Gene regulation for inflammation and inflammation resolution differs between umbilical arterial and venous endothelial cells.

Systemic inflammation affects the whole vasculature, yet whether arterial and venous endothelial cells differ in their abilities to mediate inflammation and to return to homeostasis after an inflammatory stimulus has not been addressed thoroughly. We assessed gene-expression profiles in isolated endothelial cells from human umbilical arteries (HUAEC) or veins (HUVEC) under basal conditions, after TNF-α stimulation and various time points after TNF-α removal to allow reinstatement of homeostasis. TNF-α regulates the expression of different sets of transcripts that are significantly changed only in HUAEC, only in HUVEC or changed in both. We identified three types of gene regulation, i.e. genes that were significantly regulated after 24 h of TNF-α stimulation but no longer when TNF-α was removed (homeostatic regulation), genes that maintained significantly regulated after TNF-α removal (not homeostatic regulation) and genes that were only significantly regulated when TNF-α was removed (post-regulation). HUAEC and HUVEC quantitatively differed in these types of gene regulation, with relatively more genes being post-regulated in HUAEC. In conclusion our data demonstrate that HUAEC and HUVEC respond intrinsically different to an inflammatory insult. Whether this holds true for all endothelial cells and its relevance for inflammatory insults in different organs during systemic inflammation warrants further studies.

Case report: Strong low-density-cholesterol reduction accompanied by shrinkage of low-attenuation coronary plaque during lipid-lowering treatment with bempedoic acid-serial evaluation by coronary computed tomography angiography.

Here, we present a patient with coronary artery disease and prior percutaneous coronary interventions. This patient had to discontinue taking multiple statins and ezetimibe due to intolerance with musculoskeletal complaints and nausea. Monotherapy with bempedoic acid was well tolerated and was exceptionally effective at lipid lowering, enabling patients to achieve the low-density lipoprotein target of <55 mg/dl, as recommended by current guidelines. In addition, serial coronary computed tomography angiography performed upon clinical indications, during 20 months of lipid-lowering treatment with bempedoic acid, demonstrated signs of favorable plaque component modification, with shrinkage of the low-attenuation plaque component compared to baseline findings.

Serial Changes in Coronary Plaque Formation Using CT Angiography in Patients Undergoing PCSK9-Inhibitor Therapy With 1-year Follow-up.

PURPOSE: Previous studies have shown positive effects of intensive low-density lipoprotein (LDL)-lowering therapy on atheroma volume using invasive intravascular ultrasound. This study describes the changes in coronary plaque composition on coronary computed tomography angiography in patients treated with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. MATERIALS AND METHODS: In this prospective study, coronary plaques were analyzed using third-generation dual-source computed tomography before and after 1 year of PCSK9-inhibitor treatment. Plaque markers included total plaque volume (TPV), calcified plaque volume (CPV), noncalcified plaque volume (NCPV), lumen volume and vessel volume (VV), minimal luminal area (MLA), minimal lumen diameter (MLD), corrected coronary opacification, eccentricity, remodeling index, and functional plaque parameters. Primary endpoint was defined as change in TPV; the secondary endpoint was TPV or CPV regression or nominal change in plaque parameters. RESULTS: We analyzed 74 coronary plaques in 23 patients (60±9 y, 65% male). After 1 year of PCSK9-inhibitor treatment, LDL was reduced from 148 to 66 mg/dL ( P <0.0001). Significant changes were found for VV (196 to 215 mm 3 , P =0.0340), MLA (3.1 to 2.6 mm 2 , P =0.0413), and MLD (1.7 to 1.4 mm, P =0.0048). TPV, CPV, NCPV, lumen volume, and functional plaque parameters did not change significantly ( P >0.05). CONCLUSIONS: Coronary artery plaque analysis by coronary computed tomography angiography highlights that LDL lowering therapy affects plaque composition. The primary endpoint of TPV change was not reached; however, VV, MLA, and MLD changed significantly.

The role of antirheumatics in patients with COVID-19.

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.

The effect of hydroxychloroquine on platelet activation in model experiments.

Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune conditions. While clinical series suggest anti-thrombotic properties, the way in which HCQ exerts this effect remains to be fully explained. Following a 24-h incubation of human umbilical vein endothelial cells (HUVEC) and human umbilical arterial endothelial cells (HUAEC) with HCQ (concentration 500, 1000 and 2000 ng/ml), these cells were then stimulated for an hour with tumor necrosis factor alpha (TNF-α) and were subsequently incubated in direct contact with thrombin-activated platelets. The expression of CD40L on platelets was measured by flow cytometry. The expression of CD40L on platelets significantly increased after direct incubation with 1000 ng/ml and 2000 ng/ml concentrations of HCQ. In contrast, after pre-incubation of HUAECs with 1000 ng/ml HCQ and following stimulation with platelets the expression of CD40L was significantly reduced also after stimulation with thrombin and TNF-α activated platelets. It was shown that the expression of CD40L on the platelets was not significantly reduced by different HCQ concentrations after contact with HCQ pre-incubated HUVECs. HCQ reduces the stimulatory effect of thrombin and TNF-α on platelet activation in the presence of endothelial cells. Our experiments suggest that HCQ pre-incubated HUAEC cells result in a reduced platelets activation measured by means of CD40L expression. Further, our results show that direct HCQ incubation of platelets (without the presence of EC) increased the expression of CD40L suggesting that the observed effect of HCQ on platelet activation may be EC mediated.

Characterization of circulating thrombin in patients with septic shock: a prospective observational study.

Septic shock is characterized by a dysregulated response to infection, hypotension and activation of the coagulation system. Markers of coagulation activation are commonly used to diagnose and monitor ensuing coagulopathies. In this study, we sought to determine levels of circulating thrombin in patients with septic shock. To characterize levels of circulating, active thrombin in patients with septic shock. 48 patients with septic shock were included in this prospective, observational study. Blood samples were obtained on admission, day 1, day 3 and day 6. Levels of active thrombin were measured using a standardized, clinically applicable oligonucleotide (aptamer)-based enzyme-capture assay (OECA). Thrombin levels were correlated with established indirect thrombin parameters, conventional coagulation tests, laboratory parameters, patient characteristics and outcome. Elevated levels of thrombin were detected in 27 patients (56.3%) during the course of the study. Thrombin levels were positively correlated with thrombin-antithrombin complexes (r = 0.30, p < 0.05) and negatively associated with FVII levels (r = - 0.28, p < 0.05). Thrombin levels on admission did not predict 30-day mortality (OR 0.82, 95% CI 0.23-2.92, p = 0.77). Circulating levels of active thrombin can be measured in a subset of patients with septic shock. Although thrombin levels are correlated with established markers of coagulation, they do not provide additional prognostic information.

Non-invasive measurement of hemodynamic response to postural stress using inert gas rebreathing.

In postural stress, an increased preload volume leads to higher stroke volume (SV) according to the Frank-Starling law of the heart. The present study aimed to evaluate the hemodynamic response to postural stress using non-invasive inert gas rebreathing (IGR) in patients with normal as well as impaired left ventricular function. Hemodynamic measurements were performed in 91 patients undergoing cardiac magnetic resonance imaging (CMR). Mean cardiac output and SV determined by IGR were 4.4±1.3 l/min and 60±19 ml in the upright position, which increased significantly to 5.0±1.2 l/min and 75±23 ml in the supine position (P<0.01). Left ventricular systolic function was normal [ejection fraction (EF) ≥55%] in 42 patients as determined by CMR. In 21 patients, EF was mildly abnormal (45-54%), in 16 patients moderately abnormal (30-44%) and in 12 patients severely abnormal (<30%). An overall trend for a lower percentage change in SV (%ΔSV) was indicated with increasing impairment of ejection fraction. In patients with abnormal EF in comparison to those with normal EF, the %ΔSV was significantly lower (13% vs. 22%; P=0.03). Non-invasive measurement of cardiac function using IGR during postural changes may be feasible and detected significant difference in %ΔSV in patients with normal and impaired EF according to the Frank-Starling law of the heart. Several clinical scenarios including cases of heart rhythm disturbances or pulmonary or congenital heart disease are worthy of further investigation.

Cardioprotective Effects of Dronedarone Mediated by the Influence on the Expression of Urokinase-Type Plasminogen Activator Receptor.

