Individual Atherosclerotic Plaques Research Articles

Evolving understanding of the heterogeneous natural history of individual coronary artery plaques and the role of local endothelial shear stress.

Anatomic and morphologic features of high-risk coronary plaque have been identified by novel imaging modalities, but it has been less clear which ostensibly high-risk plaques will actually destabilize and cause a new cardiac event. Different plaques with different morphologies coexist within the same artery, but the impact of this heterogeneity on the natural history of coronary artery disease has not been extensively investigated. Coronary plaques exhibit remarkable heterogeneity of local morphological and blood-flow patterns, including endothelial shear stress (ESS), along their longitudinal axis, with important implications for the heterogeneous natural history of coronary disease. The natural history of individual plaques is considerably divergent, with most plaques, even ostensibly high-risk plaques, becoming quiescent and only a minority progressing to destabilize and precipitate a new clinical event. Local areas of proinflammatory low ESS appear to be an important condition for plaque destabilization. Characterization of an individual atherosclerotic plaque based on a snapshot of morphological features at a specific location, such as the minimal lumen diameter, may not be sufficiently comprehensive to accurately reflect the risk associated with that plaque. A detailed assessment of both anatomical and functional pathobiologic characteristics in the longitudinal plaque dimension may enhance our understanding of atherosclerosis progression and improve the management of individual patients with coronary artery disease.

Abstract 220: Deficiency in Triggering Receptor Expressed in Myeloid Cells-1 Substantially Attenuates Atherosclerotic Lesion Development

TREM-1 is a potent amplifier of pro-inflammatory responses in myeloid cells. While the significance of TREM-1 in acute microbial-induced septic shock has long been acknowledged, our previous studies in experimental models of colitis have also suggested an important role for TREM-1 in driving non-infectious and chronic inflammatory diseases. Here, we aim to define the role of TREM-1 in atherosclerosis, which is recognized as a chronic inflammatory disorder of the arteries with a major involvement of monocytes and macrophages. TREM-1-deficient (Trem1-/-) mice were backcrossed with apolipoprotein E-deficient (Apoe-/-) mice and were fed a high cholesterol/fat diet for 16 weeks. Compared with Trem1+/+ Apoe-/- mice, Trem1-/- Apoe-/- mice were substantially protected from diet-induced atherosclerosis. Interestingly, while the number of individual atherosclerotic plaques did not differ between the two groups of mice, the average lesion size and total surface area of atherosclerotic lesions were significantly reduced in Trem1-/- Apoe-/- mice. Moreover, analysis of early atherosclerotic lesions revealed no difference between the two groups. Hence, TREM-1 appears to be involved in the progression, rather than the initiation of atherosclerotic lesions. In line with the reduced lesion size, FACS analysis of aortic cell preparations revealed substantially lower frequencies of infiltrating CD11b+ myeloid cells in Trem1-/- Apoe-/- mice. To gain insight into the underlying mechanisms of TREM-1-mediated effects in atherogenesis, we are currently analyzing mRNA expression profiles of aortic segments derived from Trem1+/+ Apoe-/- and Trem1-/- Apoe-/- mice. These studies will be complemented by immunohistochemistry stainings and by in vitro studies that are aimed to directly determine the impact of TREM-1 on foam cell generation and cholesterol efflux.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

The role of low endothelial shear stress in the conversion of atherosclerotic lesions from stable to unstable plaque.

Local hemodynamic factors are major determinants of the natural history of individual atherosclerotic plaque progression in coronary arteries. The purpose of this review is to summarize the role of low endothelial shear stress (ESS) in the transition of early, stable plaques to high-risk atherosclerotic lesions. Low ESS regulates multiple pathways within the atherosclerotic lesion, resulting in intense vascular inflammation, progressive lipid accumulation, and formation and expansion of a necrotic core. Upregulation of matrix-degrading proteases promotes thinning of the fibrous cap, severe internal elastic lamina fragmentation, and extracellular matrix remodeling. In the setting of plaque-induced changes of the local ESS, coronary regions persistently exposed to very low ESS develop excessive expansive remodeling, which further exacerbates the proinflammatory low ESS stimulus. Recent studies suggest that the effect of recognized cardioprotective medications may be mediated by attenuation of the proinflammatory effect of the low ESS environment in which a plaque develops. Low ESS determines the severity of vascular inflammation, the status of the extracellular matrix, and the nature of wall remodeling, all of which synergistically promote the transition of stable lesions to thin cap fibroatheromata that may rupture with subsequent formation of an occlusive thrombus and result in an acute coronary syndrome.

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Introduction Thrombomodulin (TM) is an important anti-coagulant protein that is down-regulated on endothelial cells overlying atherosclerotic plaques. We investigated the effects of the peroxisome proliferator-activated receptor (PPAR) ligands, fenofibrate and rosiglitazone, on the expression of TM ex vivo by advanced carotid atheromas, and in vitro by endothelial cells. Methods Adjacent carotid atheroma biopsies were incubated in vehicle control or PPAR ligand in explant culture for 4 days. Human aortic endothelial cells were incubated with PPAR ligands in vitro. TM expression was measured by Western blotting and flow cytometry. TM activity was assessed by generation of activated protein C. Results The PPAR-α activator, fenofibrate, up-regulated total TM expression within carotid explants by 1.7-fold ( P < 0.001) with no effect on activity. Rosiglitazone treatment had no effect on protein levels but reduced activity by 73% of the control ( P < 0.05). We noted disparate effects of PPAR ligands in atheroma samples from different patients and postulated that the response of endothelial cells to medication was influenced by the atheromatous environment. Incubation of human aortic endothelial cells with fenofibrate alone led to a dose-dependent increase in TM expression ( P < 0.05), however, in the presence of oxidized LDL a dose-dependent reduction in TM expression was induced by fenofibrate ( P < 0.05). Conclusions The ability of fenofibrate to increase endothelial cell and carotid atheroma TM protein expression suggests a potential therapeutic role for this medication. The response to PPAR ligands likely varies depending on the exact constituents of individual atherosclerotic plaques, such as the relative amount of oxidized LDL.

