Atherothrombotic Disorders Research Articles

Hematopoietic and eosinophil-specific LNK(SH2B3) deficiency promotes eosinophilia and arterial thrombosis

AbstractIncreased eosinophil counts are associated with cardiovascular disease and may be an independent predictor of major cardiovascular events. However, the causality and underlying mechanisms are poorly understood. Genome-wide association studies have shown an association of a common LNK variant (R262W, T allele) with eosinophilia and atherothrombotic disorders. LNK(TT) reduces LNK function, and Lnk-deficient mice display accelerated atherosclerosis and thrombosis. This study was undertaken to assess the role of eosinophils in arterial thrombosis in mice with hematopoietic Lnk deficiency. Hematopoietic Lnk deficiency increased circulating and activated eosinophils, JAK/STAT signaling in eosinophils, and carotid arterial thrombosis with increased eosinophil abundance and extracellular trap formation (EETosis) in thrombi. Depletion of eosinophils by anti–Siglec-F antibody or by the ΔdbIGata1 mutation eliminated eosinophils in thrombi and markedly reduced thrombosis in mice with hematopoietic Lnk deficiency but not in control mice. Eosinophil depletion reduced neutrophil abundance and NETosis in thrombi without altering circulating neutrophil counts. To assess the role of Lnk specifically in eosinophils, we crossed Lnkf/f mice with eoCre mice. LnkΔeos mice displayed isolated eosinophilia, increased eosinophil activation, and accelerated arterial thrombosis associated with increased EETosis and NETosis in thrombi. DNase I infusion abolished EETs and neutrophil extracellular traps (NETs) in thrombi and reversed the accelerated thrombosis. Human induced pluripotent stem cell–derived LNK(TT) eosinophils showed increased activation and EETosis relative to isogenic LNK(CC) eosinophils, demonstrating human relevance. These studies show a direct link between eosinophilia, EETosis, and atherothrombosis in hematopoietic Lnk deficiency and an essential role of eosinophil LNK in suppression of arterial thrombosis.

Evaluating the effect of antidiabetic treatment on haemostatic and fibrinolytic parameters among type 2 diabetics in Ilorin, Nigeria

Background: Type 2 Diabetes Mellitus is a disease of epidemic proportions and many patients are at a great risk of premature mortality and complication of atherothrombotic disorders affecting coronary, cerebral and peripheral arterial trees. Increased Plasminogen Activator Inhibitor Type 1 inhibits fibrinolysis and predicts cardiovascular risk in those living with Type 2 Diabetes. This study aimed to determine the effect of antidiabetic treatment on haemostatic and fibrinolytic parameters among Type 2 Diabetic subjects in Ilorin.
 Methods: This was a comparative cross-sectional study involving 78 Type 2 diabetic patients, (39 treatment naïve, 39 treatment experienced). Full blood count was performed using Sysmex XP 300 while Prothrombin time was determined using one stage test of Owren. Activated partial thromboplastin time was determined by method of Proctor and Rapaport. Fibrinogen and Plasminogen Activator Inhibitor type-1 were assayed using AssayMax Human Fibrinogen ELISA and AssayMax Human PAI-1 ELISA kit. Data Analysis was done using SPSS version 25.0.
 Results: Mean PAI-1 levels were significantly higher in treatment naïve diabetics when compared to treatment experienced diabetics (2.44 ±2.57 vs 2.51±1.47 ng/ml p=0.002) as were fibrinogen levels (434.65±366.15 vs 482.24± 299.64mg /dl; p = 0.048). PAI -1 levels were lowest among diabetics treated with Metformin + DPP4 inhibitors, while fibrinogen levels were lowest among those treated with Metformin + sulfonylurea combination.
 Conclusion: Oral hypoglycaemic treatment, combination therapy in particular, improves fibrinolysis in type 2 diabetics thereby reducing the risk of cardiovascular disease in type 2 diabetes mellitus patients.

