5-Lipoxygenase pathway in experimental abdominal aortic aneurysms.

OBJECTIVE: The impact of leukotriene production by the 5-lipoxygenase (5-LO) pathway in the pathophysiology of abdominal aortic aneurysms (AAAs) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. APPROACH AND RESULTS: Aneurysm formation was attenuated in 5-LO(-/-) mice, and in lethally irradiated wild-type mice reconstituted with 5-LO(-/-) bone marrow in an elastase perfusion model. Pharmacological inhibition of 5-LO-attenuated aneurysm formation in both aortic elastase perfused wild-type and angiotensin II-treated LDLr(-/-) (low-density lipoprotein receptor) mice, with resultant preservation of elastin and fewer 5-LO and MMP9 (matrix metalloproteinase)-producing cells. Separately, analysis of wild-type mice 7 days after elastase perfusion showed that 5-LO inhibition was associated with reduced polymorphonuclear leukocyte infiltration to the aortic wall. Importantly, 5-LO inhibition initiated 3 days after elastase perfusion in wild-type mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. CONCLUSIONS: Inhibition of 5-LO by pharmacological or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in 2 unique AAA models. Administration of 5-LO inhibitor in small AAA slows progression of AAA. Targeted interruption of the 5-LO pathway is a potential treatment strategy in AAA.

Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms.

Activation of the adenosine 2A receptor (A2AR) reduces inflammation in models of acute injury but contribution in development of chronic abdominal aortic aneurysms (AAAs) is unknown. Elastase perfusion to induce AAA formation in A2AR-knockout (A2ARKO) and C57BL6/J wild-type (WT) mice resulted in nearly 100% larger aneurysms in A2ARKO compared to WT at d 14 (P<0.05), with evidence of greater elastin fragmentation, more immune cell infiltration, and increased matrix metallatoproteinase (MMP) 9 expression (P<0.05). Separately, exogenous A2AR antagonism in elastase-perfused WT mice also resulted in larger aneurysms (P<0.05), while A2AR agonism limited aortic dilatation (P<0.05). Activated Thy-1.2(+) T lymphocytes from WT mice treated in vitro with A2AR antagonist increased cytokine production, and treatment with A2AR agonist decreased cytokine production (P<0.05 for all). Primary activated CD4(+) T lymphocytes from A2ARKO mice exhibited greater chemotaxis (P<0.05). A2AR antagonist increased chemotaxis of activated CD4(+) cells from WT mice in vitro, and A2AR agonist reduced this effect (P<0.05). A2AR activation attenuates AAA formation partly by inhibiting immune cell recruitment and reducing elastin fragmentation. These findings support augmenting A2AR signaling as a putative target for limiting aneurysm formation.

Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment.

BACKGROUND: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that CD4+ T-cell-produced IL-17 modulates inflammation and smooth muscle cell activation, leading to the pathogenesis of AAA and that human mesenchymal stem cell (MSC) treatment can attenuate IL-17 production and AAA formation. METHODS AND RESULTS: Human aortic tissue demonstrated a significant increase in IL-17 and IL-23 expression in AAA patients compared with control subjects as analyzed by RT-PCR and ELISA. AAA formation was assessed in C57BL/6 (wild-type; WT), IL-23(-/-) or IL-17(-/-) mice using an elastase-perfusion model. Heat-inactivated elastase was used as control. On days 3, 7, and 14 after perfusion, abdominal aorta diameter was measured by video micrometry, and aortic tissue was analyzed for cytokines, cell counts, and IL-17-producing CD4+ T cells. Aortic diameter and cytokine production (MCP-1, RANTES, KC, TNF-α, MIP-1α, and IFN-γ) was significantly attenuated in elastase-perfused IL-17(-/-) and IL-23(-/-) mice compared with WT mice on day 14. Cellular infiltration (especially IL-17-producing CD4+ T cells) was significantly attenuated in elastase-perfused IL-17(-/-) mice compared with WT mice on day 14. Primary aortic smooth muscle cells were significantly activated by elastase or IL-17 treatment. Furthermore, MSC treatment significantly attenuated AAA formation and IL-17 production in elastase-perfused WT mice. CONCLUSIONS: These results demonstrate that CD4+ T-cell-produced IL-17 plays a critical role in promoting inflammation during AAA formation and that immunomodulation of IL-17 by MSCs can offer protection against AAA formation.

Development of a novel murine model of aortic aneurysms using peri-adventitial elastase.

