels are still the number one cause of death in western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly recognized as an inflammatory disease, influenced by various immune mechanisms. The complement system is part of our innate immune system, and its diverse roles in atherosclerosis have become evident over the past years. In this review we identify points of intersection between platelets and the complement system and discuss their relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset as well as progression of the disease, a possible dual role for complement in the genesis and development of atherosclerosis, and review emerging literature revealing previously unrecognized cross-talk between platelets and the complement system and discuss its possible impact for atherosclerosis. Finally, we identify limitations of current research approaches and discuss perspectives of complement modulation in the control of the disease.

Platelets hold an important function as first line of response to seal wounds after vascular and tissue injury. However, they are much more than just a component of the haemostatic system. They are involved in tissue regeneration and play a role in different pathologic conditions such as atherosclerosis or tumour progression. Angiogenesis being involved in these processes, as well, may represent one of the (patho-) physiological mechanisms, which are modulated by platelets thereby affecting disease. In other diseases involving inflammation, the role of platelets for endothelial cells, which are the most important cell type in angiogenesis, is well established. Recent effort has now highlighted a potential role of platelets and platelet derived mediators for angiogenesis. This article reviews our current understanding of the role of platelets for angiogenesis and how this knowledge could affect future directions in research and therapy.

Background: Treatment of bipolar depression with antidepressants has often been reported to be associated with a certain risk of rapid cycling (RC). Also, non-pharmacological treatment approaches such as sleep deprivation or light therapy can induce affective shifts. Moreover, during electroconvulsive therapy (ECT), which is considered a powerful antidepressant treatment, manic switches and episodes of rapid cycling can occur., Methods: Here we report the case of a 66-year-old female patient with bipolar depression, who underwent electroconvulsive therapy because of a therapy-refractory depressive episode., Results: During ECT, highly frequent mood alternations were observed, fulfilling the criteria of ultra rapid cycling (URC). These symptoms were successfully treated with lithium carbonate while ECT was continued., Conclusion: To our knowledge, this is the first case report of URC during ECT. URC might be considered a rare but potential side effect of ECT. In our case, lithium was used successfully for the treatment of URC and might be suggested in similar cases, where anticonvulsants are not the first choice of treatment. However, in view of the risk of cognitive side effects the combination of ECT and lithium requires a careful clinical monitoring.

Rats were fed a diet poor (0.05%) in essential fatty acids (EFA) with hydrogenated coconut oil as fat component, or a control diet containing 4% of the total energy intake in the form of linoleic acid. Effects of dietary EFA deficiency were investigated during a period of 2-30 weeks. Growth retardation becomes significant after 4 weeks of deficiency and attains about 25% when the deficiency is maintained for longer than 12 weeks. Respiration, body weight and age of EFA-deficient rats and controls are in a nonlinear relationship. Basal respiration in relation to the body weight is significantly increased by EFA deficiency; it is unchanged when related to total animals under the employed experimental conditions. Oxidative phosphorylation in isolated liver mitochondria is unaffected by EFA deficiency, i.e., the increased metabolic rate of EFA-deficient rats, related to the body weight, cannot be explained from impaired functional integrity of the inner mitochondrial membrane. Respiratory chain enzyme activities in mitochondria from heart and skeletal muscle and specific amounts of mitochondria in these tissues are unchanged by EFA deficiency.

Rats were fed a diet either deficient (0.05%) in essential fatty acids (EFA), or providing 4% (control) and 10% (surplus) of the total energy intake in the form of linoleic acid. All diets were isoenergetic and provided 13.9% of the energy as fat. The rats were kept at 29 or 5 degrees C. Growth and food intake of rats fed linoleic acid surplus at either temperature for 10 wk were not different from that of controls; basal metabolism, norepinephrine-induced nonshivering thermogenesis (NST) and thermogenic variables in the brown adipose tissue (amount of mitochondria and mitochondrial uncoupling protein) also were not different. The effects of EFA deficiency were drastically enhanced in the cold: After 10 wk of consuming a diet low in EFA at 5 degrees C, the body weight of rats was 75% of that of controls (87% at 29 degrees C); the food intake was 135% of controls at 5 degrees C (120% at 29 degrees C). The resting respiration in deficient rats was 125% of controls at 5 degrees C (110% at 29 degrees C); body temperatures as low as 35.1 degrees C were measured in deficient rats after 3 wk at 5 degrees C; the cold tolerance of the rats was significantly diminished (30% died within 3 wk at 5 degrees C), thus emphasizing the essential role of dietary EFA during cold stress. Norepinephrine-induced NST and the thermogenic parameters in brown fat were not influenced by EFA deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)