Mechanisms of atherosclerosis

In this Review, Kemper and colleagues discuss the canonical and non-canonical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential new therapeutic strategies targeting the complement system for the prevention and treatment of atherosclerotic cardiovascular disease.

In this Review, Fredman and Serhan discuss the role of specialized pro-resolving mediators, a superfamily of endogenous signalling lipids that mediate resolution of inflammation processes in atherosclerosis, and appraise the therapeutic potential of specialized pro-resolving mediators for the prevention and treatment of atherosclerosis, and the resolution of uncontrolled vascular inflammation.

Macrophages in atherosclerotic plaques can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. In this Review, De Meyer and colleagues describe the various forms of programmed macrophage death in atherosclerosis and the potential therapeutic implications.

In this Review, Swirski and co-workers discuss how lifestyle factors modulate haematopoiesis and leukocyte migration in the context of cardiovascular homeostasis and disease, with particular focus on the role of the nervous system as the key executor connecting environmental influences to leukocyte behaviour.

In this Review, Riksen and colleagues discuss the molecular and cellular mechanisms of trained immunity, the activation of these mechanisms by cardiovascular risk factors, and how trained immunity might contribute to atherosclerosis and atherosclerotic cardiovascular disease. The authors also propose potential strategies for the therapeutic modulation of trained immunity in atherosclerotic cardiovascular disease.

In this Review, Jo and colleagues discuss blood flow-induced mechanisms involved in endothelial cell dysfunction and atherosclerosis, including the emerging concept of disturbed-flow-induced reprogramming of endothelial cells as a pro-atherogenic mechanism, and highlight the therapeutic potential of targeting of flow-sensitive genes, proteins and pathways.

In this Review, the authors describe the features of coronary artery vulnerable plaques as well as non-invasive and invasive diagnostic modalities that can be used to characterize them. They also discuss the prognostic utility of identifying vulnerable plaques and the best current approaches to manage these lesions, and highlight evidence gaps and future directions.

In this Review, Donato and colleagues discuss the cellular and molecular mechanisms that induce endothelial cell senescence. They also discuss how endothelial cell senescence causes arterial dysfunction and contributes to cardiometabolic diseases, and the potential therapeutic role of senolytic agents in eliminating senescent endothelial cells.

In this Review, the authors describe the mechanisms underlying lipopolysaccharide translocation from the gut to the systemic circulation and the ensuing low-grade endotoxaemia, discuss studies suggesting a role for low-grade endotoxaemia in atherothrombosis and cardiovascular complications, and highlight potential therapeutic strategies to improve gut permeability and eliminate low-grade endotoxaemia.

Sirtuins are NAD⁺-dependent deacetylase and deacylase enzymes that control important cellular processes, such as DNA damage repair, cellular metabolism and inflammation. In this Review, Grootaert and Bennett discuss the role of sirtuins in atherosclerosis and evaluate the therapeutic potential of agents designed to activate or inhibit sirtuin activity.

In this Review, Borén and colleagues provide an overview of the pathways involved in triglyceride-rich lipoprotein (TRL) assembly and intravascular processing, and discuss how the dysregulation of triglyceride transport can result in hypertriglyceridaemia.

In this Review, the authors provide an overview of the immune cells involved in atherosclerosis, discuss preclinical research and published and ongoing clinical trials assessing the therapeutic potential of targeting the immune system in atherosclerosis, highlight emerging therapeutic targets from preclinical studies and identify challenges for successful clinical translation.

In this Review, Tao and colleagues discuss the latest advances in nanoparticle-based imaging and therapeutic approaches targeting macrophages in atherosclerotic plaques, highlight opportunities for novel macrophage-targeting nanomedicines for atherosclerosis diagnosis and treatment, and provide solutions to challenges in this area to accelerate clinical translation.

In this Review, Mehta and Shapiro discuss the mechanisms by which apolipoproteins regulate lipoprotein metabolism and thereby influence vascular biology and atherosclerotic disease. Advances in the understanding of apolipoprotein biology and their translation into therapeutic agents to reduce the risk of cardiovascular disease are also highlighted.

