Tissue Factor/Factor FVII Complex Inhibitors in Cardiovascular Disease. Are Things Going Well?

Blood coagulation is a complex biological mechanism aimed to avoid bleeding in which a highly regulated and coordinated interplay of specific proteins and cellular components respond quickly to a vascular injury. However, when this mechanisms occurs in the coronary circulation, it has not a “protective” effect, but rather, it plays a pivotal role in determining acute coronary syndromes. Coagulation recognizes Tissue Factor (TF), the main physiological initiator of the extrinsic coagulation pathway, as its starter

Very late bioresorbable scaffold thrombosis and reoccurrence of dissection two years later chronic total occlusion recanalization of the left anterior descending artery

We describe the case of a patient presenting with ST-segment elevation myocardial infarction due to very late scaffold thrombosis. The patient was already admitted for an elective percutaneous recanalization of a chronically occluded left anterior descending artery (LAD). The procedure was performed according the sub-intimal tracking and re-entry (STAR) technique with 4 bioresorbable vascular scaffolds implantation. However, even though the coronary flow was preserved at the end of the procedure, the dissected segment was only partially sealed at the distal segment of the LAD. After 18 mo of regular assumption, dual antiplatelet therapy was discontinued for 10 mo before his presentation at the emergency room. This is the first reported case of a very late scaffold thrombosis after coronary chronic total occlusion (CTO) recanalization performed according to the STAR technique. This case raises concerns about the risk of very late scaffold thrombosis after complex CTO revascularization

bivalirudin inhibits thrombin mediated tissue factor expression in human endothelial cells

Thrombosis is the main pathophysiological mechanism in Acute Coronary Syndromes (ACS), and involves the activation of platelets and of Tissue Factor (TF)-dependent extrinsic coagulation pathway. TF-mRNA and antigen are detectable in the adventitia of normal vessels. On the contrary, little TF immunoreactivity is measurable in the smooth muscle cells of uninjured vessels and unperturbed endothelial cells, being in contact with circulating blood, usually do not express TF activity. However, several stimuli are able to induce TF in endothelial cells, including thrombin. Thus in an acute "scenario", thrombin might be responsible for creating a prothombotic milieau. Bivalirudin (BIVA) is a synthetic, reversible direct thrombin inhibitor actually considered a valuable alternative to heparins in patients who need anticoagulation in the setting of ACS and percutaneous coronary intervention to avoid acute thrombotic events. In the present study we have investigated whether BIVA, by inhibiting thrombin, might have effects on TF expression and procoagulant activity in endothelial cells. Human Umbilical Endothelial Cells (HUVEC) were stimulated with thrombin or with the activated coagulation factors FVIIa/FXa for 2 hrs to evaluate TF-mRNA transcription by real-time PCR and for 6 hrs to measure TF expression/activity on cell surface by FACs analysis and procoagulant activity. In additional experiments HUVEC were pre-treated with BIVA for 1 hr before being stimulated and processed as above. Thrombin induced TF-mRNA transcription as well TF expression/activity on HUVEC shifting them to a procoagulant phenotype. On the contrary, the activated coagulation factors FVIIa/FXa did not affect TF expression/activity, indicating that thrombin plays a pivotal role in mediating this phenomenon. BIVA was able to prevent these thrombin deleterious effects. Data of the present study, although in vitro, suggest that BIVA, in the context of ACS, might significantly reduce thrombogenicity not only by acting as direct thrombin inhibitor but through its effects on TF expression/activity too. </p

Upregulation of TH/IL-17 Pathway-Related Genes in Human Coronary Endothelial Cells Stimulated with Serum of Patients with Acute Coronary Syndromes

Inflammation plays an essential role in the development and complications of atherosclerosis plaques, including acute coronary syndromes (ACS). Indeed, previous reports have shown that within the coronary circulation of ACS patients, several soluble mediators are released. Moreover, it has been demonstrated that endothelial dysfunction might play an important role in atherosclerosis as well as ACS pathophysiology. However, the mechanisms by which these soluble mediators might affect endothelial functions are still largely unknown. We have evaluated whether soluble mediators contained in serum from coronary circulation of ACS patients might promote changes of gene profile in human coronary endothelial cells (HCAECs)

Obesity and ischemic heart disease. Is there a link between wellness’ diseases?

Obesity, the most common nutritional disorder in Western countries, is usually associated to cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Nowadays, the adipose tissue is considered as an endocrine organ able to produce substances called adipo(cyto)kines that have different effects on lipid metabolism, closely involved in metabolic syndrome, and cardiovascular risk. The increased cardiovascular risk can be related also to peculiar dysfunction in the endocrine activity of adipose tissue observed in obesity responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. The present review aims at providing an up-dated overview on the adipocytederived molecules potentially involved in cardiovascular pathophysiology

Oxidized Low-Density Lipoproteins Induce Tissue Factor Expression in T-Lymphocytes via activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1

T-lymphocytes plays an important role in the pathophysiology of acute coronary syndromes (ACS). T-cell activation in vitro by pro-inflammatory cytokines may lead to functional Tissue Factor (TF) expression, indicating a possible contribution of immunity to thrombosis. Oxidized low-density lipoproteins (oxLDLs) are found abundantly in atherosclerotic plaques. We aimed at evaluating the effects of oxLDLs on TF expression in T-cells and the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)

Insights into pathophysiology of smoke-related cardiovascular disease

cardiovascular morbidity and mortality are well established. Both active and passive smoking represent a major health hazard for both men and women. The great concerns related to the deleterious effects of CS on cardiovascular disease have been translated into various kinds of social interventions and targeted health policies since ever. The high health impact of cigarette smoking has driven a huge number of researches at the epidemiological, clinical and biological level. Nevertheless, even though many progresses have been made in understanding the mechanisms underlying the high disease burden associated to cigarette smoke, the exact components and the mechanisms by means of which it exerts its effects remain to be completely clarified as yet. The present paper reviews the main observations on the pathophysiology of smoke-related cardiovascular diseases, providing an up-to-date perspective about one of the main cardiovascular killers of our days

The role of neopterin in cardiovascular disease.

Inflammation plays a key role in the initiation and progression of atherosclerosis but also in the pathophysiology of atheromatous plaque disruption and the development of acute coronary syndromes. Neopterin is a marker of inflammation and of immune system activation, it is synthesized by macrophages, that, once activated, release this substance. Indeed, in clinical evaluation of patients, measurements of plasma levels of neopterin are usually used to evaluate progression of viral infections, renal transplant rejection, severe systemic inflammatory diseases, nephritic syndrome and several autoimmune diseases. This mediator is able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation. Recent data indicate that serum levels of neopterin are elevated in patients with coronary and peripheral artery disease and seem to be a prognostic marker for major adverse cardiovascular events. In particular, neopterin levels predict future major cardiac and vascular adverse events in patients presenting with chronic coronary artery disease, with acute coronary syndromes, and in those with critical limb ischemia. This renders this molecule a useful marker of atherosclerotic plaque activity, permitting the identification of the subjects at highest risk for major adverse cardiovascular events. In line with the above mentioned evidences, patients with high neopterin levels may require aggressive risk factor modification and intensive medical treatment irrespective of the severity of their coronary artery disease. This data suggest a potential clinical use of neopterin as a marker for disease activity in patients with cardiovascular disease

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy:a multicenter prospective 8 years follow up study

Background: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. Methods: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). Results: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). Conclusions: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy