Atherothrombotic Events Research Articles

Implementation of clopidogrel pharmacogenetic clinical decision support for a preemptive return of results program.

To describe our experiences implementing and iterating CYP2C19 genotype-guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system-wide, preemptive pharmacogenomics program. Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 (CYP2C19) intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g., inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype-guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability.

Evaluating thrombosis risk and patient-specific treatment strategy using an atherothrombosis-on-chip model.

Platelets play an essential role in thrombotic processes. Recent studies suggest a direct link between increased plasma glucose, lipids, and inflammatory cytokines with platelet activation and aggregation, resulting in an increased risk of atherothrombotic events in cardiovascular patients. Antiplatelet therapies are commonly used for the primary prevention of atherosclerosis. Transitioning from a population-based strategy to patient-specific care requires a better understanding of the risks and advantages of antiplatelet therapy for individuals. This proof-of-concept study evaluates the potential to assess an individual's risk of forming atherothrombosis using a dual-channel microfluidic model emulating multiple atherogenic factors in vitro, including high glucose, high cholesterol, and inflammatory cytokines along with stenosis vessel geometry. The model shows precise sensitivity toward increased plasma glucose, cholesterol, and tumour necrosis factor-alpha (TNF-α)-treated groups in thrombus formation. An in vivo-like dose-dependent increment in platelet aggregation is observed in different treated groups, benefiting the evaluation of thrombosis risk in the individual condition. Moreover, the model could help decide the effective dosing of aspirin in multi-factorial complexities. In the high glucose-treated group, a 50 μM dose of aspirin could significantly reduce platelet aggregation, while a 100 μM dose of aspirin was required to reduce platelet aggregation in the glucose-TNF-α-treated group, which proves the model's potentiality as a tailored tool for customised therapy.

Ácido acetilsalicílico versus inibidores dos receptores P2Y12 para prevenção secundária em pacientes tratados por meio de intervenção coronária percutânea

Currently, percutaneous coronary intervention with a drug-eluting stent implantation is the main method of myocardial revascularization in tertiary care hospitals, regardless of the clinical presentation of coronary artery disease. It is well known that to be effective, it requires the use of a dual antiplatelet therapy, which is a combination of acetylsalicylic acid and a P2Y12 platelet receptor inhibitor, which plays a key role in preventing thromboses after endoprosthesis implantation and is also indicated to prevent atherothrombotic events in the late clinical course, regardless of the stent model used. After a variable period of time, depending on some factors, such as the clinical presentation of coronary artery disease and the type of stent implanted, this therapy is discontinued, and the main current guidelines recommend interrupting the P2Y12 receptor inhibitor and maintaining acetylsalicylic acid in the long term, as one of the main pharmacological measures for secondary prevention of atherosclerosis. However, recently, due to their greater antiplatelet potency and probable lower potential for significant bleeding, especially in the digestive tract, P2Y12 inhibitors have been considered a valid and attractive option as an antiplatelet agent for long-term use; but this alternative has not been endorsed by guidelines yet. This review discusses the details related to this important decision that must be made by cardiologists when discontinuing the different antithrombotic therapies initially used after percutaneous coronary intervention. In principle, the scarcity of conclusive and normative clinical studies, especially in the population treated by percutaneous intervention, means that acetylsalicylic acid is the only antiplatelet agent with class I indication for secondary prevention of atherosclerosis.

Intraplaque Neovascularization, CD68+ and iNOS2+ Macrophage Infiltrate Intensity Are Associated with Atherothrombosis and Intraplaque Hemorrhage in Severe Carotid Atherosclerosis.

