Low-dose aspirin for the prevention of atherosclerotic cardiovascular disease.

During the past 30 years, several developments have occurred in the antiplatelet field, including the role of aspirin in primary prevention of atherosclerotic cardiovascular disease. There have been several attempts to develop antiplatelet drugs more effective and safer than aspirin and a shift in emphasis from efficacy to safety, advocating aspirin-free antiplatelet regimens after percutaneous coronary intervention. Evidence supporting a chemopreventive effect of low-dose aspirin against colorectal (and other digestive tract) cancer has also strengthened. The aim of this article is to revisit the role of aspirin in the prevention of atherothrombosis across the cardiovascular risk continuum, in view of developments in the antiplatelet field. The review will offer a clinical perspective on aspirin's mechanism of action, pharmacokinetics, and pharmacodynamics. This will be followed by a detailed discussion of its clinical efficacy and safety.

Factor XIa inhibition as a therapeutic strategy for atherothrombosis.

When selecting an anticoagulant, clinicians consider individual patient characteristic, the treatment indication, drug pharmacology, and safety and efficacy as demonstrated in randomized trials. An ideal anticoagulant prevents thrombosis with little or no increase in bleeding. Direct oral anticoagulants represent a major advance over traditional anticoagulants (e.g., unfractionated heparin, warfarin) but still cause bleeding, particularly from the gastrointestinal tract which can limit their use. Epidemiological studies indicate that patients with congenital factor XI (FXI) deficiency have a lower risk of venous thromboembolism (VTE) and ischemic stroke (IS) than non-deficient individuals, and do not have an increased risk of spontaneous bleeding, even with severe deficiency. These observations provide the rationale for targeting FXI as a new class of anticoagulant. Multiple FXI inhibitors have been introduced and several are being evaluated in Phase III trials. In this review, we explain why drugs that target FXI may be associated with a lower risk of bleeding than currently available anticoagulants and summarize the completed and ongoing trials.

Prognostic impact of hypercoagulability and impaired fibrinolysis in acute myocardial infarction.

AIMS: Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity. METHODS AND RESULTS: From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013-1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893-0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of 'MA ≥ 68 mm' and 'LY30 < 0.2%' was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135-2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499-2.129; P = 0.935). CONCLUSION: AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI. CLINICAL TRIAL REGISTRATION: Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.

Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study.

BACKGROUND: Patients with peripheral artery disease (PAD) are treated with preventive strategies to improve the cardiovascular risk. The incidence of cardiovascular events and mortality however remains high in PAD populations. We therefore aimed to better characterize PAD patients suffering from cardiovascular events and mortality in order to tailor preventive treatment. METHODS: Between 2018 and 2020, 246 PAD outpatients (17 newly diagnosed, 229 with known PAD) were prospectively enrolled in this observational cohort study. Patient data and blood samples were collected after inclusion, and the primary composite endpoint (myocardial infarction, elective coronary revascularization, ischemic stroke, acute limb ischemia, mortality) was evaluated after one year. Secondary outcomes included platelet reactivity, measured using the VerifyNow assay, and medication adherence, assessed using the Morisky Medication Adherence Scale-8 (MMAS-8). Logistic regression models were used to identify associations between characteristics and the occurrence of events. RESULTS: The cohort comprised 207 patients with claudication and 39 with chronic limb threatening ischemia. Twenty-six (10.6%) patients suffered from an event during follow-up. Prior myocardial infarction (OR 3.3 [1.4-7.7]), prior ischemic stroke (OR 4.5 [1.8-10.9]), higher levels of creatinine (OR 5.2 [2.2-12.6]), lower levels of high-density lipoprotein (OR 4.2 [1.5-10.6]) and lower haemoglobin levels (OR 3.1 [1.3-7.1]) were associated with events. Patients with events had more often high on-treatment platelet reactivity (HTPR) on aspirin (OR 5.9 [1.4-25.1]) or clopidogrel (OR 4.3 [1-19.3]). High adherence to medication was associated with the occurrence of events (OR 4.1 [1-18]). CONCLUSIONS: Patients suffering from cardiovascular events and mortality were characterized by prior cardiovascular events as compared to patients who did not experience any events. Antiplatelet therapy was not optimally protective despite high medication adherence, and HTPR was independently associated with the occurrence of events. More research is needed on alternative treatment strategies such as dual antiplatelet therapy or combinations with anticoagulant drugs. TRIAL REGISTRATION: The Medical Ethics Committee (METC) of the MUMC+ approved the study (NL63235.068.17) and the study was registered in the Netherlands Trial Register ( NTR7250 ).

