1-Year Patency of Biorestorative Polymeric Coronary Artery Bypass Grafts in an Ovine Model.

Many attempts have been made to inhibit or counteract saphenous vein graft (SVG) failure modes; however, only external support for SVGs has gained momentum in clinical utility. This study revealed the feasibility of implantation, and showed good patency out to 12 months of the novel biorestorative graft, in a challenging ovine coronary artery bypass graft model. This finding could trigger the first-in-man trial of using the novel material instead of SVG. We believe that, eventually, this novel biorestorative bypass graft can be one of the options for coronary artery bypass graft patients who have difficulty harvesting SVG.

One-year performance of biorestorative polymeric coronary bypass grafts in an ovine model: correlation between early biomechanics and late serial Quantitative Flow Ratio.

OBJECTIVES: This study aimed to investigate the impact of mechanical factors at baseline on the patency of a restorative conduit for coronary bypass grafts in an ovine model at serial follow-up up to 1 year. METHODS: The analyses of 4 mechanical factors [i.e. bending angle, superficial wall strain and minimum and maximum endothelial shear stress (ESS)] were performed in 3D graft models reconstructed on baseline (1-month) angiograms frame by frame by a core laboratory blinded for the late follow-up. The late patency was documented by Quantitative Flow Ratio (QFR®) that reflects the physiological status of the graft. The correlation between 4 mechanical factors and segmental QFR (△QFR) were analysed on 10 equal-length segments of each graft. RESULTS: A total of 69 graft geometries of 7 animals were performed in the study. The highest △QFR at 12 months was colocalized in segments of the grafts with the largest bending angles at baseline. Higher △QFR at 3 months were both at the anastomotic ends and were colocalized with the highest superficial wall strain at baseline. High baseline ESS was topographically associated with higher △QFR at the latest follow-up. Correlations of minimum and maximum ESS with △QFR at 3 months were the strongest among these parameters (ρ = 0.30, 95% CI [-0.05 to 0.56] and ρ = 0.27, 95% CI [-0.05 to 0.54], respectively). CONCLUSIONS: Despite the limited number of grafts, this study suggests an association between early abnormal mechanical factors and late flow metrics of the grafts. The understanding of the mechanical characteristics could help to improve this novel conduit.

A logistic regression analysis comparing minimalistic approach and intubation anaesthesia in patients undergoing transfemoral transcatheter aortic valve replacement.

AIMS: Patients with postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR) are ventilated and hospitalized longer and suffer increased in-hospital mortality. This study hypothesized that a minimalistic approach with conscious sedation during transfemoral aortic valve replacement (TF-AVR) protects against delirium, time of mechanical ventilation, and increased length of stay in intensive care unit (ICU) compared to intubation anaesthesia. METHODS AND RESULTS: 308 patients which underwent TF-AVR in our centre between 01/2013 and 08/2017 were retrospectively evaluated regarding postoperative delirium, time of mechanical ventilation, and days in ICU. TF-AVR was performed with intubation anaesthesia in 245 patients and with conscious sedation in 63. The operative risk estimated by the logEUROScore was similar in both groups (intubation: 13.28 +/-9.06%, conscious sedation: 12.24 +/-6.77%, p = 0.395). In the conscious sedation group procedure duration was shorter (0.61 +/-0.91h vs. 1.75 +/-0.96h, p<0.001). The risk for intraprocedural complications was not influenced by the anaesthesia method (OR conscious sedation instead of intubation 1.66, p = 0.117), but days on ICU (-2.21 days, p<0.0001) and minutes of mechanical ventilation (-531.2 min, p < 0.0001) were reduced. Furthermore, the risk of POD was decreased when TF-AVR was performed under conscious sedation (6.35% vs. 18.18%, OR 0.29, p = 0.021). CONCLUSIONS: Time of mechanical ventilation, risk of POD, and days on ICU were substantially reduced in patients who underwent TF-AVR under conscious sedation. Our data suggest that TF-AVR with conscious sedation is safe with a beneficial postoperative course in clinical practice, and should be considered the favoured approach.

