Volume 255 Issue December 2016
By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).
The December 2016 issue of Atherosclerosis contains several articles of authors who investigated the determinants and secular trends of atherosclerotic plaque composition by applying either microscopic techniques to ex vivo material or in vivo imaging techniques in patients. Five examples are summarized below.
Focal adhesions (FA) play an important role in tissue remodelling and in the maintenance of tissue integrity and homeostasis. Talin and vinculin are among the major proteins of FAs, contributing to cellular well-being and intercellular communication.
Von Essen and colleagues conducted microarray analysis and qRT-PCR low-density array to assess talin-1, talin-2, meta-vinculin and vinculin gene expression in circulating blood and arterial plaque. They found that these genes were significantly and consistently downregulated in plaques (carotid, abdominal aortic and femoral regions) compared to the left internal thoracic artery (LITA) control. Even though differences in expression levels between stable and unstable plaques were not statistically significant, a further negative tendency in gene expression in unstable atherosclerotic plaques was observed. The confocal tissue imaging revealed a gradient of talin-1 expression in plaque, with reduction close to the vessel lumen. A similar gradient was observed for talin-2 expression in LITA controls, but not in plaques. This suggests that impaired tissue mechanostability affects tissue remodelling and healing capabilities, leading to development of unstable plaques.
The authors speculated that downregulation of talin and vinculin genes lead to loosening of cell-extracellular matrix interactions and remodelling of the tissue.
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis with an increasing incidence worldwide and associated with high morbidity and mortality risks. Previous research in carotid arteries indicates that atherosclerotic plaque characteristics have stabilized over time in patients considered for surgery.
However, it is currently unknown whether this time-dependent stabilization occurs in ilio-femoral arteries as well.
Haitjema and collaborators assessed whether local ilio-femoral atherosclerotic plaque characteristics have changed over time. They analysed 497 patients within the Athero-Express biobank, who underwent primary endarterectomy of the iliac or femoral arteries between 2002 and 2013. They investigated six histological plaque characteristics: calcification, collagen, fat content, intraplaque haemorrhage, macrophages and smooth muscle cells. Over the course of 10 years, the authors observed a lower percentage of all plaque characteristics considered as indicators of a vulnerable plaque: when the two-year cohorts 2003–2004 and 2011–2012 were compared, plaques with a large lipid core and intraplaque haemorrhage decreased from 37.9% to 14.9% and from 69.0% to 34.8%, respectively. Multivariable analyses showed that time-dependent changes occurred independently of changing procedural and patient characteristics.
In conclusion, in peripheral arterial disease patients undergoing primary endarterectomy, a time-dependent shift of plaque characteristics towards a less lipid-rich lesion, with less intraplaque haemorrhage, was observed. These findings suggest that research in cardiovascular disease would benefit from up-to-date patient characteristics and plaque specimens, with the aim of optimizing translational potential.
Monocytes are known to play a key role in the initiation and progression of atherosclerosis and contribute to plaque destabilization through the generation of signals that promote inflammation and neoangiogenesis. Clinical studies investigating the features of circulating monocytes in patients with advanced atherosclerotic lesions are lacking.
Ammirati and colleagues analysed patients with intermediate asymptomatic carotid stenosis (40–70% in diameter) for maximal stenosis in common carotid artery, carotid bulb and internal carotid artery, and overall disease burden, as estimated by total plaque area, greyscale and neovascularization in 244 advanced carotid plaques. Absolute counts of circulating CD14+ monocytes, classical (CD14highCD16−), intermediate (CD14highCD16+) and non-classical (CD14lowCD16+) monocytes and HLA-DR+ median fluorescence intensity for each subset were assessed with flow cytometry. Monocyte numbers correlated with neither overall atherosclerotic burden, nor high sensitivity C-reactive protein (hsCRP) nor interleukin-6 (IL-6) plasma levels. By contrast, plaque signs of neovascularization were associated with significantly lower counts of circulating CD14+ monocytes and classical monocytes. The results showed that neovascularized atherosclerotic lesions selectively associate with lower blood levels of CD14+ and CD14highCD16− monocytes independently of systemic inflammatory activity, as indicated by normal hsCRP levels. Whether the reduction of circulating CD14+ and CD14highCD16− monocytes is due to a potential redistribution of these cell types into active lesions remains to be explored.
