Plaque rupture followed by intracoronary thrombus formation is recognized as the most common pathophysiological mechanism in acute coronary syndromes (ACS). The second most common underlying substrate for ACS is plaque erosion whose hallmark is thrombus formation without cap disruption. Invasive and non-invasive methods have emerged as a promising tool for evaluation of plaque features that either predict or detect plaque erosion. Optical coherence tomography (OCT), high-definition intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and near-infrared autofluorescence (NIRF) have been used to study plaque erosion. The detection of plaque erosion in the clinical setting, mainly facilitated by OCT, has shed light upon the complex pathophysiology underlying ACS not related to plaque rupture. Coronary computed tomography angiography (CCTA), which is to date the most commonly used non-invasive technique for coronary plaque evaluation, may also have a role in the evaluation of patients predisposed to erosion. Also, computational models enabling quantification of endothelial shear stress may pave the way to new research in coronary plaque pathophysiology. This review focuses on the recent imaging techniques for the evaluation of plaque erosion including invasive and non-invasive assessment.

Atherosclerosis is an underlying cause of a broad array of cardiovascular diseases characterized by plaques, arterial wall thickening initiated by hyperlipidemia, pro-inflammatory signals, endothelial dysfunction and the influx of inflammatory cells. By still incompletely characterized mechanisms, these plaques can destabilize or erode, leading to thrombosis and blood vessel occlusion and becomes clinically manifest as angina pectoris, myocardial infarction (MI) or stroke. Among the several blood cell types that are involved in the development of atherosclerosis, the role of platelets during the thrombotic occlusion of ruptured or eroded plaques is well established and clinically exploited as evident by the extensive use of platelet inhibitors. However, there is increasing evidence that platelets are also involved in the earlier stages of atheroma development by exhibiting pro-inflammatory activities. The scope of this review is to describe the role of platelets in the initiation and propagation stages of atherosclerosis and beyond; in atherothrombotic complications.

In this issue of Atherosclerosis, Ohgaku and colleagues1 performed an elegant observational study of 208 patients who received coronary angioscopy (CAS) 2 weeks following an ACS with DES stent implantation (2nd and 3rd generation everolimus-eluting DES). Interestingly, more than one-half of patients (59.6%) had evidence of in-stent thrombus (IS-thrombus) seen on CAS. In the 84 patients without IS-thrombus, higher rates of major bleeding were observed, irrespective of DAPT duration. MACE outcomes were similar with or without IS-thrombus, however higher rates of recurrent MI/unstable angina (p=0.06) were observed in those with IS-thrombus.

Background and aims The optimal duration of dual antiplatelet therapy for acute myocardial infarction is controversial because the bleeding risk outweighs the thromboembolic risk. We hypothesized that an in-stent thrombus (IS-thrombus) detected by coronary angioscopy (CAS) after stent implantation would be associated with high bleeding risk. Methods This study included 208 patients who underwent CAS at 2 weeks after stent implantation for an acute myocardial infarction. The study was approved by the ethics committee at the Nihon University Itabashi Hospital (reference number RK-200714-10). Results In 84 patients, in whom no IS-thrombus was identified in the culprit vessel using CAS, the major bleeding event rate was significantly higher than that in patients with IS-thrombi (n = 124). However, no difference was detected in major adverse cardiovascular events (MACE; stroke, hospitalization for a non-fatal myocardial infarction/unstable angina, target lesion revascularization, and cardiovascular death). After adjustments by the propensity score based on patient characteristics, the absence of IS-thrombi remained an independent predictor of major bleeding events (hazard ratio 4.73, 95% confidence interval 2.04–11.00, p < 0.001). Conclusions The absence of CAS-detected IS-thrombi in the subacute phase was independently associated with future major bleeding events, but not with MACE. These findings may help optimize the duration of dual antiplatelet therapy.