Underlying mechanisms of thrombus formation/growth in atherothrombosis and deep vein thrombosis.

Thrombosis remains a leading cause of death worldwide despite technological advances in prevention, diagnosis, and treatment. The traditional view of arterial thrombus formation is that it is a platelet-dependent process, whereas that of venous thrombus formation is a coagulation-dependent process. Current pathological and basic studies on atherothrombosis and venous thrombosis have revealed the diverse participation of platelet and coagulation activation mechanisms in both thrombus initiation and growth processes during clinical thrombotic events. Atherosclerotic plaque cell-derived tissue factor contributes to fibrin formation and platelet aggregation. The degree of plaque disruption and a blood flow alteration promote atherothrombotic occlusion. While blood stasis/turbulent flow due to luminal stenosis itself initiates venous thrombus formation. The coagulation factor XI-driven propagation phase of blood coagulation plays a major role in venous thrombus growth, but a minor role in hemostasis. These lines of evidence indicate that atherothrombosis onset is affected by the thrombogenic potential of atherosclerotic plaques, the plaque disruption size, and an alteration in blood flow. Upon onset of venous thrombosis, enhancement of the propagation phase of blood coagulation under blood stasis and a hypercoagulable state contribute to large thrombus formation.

Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis.

AIMS: Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events. METHODS AND RESULTS: The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2. CONCLUSION: Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.

Antithrombotic Therapy: Prevention and Treatment of Atherosclerosis and Atherothrombosis.

Atherosclerosis is a multifactorial vascular disease that develops in the course of a lifetime. Numerous risk factors for atherosclerosis have been identified, mostly inflicting pro-inflammatory effects. Vessel injury, such as occurring during erosion or rupture of atherosclerotic lesions triggers blood coagulation, in attempt to maintain hemostasis (protect against bleeding). However, thrombo-inflammatory mechanisms may drive blood coagulation such that thrombosis develops, the key process underlying myocardial infarction and ischemic stroke (not due to embolization from the heart). In the blood coagulation system, platelets and coagulation proteins are both essential elements. Hyperreactivity of blood coagulation aggravates atherosclerosis in preclinical models. Pharmacologic inhibition of blood coagulation, either with platelet inhibitors, or better documented with anticoagulants, or both, limits the risk of thrombosis and may potentially reverse atherosclerosis burden, although the latter evidence is still based on animal experimentation.Patients at risk of atherothrombotic complications should receive a single antiplatelet agent (acetylsalicylic acid, ASA, or clopidogrel); those who survived an atherothrombotic event will be prescribed temporary dual antiplatelet therapy (ASA plus a P2Y12 inhibitor) in case of myocardial infarction (6-12 months), or stroke (<6 weeks), followed by a single antiplatelet agent indefinitely. High risk for thrombosis patients (such as those with peripheral artery disease) benefit from a combination of an anticoagulant and ASA. The price of gained efficacy is always increased risk of (major) bleeding; while tailoring therapy to individual needs may limit the risks to some extent, new generations of agents that target less critical elements of hemostasis and coagulation mechanisms are needed to maintain efficacy while reducing bleeding risks.

Pollution and coronary risk: how much does it matter?

