The sheep as a pre-clinical model for testing intra-aortic percutaneous mechanical circulatory support devices.

The save deployment of intra-aortic percutaneous mechanical circulatory support devices is highly dependent on the inner aortic diameter. Finding the anatomically and ethically most suitable animal model for performance testing of new pMCS devices remains challenging. For this study, an ovine model using adult ewes of a large framed breed (Swiss White Alpine Sheep) was developed to test safety, reliability, and biocompatibility of catheter-mounted mechanical support devices placed in the descending thoracic aorta. Following the drawback of fluctuating aortic diameter and device malfunction in the first four animals, the model was improved by stenting the following animals with an aortic stent. Stenting the animals with an intra-aortic over the balloon stent was found to standardize the experimental set-up and to avoid early termination of the experiment due to non-device related issues.

Traumatic tracheobronchial injuries: incidence and outcome of 136.389 patients derived from the DGU traumaregister.

To describe the incidence, therapy and outcome of traumatic tracheobronchial injuries (TTBI) in trauma patients with multiple injuries derived from the DGU TraumaRegister. We analyzed the data on all patients listed on the TraumaRegister DGU (TR-DGU) in Germany between 2002 and 2015 aged 16 years or older and with an Injury Severity Score (ISS) of ≥ 9. We analyzed the data on 136,389 trauma patients, 561 of whom had suffered tracheobronchial injuries (0.4%). The majority were male (73.4%) and had a mean age of 43.7 years. In total, 84.0% of all TTBI injuries occurred secondary to blunt trauma, caused mainly by accidents (71.2%). TTBI was accompanied by several concomitant thoracic injuries such as pneumo- (41.2%) and hemothorax (23.2%), lacerations (7.8%) and contusions (32.3%) of the lung, as well as multiple rib fractures (29.6%). The severity of injury was classified via the abbreviated injury scale (AIS): 39.3% with AIS = 3, 51.3% with AIS = 4 and 60% with AIS = 5 patients underwent surgical interventions. The mortality of patients with tracheobronchial injuries was higher: 24.6%, versus 13.7% in all patients (control group). This high percentage reflects their generally severe injury burden through concomitant injuries. The incidence of TTBI in this large cohort of trauma patients is very low. However, its high mortality rate emphasizes its importance. Mortality was associated with higher ISS and AIS scores. Higher rates of concomitant injuries were therefore associated with a higher mortality rate. TTBI injuries revealed a higher rate of progression to surgical management, with 35% undergoing surgery within the first 24 h. This excessive mortality rate demonstrates a high overall injury burden in patients with TTBI and high mortality of associated injuries. A surgical intervention's impact on mortality cannot be assessed in this study, as it would need to be investigated in a case-matched study.

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.

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.

Extracorporeal life support prior to left ventricular assist device implantation leads to improvement of the patients INTERMACS levels and outcome.

BACKGROUND: The objective of this study was to evaluate the outcome of left ventricular assist device (LVAD) implantation after initial extracorporeal life support (ECLS) in patients with cardiogenic shock and the incidence of post implantation right ventricular failure. METHODS & RESULTS: All patients on ECLS therapy for cardiogenic shock prior to LVAD implantation (n = 15) between October 2011 and January 2014 were analyzed. Baseline patient characteristics, as well as detailed pre-operative treatment and postoperative outcome data were collected retrospectively. At time of admission to our unit all patients were classified INTERMACS II or higher (12 [80%] INTERMACS I). Improvement to INTERMACS III temporary cardiac support (TCS) at time of LVAD implantation was successful in 14 patients (93.3%). End-organ function recovered during ECLS support. No patient needed ongoing ECLS or additional right ventricular support after LVAD implantation. Both in-hospital and 30-day mortality was 6.7% (n = 1). The median duration of LVAD support was 687.9 ± 374.5 days. At the end of the study (follow-up 810.7 +/- 338.9 days), 13 (86.7%) patients were alive. The majority of patients (10 [66.7%]) remained on LVAD support. Transplantation could be performed in 1 (6.7%) patient, 2 (13.3%) patients could be successfully weaned. CONCLUSION: LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to-bridge therapy may help to lower mortality in primarily unstable patients.

An Atelocollagen Coating for Efficient Local Gene Silencing by Using Small Interfering RNA.