Heterogeneity of atherosclerotic plaque characteristics in human coronary artery disease: A three‐dimensional intravascular ultrasound study

The objective of this study was to describe the intraplaque variability of coronary atherosclerosis in humans. Atherosclerosis is a heterogeneous process. The degree and patterns of intraplaque heterogeneity are not well described. This study uses 3D intravascular ultrasound (IVUS) to examine variability in individual atherosclerotic plaques in human coronary arteries. IVUS images of 170 coronary plaques in 98 patients were evaluated. Each plaque was divided into proximal, middle, and distal sections. Quantitative and qualitative analyses were performed for each section using a dedicated 3D IVUS protocol. Intralesion heterogeneity was assessed between sections. Heterogeneity in composition was observed in most plaques (89%). The pattern of remodeling was heterogeneous in 23% of lesions. External elastic membrane (EEM) areas demonstrated an average percent deviation of 28.9% +/- 15.5%. Positive remodeling was associated with longer lesions (>> median length of 12.7 mm) (P = 0.031). Soft and calcific sections had a smaller mean EEM area (P = 0.034). Calcific lesions had a smaller mean lumen area (P = 0.027) and a greater percent plaque burden (PPB) (P = 0.001). Neither the location within the vessel or within the plaque was associated with plaque morphology. Greater qualitative heterogeneity was found in patients presenting with acute coronary syndrome (P < 0.001). Our results demonstrate a high degree of heterogeneity in composition and morphological features within individual atherosclerotic plaques in human coronary arteries. Intraplaque heterogeneity represents a challenge for imaging protocols correlating plaque features with cardiovascular events and for the development of future therapeutic options.

Coronary artery calcification and end-stage renal disease: vascular biology and clinical implications.

Coronary artery calcifications appear to be an indicator of total atherosclerotic disease burden, but their relation to the stability of individual atherosclerotic plaques is not well understood. Plaque rupture and acute coronary syndromes can occur without plaque calcification and may be more often associated with noncalcified, soft plaque. Pharmacologic control of calcium and phosphate metabolism should be guided by the nephrologic and endocrinologic needs of the renal failure patient and not withheld out of concern about coronary calcifications. Efforts to slow coronary artery disease progression in patients with end-stage renal disease should emphasize aggressive control of recognized cardiovascular risk factors.

Lowering Lipids Improves Coronary Arterial Anatomy-Reply

In Reply.— The primary objective of our study was to test the lipid hypothesis, that is, to determine whether reducing levels of low-density lipoproteins in plasma would inhibit progression or cause regression of atherosclerotic lesions in the coronary arteries of individuals with a specific form of primary hyperlipidemia: familial hypercholesterolemia. We employed a high-resolution technique of computer-based quantitative angiography to measure changes in dimensions of individual atherosclerotic plaques. This technique allowed us to evaluate the effects of treatment on 547 lesions in a relatively small patient group (72 individuals) over a 2-year period. Asymptomatic patients were studied in an effort to focus on early and uncomplicated lesions, so as to avoid as much as possible the potentially confounding effects of fissuring and thrombosis. Thus, the study was not designed to detect changes in the incidence of new coronary events. Analysis of change in percent area stenosis in our patients showed

Biochemical analysis of individual atherosclerotic plaque caps to investigate susceptibility to rupture

followed by trouser tear tests using specimens partially cut along their longitudinal axis. Force is applied to the free ends in opposite directions, gradually tearing the tissue apart. Information on tissue viscoelasticity is provided by equilibrium force extension measurements. This is achieved by extending the tissue over set time intervals with intermittent periods when the distance between the clamps is held constant. While the clamps are held static, tissue relaxation is observed. Our study on human atherosclerotic plaque caps involved stress-strain analyses on test strips ( 10 mm x 2 mm) punched with their long axis in the circumferential direction from intact central and peripheral plaque areas, and adjacent intima. The cap or intima was carefully dissected away from the underlying elastic lamina before mounting for mechanical testing. The results show marked differences between plaques and heterogeneity within individual plaque caps. Fracture stresses in different plaques ranged from 12 to 1938 kN m-*. Intra-plaque stress and strain values indicated discontinuity in the mechanical properties across the plaque cap in both ulcerated and non-ulcerated plaques. The magnitude of these differences was more pronounced in the ulcerated group. Biochemical analysis of mechanically tested areas within the eight non-ulcerated plaques highlighted a trend for collagen content to coincide with increased fracture stress and reduced extensibility. A similar sized group of ulcerated plaque caps failed to show these trends. Sulphated glycosaminoglycan content did not correlate with mechanical parameters in non-ulcerated plaques, but its decrease in the centres of ulcerated plaques accompanied a reduction in fracture stress and increase in extensibility. The mechanical testing device used in conjunction with biochemical analysis is a valuable tool in pinpointing the determinants of atherosclerotic plaque cap rupture.