In this Review, Fernandez and Giannarelli discuss how single-cell technologies can advance our understanding of the cellular and molecular composition of atherosclerotic plaques and how these approaches can guide the design of new, personalized immunotherapies and immune monitoring tools for the management of patients with atherosclerotic cardiovascular disease.

Fatty acids affect the pathogenesis of atherosclerosis, and accumulating evidence shows that fatty acids also modulate T cell functions and processes. This Review summarizes the effects of circulating fatty acids on the metabolism, activation, proliferation and polarization of T cells and how these changes influence the subsequent functions of T cells in the pathogenesis of atherosclerosis.

In this Review, Gotto and colleagues summarize the evolution of our understanding of HDL structure and function, current models of atheroprotection by HDL involving reverse cholesterol transport, and their identification of a correlation between the bioavailability of free cholesterol contained in HDL and atherogenesis.

Atherosclerotic plaque erosion is becoming an increasingly common characteristic of culprit lesions in acute coronary syndromes. In this Review, Fahed and Jang discuss the patient phenotype and the molecular characteristics in plaque erosion and provide their vision for a potential major shift in the management of patients with plaque erosion.

In this Review, Tyrrell and Goldstein discuss vascular intrinsic and extrinsic mechanisms of how ageing promotes atherosclerosis, including changes in myeloid cells, mitochondrial dysfunction, impaired mitophagy and elevated IL-6 levels. They propose future steps for research and potential therapeutic approaches for age-related atherosclerosis.

Accumulating evidence supports the critical role of T cells as drivers and modifiers of atherosclerosis. In this Review, Ley and colleagues describe the latest advances in our understanding of the role of T cell subsets in atherosclerosis, discuss the process of T cell homing to atherosclerotic plaques and highlight potential T cell-related therapies for atherosclerosis.

In this Review, Soehnlein and colleagues discuss the role of neutrophils in cardiovascular inflammation and repair, describing the effect of cardiovascular risk factors on neutrophil production and function, appraising the contribution of neutrophils to the different stages of atherosclerosis and its clinical manifestations, and highlighting the evolving therapeutic strategies for targeting neutrophil numbers, functional status and effector mechanisms.

This Review summarizes the role of transcription factors and epigenetic remodelling in modulating macrophage plasticity, provides an overview of the cooperative action of transcription factors and epigenetic modifiers controlling macrophage activation in the context of atherosclerosis and inflammation, and highlights the therapeutic potential of modulating transcription factor activity.

Clonal haematopoiesis of indeterminate potential (CHIP) commonly occurs as a result of mutations in transcriptional regulators and is associated with a doubling of the risk of atherosclerotic cardiovascular disease. Jaiswal and Libby propose that CHIP contributes to the increased inflammation seen in ageing and thereby explains some of the age-related risk of cardiovascular disease.

The shear stress generated by flowing blood has major effects on vascular function, with low shear stress promoting vascular dysfunction and atherosclerosis. This Review describes the latest findings on how endothelial cells decode complex shear stress environments to regulate physiological and pathophysiological responses, highlighting the role of pathways involved in embryonic development.

In this Review, Mallat and colleagues critically evaluate the studies on the origin, fate and functions of vascular smooth muscle cells (VSMCs) in atherosclerosis, highlighting the importance of developmental origin, clonal expansion and plasticity of VSMCs cells in atherosclerosis and summarizing the roles of VSMCs and VSMC-derived cells in plaque development and progression.

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.

Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. In this Review, Sage and colleagues discuss the spectrum of B cell involvement in dyslipidaemia and atherosclerotic plaque development.

Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role for this process in cellular lipid metabolism, including in atherogenic foam cells. Therefore, increasing lipophagy might be a therapeutic target to reverse lipid build-up in atherosclerosis.

IgM antibodies have gained much attention as risk markers of atherosclerotic cardiovascular disease, but the exact antigenic determinants and the full spectrum of functions remain to be defined. A better understanding of the potentially diverse nature of the antigens that they recognize will help to dissect the function of IgM in atherosclerosis.

