Mast cell-derived interleukin-4 mediates activation of dendritic cell during toll-like receptor 2-mediated inflammation.

Introduction: During an innate inflammation, immune cells form distinct pro- and anti-inflammatory regions around pathogen-containing core-regions. Mast cells are localized in an anti-inflammatory microenvironment during the resolution of an innate inflammation, suggesting antiinflammatory roles of these cells. Methods: High-content imaging was used to investigated mast cell-dependent changes in the regional distribution of immune cells during an inflammation, induced by the toll-like receptor (TLR)-2 agonist zymosan. Results: The distance between the zymosan-containing core-region and the anti-inflammatory region, described by M2-like macrophages, increased in mast cell-deficient mice. Absence of mast cells abolished dendritic cell (DC) activation, as determined by CD86-expression and localized the DCs in greater distance to zymosan particles. The CD86- DCs had a higher expression of the pro-inflammatory interleukins (IL)-1ß and IL-12/23p40 as compared to activated CD86+ DCs. IL-4 administration restored CD86 expression, cytokine expression profile and localization of the DCs in mast cell-deficient mice. The IL-4 effects were mast cell-specific, since IL-4 reduction by eosinophil depletion did not affect activation of DCs. Discussion: We found that mast cells induce DC activation selectively at the site of inflammation and thereby determine their localization within the inflammation. Overall, mast cells have antiinflammatory functions in this inflammation model and limit the size of the pro-inflammatory region surrounding the zymosan-containing core region.

Meloxicam treatment disrupts the regional structure of innate inflammation sites by targeting the pro-inflammatory effects of prostanoids.

BACKGROUND AND PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed drugs in the world due to their analgesic, antipyretic and anti-inflammatory effects. However, NSAIDs inhibit prostanoid synthesis, interfering with their pro-inflammatory and anti-inflammatory functions and potentially prolonging acute inflammation. EXPERIMENTAL APPROACH: We used high-content immunohistochemistry to define the impact of meloxicam treatment on spatially separated pro-inflammatory and anti-inflammatory processes during innate inflammation in mice induced by zymosan. This allowed us to determine the effect of meloxicam treatment on the organization of pro-inflammatory and anti-inflammatory microenvironments, thereby identifying relevant changes in immune cell localization, recruitment and activation. KEY RESULTS: Meloxicam treatment reduced zymosan-induced thermal hypersensitivity at early time points but delayed its resolution. High-content immunohistochemistry revealed that the pro-inflammatory area was smaller after treatment, diminishing neutrophil recruitment, M1-like macrophage polarization, and especially phagocytosis by neutrophils and macrophages. The polarization of macrophages towards the M2-like anti-inflammatory phenotype was unaffected, and the number of anti-inflammatory eosinophils actually increased. CONCLUSION AND IMPLICATIONS: High-content immunohistochemistry was able to identify relevant meloxicam-mediated effects on inflammatory processes based on alterations in the regional structure of inflammation sites. Meloxicam delayed the clearance of pathogens by inhibiting pro-inflammatory processes, causing prolonged inflammation. Our data suggest that the prescription of NSAIDs as a treatment during an acute pathogen-driven inflammation should be reconsidered in patients with compromised immune systems.

Eosinophil-derived IL-4 is necessary to establish the inflammatory structure in innate inflammation.

Pathogen-induced inflammation comprises pro- and anti-inflammatory processes, which ensure pathogen removal and containment of the proinflammatory activities. Here, we aimed to identify the development of inflammatory microenvironments and their maintenance throughout the course of a toll-like receptor 2-mediated paw inflammation. Within 24 h after pathogen-injection, the immune cells were organized in three zones, which comprised a pathogen-containing "core-region", a bordering proinflammatory (PI)-region and an outer anti-inflammatory (AI)-region. Eosinophils were present in all three inflammatory regions and adapted their cytokine profile according to their localization. Eosinophil depletion reduced IL-4 levels and increased edema formation as well as mechanical and thermal hypersensitivities during resolution of inflammation. Also, in the absence of eosinophils PI- and AI-regions could not be determined anymore, neutrophil numbers increased, and efferocytosis as well as M2-macrophage polarization were reduced. IL-4 administration restored in eosinophil-depleted mice PI- and AI-regions, normalized neutrophil numbers, efferocytosis, M2-macrophage polarization as well as resolution of zymosan-induced hypersensitivity. In conclusion, IL-4-expressing eosinophils support the resolution of inflammation by enabling the development of an anti-inflammatory framework, which encloses proinflammatory regions.

