Preoperative computed tomography-imaging with patient-specific computer simulation in transcatheter aortic valve implantation: Design and rationale of the GUIDE-TAVI trial.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe aortic valve stenosis, but is still associated with relatively high rates of pacemaker implantation and paravalvular regurgitation. Routine preoperative computed tomography (CT) combined with patient-specific computer modelling can predict the interaction between the TAVI device and the patient's unique anatomy, allowing physicians to assess the risk for paravalvular regurgitation and conduction disorders in advance to the procedure. The aim of this trial is to assess potential improvement in the procedural outcome of TAVI by applying CT-based patient-specific computer simulations in patients with suitable anatomy for TAVI. METHODS: The GUIDE-TAVI trial is an international multicenter randomized controlled trial including patients accepted for TAVI by the Heart Team. Patients enrolled in the study will be randomized into 2 arms of each 227 patients. In patients randomized to the use of FEops HEARTGuide (FHG), patient-specific computer simulation with FHG is performed in addition to routine preoperative CT imaging and results of the FHG are available to the operator(s) prior to the scheduled intervention. In patients randomized to no use of FHG, only routine preoperative CT imaging is performed. The primary objective is to evaluate whether the use of FHG will reduce the incidence of mild to severe PVR, according to the Valve Academic Research Consortium 3. Secondary endpoints include the incidence of new conduction disorders requiring permanent pacemaker implantation, the difference between preoperative and final selected valve size, the difference between target and final implantation depth, change of preoperative decision, failure to implant valve, early safety composite endpoint and quality of life. CONCLUSIONS: The GUIDE-TAVI trial is the first multicenter randomized controlled trial to evaluate the value of 3-dimensional computer simulations in addition to standard preprocedural planning in TAVI procedures.

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Plasma Lipoprotein Lipase Is Associated with Risk of Future Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy.

INTRODUCTION: Carotid plaque intraplaque haemorrhage (IPH) is associated with future cardiovascular events. It was hypothesised that plasma proteins associated with carotid plaque IPH are also likely to be associated with major adverse cardiovascular events (MACE) after carotid endarterectomy (CEA). METHODS: In pre-operative blood samples from patients undergoing CEA within the Athero-Express biobank, proteins involved in cardiovascular disease were measured using three OLINK proteomics immunoassays. The association between proteins and IPH was analysed using logistic regression analyses. Subsequently, the association between the IPH associated plasma proteins and the three year post-operative risk of MACE (including stroke, myocardial infarction, or cardiovascular death) was analysed. RESULTS: Within the three year follow up, 130 patients (18.9%) of 688 symptomatic and asymptomatic patients undergoing CEA developed MACE. Six of 276 plasma proteins were found to be significantly associated with IPH, from which only lipoprotein lipase (LPL) was associated with the post-operative risk of MACE undergoing CEA. Within the 30 day peri-operative period, high plasma LPL was independently associated with an increased risk of MACE (adjusted hazard ratio [HR] per standard deviation [SD] 1.60, 1.10 - 2.30), p = .014). From 30 days to three years, however, high LPL was associated with a lower risk of MACE (adjusted HR per SD 0.80, 0.65 - 0.99, p= .036). CONCLUSION: High LPL concentrations were found to be associated with a higher risk of MACE in the first 30 post-operative days but with a lower risk MACE between 30 days and three years, meaning that LPL has different hazards at different time points.

Transcatheter closure of postsurgical aortic pseudoaneurysms guided by three-dimensional image reconstruction: a single-centre experience.

BACKGROUND: Postsurgical thoracic aortic pseudoaneurysms (PTAPs) are a potentially lethal complication after cardiac or aortic surgery. Surgical management can pose a challenge with high in-hospital mortality rates. Transcatheter closure is a less-invasive alternative treatment option for selected patients, although current experience is limited. AIMS: We aimed to evaluate procedural and imaging outcomes of our first 11 cases of transcatheter PTAP closure with the use of closure devices. METHODS: Patients with a high operative risk who underwent transcatheter PTAP closure at our centre from 2019 to 2021 were retrospectively included. Suitability was evaluated on preprocedural computed tomography (CT) scans and three-dimensional (3D) reconstructions. All procedures were performed in the catheterisation laboratory. Intraprocedural aortography and postprocedural CT scans with 3D reconstructions were used to evaluate PTAP occlusion. RESULTS: Eleven consecutive patients with a high operative risk and a history of cardiac/aortic surgery who underwent transcatheter PTAP closure were included. PTAPs were predominantly located at the proximal or distal anastomosis of a supracoronary ascending aortic vascular graft or Bentall prosthesis (82%). Implanted closure devices included Amplatzer Valvular Plug III (82%), Amplatzer septal occluder (9%) and Occlutech atrial septal defect occluder (9%). No periprocedural complications occurred. After device deployment, residual flow was absent on aortography in 64% and minimal residual flow was present in 36% of patients. Subtotal or total occlusion of the PTAP on follow-up CT ranged between 45% and 73%. CONCLUSIONS: Although subtotal or total occlusion of the PTAP was found at follow-up in only 45-73% of cases, transcatheter PTAP closure guided by preprocedural 3D reconstructions can offer a valuable minimally invasive primary treatment option for patients who otherwise would face a high-risk reoperation.

National indication document and aortic valve replacement landscape in the Netherlands.

INTRODUCTION: Based on European guidelines, transcatheter aortic valve implementation (TAVI) could be the therapy of choice in patients with severe aortic stenosis aged ≥ 75 years. In the Netherlands, there has been a debate between healthcare providers and the National Health Care Institute regarding reimbursement for TAVI, which resulted in an indication document that defines TAVI patients who are eligible for reimbursement. This document has been effective since 1 January 2021. METHODS: We extracted data from the Netherlands Heart Registry for patients who underwent biological surgical aortic valve replacement (SAVR) or TAVI in the Netherlands from 2018 through 2021. We compared baseline characteristics and variables from the indication document for the subsequent years and age groups. We also analysed the annual SAVR/TAVI ratio. RESULTS: The total number of patients treated with SAVR or TAVI was constant in 2018-2021. Baseline characteristics of patients treated with TAVI did not differ throughout the years. The SAVR/TAVI ratio shifted towards a higher percentage of TAVI from 2018 to 2019. From 2019 to 2020, the TAVI percentage was constant. Since the implementation of the indication document (in 2021), a change in the SAVR/TAVI ratio was not found either. CONCLUSION: Since the implementation of the national indication document for AVR in 2021, no major effect was seen for the SAVR versus TAVI landscape in the Netherlands.

Efficacy of coronary sinus Reducer in patients with refractory angina and diabetes mellitus.

Coronary sinus Reducer (CSR) implantation is currently recommended to relieve angina in patients with refractory symptoms despite optimal medical therapy and maximally achievable revascularization. The impact of diabetes mellitus on outcome after CSR implantation is at present unknown. We aimed to explore the impact of CSR in refractory angina patients with diabetes mellitus. Data from consecutive patients undergoing CSR implantation at four different centres between 2014 and 2018 were included. Patients were divided according to the presence or absence of diabetes mellitus. Primary objective of this analysis was to evaluate the clinical response to CSR implantation defined as an improvement of ≥ 1 classes of the Canadian Cardiovascular Society (CCS) Classification. A total of 219 patients were included, 116 (53%) of whom had diabetes mellitus. The median age of the population was 69 years and 167 patients (76%) were male. There were no significant differences between groups of patients with and without diabetes mellitus with respect to CCS class at baseline (p value = 0.32) and at follow-up (p = 0.75). Over a median follow-up of 393 [224-1004] days, 84 (72%) of the patients with diabetes mellitus met the primary outcome, similarly to those without diabetes mellitus (p = 0.28). Fifty-three patients (24%) did not have an improvement in CCS class and no one experienced worsening of angina. CSR implantation was equally effective in improving angina symptoms among patients with refractory angina and diabetes mellitus compared to patients without diabetes mellitus.

