SUR1-E1506K mutation impairs glucose tolerance and promotes vulnerable atherosclerotic plaque phenotype in hypercholesterolemic mice

Background and aims Diabetes is a major risk factor of atherosclerosis and its complications. The loss-of-function mutation E1506K in the sulfonylurea receptor 1 (SUR1-E1506K) induces hyperinsulinemia in infancy, leading to impaired glucose tolerance and increased risk of type 2 diabetes. In this study, we investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice. Methods SUR1-E1506K mutated mice were cross-bred with LDLR-/- mice (SUR1Δ/LDLR-/-), 6 months old mice were fed a western-diet (WD) for 6 months to induce advanced atherosclerotic plaques. At the age of 12 months, atherosclerosis and plaque morphology were analyzed and mRNA gene expression were measured from aortic sections and macrophages. Glucose metabolism was characterized before and after WD. Results were compared to age-matched LDLR-/- mice. Results Advanced atherosclerotic plaques did not differ in size between the two strains. However, in SUR1Δ/LDLR-/- mice, plaque necrotic area was increased and smooth muscle cell number was reduced, resulting in higher plaque vulnerability index in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice. SUR1Δ/LDLR-/- mice exhibited impaired glucose tolerance and elevated fasting glucose after WD. The positive staining area of IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice, and IL-18 plasma level was elevated in SUR1Δ/LDLR-/- mice. Finally, the mRNA expression of IL-1β and IL-18 were increased in SUR1Δ/LDLR-/- bone marrow derived macrophages in comparison to LDLR-/- macrophages in response to LPS. Conclusions SUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.

Imaging Inflammation in Patients and Animals: Focus on PET Imaging the Vulnerable Plaque

Acute coronary syndrome (ACS) describes a range of conditions associated with the rupture of high-risk or vulnerable plaque. Vulnerable atherosclerotic plaque is associated with many changes in its microenvironment which could potentially cause rapid plaque progression. Present-day PET imaging presents a plethora of radiopharmaceuticals designed to image different characteristics throughout plaque progression. Improved knowledge of atherosclerotic disease pathways has facilitated a growing number of pathophysiological targets for more innovative radiotracer design aimed at identifying at-risk vulnerable plaque and earlier intervention opportunity. This paper reviews the efficacy of PET imaging radiotracers 18F-FDG, 18F-NaF, 68Ga-DOTATATE, 64Cu-DOTATATE and 68Ga-pentixafor in plaque characterisation and risk assessment, as well as the translational potential of novel radiotracers in animal studies. Finally, we discuss our murine PET imaging experience and the challenges encountered.

The Emerging Role of CT-Based Imaging in Adipose Tissue and Coronary Inflammation

A large body of evidence arising from recent randomized clinical trials demonstrate the association of vascular inflammatory mediators with coronary artery disease (CAD). Vascular inflammation localized in the coronary arteries leads to an increased risk of CAD-related events, and produces unique biological alterations to local cardiac adipose tissue depots. Coronary computed tomography angiography (CTA) provides a means of mapping inflammatory changes to both epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) as independent markers of coronary risk. Radiodensity or attenuation of PCAT on coronary CTA, notably, provides indirect quantification of coronary inflammation and is emerging as a promising non-invasive imaging implement. An increasing number of observational studies have shown robust associations between PCAT attenuation and major coronary events, including acute coronary syndrome, and ‘vulnerable’ atherosclerotic plaque phenotypes that are associated with an increased risk of the said events. This review outlines the biological characteristics of both EAT and PCAT and provides an overview of the current literature on PCAT attenuation as a surrogate marker of coronary inflammation.

Non-invasive imaging of the vulnerable atherosclerotic plaque

Cardiovascular disease remains the leading cause of death globally despite advances in medical therapy and risk stratification; ischaemic heart disease was responsible for an estimated 9.5 million deaths in 2016. To address this ongoing global burden of morbidity and mortality, there is a need for more sophisticated methods of diagnosis and prognostication, above and beyond clinical risk scores alone. The majority of myocardial infarction occurs due to ruptured atherosclerotic plaque, leading to acute thrombosis and coronary occlusion. For decades, the concept of the vulnerable plaque—plaques prone to rupture or thrombotic complications—has been central to our understanding of the pathophysiology of acute coronary syndromes. More recently, there has been a shift towards identifying the vulnerable patient through assessment of total atherosclerotic disease burden, in recognition of the fact that most plaque rupture events do not lead to clinical events. Moreover, demonstrating a strong causal link between vulnerable plaques and clinical events has previously proven difficult due to limitations in available invasive and non-invasive imaging modalities. However, we now have an array of imaging techniques that hold great potential for the advancement of vulnerable plaque imaging. These modalities are the subject of state-of-the-art clinical research, aiming to develop the role of atherosclerotic plaque imaging in modern clinical practice and ultimately to improve patient outcomes.

Enzyme-activated probes in optical imaging: a focus on atherosclerosis

This perspective provides an overview of the design requirements and fluorogenic mechanisms of enzyme-activatable probes in optical imaging, focusing particularly on detecting enzymatic targets overexpressed in vulnerable atherosclerotic plaque.