Early experiences with stentgrafts in the treatment of atherothrombotic diseases of the infrarenal aorta

Introduction: Endovascular interventions have become the first-line treatment for peripheral arterial diseases. Athero-thrombotic disorders in the infrarenal aorta are also treated with open surgery, especially if it causes critical stenosis or embolization. The use of traditional stents leads to much more complications in such lesions; however, stentgrafts can provide excellent results.Objectives: We retrospectively analyzed our patients undergoing stengraft implantation due to atherothrombotic diseases in the infrarenal aorta and our early experiences.Methods: We included patients undergoing stentgraft implantation at our department due to symptomatic infrarenal aortic atherothrombotic diseases. We established the suitability for endovascular reconstruction with CT-angiogra-phy. Control CT-angiography was performed 6 weeks after the intervention.Results: 6 patients underwent successful stentgraft implantation between 25 February 2021 and 15 September 2021 at our department due to infrarenal aorta atherothrombotic diseases. 2 patients had critical limb ischaemia and 4 had claudication. Early postoperative complications did not occur. During the follow-up, the patients reported significant walking improvement. Control CT-angiography showed good stentgraft position without stenosis in all patients. Only 1 late postoperative complication (right iliac stent occlusion) occurred. Peripheral thrombolysis was performed for 24 hours; the stent opened and there was no need to perform further interventions.Conclusions: Both our early experiences and international studies have showed that this method is suitable for the treatment of atherothrombotic diseases in the infrarenal aorta. The use of stentgrafts in the treatment of peripheral atherosclerotic diseases is hindered by the high costs of the device, so at present it is subject to individual funding in Hungary.

Hematopoiesis of Indeterminate Potential and Atherothrombotic Risk.

Hematopoiesis is the process of blood production, essential for the continued supply of immune cells and red blood cells. However, the proliferative nature of hematopoietic stem cells (HSCs) renders them susceptible to developing somatic mutations. HSCs carrying a mutation can gain a selective advantage over normal HSCs and result in hematological disorders. One such disorder is termed clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with aging, where the mutant HSCs are responsible for producing a small portion of mature immune cells in the circulation and subsequently in tissues. People with CHIP have been shown to have an increased risk of mortality due to cardiovascular disease (CVD). Why this occurs is under rigorous investigation, but the majority of the studies to date have suggested that increased atherosclerosis is due to heightened inflammatory cytokine release from mutant lesional macrophages. However, given CHIP is driven by several mutations, other hematopoietic lineages can be altered to promote CVD. In this review we explore the relationship between mutations in genes causing CHIP and atherothrombotic disorders, along with potential mechanisms of enhanced clonal outgrowth and potential therapies and strategies to slow CHIP progression.

Fibrin Clot Formation under Oxidative Stress Conditions.

During coagulation, the soluble fibrinogen is converted into insoluble fibrin. Fibrinogen is a multifunctional plasma protein, which is essential for hemostasis. Various oxidative posttranslational modifications influence fibrinogen structure as well as interactions between various partners in the coagulation process. The aim was to examine the effects of oxidative stress conditions on fibrin clot formation in arterial atherothrombotic disorders. We studied the changes in in vitro fibrin network formation in three groups of patients—with acute coronary syndrome (ACS), with significant carotid artery stenosis (SCAS), and with acute ischemic stroke (AIS), as well as a control group. The level of oxidative stress marker malondialdehyde measured by LC-MS/MS was higher in SCAS and AIS patients compared with controls. Turbidic methods revealed a higher final optical density and a prolonged lysis time in the clots of these patients. Electron microscopy was used to visualize changes in the in vitro-formed fibrin network. Fibers from patients with AIS were significantly thicker in comparison with control and ACS fibers. The number of fibrin fibers in patients with AIS was significantly lower in comparison with ACS and control groups. Thus, oxidative stress-mediated changes in fibrin clot formation, structure and dissolution may affect the effectiveness of thrombolytic therapy.

Going “Green” in the Prevention and Management of Atherothrombotic Diseases: The Role of Dietary Polyphenols

During the 20th century processed and ready-to-eat foods became routinely consumed resulting in a sharp rise of fat, salt, and sugar intake in people’s diets. Currently, the global incidence of obesity, raised blood lipids, hypertension, and diabetes in an increasingly aged population contributes to the rise of atherothrombotic events and cardiovascular diseases (CVD) mortality. Drug-based therapies are valuable strategies to tackle and help manage the socio-economic impact of atherothrombotic disorders though not without adverse side effects. The inclusion of fresh fruits and vegetables rich in flavonoids to human diets, as recommended by WHO offers a valuable nutritional strategy, alternative to drug-based therapies, to be explored in the prevention and management of atherothrombotic diseases at early stages. Though polyphenols are mostly associated to color and taste in foods, food flavonoids are emerging as modulators of cholesterol biosynthesis, appetite and food intake, blood pressure, platelet function, clot formation, and anti-inflammatory signaling, supporting the health-promoting effects of polyphenol-rich diets in mitigating the impact of risk factors in atherothrombotic disorders and CVD events. Here we overview the current knowledge on the effect of polyphenols particularly of flavonoid intake on the atherothrombotic risk factors and discuss the caveats and challenges involved with current experimental cell-based designs.