Background and aims There is extensive evidence from bone marrow transplantation studies that hematopoietic ATP binding cassette A1 (Abca1) is atheroprotective in low-density lipoprotein receptor (Ldlr) deficient mice. In contrast, studies using lysosyme M promoter-driven deletion of Abca1 in Ldlr deficient mice failed to show similar effects. It was hypothesized that the discrepancy between these studies might be due to the presence of Ldlr in bone marrow-derived cells in the transplantation model. In this study, we aim to determine the contribution of Ldlr to the atheroprotective effect of hematopoietic Abca1 in the murine bone marrow transplantation model. Methods Wild-type, Ldlr −/ −, Abca1 −/−, and Abca1 −/− Ldlr −/− bone marrow was transplanted into hypercholesterolemic Ldlr −/ − mice. Results Bone marrow Lldr deficiency did not influence the effects of Abca1 on macrophage cholesterol efflux, foam cell formation, monocytosis or plasma cholesterol. Ldlr deficiency did reduce circulating and peritoneal lymphocyte counts, albeit only in animals lacking Abca1 in bone marrow-derived cells. Importantly, the effects of Abca1 deficiency on atherosclerosis susceptibility were unaltered by the presence or absence of Ldlr. Bone marrow Ldlr deficiency did lead to marginally but consistently decreased atherosclerosis, regardless of Abca1 deficiency. Thus, Ldlr expression on bone marrow-derived cells does, to a minimal extent, influence atherosclerotic lesion development, albeit independent of Abca1. Conclusions This study provides novel insight into the relative impact of Ldlr and Abca1 in bone marrow-derived cells on macrophage foam cell formation and atherosclerosis development in vivo. We have shown that Ldlr and Abca1 differentially and independently influence atherosclerosis development in a murine bone marrow transplantation model of atherosclerosis.

Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of

Background and aims A first-time acute myocardial infarction (AMI) is a severe diagnosis that leads to initiation or intensification of lipid-lowering medication to prevent recurrent events. Individuals with familial hypercholesterolemia (FH) already use high-intensity lipid-lowering medication at the time of an incident AMI due to their diagnosis. Hence, we hypothesized that compared with matched non-FH controls, individuals with genetically verified FH have increased mortality and risk of recurrent AMI after their first event. Methods The study population comprised 4871 persons with genetically verified FH, and 96,251 age and sex matched controls randomly selected from the Norwegian population. Data were obtained from the Cardiovascular Disease in Norway Project, the Norwegian Patient Registry and the Norwegian Cause of Death Registry. Incidence of AMI, all-cause mortality and recurrent AMI after incident AMI were analyzed for the period 2001–2017. Incidence and mortality were compared using hazard ratios (HR) from Cox regression. Risk of recurrent AMI was compared using sub-hazard ratios (SHR) from competing risk regression with death as a competing event. Results We identified 232 individuals with FH and 2118 controls with an incident AMI [HR 2.10 (95% CI 1.83–2.41)]. Among survivors ≥29 days after the incident AMI, both mortality [HR = 1.45 (95% CI: 1.07–1.95)] and recurrent AMI [SHR = 2.53 (95% CI: 1.88–3.41)] were significantly increased among individuals with FH compared with non-FH controls. Conclusions Individuals with FH have increased mortality and increased risk of recurrent AMI after the first AMI event compared with controls. These findings call for intensive follow-up of individuals with FH following an AMI.

Background and aims Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. Methods Chow diet-fed atherosclerosis-prone Apoe -/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. Results We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. Conclusions Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

Background and aims Sex differences in cardiovascular prevention have been reported, yet the role of sex with regard to different modifiable risk factors such as low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (BP), and glycated hemoglobin (HbA1c) in primary care settings is unclear. Therefore, we studied sex differences in assessment and measured values of LDL-C, BP, and HbA1c in primary and secondary cardiovascular prevention delivered by general practitioners. Methods This cross-sectional study was based on electronic medical records of 59,092 primary care patients (51.9% women) aged 40-79 years in Switzerland. Multilevel regression was used to model associations of sex with assessment and measured values of LDL-C, BP, and HbA1c in 2018. Results In both primary and secondary prevention, women had lower LDL-C assessment rates (age-adjusted odds ratio (aOR) 0.71 [95% confidence interval (CI) 0.67 to 0.75] and 0.70 [CI 0.51 to 0.95]), and higher measured LDL-C values than men (age-adjusted difference 0.30 mmol/L [CI 0.25 to 0.35] and 0.28 mmol/L [CI 0.07 to 0.48]). Compared with men, women in primary prevention displayed lower BP and HbA1c assessment frequencies (aOR 0.77 [CI 0.73 to 0.81] and 0.76 [CI 0.71 to 0.80]) and measured values (age-adjusted difference -2.49 mmHg [CI -2.99 to -1.79] and -0.19% [CI -0.24 to -0.14]), while there was no sex difference in secondary prevention. Age-dependent increases in LDL-C, BP, and HbA1c were greater in women than men. Conclusions Control of LDL-C in women in primary care should be improved to reduce sex-based inequalities in prevention of cardiovascular disease.