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Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality worldwide. Several cardiovascular risk factors are implicated in atherosclerotic plaque promotion and progression and are responsible for the clinical manifestations of coronary artery disease (CAD), ranging from chronic to acute coronary syndromes and sudden coronary death. The advent of intravascular imaging (IVI), including intravascular ultrasound, optical coherence tomography and near-infrared diffuse reflectance spectroscopy has significantly improved the comprehension of CAD pathophysiology and has strengthened the prognostic relevance of coronary plaque morphology assessment. Indeed, several atherosclerotic plaque phenotype and mechanisms of plaque destabilization have been recognized with different natural history and prognosis. Finally, IVI demonstrated benefits of secondary prevention therapies, such as lipid-lowering and anti-inflammatory agents. The purpose of this review is to shed light on the principles and properties of available IVI modalities along with their prognostic significance. [ABSTRACT FROM AUTHOR]

Keywords: Air pollution; Plaque healing; Acute coronary syndromes; Thrombosis; Inflammation EN Air pollution Plaque healing Acute coronary syndromes Thrombosis Inflammation 2403 2405 3 07/11/23 20230707 NES 230707 Introduction Plaque healing plays a key role in coronary atherosclerosis[1] and represents "the second hit" required to cause an acute coronary syndrome (ACS) after plaque destabilization, this latter being the "first hit".[[1], [3]] Moreover, an impaired plaque healing has been found in patients with recurrent ACS, suggesting its importance in preventing repeated symptomatic coronary thrombosis.[3] Nonetheless, mechanisms modulating plaque healing are unknown. In first acute coronary syndrome patients, particulate matter 2.5 chronic exposure levels were similar between patients with and without healed plaques in the culprit lesion, while particulate matter 2.5 was higher in those with macrophage infiltration and thin-cap fibroatheroma at the culprit plaque. Among recurrent ACS patients, 6 patients (20.7%) had TCFA at the culprit lesion, and these patients had higher PM2.5 (17.9 ± 3.6 vs. 13.6 ± 3.4 I µ i g/m SP 3 sp , I P i = 0.030) and PM10 (28.8 ± 3.2 vs. 24.2 ± 3.9 I µ i g/m SP 3 sp , I P i = 0.014) exposure levels compared to those without TCFA. [Extracted from the article]

Endothelial erosion of atherosclerotic plaques is the underlying cause of approximately 30% of acute coronary syndromes (ACS). As the vascular endothelium is profoundly affected by the haemodynamic environment to which it is exposed, we employed computational fluid dynamic (CFD) analysis of the luminal geometry from 17 patients with optical coherence tomography (OCT)-defined plaque erosion, to determine the flow environment permissive for plaque erosion. Our results demonstrate that 15 of the 17 cases analysed occurred on stenotic plaques with median 31% diameter stenosis (interquartile range 28–52%), where all but one of the adherent thrombi located proximal to, or within the region of maximum stenosis. Consequently, all flow metrics related to elevated flow were significantly increased (time averaged wall shear stress, maximum wall shear stress, time averaged wall shear stress gradient) with a reduction in relative residence time, compared to a non-diseased reference segment. We also identified two cases that did not exhibit an elevation of flow, but occurred in a region exposed to elevated oscillatory flow. Our study demonstrates that the majority of OCT-defined erosions occur where the endothelium is exposed to elevated flow, a haemodynamic environment known to evoke a distinctive phenotypic response in endothelial cells. [ABSTRACT FROM AUTHOR]

Macrophages play a key role in coronary plaque destabilization. In-vitro human monocyte-derived macrophages (MDMs) are used to study macrophages infiltrating tissue. Optical coherence tomography (OCT) provides an in-vivo insight of the coronary arteries. We compared the MDMs morpho-phenotype and culprit plaque features at OCT in acute coronary syndrome (ACS) patients according to the underlying plaque pathobiology. Sixty-six patients undergoing coronary angiography and pre-angioplasty OCT of the culprit vessel were allocated to three groups according to mechanism of ACS at OCT and C-reactive protein levels (cut-off: 2 mg/Ll): 1) plaque rupture with systemic inflammation; 2) plaque rupture without systemic inflammation, 3) plaque with intact fibrous cap. A blood sample was collected to obtain MDMs, categorized as having "round" or "spindle" morphology. Thirty-two patients (48.5%) were assigned to Group 1, 10 (15.2%) to Group 2 and 24 (36.4%) to Group 3. The "round" MDMs were significantly more frequent in Group 1 (39.25 ± 4.98%) than in Group 2 (23.89 ± 3.10%) and Group 3 (23.02 ± 7.89%), p = 0.008. MDMs in Group 1 as compared to Groups 2 and 3 showed lower efferocytosis (8.74 ± 1.38 vs 9.74 ± 2.15 vs 11.41 ± 2.41; p = 0.012), higher tissue factor levels (369.84 ± 101.13 vs 301.89 ± 59.78 vs 231.74 ± 111.47; p = 0.001) and higher heme oxygenase-1 expression (678.78 ± 145.43 vs 419.12 ± 74.44 vs 409.78 ± 64.33; p = 0.008). MDMs of ACS patients show morpho-phenotypic heterogeneity with prevalence of pro-thrombotic and pro-oxidative properties in case of plaque rupture and systemic inflammation. Such MDMs subpopulation may take part to the cellular pathways leading to fibrous cap rupture with the subsequent thrombus formation. • Monocyte-derived macrophages to study macrophages infiltrating coronary plaques. • Optical Coherence Tomography to identify the mechanism of plaque destabilization. • Pro-thrombotic, oxidative macrophages are prevalent in ruptures with inflammation. [ABSTRACT FROM AUTHOR]