Behind the Wall-Compartment-Specific Neovascularisation during Post-Stroke Recovery in Mice.

Ischemic stroke is a highly prevalent vascular disease leading to oxygen- and glucose deprivation in the brain. In response, ischemia-induced neovascularization occurs, which is supported by circulating CD34+ endothelial progenitor cells. Here, we used the transient middle cerebral artery occlusion (tMCAO) mouse model to characterize the spatio-temporal alterations within the ischemic core from the acute to the chronic phase using multiple-epitope-ligand cartography (MELC) for sequential immunohistochemistry. We found that around 14 days post-stroke, significant angiogenesis occurs in the ischemic core, as determined by the presence of CD31+/CD34+ double-positive endothelial cells. This neovascularization was accompanied by the recruitment of CD4+ T-cells and dendritic cells as well as IBA1+ and IBA1- microglia. Neighborhood analysis identified, besides pericytes only for T-cells and dendritic cells, a statistically significant distribution as direct neighbors of CD31+/CD34+ endothelial cells, suggesting a role for these cells in aiding angiogenesis. This process was distinct from neovascularization of the peri-infarct area as it was separated by a broad astroglial scar. At day 28 post-stroke, the scar had emerged towards the cortical periphery, which seems to give rise to a neuronal regeneration within the peri-infarct area. Meanwhile, the ischemic core has condensed to a highly vascularized subpial region adjacent to the leptomeningeal compartment. In conclusion, in the course of chronic post-stroke regeneration, the astroglial scar serves as a seal between two immunologically active compartments-the peri-infarct area and the ischemic core-which exhibit distinct processes of neovascularization as a central feature of post-stroke tissue remodeling. Based on our findings, we propose that neovascularization of the ischemic core comprises arteriogenesis as well as angiogenesis originating from the leptomenigeal vasculature.

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model.

To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.

[Coronary physiology in the catheter laboratory]. / Koronarphysiologie im Herzkatheterlabor.

The regulation of coronary flow is mainly located in the resistance vessels of the microcirculation, so that the functional relevance of a coronary stenosis arises from the interaction between the epicardial stenosis and the downstream microcirculation. These complex interactions are precisely detectable by physiological measurements, such as the instantaneous wave-free ratio (iwFR) or the fractional flow reserve (FFR). In contrast, the purely visual assessment of the coronary anatomy could lead to misinterpretation and possibly to incorrect revascularization decisions. Consequently, in the current guidelines on myocardial revascularization of the European Society of Cardiology (ESC) the measurement of iwFR and FFR has a class IA indication in intermediate stenoses with unclear hemodynamic relevance. Despite this clear recommendation, physiological measurements are not yet regularly used in the clinical routine. Besides the purely hemodynamic assessment, novel methods such as co-registration and coronary mapping can be used for virtual planning of percutaneous coronary interventions, especially in vessels with diffuse lesions and serial stenoses. Furthermore, invasive flow measurements are also helpful for risk stratification between conservative and interventional treatment of patients with acute coronary syndrome, where additional factors of flow limitation, such as coronary spasm, thrombus and acute disturbance of the microcirculation play an important role.

A bicistronic vector backbone for rapid seamless cloning and chimerization of αßT-cell receptor sequences.

To facilitate preclinical testing of T-cell receptors (TCRs) derived from tumor-reactive T-cell clones it is necessary to develop convenient and rapid cloning strategies for the generation of TCR expression constructs. Herein, we describe a pDONR™221 vector backbone allowing to generate Gateway™ compatible entry clones encoding optimized bicistronic αßTCR constructs. It harbors P2A-linked TCR constant regions and head-to-head-oriented recognition sites of the Type IIS restriction enzymes BsmBI and BsaI for seamless cloning of the TCRα and TCRß V(D)J regions, respectively. Additional well-established TCR optimizations were incorporated to enhance TCR functionality. This included replacing of the human αßTCR constant regions with their codon-optimized murine counterparts for chimerization, addition of a second interchain disulfide bond and arrangement of the TCR chains in the order ß-P2A-α. We exemplified the utility of our vector backbone by cloning and functional testing of three melanoma-reactive TCRs in primary human T cells.

Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells.

Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-ß synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-ß was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-ß, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with  high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST -segment-elevation MI with <12 hours of symptom onset. We sought to visualize time-dependent necrosis in a population with ST -segment-elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI-SCAR project). Methods and Results ST -segment-elevation MI patients with single-vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0-50%, 51-75%, 76-100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom-to-balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index ( P<0.001) versus patients with symptom-to-balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom-to-balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST -segment-elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.

Transcatheter aortic valve replacement- management of patients with significant coronary artery disease undergoing aortic valve interventions: surgical compared to catheter-based approaches in hybrid procedures.

BACKGROUND: Coronary artery disease (CAD) is associated with poorer outcomes after aortic valve replacement (AVR). For high-risk patients with complex CAD, combined transcatheter aortic valve replacement (TAVR) plus off-pump/minimally-invasive coronary artery bypass (OPCAB/MIDCAB) has been proposed. METHODS: A prospective registry analysis was performed to compare the characteristics and outcomes of patients undergoing TAVR+OP/MIDCAB with those undergoing TAVR plus percutaneous coronary intervention (PCI) and surgical AVR plus coronary artery bypass grafting (CABG) between 2008 and 2015 at a single site in Germany. RESULTS: 464 patients underwent SAVR+CABG, 50 underwent TAVR+OP/MIDCAB, and 112 underwent TAVR+PCI. The mean ages (p < 0.001) and logistic EuroSCOREs (p < 0.001) were similarly higher in TAVR+OP/MIDCAB and TAVR+PCI patients compared to SAVR+CABG patients. Prior cardiac surgery was more common in TAVR+PCI than in TAVR+OP/MIDCAB and SAVR+CABG patients (p < 0.001). Procedural times were shortest (p < 0.001), creatine kinase (muscle brain) levels least elevated (p < 0.001), pericardial tamponade least common (p = 0.027), and length of hospital stay shortest (p = 0.011) in TAVR+PCI, followed by TAVR+OP/MIDCAB and SAVR+CABG patients. In-hospital mortality was highest for TAVR+OP/MIDCAB patients (18.0%) with comparable rates for TAVR+PCI and SAVR+CABG groups (9.0 and 6.9%; p = 0.009). Mortality by 12 months was more probable after TAVR+OP/MIDCAB (HR: 2.17, p = 0.002) and TAVR/PCI (HR: 1.63, p = 0.010) than after SAVR+CABG, with the same true of rehospitalisation (HR: 2.39, p = 0.003 and HR: 1.63, p = 0.033). CONCLUSIONS: TAVR+OP/MIDCAB patients share many characteristics with TAVR+PCI patients, with only slightly poorer long-term outcomes. In patients ineligible for SAVR+CABG and TAVR+PCI, hybrid interventions are reasonable second-line options.

Radial versus femoral approach for left ventricular endomyocardial biopsy.

AIMS: Despite the widespread use of the radial approach in coronary interventions, left ventricular endomyocardial biopsy (LV-EMB) is most frequently performed via the femoral artery. We sought to assess the feasibility and safety of radial compared to femoral access in a large cohort of patients undergoing LV-EMB. METHODS AND RESULTS: Data from 264 patients who underwent LV-EMB in Germany, Portugal, Japan and Canada were collected. Clinical, procedural, safety and feasibility data were evaluated and compared between the two groups. LV-EMB was successfully performed by the radial approach in 129 (99%) of 130 and in 134 (100%) patients by the femoral access. Patients in the radial group were older (mean age 55.7 versus 44.3 years) and were more likely to have moderate-severe mitral regurgitation (27.7% versus TF 0%). Sheathless guides were used in 108 (83.1%) of the radial and 2 (1.5%) of the femoral patients, so the mean guiding catheter size (radial 7.0±1.0 Fr versus femoral 8.0±0.0 Fr) was significantly smaller in the radial group (p<0.001). Mild or moderate radial artery spasm occurred in 13 (10.0%) patients but only one (0.8%) patient required conversion to femoral access due to severe spasm. No access site-related complications were reported in the radial group, while 11 (8.2%) patients in the femoral group had access-site haematomas (p=0.001). There were no major complications (mitral valve injury, pericardial tamponade requiring intervention, cerebrovascular accidents, persistent high-degree atrioventricular block, major bleeding or death) in either group. CONCLUSIONS: The radial approach for LV-EMB appears to be safe and associated with a high success rate while possibly leading to fewer access-site bleeding complications compared to the femoral access. The results of this international multicentre study support the radial approach for LV-EMB and further inspire the expansion of "radial first" in the field of interventional cardiology.

