Eduard Shantsila

Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited.

Atrial fibrillation is the most common sustained cardiac arrhythmia, which is associated with a high risk of stroke and thromboembolism. Increasing evidence suggests that the thrombogenic tendency in atrial fibrillation is related to several underlying pathophysiological mechanisms. Abnormal changes in flow are evident by stasis in the left atrium, and seen as spontaneous echocontrast. Abnormal changes in vessel walls-essentially, anatomical and structural defects-include progressive atrial dilatation, endocardial denudation, and oedematous or fibroelastic infiltration of the extracellular matrix. Additionally, abnormal changes in blood constituents are well described, and include haemostatic and platelet activation, as well as inflammation and growth factor changes. These changes result in the fulfilment of Virchows triad for thrombogenesis, and accord with a prothrombotic or hypercoagulable state in this arrhythmia. In this Review, we present an overview of the established and purported mechanisms for thrombogenesis in atrial fibrillation.

Monocytes in coronary artery disease and atherosclerosis: where are we now?

Despite improvements in interventional and pharmacological therapy of atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Atherosclerosis has long been identified as having an inflammatory component contributing to its pathogenesis, whereas the available therapy primarily targets hyperlipidemia and prevention of thrombosis. Notwithstanding a pleotropic anti-inflammatory effect to some therapies, such as acetyl salicylic acid and the statins, none of the currently approved medicines for management of either stable or complicated atherosclerosis has inflammation as a primary target. Monocytes, as representatives of the innate immune system, play a major role in the initiation, propagation, and progression of atherosclerosis from a stable to an unstable state. Experimental data support a role of monocytes in acute coronary syndromes and in outcome post-infarction; however, limited research has been done in humans. Analysis of expression of various cell surface receptors allows characterization of the different monocyte subsets phenotypically, whereas downstream assessment of inflammatory pathways provides an insight into their activity. In this review we discuss the functional role of monocytes and their different subpopulations in atherosclerosis, acute coronary syndromes, cardiac healing, and recovery with an aim of critical evaluation of potential future therapeutic targets in atherosclerosis and its complications. We will also discuss technical difficulties of delineating different monocyte subpopulations, understanding their differentiation potential and function.

The Role of Monocytes in Angiogenesis and Atherosclerosis

New vessel formation inside the arterial wall and atherosclerotic plaques plays a critical role in pathogenesis of heart attacks and strokes. The 2 known mechanisms resulting in the formation of new vessels within the plaque are local ischemia and inflammation. Blood monocytes play an important role in both processes. First, they express receptors for vascular endothelial growth factor and some of them may serve as circulating ancestors of endothelial cells. Second, monocytes are associated with inflammation by synthesis of inflammatory molecules following their activation (e.g., after stimulation of Toll-like receptors). Neovascularization is a reparative response to ischemia, and includes 3 processes: angiogenesis, arteriogenesis, and vasculogenesis. Angiogenesis, the formation of new capillary vessels is known to occur in response to a hypoxic environment. The interaction between leukocytes and vascular wall via overexpression of various molecules facilitates the migration of inflammatory cells into the plaque microenvironment. Monocytes are intimately involved in tissue damage and repair and an imbalance of these processes may have detrimental consequences for plaque development and stability. Importantly, monocytes are comprised of distinct subsets with different cell surface markers and functional characteristics and this heterogeneity may be relevant to angiogenic processes in atherosclerosis. The aim of this review article is to present an overview of the available evidence supporting a role for monocytes in angiogenesis and atherosclerosis.

The role of monocytes and inflammation in the pathophysiology of heart failure.

There is growing evidence to support an important role of inflammation in the underlying pathophysiology of heart failure (HF). Indeed, inflammatory cytokine levels are well recognized to be increased in patients with left ventricular dysfunction and appear to have prognostic implications. Monocytes play a pivotal role in the inflammatory cascade and are a major source of both pro‐ and anti‐inflammatory cytokines. They are intimately involved in tissue damage and repair and an imbalance of these processes may have detrimental consequences for the failing myocardium. Importantly, monocytes comprise of distinct subsets with different cell surface markers and functional characteristics and this heterogeneity may be important in understanding their specific role in HF. In HF, monocyte activation involves interplay between pattern recognition molecules, endotoxins, cytokines, and acute phase proteins. Activated monocytes migrate to the myocardium in response to powerful chemokines, where they must then attach to the endothelial wall before infiltrating into the myocardium itself. This review article aims to discuss the role of monocytes and inflammation in HF, focusing on monocyte activation, mobilisation, recruitment and endothelial adherence, as well as the effects they may have on myocardial performance. The therapeutic modulation of inflammation and monocyte activation in HF treatment will also be reviewed.

Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis

Summary.  The complex and multifactorial nature of atherogenesis and development of atherothrombotic complications involves numerous interactions between various cell types inside the vascular wall (e.g. macrophages and smooth muscle cells) and in the blood (e.g. leukocytes and platelets). One relatively recent advance in this area is the discovery of circulating microparticles and their role in endothelial damage, platelet activation, hypercoagulability and regulation of inter‐cellular interactions. Microparticles are small anucleoid phospholipid vesicles released from different cells, such as platelets, erythrocytes, leukocytes and endothelial cells. Microparticles carry surface proteins and include cytoplasmic material of the parental cells responsible for the exertion of microparticle‐mediated biological effects. About 25% of the procoagulant activity of stimulated platelet suspensions is associated with microparticles released upon platelet activation and their surface may be approximately 50–100‐fold more procoagulant than the surface of activated platelets per se. The available lines of evidence indicate that shedding of microparticles from the parental cells is not just a passive process accompanying cellular dysfunction and apoptosis, but a tightly regulated mechanism implicated in the interactions between various cell types. The role of microparticles as biological messengers is supported by their differential and specific involvement in the pathophysiology of different cardiovascular disorders, including atherogogenesis and thrombosis.

Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology

Summary.  Objectives: Monocytes include several subsets with different and sometimes divergent roles in immunity, atherogenesis and reparative processes. Objectives: We aimed to perform detailed immunophenotypic and functional characterization of human monocyte subsets. Patients/methods: Analysis of surface markers of blood and bone marrow monocyte subsets and functional characterization of blood monocyte subsets in healthy volunteers was performed using flow cytometry. Results: In the present study, we show the presence of three subsets which could be unequivocally distinguished by surface expression of CD14, CD16 and CCR2 as CD14+CD16−CCR2+(Mon1), CD14+CD16+CCR2+(Mon2) and CD14lowCD16+CCR2−(Mon3) subsets. In comparison with the classic Mon1, the Mon2 subset had the highest expression of Tie2, CXCR4, CD163, CD115, receptors to inter‐cellular adhesion molecule‐1 (ICAM‐1), vascular endothelial growth factor (VEGF), and the highest surface levels of apolipoprotein B and ferritin. In contrast, Mon3 had maximal expression of VCAM‐1 receptors and CD204. The Mon2 and Mon3 subsets had significantly lower activity of the NFκB pathway than Mon1. Mon1 and Mon2 had similar phagocytic activity, which was significantly higher compared with Mon3. All three subsets were present in bone marrow, although the relative proportion of Mon2 in bone marrow was about 2.5‐fold higher compared with that seen in blood. Significant differences in cytokine production in response to endotoxin stimulation were observed between the three monocyte subsets. Conclusion: Given their immunophenotypic similarity, the newly characterized Mon2 population may represent the previously reported pluripotent progenitor/pro‐angiogenic monocytes.

Heparin-Induced Thrombocytopenia: A Contemporary Clinical Approach to Diagnosis and Management

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications.

Atrial fibrillation (AF) is associated with structural, electrical, and contractile remodeling of the atria. Development and progression of atrial fibrosis is the hallmark of structural remodeling in AF and is considered the substrate for AF perpetuation. In contrast, experimental and clinical data on the effect of ventricular fibrotic processes in the pathogenesis of AF and its complications are controversial. Ventricular fibrosis seems to contribute to abnormalities in cardiac relaxation and contractility and to the development of heart failure, a common finding in AF. Given that AF and heart failure frequently coexist and that both conditions affect patient prognosis, a better understanding of the mutual effect of fibrosis in AF and heart failure is of particular interest. In this review paper, we provide an overview of the general mechanisms of cardiac fibrosis in AF, differences between fibrotic processes in atria and ventricles, and the clinical and prognostic significance of cardiac fibrosis in AF.

The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction.

Summary.  Aim:  Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST‐elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI.

The role of monocytes in thrombotic disorders: Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms

Although, the main physiological role of monocytes is attributed to innate immunity (that is, phagocytosis) and the development of tissue macrophages and dendritic cells, the pathophysiological role of these goes far behind these (simplistic) limits. Indeed, monocytes constitute a major source of blood tissue factor, a key element of the extrinsic coagulation cascade. Monocytes actively bind to platelets, thus forming very prothrombotic monocyte-platelet aggregates. Additionally, these cells link inflammation and the procoagulant state observed in various prothrombotic conditions. However, monocytes are also crucial for successful thrombus recanalisation. In this article, we review the available data on potential mechanisms that link monocytes with thrombosis-related processes.