Air pollutants are a complex mixture of gaseous substances and particulate matter (PM). Each component potentially has specific harmful effects on human health, but several experimental and clinical studies have shown a strong impact of fine particles on major adverse cardiovascular events. Most of the available evidence concerns the effects of exposure to PM with a diameter of <2.5 µm (PM2.5) and the risk of developing coronary heart disease through inflammation and oxidative stress. While prolonged exposure to PM2.5 has been shown to be associated with the development of atherosclerosis and cardio-metabolic risk factors, short-term exposure has instead proved to be a trigger for acute coronary events, and especially in subjects with pre-existing coronary artery disease. As such, environmental PM2.5 is a major risk element for global public health. This underlines on the one hand not only the need to adopt and encourage preventive measures especially for individuals with a higher risk profile but also to practice environmental policies that are effective in promoting the reduction of exposure to pollutants.

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

AIMS: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. METHODS AND RESULTS: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001). CONCLUSION: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1ß blockade with canakinumab.

Protease-Activated Receptor 1 in Human Carotid Atheroma Is Significantly Related to Iron Metabolism, Plaque Vulnerability, and the Patient's Age.

(1) Background: Protease-activated receptor 1 (PAR1) has regulatory functions in inflammation, atherogenesis, and atherothrombosis. Chronic iron administration accelerates arterial thrombosis. Intraplaque hemorrhage and hemoglobin catabolism by macrophages are associated with dysregulated iron metabolism and atherosclerotic lesion instability. However, it remains unknown whether expressions of PAR1 in human atherosclerotic lesions are related to plaque severity, accumulation of macrophages, and iron-related proteins. We investigated the expression of PAR1 and its relation to the expression of ferritin and transferrin receptors in human carotid atherosclerotic plaques and then explored potential connections between their expressions, plaque development, and classical risk factors. (2) Methods: Carotid samples from 39 patients (25 males and 14 females) were immunostained with PAR1, macrophages, ferritin, and transferrin receptor. Double immunocytochemistry of PAR1 and ferritin was performed on THP-1 macrophages exposed to iron. (3) Results: PAR1 expression significantly increases with the patient's age and the progression of human atherosclerotic plaques. Expressions of PAR1 are significantly correlated with the accumulation of CD68-positive macrophages, ferritin, and transferrin receptor 1 (TfR1), and inversely correlated with levels of high-density lipoprotein. In vitro, PAR1 is significantly increased in macrophages exposed to iron, and the expression of PAR1 is colocalized with ferritin expression. (4) Conclusions: PAR1 is significantly related to the progression of human atherosclerotic lesions and the patient's age. PAR1 is also associated with macrophage infiltration and accumulation of iron metabolic proteins in human atherosclerotic lesions. Cellular iron-mediated induction of PAR1 and its colocalization with ferritin in macrophages may further indicate an important role of cellular iron in atherothrombosis.

Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging.

Vascular disease was for a long time considered a disease of the old age, but it is becoming increasingly clear that a cumulus of factors can cause early vascular aging (EVA). Inflammation plays a key role in vascular stiffening and also in other pathologies that induce vascular damage. There is a known and confirmed connection between inflammation and atherosclerosis. However, it has taken a long time to prove the beneficial effects of anti-inflammatory drugs on cardiovascular events. Diabetes can be both a product of inflammation and a cofactor implicated in the progression of vascular disease. When diabetes and inflammation are accompanied by obesity, this ominous trifecta leads to an increased incidence of atherothrombotic events. Research into earlier stages of vascular disease, and documentation of vulnerability to premature vascular disease, might be the key to success in preventing clinical events. Modulation of inflammation, combined with strict control of classical cardiovascular risk factors, seems to be the winning recipe. Identification of population subsets with a successful vascular aging (supernormal vascular aging-SUPERNOVA) pattern could also bring forth novel therapeutic interventions.

Inflammation and vascular diseases.