Direct factor IXa inhibition with the RNA-aptamer pegnivacogin reduces platelet reactivity in vitro and residual platelet aggregation in patients with acute coronary syndromes.

BACKGROUND: Residual platelet reactivity is a predictor of poor prognosis in patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention. Thrombin is a major platelet activator and upon initiation of the coagulation cascade, it is subsequently produced downstream of factor IXa, which itself is known to be increased in ACS. Pegnivacogin is a novel RNA-aptamer based factor IXa inhibitor featuring a reversal agent, anivamersen. We hypothesized that pegnivacogin could reduce platelet reactivity. METHODS: Whole blood samples from healthy volunteers were incubated in vitro in the presence and absence of pegnivacogin and platelet reactivity was analysed. In addition, platelet aggregometry was performed in blood samples from ACS patients in the RADAR trial featuring the intravenous administration of pegnivacogin as well as reversal by anivamersen. RESULTS: In vitro, pegnivacogin significantly reduced adenosine diphosphate-induced CD62P-expression (100% vs. 89.79±4.04%, p=0.027, n=9) and PAC-1 binding (100% vs. 83.02±4.08%, p=0.010, n=11). Platelet aggregation was reduced (97.71±5.30% vs. 66.53±9.92%, p=0.013, n=10) as evaluated by light transmission aggregometry. In the presence of the RNA-aptamer reversal agent anivamersen, neither CD62P-expression nor platelet aggregation was attenuated. In patients with ACS treated with aspirin and clopidogrel, residual platelet aggregation was significantly reduced 20 min after intravenous bolus of 1 mg/kg pegnivacogin (100% versus 43.21±8.23%, p=0.020). CONCLUSION: Inhibition of factor IXa by pegnivacogin decreases platelet activation and aggregation in vitro. This effect was negated by anivamersen. In ACS patients, platelet aggregation was significantly reduced after intravenous pegnivacogin. An aptamer-based anticoagulant inhibiting factor IXa therefore might be a promising antithrombotic strategy in ACS patients.

The mitochondria-targeting peptide elamipretide diminishes circulating HtrA2 in ST-segment elevation myocardial infarction.

BACKGROUND: The extent of myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) depends on both the time to reperfusion as well as injury induced by ischaemia-reperfusion resulting in a cascade of cellular and humoral reactions. As a consequence of ischaemia-reperfusion in the heart, the high-temperature requirement serine peptidase 2 (HtrA2) is translocated from the mitochondria to the cytosol, whereupon it induces protease activity-dependent apoptosis mediated via caspases. Myocardial damage induced by reperfusion cannot be monitored due to a current lack in specific biomarkers. We examined the serum level of HtrA2 as a potentially novel biomarker for mitochondrial-induced cardiomyocyte apoptosis. METHODS: After informed consent, peripheral blood was obtained from patients (n=19) with first-time acute anterior STEMI after percutaneous coronary intervention. Within this group, 10 of the patients received the mitochondria-targeting peptide elamipretide (phase 2a clinical study EMBRACE (NCT01572909)). Blood was also obtained from a control group of healthy donors (n=16). The serum level of HtrA2 was measured by an enzyme-linked immunosorbent assay (ELISA). In a murine model of myocardial ischaemia-reperfusion injury, HtrA2 was determined in plasma by ELISA after left anterior descending artery occlusion. RESULTS: HtrA2 median was significantly increased in patients with STEMI compared to healthy controls 392.4 (240.7-502.8) pg/mL vs. 1805.5 (981.3-2220.1) pg/mL (P⩽0.05). Elamipretide significantly reduced the HtrA2 median serum level after myocardial infarction 1805.5 (981.3-2220.1) pg/mL vs. 496.5 (379.4-703.8) pg/mL (P⩽0.05). Left anterior descending artery occlusion in mice significantly increased HtrA2 mean in plasma (117.4 fg/ml±SEM 28.1 vs. 525.2 fg/ml±SEM 96; P⩽0.05). CONCLUSION: Compared to healthy controls, we found significantly increased serum levels of HtrA2 in patients with STEMI. The result was validated in a murine model of myocardial ischaemia-reperfusion injury. In humans the increased serum level was significantly reduced by the mitochondria-targeting peptide elamipretide. In conclusion, HtrA2 is detectable in serum of patients with STEMI and might present a novel biomarker for mitochondrial-induced cardiomyocyte apoptosis. Consequently, HtrA2 may also show promise as a biomarker for the identification of ischaemia-reperfusion injury. However, this must be validated in a lager clinical trial.

