Faculty Bibliography

Matrix metalloproteinases (MMPs) play key roles in vascular remodeling. We characterized the role of inflammatory mediators and extracellular signal-regulated kinases (ERKs) in the control of arterialized vein graft expression of MMP-9, MMP-2, and membrane-type 1-MMP (MT1-MMP) and of the tissue inhibitor of metalloproteinases-2 (TIMP-2). For this purpose we used a canine model of jugular vein to carotid artery interposition graft and analyzed the vein grafts at various postoperative times (30 min to 28 days) using the contralateral vein as a control. To study the role of ERK-1/2, veins were incubated with the mitogen-activated protein kinase kinase (MEK-1/2) inhibitor UO126 for 30 min before being grafted. Vein graft extracts were analyzed for MMPs, TIMP-2, tumor necrosis factor-alpha (TNF-alpha), polymorphonuclear neutrophil (PMN) infiltration, myeloperoxidase (MPO), and thrombin activity, and for ERK-1/2 activation. Vein graft arterialization resulted in rapid and sustained (8 h to 28 days) upregulation of vein graft-associated MMP-9, MMP-2, MT1-MMP, thrombin activity, and TNF-alpha levels with concomitant TIMP-2 downregulation. MMP-2 activation preceded MT1-MMP upregulation. PMN infiltration and vein graft-associated MPO activity increased within hours after arterialization, indicating a prompt, local inflammatory response. In cultured smooth muscle cells, both thrombin and TNF-alpha upregulated MT1-MMP expression; however, only thrombin activated MMP-2. Inhibition of ERK-1/2 activation blocked arterialization-induced upregulation of MMP-2, MMP-9, and MT1-MMP. Thus, thrombin, inflammatory mediators, and activation of the ERK-1/2 pathway control MMP and TIMP-2 expression in arterialized vein grafts

OBJECTIVE: Minimally invasive, nonsternotomy approaches for valve procedures may reduce the risks associated with cardiac surgery after prior sternotomy and may improve outcomes. We analyzed our institutional experience to test this hypothesis. METHODS: Between 1995 and 2002, 498 patients with previous cardiac operations via sternotomy underwent isolated valve surgery: 337 via median sternotomy (aortic = 160; mitral = 177) and 161 via mini-thoracotomy (aortic = 61; mitral = 100). Data were collected prospectively using the New York State Cardiac Surgery Report Form. RESULTS: Preoperative incidences of congestive heart failure, renal disease, and nonelective procedures were higher in the sternotomy group. Hospital mortality was significantly lower with the minimally invasive approach, 5.6% (9/161) versus 11.3% (38/337) (univariate, p = 0.04). However, multivariate analysis (odds ratio: 95% confidence intervals, p value) revealed that chronic obstructive pulmonary disease (6.6: 1.4 to 3.1, p = 0.001), renal disease (4.1: 1.52 to 11.2, p = 0.01), cerebrovascular disease (2.2: 1.03 to 4.78, p = 0.04), and ejection faction <30% (1.5: 0.96 to 5.5, p = 0.06) were associated with increased mortality. While mean bypass time, cross-clamp times, and stroke rates were comparable between groups, patients undergoing minimally invasive valve surgery had no deep wound infections (0% vs 2.4%, p = 0.05), less need for blood products (p = 0.02), and shorter hospital stays (p = 0.009). Five-year survival was higher with minimally invasive techniques as compared to a sternotomy approach (92.4 +/- 2% and 86.0 +/- 2%, respectively, p = 0.08). CONCLUSIONS: Reoperative valve surgery can be safely performed using a nonsternotomy, minimally invasive approach, with at least equal mortality, less hospital morbidity, decreased hospital length of stay, and slightly favorable mid-term survival as compared to sternotomy

BACKGROUND: Mild and moderate functional ischemic mitral insufficiency present at the time of surgical revascularization present clinical uncertainty. It is unclear whether the relatively poor outcomes in this cohort are dependent on valvular function or related to left ventricular dysfunction. The purpose of this study was to examine the early and late outcomes in patients with less-than-severe functional ischemic mitral insufficiency at the time of isolated coronary artery bypass grafting (CABG). METHODS AND RESULTS: From 1996 through 2004, 2242 consecutive patients undergoing isolated CABG were identified as having none to moderate mitral regurgitation (MR) and no valve leaflet pathology. All of the patients at this single institution routinely had an intraoperative transesophageal echocardiography, prospectively quantified MR, and ejection fraction (EF). The New York State Cardiac Surgery Reporting System infrastructure was used to prospectively collect in-hospital patient variables and outcomes. Social Security Death Benefit Index was used to determine long-term survival. Odds ratio and significance (P value) are presented for each determined risk factor. There were 841 patients (37.5%) with no MR, 1137 (50.7%) with mild MR, and 264 (11.8%) with moderate MR. The patients with moderate MR were more likely to be older, female, and have more renal disease, previous MI, congestive heart failure, previous cardiac surgery, and lower EFs. Hospital mortality was independently and significantly associated with renal disease, decreasing EF, increasing age, previous cardiac operation, and cerebral vascular disease. Multivariable analysis revealed decreased survival with increasing age, previous operation, congestive heart failure, diabetes, nonelective operation, decreasing EF, and the presence of moderate MR (expbeta = 1.49; P=0.007) and mild MR (expbeta = 1.34; P=0.033). CONCLUSIONS: Independent of ventricular function, mild and moderate functional mitral insufficiency are associated with significantly decreased survival in patients undergoing CABG. Whether correction of moderate functional MR at the time of CABG improves outcome still needs to be determined