PURPOSE: Dronedarone is a multichannel-blocking antiarrhythmic drug for the treatment of atrial fibrillation. Observational data hypothesized a cardioprotective effect. In an in vitro endothelial cell-platelet model, we evaluated the molecular atheroprotective effects of dronedarone. METHODS: Following a 24-h incubation of human umbilical vein endothelial cells (HUVECs) with dronedarone (concentration 50, 100, and 150 ng/mL), they were then stimulated for 1 h with lipopolysaccharide (LPS) and were subsequently incubated in direct contact with thrombin-activated platelets. After incubation, the expression of CD40L and CD62P on platelets, and the expression of ICAM-1, VCAM-1, urokinase-type plasminogen activator receptor (uPAR), and membrane type 1 matrix metalloproteinase (MT1-MMP) on endothelial cells were measured by flow cytometry. RESULTS: Preincubation with 150 ng/mL of dronedarone reduced the expression of uPAR on endothelial cells after proinflammatory stimulation with LPS and also by direct endothelial contact with activated platelets (p = 0.0038). In contrast, the expression of CD40L and CD62P on platelets after proinflammatory stimulation with thrombin was significantly increased through direct preincubation with 50/100/150 ng/mL of dronedarone. However, dronedarone had no effects on the expression of MT1-MMP and ICAM-1 in HUVECs. CONCLUSION: In this in vitro analysis, dronedarone directly increased platelet activation but showed significant direct effects on endothelial cells and indirect effects on platelets on selected markers of atherosclerosis.

Association of Serum Lipid Profile With Coronary Computed Tomographic Angiography-derived Morphologic and Functional Quantitative Plaque Markers.

PURPOSE: Recent advances in image quality of coronary computed tomographic angiography (cCTA) have enabled improved characterization of coronary plaques. Thus, we investigated the association between quantitative morphological plaque markers obtained by cCTA and serum lipid levels in patients with suspected or known coronary artery disease. MATERIALS AND METHODS: We retrospectively analyzed data of 119 statin-naive patients (55±14 y, 66% men) who underwent clinically indicated cCTA between January 2013 and February 2017. Patients were subdivided into a plaque and a no-plaque group. Quantitative and morphologic plaque markers, such as segment involvement score, segment stenosis score, remodeling index, napkin-ring sign, total plaque volume, calcified plaque volume, and noncalcified plaque volume (NCPV) and plaque composition, were analyzed using a semiautomated plaque software prototype. Total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein, low-density lipoprotein/high-density lipoprotein ratio, and triglycerides were determine in both groups. RESULTS: Higher age (61±11 y vs. 52±14 y, P<0.0001) and a higher likelihood of male gender (77% vs. 56%, P<0.0001) were observed in the plaque group. Differences in lipid levels were neither observed for differentiation between plaque presence or absence, nor after subcategorization for plaque composition. LDL serum levels >160 mg/dL correlated with higher NCPV compared with patients with LDL between 100 and 160 mg/dL (112 vs. 27 mm, P=0.037). Other markers were comparable between the different groups. CONCLUSION: Statin-naive patients with known or suspected coronary artery disease did not show differences in lipid levels related to plaque composition by cCTA. Patients with plaques tended to be men and were significantly older. High LDL levels correlated with high NCPV.

Small Airway Disease in Pulmonary Hypertension-Additional Diagnostic Value of Multiple Breath Washout and Impulse Oscillometry.

Airways obstruction is frequent in patients with pulmonary hypertension (PH). Small airway disease (SAD) was identified as a major contributor to resistance and symptoms. However, it is easily missed using current diagnostic approaches. We aimed to evaluate more elaborate diagnostic tests such as impulse oscillometry (IOS) and SF6-multiple-breath-washout (MBW) for the assessment of SAD in PH. Twenty-five PH patients undergoing body-plethysmography, IOS and MBW testing were prospectively included and equally matched to pulmonary healthy and non-healthy controls. Lung clearance index (LCI) and acinar ventilation heterogeneity (Sacin) differed significantly between PH, healthy and non-healthy controls. Likewise, differences were found for all IOS parameters between PH and healthy, but not non-healthy controls. Transfer factor corrected for ventilated alveolar volume (TLCO/VA), frequency dependency of resistance (D5-20), resonance frequency (Fres) and Sacin allowed complete differentiation between PH and healthy controls (AUC (area under the curve) = 1.0). Likewise, PH patients were separated from non-healthy controls (AUC 0.762) by D5-20, LCI and conductive ventilation heterogeneity (Scond). Maximal expiratory flow (MEF) values were not associated with additional diagnostic values. MBW and IOS are feasible in PH patients both providing additional information. This can be used to discriminate PH from healthy and non-healthy controls. Therefore, further research targeting SAD in PH and evaluation of therapeutic implications is justified.

The evolution of activated protein C plasma levels in septic shock and its association with mortality: A prospective observational study.