Volume-outcome relationship in transcatheter aortic valve implantations in Germany 2008-2014: a secondary data analysis of electronic health records.

OBJECTIVES: We examine the volume-outcome relationship in isolated transcatheter aortic valve implantations (TAVI). Our interest was whether the volume-outcome relationship for TAVI exists on the centre level, whether it occurs equally for different outcomes and how it develops over time. DESIGN: Secondary data analysis of electronic health records. The comprehensive German Federal Bureau of Statistics Diagnosis Related Groups database was queried for data on all isolated TAVI procedures performed in Germany between 2008 and 2014. Logistic and linear regression analyses were carried out. Risk adjustment was applied using a predefined set of patient characteristics to account for differences in the risk factor composition of the patient populations between centres and over time. Centres performing TAVI were stratified into groups performing <50, 50-99 and ≥100 procedures per year. SETTING: Germany 2008-2014. PARTICIPANTS: All patients undergoing isolated TAVI in the observation period. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: In-hospital mortality, bleeding, stroke, probability of ventilation >48 hours, length of hospital stay and reimbursement. RESULTS: Between 2008 and 2014, a total of 43 996 TAVI procedures were performed in 113 different centres in Germany with a total of 2532 cases of in-hospital mortality. Risk-adjusted in-hospital mortality decreases over the years and is lower the higher the annual procedure volume at the centre is. The magnitude of the latter effect declines over the observation period. Our results indicate a ceiling effect in the volume-outcome relationship: the volume-outcome relationship is eminent in circumstances of relatively unfavourable outcomes. Alongside improving outcomes, however, the volume-outcome relationship decreases. Also, a volume-outcome relationship seems to be absent in circumstances of constantly low event rates. CONCLUSIONS: The hypothesised volume-outcome relationship for TAVI exists but diminishes and may disappear over time. This should be taken into account when considering mandatory minimum thresholds.

Sex-Specific Differences in Outcome of Transcatheter or Surgical Aortic Valve Replacement.

BACKGROUND: Differences in baseline characteristics and anatomy between female and male patients with aortic valve stenosis may influence outcomes after surgical and transcatheter aortic valve replacement (TAVR). We evaluated the effect of sex on in-hospital outcomes after transfemoral (TF-TAVR), transapical (TA-TAVR), or surgical (SAVR) aortic valve replacement in a nationwide cohort. METHODS: Baseline characteristics and outcomes from all isolated TAVR or SAVR procedures performed between 2011 and 2014 in German hospitals were analyzed (N = 64,794). Primary outcome was in-hospital mortality. Unadjusted and adjusted comparisons between women and men were performed within each treatment group. RESULTS: Females were generally older and had a higher EuroSCORE. Thus, they were preferentially treated with TF-TAVR, whereas the share of TF-TAVR and SAVR was similar in males. Females suffered more relevant bleeding after TF-TAVR and SAVR (TF-TAVR: adjusted odds ratio [aOR] = 1.16, P = 0.018; TA-TAVR: aOR = 0.98, P = 0.799; SAVR: aOR = 1.12, P = 0.005). However, prolonged postoperative ventilation was less frequently necessary in females (aOR TF-TAVR: 0.69, P < 0.001; TA-TAVR: 0.69, P < 0.001; SAVR: 0.76, P < 0.001) and stroke risk was lower (TA-TAVR: aOR = 0.60, P = 0.001; TF-TAVR: aOR = 0.74, P = 0.001; SAVR: aOR = 0.61, P < 0.001). In-hospital mortality was slightly decreased in females undergoing TF-TAVR after adjustment (aOR = 0.87, P = 0.047), and equal in TA-TAVR (aOR = 0.96, P = 0.640) or SAVR (aOR = 1.02, P = 0.807). CONCLUSIONS: This nation-wide analysis of sex-specific outcomes after aortic-valve replacement procedures showed that women are higher-risk for bleeding, but lower-risk for stroke, mechanical ventilation, and TF-TAVR mortality. Understanding these differences and their basis may help improve outcomes.

