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Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies - Figure 1

Eur. Heart J. (2009), 30 (23), 2838-2844; 10.1093/eurheartj/ehp477 - Click here to view abstract

Emerging anti-inflammatory therapies in clinical atherosclerosis. Anti-inflammatory treatment options are shown for the distinct stages in the development of clinical atherosclerosis.

Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies - Figure 2

Eur. Heart J. (2009), 30 (23), 2838-2844; 10.1093/eurheartj/ehp477 - Click here to view abstract

Leukocyte diversity in atherosclerosis. Circulating monocytes, neutrophils and T cells are recruited from circulation into the developing atherosclerotic lesion where they differentiate into effector subsets exerting predominantly pro- or anti-inflammatory effects. Subsequent to antigen-presentation in specialised lymphoid compartments [termed 2° (lymph node) or 3° lymphoid organs (adventitia)] naïve T helper (Th0) cells become activated and differentiate into distinct subsets: Th1, Th2, Th17, and induced regulatory (iTreg) T cells. Mφ, macrophages; hsps, heat shock proteins; SMC, smooth muscle cells; DC, dendritic cells; MHC II–TCR complex, major histocompatibility complex class II–T cell receptor complex.

C-reactive protein improves risk prediction in patients with acute coronary syndrome, or does it? - Figure 1

Eur. Heart J. (2010), 31 (3), 274-277; 10.1093/eurheartj/ehp435 - Click here to view abstract

Prognostic role of clinical risk scores and biomarkers of cardiovascular risk. Biomarkers of inflammation, high-sensitivity C-reactive protein in particular, have been suggested to improve the prognostic accuracy of clinical and electrocardiographic variables in patients with ACS. It has also been speculated that the use of biomics (i.e. genomics, proteomics, transcriptomics and metabolomics) data can improve prognosis further but this remains to be proven objectively in the clinical setting. In the general population, the use of a multimarker approach in different studies resulted in better risk prediction compared with single markers.

Structural and functional manifestations of human atherosclerosis: do they run in parallel? - Figure 1

Eur. Heart J. (2009), 30 (13), 1556-1558; 10.1093/eurheartj/ehp238 - Click here to view abstract

To evaluate coronary vasoreactivity, a small catheter is positioned in a proximal coronary artery for the infusion of acetylcholine (Ach) or nitroglycerin (NTG) to assess conduit artery endothelium-dependent and -independent vasodilation, respectively, as measured by quantitive coronary arteriography (QCA). A Doppler coronary flow-velocity measurement assesses small vessel vasoreactivity, typically to Ach for endothelium-dependent and to adenosine for endothelium-independent responses.

Clinical implications of inflammation for cardiovascular primary prevention - Figure 2

Eur. Heart J. (2010), 31 (7), 777-783; 10.1093/eurheartj/ehq022 - Click here to view abstract

Risk modifiers influence atherogenesis through effects on inflammation as reflected by biomarkers of the acute phsae response. The top shows a selection of risk factors for atherosclerosis that can instigate production of pro-inflammatory cytokines such as interleukin-1 (IL-1) ir tumour necrosis factor-alpha (TNF-α). These inflammatory mediators can act directly at the level of the arterial wall to promote atheroma-formation, progression, and thrombotic complication (left). Pro-inflammatory cytokines also elicit the acute phase response from the liver, through the intermediary of interleukin-6, the 'messenger cytokine' (right). The acute phase reactants include proteins involved in the casual pathway of atherothrombosis (e.g. fibrinogen or plasminogen activator inhibitor-1, PAI-1) or soluble biomarkers such as C-reactive protein or serum amyloid A (SAA) that can be sampled in peripheral blood (bottom). Factors that mitigate atherothrombosis (middle), some of which are hard to quantitate in clinical practice (e.g. dietary factors or physical activity), can also influence biomarkers of inflammation, enhancing their ability to add to traditional risk factors in predicting outcomes and targeting therapies.