PURPOSE: Septic shock is commonly associated with hemostatic abnormalities. The endothelium-activated serine protease activated protein C (APC) plays a pivotal role in limiting coagulation and possesses anti-apoptotic and anti-inflammatory properties. We hypothesized that APC levels correlate with established coagulation parameters and provide prognostic information in patients with septic shock. METHODS: We conducted a prospective, observational cohort study in patients with septic shock. APC was measured on admission (day 0) and on days 1, 3, and 6 by a clinically applicable oligonucleotide (aptamer)-based enzyme-capture assay (OECA). The primary endpoint was defined as sepsis-associated 30-day mortality. Furthermore, we analyzed the correlation of APC levels with established coagulation markers. RESULTS: 48 consecutive patients admitted with septic shock were included (mortality 39.6%). APC levels were elevated upon admission (0.59 ng/ml, IQR 0.26-0.97) and showed a strong correlation with established markers of coagulation and lactate. Multivariable logistic regression identified APC (OR 4.3, 95% CI 1.1-17.8, p = 0.04) and lactate levels (OR 7.0, 95% CI 4.1-18.2, p = 0.04) as independent predictors of 30-day mortality. CONCLUSIONS: APC levels are increased in patients with septic shock and are correlated with established markers of coagulation. Elevated APC levels on admission are an independent predictor of mortality.

Therapy optimization in patients with heart failure: the role of the wearable cardioverter-defibrillator in a real-world setting.

BACKGROUND: The wearable cardioverter-defibrillator (WCD) has emerged as a valuable tool to temporarily protect patients at risk for sudden cardiac death (SCD). The aim of this study was to determine the value of the WCD for therapy optimization of heart failure patients. METHODS: One hundred five consecutive patients that received WCD between 4/2012 and 9/2016 were included in the study. All patients were followed for clinical outcome and echocardiographic parameters during WCD therapy and had continued follow-up after WCD therapy, irrespective of subsequent implantable cardioverter-defibrillator (ICD) implantation. RESULTS: The most common indication for WCD were newly diagnosed ischemic (ICM) or non-ischemic cardiomyopathy (NICM) with left ventricular ejection fraction (LVEF) ≤35%. Mean WCD wear time was 68.8 ± 50.4 days with a mean daily use of 21.5 ± 3.5 h. Five patients (4.8%) received a total of five appropriate WCD shocks. During WCD wear, patients with ICM and NICM showed significant improvement in LVEF, reducing the proportion of patients with a need for primary preventive ICD implantation to 54.8% (ICM) and 48.8% (NICM). An ICD was finally implanted in 51.4% of the study patients (24 trans-venous ICDs, 30 subcutaneous ICDs). After discontinuation of WCD therapy, all patients were followed for a mean of 18.6 ± 12.3 months. 5.6% of patients with implanted ICDs received appropriate therapies. No patient with subcutaneous ICD needed change to a trans-venous device. None of the patients without an implanted ICD suffered from ventricular tachyarrhythmias and no patient died suddenly. In patients with NICM a significant LVEF improvement was observed during long-term follow-up (from 34.8 ± 11.1% to 41.0 ± 10.2%). CONCLUSIONS: WCD therapy successfully bridged all patients to either LVEF recovery or ICD implantation. Following WCD, ICD implantation could be avoided in almost half of the patients. In selected patients, prolongation of WCD therapy beyond 3 months might further prevent unnecessary ICD implantation. The WCD as an external monitoring system contributed important information to optimize device selection in patients that needed ICD implantation.

Short- and long-term effects of hemodialysis on platelet and monocyte activity markers of atherosclerosis in patients with end-stage renal disease.

BACKGROUND: In hemodialysis (HD) patients cardiovascular events represent the predominant cause of mortality. Since platelet and monocyte activity markers play an important role in cardiovascular mortality, this study assessed the influence of HD on these markers. METHODS: Forty one HD patients (25 male, 16 female) were included. Blood samples were obtained before and after a single HD session at baseline and again after an elapsed period of 114 ± 21 days (91-175 days) on maintenance hemodialysis. Surface expression of CD40L and CD62P on platelets, tissue factor binding on monocytes and platelet-monocyte aggregates were measured by flow cytometry. Plasma levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa) and soluble CD40L were analyzed by enzyme linked immunosorbent assay. RESULTS: Tissue factor on monocytes was significantly increased after a single HD session at baseline (p = 0.041), whereas platelet-monocyte aggregates, the expression of CD40L and CD62P on platelets did not change significantly. After a mean of 114 ± 21 days of HD therapy, tissue factor on monocytes (p < 0.0001), platelet-monocytes aggregates (p < 0.0001), plasma levels of MCP-1 (p = 0.012) and TNFa (p = 0.046) were significantly decreased compared to baseline values. In contrast, platelet surface expression of CD40L and CD62P as well as plasma levels of sCD40L and IL-6 were not attenuated significantly. There was no significant correlation detected between the markers examined and the cumulative time on hemodialysis. CONCLUSIONS: Platelet and monocyte activity markers assessed in this study do not appear to be significantly increased by HD therapy. Therefore, these markers probably cannot be accountable for increased cardiovascular mortality in chronic HD patients.

