The complement system in neurodegenerative diseases.

Complement is an important component of innate immune defence against pathogens and crucial for efficient immune complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence of activating triggers, is a cause of pathological inflammation in numerous diseases, including neurological diseases. Increasingly, this has become apparent not only in well-recognized neuroinflammatory diseases like multiple sclerosis but also in neurodegenerative and neuropsychiatric diseases where inflammation was previously either ignored or dismissed as a secondary event. There is now a large and rapidly growing body of evidence implicating complement in neurological diseases that cannot be comprehensively addressed in a brief review. Here, we will focus on neurodegenerative diseases, including not only the 'classical' neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, but also two other neurological diseases where neurodegeneration is a neglected feature and complement is implicated, namely, schizophrenia, a neurodevelopmental disorder with many mechanistic features of neurodegeneration, and multiple sclerosis, a demyelinating disorder where neurodegeneration is a major cause of progressive decline. We will discuss the evidence implicating complement as a driver of pathology in these diverse diseases and address briefly the potential and pitfalls of anti-complement drug therapy for neurodegenerative diseases.

Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

BACKGROUND AND AIMS: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. METHODS: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. RESULTS: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. CONCLUSIONS: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

2022 Joint ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease in patients at low surgical risk and anatomy suitable for PCI or CABG.

In October 2021, the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) jointly agreed to establish a Task Force (TF) to review recommendations of the 2018 ESC/EACTS Guidelines on myocardial revascularization as they apply to patients with left main (LM) disease with low-to-intermediate SYNTAX score (0-32). This followed the withdrawal of support by the EACTS in 2019 for the recommendations about the management of LM disease of the previous guideline. The TF was asked to review all new relevant data since the 2018 guidelines including updated aggregated data from the four randomized trials comparing percutaneous coronary intervention (PCI) with drug-eluting stents vs. coronary artery bypass grafting (CABG) in patients with LM disease. This document represents a summary of the work of the TF; suggested updated recommendations for the choice of revascularization modality in patients undergoing myocardial revascularization for LM disease are included. In stable patients with an indication for revascularization for LM disease, with coronary anatomy suitable for both procedures and a low predicted surgical mortality, the TF concludes that both treatment options are clinically reasonable based on patient preference, available expertise, and local operator volumes. The suggested recommendations for revascularization with CABG are Class I, Level of Evidence A. The recommendations for PCI are Class IIa, Level of Evidence A. The TF recognized several important gaps in knowledge related to revascularization in patients with LM disease and recognizes that aggregated data from the four randomized trials were still only large enough to exclude large differences in mortality.

2022 Joint ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease in patients at low surgical risk and anatomy suitable for PCI or CABG.

Task Force structure and summary of clinical evidence of 2022 ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; LM, left main; SYNTAX, Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery. a'Event' refers to the composite of death, myocardial infarction (according to Universal Definition of Myocardial Infarction if available, otherwise protocol defined) or stroke. In October 2021, the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) jointly agreed to establish a Task Force (TF) to review recommendations of the 2018 ESC/EACTS Guidelines on myocardial revascularization as they apply to patients with left main (LM) disease with low-to-intermediate SYNTAX score (0-32). This followed the withdrawal of support by the EACTS in 2019 for the recommendations about the management of LM disease of the previous guideline. The TF was asked to review all new relevant data since the 2018 guidelines including updated aggregated data from the four randomized trials comparing percutaneous coronary intervention (PCI) with drug-eluting stents vs. coronary artery bypass grafting (CABG) in patients with LM disease. This document represents a summary of the work of the TF; suggested updated recommendations for the choice of revascularization modality in patients undergoing myocardial revascularization for LM disease are included. In stable patients with an indication for revascularization for LM disease, with coronary anatomy suitable for both procedures and a low predicted surgical mortality, the TF concludes that both treatment options are clinically reasonable based on patient preference, available expertise, and local operator volumes. The suggested recommendations for revascularization with CABG are Class I, Level of Evidence A. The recommendations for PCI are Class IIa, Level of Evidence A. The TF recognized several important gaps in knowledge related to revascularization in patients with LM disease and recognizes that aggregated data from the four randomized trials were still only large enough to exclude large differences in mortality.

Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization. Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT). Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT. Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care. Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use. Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001). Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Deferred Testing in Stable Outpatients With Suspected Coronary Artery Disease: A Prespecified Secondary Analysis of the PRECISE Randomized Clinical Trial.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy. Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred. Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included. Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk. Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months. Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups. Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Glu298Asp variant of the endothelial nitric oxide synthase gene and acute coronary syndrome or premature coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Several published studies have reported an association between the Glu298Asp polymorphism (rs1799983), residing in the endothelial nitric oxide synthase (NOS3) gene, and lower levels of circulating nitric oxide, as well as an increased risk of coronary artery disease (CAD). However, association status of this genetic variant with acute coronary syndrome (ACS) or premature CAD (PCAD) is still unclear. Against this background, we conducted a systematic review and study level meta-analysis to assess the association of the NOS3 Glu298Asp polymorphism with ACS or PCAD. MATERIALS AND METHODS: A comprehensive online search to identify relevant studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science. The identified studies were stratified into two ancestral subgroups: 'European ancestry' and 'All other ancestries combined'. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random/fixed effects employing a Z test. RESULTS: Out of a total of 195 distinct records identified through online search, 37 articles with 39 different studies, with a total sample size of 27,441 (11,516 cases/15,925 controls) were included for quantitative synthesis. Pooled results suggested significant associations of the NOS3 Glu298Asp polymorphism with ACS or PCAD through dominant as well as allelic genetic models (p ≤ 0.002), primarily driven by the 'All other ancestries combined' subgroup. The 'All other ancestries combined' subgroup demonstrated an additional risk of 36% for ACS or PCAD, through both dominant and allelic genetic models (OR = 1.36, 95%CI = 1.13, 1.63, p = 0.001 and OR = 1.36, 95%CI = 1.14, 1.61, p = 0.0005 respectively). On the other hand, the 'European ancestry' subgroup did not show any significant associations. Sensitivity analysis and a sub-analysis for the myocardial infarction endpoint further supported these observed associations. CONCLUSIONS: This meta-analysis indicates towards an association between the NOS3 Glu298Asp polymorphism and ACS or PCAD, predominantly driven by 'All other ancestries combined' subgroup. In contrast, the 'European ancestry' subgroup did not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.

Design and rationale of a prospective, randomized, non-inferiority trial to determine the safety and efficacy of the Biolimus A9™ drug coated balloon for the treatment of in-stent restenosis: First-in-man trial (REFORM).

BACKGROUND: Drug-coated balloon (DCB) angioplasty with paclitaxel-eluting devices is an established treatment for coronary in-stent restenosis (ISR). Biolimus A9™ (BA9), a sirolimus analogue with enhanced lipophilicity, may facilitate enhanced local drug delivery into vascular tissue. A novel DCB coated with Biolimus A9™ represents an alternative to traditional paclitaxel- and sirolimus-coated devices. Hence, we sought to investigate the safety and efficacy of this novel DCB in the treatment of coronary ISR. METHODS AND DESIGN: REFORM (NCT04079192) is a prospective, multicenter, single blind, randomized controlled trial comparing the BA9-DCB (Biosensors Europe SA, Morges, Switzerland) to the paclitaxel-coated SeQuent® Please DCB (Braun Melsungen AG, Germany) in the treatment of coronary ISR. A total of 201 patients with coronary artery disease and an indication for interventional treatment of ISR in a bare-metal stent (BMS) or drug-eluting stent (DES) have been randomized 2:1 to receive treatment with the BA9- or the paclitaxel-DCB comparator. Patients were enrolled across 24 investigational centers in Europe and Asia. The primary endpoint is percent diameter stenosis (%DS) of the target segment as assessed by quantitative coronary angiography (QCA) at 6 months. Key secondary endpoints are in-stent late lumen loss, binary restenosis, target lesion failure, target vessel failure, myocardial infarction and death at 6 months. Subjects will be followed for 24 months from enrolment. IMPLICATIONS: The REFORM trial will seek to prove that the BA9-DCB is non-inferior to the standard paclitaxel-DCB comparator in the treatment of coronary ISR with respect to %DS at 6 months and has similar safety characteristics.