Chronic venous disease and cardiovascular atherothrombotic diseases have a high prevalence worldwide. The aetiopathogenesis of both these vascular conditions may share certain aetiopathogenetic moments. Abnormal blood flow, altered intravascular tension, and subsequent endothelial dysfunction may all play an important role. Another plausible alternative is the correlation of some risk factors of both diseases, in particular obesity and metabolic syndrome with all its components and an impact on atherogenesis as well as chronic venous disease. The relationship may even be causal, that is a chronic vessel wall inflammation which is present in advanced venous insufficiency might accelerate atherogenesis. On the other hand, altered haemodynamics in right ventricular dysfunction with a subsequent elevation in venous pressure can worsen or induce venous insufficiency, and/or undoubtedly cause symptoms and signs typical of chronic venous disease. As suggested by the findings published recently in the Gutenberg Health Study, particularly its subanalysis regarding the relationship of venous disease and cardiovascular diseases, the venous and arterial beds can be affected by common aetiopathogenetic factors or both the systems can interfere with each other.

Cardiovascular 18F-fluoride positron emission tomography-magnetic resonance imaging: A comparison study.

BACKGROUND: 18F-Fluoride uptake denotes calcification activity in aortic stenosis and atherosclerosis. While PET/MR has several advantages over PET/CT, attenuation correction of PET/MR data is challenging, limiting cardiovascular application. We compared PET/MR and PET/CT assessments of 18F-fluoride uptake in the aortic valve and coronary arteries. METHODS AND RESULTS: 18 patients with aortic stenosis or recent myocardial infarction underwent 18F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as tissue-to-background ratios (TBRs). Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58 ± 0.34, P = 0.66; 95% limits of agreement - 27% to + 25%) but performed less well with Dixon AC (1.38 ± 0.44, P = 0.06; bias (-)14%; 95% limits of agreement - 25% to + 53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT; however, stents caused artifact on PET/MR making assessment of 18F-fluoride uptake challenging. CONCLUSION: Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artifacts currently limiting clinical application.

Oral microbiota and atherothrombotic carotid plaque vulnerability in periodontitis patients. A cross-sectional study.

BACKGROUND: An increased risk of atherothrombotic vascular events has been reported in periodontitis patients. Periodontitis is associated with dysbiotic subgingival biofilms and bacteremia. OBJECTIVE: We hypothesized (a) that the oral microbiome is associated with the carotid microbiome and (b) that periodontitis could contribute to plaque vulnerability. The aim of this study was to determine the associations between periodontitis, the carotid microbiome, and the local innate immune response in carotid atherothrombotic plaques vulnerable to rupture. METHODS: In this cross-sectional study, 45 patients admitted for carotid endarterectomy underwent a preoperative periodontal examination. The volume of intraplaque hemorrhage reflected by the hemoglobin level released in carotid-conditioned media was considered as a criterion of carotid plaque vulnerability. Levels of antibodies against periodontal bacteria were determined in sera. The signature of the oral microbiota was assessed by microbial whole-genome sequencing, nested PCR, and immunostaining in carotid plaque samples. Markers of neutrophil recruitment (leukotriene B4), neutrophil activation (myeloperoxidase, defensins), and cytokines were measured in carotid-conditioned media and/or plasma. RESULTS: All patients exhibited periodontitis. One hundred and forty-four bacterial genera were detected in the carotid microbiome. While Streptococcus was found in 84% of the carotid samples, periodontitis-associated genera were detected in 21%. P. gingivalis DNA and gingipains were also identified in carotid samples. There were significant inverse correlations between periodontal attachment loss/serum anti-P. gingivalis Immunoglobulin A and cytokine inhibiting neutrophils (all P < .01). There were also significant positive correlations between lipopolysaccharides, myeloperoxidase/human neutrophil peptides1-3, and hemoglobin levels (all P < .01). CONCLUSIONS: In patients at risk of stroke, the carotid plaque microbiome was highly diverse and compatible with an oral origin. Periodontitis was significantly associated with neutrophil activation markers and plaque vulnerability to rupture.

Novel approaches to P2Y12 inhibition and aspirin dosing.