Stroke risk in AF: do AF patterns matter? - Figure 1

Eur. Heart J. (2010), 31 (8), 908-910; 10.1093/eurheartj/ehq074 - Click to view abstract

Risk of stroke in AF. Patterns of reccurent AF may be classified as paroxysmal, persistent, or permanent. A hypothetical paradigm is displayed in which the probability of a given pattern of AF varies of the lifecourse of AF, with darker blue shading indicating a higher probability corresponding to a given pattern. Shared risk factors for incident AF and stroke are indicated, as are several mediators of stroke once a patient develops AF. The risk of stroke, displayed in red at the bottom of the figure, is greater once in AF as compared with sinus rhythm, and is generally similar across paroxysmal, persistent and permanent patterns of AF.

Cardiovascular implications from untreated human immunodeficiency virus infection - Figure 1

Eur. Heart J. (2011), 32 (8), 945-951; 10.1093/eurheartj/ehq483 - Click here to view abstract

Pro-atherogenic factors related to untreated human immunodeficiency virus (HIV) infection. Key pro-atherogenic factors amplified in the setting of untreated HIV infection are presented. HIV replication and activation of lymphocytes and monocytes is associated with release of inflammatory cytokines and early vessel dysfunction. Key candidate drivers of immune activation include, but may not be limited to, HIV persistence (including low-level viral replication below level of detection for clinical assays), permanent damage to mucosal lymphatic tissue with increased microbial translocation, and the presence of co-pathogens (e.g. cytomegalovirus). Subsequent coagulation and thrombotic activity, via cell damage and up-regulation of tissue factor pathways, platelet activation, or other mechanisms may contribute to premature atherosclerosis. Pro-atherogenic changes in lipids and lipoprotein metabolism are also consequences of both HIV infection and chronic inflammation. Some of these mechanisms are attenuated, though incompletely, with antiretroviral therapy and suppression of HIV replication.

Cardiovascular implications from untreated human immunodeficiency virus infection - Figure 3

Eur. Heart J. (2011), 32 (8), 945-951; 10.1093/eurheartj/ehq483 - Click here to view abstract

Antiretroviral therapy has both positive and negative effects on cardiovascular risk. Progression of atherosclerosis is depicted in the setting of human immunodeficiency virus (HIV) infection. Antiretroviral therapy-related suppression of HIV replication may reduce HIV-related cardiovascular disease risk, but is also associated with variable toxicity that may, itself, increase cardiovascular disease risk. Antiretroviral therapy toxicity varies by the specific antiretroviral but, in part, may include adverse lipoprotein changes, insulin resistance, inflammation, platelet dysfunction, and vascular injury. Thus, compared with untreated HIV infection, the net effect of starting antiretroviral therapy on cardiovascular disease risk is unknown as it may increase or decrease risk overall. Traditional risk factors remain of high importance in this context, and should be targeted by prevention strategies.

Transforming growth factor-β: transforming plaque to stability - Figure 1

Eur Heart J (2013) 34 (48): 3684-3686; 10.1093/eurheartj/ehs228 - Click here to view abstract

(A) Soluble transforming growth factor β (TGFβ) binds to TGFβ receptor II (TGFβRII), which recruits TGFβ receptor I (TGFβRI) to form a tetramer. Once the TGFβR complex is formed, TGFβRII phosphorylates SMAD 2/3 (red circles) and causes transcription of effector genes. (B) Addition of anti-TGFβ monoclonal antibody (light blue) or a truncated soluble TGFβRII:Fc protein (dark blue) binds soluble TGFβ, leading to loss of TGFβ signalling in all cells that express TGFβR. (C) A dominant negative TGFβRII transgene driven by a CD2 or CD4 promoter abrogates TGFβRII signalling in all T cells, but not in dendritic cells (DCs). (D) In the study of Lievens et al., CD11c promoter was used to drive dominant negative TGFβRII in DCs and CD11c-expressing macrophages.

