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.

Effect of Availability of Transcatheter Aortic-Valve Replacement on Clinical Practice.

BACKGROUND: Since the adoption of transcatheter aortic-valve replacement (TAVR), questions have been raised about its effect on clinical practice in comparison with the effect of surgical aortic-valve replacement, which is considered the current standard of care. Complete nationwide data are useful in examining how the introduction of a new technique influences previous clinical standards. METHODS: We analyzed data on characteristics of patients and in-hospital outcomes for all isolated TAVR and surgical aortic-valve replacement procedures performed in Germany from 2007 to 2013. RESULTS: In total, 32,581 TAVR and 55,992 surgical aortic-valve replacement procedures were performed. The number of TAVR procedures increased from 144 in 2007 to 9147 in 2013, whereas the number of surgical aortic-valve replacement procedures decreased slightly, from 8622 to 7048. Patients undergoing TAVR were older than those undergoing surgical aortic-valve replacement (mean [±SD] age, 81.0±6.1 years vs. 70.2±10.0 years) and at higher preoperative risk (estimated logistic EuroSCORE [European System for Cardiac Operative Risk Evaluation], 22.4% vs. 6.3%, on a scale of 0 to 100%, with higher scores indicating greater risk and a score of more than 20% indicating high surgical risk). In-hospital mortality decreased in both groups between 2007 and 2013 (from 13.2% to 5.4% with TAVR and from 3.8% to 2.2% with surgical aortic-valve replacement). The incidences of stroke, bleeding, and pacemaker implantation (but not acute kidney injury) also declined. CONCLUSIONS: The use of TAVR increased markedly in Germany between 2007 and 2013; the concomitant reduction in the use of surgical aortic-valve replacement was moderate. Patients undergoing TAVR were older and at higher procedural risk than those undergoing surgical aortic-valve replacement. In-hospital mortality decreased in both groups but to a greater extent among patients undergoing TAVR. (Funded by the Heart Center, Freiburg University.).

Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y2 in Mice.

OBJECTIVE: A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y2 in vascular inflammation and atherosclerosis. APPROACH AND RESULTS: Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor(-/-) mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2; P=0.01). To gain into the role of ATP-receptor P2Y2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or P2Y2-competent mice. In P2Y2-deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient low-density lipoprotein receptor(-/-) mice consumed high cholesterol diet. After 16 weeks, P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y2-competent mice (n=11; aortic arch: control group, 0.25 mm(2); P2Y2-deficient, 0.14 mm2; P=0.04). Mechanistically, atherosclerotic lesions from P2Y2-deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA. CONCLUSIONS: We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y2.

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 .

Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages.

Clinical, but not experimental evidence has suggested that air pollution particulate matter (PM) aggravates myocardial infarction (MI). Here, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. C57BL/6J mice were challenged with a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation before MI was induced by permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium 7 days after MI demonstrated an increase in infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Mechanistically, ROFA exposure increased the levels of the circulating pro-inflammatory cytokines TNF-α, IL-6, and MCP-1, activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. Notably, these effects on endothelial cells and circulating leukocytes could be reversed by neutralizing anti-TNF-α treatment. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of alveolar macrophages by intranasal clodronate attenuated inflammation and cell recruitment to infarcted tissue of ROFA-exposed mice. Taken together, our data demonstrate that exposure to environmental PM induces the release of inflammatory cytokines from alveolar macrophages which directly worsens the course of MI in mice. These findings uncover a novel link between air pollution PM exposure and inflammatory pathways, highlighting the importance of environmental factors in cardiovascular disease.

Aortic root volume is associated with contained rupture of the aortic annulus in balloon-expandable transcatheter aortic valve replacement.