A Randomized Trial to Assess Regional Left Ventricular Function After Stent Implantation in Chronic Total Occlusion: The REVASC Trial.

OBJECTIVES: The aim of this study was to investigate whether percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) improves left ventricular function. BACKGROUND: The benefit of PCI in CTOs is still controversial. METHODS: Patients with CTOs who were candidates for PCI were eligible for the study and were randomized to PCI or no PCI of CTO. Relevant coexisting non-CTO lesions were treated as indicated. Patients underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary endpoint was the change in segmental wall thickening (SWT) in the CTO territory. Secondary endpoints were improvement of regional wall motion and changes in left ventricular volumes and ejection fraction. Furthermore, major adverse coronary events after 12 months were assessed. RESULTS: The CTO PCI group comprised 101 patients and the no CTO PCI group 104 patients. The change in SWT did not differ between the CTO PCI (4.1% [interquartile range: 14.6 to 19.3]) and no CTO PCI (6.0% [interquartile range: 8.6 to 6.0]) groups (p = 0.57). Similar results were obtained for other indexes of regional and global left ventricular function. Subgroup analysis revealed that only in patients without major non-CTO lesions (basal SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] score ≤13) CTO PCI was associated with larger improvement in SWT than no CTO PCI (p for interaction = 0.002). Driven by repeat intervention, major adverse coronary event rates at 12 months were significantly lower in the CTO PCI group (16.3% vs. 5.9%; p = 0.02). CONCLUSIONS: No benefit was seen for CTO PCI in terms of the primary endpoint, SWT, or other indexes of left ventricular function. CTO PCI resulted in clinical benefit over no CTO PCI, as evidenced by reduced major adverse coronary event rates at 12 months.

Transradial Approach for Left Ventricular Endomyocardial Biopsy.

BACKGROUND: Left ventricular endomyocardial biopsy (LV-EMB) may offer a superior diagnostic yield compared with right ventricular endomyocardial biopsy (RV-EMB) in conditions predominantly affecting the LV but is underused compared with RV-EMB. Despite the steep uptake of radial approach in coronary interventions, LV-EMB is usually performed via the femoral artery in contemporary practice. Therefore, the aim of this study was to assess the safety and feasibility of LV-EMB via a transradial approach in a multicentre registry. METHODS: One-hundred and two patients who underwent LV-EMB via transradial approach were included. Clinical characteristics, procedural, safety and feasibility data were evaluated. RESULTS: LV-EMB was successfully performed via transradial access in 101 (99%) patients. Mild or moderate radial artery spasm occurred in 12 (12%) patients, but only 1 (0.98%) patient required conversion to femoral access due to severe spasm. A total of 80 (78%) patients had LV-EMB via a sheathless guide catheter. Among those, 77 (96.3%) patients had 7.5-French sheathless guides, and 3 (3.8%) patients had 8.5-French sheathless guides inserted. Radial sheaths were used in the remaining 22 patients, with 5-French sheaths in 21 of 22 patients. Heparin was administered to 93.1% of patients at a median dose of 5000 (3000-5000) IU. The remaining patients followed a provisional strategy upon patent hemostasis achievement. No access site-related complications were reported. There were no major complications (pericardial tamponade, life-threatening arrhythmia, cerebrovascular accident or death). CONCLUSIONS: In a population of patients undergoing transradial LV-EMB, the procedural success rate was high and showed an excellent safety profile. Further studies comparing transradial and transfemoral routes may help expand the use of transradial access for LV-EMB.

Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction.

BACKGROUND: Patients with angina yet having unobstructed coronaries are found in ∼50% of cases undergoing invasive angiography. Coronary spasm and microvascular dysfunction can be responsible for the clinical presentation in ∼60% of cases. However, little is known about structural changes in the myocardium. The aim of this study was to describe findings in endomyocardial biopsies of symptomatic patients with unobstructed coronaries. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 1416 consecutive patients who underwent endomyocardial biopsy sampling and coronary angiography between 2002 and 2016 for various clinical indications. Of them, 309 patients had also undergone intracoronary acetylcholine testing (ACH-test). To be eligible for the study, patients had to have normal left ventricular ejection fraction, unobstructed coronaries and absence of viral genomes in the myocardium. RESULTS: Among the final cohort of 33 (70% female, mean age 53) patients, the ACH-test revealed coronary microvascular spasm in 11 (33.3%) patients. Twelve (36.4%) patients had epicardial spasm and 10 (30.3%) had an uneventful ACH-test. Immunohistology revealed activated macrophages in 10 (30%) cases and activated endothelial cells as well as perivascular or interstitial fibrosis in 17 (52%). Myocardial hypertrophy was seen in nine (27%) patients, and smooth muscle cell proliferation was present in 11 (33%) cases. Compared with the rest of the cohort, patients with microvascular spasm significantly more often had activated endothelial cells (P=0.003). CONCLUSION: This study gives unique insights into structural myocardial alterations in patients with angina, unobstructed coronaries and abnormal coronary vasomotion, suggesting that a combination of both structural and functional alterations is frequent.

Cerebral Embolic Protection Devices During Transcatheter Aortic Valve Implantation: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Silent ischemic embolic lesions are common after transcatheter aortic valve implantation (TAVI). The use of embolic protection devices (EPD) may reduce the occurrence of these embolic lesions. Thus, a quantitative overview and credibility assessment of the literature was necessary to draw a robust message about EPD. Therefore, the aim of this meta-analysis was to study whether the use of EPD reduces silent ischemic and clinically evident cerebrovascular events associated with TAVI. METHODS: We conducted a comprehensive search to identify studies that evaluated patients undergoing TAVI with or without EPD. Random-effects meta-analyses were performed to estimate the effect of EPD compared with no-EPD during TAVI using aggregate data. RESULTS: Sixteen studies involving 1170 patients (865/305 with/without EPD) fulfilled the inclusion criteria. The EPD delivery success rate was reported in all studies and was achieved in 94.5% of patients. Meta-analyses evaluating EPD versus without EPD strategies could not confirm or exclude any differences in terms of clinically evident stroke (relative risk, 0.70; 95% confidence interval [CI], 0.38-1.29; P=0.26) or 30-day mortality (relative risk, 0.58; 95% CI, 0.20-1.64; P=0.30). There were no significant differences in new-single, multiple, or total number of lesions. The use of EPD was associated with a significantly smaller ischemic volume per lesion (standardized mean difference, -0.52; 95% CI, -0.85 to -0.20; P=0.002) and smaller total volume of lesions (standardized mean difference, -0.23; 95% CI, -0.42 to -0.03; P=0.02). Subgroup analysis by type of valve showed an overall trend toward significant reduction in new lesions per patient using EPD (standardized mean difference, -0.41; 95% CI, -0.82 to 0.00; P=0.05), driven by self-expanding devices. CONCLUSIONS: The use of EPD during TAVI may be associated with smaller volume of silent ischemic lesions and smaller total volume of silent ischemic lesions. However, EPD may not reduce the number of new-single, multiple, or total number of lesions. There was only very low quality of evidence showing no significant differences between patients undergoing TAVI with or without EPD with respect to clinically evident stroke and mortality.

Concomitant therapy: off-pump coronary revascularization and transcatheter aortic valve implantation.