In the last decades, many efforts have been made to counteract adverse effects after stenting atherosclerotic coronary arteries. A breakthrough in better vascular wall regeneration was noted in the new era of drug-eluting stents. A novel personalized approach is the development of gene-eluting stents promising an alteration in gene expression involved in regeneration. We investigated a coating system consisting of the polymer atelocollagen (ATCOL) and a specific small interfering RNA (siRNA) for intercellular adhesion molecule-1 (ICAM-1) found on the surface of defective endothelial cells (ECs). We demonstrated very high cell viability, in which EA.hy926 grew on 0.008% or 0.032% ATCOL layers. Additionally, hemocompatibility assays proved the biocompatibility of this coating. The highest transfection efficiency with EA.hy926 was achieved with 5 µg siRNA immobilized in ATCOL after 2 days. The release of fluorescent-labeled siRNA was about 9 days. Long-term knockdown of ICAM-1 was analyzed by flow cytometry, revealing that the coating with 0.008% ATCOL and 5 µg siICAM-1 provoked gene silencing up to 8 days. 5'-RNA ligase-mediated rapid amplification of cDNA ends PCR (RLM-RACE-PCR) demonstrated the specificity of our established ATCOL gene-silencing coating, meaning that our coating is well suited for further investigations in in vivo studies. Herein, we would like to demonstrate that our ATCOL is well-suited for better artery wall regeneration after stent implantation.

RNA-Eluting Surfaces for the Modulation of Gene Expression as A Novel Stent Concept.

Presently, a new era of drug-eluting stents is continuing to improve late adverse effects such as thrombosis after coronary stent implantation in atherosclerotic vessels. The application of gene expression-modulating stents releasing specific small interfering RNAs (siRNAs) or messenger RNAs (mRNAs) to the vascular wall might have the potential to improve the regeneration of the vessel wall and to inhibit adverse effects as a new promising therapeutic strategy. Different poly (lactic-co-glycolic acid) (PLGA) resomers for their ability as an siRNA delivery carrier against intercellular adhesion molecule (ICAM)-1 with a depot effect were tested. Biodegradability, hemocompatibility, and high cell viability were found in all PLGAs. We generated PLGA coatings with incorporated siRNA that were able to transfect EA.hy926 and human vascular endothelial cells. Transfected EA.hy926 showed significant siICAM-1 knockdown. Furthermore, co-transfection of siRNA and enhanced green fluorescent protein (eGFP) mRNA led to the expression of eGFP as well as to the siRNA transfection. Using our PLGA and siRNA multilayers, we reached high transfection efficiencies in EA.hy926 cells until day six and long-lasting transfection until day 20. Our results indicate that siRNA and mRNA nanoparticles incorporated in PLGA films have the potential for the modulation of gene expression after stent implantation to achieve accelerated regeneration of endothelial cells and to reduce the risk of restenosis.

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.

Impella 5.0 as a Second-Line Mechanical Circulatory Support Strategy After Extracorporeal Life Support.

The catheter-based Impella 5.0 left ventricular assist device is a powerful and less invasive alternative for patients in cardiogenic shock. The use as second-line therapy in patients with precedent extracorporeal life support (ECLS) has not been described before now. We analyzed our experience of consecutive patients treated with this alternative strategy. From April 2014 to December 2014, eight patients had been implanted as a second-line option after ECLS support. The reason for the change from ECLS to Impella 5.0 was absence of cardiac recovery for primary weaning and complications of ECLS therapy. The mean time of ECLS support prior to Impella implantation was 12 ± 7 days. The implantation of the Impella 5.0/CP was technically successful in all patients, and the ECLS could be explanted in all eight patients who received Impella implantation as a second-line treatment. The second-line Impella 5.0 therapy resulted in two patients who turned into left ventricular assist device (LVAD) candidates, two primary weaning candidates, and four patients who died in the setting of sepsis or absent cardiac recovery and contraindications for durable LVAD therapy. Thereby, the overall hospital discharge survival as well as the 180-day survival was 50% for Impella 5.0 implantations as second-line procedure after ECLS. The latest follow-up survival of this second-line strategy after ECLS was three out of eight, as one patient died after 299 days of LVAD support due to sepsis. The use of Impella 5.0 constitutes a possible second-line therapeutic option for those patients who do not show cardiac recovery during prolonged ECLS support or suffer from complications of ECLS therapy. This treatment allows additional time for decisions regarding cardiac recovery or indication for durable LVAD therapy.

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.

Identification of Predictive Early Biomarkers for Sterile-SIRS after Cardiovascular Surgery.