Aspirin and P2Y12 inhibitors remain commonly prescribed antiplatelet drugs in the treatment of atherothrombotic conditions. Despite established benefits of dual antiplatelet therapy (DAPT) in the setting of acute coronary syndromes, there remains residual ischemic risk in this group and the problem of bleeding complications is an ongoing issue. DAPT with aspirin and ticagrelor has now been studied in other patient groups such as those with concurrent diabetes and stable coronary artery disease, and those undergoing elective percutaneous coronary intervention (PCI). Recent trials of ticagrelor monotherapy have suggested this may have benefits over standard-of-care in some settings, such as PCI, but not in others such as peripheral arterial disease or stroke. A novel subcutaneously administered P2Y12 inhibitor, selatogrel, has shown powerful, rapid and consistent effect in a phase 2 study. Aspirin dosing remains an area of investigation, particularly in the setting of DAPT. A novel regimen of very-low-dose twice-daily aspirin has hypothetical advantages in pharmacodynamic and pharmacokinetic effects, maintaining antiplatelet effect whilst reducing potentially harmful peak-trough variation.

Novel antiplatelet targets in the treatment of acute coronary syndromes.

Acute coronary syndromes (ACS) are a global cause of mortality and morbidity that affect millions of lives worldwide. Following atherosclerotic plaque rupture, platelet activation and aggregation are the two major elements that initiate thrombus formation inside a coronary artery, which can obstruct blood flow and cause myocardial ischemia; ergo, antiplatelet therapy forms a major part of the treatment strategy for ACS. Patients with ACS routinely receive dual antiplatelet therapy (DAPT), which consists of aspirin and a platelet P2Y12 inhibitor to both treat and prevent atherothrombosis. Use of platelet glycoprotein (GP) IIb/IIIa inhibitors is now limited due to the risk of severe bleeding and thrombocytopenia. Thus, administration of GPIIb/IIIa inhibitors is generally restricted to bail out thrombotic events associated with PCI. Furthermore, current antiplatelet medications mainly rely on thromboxane A2 and P2Y12 inhibition, which have broad-acting effects on platelets and are known to cause bleeding, which especially limits the long-term use of these agents. In addition, not all ACS patients treated with current antiplatelet treatments are protected from recurrence of arterial thrombosis, since many platelet mechanisms and activation pathways remain uninhibited by current antiplatelet therapy. Pharmacological antagonism of novel targets involved in platelet function could shape future antiplatelet therapies that could ultimately lead to more effective or safer therapeutic approaches. In this article, we focus on inhibitors of promising targets that have not yet been introduced into clinical practice, including inhibitors of GPVI, protease-activated receptor (PAR)-4, GPIb, 5-hydroxytryptamine receptor subtype 2A (5-HT2A), protein disulfide isomerase, P-selectin and phosphoinositide 3-kinase ß.

Anti-inflammatory therapy in ischaemic heart disease: from canakinumab to colchicine.

Four large trials have recently evaluated the effects of anti-inflammatory drugs in the secondary prevention of major cardiovascular events (MACE) in over 25 000 patients followed for 1.9-3.7 years. CANTOS tested subcutaneous canakinumab [an anti-interleukin (IL) 1ß antibody] 300 mg every 3 months against placebo in patients with a history of myocardial infarction (MI) and serum C-reactive protein (CRP) >2 mg/L, demonstrating efficacy in preventing MACE but increased rates of fatal infections. COLCOT (in patients with recent MI) and LoDoCo2 (in patients with chronic coronary syndromes) tested oral colchicine (an NLRP3 inflammasome inhibitor) 0.5 mg daily vs. placebo, demonstrating prevention of MACE with a slightly increased risk of pneumonia in COLCOT (0.9 vs. 0.4%) but not in LoDoCo2. CIRT tested oral methotrexate (an anti-rheumatic anti-nuclear factor-kB) 15-20 mg per week against placebo in ischaemic heart disease patients with diabetes or metabolic syndrome, without significant reduction in MACE rates or in circulating IL6 or CRP levels, and with increased risk of skin cancers. In summary, canakinumab and colchicine have shown efficacy in preventing MACE in ischaemic heart disease patients, but only colchicine has acceptable safety (and cost) for use in secondary cardiovascular prevention. Clinical results are expected with the anti-IL6 ziltivekimab.