BACKGROUND: Aortic annulus rupture is a rare, but potentially fatal complication of transcatheter aortic valve replacement (TAVR), especially when it occurs by balloon-expandable devices. In order to improve the predictability of procedures and avoid ruptures we investigated whether or not the aortic root volume measures is a useful indicator of risk, and if it could be useful for the prosthesis size selection. METHODS AND RESULTS: From a retrospective series of 172 TAVR patients, seven experienced contained aortic annulus ruptures. The receiver operating curves were used to illustrate sensitivity and specificity of the different aortic annulus size and aortic root volume measures. The annulus area oversizing of ≥20% resulted in a sensitivity of 100%, specificity of 55.76%, and positive predictive value (PPV) of 8.75%. In patients receiving 26 mm prostheses, the aortic root volume (ARV <13600 mm(3)) provided a better specificity and PPV (79.63 and 18.52%, respectively). A two-step testing procedure considering the area derived average annulus diameter (Darea <23 mm) as a first separating parameter and then the ARV (<13,600 mm(3)) as a further indicator showed the most promising results with the PPV of 31.25%. Regardless of the procedure steps no false negative results were predicted. CONCLUSIONS: Our data show that the ARV provides a better predictive value for correct prosthesis sizing than established annulus measurements, especially in 'borderline' annuli. We suggest a two-step testing procedure for prostheses size selection, considering Darea and ARV to minimize the risk of annulus rupture. Prospective studies and examination of larger datasets are warranted to confirm these findings.

Quality of life among elderly patients undergoing transcatheter or surgical aortic valve replacement- a model-based longitudinal data analysis.

BACKGROUND: Quality of life (QoL) measurements reported in observational studies are often biased, since patients who failed to improve are more likely to be unable to respond due to death or impairment. In order to observe the development of QoL in patients close to death, we analyzed a set of monthly QoL measurements for a cohort of elderly patients treated for aortic valve stenosis (AS) with special consideration of the effect of distance to death. METHODS: QoL in 169 elderly patients (age ≥ 75 years), treated either with transcatheter aortic valve replacement (TAVR; n = 92), surgical aortic-valve replacement (n = 70), or drug-based therapy (n = 7), was evaluated using the standardized EQ-5D questionnaire. Over a two-year period, patients were consulted using monthly telephone interviews or outpatient visits, leading to a total of 2463 time points at which QoL values, New York Heart Association (NYHA) Functional Classification and their status of assistance were assessed. Furthermore, post-procedural clinical events and complications were monitored. Linear and ordered logistic regression analyses with random intercept were carried out, taking into account overall trends and distance to death. RESULTS: QoL measures decreased slightly over time, were temporarily impaired at month 1 after the initial episode of hospitalization and decreased substantially at the end of life with a measurable effect starting at the sixth from last follow-up (month) before death. Many clinical complications (bleeding complications, stroke, acute kidney injury) showed an impairment of QoL measurements, but the inclusion of lagged variables demonstrated medium term (three months) QoL impairments for access site bleeding only. All other complications are associated with event-related impairments that decreased dramatically at the second and third follow-up interviews (month) after event. CONCLUSIONS: Distance to death shows clear effects on QoL and should be taken into account when analyzing QoL measures in the elderly patients treated for aortic valve stenosis. TRIAL REGISTRATION: German Clinical Trial Register Nr. DRKS00000797.

A prospective randomized evaluation of the TriGuard™ HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial.

AIMS: To evaluate the safety, efficacy, and performance of the TriGuard™ HDH Embolic Deflection Device (TriGuard) compared with no cerebral protection in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: From February 2014 to March 2015, 85 subjects undergoing TAVI at 13 centres in Europe and Israel were randomized to TriGuard protection vs. no protection. Subjects underwent neurologic and cognitive evaluation at baseline, pre-discharge and 30 days; cerebral diffusion-weighted magnetic resonance imaging was performed at 4 ± 2 days post-procedure and at 30 days. Technical success, which included complete 3-vessel cerebral coverage, was achieved in 88.9% (40/45) of cases. The primary in-hospital procedural safety endpoint (death, stroke, life-threatening or disabling bleeding, stage 2 or 3 acute kidney injury, or major vascular complications) occurred in 21.7% of TriGuard and 30.8% of control subjects (P = 0.34). In the Per Treatment population (subjects with complete three-vessel cerebral coverage), TriGuard use was associated with greater freedom from new ischaemic brain lesions (26.9 vs. 11.5%), fewer new neurologic deficits detected by the National Institutes of Health Stroke Scale (3.1 vs. 15.4%), improved Montreal Cognitive Assessment (MoCA) scores, better performance on a delayed memory task (P = 0.028) at discharge, and a >2-fold increase in recovery of normal cognitive function (MoCA score >26) at 30 days. CONCLUSION: TriGuard cerebral protection during TAVI is safe and complete cerebral vessel coverage was achieved in 89% of subjects. In this exploratory study, subjects undergoing protected TAVI had more freedom from ischaemic brain lesions, fewer neurologic deficits, and improved cognitive function in some domains at discharge and 30 days compared with controls.

