Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure ‘inflammation’ are insufficiently precise and do not provide information about disease site, activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction (AMI), by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including current limitations and challenges that are the focus of ongoing study.
Background: Cardiovascular risk in diabetes remains elevated despite glucose lowering therapies. We hypothesised that hyperglycaemia induces trained immunity in macrophages, promoting persistent pro-atherogenic characteristics. Methods: Bone marrow derived macrophages from control and mice with diabetes were grown in physiological glucose (5 mM) and subject to RNA-sequencing (n=6), ATAC-sequencing (n=6) and ChIP-sequencing (n=6) for determination of hyperglycaemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into [normoglycaemic] Ldlr -/- mice was used to assess its functional significance in vivo . Evidence of hyperglycaemia-induced trained immunity was sought in human peripheral blood mononuclear cells (PBMCs) from patients with diabetes (n=8) compared with case controls (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. Results: In macrophages, high extracellular glucose promoted pro-inflammatory gene expression and pro-atherogenic functional characteristics, through glycolysis-dependent mechanisms. Bone marrow-derived macrophages (BMDM) from diabetic mice, retained these characteristics, even when cultured in physiological glucose, indicating hyperglycaemia-induced trained immunity. Bone marrow transplantation from diabetic mice into [normoglycaemic] Ldlr -/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated ATAC-seq, ChIP-seq and RNA-seq analyses of haematopoietic stem cells and BMDM revealed a pro-inflammatory "priming effect" in diabetes. The pattern of open chromatin implicated transcription factor, RUNX1, while transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for RUNX1 targets, consistent with a potential role in human disease. Pharmacological inhibition of RUNX1 in vitro inhibited the trained phenotype. Conclusions: Hyperglycaemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.
Objective-Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. Methods and Results-In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-␣ (by 49.2Ϯ4.5%); interleukin-6 (by 56.2Ϯ2.8%), and monocyte chemoattractant protein-1 (by 43.2Ϯ3.1%) (PϽ0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-␣ (by 48.6Ϯ7.1%), interleukin-6 (by 60.9Ϯ1.6%), and monocyte chemoattractant protein-1 (by 59.3Ϯ5.3%) (PϽ0.01; nϭ7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D 2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKK by 42Ϯ2% (PϽ0.001) IKB-␣ by 54Ϯ14% (PϽ0.01). Accumulation of nuclear p65 NF-B in response to lipopolysaccharide treatment was also profoundly inhibited, by 89Ϯ1.3% (nϭ4; PϽ0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7Ϯ1.2%; PϽ0.001). Conclusion-NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia. (Arterioscler Thromb Vasc Biol. 2012;32:669-676.)Key Words: atherosclerosis Ⅲ cholesterol-lowering drugs Ⅲ macrophages Ⅲ receptors Ⅲ vascular biology I n patients with prior myocardial infarction, nicotinic acid (NA) reduces long-term mortality 1 and may confer additional antiatherogenic benefits when used in conjunction with statins. 2,3 These effects are generally attributed to favorable actions on the lipoprotein profile, which include LDL-cholesterol reduction and HDL-cholesterol elevation.In addition, NA reduces systemic markers of inflammation (eg, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1 [MCP-1], and TNF-␣) and increases adiponectin, an adipokine with insulin sensitizing, antiatherogenic, and antiinflammatory properties. 2,4 These observations raise the possibility of additional nonlipoprotein-mediated effects of NA. The receptor for NA, GPR109A, is abundantly expressed in adipocytes, where it suppresses free fatty acid release 5 and has G-protein coupled rece...
BackgroundAtherosclerotic plaques in carotid arteries can be characterized in-vivo by multicontrast cardiovascular magnetic resonance (CMR), which has been thoroughly validated with histology. However, the non-quantitative nature of multicontrast CMR and the need for extensive post-acquisition interpretation limit the widespread clinical application of in-vivo CMR plaque characterization. Quantitative T2 mapping is a promising alternative since it can provide absolute physical measurements of plaque components that can be standardized among different CMR systems and widely adopted in multi-centre studies. The purpose of this study was to investigate the use of in-vivo T2 mapping for atherosclerotic plaque characterization by performing American Heart Association (AHA) plaque type classification, segmenting carotid T2 maps and measuring in-vivo T2 values of plaque components.MethodsThe carotid arteries of 15 atherosclerotic patients (11 males, 71 ± 10 years) were imaged at 3 T using the conventional multicontrast protocol and Multiple-Spin-Echo (Multi-SE). T2 maps of carotid arteries were generated by mono-exponential fitting to the series of images acquired by Multi-SE using nonlinear least-squares regression. Two reviewers independently classified carotid plaque types following the CMR-modified AHA scheme, one using multicontrast CMR and the other using T2 maps and time-of-flight (TOF) angiography. A semi-automated method based on Bayes classifiers segmented the T2 maps of carotid arteries into 4 classes: calcification, lipid-rich necrotic core (LRNC), fibrous tissue and recent IPH. Mean ± SD of the T2 values of voxels classified as LRNC, fibrous tissue and recent IPH were calculated.ResultsIn 37 images of carotid arteries from 15 patients, AHA plaque type classified by multicontrast CMR and by T2 maps (+ TOF) showed good agreement (76% of matching classifications and Cohen’s κ = 0.68). The T2 maps of 14 normal arteries were used to measure T2 of tunica intima and media (T2 = 54 ± 13 ms). From 11865 voxels in the T2 maps of 15 arteries with advanced atherosclerosis, 2394 voxels were classified by the segmentation algorithm as LRNC (T2 = 37 ± 5 ms) and 7511 voxels as fibrous tissue (T2 = 56 ± 9 ms); 192 voxels were identified as calcification and one recent IPH (236 voxels, T2 = 107 ± 25 ms) was detected on T2 maps and confirmed by multicontrast CMR.ConclusionsThis carotid CMR study shows the potential of in-vivo T2 mapping for atherosclerotic plaque characterization. Agreement between AHA plaque types classified by T2 maps (+TOF) and by conventional multicontrast CMR was good, and T2 measured in-vivo in LRNC, fibrous tissue and recent IPH demonstrated the ability to discriminate plaque components on T2 maps.
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