Faculty Bibliography

Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with a short cytoplasmic domain and an extracellular catalytic domain, controls a variety of physiological and pathological processes through the proteolytic degradation of extracellular or transmembrane proteins. MT1-MMP forms a complex on the cell membrane with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). Here we show that, in addition to extracellular proteolysis, MT1-MMP and TIMP-2 control cell proliferation and migration through a non-proteolytic mechanism. TIMP-2 binding to MT1-MMP induces activation of ERK1/2 by a mechanism that does not require the proteolytic activity and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 up-regulates cell migration and proliferation in vitro independently of extracellular matrix proteolysis. Proteolytically inactive MT1-MMP promotes tumor growth in vivo, whereas proteolytically active MT1-MMP devoid of cytoplasmic tail does not have this effect. These findings illustrate a novel role for MT1-MMP-TIMP-2 interaction, which controls cell functions by a mechanism independent of extracellular matrix degradation

OBJECTIVES: This study analyzed the differences in clinical presentation, etiology, and hospital outcome between Hispanic and non-Hispanic patients who underwent surgical correction of mitral valve disease at a large urban medical center. DESIGN: All adult patients undergoing isolated mitral valve repair or replacement surgery at two hospitals between 1993 and 2003 were studied. Patients were grouped according to ethnicity as reported to the New York State Cardiac Surgery Reporting System. Preoperative variables compared included age, congestive heart failure (CHF), etiology, and pertinent medical and surgical histories, while perioperative variables included type of operation, mortality, and hospital complications. RESULTS: A total of 1683 patients (135 Hispanic,1548 non-Hispanic) underwent mitral valve surgery. Hispanic patients were younger (48.3+/-16.0 vs 59.7+/-15.9 years, P<.001) and had higher incidences of CHF (48.9% vs 35.3%, P=.002), endocarditis (8.9% vs 5.0%, P=.05), and rheumatic disease (12.6% vs 5.4%, P<.001). Non-Hispanic patients had a higher incidence of degenerative disease (68.0% vs 54.8%, P<.01). No differences in hospital mortality (Hispanic 5.9% vs 5.3%, P=.76) or perioperative complications were observed between the two groups, although Hispanic patients were less likely to undergo mitral valve repair than mitral valve replacement (35.6% vs 61.2%, P<.001). CONCLUSIONS: In the urban population studied, Hispanic patients presented for mitral valve surgery at a younger age and with a higher prevalence of CHF and rheumatic disease. Public health strategies to prevent rheumatic fever among Hispanics are needed, and improved screening might facilitate earlier referral for Hispanic patients, increasing the potential for benefitting from mitral valve repair

Chronic heart failure (CHF) has become an epidemic in the United States, with approximately 550,000 new cases annually. With the evolution of pharmacotherapy targeting neurohormonal pathways, the annual mortality in subjects with New York Heart Association (NYHA) class IV CHF has dramatically improved from 52% in the seminal CONSENSUS trial to less than 20% in more recent trials. Suppression of the renin-angiotensin-aldosterone system remains the first line of neurohormonal blockade followed by the addition of selective beta-adrenoreceptor blockers. For patients with NYHA class I and II symptoms, mortality rates have decreased to approximately 5% or less per year with the use of angiotensin-converting enzyme inhibitors, beta-blockers and aldosterone receptor blockers. However, after achieving optimal doses of the indicated pharmacotherapy, and despite the additional benefits obtained with biventricular pacemakers, there are still many patients who continue to experience signs and symptoms of CHF. Recognizing the beneficial effects of the above treatments on left ventricular (LV) remodeling, strategies have been developed to surgically reshape the left ventricle in patients with LV dilation who have associated poor LV function. This review will discuss the techniques and recent developments regarding surgical reshaping of the dilated, dysfunctional, and remodeled left ventricle

After over thirty years from its discovery, research on basic fibroblast growth factor (FGF-2) keeps revealing new aspects of the complexity of its gene expression as it evolved in the eukaryotic organisms. The discovery of multiple forms of FGF-2 generated by alternative translation from AUG and non-canonical CUG codons on the same mRNA transcript has led to the characterization of a low molecular weight (LMW) FGF-2 form and various high molecular weight (HMW) forms (four in humans). In this review, we discuss the biochemical features and biological activities of the different FGF-2 forms. In particular, we focus on the properties that are unique to the HMW forms and its biological functions