Coronary sinus anatomical features: Description and procedural implications during coronary sinus Reducer implantation.

OBJECTIVES: We hypothesized that some coronary sinus (CS) anatomies allow a more straightforward CS Reducer (CSR) implantation. BACKGROUND: Recent decades have seen a rise in patients with chronic angina. When complete revascularization and maximal medical therapy fail to reduce symptoms, CSR has become a new therapeutic option. METHODS: We identified a classical C-shape-a near horizontal course of the proximal portion of a circular CS-in a retrospective analysis of 47 CSR implantations and compared the procedural time, fluoroscopic time, contrast use, presence of valves or bifurcations and procedural complications with the non-C-shape CS anatomy. RESULTS: We found a significant difference in procedural (20.0 [19.0-24.7] min vs. 24.5 [20.7-51.0] min; p = .028 and fluoroscopic time (9.5 [7.5-14.5] min vs. 11.0 [7.9-30.0] min; p = .016). There was no significant difference in contrast use. The presence of bifurcations or valves along the CS course did not influence the procedural timings. CONCLUSION: This study is the first systematic evaluation of CS anatomy and its procedural implications. We identified a favorable C-shape anatomy which allows for a more straightforward implantation. Operators should be aware of the different implications of CS anatomy, their influence on guiding catheter stability and overall procedure complexity.

Experimental parameters and infarct size in closed chest pig LAD ischemia reperfusion models; lessons learned.

BACKGROUND: Preclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction. Closed chest pig left anterior descending coronary artery (LAD) ischemia reperfusion (I/R) models are valuable and clinically relevant. Knowledge on the influence of experimental design on infarct size (IS) in these models is a prerequisite for suitable models. To this end, we investigated the impact of several experimental features (occlusion and follow-up time and influence of area at risk (AAR)) on IS. METHODS: A total of fifty-one female Landrace pigs were subjected to closed chest LAD balloon occlusion and evaluated in three substudies with varying protocols. To assess the relationship between time of occlusion and the IS, 18 pigs were subjected to 60-, 75- and 90 min of occlusion and terminated after 24 h of follow-up. Influence of prolonged follow-up on IS was studied in 18 pigs after 75 min of occlusion that were terminated at 1, 3 and 7 days. The relation between AAR and IS was studied in 28 pigs after 60 min of occlusion and 24 h of follow-up. The relation between VF, number of shocks and IS was studied in the same 28 pigs after 60 min of occlusion. RESULTS: Increasing occlusion time resulted in an increased IS as a ratio of the AAR (IS/AAR). This ranged from 53 ± 23% after 60 min of occlusion to 88 ± 2.2% after 90 min (P = 0.01). Increasing follow-up, from 1 to 3 or 7 days after 75 min of occlusion did not effect IS/AAR. Increasing AAR led to a larger IS/AAR (r2 = 0.34, P = 0.002), earlier VF (r2 = 0.32, P = 0.027) and a higher number of shocks (r2 = 0.29, P = 0.004) in pigs subjected to 60 min of occlusion. CONCLUSIONS: These experiments describe the association of occlusion time, follow-up duration, AAR and VF with IS in closed chest pig LAD I/R models. These results have important implications for future I/R studies in pigs and can serve as a guideline for the selection of appropriate parameters and the optimal experimental design.

Randomized All-Comers Evaluation of a Permanent Polymer Zotarolimus-Eluting Stent Versus a Polymer-Free Amphilimus-Eluting Stent.