Organic Extracts of Asian Plants Potentially Support Thrombolysis in Varied BMI Groups

A number of plant-derived drugs have been prescribed for treating atherothrombotic disorders such as myocardial or cerebral infarction. Therefore, this study investigated the individual and combined antithrombotic effects of six Asian plants on individuals with various BMIs. Venous blood drawn from healthy volunteers was allowed to form clots and treated with six organic fractions of Ophiorrhiza harrisiana Heyne, Haldina cordifolia (Roxb.) Ridsdale, Eclipta alba (L.) Hassk, Syzygium operculatum L., Lantana camara L., and Acanthus ilicifolius Linn. using the clot-lysis method. The weight of the clot before and after treatment provided the percentage of clot lysis. Variations in clot lysis in different BMI groups were assessed. A. ilicifolius induced the most thrombolytic activity, whereas L. camara showed slightly lower thrombolytic activity. The maximum clot-lysis activity was primarily observed in different fractions of O. harrisana, H. cordifolia, E. alba, S. operculatum, and A. ilicifolius. However, chloroform fractions of all plants except O. harrisana and L. camara showed maximum activity in individual plants. O. harrisana, H. cordifolia, E. alba, S. operculatum, L. camara, and A. ilicifolius showed the highest significant (P < 0.5 and P < 0.001) clotlysis activity viz., 46.60±0.79% (ethyl acetate), 55.40±1.023% (chloroform), 48.86±1.35% (CCl4 ), 44.89±1.76% (chloroform), 29.17±1.12% (ethanol), and 56.318±1.64% (chloroform). Obtained results were verified by ligandreceptor interaction through in silico approach. In conclusion, H. cordifolia, E. alba, and A. ilicifolius demonstrated promising thrombolytic effects; therefore, it is recommended that they be studied further for their therapeutic potential.

Circulating microparticle subpopulation in metabolic syndrome: relation to oxidative stress and coagulation markers.

BackgroundCirculating microparticles (MPs) contribute to the pathogenesis of atherothrombotic disorders and are raised in cardiovascular diseases. Herein, we aimed to investigate the effect of moderate metabolic abnormalities in an early stage of metabolic syndrome (MetS) on the level of MP subpopulations and to study relationships between MP subpopulations and both oxidative stress and coagulation markers.MethodsFlow cytometry used to evaluate circulating MPs subpopulations in 40 patients with an early stage MetS and 30 healthy controls. ELISA was used to quantify plasminogen activator inhibitor type 1/tissue plasminogen activator (PAI-1/TPA) while plasma glutathione peroxidase (GPx) activity was measured spectrophotometrically.ResultsTotal MPs were significantly elevated in MetS (P<0.001). Glutathione peroxidase and PAI1/TPA activity was significantly increased in subjects with MetS (P<0.001). Waist circumference, diastolic blood pressure, and total cholesterol positively influenced levels of total MPs, platelet-derived microparticles, and endothelium-derived microparticles. Fasting blood glucose, cholesterol, triglycerides, and low-density lipoprotein positively influenced the coagulation factors (TPA, PAI1). However, high-density lipoprotein negatively influenced platelet-derived MPs and factors associated with fibrinolysis (TPA, PAI1).ConclusionElevated circulating MPs are associated with MetS abnormalities, oxidative stress and coagulation factors and may act as early predictor of metabolic syndrome with risk of cardiovascular disease.

High Sensitivity of T-Ray for Thrombus Sensing

Atherosclerotic plaque rupture or erosion and subsequent development of platelet-containing thrombus formation is the fundamental cause of cardiovascular disease, which is the most common cause of death and disability worldwide. Here we show the high sensitivity of 200–270 GHz T-ray to distinguish thrombus formation at its early stage from uncoagulated blood. A clinical observational study was conducted to longitudinally monitor the T-ray absorption constant of ex-vivo human blood during the thrombus formation from 29 subjects. Compared with the control group (28 subjects) with uncoagulated blood samples, our analysis indicates the high sensitivity of 200–270 GHz T-Ray to detect thrombus with a low p-value < 10−5. Further analysis supports the significant role of platelet-activated thrombotic cascade, which modified the solvation dynamics of blood and occurred during the early coagulation stage, on the measured T-Ray absorption change. The ability to sense the thrombus formation at its early stage would hold promise for timely identification of patients at risk of various atherothrombotic disorders and save billions of lives.