Phospholipase A2 enzymes and the risk of atherosclerosis - Figure 2

Eur Heart J (2012) 33 (23): 2899-2909; 10.1093/eurheartj/ehs148 - Click here to view abstract

Effects of phospholipase A2 enzymatic activity on circulating lipoproteins. Secretory phospholipase A2 (sPLA2) hydrolyzes phospholipids from the surface of native lipoproteins and oxidatively-modified lipoproteins, whereas lipoportein-associated phospholipase A2 acts only on oxidatively-modified lipoproteins. Phosphoatidylcholine hydrolysis by sPLA2 results in small VLDL and LDL particles with altered confirmation of apolipoprotein B (apoB). The conformational change in apoB reduces binding and internalization of apoB-containing lipoproteins by the apoB/E (LDL) receptor resulting in prolonged residence time in the circulation. This prolonged circulation time of LDL particles increases exposure to reactive oxygen species (ROS) resulting in an oxidized LDL particle (Ox-LDL) that may serve as a substrate for group IIA sPLA2 (GIIA sPLA2) and Lp-PLA2. Phospholipid hydrolysis of Ox-LDL particles generates oxidized non-esterified fatty acids (Ox-NEFA) and lysophophotidylcholine (Lyso-PC). sPLA2 acts on cellular membranes resulting in elaboration of arachidonic acid that serves as the substrate for eicosanoids, thromboxanes and leukotrienes.

Phospholipase A2 enzymes and the risk of atherosclerosis - Figure 4

Eur Heart J (2012) 33 (23): 2899-2909; 10.1093/eurheartj/ehs148 - Click here to view abstract

Phospholipase A enzymatic activity and foam cell formation. Secretory phospholipase A2 (sPLA2) and lipoprotein-associated phospholipase A2 (Lp-PLA2) increase oxidation of LDL particles allowing for enhanced internalization into the macrophage via the conventional scavenger receptor resulting in foam cell formation. In addition, group V (GV sPLA2) and group X sPLA2 (GX sPLA2)-modified LDL particles are incorporated into macrophages via a putative M-type receptor, which contributes to cholesterol content of tissue macrophages via this distinct pathway.

Stabilization of atherosclerotic plaques: an update - Figure 2

Eur Heart J (2013) 34 (42): 3251-3258; 10.1093/eurheartj/eht301 - Click here to view abstract

Factors contributing to the formation of vulnerable plaques. MCP-1, monocyte chemotactic protein-1; MIF, migration inhibitory factor; TNFα, tumour necrosis factor-α; ILs, interleukins; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases; PDGFs, platelet-derived growth factors; VEGFs, vascular endothelial growth factors; FGFs, fibroblast growth factors; Mφ, macrophages.

Air pollution and traffic noise: do they cause atherosclerosis? Figure 1

Eur Heart J (2014) 35 (13): 826-828; 10.1093/eurheartj/eht490 - Click here to view the abstract

Simplified diagram of hypothesized causal associations of thoracic aortic calcification with particulate air pollution, traffic noise (Noise), intermediate causes (Mediators), lifestyle risk factors (Lifestyle), and socio-economic status.

Rheumatoid arthritis and coronary atherosclerosis: two cousins engaging in a dangerous liaison

Eur. Heart J. (2015), 36 (48), 3423-3425, Fig 1; 10.1093/eurheartj/ehv489 - click here to view abstract

(A) Atherosclerosis: lesion progression culminating in atherothrombosis. (B) Rheumatoid arthritis: cartilage degradation in the synovial joint. B, B cell producing antibodies; DC, dendritic cell; ECM, extracellular matrix; FLS, fibroblast-like synoviocytes; IFN, interferon; IL, interleukin; MHCII-TCR, major histocompatibility complex class II–T cell receptor; Th, T helper cell subset; Treg, regulatory T cell subset; TNF, tumour necrosis factor; VSMC, vascular smooth muscle cell.

Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction?

Eur. Heart J. (2016) 37(11) doi: 10.1093/eurheartj/ehv453 - Click here to view the abstract

Processes leading to secondary ischaemia. Several risk factors, especially hyperlipidaemia, increase production of leucocytes which give rise to a first ischaemic event. This ischaemic event itself accelerates haematopoiesis, for instance via increased sympathetic nervous system activity, leading to a second within a short time span after the first.

Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction?