BACKGROUND: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES as compared with latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have not yet been investigated in a large randomized trial. METHODS: In this physician-initiated, prospective, multicenter, randomized, noninferiority trial, an all-comers population requiring percutaneous coronary intervention was enrolled across 3 European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after stratification for troponin status and diabetes mellitus. In both treatment arms, troponin-positive patients were planned for 12-month dual antiplatelet therapy, whereas troponin-negative patients were planned for 1-month dual antiplatelet therapy. Outcome assessors were blinded to the allocated treatment. The device-oriented primary end point of target-lesion failure was defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed by modified intention-to-treat (80% power, and a 3.5% noninferiority margin). RESULTS: In total, 1502 patients were randomized and 1491 treated with the assigned stent and available for follow-up. The primary end point occurred in 42 (5.6%) of the 744 patients receiving PP-ZES versus 46 (6.2%) of the 747 patients receiving PF-AES. PF-AES were clinically noninferior to PP-ZES (risk difference, 0.5%; upper limit 1-sided 95% confidence interval, 2.6%; Pnoninferiority=0.0086). Cardiac death occurred in 10 (1.3%) versus 10 patients (1.3%; P value for difference, 1.00), target-vessel myocardial infarction occurred in 18 (2.4%) versus 17 patients (2.3%; P value for difference, 0.87), and target-lesion revascularization occurred in 22 (2.9%) versus 20 patients (2.6%; P value for difference, 0.75) for PF-AES as compared with PP-ZES. Overall, definite or probable stent thrombosis occurred in 1.0%. CONCLUSIONS: PF-AES were noninferior to PP-ZES regarding target-lesion failure at 12 months. Findings regarding the secondary end point and prespecified subgroups were generally consistent with that of the primary end point. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02328898.

Can TAVR Be Effectively and Safely Performed Without Intraprocedural TEE?

PURPOSE OF REVIEW: The TAVR procedure is a well-established therapy for patients with severe aortic stenosis at intermediate/high risk for surgery and a potential treatment for low-risk patients. It is much less invasive with short hospital stays and presents similar results compared with SAVR. Different "minimalist approach strategies" were proposed in order to obtain this performance. In these settings, transesophageal echocardiography (TEE) became less relevant for the TAVR procedure. The present review provides an update regarding the safety of TAVR without intraprocedural TEE. RECENT FINDINGS: Transthoracic echocardiography and fluoroscopy are the primary imaging tools during TAVR. Several studies proved that TAVR under local anesthesia without TEE is as safe as that performed under TEE guidance. However, not all patients have a proper window for TTE, and particular cases with complex anatomy can benefit from TEE support during the intervention. Intraprocedural TEE no longer plays a crucial role in the TAVR procedure, but in some instances, it remains of great help to detect and avoid complications.

Extracellular Vesicles in Diagnosing Chronic Coronary Syndromes the Bumpy Road to Clinical Implementation.

Coronary artery disease (CAD), comprising both acute coronary syndromes (ACS) and chronic coronary syndromes (CCS), remains one of the most important killers throughout the entire world. ACS is often quickly diagnosed by either deviation on an electrocardiogram or elevated levels of troponin, but CCS appears to be more complicated. The most used noninvasive strategies to diagnose CCS are coronary computed tomography and perfusion imaging. Although both show reasonable accuracy (80-90%), these modalities are becoming more and more subject of debate due to costs, radiation and increasing inappropriate use in low-risk patients. A reliable, blood-based biomarker is not available for CCS but would be of great clinical importance. Extracellular vesicles (EVs) are lipid-bilayer membrane vesicles containing bioactive contents e.g., proteins, lipids and nucleic acids. EVs are often referred to as the "liquid biopsy" since their contents reflect changes in the condition of the cell they originate from. Although EVs are studied extensively for their role as biomarkers in the cardiovascular field during the last decade, they are still not incorporated into clinical practice in this field. This review provides an overview on EV biomarkers in CCS and discusses the clinical and technological aspects important for successful clinical application of EVs.

One-year clinical outcomes of patients treated with polymer-free amphilimus-eluting stents or zotarolimus-eluting stents: A propensity-score adjusted analysis.