Atherosclerosis is a progressive disease that results from endothelial dysfunction, inflammatory arterial wall disorder and the formation of the atheromatous plaque. This results in carotid artery stenosis and is responsible for atherothrombotic stroke and ischemic injury. Low-grade plaque inflammation determines biological stability and lesion progression. Sixty-seven cases with active perilesional inflammatory cell infiltrate were selected from a larger cohort of patients undergoing carotid endarterectomy. CD68+, iNOS2+ and Arg1+ macrophages and CD31+ endothelial cells were quantified around the atheroma lipid core using digital morphometry, and expression levels were correlated with determinants of instability: ulceration, thrombosis, plaque hemorrhage, calcification patterns and neovessel formation. Patients with intraplaque hemorrhage had greater CD68+ macrophage infiltration (p = 0.003). In 12 cases where iNOS2 predominated over Arg1 positivity, the occurrence of atherothrombotic events was significantly more frequent (p = 0.046). CD31 expression, representing neovessel formation, correlated positively with atherothrombosis (p = 0.020). Intraplaque hemorrhage is often described against the background of an intense inflammatory cell infiltrate. Atherothrombosis is associated with the presence of neovessels and pro-inflammatory macrophages expressing iNOS2. Modulating macrophage polarization may be a successful therapeutic approach to prevent plaque destabilization.

Pharmacogenomic evaluation of CYP2C19 alleles linking low clopidogrel response and the risk of acute coronary syndrome in Indians.

Clopidogrel is an antiplatelet drug widely prescribed to prevent atherothrombotic events in coronary artery disease patients. However, there is evidence to suggest that the effectiveness of clopidogrel varies owing to genetic diversity in CYP2C19. This heterogeneity in South Asians, who are also known to have high risk of cardiac events than other population groups, highlights the importance of investigating CYP2C19 variants to estimate the risk proportion in the groups. Given the high prevalence and genetic heterogeneity, the population-based case control was conducted in a cohort of 1191 subjects comprising 645 acute coronary syndrome (ACS) cases (unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) and 546 healthy controls of South Asian Indian origin. The metabolization status of CYP2C19 was assessed using *2, *3 and *17 variants in the stated cohorts to determine the prevalence of metabolization and its association with phenotypes. The results suggest a possible genetic association between studied CYP2C19 polymorphisms and ACS, since there was a higher proportion of intermediate and poor metabolizers present in the studied cohorts. The association analyses revealed that the *2 allele of CYP2C19 confers a significant risk for ACS, while the *17 allele provides protection. These findings contribute to the understanding of CYP2C19 genetic variants and their impact on clopidogrel response in South Asian Indians. Additionally, they underline the significance of assessing CYP2C19 variations in patients receiving clopidogrel therapy in order to improve therapeutic outcomes.

Development of a Hypercoagulable-Hypofibrinolytic State Early After Spinal Cord Injury

ObjectivesTo determine whether spinal cord injury (SCI) is associated with adverse changes in coagulation and fibrinolytic factors that underlie thrombogenesis and contribute to atherothrombotic events such as myocardial infarctions (MIs) and strokes. DesignCross-sectional study. SettingNeurorehabilitation hospital and general community. ParticipantsThirty young and middle-aged (20-58 years) adults (N=30) were studied: 14 non-injured community dwelling adults. (11M/4F) and 16 with subacute tetraplegic motor complete SCI during initial inpatient rehabilitation (13M/3F; time since injury: 11.8±5.3 wk). InterventionsNot applicable. Main Outcome MeasuresCirculating markers of coagulation [von Willebrand factor (vWf) and factors VII, VIII, and X], the fibrinolytic system [tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) antigen and activity], and fibrin formation (D-dimer) were determined by enzyme immunoassay. ResultsThirty young and middle-aged (20-58 years) adults were studied: 14 non-injured (11M/4F) and 16 with subacute tetraplegic motor complete SCI (13M/3F; time since injury: range 4-25 wk). Circulating levels of coagulation factors VII, VIII, and X were significantly higher (∼20%-45%; P<.05) in the adults with SCI than non-injured adults, whereas vWf was similar between groups. Fibrinolytic markers were adversely disrupted with SCI with t-PA antigen, PAI-1 antigen and PAI-1 activity were markedly higher (∼50%-800%; P<.05) in adults with SCI compared with non-injured adults. The molar concentration ratio of active t-PA to PAI-1 was significantly higher (∼350%) in adults with SCI. Concordant with coagulation cascade activation and fibrinolytic system inhibition, D-dimer concentrations were markedly ∼70% higher (P<.05) in adults with SCI compared with non-injured adults. ConclusionsSubacute tetraplegic motor complete SCI is associated with a prothrombotic hemostatic profile. Adverse changes in the coagulation cascade and fibrinolytic system appear to occur early after injury and may contribute to the increased atherothrombotic risk in adults living with SCI.