Multiple breath washout testing in adults with pulmonary disease and healthy controls - can fewer measurements eventually be more?

BACKGROUND: Multiple breath washout (MBW) became a valuable research tool assessing ventilation heterogeneity. However, routine clinical application still faces several challenges. Deriving MBW parameters from three technically acceptable measurements according to current recommendations prolongs test times. We therefore aimed to evaluate reporting only duplicate measurements in healthy adults and pulmonary disease. METHODS: One hundred and fifty-three subjects prospectively underwent conventional lung function testing and closed-circuit SF6-MBW. Three technically acceptable MBW-measurements were obtained in 103 subjects. RESULTS: Lung clearance index (LCI) differed significantly among 19 controls (7.4 ± 0.8), 19 patients with sarcoidosis (8.1 ± 1.2), 32 with bronchial asthma (9.2 ± 1.9) and 33 with COPD (10.8 ± 2.2, p < 0.001). Within-test repeatability was high (coefficient of variation between 2.5% in controls and 3.6% in COPD) and remained unchanged when only including the first two measurements. Likewise, LCI remained stable with mean absolute changes ranging from 0.9 ± 0.8% in controls to 1.5 ± 0.9% in COPD (p = 0.1). Mean test time reduction differed significantly between groups reaching 200 s in COPD (p = 0.01). CONCLUSIONS: Duplicate SF6-MBW-measurements are sufficient in adult patients with pulmonary disease and healthy controls. LCI values and intra-test repeatability are not affected reducing total test time statistically significant. Our findings have the potential to further facilitate application of MBW in research and clinical routine. TRIAL REGISTRATION: NCT03176745 , June 2, 2017 retrospectively registered.

Low Prevalence of Inappropriate Shocks in Patients With Inherited Arrhythmia Syndromes With the Subcutaneous Implantable Defibrillator Single Center Experience and Long-Term Follow-Up.

BACKGROUND: Up to 40% of patients with transvenous implantable cardioverter-defibrillator (ICD) experience lead-associated complications and may suffer from high complication rates when lead extraction is indicated. Subcutaneous ICD may represent a feasible alternative; however, the efficacy of the subcutaneous ICD in the detection and treatment of ventricular arrhythmias in patients with hereditary arrhythmia syndromes has not been fully evaluated. METHODS AND RESULTS: Patients with primary hereditary arrhythmia syndromes who fulfilled indication for defibrillator placement were eligible for enrollment. Between 2010 and 2016, 62 consecutive patients with primary hereditary arrhythmia syndromes, without indication for antibradycardia therapy, were enrolled in the study. Mean follow-up was 31.0±14.2 months. The study cohort comprised of 24 patients with Brugada syndrome, 17 with idiopathic ventricular fibrillation, 6 with long-QT syndrome, 1 with short-QT syndrome, 3 with catecholaminergic polymorphic ventricular tachycardia, 8 with hypertrophic cardiomyopathy, and 3 with arrhythmogenic right ventricular cardiomyopathy. Thirty-nine patients were implanted for secondary prevention. Twenty-two patients had a previous transvenous ICD implanted, but required revision because of infection or lead defects. A total of 20 spontaneous ventricular tachyarrhythmias requiring shock intervention occurred in 10 patients during follow-up. All episodes were terminated within the first ICD shock delivery with 80 J. Two patients had inappropriate therapies caused by oversensing following an uneventful implantation. No pocket-site infections and no premature revisions have occurred during follow-up. CONCLUSIONS: Our study supports the use of the subcutaneous ICD for both secondary and primary prevention of sudden cardiac death as a reliable alternative to the conventional transvenous ICD.

Elevation of Platelet and Monocyte Activity Markers of Atherosclerosis in Haemodialysis Patients Compared to Peritoneal Dialysis Patients.

