Gaurav S. Mehta

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-&agr;, MIP-1&agr;, and IFN-&ggr;) 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.

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.

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.—Bhamidipati, C. M., Mehta, G. S., Moehle, C. W., Meher, A. K., Su, G., Vigneshwar, N. G., Barbery, C., Sharma, A. K., Kron, I. L., Laubach, V. E., Owens, G. K., Upchurch Jr., G. R., Ailawadi, G. Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms. FASEB J. 27, 2122–2131 (2013). www.fasebj.org

Repair of Abdominal Aortic Aneurysm in Heart Transplant Patients: Before or after Left Ventricular Assist Device Implantation?

Endovascular abdominal aortic aneurysm repair in decompensated heart failure patients requiring ventricular assist device (VAD) placement needs careful consideration of both complex disease states. We present this clinical dilemma and describe our choice of transcatheter aneurysm repair in the face of advanced refractory heart failure following VAD implantation.