Platelet Cyclic GMP Levels Are Reduced in Patients with Primary Aldosteronism.

Nitric oxide inhibits platelet aggregation by increasing the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) through the activation of soluble guanylyl cyclase in target cells. Within this context, the oxidative stress associated with the aldosterone excess impairs the nitric oxide availability. Thus, the aim of the present study was to assess the impact of chronic aldosterone excess on the platelet nitric oxide/cGMP pathway in humans. The levels of cGMP were evaluated in platelets of male patients, 12 with primary aldosteronism (PA) and 32 with uncomplicated essential hypertension (EH), matched for age and blood pressure (BP) values. PA and EH patients were 52.8 ± 3 years old and 51.6 ± 1.6 years old, respectively. Systolic and diastolic BP were 158 ± 5.0 mmHg and 105.9 ± 2.3 mmHg in PA and did not differ compared to EH patients (156.6 ± 2.4 mmHg and 104.7 ± 1.2 mmHg). Mean aldosterone levels were significantly higher in PA (25.5 ± 8.8 ng/dL) compared toEH (8.11 ± 0.73 ng/dL), whereas potassium was significantly lower in PA (3.52 ± 0.18 mEq/L) compared to EH (4.08 ± 0.04 mEq/L). Aldosterone and potassium were inversely related (r = -0.49, p = 0.0006) in the whole study population (n = 44). Platelet cGMP was significantly lower in PA (5.1 ± 0.36 pM/109 cells) than in EH (7.1 ± 0.53 pM/109 cells), and in the entire study cohort, it was directly related to plasma potassium (r = 0.43, p = 0.0321). These results show an impairment of nitric oxide/cGMP signaling in platelets of PA patients. This effect is likely related to the potassium-depleting effect of chronic aldosterone excess. Future studies are needed to understand whether the platelet nitric oxide/cGMP system is involved in the atherothrombotic events in these patients.

Impact of CYP2C19 genotype status on clinical outcomes in patients with symptomatic coronary artery disease, stroke, and peripheral arterial disease

Abstract Background Coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD) are clinical manifestations of atherosclerosis. Clopidogrel is widely used for the secondary prevention of atherothrombotic events in these patients. CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. Purpose To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). Methods A comprehensive search in Pubmed, EMBASE and MEDLINE from their inception to April 8th 2022 was performed. For CAD, randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment were included. For stroke and PAD, cohort studies and post-hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. Results Forty-two studies were identified: 11 studies on CAD, 27 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE (RR 0.60, 95% CI 0.43 – 0.83), myocardial infarction (RR 0.53, 95% CI 0.42 – 0.68), and stent thrombosis (RR 0.64, 95% CI 0.43 – 0.94) compared to standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70 – 1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.62, 95% CI 1.24 – 2.11) and recurrent ischemic stroke (RR 2.00, 95% CI 1.49 – 2.67) compared to non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43 – 1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. Conclusion The available evidence in PAD is too limited to draw meaningful conclusions. In stroke patients, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI.