Upon injury, blood vessels undergo a significant remodeling characterized by intimal damage and dedifferentiation of medial smooth muscle cells. Normally quiescent medial cells lose their contractile phenotype and begin to proliferate, migrate, and secrete abundant extracellular matrix. The resulting neointima formation, also referred to as intimal hyperplasia, precedes atherosclerosis of the vascular conduits. Restenosis greatly limits the success of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), two common procedures widely used to restore circulation in occluded vascular districts. Growth factors, cytokines, inflammatory mediators, and oxidative and shear stress are among the culprits that initiate this process. More recent studies have been directed towards the intracellular sensors of these stimuli in the hope of discovering the common mechanisms that control the response to injury. A group of enzymes called mitogen-activated protein kinases (MAPKs) play a central role in relaying extracellular stimuli to the cellular core, the nucleus. The discovery that MAPK intracellular signaling pathways control processes as diverse as cell proliferation, migration, and survival via fine modulation of gene expression has prompted a number of studies on MAPK involvement in the response to vascular injury. Here we review the studies that characterized MAPK activation upon arterial or vein graft injury and its involvement in vascular remodeling. The experimental findings indicate that the MAPK signaling pathways are suitable targets for novel therapies to prevent restenosis of blood conduits and extend their life span

Basic fibroblast growth factor (FGF-2) and platelet-derived growth factor (PDGF) are implicated in vascular remodeling secondary to injury. Both growth factors control vascular endothelial and smooth muscle cell proliferation, migration, and survival through overlapping intracellular signaling pathways. In vascular smooth muscle cells PDGF-BB induces FGF-2 expression. However, the effect of PDGF on the different forms of FGF-2 has not been elucidated. Here, we report that treatment of vascular aortic smooth muscle cells with PDGF-BB rapidly induces expression of 20.5 and 21 kDa, high molecular weight (HMW) FGF-2 that accumulates in the nucleus and nucleolus. Conversely, PDGF treatment has little or no effect on 18 kDa, low-molecular weight FGF-2 expression. PDGF-BB-induced upregulation of HMW FGF-2 expression is controlled by sustained activation of extracellular signal-regulated kinase (ERK)-1/2 and is abolished by actinomycin D. These data describe a novel interaction between PDGF-BB and FGF-2, and indicate that the nuclear forms of FGF-2 may mediate the effect of PDGF activity on vascular smooth muscle cells. (c) 2005 Wiley-Liss, Inc

Although minimally invasive (MI) cardiac surgery reduces blood loss, hospital stay, and recovery time, some MI approaches require femoral arterial cannulation, which introduces a heretofore unknown risk of femoral arterial injury. This study was performed to examine the risk of femoral arterial injury after Port Access MI cardiac surgery (PA-MICS) with femoral cannulation. Data were prospectively obtained on 739 consecutive patients who had PA-MICS with femoral cannulation between June 1996 and April 2000, identifying any patient with new (<30 days postoperative) arterial insufficiency from the cannulation site. Patient characteristics (gender, age, height, weight, body surface area, smoking, peripheral vascular disease, diabetes) and operative variables (cannula size, cross-clamp time) were examined with univariate and multivariate analysis to identify risk factors for arterial injury. Injuries were defined and classified by radiologic and intraoperative assessment, and follow-up was obtained by patient examination and from the medical records. Femoral arterial occlusion (FAC) occurred in 0.68% (5/739) of patients (4 women, 1 man; age range 26-74 years). The risk of femoral injury was higher in women: 1.31% vs 0.23% (p = 0.07). One patient had intraoperative limb ischemia from iliofemoral dissection and was treated by axillopopliteal bypass. Four patients presented postoperatively with claudication. Three of these had iliofemoral arterial occlusion or localized iliofemoral dissection and were treated with iliofemoral bypass, and 1 patient had localized femoral artery stenosis treated by angioplasty. With a mean follow-up of 17.8 months (range 13-26 months) limb salvage was achieved in all patients. Secondary or tertiary interventions were required in 40% (2/5), both in patients with iliofemoral occlusion, and 1 patient (20% of femoral injuries, 0.135% of overall series) has chronic graft occlusion and long-term claudication. The risk of arterial injury after femoral arterial cannulation and perfusion for Port Access surgery was low (0.68%). This risk is increased in women and is unpredictable. Initial vascular repair has a significant failure rate, and secondary interventions are often necessary. Although the femoral cannulation and perfusion technique is safe overall, the risk must be clearly recognized

Triangular resection is a reconstructive option for treatment of anterior leaflet mitral disease with segmental prolapse. In our experience, it is a safe and reproducible technique, associated with low rates of recurrent MR or need for reoperation, as well as decreased likelihood for systolic anterior motion after mitral repair. We review our experience with this technique over a 25-year experience with mitral valve reconstruction