Risk factors and outcome of postoperative delirium after transcatheter aortic valve replacement.

BACKGROUND: POD is associated with a worse postoperative course in patients after cardiac surgery, but its incidence and effects after TAVR are not well-understood. The aim of the present study was to analyze incidence, risk factors, and in-hospital outcomes of postoperative delirium (POD) after transfemoral (TF-AVR) and transapical (TA-AVR) transcatheter aortic valve replacement (TAVR) in a nationwide cohort. METHODS AND RESULTS: Administrative data on all patients undergoing isolated TAVR in Germany in 2014 were analyzed. 9038 TF-AVR and 2522 TA-AVR procedures were performed. POD incidence was 7% after TF-AVR and 12% after TA-AVR. Atrial fibrillation (TF: OR 1.35, p < 0.001; TA: OR 1.53, p = 0.001) and NYHA III/IV (TF: OR 1.23, p = 0.017, TA: OR 1.51, p = 0.001) were independent risk factors for POD. Dementia was a risk factor only in TF-AVR (OR 3.04, p < 0.001). Female sex was protective (TF: OR 0.56, p < 0.001, TA: OR 0.51, p < 0.001). We found the occurrence of POD to be associated with more postoperative complications such as stroke and bleeding. Consequently, patients with POD were ventilated and hospitalized longer and suffered an increased risk of in-hospital mortality (unadjusted OR TF: 1.83, p = 0.001, TA: 1.82, p = 0.01). After adjusting for postoperative events and comorbidities, POD's effect on in-hospital mortality disappeared. In contrast, stroke and bleeding remained independent predictors for mortality irrespective of POD. CONCLUSIONS: Patients with POD after TAVR are at increased risk for in-hospital mortality. However, after adjusting for postoperative events and comorbidities, stroke and bleeding, but not POD, are independent mortality predictors.

A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense.

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.

Coronary magnetic resonance imaging after routine implantation of bioresorbable vascular scaffolds allows non-invasive evaluation of vascular patency.

BACKGROUND: Evaluation of recurrent angina after percutaneous coronary interventions is challenging. Since bioresorbable vascular scaffolds (BVS) cause no artefacts in magnetic resonance imaging (MRI) due to their polylactate-based backbone, evaluation of vascular patency by MRI might allow for non-invasive assessment and triage of patients with suspected BVS failure. METHODS: Patients with polylactate-based ABSORB-BVS in proximal coronary segments were examined with 3 Tesla MRI directly (baseline) and one year after implantation. For assessment of coronary patency, a high-resolution 3D spoiled gradient echo pulse sequence with fat-saturation, T2-preparation (TE: 40 ms), respiratory and end-diastolic cardiac gating, and a spatial resolution of (1.08 mm)3 was positioned parallel to the course of the vessel for bright blood imaging. In addition, a 3D navigator-gated T2-weighted variable flip angle turbo spin echo (TSE) sequence with dual-inversion recovery black-blood preparation and elliptical k-space coverage was applied with a voxel size of (1.14 mm)3. For quantitative evaluation lumen diameters of the scaffolded areas were measured in reformatted bright and black blood MR angiography data. RESULTS: 11 patients with implantation of 16 BVS in the proximal coronary segments were included, of which none suffered from major adverse cardiac events during the one year follow up. Vascular patency in all segments implanted with BVS could be reliably assessed by MRI at baseline and after one year, whereas segments with metal stents could not be evaluated due to artefacts. Luminal diameter within the BVS remained constant during the one year period. One patient with atypical angina after BVS implantation was noninvasively evaluated showing a patent vessel, also confirmed by coronary angiography. CONCLUSIONS: Coronary MRI allows contrast-agent free and non-invasive assessment of vascular patency after ABSORB-BVS implantation. This approach might be supportive in the triage and improvement of diagnostic workflows in patients with postinterventional angina and scaffold implantation. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00007456.