The influence of immunoglobulin class G from blood plasma of patients with stroke on the activity of some parameters of hemostasis system.

Today, cardiovascular diseases are one of the main causes of disability of the population. Most of the illnesses, including stroke, are accompanied by the appearance immunoglobulin G (IgG) in the blood circulation. According to the literature sources and previous experiments, it is known that IgG made influence on the hemostasis system. Objectives of the investigation are pure enzymes: thrombin, factor X, proenzyme of protein C and prothrombin under the influence of IgG fraction that were separated from the plasma of patients with atherothrombotic and cardioembolic ischemic stroke and patients with other neurological diseases. IgG was separated by affinity chromatography. Disc electrophoresis was used to control antibodies' purity. The main goal of the experiment is to test the potential influence of all fractions of separated IgG on the process of hydrolysis of specific chromogenic substrates by the key factors of the hemostasis system such as thrombin, factor X and protein C. The appearance of IgG in the blood stream during the atherothrombotic and cardioembolic ischemic stroke and other neurological diseases was proved. Concentration of the IgG in plasma of patients with cardioembolic ischemic stroke was significantly higher compared with healthy donors, whereas the IgG in plasma of patients with atherothrombotic ischemic stroke and other neurological disorders was not significantly different. Their potential ability to influence the enzymes such as thrombin, factor X, proenzyme of protein C and prothrombin was shown. It was proved that the antibody fractions of all experimental groups significantly accelerate the process of splitting chromogenic substrate by thrombin but inhibited cleavage of a specific chromogenic substrate by protein C.

The effectiveness of antioxidant therapy in aspirin resistance, diabetes population for prevention of thrombosis.

Thrombosis as the main complication of coronary heart disease (CHD) represents the primary cause of morbidity and mortality in patients with diabetes mellitus (DM). In the course of diabetes mellitus some coagulation abnormalities occur, that may result in a thrombogenic propensity. Aspirin (ASA) as a platelet-inhibiting agent through inactivation of Cyclooxygenase-1 (COX-1) is mostly used for the prevention and treatment of atherothrombotic disorders. ASA inhibits the COX-1 enzyme and therefore blocks platelet thromboxane A2 (TXA2) synthesis. However, some of the serious vascular events in high-risk vascular patients are attributable to a failure of ASA to suppress platelet aggregation. The consumption of antioxidant or antioxidant rich foods such as vitamin C, E, and polyphenols might impart anti-thrombotic and cardiovascular protective effects via their inhibition of platelet hyper-activation or aggregation similar to the action of aspirin. This review will discuss the risk of thrombosis in diabetes, what aspirin resistance means, and the effectiveness of antioxidant therapy in the prevention and possible treatment of atherothrombotic disorders.

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein.

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis

Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14⁻/⁻ mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14⁻/⁻ mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14⁻/⁻ mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

Effects of warfarin and l-carnitine on hemostatic function and oxidative stress in streptozotocin-induced diabetic rats

Diabetes mellitus (DM) is a complex progressive disease characterized by hyperglycemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral, and peripheral arterial trees. Oxidative stress is reported in diabetic patients. We investigated the hemostatic functions and oxidative stress in streptozotocin (STZ)-induced diabetic rats and the effects of warfarin and L-carnitine on those parameters. Forty male Sprague-Dawley rats were divided into four groups: control, DM, and DM received warfarin or L-carnitine. In all rats, blood glucose, insulin, hemoglobin A1c (HbA1c), fibrinogen, factor VII (FVII), plasminogen activator inhibitor-1 (PAI-1), fibrin degradation products (FDP), protein C, antithrombin III (ATIII), malondialdehydes (MDA), and antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione) were measured. Also, prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation time, and platelet aggregation were evaluated. In diabetic rats, plasma glucose, HbA1c, MDA, fibrinogen, FVII, FDP, PAI-1, and platelet aggregation increased while insulin, PT, aPTT, coagulation time, protein C, ATIII, and antioxidants decreased. Warfarin administration to diabetic rats decreased FVII and FDP and increased PT, aPTT, and coagulation time with no effect on MDA, antioxidants, PAI-1, protein C, ATIII, and platelet aggregation. On the other hand, L-carnitine decreased fibrinogen, FVII, FDP, PAI-1, MDA, and platelet aggregation and increased PT, aPTT, coagulation time, protein C, ATIII, and antioxidants in diabetic rats. Therefore, we concluded that hyperglycemia plays an important role in hypercoagulation state and oxidative stress in STZ-induced DM. While L-carnitine improves oxidative stress and decreases the hypercoagulation state in DM, warfarin normalizes the hypercoagulation state with no effect on oxidative stress.