Elevated plasma factor XI is predicts cardiovascular complications in patients with type 2 diabetes mellitus

Abstract Background Atherothrombotic complications are common in patients with type 2 diabetes mellitus (T2DM), reflecting a chronic prothrombotic state. Circulating factor XI (FXI) has been associated with a prothrombotic fibrin clot phenotype and predicted myocardial infarction, stroke and cardiovascular (CV) death in a number of diseases, including CAD. Its role in T2DM is largely unknown. Purpose The purpose of this study was to assess plasma FXI as a predictor of atherothrombotic events in T2DM patients. We also aimed to establish the determinants of elevated plasma FXI in this group of patients. Methods In a cohort of 156 patients aged 43–83 years, 56% male, with T2DM of a median duration time of five years, 64.7% with diagnosed CAD, we measured FXI along with a number of fibrin clot parameters, including turbidity, permeation, compaction, lysability, maximum concentration of D-dimer (D-D max), and rate of D-dimer release during tissue plasminogen activator-induced clot lysis. Patients were followed for a median time of 72 (68-74) months for a composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death. Results Follow-up was complete for 133 (85.3%) patients. There were 21 (16%) cases of the composite endpoint, including one nonfatal MI, four nonfatal strokes and 16 cases of CV death. Patients with and without the composite endpoint shared a similar demographic and clinical profile with the exception of age and white blood cell count – patients with the endpoint were older (69.4 [8.4] vs. 65.4 [7.8] years, p=0.03) and had a higher leukocyte count (7.8 [1.9] vs. 7.0 [1.3], p=0.02) as compared with the remainder. FXI was elevated above the upper limit of 120% in 25 (18.8%) patients, including 16 (61.9%) with the composite endpoint vs. 12 (10.7%) without the composite endpoint, p&amp;lt;0.001. Individuals with the composite endpoint had higher baseline FXI concentrations as compared with the remainder (120.1±16.8 vs. 104.9±10.7%. p &amp;lt; 0.001), along with higher D-D max (4.1 [3.8-4.3] vs. 3.8 [3.6-4.1] mg/l, p = 0.006) and slightly longer lysis time (t50% 10.1 [9.8-10.9] vs. 9.8 [8.9-10.4] min, p = 0.03). On multivariable analysis, co-existing CAD, LDL cholesterol, and thrombin activatable fibrinolysis inhibitor activity were independent predictors of elevated FXI in T2DM patients. Conclusion Elevated plasma FXI in T2DM patients is associated with CAD, LDL cholesterol and TAFI, and predicts myocardial infarction, stroke, and CV death in long term follow-up. Our finding may have implications for risk stratification and suggests a role for FXI inhibitors in T2DM patients with a high risk of atherothrombotic complications.

Abstract 11735: The Effect of Different NLRP3 Inflammasome Inhibitors on High-Sensitivity C-reactive Protein in Patients After Percutaneous Coronary Intervention

Background: Colchicine treatment inhibits the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome assembly and reduces atherothrombotic cardiovascular events in coronary artery disease (CAD). However, the effects of other inhibitors targeting NLRP3 inflammasome needs further verification in CAD. Aims: This study aimed to investigate whether inhibitors targeting NLRP3 inflammasome besides colchicine are effective in patients after percutaneous coronary interventions (PCI). Methods: The study included 132 patients aged 18-80 years who completed the planned PCI and were treated with aggressive secondary prevention strategies for four weeks. The subjects were randomly assigned to one of the following treatment groups for four weeks: (1) control: no additional intervention; (2) colchicine: 0.5 mg once a day; (3) tranilast: 0.1 g thrice a day; or (4) oridonin: 0.5 g thrice a day. The primary outcome was the percentage change in hsCRP levels at the end of four weeks. Results: In total, 109 patients completed the study. The mean age was 58.33 years, 81 (74.31%) were male and 28 (25.69%) were female. The percentage changes in hsCRP after four weeks of treatment were -11.62%, -48.28%, -21.60%, and -7.81%, in the control, colchicine, tranilast, and the oridonin groups respectively. Compared with the control group, the colchicine group showed significantly greater reduction in hsCRP levels (P=0.022). The tranilast and oridonin groups did not show obvious changes. In targeted proteomic analysis, proteins associated with neutrophil activation (azurocidin,myeloperoxidase, myeloblastin), platelet aggregation (glycoprotein VI) and endothelial damage (galectin-3) were reduced with colchicine therapy. Conclusions: Colchicine could reduce hsCRP in patients after PCI, which is likely to act on neutrophils. Colchicine may still be the important choice for anti-inflammatory treatment of CAD.