Systemic inflammatory response syndrome (SIRS) is a common complication after cardiovascular surgery that in severe cases can lead to multiple organ dysfunction syndrome and even death. We therefore set out to identify reliable early biomarkers for SIRS in a prospective small patient study for timely intervention. 21 Patients scheduled for planned cardiovascular surgery were recruited in the study, monitored for signs of SIRS and blood samples were taken to investigate biomarkers at pre-assigned time points: day of admission, start of surgery, end of surgery, days 1, 2, 3, 5 and 8 post surgery. Stored plasma and cryopreserved blood samples were analyzed for cytokine expression (IL1ß, IL2, IL6, IL8, IL10, TNFα, IFNγ), other pro-inflammatory markers (sCD163, sTREM-1, ESM-1) and response to endotoxin. Acute phase proteins CRP, PCT and pro-inflammatory cytokines IL6 and IL8 were significantly increased (p<0.001) at the end of surgery in all patients but could not distinguish between groups. Normalization of samples revealed significant increases in IL1ß changes (p<0.05) and decreased responses to endotoxin (p<0.01) in the SIRS group at the end of surgery. Soluble TREM-1 plasma concentrations were significantly increased in patients with SIRS (p<0.01). This small scale patient study could show that common sepsis markers PCT, CRP, IL6 and TNFα had low predictive value for early diagnosis of SIRS after cardiovascular surgery. A combination of normalized IL1ß plasma levels, responses to endotoxin and soluble TREM-1 plasma concentrations at the end of surgery are predictive markers of SIRS development in this small scale study and could act as an indicator for starting early therapeutic interventions.

Hemocompatibility of Axial Versus Centrifugal Pump Technology in Mechanical Circulatory Support Devices.

The hemocompatible properties of rotary blood pumps commonly used in mechanical circulatory support (MCS) are widely unknown regarding specific biocompatibility profiles of different pump technologies. Therefore, we analyzed the hemocompatibility indicating markers of an axial flow and a magnetically levitated centrifugal device within an in vitro mock loop. The HeartMate II (HM II; n = 3) device and a CentriMag (CM; n = 3) adult pump were investigated in a human whole blood mock loop for 360 min using the MCS devices as a driving component. Blood samples were analyzed by enzyme-linked immunosorbent assay for markers of coagulation, complement system, and inflammatory response. There was a time-dependent activation of the coagulation (thrombin-antithrombin complexes [TAT]), complement (SC5b-9), and inflammation system (polymorphonuclear [PMN] elastase) in both groups. The mean value of TAT (CM: 4.0 µg/L vs. 29.4 µg/L, P < 0.001; HM II: 4.5 µg/L vs. 232.2 µg/L, P < 0.05) and PMN elastase (CM: 53.4 ng/mL vs. 253.8 ng/mL, P < 0.05; HM II: 28.0 ng/mL vs. 738.8 ng/mL, P < 0.001) significantly increased from baseline until the end of the experiments (360 min). After 360 min, TAT and PMN values were significantly higher in the HM II group compared with the values in the CM adult group. The values of SC5b-9 increased from baseline to 360 min in the CM group (CM: 141.8 ng/mL vs. 967.9 ng/mL, P < 0.05) and the HM II group. However, the increase within the HM II group (97.3 vs. 2462.0, P = 0.06) and the comparison of the 360-min values between CM group and HM II group did not reach significance (P = 0.18). The activation of complement, coagulation, and inflammation system showed a time-dependent manner in both devices. The centrifugal CM device showed significantly lower activation of coagulation and inflammation than that of the HM II axial flow pump. Both HM II and CM have demonstrated an acceptable hemocompatibility profile in patients. However, there is a great opportunity to gain a clinical benefit by developing techniques to lower the blood surface interaction within both pump technologies and a magnetically levitated centrifugal pump design might be superior.

Impella 5.0 Support in INTERMACS II Cardiogenic Shock Patients Using Right and Left Axillary Artery Access.

The catheter-based Impella 5.0 left ventricular assist device (LVAD) is a powerful and less invasive alternative for patients in cardiogenic shock. The use of this device as a primary mechanical circulatory support strategy in INTERMACS II patients should be evaluated. From April 2014 to August 2014, eight Impella 5.0 devices were implanted in seven patients via the axillary artery access (six right and two left). We analyzed the outcome of the four patients in whom the Impella 5.0 device was implanted for the purpose of primary stabilization of cardiogenic shock (INTERMACS II). The remaining three patients had a contraindication for a permanent LVAD and received the device for prolonged weaning from extracorporeal life support (ECLS) system. The implantation of the Impella 5.0 was technically successful in all patients and resulted in the stabilization of the clinical situation. All four patients could be bridged to a long-term device (n = 3) or to cardiac recovery (n = 1). In one patient, 2 days of ECLS support was necessary because of pump thrombosis after 31 days of Impella 5.0 support. One patient with bronchopneumonia had the Impella 5.0 exchanged from the right to the left axillary artery after 22 days of support because of the progressive loss of purge flow and the need for longer bridging to a permanent LVAD. The last patient was supported for giant-cell myocarditis for 22 days and bridged to cardiac recovery. All patients were transferred to the intensive care unit with the Impella device in place. In INTERMACS II situations, the implantation of the Impella 5.0 via the right or left axillary access allowed additional time for decision making. Early patient mobilization, including walking with the Impella device in place, optimized the conditions for either weaning or the implantation of a permanent LVAD. This novel technique of left axillary approach leads to more flexibility in the case of anatomical- or device-related contraindications to right-side access, or when the device needs to be exchanged while continuous support is necessary.