Patients with an acute coronary syndrome (ACS) due to plaque rupture had a worse prognosis when compared with those without plaque rupture with a higher rate of target vessel revascularization and readmission for unstable angina, suggesting that both stent failure and disease progression occur more frequently. However, it is not known whether recurrent episodes of coronary instability in the same patient are caused by the same pathogenetic mechanism. Thus, we sought to investigate the mechanisms of coronary instability imaged by optical coherence tomography in patients with recurrent ACS events. The present case series, with 4 patients having recurrent ACS, shows that the same mechanism of coronary instability is present during both first and recurrent instability. This hypothesis-generating finding may support further studies targeted at assessing the mechanisms of coronary instability recurrence and how to tailor preventive measures to the underlying mechanism of instability. [ABSTRACT FROM AUTHOR]

Abstract: Post-mortem observations demonstrated that plaque fissure was the final event leading to coronary thrombosis and occlusion in about two-thirds of cases of sudden coronary death. Plaques prone to fissure have, therefore, been defined “vulnerable plaques” and are identified by specific anatomic features including thin inflamed fibrous cap, large lipidic core and positive remodeling. Accordingly, elegant imaging modalities have been developed in order to identify this “holy grail”. However, the results of prognostic studies based on the identification of vulnerable plaques have not been encouraging because of the low positive predictive value for major cardiovascular events. This observation is not surprising as the pathogenesis of acute coronary syndromes is complex and multifactorial. In this review we propose a pathogenetic classification of acute coronary syndromes in the attempt to identify homogeneous groups of patients with a common mechanism of coronary instability which can be identified by using specific biomarkers and imaging techniques, and become a specific therapeutic target. [Copyright &y& Elsevier]

Abstract: Aims: Coronary atherosclerosis is a chronic inflammatory disease, but different inflammatory biomarkers may reflect different phases of atherosclerotic plaque evolution. We aimed at assessing the role of eosinophil cationic protein (ECP), a sensitive marker of eosinophil activation, and C-reactive protein (CRP) in coronary artery disease (CAD). Methods and results: Consecutive anginal patients with angiographic evidence of CAD [stable angina (SA) or non-ST-elevation acute coronary syndrome (NSTE-ACS)], or with angiographically normal coronary arteries (NCA) were enrolled. The severity of CAD was graded according to Bogaty''s score and coronary lesion morphology was defined as smooth or complex. Baseline ECP and high sensitivity CRP were measured in all patients. Of 198 patients (64±10 years, male 74%), 91 had SA, 57 had NSTE-ACS and 50 had NCA. ECP levels were significantly higher in SA [30μg/L (13.8–46.9), p <0.001] and NSTE-ACS [21.8μg/L (5.5–46.3), p =0.016] compared to NCA [9.7μg/L (6.1–13.6)], without significant difference between SA and NSTE-ACS (p =0.45). CRP levels were significantly higher in NSTE-ACS [2.38mg/L (1.11–11.94)] compared to SA [1.48mg/L (0.82–2.83), p =0.03], and NCA [1.09mg/L (0.8–2.1), p <0.001], without significant difference between SA and NCA (p =0.20). The addition of ECP to main cardiovascular risk factors improved the area under the curve from 0.88 to 0.92, p =0.007 for the angiographic diagnosis of CAD; further addition of CRP increased the area to 0.94, p =0.014. At multiple linear regression analysis ECP levels independently predicted CAD severity (p =0.001), whereas CRP levels independently predicted lesion complexity (p =0.01). Conclusions: Our study shows that ECP is a marker of CAD and that different inflammatory biomarkers reflect different phases of atherosclerotic plaque evolution. [Copyright &y& Elsevier]