Abstract 16947: Sotagliflozin, a Dual SGLT 1 and 2 Inhibitor, Has High Membrane Affinity and Hydrocarbon Core Location Compared With Empagliflozin

Background: The dual SGLT-1 and 2 inhibitor sotagliflozin (sota) reduced atherothrombotic events and hospitalization for worsening heart failure in patients with diabetes in clinical trials (SCORED, SOLOIST). Unlike selective SGLT2 inhibitors such as empagliflozin (empa), sota binds with higher affinity to SGLT1, which is located in the intestine, kidney, heart, brain, and vascular endothelial cells. To elucidate the physico-chemical basis for differences in tissue distribution and receptor affinity, we compared the effects of these drugs on membrane binding and molecular location. Methods: Membranes reconstituted from cardiac phospholipid and cholesterol were used to measure drug partitioning across a range of cholesterol concentrations. Multilamellar vesicles were prepared as mixtures of cardiac phospholipid (CPL), cholesterol, and each agent at 30 μM or vehicle. Drug-membrane partitioning was determined by rapid centrifugation and UV/Vis spectrophotometry. In parallel experiments, we used small angle x-ray scattering (SAXS) to identify drug location in model membranes containing phosphatidylcholine and cholesterol. Results: Sota had a membrane partition coefficient (8590 ± 2078) that was 16-fold higher than empa (519 ± 195, p&lt;0.001) in CPL membranes. This high membrane affinity was preserved over a range of cholesterol levels compared to empa (p&lt;0.001). Consistent with high membrane affinity, SAXS analysis showed that sota had a location evidenced by a broad increase in electron density in the hydrocarbon core extending to approximately 20 Å from the membrane center. By contrast, empa had a location limited to the polar headgroup region, consistent with its lower lipophilicity and tissue penetration. Conclusions: Sota had high membrane affinity and distinct location in the hydrocarbon core compared to empa. This may contribute to the effect of its dual SGLT-1 and 2 inhibition in vivo across various tissues including the heart. These distinct membrane interactions may also partially explain the reduced atherothrombotic risk as demonstrated in outcome trials with sota but not selective SGLT-2 inhibitors.

Cardiovascular risk factors in patients with ulcerative colitis

Given the current trends in increasing the life expectancy of patients with ulcerative colitis (UC), the study of the risk of atherothrombotic events in them requires study. For effective prevention of cardiovascular diseases, it is necessary to assess cardiovascular risk factors since the concept of their timely detection is the basic one when planning preventive measures. To assess the prevalence of cardiovascular risk factors in patients with UC. One hundred eighty four UC patients participated in the case-control study; 56 participants were included in the control group. The studied parameters are unmodified, behavioral, and biological factors of cardiovascular risk. The study participants were surveyed, examined, measured blood pressure, height, weight, the level of total cholesterol was studied, and the lipid spectrum was analyzed in 80 patients with UC. Parametric and nonparametric statistical methods were used. UC patients consumed fruit less often, drank tea and coffee with sugar more often, exercised less often and experienced high levels of stress. A higher incidence of arterial hypertension in UC patients was established, even though the fact of taking glucocorticosteroids was considered. No significant differences were found in the assessment of relative and total cardiovascular risk. Risk management of cardiovascular diseases in UC patients should focus on a personalized approach and timely screening of modifiable cardiovascular risk factors with their subsequent correction. The absence of significant differences in the level of relative and total cardiovascular risk indicates a limited contribution of traditional risk factors to the development of cardiovascular diseases in UC patients.

