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To mark the 10^th anniversary of Nature Reviews Cardiology, five of our Advisory Board members were invited to consider a topic within cardiology about which we know too little. The key opinion leaders from around the globe also suggest ways in which future research could be targeted to address the deficits in our understanding, with the aim of preventing cardiovascular disease, improving patient care, and reducing morbidity and mortality.

A large number of acute coronary syndrome (ACS) events originate from plaques with an intact fibrous cap (IFC). In this Review, Kanwar et al. provide an overview of the latest advances in our understanding of plaque morphology in ACS with IFC, reviewing contemporary data from multimodality imaging. They also discuss whether the use of such imaging might result in more effective management of patients with ACS.

The structural and temporal characteristics of atherosclerotic plaques differ between native coronary artery disease, vein-graft atherosclerosis, and in-stent neoatherosclerosis. In this Review, Yahagi et al. compare the shared and divergent morphological features, giving insight into the pathogenesis of atheroma formation, and provide an updated classification scheme for atherosclerotic lesions.

Quantitative assessment of plaque composition has not been possible with grayscale IVUS analysis—until now. Here König and coworkers examine intravascular ultrasonography-derived virtual histology, a method which can provide detailed analysis of plaque morphology, providing more information on the vulnerability of coronary plaques and, in turn, the risk of acute clinical events.

Arterial injury is an inevitable consequence of all interventional coronary procedures. In this Review, the authors explain the importance of a competent, functional endothelium for vascular health and describe the processes that are required for full endothelial recovery after arterial injury.

In this Review, Otsuka et al. describe how optical coherence tomography (OCT)—an intravascular imaging modality with high resolution—can be used to define various stages of plaque progression. The authors also highlight how OCT might be used in the identification of high-risk plaques vulnerable to rupture in patients with coronary disease, to enable pre-emptive interventional treatment, and how OCT might be used in the management of acute coronary syndromes.

Mokry et al. performed bulk RNA sequencing of 654 advanced human carotid plaques from the Athero-Express biobank and 162 coronary samples, and they show that unsupervised clustering defines plaque types corresponding to different cell compositions and clinical presentations. Circulating biomarkers can be potentially used to mark the different transcriptomic-defined plaque phenotypes.

Newman et al. explore the origins of myofibroblasts in atherosclerotic fibrous caps, finding that while composed of cells from multiple origins, smooth muscle cells predominate and are required for long-term plaque stability.

Platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs) promotes atherogenesis. Here, the authors show that mutant mice with increased PDGF activity in VSMCs have augmented STAT1-dependent chemokine signals resulting in artery wall inflammation and formation of advanced plaque morphologies clinically relevant in humans.

Optical coherence tomography (OCT) has been widely adopted in research on coronary atherosclerosis and adopted clinically to optimize percutaneous coronary intervention. In this Review, Jang and colleagues summarize this rapidly progressing field, with the aim of standardizing the use of OCT in coronary atherosclerosis.

The causes of progression from an asymptomatic fi broatheromatous lesion to a high-risk vulnerable plaque are not fully understood, but data suggest that intraplaque hemorrhage could be critical in this process. Here, Jainet al. focus on angiogenesis and intraplaque hemorrhage in atherosclerotic lesion progression. They discuss evidence for the role of antiangiogenic agents in normalizing the immature vasculature and examine the obstacles faced in testing their hypothesis both in preclinical models and in humans.

PET imaging using 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) has been widely used for the detection of plaque inflammation. Here, however, Nobuhiro Tahara and colleagues explore the possibility of using ¹⁸F-labeled mannose (2-deoxy-2-[¹⁸F]fluoro-d-mannose, [¹⁸F]FDM), a structural analog to FDG, as an alternative and potentially more specific PET tracer than FDG for assessing the risk of acute vascular events in patients. The approach targets the mannose receptor–bearing macrophages that are abundant in high-risk atherosclerotic plaques, with feasibility demonstrated in a rabbit model of atherosclerosis.

This Review outlines the drawbacks and lessons learned from first-generation drug-eluting stents, and then discusses design features and preclinical, pathology and clinical data from newer-generation devices. The authors focus on how evolution in stent design has improved biomaterial–blood interactions and vascular healing.

Fully bioresorbable scaffolds (BRS) were designed to overcome the limitations of metallic drug-eluting stents, but long-term results with these devices have been disappointing. In this Review, the authors discuss the available preclinical and clinical data for BRS and how this information can inform the development of next-generation BRS.

In many clinical trials, procedure-related myocardial infarctions are assigned a similar prognostic value to spontaneous myocardial infarctions. Robbert de Winter and colleagues argue that procedure-related myocardial infarctions do not necessarily have important prognostic implications, and that the recent definition of a procedure-related myocardial infarction, including a relevant biomarker increase and supporting evidence, needs to be closely followed.