Abstract: Background: Cytotoxin-associated gene-A (CagA) antigen is expressed by some virulent strains of Helicobacter pylori (H. pylori). The role of CagA antigen in coronary instability is unknown. We performed a clinico-pathological study and a meta-analysis in the attempt to shed new light on this complex issue. Methods: In the clinico-pathological study, 38 patients with unstable angina (UA), 25 patients with stable angina (SA), 21 patients with normal coronary arteries (NCA) and 50 age and sex matched healthy volunteers were enrolled. Serology for CagA was assessed in all patients. Specimens of atherosclerotic plaques were obtained from all patients by directional coronary atherectomy, and prepared for immunohistochemistry using anti-CagA monoclonal antibodies. The meta-analysis includes 9 studies assessing the association between seropositivity to CagA strains and acute coronary events. Results: The titre of anti-CagA antibodies was significantly higher in patients with unstable angina (161±90RU/ml) compared to those with stable angina (83±59RU/ml p <0.02), NCA (47.3±29RU/ml p <0.01) and healthy controls (73±69 p <0.02). Anti-CagA antibodies recognized antigens localized inside coronary atherosclerotic plaques in all specimens from both stable and unstable patients. In the meta-analysis, seropositivity to CagA was significantly associated with the occurrence of acute coronary events with an odds ratio (OR) of 1.34 (95% CI, 1.15–1.58, p =0.0003). Conclusions: Taken together these findings suggest that in a subset of patients with unstable angina, an intense immune response against CagA-positive H. pylori strains might be critical to precipitate coronary instability mediated by antigen mimicry between CagA antigen and a protein contained in coronary atherosclerotic plaques. [Copyright &y& Elsevier]

Coronary artery disease (CAD) patients are at high ischemic risk, and new biomarkers reflecting atherosclerotic disease severity and coronary plaque vulnerability are required. The Brain-Derived Neurotrophic Factor (BDNF) affects endothelial and macrophage activation suggesting its involvement in atherosclerotic plaque behavior. To investigate whether plasma BDNF is associated with in vivo coronary plaque features, assessed by optical coherence tomography (OCT), in both acute myocardial infarction (AMI) and stable angina (SA) patients, we enrolled 55 CAD patients (31 SA and 24 AMI), and 21 healthy subjects (HS). BDNF was lower in CAD patients than in HS (p < 0.0001), and it decreased with the presence, clinical acuity and severity of CAD. The greater BDNF levels were associated with OCT features of plaque vulnerability in overall CAD as well as in SA and AMI patients (p < 0.03). Specifically, in SA patients, BDNF correlated positively with macrophages' infiltration within atherosclerotic plaque (p = 0.01) and inversely with minimal lumen area (p = 0.02). In AMI patients a negative correlation between BDNF and cap thickness was found (p = 0.02). Despite a small study population, our data suggest a relationship between BDNF and coronary plaque vulnerability, showing that vulnerable plaque is positively associated with plasma BDNF levels, regardless of the clinical CAD manifestation. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) induce nuclear factor erythroid 2–related factor 2 (Nrf2) activation as an adaptive defense mechanism, determining the synthesis of antioxidant molecules, including heme-oxygenase-1 (HO-1). HO-1 protects cells against oxidative injury, degrading free heme and inhibiting ROS production. HO-1 is highly expressed in macrophages during plaque growth. Macrophages are morpho-functionally heterogeneous, and the prevalence of a specific phenotype may influence the plaque fate. This heterogeneity has also been observed in monocyte-derived macrophages (MDMs), a model of macrophages infiltrating tissue. The study aims to assess oxidative stress status and Nrf2/HO-1 axis in MDM morphotypes obtained from healthy subjects and coronary artery disease (CAD) patients, in relation to coronary plaque features evaluated in vivo by optical coherence tomography (OCT). We found that MDMs of healthy subjects exhibited a lower oxidative stress status, lower Nrf2 and HO-1 levels as compared to CAD patients. High HO-1 levels in MDMs were associated with the presence of a higher macrophage content, a thinner fibrous cap, and a ruptured plaque with thrombus formation, detected by OCT analysis. These findings suggest the presence of a relationship between in vivo plaque characteristics and in vitro MDM profile, and may help to identify patients with rupture-prone coronary plaque. [ABSTRACT FROM AUTHOR]