A-149 Performance Characteristics of VerifyNow PRU and ARU Tests During a Clinical Method Verification Exercise

Abstract Background Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor antagonist is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary intervention procedure. Two different assays are available in the VerifyNow Test device for monitoring the anti-platelet therapy response. The aspirin assay (ARU Test) utilizes arachidonic acid as an agonist and is sensitive to acyl salicylic acid. The P2Y12 assay (PRU test) is sensitive to thienopyridines (such as clopidogrel, prasugrel, ticagrelor) and uses adenosine diphosphate (ADP) as an agonist. The PRU test is a non-waived test and ARU test is a waived test. A comprehensive method performance verification is required for the PRU test. We evaluated performance characteristics of the VerifyNow PRU Test and ARU Test for clinical use. Methods The standard precision and accuracy study using two levels (low and high) of quality control materials were performed (N = 10) for both the assays. Alternative qualitative method comparison was carried out (N = 49) using the VerifyNow PRU Test in a reference lab and in-house. The in-house inter-instrument comparisons were carried out (N = 42). The blood samples were obtained from patients taking P2Y12 inhibitors and from normal donors not on any drugs. The results of the PRU Test are expressed in P2YI2 reaction units (PRU). The VerifyNow-Aspirin assay results are expressed as aspirin reaction units (ARU). The statistical analysis to evaluate performance characteristics was carried out using the EP Evaluator. Results The VerifyNow device 1561 precision characteristics for low QC (Obs Mean = 1.5 PRU (N = 10), SD = 0.2; 95% CI for Obs Mean 1.0 to 2.0 PRU) and high QC (Obs Mean = 258.3 PRU (N = 10), SD = 8.2; 95% CI for Obs Mean 252.4 to 264.2 PRU) were within acceptable performance limits. The CV for high QC was 3.2%. The ARU test also demonstrated high precision for two levels (Low QC Obs Mean = 350ARU (N = 10), SD = 0.0); High QC Obs Mean = 583.3 (N = 10), SD = 7.2; 95% CI for Obs Mean = 578.1–588.5) with a CV of 1.2%. The PRU Test Method PRU 1561 In House vs Ref Method Verify Now PRU Test (N = 49) demonstrated overall agreement of 93.9% with positive agreement (intended use population on drugs, N = 27) of 92% and negative agreement (normal non-drug group, N = 22) of 95.8% (Cohen’s Kappa = 87.8%; Kappa &amp;gt;75% indicates “"high” agreement). The McNemar Test for Symmetry passed (P &amp;gt; 0.999, Fisher’s Exact test) in this qualitative method comparison. A value of P &amp;lt; 0.05 would suggest the methods are significantly different. The other in-house instrument 1562 also demonstrated comparable or better performance characteristics. Conclusion It is important to confirm the medical decision limit for the intended use population and determine acceptance criteria while considering biologic variability. However, the reference range verifications with drug responders and non-responders are not always feasible and cost-effective. Based on the qualitative method comparison in this study, we have transferred the medical decision limits from the peer group. The in-house multi-instrument comparison should be repeated every six months to monitor the performance of the instruments.

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium

BackgroundDiabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients.MethodsThe Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke.ResultsBetween July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001).ConclusionThe levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT04734028.