PURPOSE: The predominant cause of mortality in dialysis patients are cardiovascular events. Platelet and monocyte activity markers play an important role in cardiovascular mortality and were assessed and related to dialysis quality criteria in haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: For this prospective comparative study, HD patients (n = 41) and PD patients (n = 10) were included. In whole blood samples, surface expression of CD62P and CD40L on platelets, tissue factor binding on monocytes, and platelet-monocyte aggregates were measured by flow cytometry. Plasma levels of MCP-1, IL-6, TNFα, and soluble CD40L were analysed by enzyme-linked immunosorbent assay. RESULTS: Haemodialysis patients showed a significantly higher CD62P expression on platelets (p = 0.017), significantly higher amount of platelet-monocyte aggregates (p < 0.0001), and significantly more tissue factor binding on monocytes (p < 0.0001) compared to PD patients. In PD patients, a significant correlation between Kt/V and platelet CD40L expression (r = 0.867; 0.001) and between Kt/V and platelet CD62P expression (r = 0.686; p = 0.028) was observed, while there was no significant correlation between Kt/V and tissue factor binding on monocytes and platelet-monocyte aggregates, respectively. CONCLUSION: Platelet and monocyte activity markers are higher in HD patients in comparison with those in PD patients, possibly suggesting a higher risk of cardiovascular morbidity and mortality.

Ezetimibe inhibits platelet activation and uPAR expression on endothelial cells.

PURPOSE: Lipid lowering therapy constitutes the basis of cardiovascular disease therapy. The purpose of this study was to investigate effects of ezetimibe, a selective inhibitor of intestinal cholesterol absorption, on platelets and endothelial cells in an in vitro endothelial cell model. METHODS: After a 24h incubation period with ezetimibe (concentrations 1, 50, 100 and 1000ng/ml), human umbilical vein endothelial cells (HUVEC) were stimulated for 1h with lipopolysaccharide (LPS) and were then incubated in direct contact with activated platelets. Following this, the expression of CD40L and CD62P on platelets, and the expression of ICAM-1, VCAM-1, uPAR, and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analysed by enzyme linked immunosorbent assay for soluble MCP-1, IL-6 and MMP-1. RESULTS: The increased expression of uPAR on endothelial cells by proinflammatory stimulation with LPS and by direct endothelial contact with activated platelets was significantly reduced through pre-incubation with 100ng/ml and 1000ng/ml ezetimibe (p<0.05). Platelets directly incubated with ezetimibe but without endothelial cell contact showed significantly reduced CD62P and CD40L surface expression (p<0.05). Ezetimibe had no significant effects on HUVEC expression of MT1-MMP, ICAM-1 and VCAM-1 and on CD40L expression on platelets in direct contact with endothelial cells. Levels of soluble IL-6 in HUVEC supernatants were significantly lower after pre-incubation with ezetimibe. CONCLUSION: In this in vitro analysis, ezetimibe directly attenuates platelet activation and has significant endothelial cell mediated effects on selected markers of atherosclerosis.

Subcutaneous implantable cardioverter-defibrillator: First single-center experience with other cardiac implantable electronic devices.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an implantable device for antiarrhythmic therapy with no intravascular leads. OBJECTIVE: The purpose of this study was to describe the technical feasibility of combining the S-ICD with other cardiac implantable electronic devices (CIEDs), including pacemakers with transvenous or epicardial electrodes. We also provide the first experience of combining an S-ICD with catheter-based therapies, including cardiac contractility modulation (CCM) and vagus nerve stimulation. METHODS: Between July 2011 and November 2014, 6 patients received a CCM device and S-ICD, 3 patients with a single-chamber pacemaker using either transvenous or epicardial pacing electrodes received and S-ICD, and 1 patient with an implanted S-ICD received vagus nerve stimulation. In all patients, intraoperative S-ICD testing, crosstalk tests, and postoperative ergometric testing were performed. RESULTS: In all 10 patients, device implantations were successfully performed without complications. S-ICD therapy was shown to be technically feasible with concomitant CIED. Mean follow-up was nearly 17 months. S-ICD testing and crosstalk testing before and during exercise enabled device programming across a broad range of test conditions and was associated with no subsequent evidence of adverse device interaction. None of the devices required permanent inactivation or removal, and no patient received an inappropriate shock. CONCLUSION: In suitable patients, combining an S-ICD with CCM or pacemaker may provide an acceptable means to reduce the number of transvascular leads. S-ICD appeared safe with CCM over an intermediate follow-up period. Additional prospective randomized controlled trials examining S-ICD in conjunction with CIEDs are warranted.