Contemporary tools to predict cardiovascular risk lack accuracy on an individual-patient level. The use of single-cell RNA sequencing to identify specific leukocyte patterns might overcome some of these limitations, propelling us towards a precision medicine approach.

Excessive salt intake is a known risk factor for cardiovascular disease commonly associated with hypertension. However, we propose that a high-salt diet can promote cardiovascular and other diseases independently of high blood pressure through inflammatory pathways that increase the production of myeloid cells.

Clonal haematopoiesis of indeterminate potential (CHIP) is defined as an expansion of mutant blood stem cells in individuals without haematological malignancies. CHIP is linked to an increased risk of non-cancerous disorders such as atherosclerotic cardiovascular disease, possibly because mutant innate immune cells have pro-inflammatory phenotypes. Prospective studies are needed to determine whether individuals with CHIP might benefit from anti-inflammatory therapies.

The AIM2 inflammasome is activated by host and pathogen DNA. Work from the past 5 years indicates that the AIM2 inflammasome has an important role in advanced atherosclerosis driven by clonal haematopoiesis and possibly in atherosclerosis accelerated by acute infection. Therefore, the AIM2 inflammasome might be an important target for precision medicine.

Important lessons about human susceptibility to coronary atherosclerosis can be learned from the relative resilience of chimpanzees to coronary artery disease (CAD), despite their higher baseline plasma levels of LDL cholesterol and lipoprotein(a) than in humans. Evolutionary pressure and hyper-reactive T cells might have a role in the unique susceptibility of humans to CAD.

The soybean flavonoid genistein can attenuate cannabis-induced inflammation, oxidative stress and atherosclerosis by binding to and inhibiting cannabinoid receptor 1.

The adventitia of atherosclerotic arteries is innervated by efferent and afferent neurons that form neuroimmune cardiovascular interfaces and modulate disease progression; ablating the sympathetic innervation to these regions is a potential therapeutic strategy.

In patients with acute myocardial infarction, the addition of the PCSK9 inhibitor alirocumab to high-intensity statin therapy leads to a greater regression of atherosclerotic plaques in non-infarct-related arteries after 52 weeks than statin therapy alone, according to findings from the PACMAN-AMI trial.

Statins increase the rate of macrophage efferocytosis through suppression of the expression of the ‘don’t-eat-me’ molecule CD47 on atherosclerotic plaque apoptotic cells, and pro-efferocytic therapies amplify the anti-atherosclerotic effects of statin treatment in an additive manner and independently of any lipid-lowering effects of statins.

A new study shows that cardiovascular diseases remodel the bone marrow vasculature, inducing endothelial dysfunction, vascular leakage, fibrosis and angiogenesis and ultimately leading to overproduction of the inflammatory leukocytes implicated in these conditions.

Atherosclerosis causes myocardial infarction, ischaemic cardiomyopathy, many ischaemic strokes and jeopardized limbs. Despite enormous progress, atherosclerosis has become the major cause of death worldwide. This Comment intertwines clinical and basic advances in atherosclerosis to illustrate their interdependence, which provides a template for a way forwards to conquer the scourge of atherosclerotic cardiovascular disease.

Sequencing studies demonstrate a strong clinical association between clonal haematopoiesis driven by acquired mutations and atherosclerotic disease. Previous research supports the idea that this association reflects a direct contribution of some clonal haematopoiesis-related mutations to atherosclerosis. Now, mathematical modelling suggests that atherosclerosis could instead accelerate clonal haematopoiesis.

High levels of extracellular glucose induce trained immunity in macrophages, promoting a pro-atherosclerotic phenotype that persists even after normalization of glucose levels.

The CD200 inhibitory immune checkpoint promotes arterial homeostasis and reduces atherosclerotic plaque progression and inflammation in mice by limiting the excessive supply, recruitment and activation of monocytes and macrophages during atherogenesis, according to a new study.