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Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.Atherosclerosis is characterized by low-grade, chronic inflammation, and the balance between pro-inflammatory and inflammation-resolving mechanisms dictates the clinical outcomes. This Review discusses the specific causes of inflammation and the mechanisms underlying the impaired resolution of inflammation that characterize clinically dangerous atherosclerotic lesions and highlights the potential of pro-resolving mediator therapy for the prevention and treatment of atherosclerotic cardiovascular disease.

A non-resolving inflammation results in a chronic inflammatory response, characteristic of atherosclerosis, abdominal aortic aneurysms and several other cardiovascular diseases. Restoring the levels of specialized proresolving mediators to drive the chronic cardiovascular inflammation toward resolution is emerging as a novel therapeutic principle. The lipid mediators lipoxins and resolvins exert their proresolving actions through specific G-protein coupled receptors (GPCR). So far, four GPCR have been identified as the receptors for lipoxin A4 and the D- and E-series of resolvins, namely ALX/FPR2, DRV1/GPR32, DRV2/GPR18, and ERV1/ChemR23. At the same time, other pro-inflammatory ligands also activate some of these receptors. Recent studies of genetic targeting of these receptors in atherosclerotic mouse strains have revealed a major role for proresolving receptors in atherosclerosis. The present review addresses the complex pharmacology of these four proresolving GPCRs with focus on their therapeutic implications and opportunities for inducing the resolution of inflammation in cardiovascular disease.

Key Points Atherosclerosis is characterized by lipid deposition and chronic inflammation, associated with immune activation and the induction of inflammatory mediators and signalling pathways Putative therapeutic strategies specifically targeting chronic inflammation in atherosclerosis include classic anti-inflammatory drugs, biologic therapies targeting cytokines and chemokines, and small molecule enzyme inhibitors and receptor antagonists Inducing immune tolerance through vaccination against atherosclerosis-associated immunogens can potentially offer an additional strategy for protection against atherosclerosis Evidence in support of the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies to evaluate surrogate markers of disease activity Randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes are ongoing and might lead the way for additional therapeutic strategies Atherosclerosis is a chronic inflammatory disease of the arterial wall with multiple immune mediators implicated in its pathogenesis. Despite the wide range of anti-inflammatory drugs already in use to treat immune disorders, studies to determine whether anti-inflammatory therapies can improve cardiovascular outcomes are necessary before these treatments become a part of cardiovascular prevention. In this Review, Bäck and Hansson describe existing therapies in use for inflammatory diseases and explore the therapeutic potential of targeting immune activation in patients with atherosclerosis. The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes.

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder characterized by excessive heart rate increase on standing, leading to debilitating symptoms with limited therapeutic possibilities. Proteomics is a large-scale study of proteins that enables a systematic unbiased view on disease and health, allowing stratification of patients based on their protein background. The aim of the present study was to determine plasma protein biomarkers of POTS and to reveal proteomic pathways differentially regulated in POTS. We performed an age- and sex-matched, case–control study in 130 individuals (case–control ratio 1:1) including POTS and healthy controls. Mean age in POTS was 30 ± 9.8 years (84.6% women) versus controls 31 ± 9.8 years (80.0% women). We analyzed plasma proteins using data-independent acquisition (DIA) mass spectrometry. Pathway analysis of significantly differently expressed proteins was executed using a cutoff log2 fold change set to 1.2 and false discovery rate (p-value) of < 0.05. A total of 393 differential plasma proteins were identified. Label-free quantification of DIA-data identified 30 differentially expressed proteins in POTS compared with healthy controls. Pathway analysis identified the strongest network interactions particularly for proteins involved in thrombogenicity and enhanced platelet activity, but also inflammation, cardiac contractility and hypertrophy, and increased adrenergic activity. Our observations generated by the first use a label-free unbiased quantification reveal the proteomic footprint of POTS in terms of a hypercoagulable state, proinflammatory state, enhanced cardiac contractility and hypertrophy, skeletal muscle expression, and adrenergic activity. These findings support the hypothesis that POTS may be an autoimmune, inflammatory and hyperadrenergic disorder.

Introduction The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A 2 serves as substrate for the production of a group of lipid mediators known as the leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors. Discussion Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that leukotriene signaling in addition may be involved in the development of ischemic injury. Conclusion Both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process.

The G protein-coupled receptor GPR18, engaged by pro-resolving and cannabinoid-related lipid ligands, plays a vascular bed-specific protective role in endothelial function. The aim of the present study was to establish the vasoreactivity and passive biomechanical properties of the thoracic aorta and femoral artery of adult GPR18 knockout compared with wildtype mice, using ex vivo myography, arterial morphology, and immunohistochemistry. The results revealed heightened receptor-independent contractility, loss of prostanoid-dependent contractile responses, altered vascular smooth muscle cell (VSMC) calcium handling, and an attenuated stress–tension relationship in the thoracic aorta of GPR18 knockout mice. This phenotype was almost entirely reversed in the femoral artery, with attenuated receptor-independent contractility, unchanged VSMC calcium handling, and a heightened stress–tension relationship in GPR18 knockout mice. These vascular bed-specific differences highlight the need to consider tissue context in the development of GPR18-based vasculoprotective therapies for cardiovascular disease.

The most common cause for interventional valve treatment is aortic stenosis. A cardinal symptom of aortic stenosis is heart failure due to the increased load exerted on the left ventricle. However, the left ventricular load is not solely determined based on the degree of aortic stenosis but is also impacted by arterial stiffness. The combined load can be determined by valvulo-arterial impedance (Zva), which is associated with poor outcome in aortic stenosis. We recently demonstrated low measures of systemic arterial stiffness in patients with aortic stenosis, and that arterial stiffness was increased after surgical aortic valve replacement. The results indicated a masked arterial stiffness in aortic stenosis when using methods incorporating peripheral arterial segments. Available studies using several different methods to assess arterial stiffness in relatively small aortic stenosis cohorts examined before and after either surgical or transcatheter aortic valve replacement/intervention have generated contradictory results. In this commentary, we present a detailed literature review to explore how different methods and measures of arterial stiffness in aortic stenosis capture or not, a masked arterial stiffness in aortic stenosis and possible reasons for the observed results. Future studies validating a non-invasive reproducible method to assess arterial stiffness in aortic stenosis patients could potentially lead to an implementation in pre-interventional risk assessment for aortic stenosis.