Revascularization to the ACA: effectiveness and variation of the STA-RAG-A3 bonnet bypass.

BACKGROUND: The effectiveness of bypass surgery in patients with atherothrombotic ischemia in the anterior cerebral artery (ACA) domain remains unclear. In this study, three cases with ischemia in the ACA territory underwent revascularization surgery using superficial temporal artery (STA)-radial artery graft (RAG)-A3 (pericallosal artery) bonnet bypass. Herein, we discuss the effectiveness and variations of this approach. METHODS: Among 182 consecutive patients with atherothrombotic ischemic stroke admitted to the NTT Medical Center, Tokyo, from April 2017 to May 2021, three patients with hemodynamic insufficiency in the extensive ACA territory beyond the recent infarct area were treated using STA-RAG-A3 bonnet bypass. RESULTS: One patient with bilateral severe cerebral blood flow (CBF) deficiency required additional A3-A3 and STA-middle cerebral artery single bypass in conjunction with STA-RAG-A3 bypass. There were no complications associated with the surgical procedure. The patients' hemodynamic study results and neurocognitive performances improved dramatically after surgery. CONCLUSION: Our results suggest the efficacy of STA-RAG-A3 bypass for atherothrombotic ACA ischemia. However, because the number of cases was too small to generalize our results, more cases and thorough pre- and postoperative hemodynamic studies are necessary to prove the validity of the approach.

Peripheral artery disease in outpatients with a recent history of acute coronary syndrome or at high atherothrombotic risk.

OBJECTIVES: The frequency and implications of peripheral artery disease (PAD) in some risk groups are not entirely characterized in Latin America. We studied PAD prevalence, risk factors, and six-month outcomes in stable outpatients with a history of a recent acute coronary syndrome (ACS), or at high coronary risk. METHODS: We recruited 830 outpatients in 43 Mexican sites (median age: 64.8 years; 57.8% men). Inclusion criteria were age >18 years, and ACS within 30 days, or age <55 years plus ≥2 major vascular risk factors, or age ≥55 years plus ≥1 vascular risk factors. Patients received standardized assessments at baseline and six-month follow-up for medical history, ankle-brachial index (ABI), and the Edinburgh Claudication Questionnaire (ECQ). RESULTS: ABI <0.8 was found in 10.5%, <0.9 in 22.5%, >1.3 in 4.8%, and >1.4 in 3.6%, without differences according to sex or selection criteria. Positive ECQ was found in 7.6%. ABI <0.9 was directly associated with age, diabetes, ACS, and chronic kidney disease, but inversely associated with BMI >27. The six-month case-fatality and atherothrombotic events rates were 1.6% and 3.6%, respectively. In patients with ABI <0.9 and ABI <0.8, the six-month case-fatality rates were 2.5% (p = 0.27) and 5.4% (p = 0.03), respectively. In a Cox proportional-hazards model, baseline factors associated with death were age ≥65, ABI <0.8, and ACS. CONCLUSIONS: Subclinical PAD is more common than symptomatic claudication in high-risk coronary outpatients. Low ABI is associated with reduced short-term survival in patients with recent ACS or at high coronary risk.

The Role of the Proteasome in Platelet Function.

Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their limited protein synthesis, platelets are equipped with multiple protein degradation mechanisms, such as the proteasome. In nucleated cells, the functions of the proteasome are well established and primarily include proteostasis among a myriad of other signaling processes. However, the role of proteasome-mediated protein degradation in platelets remains elusive. In this review article, we recapitulate the developing literature on the functions of the proteasome in platelets, discussing its emerging regulatory role in platelet viability and function and highlighting how its functional coupling with the transcription factor NF-κB constitutes a novel potential therapeutic target in atherothrombotic diseases.