Eur. Heart J. (2016) 37(11) doi: 10.1093/eurheartj/ehv453 - Click here to view the abstract

Innate immune pathways leading to increased myeloid cell production and acceleration of atherosclerosis. A number of pathways and signals increase their input on haematopoietic tissues after a first organ ischaemia. The signals can either be sensed by haematopoietic stem cells or by niche cells which instruct HSC behaviour. Altered niche haematopoietic signals may increase haematopoietic stem cell proliferation (i.e. leucocyte production) and increase their migration out of the bone marrow. As a consequence, splenic leucocyte production increases as well. Altogether, the systemic pool of innate immune cells, including plaque macrophages, expands.

Disordered haematopoiesis and athero-thrombosis

Eur. Heart J. (2016) 37(14) doi: 10.1093/eurheartj/ehv718 - Click here to view the abstract

Cardiovascular risk factors promote myelopoiesis and contribute to athero-thrombosis. (A) Increased plasma low-density lipoproteins and decreased high-density lipoproteins levels, (B) hyperglycaemia, and (C) obesity are major cardiovascular risk factors. Through various mechanisms, these risk factors directly or indirectly stimulate the production of myeloid cells (monocytes, neutrophils, and reticulated platelets) increasing the abundance in circulation. Hypercholesterolaemia also promotes the mobilization of haematopoietic stem cells (HSCs) to the spleen resulting in extramedullary haematopoiesis further contributing to the circulating pool of myeloid cells. (1) The increased abundance in circulating myeloid cells enhances the progression and impairs the regression of the atheroma. (2) There is also increased platelet–leucocyte interactions that enhance the recruitment of the leucocytes to the atherosclerotic lesion. (3) Neutrophils activation can also result in the formation of neutrophil extracellular traps (NETs), which contribute to enhanced atherogenesis and athero-thrombosis by binding platelets.

Disordered haematopoiesis and athero-thrombosis

Eur. Heart J. (2016) 37(14) doi: 10.1093/eurheartj/ehv718 - Click here to view the abstract

Defects in cellular cholesterol efflux pathways trigger myelopoiesis, extramedullary haematopoiesis, and enhanced atherosclerosis. In the bone marrow, defects in intrinsic cellular efflux pathways in haematopoietic stem (HSC) and myeloid progenitor cells result in increased membrane cholesterol levels and increased sensitivity to growth factor and cytokines. Deletion of ABCG4 in megakaryocyte progenitors (MkPs) results in increased c-MPL expression and enhanced thrombopoietin (TPO) signalling. This stimulates the production of immature reticulated platelets that can enhance atherogenesis via a number of mechanisms including deposition of cytokines (CCL5) and binding and activating leucocytes. Defective cholesterol efflux in haematopoietic stem cell and myeloid progenitors increased the cell surface abundance of the common β-subunit (CBS) of the IL-3, IL-5, and GM-CSF receptors resulting in enhanced proliferation. Inflammatory stimuli from a myocardial infarction including damage-associated molecular pattern molecules and IL-1β can influence haematopoietic stem cell proliferation and lineage fate. HSCs can also mobilize and migrate to the spleen when efferocytosis fails in macrophages with defective cholesterol efflux as there is a failure to shut down the expression of IL-23; thus, IL-17 and in turn G-CSF levels remain increased. In the spleen, there is an increased abundance of the innate response activator B cells (IRA B-cells) in the setting of hypercholesterolaemia, which produce GM-CSF driving the haematopoietic stem cells to produce monocytes and neutrophils. Defective cholesterol efflux in splenic macrophages also promotes M-CSF production to enhance myelopoiesis and CCL2 to promote monocyte migration. Together, the increased abundance of platelets, monocytes, and neutrophils all contribute to promoting the accumulation of macrophages in the atherosclerotic lesion.