The impact of post-procedural complications on reimbursement, length of stay and mechanical ventilation among patients undergoing transcatheter aortic valve implantation in Germany.

BACKGROUND: The impact of various post-procedural complications after transcatheter aortic valve implantation (TAVI) on resource use and their consequences in the German reimbursement system has still not been properly quantified. METHODS: In a retrospective observational study, we use data from the German DRG statistic on patient characteristics and in-hospital outcomes of all isolated TAVI procedures in 2013 (N = 9147). The impact of post-procedural complications on reimbursement, length of stay and mechanical ventilation was analyzed using both unadjusted and risk-adjusted linear and logistic regression analyses. RESULTS: A total of 235 (2.57%) strokes, 583 (6.37%) bleeding events, 474 (5.18%) cases of acute kidney injury and 1428 (15.61%) pacemaker implantations were documented. The predicted reimbursement of an uncomplicated TAVI procedure was €33,272, and bleeding events were associated with highest additional reimbursement (€12,839, p < 0.001), extra length of stay (14.58 days, p < 0.001), and increased likelihood of mechanical ventilation for more than 48 h (OR 17.91, p < 0.001). A more moderate complication-related impact on resource use and reimbursement was found for acute kidney injury (additional reimbursement: €5963, p < 0.001; extra length of stay: 7.92 days, p < 0.001; ventilation >48 h: OR 6.93, p < 0.001) as well as for stroke (additional reimbursement: €4125, p < 0.001; extra length of stay: 4.68 days, p < 0.001; ventilation >48 h: OR 5.73, p < 0.001). Pacemaker implantations, in contrast, were associated with comparably small increases in reimbursement (€662, p = 0.006) and length of stay (3.54 days, p = 0.006) and no impaired likelihood of mechanical ventilation more than 48 h (OR 1.22, p = 0.156). Interestingly, these complication-related consequences remain mostly unchanged after baseline risk-adjustment. CONCLUSIONS: Post procedural complications such as bleeding events, acute kidney injuries and strokes are associated with increased resource use and substantial amounts of additional reimbursement in Germany, which has important implications for decision making outside of the usual clinical sphere.

A molecular intravascular ultrasound contrast agent allows detection of activated platelets on the surface of symptomatic human plaques.