BACKGROUND: Our aim was to establish a novel model of abdominal aortic aneurysms (AAA) in mice using application of peri-adventitial elastase. METHODS: C57BL/6J male mice underwent infrarenal peri-adventitial application of either (1) sodium chloride (control; n = 7), (2) porcine pancreatic elastase (PPE; n = 14), or (3) PPE and doxycycline (PPE + doxycycline 200 mg/kg; n = 11) for 14 days. Aortas were analyzed by video micrometry, immunohistochemistry, qualitative polymerase chain reaction, and zymography. Groups underwent Mann-Whitney U comparisons. RESULTS: At day 14 compared with baseline, control animals had minimal aortic dilation, whereas fusiform aneurysms were seen in PPE (control, 20 ± 3%; PPE, 82 ± 15%; P ≤ .003). Doxycycline abrogated aneurysm formation (PPE, 82 ± 15%; PPE + doxycycline, 37 ± 10%; P ≤ .03). Compared with control and PPE + doxycycline, immunohistochemistry demonstrated greater elastin fiber degradation, macrophage infiltration, and matrix metalloproteinase-9 expression in PPE. Ki-67 and cleaved caspase-3 were lower in control versus PPE. The loss of smooth muscle marker expression seen with PPE was preserved in PPE + doxycycline. Zymography confirmed that both MMP-2 and -9 were more active in PPE than PPE + doxycycline. CONCLUSION: Peri-adventitial application of elastase is a simple, reproducible in vivo model of aneurysm formation leading to consistent infrarenal aortic aneurysm development by day 14, with inflammatory cell infiltration and MMP upregulation. Doxycycline inhibits AAA progression in this model via limiting matrix degradation and preserving differentiated smooth muscle cells.

Previous percutaneous coronary intervention increases morbidity after coronary artery bypass grafting.

BACKGROUND: We hypothesized that the incidence of previous percutaneous coronary intervention (PCI) is increasing and that prior PCI influences patient morbidity and mortality after coronary artery bypass grafting (CABG). METHODS: A total of 34,316 patients underwent isolated CABG operations at 16 different statewide, institutions from 2001 to 2008. Patients were stratified into prior PCI (n = 4346; 12.7%) and no prior PCI (n = 29,970). Patient risk factors, intraoperative variables, and outcomes were compared by univariate and multivariate analyses. RESULTS: The incidence of prior PCI in CABG has risen from <1% to 22.0% from 2001 to 2008 (P < .001). Prior PCI patients were younger (P < .001) and more commonly had previous myocardial infarction (P < .001), but less commonly had heart failure (P < .001). The operative mortality was similar between groups (2.3% vs 1.9%; P = .13). Prior PCI patients had more major complications (15.0% vs 12.0%; P < .001), longer hospitalization (P = .01), and higher readmission rates (P = .01). Importantly, by multivariate analyses, prior PCI was not associated with mortality, but was an independent predictor of major complications after CABG (odds ratio, 1.15; P = .01). CONCLUSION: The incidence of prior PCI in patients undergoing CABG is increasing. Previous PCI is associated with a higher risk of major complications, greater hospital length of stay, and higher readmission rates after CABG.

Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation.

OBJECTIVES: This study tested the hypothesis that monocyte chemotactic protein 1 (MCP1) is required for abdominal aortic aneurysm (AAA) and smooth muscle phenotypic modulation in a mouse elastase perfusion model. METHODS: Infrarenal aortas of C57BL/6 (wild type [WT]) and MCP1 knockout (KO) mice were analyzed at 14 days after perfusion. Key cellular sources of MCP1 were identified using bone marrow transplantation. Cultured aortic smooth muscle cells (SMCs) were treated with MCP1 to assess its potential to directly regulate SMC contractile protein expression and matrix metalloproteinases (MMPs). RESULTS: Elastase perfused WT aortas had a mean dilation of 102% (n = 9) versus 53.7% for MCP1KO aortas (n = 9, P < .0001) and 56.3% for WT saline-perfused controls (n = 8). Cells positive for MMP9 and Mac-2 were nearly absent in the KO aortas. Complimentarily, the media of the KO vessels had abundant differentiated smooth muscle and intact elastic fibers and markedly less MMP2. Experiments in cultured SMCs showed MCP1 can directly repress smooth muscle markers and induce MMP2 and MMP9. Bone marrow transplantation studies showed that KO of MCP1 in bone marrow-derived cells protects from AAA formation. Moreover, KO in the bone was significantly more protective than global KO, suggesting an unexpected benefit to selectively depleting MCP1 in bone marrow-derived cells. CONCLUSIONS: These results have shown that MCP1 derived from bone marrow cells is required for experimental AAA formation and that retention of nonbone marrow MCP1 limits AAA compared with global depletion. This protein contributes to macrophage infiltration into the AAA and can act directly on SMCs to reduce contractile proteins and induce MMPs.

Albumin is a better predictor of outcomes than body mass index following coronary artery bypass grafting.

