Faculty Bibliography

OBJECTIVE: Vein graft arterialization results in activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases-1 and -2 (ERK1/2), which have been implicated in cell proliferation, migration, and apoptosis. The goal of our study was to characterize the effect of MAPK inhibition on intimal hyperplasia (IH) in arterialized vein grafts in hypercholesterolemic rabbits. METHODS: Reversed bilateral jugular vein to common carotid artery interposition grafts were constructed in 16 New Zealand White rabbits. The veins were incubated for 30 min prior to grafting with either the synthetic ERK1/2 activation inhibitor UO126 or the control vehicle. Vein graft and control jugular vein were harvested 3 h, 1 d, and 28 d after arterialization for histological and biochemical analyses. RESULTS: Treatment with UO126 was associated with 31% reduction in mean intimal area (1.68 +/- 0.78 mm(2)versus 2.44 +/- 1.65 mm(2); mean +/- SD; P = 0.036) relative to controls. The intima-to-media ratio of UO126-treated vein grafts decreased by 29% (0.53 +/- 0.04 versus 0.74 +/- 0.06; mean +/- SD; P < 0.01) compared to controls, vehicle-treated vein grafts. There was also significant increase in apoptosis in UO126-treated vein graft medial cell layer at 1 d. CONCLUSION: Topical administration of UO126 before vein grafting significantly decreases IH in arterialized vein grafts in hypercholesterolemic rabbits. These results may have significant implications for the development of strategies aimed at blocking or reducing IH in bypass grafts. Therefore, further evaluation of this simple strategy to improve vein graft patency following coronary artery or peripheral vascular bypass surgery is warranted

The fgf-2 gene encodes low molecular weight (LMW, 18 kDa) and high molecular weight (HMW, 22-24 kDa) forms that originate from alternative translation of a single mRNA and exhibit diverse biological functions. HMW fibroblast growth factor-2 (FGF-2) inhibits cell migration and induces cell transformation or growth arrest in a cell type- and dose-dependent fashion. Conversely, LMW FGF-2 upregulates both cell proliferation and migration in most cell types. Although transcriptional and translational regulation of HMW and LMW FGF-2 has been extensively investigated, little is known about post-translational control of their relative expression. Here we report that thrombin, a key coagulation factor and inflammatory mediator, cleaves HMW FGF-2 into an LMW FGF-2-like form that stimulates endothelial cell migration and proliferation. The effect of thrombin on these cell functions requires HMW FGF-2 cleavage. This post-translational control mechanism adds a novel level of complexity to the regulation of FGF-2, and links the activities of thrombin and FGF-2 in patho-physiological processes in which both molecules are expressed

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: 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

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

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

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

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