Time and flow-dependent changes in the p27(kip1) gene network drive maladaptive vascular remodeling.

OBJECTIVE: Although clinical studies have identified that a single nucleotide polymorphism in the p27(kip1) gene is associated with success or failure after vein bypass grafting, the underlying mechanisms for this difference are not well defined. Using a high-throughput approach in a flow-dependent vein graft model, we explored the differences in p27(kip1)-related genes that drive the enhanced hyperplastic response under low-flow conditions. METHODS: Bilateral rabbit carotid artery interposition grafts with jugular vein were placed with a unilateral distal outflow branch ligation to create differential flow states. Grafts were harvested at 2 hours and at 1, 3, 7, 14, and 28 days after implantation, measured for neointimal area, and assayed for cell proliferation. Whole-vessel messenger RNA was isolated and analyzed using an Affymetrix (Santa Clara, Calif) gene array platform. Ingenuity Pathway Analysis (Ingenuity, Redwood City, Calif) was used to identify the gene networks surrounding p27(kip1). This gene set was then analyzed for temporal expression changes after graft placement and for differential expression in the alternate flow conditions. RESULTS: Outflow branch ligation resulted in an eightfold difference in mean flow rates throughout the 28-day perfusion period (P < .001). Flow reduction led to a robust hyperplastic response, resulting in a significant increase in intimal area by 7 days (0.13 ± 0.04 mm(2) vs 0.014 ± 0.006 mm(2); P < .005) and progressive growth to 28 days (1.37 ± 0.05 mm(2) vs 0.39 ± 0.06 mm(2); P < .001). At 7 days, low-flow grafts demonstrated a burst of actively dividing intimal cells (36.4 ± 9.4 cells/mm(2) vs 11.5 ± 1.9 cells/mm(2); P = .04). Sixty-five unique genes within the microarray were identified as components of the p27(kip1) network. At a false discovery rate of 0.05, 26 genes demonstrated significant temporal changes, and two dominant patterns of expression were identified. Class comparison analysis identified differential expression of 11 genes at 2 hours and seven genes and 14 days between the high-flow and low-flow grafts (P < .05). At 2 hours, oncostatin M and cadherin 1 were the most differentially expressed. Cadherin 1 and protein kinase B exhibited the greatest differential expression at 14 days. CONCLUSIONS: Alterations in flow and shear stress result in divergent patterns of vein graft remodeling. Associated with the dramatic increase in neointimal expansion observed in low-flow vs high-flow grafts is a subset of differentially expressed p27(kip1)-associated genes that correlate with critical stages in the adaptive response. These represent potential biologic targets whose activity may be altered to augment maladaptive vascular remodeling.

Pathology-specific secondary aortic interventions after thoracic endovascular aortic repair.

OBJECTIVE: Despite improved short-term outcomes, concerns remain regarding durability of thoracic endovascular aortic repair (TEVAR). The purpose of this analysis was to evaluate the pathology-specific incidence of secondary aortic interventions (SAI) after TEVAR and their impact on survival. METHODS: Retrospective review was performed of all TEVAR procedures and SAI at one institution from 2004-2011. Kaplan-Meier analysis was used to estimate survival. RESULTS: Of 585 patients, 72 (12%) required SAI at a median of 5.6 months (interquartile range, 1.4-14.2) with 22 (3.7%) requiring multiple SAI. SAI incidence differed significantly by pathology (P = .002) [acute dissection (21.3%), postsurgical (20.0%), chronic dissection (16.7%), degenerative aneurysm (10.8%), traumatic transection (8.1%), penetrating ulcer (1.5%), and other etiologies (14.8%)]. Most common indications after dissection were persistent false lumen flow and proximal/distal extension of disease. For degenerative aneurysms, SAI was performed primarily to treat type I/III endoleaks. SAI patients had a greater mean number of comorbidities (P < .0005), stents placed (P = .0002), and postoperative complications after the index TEVAR (P < .0005) compared with those without SAI. Freedom from SAI at 1 and 5 years (95% confidence interval) was estimated to be 86% (82%-90%) and 68% (57%-76%), respectively. There were no differences in survival (95% confidence interval) between patients requiring SAI and those who did not [SAI 1-year, 88% (77%-93%); 5-year, 51% (37%-63%); and no SAI 1-year, 82% (79%-85%); 5-year, 67% (62%-71%) (log-rank, P = .2)]. CONCLUSIONS: SAI after TEVAR is not uncommon, particularly in patients with dissection, but does not affect long-term survival. Aortic pathology is the most important variable impacting survival and dictated need, timing, and mode of SAI. The varying incidence of SAI by indication underscores the need for diligent surveillance protocols that should be pathology-specific.