Cardiovascular interventions that restore blood circulation to ischemic areas are accompanied by significant tissue damage, which triggers a vascular remodeling response that may result in restenosis of blood conduits. Early endothelial dysfunction and/or impairment is the early event of a cascade that leads, through an inflammatory response and dedifferentiation of medial smooth muscle cells with abundant deposition of extracellular matrix, to intimal hyperplasia. Here we present the molecular and cellular mechanisms of intimal hyperplasia secondary to vascular injury and discuss the potential role of therapeutic modulation of the intracellular signaling pathways that differentially effect vascular endothelial and smooth muscle cells. The role of mitogen-activated protein kinases (MAPKs) and the outcome of their modulation in these processes are highlighted here as they provide a promising therapeutic target for prevention of restenosis

Mitral valve prolapse (MVP) is a very common clinical condition that refers to a systolic billowing of one or both mitral valve leaflets into the left atrium. Improvements of echocardiographic techniques and new insights in mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. MVP can be sporadic or familial, demonstrating autosomal dominant and X-linked inheritance. Three different loci on chromosomes 16, 11 and 13 have been found to be linked to MVP, but no specific gene has been described. Another locus on chromosome X was found to cosegregate with a rare form of MVP called 'X-linked myxomatous valvular dystrophy'. MVP is more frequent in patients with connective tissue disorders including Marfan syndrome, Ehlers-Danlos and osteogenesis imperfecta. The purpose of this review is to describe previous studies on the genetics and prevalence of MVP. The report warrants the need for further genetically based studies on this common, albeit not fully understood, clinical entity

VEGF and TGF-beta1 are potent angiogenesis inducers with opposing effects on endothelial cells. TGF-beta1 induces apoptosis; VEGF protects endothelial cells from apoptosis. We found that TGF-beta1 promotes endothelial cell expression of FGF-2, which up-regulates VEGF synthesis. Inhibition of VEGF signaling through VEGF receptor 2 (flk-1) abrogates TGF-beta1-induced apoptosis and p38(MAPK) activation. Inhibition of p38(MAPK) blocks TGF-beta1-induced apoptosis, showing that VEGF/flk-1-mediated activation of p38(MAPK) is required for TGF-beta1 induction of apoptosis. In the absence of TGF-beta1, VEGF activates p38(MAPK) and promotes endothelial cell survival. However, in context with TGF-beta1, VEGF/flk-1-mediated activation of p38(MAPK) results in apoptosis. Thus, cross-talk between TGF-beta1 and VEGF signaling converts VEGF/flk-1-activated p38(MAPK) into a proapoptotic signal. This finding illustrates an unexpected role of VEGF and indicates that VEGF can be pharmacologically converted into an apoptotic factor, a novel approach to antiangiogenesis therapy

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: C-reactive protein (CRP), an acute phase reactant, is an independent predictor of coronary artery syndromes and a mediator of the vascular response to injury. CRP has been found in arterialized vein grafts and has been linked to atherogenesis; however, its involvement in vein graft early failure or intimal hyperplasia has not been assessed. This study was designed to investigate the mechanism(s) of CRP up-regulation in arterialized vein grafts. METHODS: Carotid artery bypass with arterialized jugular vein grafts (AVG) was performed in 18 dogs. AVG were harvested at 3, 8, and 24 hours and 4, 14, and 28 days, using the femoral vein obtained at the time of AVG harvest as a control. Serum CRP levels were characterized by enzyme-linked immunosorbent assay; AVG expression of CRP was studied by immunofluorescence, Western blotting, in situ hybridization, Northern blotting, and quantitative RT-PCR. RESULTS: CRP levels peaked at 24 hours in serum and AVG but remained at baseline in control veins. By double immunofluorescence, CRP was associated with the media and adventitia of AVG. However, Northern blotting analysis showed no CRP mRNA expression in AVG. Reverse transcriptase polymerase chain reaction analysis confirmed the lack of up-regulation of CRP in AVG. CONCLUSION: CRP levels are increased in AVG, peaking 24 hours after arterialization. However, no significant production of CRP was detected in AVG. Therefore, increased CRP levels within AVG appear to originate mostly from CRP diffusion from the systemic circulation. These results have significant implications for the development of strategies aimed at blocking CRP up-regulation in bypass grafts