Atrial fibrillation in the elderly and long-livers: a retrospective analysis of the clinical profile of patients using artificial intelligence

Aim. Retrospective analysis of the clinical characteristics of elderly patients with atrial fibrillation (AF) and long-livers in individual subjects of the Russian Federation using artificial intelligence.Material and methods. The information was obtained from the Webiomed predictive analytics platform. The main database included 144431 patients with AF who received care in medical organizations in 6 constituent entities of the Russian Federation in the period 2016-2019. Of these, 56830 (39,3%) persons were aged ≥75 years: 47595 aged 75-89 years, 9235 aged ≥90 years.Results. Patients with AF aged ≥75 years compared with persons aged 18-74 years were characterized by a significantly higher incidence of hypertension, type 2 diabetes, estimated glomerular filtration rate &lt;60 ml/min/1,73 m2, heart failure and peripheral atherosclerosis, thromboembolic (TEE), atherothrombotic and hemorrhagic events. The prescription rate of anticoagulant therapy (ACT) was 29,6% and was lower (p&lt;0,001) compared with a subgroup of people with AF aged 1874 years with a high risk of TEE (41,2%). Among patients with AF aged ≥75 years, in 9,4% of cases, no additional (in relation to age and sex) CHA2DS2-VASc points were found, and in 1/3 of individuals there was only one additional points. With an increase CHA2DS2-VASc score in these patients, the ACT prescription rate increased from 13 to 55,5%. The prescription rate of acetylsalicylic acid was 12,8%. Only 33% of people with AF aged ≥75 years who had an ischemic stroke were prescribed ACT.Conclusion. The retrospective analysis indicates a high proportion of people aged ≥75 years in the structure of all patients with AF. This group is characterized by a significant comorbidity, a high TEE risk, hemorrhagic and atherothrombotic events. At the same time, the ACT prescription rate as of 2016-2019 in individual subjects of the Russian Federation did not meet the requirements of the clinical guidelines.

Rivaroxaban: Management of Coronary Artery Thrombosis in a Patient Presenting with Anterior Wall Myocardial Infarction

Coronary artery thrombosis is one of the most common clinically manifested disease that if not treated timely leads to morbidity and mortality particularly stroke or myocardial infarction. Anti-platelets are already the first line of treatment that are adopted for the prevention of coronary artery thrombosis however, there is need of a novel and potent anticoagulant that could help to reduce the frequency of coronary or atherothrombotic events in patients presenting with coronary diseases. Case Summary: We present a case of anterior wall myocardial infarction (AWMI) driven by coronary artery thrombosis. The patient upon diagnosis was found to have a clot in proximal left anterior descending artery (LAD). The patient was treated and discharged on anticoagulation therapy. We examined and report the effectiveness of anticoagulation therapy via a novel oral anticoagulant. i.e. Rivaroxaban for managing the risk of coronary artery thrombosis associated with AWMI within our patient. Onset of coronary artery thrombosis is associated with the mortality in myocardial infarct patients, regardless of its timing. This calls out for the need to manage the disease by adopting strategies that would prevent the frequent onset of these events in myocardial infarction survivors. Treatment with Rivaroxaban has emerged as a promising oral anticoagulant that could potentially serve as a long-term anticoagulant for managing coronary artery thrombosis in patients with heart complications.

Uric acid plasma levels are associated with C-reactive protein concentrations and the extent of coronary artery lesions in patients with acute coronary syndromes.

Many studies have pointed out that inflammation plays a pivotal role in pathophysiology of acute coronary syndromes (ACS) because several inflammatory molecules impair the endothelial functions in the coronary circulation and promote atherothrombotic events. Recently, many clinical/experimental evidences indicate that elevated plasma levels of uric acid (UA) might be considered a risk factor for developing ACS. It has been reported that elevated UA doses impair physiologic functions of endothelial cells, shifting them toward a pro atherothrombotic phenotype. In the present manuscript, we investigated the relationship between UA plasma levels, inflammatory burden, and extension of coronary atherosclerotic disease in patients with ACS. Patients with a clinical presentation of ACS (ST-elevated and non-ST-elevated myocardial infarction) admitted to the Vanvitelli Catheterization Laboratory at Monaldi Hospital in 2019, before the COVID-19 pandemia, were retrospectively analyzed. Biochemical profile, type of ACS presentation, as well as extension of coronary atherosclerosis were assessed. A total of 132 ACS patients were included in the analysis, and grouped into 3 tertiles according to the UA values (UA < 4.72mg/dl, UA between 4.72 and 6.15mg/dl, and UA > 6.15mg/dl). Patients with UA plasma levels ≥ 6.15mg/dL showed higher levels of C-reactive protein (mean of 5.1mg/dL) as compared to patients with lower UA plasma levels. Moreover, the former group of patients showed higher levels of cardiac troponin and CPK, and presented more often with multivessel disease and complex coronary stenosis (type C of Ellis classification). Even though monocentric and with limited sample size, the present study shows that plasma levels of UA and hs-CRP are elevated in ACS patients and are associated with a more severe coronary disease, suggesting a potential role of UA in the pathophysiology of acute coronary events.

Agomelatine inhibits platelet aggregation through melatonin receptor-dependent and independent mechanisms

AimsMelatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant with agonist activity at melatonin receptor 1 (MT1) and MT2 could reduce platelets aggregation and adhesion. Main methodsHuman platelets from healthy donors were used to test the in vitro effects of Ago in the presence of different platelet activators. We performed aggregation and adhesion assays, thromboxane B2 (TxB2), cAMP and cGMP measurements, intra-platelet calcium registration and flow cytometry assays. Key findingsOur data revealed that different concentrations of Ago reduced AA- and collagen-induced human platelet aggregation in vitro. Ago also reduced AA-induced increase in thromboxane B2 (TxB2) production, intracellular calcium levels and P-selectin expression at plasma membrane. The effects of Ago in AA-activated platelets were likely dependent on MT1 as they were blocked by luzindole (a MT1/MT2 antagonist) and mimicked by the MT1 agonist UCM871 in a luzindole-sensitive manner. The MT2 agonist UCM924 was also able to inhibit platelet aggregation, but this response was not affected by luzindole. On the other hand, although UCM871 and UCM924 reduced collagen-induced platelet aggregation and adhesion, inhibition of collagen-induced platelet aggregation by Ago was not mediated by melatonin receptors because it was not affected by luzindole. SignificanceThe present data show that Ago suppresses human platelet aggregation and suggest that this antidepressant may have the potential to prevent atherothrombotic ischemic events by reducing thrombus formation and vessel occlusion.

Association between Low-Density Lipoprotein Cholesterol and Vascular Biomarkers in Primary Prevention.

Several noninvasive vascular biomarkers have been proposed to improve risk stratification for atherothrombotic events. To identify biomarkers suitable for detecting intermediate-risk individuals who might benefit from lipid-lowering treatment in primary prevention, the present study tested the association of plasma LDL-cholesterol with coronary artery calcification (CAC) Agatston score, high carotid and femoral intima-media thickness (IMT), low carotid distensibility and high carotid-femoral pulse-wave velocity in 260 asymptomatic individuals at intermediate cardiovascular risk and without diabetes and lipid-lowering treatment. High or low vascular biomarkers were considered when their value was above the 95th or below the 5th percentile, respectively, of the distribution in the healthy or in the study population. LDL-cholesterol was independently associated with the CAC score = 0 (OR 0.67; 95%CI 0.48-0.92, p = 0.01), CAC score > 100 (1.59; 1.08-2.39, p = 0.01) and high common femoral artery (CFA) IMT (1.89; 1.19-3.06, p < 0.01), but not with other biomarkers. Our data confirm that in individuals at intermediate risk, lipid-lowering treatment can be avoided in the presence of a CAC score = 0, while it should be used with a CAC score > 100. CFA IMT could represent a useful biomarker for decisions regarding lipid-lowering treatment. However, sex- and age-specific reference values should be established in a large healthy population.

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus

BackgroundRisk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention. ObjectivesThe purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM. MethodsWe developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively. ResultsSixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%). ConclusionsWe developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.