BACKGROUND AND AIMS: Activated platelets are amongst the most attractive imaging targets in atherosclerosis due to their important role in early processes of atherogenesis and thrombus formation. We developed a molecular intravascular ultrasound (IVUS) approach to detect activated platelets ex vivo on the surface of human plaques, using an IVUS system applied in clinical routine. METHODS: Human carotid endarterectomy specimens were obtained directly from the operating room and exposed to artificial arterial flow conditions for incubation with the contrast agent. This consists of microbubbles (MB), which are linked to an antibody against the ligand induced binding site (LIBS) of the activated platelet glycoprotein IIb/IIa, and a sialyl Lewis polymer (SL), which mediates binding to selectins (LIBS-SL-MB). IVUS was performed pre and post incubation with LIBS-SL-MB and after rinsing with PBS. In comparison, IVUS was performed pre and post incubation with MBs linked to an unspecific control antibody and a dysfunctional polymer (control-MB). All imaging results were correlated to histology findings. RESULTS: IVUS imaging showed a high signal enhancement after administration of LIBS-SL-MB. After rinsing with PBS, the signal enhancement remained stable. Immunofluorescence and immunohistochemistry confirmed significant binding of microbubbles to thrombi on the plaque surface. Moreover, thrombus size and number of bound MBs correlated well. CONCLUSIONS: LIBS-SL-MB allows ex vivo IVUS imaging of even small numbers of activated platelets on the surface of human carotid endarterectomy specimens. This diagnostic approach could deliver valuable additional information for risk stratification of atherosclerotic plaques, especially since we apply a clinically well-established IVUS imaging system.

Prevalence and impact of critical limb ischaemia on in-hospital outcome in transcatheter aortic valve implantation in Germany.

AIMS: Peripheral artery disease (PAD) is common in patients with aortic valve stenosis (AS). This study sought to assess the prevalence of critical limb ischaemia (CLI) and its impact on in-hospital outcome in patients undergoing transcatheter aortic valve implantation (TAVI) for severe AS. METHODS AND RESULTS: All isolated TAVI procedures for AS in Germany between 2007 and 2013 were analysed regarding the stage-specific prevalence of PAD, comorbidities, in-hospital complications and mortality using diagnostic and procedural codes. Among 32,044 patients with TAVI, 3,375 (10.5%) had PAD and 654 (2.0%) CLI. TAVI patients with PAD, particularly those with CLI, had a higher incidence of periprocedural stroke, bleeding and acute kidney injury (p<0.001). The overall in-hospital mortality among TAVI without PAD, non-CLI PAD and CLI was 6.1%, 8.4% and 14.7%, respectively (p<0.001). In a multivariate logistic regression analysis, CLI was an independent predictor of in-hospital mortality (odds ratio 1.96, 95% confidence interval 1.56-2.47; p<0.001). CONCLUSIONS: In patients undergoing TAVI, the presence of PAD is associated with an increased risk of periprocedural complications, while only CLI independently predicts increased in-hospital mortality. Whether CLI represents a marker of general poor health status resulting in poor outcome or is a modifiable risk factor whose treatment prior to TAVI can improve the outcome requires prospective studies.

Two-year post-discharge costs of care among patients treated with transcatheter or surgical aortic valve replacement in Germany.

BACKGROUND: This study presents data on post-discharge costs of care among patients treated with transcatheter or surgical aortic valve replacement over a two year period. METHODS: Based on a prospective clinical trial, post-discharge utilization of health services and status of assistance were collected for 151 elderly patients via 2250 monthly telephone interviews, valued using standardized unit costs and analysed using two-part regression models. RESULTS: At month 1 post-discharge, total costs of care are substantially elevated (monthly mean: €3506.7) and then remain relatively stable over the following 23 months (monthly mean: €622.3). As expected, the majority of these costs are related to in-hospital care (~98% in month 1 post-discharge and ~72% in months 2-24). Patients that died during follow-up were associated with substantially higher cost estimates of in-hospital care than those surviving the two-year study period, while patients' age and other patient characteristics were of minor relevance. Estimated costs of outpatient care are lower at month 1 than during the rest of the study period, and not affected by the event of death during follow-up. The estimated costs of nursing care are, in contrast, much higher in year 2 than in year 1 and differ substantially by gender and type of procedure as well as by patients' age. Overall, these monthly cost estimates add up to €10,352 for the first and €7467.6 for the second year post-discharge. CONCLUSIONS: Substantial cost increases at month 1 post-discharge and in case of death during follow-up are the main findings of the study, which should be taken into account in future economic evaluations on the topic. Application of standardized unit costs in combination with monthly patient interviews allows for a far more precise estimate of the variability in post-discharge health service utilization in this group of patients than the ones given in previous studies. TRIAL REGISTRATION: German Clinical Trial Register Nr. DRKS00000797 .