OBJECTIVE: Body mass index (BMI) influences risk in coronary artery bypass grafting (CABG) patients, but albumin level is not collected by the Society of Thoracic Surgeons database. We postulate that preoperative albumin is a better predictor of mortality than BMI following CABG. METHODS: BMI from patients with serum albumin level within 6 months of isolated CABG during 1995-2010 from our institutional databases were identified. Patients were stratified by National Heart, Lung, and Blood Institute (NHLBI) BMI class, and by preoperative albumin. Regression models were used to assess predictors of morbidity and mortality. RESULTS: We analyzed 2,794 isolated CABG patients at our institution. Unadjusted mortality was highest with lowest BMI (P ≤ .05), and in patients with 2-3 g/dL albumin (P = .02). Ejection fraction (EF) and intra-aortic balloon pump (IABP) use were similar despite BMI; however, EF was lowest and IABP use highest in the 2-3 g/dL albumin group (P < .001, respectively). Unlike BMI groups, increasing albumin was associated with lower major complication rates (P = .001). Similarly, adjusted mortality was not influenced by BMI (AOR 0.97, 95% CI 0.93-1.02), but increasing albumin levels reduced the adjusted odds of death (AOR 0.61, 95% CI 0.42-0.90). CONCLUSION: Albumin, more than body mass index, is associated with mortality and morbidity in isolated CABG recipients and may be a better indicator for outcomes.

Have thoracic endografting outcomes improved since US Food and Drug Administration approval?

BACKGROUND: Thoracic endovascular aneurysm repair (TEVAR) is gaining acceptance since Food and Drug Administration approval in 2005. We hypothesize that, compared with open repair (OPEN), mortality and complication rate after TEVAR have continued to improve. METHODS: All patients who underwent thoracic and (or) thoracoabdominal aneurysm repair from 2005 to 2007 in the Nationwide Inpatient Sample were examined. Patients were stratified by TEVAR or OPEN. Demographics, hospital characteristics, and outcomes were analyzed. Multivariable logistic regression models for complications and in-hospital mortality were developed. RESULTS: A weighted total of 7,644 had TEVAR, while 32,948 patients underwent OPEN. The TEVAR utilization increased from 5.5% (2005) to 24.1% (2007). Mortality for all patients undergoing thoracic aneurysm repair decreased yearly (p<0.001). Mortality (TEVAR: 7.3%, OPEN: 9.8%, p<0.001) and complication rate (TEVAR: 24.3%, OPEN: 42.1%, p<0.001) were superior with TEVAR. The unadjusted annual mortality (7%) and complication rate (24%) after TEVAR did not improve each year; however, after risk adjustment, mortality after TEVAR steadily decreased annually. Moreover, risk-adjusted mortality for OPEN has improved since 2005. Multivariate analysis revealed age and ruptured aneurysm were highly predictive of death (p<0.001, respectively), while TEVAR lowered the adjusted odds of death by 18% (p<0.05). CONCLUSIONS: Mortality in patients undergoing repair of thoracic aneurysms has decreased in the United States since Food and Drug Administration approval of stent grafts in 2005. This is due to wider adoption of TEVAR and improved mortality in patients undergoing TEVAR or open repair.

Robot-assisted mitral valve repair: a single institution review.

OBJECTIVE: Mitral valve repair (MVR) is the definitive therapy for mitral myxomatous degeneration. Median sternotomy has been the traditional approach to repair until the advent of the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA). Minimally invasive surgical approaches for mitral repair have been slow to gain acceptance in cardiac surgery. We review the MVR results from our single-institution academic robotic program. METHODS: From August 2004 through April 2008, patients who underwent a robotic-assisted (RA) MVR were identified. RA technique included a 4-cm right minithoracotomy, femoral cardiopulmonary bypass with transthoracic aortic occlusion, and RA-MVR. Repair types were combinations of quadrangular/triangular leaflet resection, sliding plasty, chordal transfer/replacement, and edge-to-edge approximation, with band annuloplasty in all cases. Postrepair echocardiography and morbidity follow-ups were completed in all patients. Our primary outcome was adequacy of repair, and secondary outcome was major complications. RESULTS: There were 43 patients (29 male and 14 female) who underwent RA-MVR for severe (4+) mitral regurgitation during the 4-year review. Average operative time was 272.26 minutes. Only one patient had mild postoperative mitral regurgitation, whereas 20 had trace and 22 had no regurgitation after repair. Mean ventilator time was 32.1 hours, and length of stay was 5.7 days. One third of the patients (33%) received postoperative-packed red blood cell transfusions (average: 2.4 units per patient). Twenty-eight percent of patients developed atrial fibrillation after repair. Most of the patients (95.3%) were discharged home. There were no 30-day mortalities. CONCLUSIONS: Based on our small single-institution experience, RA-MVR provides an effective treatment for severe mitral valve regurgitation. Although procedure durability is slowly being established, preliminary results are promising. Careful programmatic advances with an integrated team approach can facilitate acceptable postoperative outcomes and excellent MVR.