Disordered haematopoiesis and athero-thrombosis

Eur. Heart J. (2016) 37(14) doi: 10.1093/eurheartj/ehv718 - Click here to view the abstract

Mechanisms contributing to myeloid production in metabolic disorders. Hyperglycaemia: In the setting of elevated blood glucose, neutrophils are stimulated to produce S100A8/A9, which travels to the bone marrow to interact with RAGE on the surface of macrophages and common myeloid progenitors (CMPs) triggering the production of M-CSF and GM-CSF. These cytokines increase the abundance of common myeloid progenitors and granulocyte–macrophage progenitors (GMPs) promoting the production of monocytes and neutrophils. Obesity: In the context of obesity, local inflammation in the adipose tissue occurs which appears to be initiated by S100A8/A9 interacting with TLR4 on adipose tissue macrophages (ATMs). This induces IL-1β, which is processed by the NLRP3 inflammasome to its mature form. IL-1β then travels to the bone marrow and binds the IL-1 receptor, which is up-regulated on common myeloid progenitors and granulocyte–macrophage progenitors in the obese state. This interaction drives myelopoiesis. As people with diabetes and obesity have increased diabetes and common myeloid progenitor cells are precursors of megakaryocytes, this may be a mechanism contributing to increased platelets. The enhanced production of myeloid cells in diabetes impairs the regression of atherosclerotic lesions due to persistent entry of monocytes.

Inflammatory cytokines in atherosclerosis: current therapeutic approaches

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehv759 - Click here to view the abstract

Cytokine-related therapeutic approaches in atherosclerosis. In the context of atherosclerosis, several methods have been studied to modify the inflammatory cascade. 1. Broad-based immunomodulatory agents. 2. Blockade of pro-inflammatory cytokines. 3. Delivery of anti-inflammatory cytokines with adenovirus vectors or liposomes. 4. Induction of regulatory T cells. 5. In vivo transfection with oligonucleotides. IL, interleukin; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cell.

Inflammatory cytokines in atherosclerosis: current therapeutic approaches

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehv759 - Click here to view the abstract

Examples of cytokine-related statin effects in the microenvironment of an atherosclerotic plaque. Statins have been shown to antagonize the effects of inflammatory cytokines. For example, simvastatin neutralizes the pro-atherogenic actions of tumour necrosis factor-α through inhibition of the tumour necrosis factor-α-induced expression of vascular cell adhesion molecule 1 and suppression of thrombomodulin, whereas atorvastatin improves vascular nitric oxide bioavailability. Simvastatin can potently down-regulate the production of known pro-inflammatory cytokines such as interleukin-1 while also up-regulating the expression of anti-inflammatory cytokines such as interleukin-10. Finally, simvastatin is also able to counteract the combined pro-proliferative effects of tumour necrosis factor-α and interleukin-18 on aortic smooth muscle cells. IL, interleukin; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.

C1q/TNF-related protein 1: a novel link between visceral fat and athero-inflammation

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehv754 - Click here to view the abstract

The adipokine CTRP1 (C1q/tumour necrosis factor-related protein 1) is produced in adipose tissue (yellow area) as well by oxidized LDL (OxLDL)- or interleukin-1β (IL-1β)-stimulated macrophages and endothelial cells in the atherosclerotic plaque (purple area). In the plaque, CTRP1 activates endothelial cells and macrophages themselves to produce leucocyte adhesion molecules and tumour necrosis factor α (TNFα), which enhance leucocyte entry and inflammatory activation. An increase in CTRP1 levels in blood is associated with increased coronary artery disease risk. Plasma CTRP1 originates from visceral adipose tissue as well as from monocytes and from areas with ongoing inflammation. MAPK, mitogen-acivated protein kinase; NF-κB, nuclear factor-κB; VCAM, vascular cell adhesion molecule; M1, macrophage.

MicroRNAs: small molecule, big potential for coronary artery disease

Eur. Heart J. (2016) 37(22) doi: 10.1093/eurheartj/ehw067 - Click here to view the abstract

Proposed timeline of coronary atherosclerosis and contribution of microRNA (miR) transcoronary gradients (TCGs) at each step. Interestingly, at most stages, miR-126, miR133, and mi-155 appear to be in abundance throughout the disease process, while very few miRs have reduced gradients (or are ‘retained’ in the circulation). ACS, acute coronary syndrome; CAD, coronary artery disease; CED, coronary endothelial dysfunction.

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