Patient-specific computational modeling of subendothelial LDL accumulation in a stenosed right coronary artery: effect of hemodynamic and biological factors

Patient-specific computational modeling of subendothelial LDL accumulation in a stenosed right coronary artery: effect of hemodynamic and biological factors. Am J Physiol Heart Circ Physiol 304: H1455-H1470, 2013. First published March 15, 2013; doi:10.1152/ajpheart.00539.2012.-Atherosclerosis is a systemic disease with local manifestations. Low-density lipoprotein (LDL) accumulation in the subendothelial layer is one of the hallmarks of atherosclerosis onset and ignites plaque development and progression. Blood flow-induced endothelial shear stress (ESS) is causally related to the heterogenic distribution of atherosclerotic lesions and critically affects LDL deposition in the vessel wall. In this work we modeled blood flow and LDL transport in the coronary arterial wall and investigated the influence of several hemodynamic and biological factors that may regulate LDL accumulation. We used a three-dimensional model of a stenosed right coronary artery reconstructed from angiographic and intravascular ultrasound patient data. We also reconstructed a second model after restoring the patency of the stenosed lumen to its nondiseased state to assess the effect of the stenosis on LDL accumulation

Natural History of Experimental Coronary Atherosclerosis and Vascular Remodeling in Relation to Endothelial Shear Stress

Author Manuscript: 2011 May 18.Background— The natural history of heterogeneous atherosclerotic plaques and the role of local hemodynamic factors throughout their development are unknown. We performed a serial study to assess the role of endothelial shear stress (ESS) and vascular remodeling in the natural history of coronary atherosclerosis. Methods and Results— Intravascular ultrasound-based 3-dimensional reconstruction of all major coronary arteries (n=15) was performed serially in vivo in 5 swine 4, 11, 16, 23, and 36 weeks after induction of diabetes mellitus and hyperlipidemia. The reconstructed arteries were divided into 3-mm-long segments (n=304). ESS was calculated in all segments at all time points through the use of computational fluid dynamics. Vascular remodeling was assessed at each time point in all segments containing significant plaque, defined as maximal intima-media thickness ≥0.5 mm, at week 36 (n=220). Plaque started to develop at week 11 and progressively advanced toward heterogeneous, multifocal lesions at all subsequent time points. Low ESS promoted the initiation and subsequent progression of plaques. The local remodeling response changed substantially over time and determined future plaque evolution. Excessive expansive remodeling developed in regions of very low ESS, further exacerbated the low ESS, and was associated with the most marked plaque progression. The combined assessment of ESS, remodeling, and plaque severity enabled the early identification of plaques that evolved to high-risk lesions at week 36. Conclusions— The synergistic effect of local ESS and the remodeling response to plaque formation determine the natural history of individual lesions. Combined in vivo assessment of ESS and remodeling may predict the focal formation of high-risk coronary plaque

Augmented Expression and Activity of Extracellular Matrix-Degrading Enzymes in Regions of Low Endothelial Shear Stress Colocalize With Coronary Atheromata With Thin Fibrous Caps in Pigs

Background—The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. : Methods and Results—Intravascular ultrasound–based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. : Conclusions—Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps.Novartis Pharmaceuticals CorporationBoston Scientific CorporationHellenic Heart FoundationHellenic Atherosclerosis SocietyAlexander S. Onassis Public Benefit FoundationPropondis FoundationHellenic Harvard FoundationA.G. Leventis FoundationPhilip Morris International. External Research ProgramAmerican Heart Association (Scientist Development Grant)National Institutes of Health (U.S.) (Grant NIHR01 GM49039

Thin-Capped Atheromata With Reduced Collagen Content in Pigs Develop in Coronary Arterial Regions Exposed to Persistently Low Endothelial Shear Stress

Objective—The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. Approach and Results—Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. Conclusions—Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps—2 critical determinants of coronary plaque vulnerability.Novartis (Firm)Boston Scientific CorporationBehrakis Foundation (Research Fellowship)Hellenic Heart FoundationHellenic Atherosclerosis SocietyNational Institutes of Health (U.S.) (Grant RO1 GM49039

Arterial Remodeling and Endothelial Shear Stress Exhibit Significant Longitudinal Heterogeneity Along the Length of Coronary Plaques

Atherosclerosis is determined by both systemic risk factors and local vascular mechanisms. The arterial remodeling in response to plaque development plays a key role in atherosclerosis. Compensatory expansive remodeling is an adaptive mechanism that maintains lumen patency as a plaque develops. In contrast, excessive expansive remodeling, signifying an enlargement in vascular and lumen volume as a result of local plaque buildup, is a consistent attribute of high-risk plaques. Local hemodynamic factors, in particular low endothelial shear stress (ESS), is an intensely proinflammatory and proatherogenic stimulus and largely accounts for the spatially diverse distribution of atherosclerotic plaques. However, plaque, remodeling and ESS have hitherto been investigated only in the cross-sectional arterial axis and their distribution in the longitudinal axis of individual plaques has not been characterized

Effects of Low Endothelial Shear Stress After Stent Implantation on Subsequent Neointimal Hyperplasia and Clinical Outcomes in Humans

Background: In‐stent hyperplasia (ISH) may develop in regions of low endothelial shear stress (ESS), but the relationship between the magnitude of low ESS, the extent of ISH, and subsequent clinical events has not been investigated. Methods and Results: We assessed the association of poststent ESS with neointimal ISH and clinical outcomes in patients treated with percutaneous coronary interventions (PCI). Three‐dimensional coronary reconstruction was performed in 374 post‐PCI patients at baseline and 6 to 10 months follow‐up as part of the PREDICTION Study. Each vessel was divided into 1.5‐mm‐long segments, and we calculated the local ESS within each stented segment at baseline. At follow‐up, we assessed ISH and the occurrence of a clinically indicated repeat PCI for in‐stent restenosis. In 246 total stents (54 overlapping), 100 (40.7%) were bare‐metal stents (BMS), 104 (42.3%) sirolimus‐eluting stents, and 42 (17.1%) paclitaxel‐eluting stents. In BMS, low ESS post‐PCI at baseline was independently associated with ISH (β=1.47 mm2 per 1‐Pa decrease; 95% CI, 0.38–2.56; P<0.01). ISH was minimal in drug‐eluting stents. During follow‐up, repeat PCI in BMS was performed in 21 stents (8.5%). There was no significant association between post‐PCI ESS and in‐stent restenosis requiring PCI. Conclusions: Low ESS after BMS implantation is associated with subsequent ISH. ISH is strongly inhibited by drug‐eluting stents. Post‐PCI ESS is not associated with in‐stent restenosis requiring repeat PCI. ESS is an important determinant of ISH in BMS, but ISH of large magnitude to require PCI for in‐stent restenosis is likely attributed to factors other than ESS within the stent

Stent fracture and restenosis of a paclitaxel-eluting stent

We describe the case of a patient with restenosis six months after stent implantation, at two points where stent fracture had occurred. Fracture is an unusual and probably underestimated cause of restenosis, which acquires special significance in this era of drug-eluting stents.</p