Air pollution is emerging as an important risk factor for acute coronary syndrome (ACS). In this study, we investigated the association between short-term air pollution exposure and mechanisms of coronary plaque instability evaluated by optical coherence tomography (OCT) imaging in ACS patients. Patients with ACS undergoing OCT imaging were retrospectively selected. Mechanism of culprit lesion instability was classified as plaque rupture (PR) or intact fibrous cap (IFC) by OCT. Based on each case's home address, the mean daily exposures to several pollutants, including particulate matter 2.5 (PM 2.5), on the same day of ACS and in the immediate days (up to 6 days) prior to the index ACS, were collected. 139 ACS patients were included [69 (49.6%) had PR and 70 (50.4%) IFC]. Patients with PR, compared to those with IFC, had higher PM 2.5 exposure levels on the same day of ACS, without differences in the immediate 6 days before index ACS. At multivariate analysis, PM 2.5 exposure on the same day of ACS was the only independent predictor of PR [OR = 1.912 per SD (8.6 μg/m3), CI95 % (1.087–3.364), p = 0.025]. Patients with PR presented a steady increase in PM 2.5 daily exposure levels in the days preceding the occurrence of ACS, with a peak the day of ACS (p for trend = 0.042) This study demonstrates for the first time that a higher short-term PM2.5 exposure, on the same day of ACS, is associated with an increased risk of PR as a pathobiological mechanism of coronary plaque instability. [Display omitted] • Air pollution is emerging as an important risk factor for acute coronary syndrome (ACS). • Acute PM 2.5 exposure, especially on the same day of ACS, is associated with an increased risk of plaque rupture as mechanism of coronary plaque instability. • Mitigation strategies are crucial to reduce the burden of ischemic heart disease, especially in patients with a higher risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is the leading cause of disability and death in both women and men; considerable differences in clinical presentation, natural history and prognosis are reported between sexes. Different pathophysiological mechanisms play a major role, including sex-related and gender-related features or a combination of both. Reports from intracoronary imaging studies pointed towards morphological plaque features, which seemed to differ between men and women, albeit results reported so far were not conclusive. The purpose of this review is to shed light on differences in the pathophysiology underlying CAD in women vs men including the description of coronary plaque phenotype and mechanisms of plaque instability, as assessed by intracoronary imaging. We will also discuss potential clinical implications with the aim to move towards a sex and gender-based personalized approach in CAD patients. [Display omitted] • Women develop CAD later, as compared to men, and experience worse prognosis. • Sex- and gender-related features are implicated in differences in CAD between sexes. • Intracoronary imaging pointed out differences in plaque phenotype and mechanisms of plaque instability between sexes. • Biological and psychosocial characteristics lead to an accelerated atherosclerosis in women with aging. • A broader and targeted therapeutic approach is required in women with CAD. [ABSTRACT FROM AUTHOR]

Abstract Background A sizeable proportion of patients with Acute Coronary Syndromes (ACS) shows a unique adaptive immune system profile, associated to a worse outcome, characterized by higher CD4+CD28null T-cells, lower regulatory T-cells (Treg) and increased CD4+CD28null/Treg ratio. We sought to investigate the correlation between CD4+CD28null T-cells, Treg, CD4+CD28null/Treg ratio and plaque phenotype as assessed by Optical Coherence Tomography (OCT). Methods Peripheral blood mononuclear cells (PBMC) were collected from 30 Non-ST Elevation Myocardial Infarction (NSTEMI) patients, sub-grouped according to OCT analysis of culprit lesions into two cohorts: Ruptured Fibrous Cap (NSTEMI-RFC, n = 12) and Intact Fibrous Cap (NSTEMI-IFC, n = 18). Stable Angina patients (SA, n = 18) were used as controls. We examined the frequency of CD4+CD28null and Treg (defined as CD4+CD25highCD127lowFoxp3+ T-cells) by flow-cytometry. Results CD4+CD28null frequency (median, range) was significantly higher in NSTEMI-RFC patients (17.3%, 12.5–33.8) as compared with NSTEMI-IFC (3.8%, 0.3–14.1) and SA (3%, 0.6–17.7) (P < 0.001 for all comparisons). We also found a higher CD4+CD28null/Treg ratio in NSTEMI-RFC patients (6.6%, 3.7–13.9) than in NSTEMI-IFC (1.6%, 0.3–5.2) and SA (1.2%, 0.3–8.7) (P < 0.001 for all comparisons). Finally, there was an inverse correlation between CD4+CD28null/Treg ratio and cap-thickness (R = −0.44; P = 0.002). Conclusion Patients with NSTEMI presenting with RFC as culprit lesion at OCT evaluation have a specific perturbation of adaptive immunity, mostly involving CD4+CD28null T- cells and Tregs, as compared with patients with IFC and SA. This specific imbalance of T-cells might play a key role in fibrous cap thinning, predisposing atherosclerotic plaque to rupture. Highlights • Plaque rupture at OCT evaluation is associated to a specific adaptive immune system signature. • A deeper perturbation of adaptive immunity might be involved in fibrous cap thinning. • Molecular and morphological plaque phenotyping might be a new frontier for personalized medicine. [ABSTRACT FROM AUTHOR]