P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.

OBJECTIVE: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. APPROACH AND RESULTS: Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. CONCLUSIONS: We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.

In-hospital resource utilization in surgical and transcatheter aortic valve replacement.

BACKGROUND: Little is known about preoperative predictors of resource utilization in the treatment of high-risk patients with severe symptomatic aortic valve stenosis. We report results from the prospective, medical-economic "TAVI Calculation of Costs Trial". METHODS: In-hospital resource utilization was evaluated in 110 elderly patients (age ≥ 75 years) treated either with transfemoral (TF) or transapical (TA) transcatheter aortic valve implantation (TAVI, N = 83), or surgical aortic valve replacement (AVR, N = 27). Overall, 22 patient-specific baseline parameters were tested for within-group prediction of resource use. RESULTS: Baseline characteristics differed between groups and reflected the non-randomized, real-world allocation of treatment options. Overall procedural times were shortest for TAVI, intensive care unit (ICU) length of stay (LoS) was lowest for AVR. Length of total hospitalization since procedure (THsP) was lowest for TF-TAVI; 13.4 ± 11.4 days as compared to 15.7 ± 10.5 and 21.2 ± 15.4 days for AVR and TA-TAVI, respectively. For TAVI and AVR, EuroScore I remained the main predictor for prolonged THsP (p <0.01). Within the TAVI group, multivariate regression analyses showed that TA-TAVI was associated with a substantial increase in THsP (55 to 61 %, p <0.01). Additionally, preoperative aortic valve area (AVA) was identified as an independent predictor of prolonged THsP in TAVI patients, irrespective of risk scores (p <0.05). CONCLUSIONS: Our results demonstrate significant heterogeneity in patients baseline characteristics dependent on treatment and corresponding differences in resource utilization. Prolonged ThsP is not only predicted by risk scores but also by baseline AVA, which might be useful in stratifying TAVI patients. TRIAL REGISTRATION: German Clinical Trial Register Nr. DRKS00000797.

TAVI 2012: state of the art.

The development of "transcatheter aortic valve implantation (TAVI)" is changing the field of cardiovascular medicine rapidly. The basic principle of TAVI is the percutaneous implantation of a bioprosthesis mounted in a metal frame. The prosthesis, which is attached to the tip of the catheter, is positioned in the native aortic valve and expanded. The first successful implantation was made by Alain Cribier in 2002. Several smaller mono- and multicenter studies later confirmed the technical feasibility of this procedure. Its true value as an important, therapeutic alternative to open heart surgery in inoperable and high-risk patients is now confirmed in large multicenter registries and by the prospective, randomized PARTNER trial. Decisive for the future acceptance of the procedure and for a possible expansion of the indication spectrum will be (1) continuous further development of the implantation technique and the prosthesis design, (2) reduction of TAVI-associated complications, (3) confirmation of the initial positive long-term results and (4) confirmation of the promising results in the treatment of surgical prosthesis dysfunctions and of patients with low to intermediate risk.

Transfemoral aortic valve implantation: bleeding events, related costs and outcomes.