Very long-term outlook of acute coronary syndromes after percutaneous coronary intervention with implantation of polymer-free versus durable-polymer new-generation drug-eluting stents.

BACKGROUND: Detailed long-term follow-up data on patients with acute coronary syndromes (ACS) in general, and those with ST-elevation myocardial infarction (STEMI) in particular, are limited. We aimed to appraise the long-term outlook of patients undergoing percutaneous coronary intervention (PCI) with state-of-the-art coronary stents for STEMI, other types of ACS and stable coronary artery disease (CAD), and also explore the potential beneficial impact of new-generation polymer-free drug-eluting stents (DES) in this setting. METHODS: Baseline, procedural and very long-term outcome data on patients undergoing PCI and randomized to implantation of new-generation polymer-free vs. durable polymer DES were systematically collected, explicitly distinguishing subjects with admission diagnosis of STEMI, non-ST-elevation ACS (NSTEACS), and stable CAD. Outcomes of interest included death, myocardial infarction, revascularization (i.e. patient-oriented composite endpoints [POCE]), major adverse cardiac events (MACE), and device-oriented composite endpoints (DOCE). RESULTS: A total of 3002 patients were included, 1770 (59.0%) with stable CAD, 921 (30.7%) with NSTEACS, and 311 (10.4%) with STEMI. At long-term follow-up (7.5±3.1 years), all clinical events were significantly more common in the NSTEACS group and, to a lesser extent, in the stable CAD group (e.g. POCE occurred in, respectively, 637 [44.7%] vs. 964 [37.9%] vs. 133 [31.5%], P<0.001). While these differences were largely attributable to adverse coexisting features in patients with NSTEACS (e.g. advanced age, insulin-dependent diabetes, and extent of CAD), the unfavorable outlook of patients presenting with NSTEACS persisted even after multivariable adjustment including several prognostically relevant factors (hazard ratio [HR] of NSTEACS vs. stable CAD 1.19 [95% confidence interval 1.03-1.38], P=0.016). Notably, even after encompassing all prognostically impactful features, no difference between polymer-free and permanent polymer drug-eluting stents appeared (HR=0.96 [0.84-1.10], P=0.560). CONCLUSIONS: Unstable coronary artery disease, especially when presenting without ST-elevation, represents an informative marker of adverse long-term prognosis in current state-of-the-art invasive cardiology practice. Even considering admission diagnosis, and despite of using no polymer, polymer-free DES showed similar results with regards to safety and efficacy when compared with DES with permanent polymer.

Fractional flow reserve or 3D-quantitative-coronary-angiography based vessel-FFR guided revascularization. Rationale and study design of the prospective randomized fast III trial.

BACKGROUND: Physiological assessment of intermediate coronary lesions to guide coronary revascularization is currently recommended by international guidelines. Vessel fractional flow reserve (vFFR) has emerged as a new approach to derive fractional flow reserve (FFR) from 3D-quantitative coronary angiography (3D-QCA) without the need for hyperemic agents or pressure wires. STUDY DESIGN AND OBJECTIVES: The FAST III is an investigator-initiated, open label, multicenter randomized trial comparing vFFR guided versus FFR guided coronary revascularization in approximately 2228 patients with intermediate coronary lesions (defined as 30%-80% stenosis by visual assessment or QCA). Intermediate lesions are physiologically assessed using on-line vFFR or FFR and treated if vFFR or FFR ≤0.80. The primary end point is a composite of all-cause death, any myocardial infarction, or any revascularization at 1-year post-randomization. Secondary end points include the individual components of the primary end point and cost-effectiveness will be investigated. CONCLUSIONS: FAST III is the first randomized trial to explore whether a vFFR guided revascularization strategy is non-inferior to an FFR guided strategy in terms of clinical outcomes at 1-year follow-up in patients with intermediate coronary artery lesions.

