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

BACKGROUND: Percutaneous aortic valve replacement (PAVR) trials are ongoing in patients with an elevated European System for Cardiac Operative Risk Evaluation (EuroSCOREs), patients believed to have high mortality rates and poor long-term prognoses with valve replacement surgery. It is, however, uncertain that the EuroSCORE model is well calibrated for such high-risk AVR patients. We evaluated EuroSCORE prediction vs a single institution's surgical results in this target population. METHODS: From January 1996 through March 2006, 731 patients with EuroSCOREs of 7 or higher underwent isolated AVR. In this cohort, 313 (42.8%) were septuagenarians, 322 (44.0%) were octogenarians or nonagenarians, 233 (31.9%) had had previous cardiac procedures, 237 (32.4%) had atheromatous aortas, and 127 (17.4%) had cerebrovascular disease. A minimally invasive approach was used in 469 (64.2%). Data collection was prospective. Long-term survival was computed from the Social Security Death Benefit Index. RESULTS: The mean EuroSCORE was 9.7 (median, 10), and the mean logistic EuroSCORE was 17.2%. Actual hospital mortality was 7.8% (57 of 731). Multivariate analysis showed ejection fraction of less than 0.30 (p = 0.002; odds ratio [OR], 3.13), chronic obstructive pulmonary disease (p = 0.019; OR, 2.14), and peripheral vascular disease (p = 0.048; OR, 2.13) were significant predictors of hospital mortality. Complication(s) occurred in 73 patients (9.9%). Freedom from all-cause death (including hospital mortality) was 72.4% at 5 years (n = 152). Age (p < 0.001), previous cardiac operations (p < 0.014; OR, 1.51), renal failure (p < 0.002; OR, 2.37), and chronic obstructive pulmonary disease (p < 0.007; OR, 1.30) were predictors of worse survival. CONCLUSIONS: Logistic EuroSCORE greatly overpredicts mortality in these patients. Five-year survival is good, unlike suggestions from earlier EuroSCORE analyses. This raises concern about unknown long-term percutaneous prosthesis function. Clinical trials for these patients must include randomized surgical controls and have long-term end points

BACKGROUND: Disparities associated with race, particularly African-American race, in access to medical and surgical care for patients with cardiac disease have previously been documented. The purpose of this study was to determine the presentation, etiology, and hospital outcome differences between African-American patients and white patients with regard to surgically corrected mitral valve disease. METHODS: All 1,425 adult patients who underwent first time, isolated mitral valvuloplasty or mitral valve replacement by the same group of surgeons at New York University Medical Center and Bellevue Hospital Center between 1993 and 2003 were studied. RESULTS: African Americans (n = 123, 8.6%) were significantly younger (45.6 +/- 14.4 versus 60.5 +/- 15.3 years) and had significantly higher incidences of diabetes mellitus, renal failure, congestive heart failure, endocarditis, and rheumatic mitral disease; whereas whites (n = 1,302, 91.4%) more commonly had degenerative mitral disease. African Americans were less likely to undergo mitral valvuloplasty. There were no significant differences in the incidences of postoperative complications or hospital mortality (2.4% African American versus 5.1% white, p = 0.19). CONCLUSIONS: African Americans present for mitral valve surgery at a significantly younger age than whites and with higher incidences of many risk factors. Whether presentation at a significantly earlier age in African Americans is a result of failures in primary care or an enhanced susceptibility to the process of mitral disease and comorbidities remains to be determined. African Americans were less likely to undergo mitral valvuloplasty, which may have an effect on long-term outcome. Improved screening in this racial group will facilitate earlier referral, increasing the potential for mitral valvuloplasty

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

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

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