Impact of pulmonary hypertension on in-hospital outcome after surgical or transcatheter aortic valve replacement.

AIMS: We aimed to analyse the impact of pulmonary hypertension (PH) on the in-hospital outcome of either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Data from all 107,057 patients undergoing isolated SAVR or TAVR in Germany between 2007 and 2014 were provided by the German Federal Bureau of Statistics. About 18% of patients with aortic valve stenosis suffered from PH. Patients with PH had more comorbidities with consequently increased EuroSCORE (TAVR without PH: 12.3%; with PH: 24%). The presence of PH led to an increase of in-hospital strokes, bleedings, acute kidney injuries, and pacemaker implantations in both treatment groups (TAVR and SAVR), but the PH-associated increase of complications and mortality was less pronounced among patients receiving TAVR (mortality after TAVR without PH: 5.4%; with PH: 7.2%). After baseline risk adjustment, the TAVR procedure was associated with a reduced risk of in-hospital stroke (OR 0.81, p=0.011), bleeding (OR 0.22, p<0.001), and mortality (OR 0.70, p=0.005) among PH patients, and in comparison to surgical treatment. CONCLUSIONS: PH is a risk factor for worse outcome of SAVR and TAVR. This fact is less pronounced among TAVR patients. Our data suggest a shift towards the transcatheter approach in patients suffering from PH.

P2X7 Deficiency Blocks Lesional Inflammasome Activity and Ameliorates Atherosclerosis in Mice.

BACKGROUND: Extracellular adenosine triphosphate (ATP) binds as a danger signal to purinergic receptor P2X7 and promotes inflammasome assembly and interleukin-1ß expression. We hypothesized a functional role of the signal axis ATP-P2X7 in inflammasome activation and the chronic inflammation driving atherosclerosis. METHODS: P2X7-competent and P2X7-deficient macrophages were isolated and stimulated with lipopolysaccharide, ATP, or both. To assess whether P2X7 may have a role in atherosclerosis, P2X7 expression was analyzed in aortic arches from low density lipoprotein receptor-/- mice consuming a high-cholesterol or chow diet. P2X7+/+ and P2X7-/- low density lipoprotein receptor-/- mice were fed a high-cholesterol diet to investigate the functional role of P2X7 knockout in atherosclerosis. Human plaques were derived from carotid endarterectomy and stained against P2X7. RESULTS: Lipopolysaccharide or ATP stimulation alone did not activate caspase 1 in isolated macrophages. However, priming with lipopolysaccharide, followed by stimulation with ATP, led to an activation of caspase 1 and interleukin-1ß in P2X7-competent macrophages. In contrast, P2X7-deficient macrophages showed no activation of caspase 1 after sequential stimulation while still expressing a basal amount of interleukin-1ß. P2X7 receptor was higher expressed in murine atherosclerotic lesions, particularly by lesional macrophages. After 16 weeks of a high-cholesterol diet, P2X7-deficient mice showed smaller atherosclerotic lesions than P2X7-competent mice (0.162 cm2±0.023 [n=9], P2X7-/- low density lipoprotein receptor-/- : 0.084 cm2±0.01 [n=11], P=0.004) with a reduced amount of lesional macrophages. In accord with our in vitro findings, lesional caspase 1 activity was abolished in P2X7-/- mice. In addition, intravital microscopy revealed reduced leukocyte rolling and adhesion in P2X7-deficient mice. Last, we observe increased P2X7 expression in human atherosclerotic lesions, suggesting that our findings in mice are relevant for human disease. CONCLUSIONS: P2X7 deficiency resolved plaque inflammation by inhibition of lesional inflammasome activation and reduced experimental atherosclerosis. Therefore, P2X7 represents an interesting potential new target to combat atherosclerosis.