BACKGROUND: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution-technology in coronary stenting. We aimed to assess 1-year clinical outcomes of PF-AES as compared to latest-generation permanent polymer zotarolimus-eluting stents (PP-ZES) in a real-world all-comers setting. METHODS: A prospective registry of patients treated with either PF-AES or PP-ZES between 2014 and 2016 was conducted. The primary outcome was defined as major adverse cardiac and cerebrovascular events (MACCE), and the secondary outcome was defined as target-lesion failure (TLF) at 1 year. To account for measured confounders, a propensity-score adjusted Cox proportional-hazard model was built to evaluate clinical outcomes. RESULTS: A total of 734 consecutive patients with 1,269 DES implantations were enrolled. The population was characterized by 28% diabetes, 24% ST-segment elevation myocardial infarction, and a high number of complex lesions (69%). The rate of MACCE was 11.5% for PF-AES and 13.6% for PP-ZES, plog-rank = 0.11. TLF was numerically lower in PF-AES as compared to PP-ZES (5.4 vs. 6.1%, plog-rank = 0.68). After propensity-score adjustment, PF-AES showed a trend toward a lower rate of MACCE and a favorable rate of TLF as compared to PP-ZES (HR 0.70; 95%CI 0.45 to 1.10, P = 0.12; and HR 0.88; 95%CI 0.47 to 1.65, P = 0.68, respectively). Rates of definite ST were low (0.8 vs. 0.3%, plog-rank = 0.62). CONCLUSIONS: Our study suggests that implantation of PF-AES was safe and effective in real-world patients, with low-rates of MACCE and TLF at 1 year. Our data needs to be confirmed by a large trial to evaluate the clinical outcomes of this novel polymer-free, eluting-technology used in PF-AES.

Renin and aldosterone are not associated with vulnerable plaque characteristics in patients with carotid artery disease.

BACKGROUND: The renin-angiotensin-aldosterone system is increasingly being recognized to play an important role in the development and clinical course of cardiovascular diseases. Renin-angiotensin-aldosterone system activation is associated with clinical outcome in various populations of cardiovascular patients, such as patients with coronary artery, peripheral artery, and cerebrovascular disease. In this study, we investigated the associations between plasma renin and aldosterone concentrations and atherosclerotic plaque characteristics and secondary vascular events in patients undergoing carotid endarterectomy. METHODS AND RESULTS: Baseline plasma renin and aldosterone concentrations from 506 subjects undergoing carotid endarterectomy (mean age, 67 ± 9 years; 65% male) were correlated with histopathologic characteristics and inflammatory protein concentrations of the excised atherosclerotic plaque. Ordinal logistic regression (for ordinal outcome parameters) or linear regression (for linear outcome) analysis did not show a statistically significant relationship between plasma renin or aldosterone concentrations and plaque fat, thrombus, calcifications, collagen, smooth muscle cells, or macrophage content. Neither could any association be found with intraplaque inflammatory mediators. During a median follow-up of 3 years, 102 (20%) patients experienced a major secondary vascular event (composite of stroke, myocardial infarction, leg amputation, vascular death, or coronary revascularization or peripheral intervention). In multivariable Cox regression analysis, including both renin and aldosterone, baseline renin concentrations were associated with the occurrence of secondary events. CONCLUSIONS: In patients with established atherosclerotic disease undergoing carotid endarterectomy, plasma renin and aldosterone concentrations were not associated with atherosclerotic plaque characteristics. Plasma renin concentration was positively associated with the occurrence of major secondary vascular events.

Rationale and design of amphilimus sirolimus-eluting stents versus zotarolimus-eluting stents in all-comers requiring percutaneous coronary intervention (ReCre8): A multicenter randomized clinical trial.