Platelet Transcriptional Profiling and Atherothrombosis

Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. We profiled platelet mRNA from patients with acute ST-segment–elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated one candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14 also known as S100A8/A9; odds ratio 3.3, P=0.002). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (P trend <0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). We evaluated vascular inflammation in wild-type and MRP-14-deficient (MRP-14-/-) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14-/- mice had significant reductions in leukocyte accumulation, cellular proliferation, and neointimal formation compared with wild-type mice. In a cytokine-induced local Shwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14-/- mice had significant reductions in neutrophil accumulation, lesion severity, and hemorrhagic area. In response to high-fat feeding, mice doubly deficient in apolipoprotein E and MRP-8/14 complexes had attenuation in atherosclerotic lesion area and in macrophage accumulation in plaques compared with mice deficient in apolipoprotein E alone. These findings indicate that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment. However, a causal role for MRP-14 in thrombosis has not been established and a viable molecular mechanism remains unknown. Here we show that time to thrombotic occlusion was prolonged markedly in MRP-14-/- mice. We observed that MRP-14 and MRP-8/14 are expressed in, and secreted by platelets, and that thrombus formation is reduced in whole blood from MRP-14-/-mice. Infusion of WT platelets or purified MRP-14 (or MRP-8/14) into MRP-14-/- mice shortened the carotid artery occlusion time, indicating that platelet-derived MRP-14 directly regulates thrombosis. Thus, a new pathway of inflammation and thrombosis involving MRP-14 is identified. MRP-14 represents a novel target for treating atherothrombotic disorders, including myocardial infarction and stroke. Disclosures:Simon:Cordis/J&J: Consultancy; Janssen/J&J: Consultancy; Medtronic Vascular: Consultancy; Merck: Consultancy; Medtronic Foundation: Research Funding.

Results of the PERFORM magnetic resonance imaging study

The PERFORM MRI Project was an ancillary study of the PERFORM trial. Its aim was to investigate the potential effects of terutroban in patients with atherothrombotic disorders, in comparison to aspirin, on the evolution of magnetic resonance imaging (MRI) lesions after a recent ischemic stroke or transient ischemic attack (TIA). The change in both hypointense and hyperintense lesions on the fluid attenuated inversion recovery (FLAIR) sequence, in the total brain volume and in the hippocampal volume from baseline (M1) to the final visit (M24) was assessed as well as the number of emergent microbleeds. A total of 748 patients had their MRI examination validated both at M1 and M24 during the study. At baseline, the volume of hypointense and hyperintense lesions on FLAIR images, the total brain volume, the hippocampal volume and the number of patients with microbleeds did not differ between the two groups. During follow-up, the mean volumetric increase of lesions hypointense or hyperintense on FLAIR images (from 5 to 8 %), the mean reduction of total brain volume (−0.4 %) and of hippocampal volume (−4 %), did not differ between the two treatment arms. The same parameters analysed ipsilateral to the ischaemic lesion did not differ either between the two groups. In the terutroban group, 16.3 % of patients presented with emergent microbleeds, 10.7 % in the aspirin group; this difference was not significant. In the PERFORM study, the progression of FLAIR lesions, of cerebral or hippocampal atrophy and of microbleeds did not differ between patients treated by terutroban and those treated by aspirin.

MicroRNAs in the Diagnosis and Treatment of Unstable Angina

During the last decade, a growing body of evidence has shown an interplay of genetics and inflammation which leads to a greater understanding of the complex pathophysiology of atherosclerotic vascular disease. Of great interest are non-coding RNAs, called microRNAs due to their importance for many aspects of homeostasis and disease. According significant data, they have been implicated in the regulation of several human physiological processes, while they seem to participate in cardiovascular disease pathogenesis including atherosclerosis and acute coronary syndromes. Accordingly, other biomarkers beyond troponins such as microRNAs, could be proved very useful in the aim of enhancing diagnostic or therapeutic effectiveness. Notably, there is evidence that patients with unstable angina pectoris could be discriminated from stable patients, given higher expression levels of several microRNAs, suggesting that they could be used to identify patients at risk for acute coronary syndromes. Also, they may have a substantial therapeutic impact in the management of athero-thrombotic vascular disorders, even though there are still obstacles in their use for that purposes, such as the delivery of the drug to target cells. Thus, it will be necessary to further explore their complications, before their use as therapeutic option.