Although less invasive then SAVR, TAVI is associated with a significant rate of access site and non-access site bleeding. These complications are major determinants of therapy outcome, however, the economic consequences are not well defined. The purpose of this study was to determine the relationship between bleeding, in-hospital resource utilization and costs among patients undergoing transfemoral aortic valve implantation (TF-AVI) at a representative university hospital in Germany. Between February 2010 and December 2011, we prospectively enrolled 60 consecutive patients undergoing TAVI using a 18F transfemoral approach at our institution. The relationship between overt bleeding (OVB), defined according to the definitions provided by the Valve Academic Research Consortium, in-hospital resource utilization and in-hospital costs was investigated. The mean age was 82 (±6) years, 53% were female and the mean EuroScore was 17.2% (±8, 7). Thirty-eight percent (23/60) of the patients had an OVB following TF-AVI procedure. In-hospital mortality was 8.7% in the OVB patients (2/23) and 2.7% among patients without any OVB (1/37; NOVB), which was not statistically significant (p = 0.3). The total length of stay (LOS) of patients with and without bleeding complication were 15.0 ± 6.4 and 10.4 ± 5.1 days, respectively (p < 0.01). Time spent on ICU in the OVB group was twice as long as compared to the NOVB group (120.5 ± 98.5 min vs. 63.6 ± 26.5 min, p < 0.01). Consequently, in-hospital costs were statistically significant higher in OVB patients (40.051 ± 9.293 vs. 33.625 ± 4.368, p < 0.01). Bleeding is associated with increased resource use and in-hospital costs among TF-AVI patients. Our data indicates that strategies reducing bleeding risk may have the potential to generate important in-hospital costs reductions in TF-AVI patients.

Current periprocedural anticoagulation in transcatheter aortic valve replacement: could bivalirudin be an option? Rationale and design of the BRAVO 2/3 studies.

Transcatheter aortic valve replacement (TAVR) is considered an important option in the management of patients with critical aortic valve stenosis that are either inoperable or have a high surgical risk. Despite continued advances in the procedural aspects of TAVR and decreasing complications rates, the risks of major vascular complications and stroke remain significant, which may in turn confer worse clinical outcomes and impact morbidity and mortality. In this review, we outline certain limitations of the currently recommended periprocedural anticoagulation in TAVR, namely unfractionated heparin that is guided by activated clotting times and protamine use if the bleeding risk is high. We will explore the potential for bivalirudin in this setting, which has become a frontrunner in acute coronary syndrome management because of favorable pharmacokinetics and lower bleeding complications. Finally, we will describe an ongoing large multicenter multinational trial that compares intravenous bivalirudin to unfractionated heparin during TAVR procedures using standardized clinical endpoints.

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.

Combined assessment of aortic root anatomy and aortoiliac vasculature with dual-source CT as a screening tool in patients evaluated for transcatheter aortic valve implantation.

OBJECTIVE: The objective of our study was to investigate the feasibility, image quality, and clinical implications of a combined dual-source CT angiography (CTA) protocol to assess aortic root anatomy and aortoiliac vasculature in patients with severe aortic stenosis evaluated for transcatheter aortic valve implantation. SUBJECTS AND METHODS: Eighty consecutive patients (47 women and 33 men; mean age, 82.3 ± 7.8 [SD] years) with severe aortic stenosis evaluated for transcatheter aortic valve implantation underwent a combined single-dose contrast-enhanced dual-source CTA protocol (body weight < 70 kg, 110 mL of contrast medium; ≥ 70 kg, 130 mL) consisting of ECG-gated dual-source CTA of the chest with integrated cardiac CT and ungated CTA of the abdomen and pelvis. Two independent observers measured the dimensions of the aortic root and the aortoiliac vasculature and rated image quality semiquantitatively. Vessel attenuation was assessed. Amenability to transfemoral access was evaluated on the basis of vessel diameter (> 7 mm), anatomy, and the presence of vascular disease. RESULTS: Image quality of the aortic root was diagnostic in all 80 patients, and image quality of the aortoiliac vasculature was diagnostic in 79 patients. Vascular attenuation was greater than 200 HU at any vessel level. The mean diameter of the aortic annulus was 24.1 ± 2.9 (SD) mm. Inter- and intraobserver correlations for aortic root and aortoiliac measurements were high (r = 0.93-0.99). Aortic root dimensions were suitable for transcatheter aortic valve implantation in 65 patients (81%). Thirty-eight patients (48%) were deemed amenable to instant transfemoral access without another vasculature intervention. CONCLUSION: The dimensions of the aortic root and the aortoiliac vasculature can be assessed with a combined single-dose contrast-enhanced dual-source CTA protocol, thereby allowing determination of patient eligibility for transcatheter aortic valve implantation, prosthesis sizing, and evaluation of the access route in one examination.

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.