BACKGROUND: Amphilimus sirolimus-eluting stents (A-SES) represent a novel elution technology in the current era of drug-eluting stents with promising results in patients with diabetes mellitus. At present no large trial has been designed to evaluate clinical outcomes of A-SES as compared to new-generation drug-eluting stents in unselected patients. Accordingly, we designed this trial to evaluate clinical noninferiority of A-SES as compared with zotarolimus-eluting stents (ZES) in a real-world, all-comers setting. STUDY DESIGN: ReCre8 is a prospective multicenter randomized clinical trial evaluating the clinical outcomes of A-SES as compared with ZES in all-comers requiring percutaneous coronary intervention. Patients are randomized 1:1 to receive either A-SES or ZES. On-site block-randomization is stratified by diabetes mellitus, and troponin status to perform prespecified subanalyses. Patients receive 1-month of dual antiplatelet therapy (DAPT) when troponin-negative, or 12-months of DAPT when troponin-positive. The primary endpoint is target-lesion failure at 1-year follow-up. A total of 1,532 patients will be enrolled to demonstrate clinical noninferiority of A-SES with at least 80% power, a noninferiority margin of 3.5% and a type-I-error of 0.05. CONCLUSIONS: ReCre8 (NCT02328898) is the first randomized multicenter trial with a head-to-head comparison of A-SES as compared with ZES to investigate the clinical safety and efficacy of these new-generation DES in a real-world, all-comers population.

Subadventitial stenting around occluded stents: A bailout technique to recanalize in-stent chronic total occlusions.

OBJECTIVES: To evaluate the outcomes of subadventitial stenting (SS) around occluded stents for recanalizing in-stent chronic total occlusions (IS-CTOs). BACKGROUND: There is little evidence on the outcomes of SS for IS-CTO. METHODS: We examined the outcomes of SS for IS-CTO PCI at 14 centers between July 2011 and June 2017, and compared them to historical controls recanalized using within-stent stenting (WSS). Target-vessel failure (TVF) on follow-up was the endpoint of this study, and was defined as a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization. RESULTS: During study period, 422 IS-CTO PCIs were performed, of which 32 (7.6%) were recanalized with SS, usually when conventional approaches failed. The most frequent CTO vessel was the right coronary artery (72%). Mean J-CTO score was 3.1 ± 0.9. SS was antegrade in 53%, and retrograde in 47%. Part of the occluded stent was crushed in 37%, while the whole stent was crushed in 63%. Intravascular imaging was used in 59%. One patient (3.1%) suffered tamponade. Angiographic follow-up was performed in 10/32 patients: stents were patent in six cases, one had mild neointimal hyperplasia, and three had severe restenosis at the SS site. Clinical follow-up was available for 29/32 patients for a mean of 388 ± 303 days. The 24-month incidence of TVF was 13.8%, which was similar to historical controls treated with WSS (19.5%, P = 0.49). CONCLUSIONS: SS is rarely performed, usually as last resort, to recanalize complex IS-CTOs. It is associated with favorable acute and mid-term outcomes, but given the small sample size of our study additional research is warranted.

Lowering Low-Density Lipoprotein Particles in Plasma Using Dextran Sulphate Co-Precipitates Procoagulant Extracellular Vesicles.

Plasma extracellular vesicles (EVs) are lipid membrane vesicles involved in several biological processes including coagulation. Both coagulation and lipid metabolism are strongly associated with cardiovascular events. Lowering very-low- and low-density lipoprotein ((V)LDL) particles via dextran sulphate LDL apheresis also removes coagulation proteins. It remains unknown, however, how coagulation proteins are removed in apheresis. We hypothesize that plasma EVs that contain high levels of coagulation proteins are concomitantly removed with (V)LDL particles by dextran sulphate apheresis. For this, we precipitated (V)LDL particles from human plasma with dextran sulphate and analyzed the abundance of coagulation proteins and EVs in the precipitate. Coagulation pathway proteins, as demonstrated by proteomics and a bead-based immunoassay, were over-represented in the (V)LDL precipitate. In this precipitate, both bilayer EVs and monolayer (V)LDL particles were observed by electron microscopy. Separation of EVs from (V)LDL particles using density gradient centrifugation revealed that almost all coagulation proteins were present in the EVs and not in the (V)LDL particles. These EVs also showed a strong procoagulant activity. Our study suggests that dextran sulphate used in LDL apheresis may remove procoagulant EVs concomitantly with (V)LDL particles, leading to a loss of coagulation proteins from the blood.

Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction.

Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced genes, TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R=0.48, p=0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.

Lack of haptoglobin results in unbalanced VEGFα/angiopoietin-1 expression, intramural hemorrhage and impaired wound healing after myocardial infarction.

Decreased haptoglobin (Hp) functionality due to allelic variations is associated with worsened outcome in patients after myocardial infarction (MI). However, mechanisms through which haptoglobin deficiency impairs cardiac repair remain to be elucidated. In the present study, we identified novel molecular alterations mediated by Hp involved in early and late cardiac repair responses after left coronary artery ligation in Hp(-/-) and wild-type (WT) mice. We observed a higher mortality rate in Hp(-/-) mice despite similar infarct size between groups. Deaths were commonly caused by cardiac rupture in Hp(-/-) animals. Histological analysis of 3 and 7days old non-ruptured infarcted hearts revealed more frequent and more severe intramural hemorrhage and increased leukocyte infiltration in Hp(-/-) mice. Analyses of non-ruptured hearts revealed increased oxidative stress, reduced PAI-1 activity and enhanced VEGFα transcription in Hp(-/-) mice. In line with these observations, we found increased microvascular permeability in Hp(-/-) hearts 3days after infarction. In vitro, haptoglobin prevented hemoglobin-induced oxidative stress and restored VEGF/Ang-1 balance in endothelial cell cultures. During long-term follow-up of the surviving animals, we observed altered matrix turnover, impaired scar formation and worsened cardiac function and geometry in Hp(-/-)mice. In conclusion, haptoglobin deficiency severely deteriorates tissue repair and cardiac performance after experimental MI. Haptoglobin plays a crucial role in both short- and long-term cardiac repair responses by reducing oxidative stress, maintaining microvascular integrity, myocardial architecture and proper scar formation.

Periprocedural continuation versus interruption of oral anticoagulant drugs during transcatheter aortic valve implantation: rationale and design of the POPular PAUSE TAVI trial.

About one-third of patients undergoing transcatheter aortic valve implantation (TAVI) use oral anticoagulants (OAC), mainly due to atrial fibrillation. General guidelines advise interrupting OAC in patients with a high risk of bleeding undergoing interventions. However, preliminary observational data suggest that the continuation of OAC during TAVI is safe and may reduce the risk of periprocedural thromboembolic events. The Periprocedural Continuation Versus Interruption of Oral Anticoagulant Drugs During Transcatheter Aortic Valve Implantation (POPular PAUSE TAVI) is a multicentre, randomised clinical trial with open-label treatment and blinded endpoint assessment. Patients are randomised 1:1 to periprocedural continuation versus interruption of OAC and are stratified for vitamin K antagonist or direct oral anticoagulant use. The primary endpoint is a composite of cardiovascular mortality, all stroke, myocardial infarction, major vascular complications and type 2-4 bleeding within 30 days after TAVI, according to the Valve Academic Research Consortium-3 criteria. Secondary endpoints include separate individual and composite outcomes, quality of life and cost-effectiveness. Since continuation of OAC is associated with the ancillary benefit that it simplifies periprocedural management, the primary outcome is first analysed for non-inferiority; if non-inferiority is proven, superiority will be tested. Recruitment started in November 2020, and the trial will continue until a total of 858 patients have been included and followed for 90 days. In summary, POPular PAUSE TAVI is the first randomised clinical trial to assess the safety and efficacy of periprocedural continuation versus interruption of OAC in patients undergoing TAVI.