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Thomas F. Lüscher
Bernard J. Gersh
Emerging anti-inflammatory therapies in clinical atherosclerosis. Anti-inflammatory treatment options are shown for the distinct stages in the development of clinical atherosclerosis.
Leukocyte diversity in atherosclerosis. Circulating monocytes, neurophils 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 28 (lymph node) or 38 lymphoid organs (adventitia)] naïve T helper (Th0) cells become activated and differentiate into distinct subsets: Th1, Th2, Th17, and induced regulatory (iTreg) T cells.
Mf, macrophages; hsps, heat shock proteins ; SMC, smooth muscle cells; DC, dendritic cells; MHC 11-TCR complex, major histocompatibility complex class II-T cell receptor complex.
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.
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.
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.
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.
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.
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.
(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.
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 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.
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.
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