Interleukin-10 -1082 G/A polymorphism and its association with early or severe presentation of coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Interleukin-10 (IL-10) is an anti-inflammatory cytokine with potent deactivating properties on macrophages and T cells; and plays an important role in atherosclerotic plaque maturation and rupture. A guanine (G) to adenine (A) substitution in the IL-10 gene at -1082 bp (rs1800896) has been associated with reduced in IL-10 production in vitro. Against this background, we tested the association of IL-10 -1082G/A with early or severe presentation of coronary artery disease (CAD) using a systematic review and updated meta-analysis of published association studies. MATERIALS AND METHODS: Relevant studies were identified following a comprehensive online search on PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science databases and stratified into two subgroups based on mode of CAD presentation: early or severe and non-severe. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random effects employing a Z test. RESULTS: A total of 24 studies were included for quantitative synthesis with a cumulative sample of 19,135 (11,143 cases / 7,992 controls). A significant association was derived for IL-10 -1082G/A and early or severe CAD via dominant, recessive, and allelic genetic model comparisons [OR 1.24 (95 % CI 1.02, 1.50), p = 0.03; OR 1.32 (95 % CI 1.03, 1.69), p = 0.03 and OR 1.18 (95 % CI 1.02, 1.36), p = 0.02 respectively]. In contrast, no significant association was seen for the pooled group or non-severe CAD subgroup (p = NS). Sensitivity analysis showed consistent results. CONCLUSIONS: IL-10 -1082G/A appears to be associated with early or severe presentation of CAD. Further studies are warranted to confirm this association.

Rotational Atherectomy or Balloon-Based Techniques to Prepare Severely Calcified Coronary Lesions.

BACKGROUND: The comparative efficacy of percutaneous techniques for the preparation of calcified lesions before stenting remains poorly studied. OBJECTIVES: This study sought to compare the performance of up-front rotational atherectomy (RA) or balloon-based techniques before drug-eluting stent implantation in severely calcified coronary lesions as assessed by angiography and optical coherence tomography (OCT). METHODS: Patient-level data from the PREPARE-CALC (Comparison of Strategies to Prepare Severely Calcified Coronary Lesions) and ISAR-CALC (Comparison of Strategies to Prepare Severely Calcified Coronary Lesions) randomized trials were pooled. The primary endpoint was stent expansion as assessed by OCT imaging. The secondary endpoints included stent eccentricity, stent asymmetry, angiographic acute lumen gain, strategy success and in-hospital occurrence of cardiac death, target vessel myocardial infarction, and repeat revascularization. RESULTS: Among 274 patients originally randomized, 200 participants with available OCT data after lesion preparation with RA (n = 63), a modified balloon (MB, n = 103), or a super high-pressure balloon (n = 34) before stenting were analyzed. The use of RA versus MB or a super high-pressure balloon led to comparable stent expansion (73.2% ± 11.6% vs 70.8% ± 13.6% vs 71.8% ± 12.2%, P = 0.49) and stent asymmetry (P = 0.83). Compared with RA or MB, a super high-pressure balloon was associated with less stent eccentricity (P = 0.03) with a numerically higher acute lumen gain, albeit not significantly different (P = 0.08). Strategy success was more frequent with RA versus MB (P = 0.002) and numerically more frequent with RA versus a super high-pressure balloon (P = 0.06). Clinical outcomes did not differ between groups. CONCLUSIONS: In patients with severely calcified lesions undergoing drug-eluting stent implantation, lesion preparation with RA, MB, or a super high-pressure balloon was associated with comparable stent expansion. A super high-pressure balloon is associated with less stent eccentricity, whereas strategy success is more frequent with RA.