Patients with Prior Exposure to a Combination of Statins & Angiotensin-Converting Enzyme Inhibitors (ACE-Is)/Angiotensin Receptor Blockers (ARBs) Have Better Outcomes after Carotid Revascularization than Patients with Prior Exposure to Statins Alone: A MultiCenter Analysis.

BACKGROUND: Statin use has been studied and confirmed to have a beneficial impact on perioperative carotid endarterectomy (CEA) and carotid artery stenting (CAS) outcomes. The benefits of Angiotensin-converting enzyme inhibitors (ACE-I) in hypertension, ischemic heart disease, heart failure, diabetes mellitus, and renal disease are well-known; however, the impact of continuing or withholding ACE-Is/angiotensin receptor blockers (ARBs) on CEA and CAS outcomes is not addressed well in the literature. This study aimed to evaluate the impact of preoperative statin use combined with ACE-Is/ARBs in patients undergoing CEA or CAS on mortality and morbidity using a multi-institutional database. METHODS: Using the data of all patients who underwent carotid artery revascularization, including CEA, transcarotid artery revascularization, and transfemoral carotid artery stenting from 2016 to 2021 in the Vascular Quality Initiative data, we determined as our primary outcome 30-day mortality/stroke after carotid revascularization based on periop exposure to statins alone, or the combination of statins and ACE-Is/ARBs. Secondary outcomes were postop myocardial infarction and postop congestive heart failure. Poisson regression with robust variance was used to determine postop outcomes comparing the combination of statin and ACE-Is/ARBs group with statins alone group. RESULTS: A total of 131,285 patients were included in the study, with 59,860 (46%) patients receiving statin only, and 71,425 (54%) receiving both statin and ACE-Is/ARBs preoperatively. Both patient groups differed significantly in preop clinical and demographic characteristics. After adjusting for potential confounders, the statins plus ACE-I/ARB group had a 12% lower risk of postop mortality/stroke (Incident Rate Ratio comparing Statin/ACE group to Statins Only group [IRR] 0.88, 95% confidence interval 0.81-0.95, P = 0.001), 18% lower risk of postop congestive heart failure (IRR 0.82, 95% CI 0.68-0.98, P = 0.029), and similar risk of postop myocardial infarction (IRR 1.05 95% confidence interval 0.91-1.20, P = 0.54) compared to the statin-only group. CONCLUSION: Statins combined with ACE-Is/ARBs perioperatively offer better protection compared to statins alone in patients undergoing carotid revascularization surgery. We recommend the continuation of ACE-Is/ARBs use in patients undergoing carotid revascularization, especially if they have concurrent hypertension. Further prospective studies are needed to evaluate the benefit of adding ACE-Is/ARBs.

Matrix metalloproteinase-1-mediated up-regulation of vascular endothelial growth factor-2 in endothelial cells.

Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression. Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions. Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown. In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2. The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response. Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2. Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment. MMP-1 caused activation of the nuclear factor-κB (NF-κB) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1). Chromatin immunoprecipitation was used to confirm NF-κB-mediated active transcription of the VEGFR2 (KDR) gene. Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-κB specific inhibition. We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-κB. These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions.

Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine.

Loss of integrity of the epithelial/mucosal barrier in the small intestine has been associated with different pathologies that originate and/or develop in the gastrointestinal tract. We showed recently that mucin, the main protein in the mucus layer, is disrupted during early periods of intestinal ischemia. This event is accompanied by entry of pancreatic digestive enzymes into the intestinal wall. We hypothesize that the mucin-containing mucus layer is the main barrier preventing digestive enzymes from contacting the epithelium. Mucin breakdown may render the epithelium accessible to pancreatic enzymes, causing its disruption and increased permeability. The objective of this study was to investigate the role of mucin as a protection for epithelial integrity and function. A rat model of 30 min splanchnic arterial occlusion (SAO) was used to study the degradation of two mucin isoforms (mucin 2 and 13) and two epithelial membrane proteins (E-cadherin and toll-like receptor 4, TLR4). In addition, the role of digestive enzymes in mucin breakdown was assessed in this model by luminal inhibition with acarbose, tranexamic acid, or nafamostat mesilate. Furthermore, the protective effect of the mucin layer against trypsin-mediated disruption of the intestinal epithelium was studied in vitro. Rats after SAO showed degradation of mucin 2 and fragmentation of mucin 13, which was not prevented by protease inhibition. Mucin breakdown was accompanied by increased intestinal permeability to FITC-dextran as well as degradation of E-cadherin and TLR4. Addition of mucin to intestinal epithelial cells in vitro protected against trypsin-mediated degradation of E-cadherin and TLR4 and reduced permeability of FITC-dextran across the monolayer. These results indicate that mucin plays an important role in the preservation of the mucosal barrier and that ischemia but not digestive enzymes disturbs mucin integrity, while digestive enzymes actively mediate epithelial cell disruption.