Vorapaxar

Antiplatelet drugs are the cornerstone of treatment for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Clopidogrel and aspirin improve long-term vascular clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events, and it appears that insufficient response to both aspirin and clopidogrel contribute to this failure. Newer P2Y12 receptor blocker therapy resulted in only an approximately 2% reduction in absolute risk compared with clopidogrel. This indicates that residual ischemic events are mediated by other pathways that are unblocked by current dual antiplatelet therapy. Thrombin is the most potent platelet agonist (over 1000 times more than adenosine diphosphate on a molar basis). Thrombin-mediated platelet activation depends on proteaseactivated receptor (PAR) binding. PAR-1 is the main receptor for thrombin on human platelets; PAR-4 may contribute to platelet activation at much higher concentrations of thrombin. Inhibition of the PAR-1 may provide additional benefits over the standard dual antiplatelet therapy in attenuating ischemic event in patients with ACS. Vorapaxar is a new highly selective oral PAR-1 antagonist that inhibits thrombin-induced platelet activation. We review the pharmacokinetic, pharmacodynamic and clinical profile of vorapaxar. Although preliminary data indicated that vorapaxar may have the potential to improve ischemic outcomes without significantly increasing bleeding, more recent larger clinical trials seem to be less optimistic about both its effectiveness and safety. At this time, the role of vorapaxar in the settings of atherothrombotic disorders is not clear. Although it may be associated with less bleeding than P2Y12 receptor blockers, its antithrombotic effectiveness and side effects are major concerns.

Clinical Presentation of Acute Pulmonary Embolism: Survey of 800 Cases

BackgroundPulmonary embolism (PE) is a common and potentially fatal disease that is still underdiagnosed. The objective of our study was to reappraise the clinical presentation of PE with emphasis on the identification of the symptoms and signs that prompt the patients to seek medical attention.Methodology/Principal FindingsWe studied 800 patients with PE from two different clinical settings: 440 were recruited in Pisa (Italy) as part of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISAPED); 360 were diagnosed with and treated for PE in seven hospitals of central Tuscany, and evaluated at the Atherothrombotic Disorders Unit, Firenze (Italy), shortly after hospital discharge. We interviewed the patients directly using a standardized, self-administered questionnaire originally utilized in the PISAPED. The two samples differed significantly as regards age, proportion of outpatients, prevalence of unprovoked PE, and of active cancer. Sudden onset dyspnea was the most frequent symptom in both samples (81 and 78%), followed by chest pain (56 and 39%), fainting or syncope (26 and 22%), and hemoptysis (7 and 5%). At least one of the above symptoms was reported by 756 (94%) of 800 patients. Isolated symptoms and signs of deep vein thrombosis occurred in 3% of the cases. Only 7 (1%) of 800 patients had no symptoms before PE was diagnosed.Conclusions/SignificanceMost patients with PE feature at least one of four symptoms which, in decreasing order of frequency, are sudden onset dyspnea, chest pain, fainting (or syncope), and hemoptysis. The occurrence of such symptoms, if not explained otherwise, should alert the clinicians to consider PE in differential diagnosis, and order the appropriate objective test.

Hypothesis: Hyperhomocysteinemia is an indicator of oxidant stress

Elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and thrombosis, as well as a variety of other pathologies such as birth defects, Alzheimer’s disease and other dementias, osteoporosis, diabetes and renal disease. Homocysteine metabolism is catalyzed by a number of enzymes that require B-vitamins as cofactors, and homocysteine levels are particularly responsive to folate status. The predictive power of plasma homocysteine level as a risk factor for atherothrombotic orders raised the appealing hypothesis that reduction of homocysteine levels by vitamin supplementation might result in a commensurate reduction is the risk of atherothrombotic events. Unfortunately, most clinical trials failed to show a significant benefit of vitamin supplementation on cardiovascular events, in spite of significant lowering of plasma homocysteine levels. Thus, it is not clear whether homocysteine actually plays a causal role in many pathologies with which it is associated, or whether it is instead a marker for some other underlying mechanism. A large body of data links hyperhomocysteinemia and folate status with oxidant stress. In this article I review data that suggests that homocysteine not only promotes cellular and protein injury via oxidant mechanisms, but is also a marker for the presence of pathological oxidant stress. Thus, it is possible that hyperhomocysteinemia is not a common primary cause of atherothrombotic disorders in the general population, but rather a marker of systemic or endothelial oxidant stress that is a major mediator of these disorders.