Highlighted articles Atherosclerosis May 2016 Issue
18 May 2016
Posted by: Charlotta Johansson
Volume 248 Issue May 2016
By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief)
In atherosclerotic lesions, cholesterol-laden macrophage foam cells are formed and exposed to M1- and M2-polarizing factors. Da Silva et al. investigated the effects of M1- and M2-polarizing factors on the expression of pro- and anti-inflammatory genes in cultured human macrophage foam cells. To this purpose, human monocytes were differentiated into macrophages in the presence of M-CSF, and then converted into cholesterol-laden foam cells by incubation with acetylated LDL. The generated macrophages and foam cells were then polarized into the M1 phenotype by classical activation with LPS and IFN-γ, or into the M2 phenotype by alternative activation with IL-4. The authors showed that macrophages exposed to M1-polarizing factors responded by typical upregulation of several key proinflammatory genes (TNFA, IL1B, CXCL8, CCL19, and COX2), while the anti-inflammatory genes (MRC1, CCL17, and IL10) displayed variable responses.
The foam cells, again, showed a weaker response to the M1-polarizing factors, as indicated by reduced upregulation of the proinflammatory genes, reduced secretion of TNF-α, and a trend towards lower NF-κB activity. Macrophages and foam cells, undergoing alternative M2 polarization, responded by a typical upregulation of the anti-inflammatory genes, which was of equal magnitude in both cell types.
In conclusion, conversion of cultured human macrophages into foam cells suppressed their pro-inflammatory responses to M1-polarizing factors. Thus, in the M1-polarizing microenvironment of atherosclerotic lesions, foam cell formation may locally weaken the macrophage-dependent inflammatory component of atherogenesis.
Experimental studies have suggested that proprotein convertase substilisin/kexin type 9 (PCSK9) directly promotes inflammatory processes contributing to atherosclerosis by mechanisms independent of low-density lipoprotein (LDL) cholesterol levels.
Cheng et al. investigated the association between serum PCSK9 levels and the fraction and amount of necrotic core tissue in coronary atherosclerotic plaques, as assessed by intravascular ultrasound virtual histology (IVUS-VH) imaging.
Between 2008 and 2011, IVUS-VH imaging of non-culprit coronary arteries was performed in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina. PCSK9 concentrations were measured in serum samples obtained prior to coronary angiography. None of the patients received PCSK9 inhibitors.
After adjustment for established cardiac risk factors, statin use and serum LDL cholesterol, serum PCSK9 levels were directly associated with the fraction of plaque consisting of necrotic core tissue and with the absolute volume of necrotic core tissue, but not with plaque burden, plaque volume or the presence of IVUS-VH-derived thin-cap fibroatheroma lesions.
In conclusion, the association of serum PCSK9 levels with the fraction and amount of necrotic core tissue in coronary atherosclerosis, independently of serum LDL cholesterol levels and statin use, suggests PCSK9 as an interesting therapeutic target for the treatment of atherosclerotic disease beyond lowering of LDL cholesterol.
Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques generating pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. López-Melgar and collaborators determined the accuracy of 3DVUS for plaque volume measurement with special emphasis on small plaques, which is a hallmark of early atherosclerosis. The in vitro study was performed on nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface. The volumes determined by 3DVUS were compared with the real phantom volumes. The in vivo study was performed in a rabbit model of atherosclerosis, in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements.
Homozygous familial hypercholesterolaemia (HoFH) is a rare disorder usually caused by mutations in both alleles of the low-density lipoprotein receptor gene (LDLR). Premature death, often before the age of 20 years, was a common fate for patients with HoFH prior to the introduction of statins in 1990 and the use of lipoprotein apheresis. Consequently, HoFH has been widely considered a condition restricted to a population comprising very young patients, with extremely high LDL cholesterol (LDL-C) levels. However, recent epidemiologic and genetic studies have shown that the HoFH patient population is far more diverse in terms of age, LDL-C levels, and genetic aetiology than previously thought.
In the in vitro setting, 3DVUS measures and real phantom volume correlated strongly, both for small and medium-large phantoms embedded superficially, but only moderately when phantoms were placed at >5 cm. In the in vivo setting, there was a strong correlation between 3DVUS-measured plaque volumes and the histological gold standard. Conversely, the correlation between 2D/3D values and the histological gold standard was weaker, with large dispersion of the differences between measurements in Bland-Altman plots.
Taking these results into account, the authors concluded that 3DVUS, using the volumetric-linear array method, represents an accurate measure of plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories.
Raal and colleagues investigated the clinical characteristics of 167 patients with HoFH from three recent international studies. The age of the patients ranged from 1 to 75 years, and a large proportion of them, both treated and untreated, exhibited LDL-C levels below the recommended clinical diagnostic threshold for HoFH, regardless the LDLR mutation status.
The authors concluded that HoFH is not restricted to very young patients or patients with extremely high LDL-C levels.
As highlighted in the accompanying commentary by Raul D. Santos, HoFH is more heterogeneous than previously thought. This heterogeneity and phenotypic overlap with heterozygous familial hypercholesterolaemia (HeFH) is important for clinical management. The phenotype rather than the genotype should be the physicians' main concern, and those subjects with the most severe phenotype should be more aggressively treated.