The authors emphasize the need of further in-depth studies investigating monocyte-subset compositions in relation to other disease markers over longer periods, in patients at risk, to determine the prognostic value of this cell type. In their editorial, Gostner and Fuchs compared the work by Ammirati with some other recently published studies on monocytes subsets and highlighted the inconsistency of previous results depending on whether markers for neovascularization, plaque instability or prediction of cardiovascular events are used to calculate associations.
Diabetes mellitus is a well-known risk factor for coronary artery disease (CAD).
Nakanishi and colleagues investigated whether diabetes is associated with progression in coronary plaque components. To this aim, they analysed 142 study subjects undergoing serial coronary computed tomography angiography. The resulting propensity score was applied 1:1 to match diabetic patients to non-diabetic patients for clinical risk factors, prior coronary stenting, coronary artery calcium (CAC) score and the serial scan interval, resulting in 71 diabetic and 71 non-diabetic patients, respectively. Coronary plaque (total, calcified, non-calcified including fibrous, fibrous-fatty and low attenuation plaque (LAP)) volume normalized by total coronary artery length was measured using semi-automated plaque software and its change overtime between diabetic and non-diabetic patients was evaluated. The authors found that the matching was successful without significant differences between the two groups in all matched variables. In addition, baseline volumes in each plaque did not differ. During a mean scan interval of 3.4 ± 1.8 years, diabetic patients showed a 2-fold greater progression in normalized total plaque volume (TPV) than non-diabetic patients. Multivariable linear regression model revealed that diabetes was associated with normalized TPV progression. A similar trend was observed for non-calcified components, but not for the calcified plaque. Higher baseline CAC score was found to be associated with total, non-calcified and calcified plaque progression. However, baseline non-calcified volume, but not CAC score, was associated with LAP progression.
In conclusion, this study among matched patients indicates that diabetes is associated with a greater plaque progression. These results suggest the need for strict adherence of diabetic patients to the current preventive guidelines.
Information on determinants of plaque burden and lumen volume in the general population remains scarce. In addition, it is still unclear how (vulnerable) plaque components relate to overall plaque burden and lumen reduction.
In a large stroke-free population, Selwaness and collaborators aimed to identify cardiovascular risk factors and carotid plaque components associated with carotid plaque burden, lumen volume and stenosis. To this purpose, the carotid arteries of 1562 stroke-free participants from The Rotterdam Study were imaged with a 1.5-Tesla MRI scanner. Inner and outer walls of the carotid arteries were automatically segmented and lumen volume, wall volume, and plaque burden were quantified. Plaque components were visually determined and luminal stenosis was assessed. Regression analysis was used to study the association of cardiovascular risk factors and carotid plaque components with plaque burden and lumen volumes. The analysis of 2821 carotid plaques showed that women had larger plaque burden and smaller lumen volumes than men. In women, age, HDL-cholesterol and systolic blood pressure, and in men, total cholesterol, non-HDL cholesterol and statin use were independently associated with higher plaque burden and lumen volume, respectively. Furthermore, smoking and diabetes were associated with lumen volume in men. Intraplaque hemorrhage (IPH) and lipid were related to a larger plaque burden. Finally, within the highest quartile of plaque burden, IPH was strongly associated with luminal stenosis independent of age, sex, plaque burden and composition.
In conclusion, the authors found that several cardiovascular risk factors and plaque components, in particular IPH, are associated with higher plaque burden. Carotid IPH is strongly associated with an increased luminal stenosis.
In his editorial, J.D Spence further comments on the results obtained in the study and highlights advantages and disadvantages of MRI in the determination of plaque composition.