OBJECTIVES: Significant coronary artery disease (CAD) is common among patients evaluated for transcatheter aortic valve implantation (TAVI). Only little data exist on outcome of patients undergoing concomitant off-pump coronary revascularization and TAVI. The goal of this study was to analyse the impact of concomitant off-pump revascularization on early clinical outcome and 2-year follow-up of patients undergoing TAVI. METHODS: A total of 70 patients with significant CAD and aortic valve stenosis were included between January 2011 and January 2016. Decision to perform concomitant off-pump coronary revascularization and TAVI was made by the interdisciplinary heart team according to the SYNTAX score. Prospectively assigned data were analysed retrospectively and follow-up was performed up to 2 years. RESULTS: Mean age was 82.2 ± 4.0 years and 43 (61.4%) patients were male. Mean logistic European system for cardiac operative risk evaluation and Society of Thoracic Surgeons European system for cardiac operative risk evaluation score were 35.9 ± 21.9% and 12.2 ± 7.9%, respectively. SYNTAX score was 29.0 ± 12.9. Access site for TAVI was transapical in 60.0% and transaortic in 40.0%. Procedural success was 94.3%. Eighty percent of the patients had none or trace paravalvular leakage after TAVI. Severe complications requiring consecutive surgical aortic valve replacement occurred in 2 patients (2.9%). The use of cardiopulmonary bypass due to haemodynamic instability or conversion to surgical aortic valve replacement was necessary in 7 patients (10.0%). Stroke occurred in 1 patient (1.4%). Re-exploration for bleeding was necessary in 6 patients (8.6%). Thirty-day mortality was 14.3%. Two-year survival was 68.4% (95% confidence interval: 55.7-81.1%). CONCLUSIONS: Simultaneously performed complete off-pump coronary revascularization is a feasible and valid option in patients with significant CAD undergoing TAVI.

Conventional versus Transapical Aortic Valve Replacement: Is It Time for Shift in Indications?

Background The incidence of degenerative aortic valve diseases has increased along with the life expectancy of our population. Although conventional aortic valve replacement (AVR) is the gold standard for symptomatic aortic stenosis, transcatheter procedures have proven to be a valid therapeutic option in high-risk patients. The aim of this study was to compare these procedures in a high-risk cohort. Methods We retrospectively analyzed all symptomatic (dyspnea or angina) high-risk patients (logistic EuroSCORE ≥ 15%) fulfilling the transcatheter aortic valve implantation (TAVI) indications. Most of the AVR patients (n = 180) were operated on before the implementation of TAVI. All TAVI procedures (n = 127) were performed transapically (TA). After matching for age, logistic EuroSCORE, and left ventricular ejection fraction, 82 pairs of patients were evaluated. Results When comparing AVR with TA-TAVI, there was no difference between groups in survival after 1 year (Kaplan-Meier analysis, 81.1% [95% CI: 72.5-89.7%] vs. 75.8% [95% CI: 66.2-75.9%], Log tank p = 0.660) and the complication rates (n for AVR vs. TA-TAVI: stroke, 2 vs. 0, p = 0.580; acute renal insufficiency, 8 vs. 12, p = 0.340; atrial fibrillation, 24 vs. 26, p = 0.813; pacemaker implantation, 4 vs. 4, p > 0.999). In addition, quality of life did not differ between groups. Patients in the TA-TAVI group had lower mean valvular gradients postoperatively compared with the AVR group (14.6 ± 6.6 vs. 10.2 ± 4.9 mm Hg, p < 0.001). Conclusion For high-risk patients, the TAVI procedure is comparable with conventional AVR, but is not advantageous. These results do not support the expansion of TAVI to low- or intermediate-risk patients.

Transaortic Transcatheter Aortic Valve Implantation and Concomitant Off Pump Revascularization.

An increasing number of patients with severe aortic stenosis and concomitant critical coronary artery disease were referred to our hospital. Some of those patients were classified as high-risk patients qualifying for a transcatheter therapy with the additional need for coronary revascularization. As a consequence of their comorbidities, the established transapical as well as transfemoral approach were either not possible or not favored owing to the indispensable need for coronary revascularization. We present 4 successfully combined off-pump procedures consisting of a transcatheter aortic valve implantation (Edwards SAPIEN XT) via the transaortic approach and an off-pump coronary artery bypass grafting. All patients were discharged free from stroke, myocardial infarction, or access site complications either to rehabilitation facility or to the referring hospital with none or trace aortic regurgitation and patent grafts. These cases confirm the feasibility of those combined operations and should be considered as realistic alternative for surgical treatment in high-risk patients who are clearly identified to benefit from transcatheter approach to treat aortic stenosis and who have severe concomitant coronary artery disease.

Testing in Patients With Stable Coronary Artery Disease　- The Debate Continues.

The major guidelines on stable coronary artery disease recommend revascularizing patients with large areas of myocardium at risk. The algorithms on how to prove that such high risk is present differ considerably. The opinions on the use of coronary CT (calcium scoring and angiography) vary widely. This review aims to summarize the recommendations of the major guidelines, commenting on differences between the guidelines and discussing whether extending the role of coronary CT angiography should be considered in the light of new CT data.