Veins grafted into an arterial environment undergo a complex vascular remodeling process. Pathologic vascular remodeling often results in stenosed or occluded conduit grafts. Understanding this complex process is important for improving the outcome of patients with coronary and peripheral artery disease undergoing surgical revascularization. Using in vivo murine cell lineage-tracing models, we show that endothelial-derived cells contribute to neointimal formation through endothelial to mesenchymal transition (EndMT), which is dependent upon early activation of the Smad2/3-Slug signaling pathway. Antagonism of TGF-β signaling by TGF-β neutralizing antibody, shRNA-mediated Smad3 or Smad2 knockdown, Smad3 haploinsufficiency, or endothelial cell-specific Smad2 deletion resulted in decreased EndMT and less neointimal formation compared to controls. Histological examination of postmortem human vein graft tissue corroborated the changes observed in our mouse vein graft model, suggesting that EndMT is operative during human vein graft remodeling. These data establish that EndMT is an important mechanism underlying neointimal formation in interpositional vein grafts, and identifies the TGF-β/Smad2/3-Slug signaling pathway as a potential therapeutic target to prevent clinical vein graft restenosis.
Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.
BackgroundScar burden by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is associated with functional recovery after coronary artery bypass surgery (CABG). There is limited data on long-term mortality after CABG based on left ventricular (LV) scar burden.MethodsPatients who underwent LGE CMR between January 2003 and February 2010 within 1 month prior to CABG were included. A standard 16 segment model was used for scar quantification. A score of 1 for no scar, 2 for ≤ 50 % and 3 for > 50 % transmurality was assigned for each segment. LV scar score (LVSS) defined as the sum of segment scores divided by 16. All-cause mortality was ascertained by social security death index.ResultsOne hundred ninety-six patients met the inclusion criteria. 185 CMR studies were available. History of prior MI was present in 64 % and prior CABG in 5.4 % of patients. Scar was present in 72 % of patients and median LVEF was 38 %. Over a median follow up of 8.3 years, there were 64 deaths (34.6 %). There was no statistically significant difference in mortality between Scar and No-scar groups (37 % versus 29 %). In the group with scar, a lower scar burden (defined either < 4 segments with scar or based on LVSS) was independently associated with increased survival.ConclusionIn patients undergoing surgical revascularization, scar burden is negatively associated with survival in patients with scar. However, there is no difference in survival based on presence or absence of scar alone. CMR prior to CABG adds additional prognostic information.
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