Johannes Patzelt

Platelets in angiogenesis.

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.

Platelets and the complement cascade in atherosclerosis

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.

Effects of Mechanical Ventilation on Heart Geometry and Mitral Valve Leaflet Coaptation During Percutaneous Edge-to-Edge Mitral Valve Repair

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.

Percutaneous Mitral Valve Edge-to-Edge Repair With Simultaneous Biatrial Intracardiac Echocardiography First-in-Human Experience

Recently, we described a percutaneous mitral valve edge-to-edge repair (PMVR) procedure in a patient using both transesophageal echocardiography (TOE) and intracardiac echocardiography (ICE).1 In that patient, however, central steps of PMVR were guided primarily by TOE. Advantages of intracardiac echocardiography are avoidance of TOE and thus general anesthesia. The procedure can be performed in a conscious patient. Accordingly, the need for catecholamines, the risk of hypotension, prolonged periods of weaning from mechanical ventilation, and postinterventional delirium are reduced. Although in theory the use of left atrial ICE is sufficient to guide PMVR, ICE has not been used as the only imaging modality to guide PMVR because of disadvantages such as the lack of 3-dimensional (3D) vision with X-plane views and particularly the lack of experience using ICE for PMVR. Here, we report a PMVR procedure in a patient with functional mitral regurgitation (MR) using ICE because TOE guidance was not possible. A 78-year-old patient presented with decompensated heart failure with MR grade IV (Figure, A and B). He had a history of repeated hospitalizations for heart failure caused by ischemic cardiomyopathy with severely reduced left ventricular function. An internal cardioverter-defibrillator had been implanted because he had repeated ventricular arrhythmias. As a result of severe comorbidities, a decision for PMVR was made by our interdisciplinary heart team. TOE was not possible (even with endoscopic guidance) because …

Immediate increase of cardiac output after percutaneous mitral valve repair (PMVR) determined by echocardiographic and invasive parameters:Patzelt: Increase of cardiac output after PMVR

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.

Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral valve repair (PMVR) using the MitraClip system

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.

Galectin-3 is associated with left ventricular reverse remodeling and outcome after percutaneous mitral valve repair

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.

Comparison of Deep Sedation With General Anesthesia in Patients Undergoing Percutaneous Mitral Valve Repair

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.

Platelet bound oxLDL shows an inverse correlation with plasma anaphylatoxin C5a in patients with coronary artery disease

Abstract 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.

First Experience with the MitraClip XTR® Compared to the MitraClip NTR® System in a Patient with Severe Mitral Regurgitation and Complex Mitral Valve Anatomy

Percutaneous edge-to-edge mitral valve repair (PMVR) is a successful treatment option in patients with severe mitral regurgitation (MR) not eligible for conventional open surgery. There are two new MitraClip® systems available (Abbott Vascular, Wetzlar, Germany), the MitraClip XTR® and the MitraClip NTR®. While the latter has the same clip geometry as the contemporary MitraClip NT® system, the XTR® system has longer clip-arms (extended 3 mm of length for each arm) and improved grippers with two additional rows of frictional elements. Here, we report the case of a patient with complex mitral valve anatomy and severe MR. While grasping with the NTR® system was difficult, we experienced a straightforward implantation using the XTR® system instead. The patient presented with a history of repeated hospitalization due to decompensated heart failure. Echocardiography showed a good systolic left ventricular (LV) function with severe primary MR with a prolapse of the anterior mitral valve (MV) leaflet (AML) in segment 2 with an eccentric posterior-directed jet (Figure 1A,B). Furthermore, calcifications were present with a restrictive posterior MV leaflet (PML) (Figure 1C). 3D EROA (effective regurgitant orifice area) was measured as 1.46 cm (Figure 1D). A decision for PMVR was made by our interdisciplinary heart team due to severe comorbidities. Although in difficult mitral valve anatomies mechanical ventilation with elevated positive endexpiratory pressure may facilitate PMVR, we chose to carry out the intervention in conscious sedation considering the frailty of our patient. First, a MitraClip NTR® was advanced and positioned underneath the mitral valve plane. However, due to the prolapse of the AML and the restrictive PML, no sufficient grasp of both leaflets could be promptly achieved. Thus, the MitraClip NTR® was removed and a MitraClip XTR® was introduced, instead. In our experience, the location of the transseptal puncture does not differ between the NTR® and the XTR® clip. Due to its extended arms, sufficient leaflet material could be loaded rather easily on both arms of the device (Figure 1E). 3D view of the mitral valve confirmed optimal orientation of the opened clip device (Figure 1F) and implantation of the clip resulted in good coaptation and a clear reduction of MR. Subsequently, a second MitraClip XTR® (Figure 1G) further improved the result with only mild residual MR (Figure 1H). 3D EROA showed two small residual regurgitant orifices with a total area of 0.26 cm (Figure 1I).