Association of CKD with Outcomes Among Patients Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND AND OBJECTIVES: Despitethe multiple depicted associations of CKD with reduced cardiovascular and overall prognoses, the association of CKD with outcome of patients undergoing transcatheter aortic valve implantation has still not been well described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from all hospitalized patients who underwent transcatheter aortic valve implantation procedures between January 1, 2010 and December 31, 2013 in Germany were evaluated regarding influence of CKD, even in the earlier stages, on morbidity, in-hospital outcomes, and costs. RESULTS: A total of 28,716 patients were treated with transcatheter aortic valve implantation. A total of 11,189 (39.0%) suffered from CKD. Patients with CKD were predominantly women; had higher rates of comorbidities, such as coronary artery disease, heart failure at New York Heart Association 3/4, peripheral artery disease, and diabetes; and had a 1.3-fold higher estimated logistic European System for Cardiac Operative Risk Evaluation value. In-hospital mortality was independently associated with CKD stage ≥3 (up to odds ratio, 1.71; 95% confidence interval, 1.35 to 2.17; P<0.05), bleeding was independently associated with CKD stage ≥4 (up to odds ratio, 1.82; 95% confidence interval, 1.47 to 2.24; P<0.001), and AKI was independently associated with CKD stages 3 (odds ratio, 1.83; 95% confidence interval, 1.62 to 2.06) and 4 (odds ratio, 2.33; 95% confidence interval, 1.92 to 2.83 both P<0.001). The stroke risk, in contrast, was lower for patients with CKD stages 4 (odds ratio, 0.23; 95% confidence interval, 0.16 to 0.33) and 5 (odds ratio, 0.24; 95% confidence interval, 0.15 to 0.39; both P<0.001). Lengths of hospital stay were, on average, 1.2-fold longer, whereas reimbursements were, on average, only 1.03-fold higher in patients who suffered from CKD. CONCLUSIONS: This analysis illustrates for the first time on a nationwide basis the association of CKD with adverse outcomes in patients who underwent transcatheter aortic valve implantation. Thus, classification of CKD stages before transcatheter aortic valve implantation is important for appropriate risk stratification.

Learning Curves Among All Patients Undergoing Transcatheter Aortic Valve Implantation in Germany: A Retrospective Observational Study.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a rapidly evolving technique for therapy of aortic stenosis. Previous studies report learning curves with respect to in-hospital mortality and clinical complications. We aim to determine whether observed improvements of in-hospital outcomes after TAVI are the result of improvements in procedures or due to a change in the patient population, and whether improvements differ between the transfemoral (TF) and the transapical (TA) approach. METHODS: Data was analyzed using risk-adjusted regression analyses in order to track the development of clinical outcomes of all isolated TAVI procedures performed in Germany from 2008 to 2013 (N=32.436) in all German hospitals performing TAVI. Measurements include in-hospital mortality, stroke, bleeding, and mechanical ventilation. RESULTS: Unadjusted mortality rates decrease over time for both TA-TAVI and TF-TAVI. Reductions in mortality were smaller for TA-TAVI than for TF-TAVI. These trends could also be observed for risk-adjusted (standardized) mortality rates, indicating that time trends and differences between TA-TAVI (around 7% in 2013) and TF-TAVI (around 4% in 2013) cannot be explained by changes in the risk factor composition of the patient populations. Bleeding complications decreased for both access routes. Both unadjusted and standardized bleeding rates were substantially higher for TA-TAVI. In addition, TA-TAVI procedures were associated with an increased likelihood of requiring >48h of mechanical ventilation. CONCLUSIONS: Observed improvements in TAVI-related in-hospital mortality are not due to a change in patient population. The results indicate the superiority of a TF-first approach.

Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO).

Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMß2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1-/-) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1-/- mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1-/- mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1's adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.