Faculty Bibliography

OBJECTIVE: Atheromatous aortic disease is a risk factor for excessive mortality and stroke in patients undergoing coronary artery bypass grafting. Outcomes of off-pump coronary artery bypass grafting and coronary artery bypass grafting with cardiopulmonary bypass in patients with severe atheromatous aortic disease were compared by propensity case-match methods. METHODS: Routine intraoperative transesophageal echocardiography identified 985 patients undergoing isolated coronary artery bypass grafting with severe atheromatous disease in the aortic arch or ascending aorta. Off-pump coronary artery bypass grafting was performed in 281 patients (28.5%). Propensity matched-pairs analysis was used to match patients undergoing off-pump coronary artery bypass grafting (n = 245) with patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. RESULTS: Univariate analysis revealed decreased hospital mortality (16/245, 6.5% vs 28/245, 11.4%; P =.058) and stroke prevalence (4/245, 1.6% vs 14/245, 5.7%; P =.03) in off-pump coronary artery bypass grafting compared with coronary artery bypass grafting with cardiopulmonary bypass. Freedom from any postoperative complication was higher in off-pump coronary artery bypass grafting compared with coronary artery bypass grafting with cardiopulmonary bypass (226/245, 92.2% vs 196/245, 80.0%; P <.001). Multivariable analysis of preoperative risk factors showed that increased hospital mortality was associated with coronary artery bypass grafting with cardiopulmonary bypass (odds ratio = 2.7; P =.01), fewer grafts (P =.05), acute myocardial infarction (odds ratio = 11.5; P <.001), chronic obstructive pulmonary disease (odds ratio = 2.4; P =.03), previous cardiac surgery (odds ratio = 10.2, P =.05), and peripheral vascular disease (odds ratio = 2.1; P =.05). Cardiopulmonary bypass was the only independent risk factor for stroke (odds ratio = 3.6, P =.03). At 36 months' follow-up, comparable survival was observed in the off-pump coronary artery bypass grafting and coronary artery bypass grafting with cardiopulmonary bypass groups (74% vs 72%). Multivariable analysis revealed that renal disease (P <.001), advanced age (P <.001), previous myocardial infarction (P =.03), and lower number of grafts (P =.02) were independent risks for late mortality. CONCLUSIONS: Patients with severe atherosclerotic aortic disease who undergo off-pump coronary artery bypass grafting have a significantly lower prevalence of hospital mortality, perioperative stroke, and overall complications than matched patients who underwent coronary artery bypass grafting with cardiopulmonary bypass. Routine intraoperative transesophageal echocardiography identifies severe atheromatous aortic disease and directs the choice of surgical technique

OBJECTIVE: Long-term durability of saphenous vein grafts used for coronary artery bypass grafting is limited by neointimal formation. Arterial vascular injury is known to activate intracellular mitogen-activated protein kinases, including extracellular signal-regulated kinases and c-jun N-terminal kinases, that affect cell differentiation, proliferation, migration, and apoptosis. This study tests the hypothesis that these mitogen-activated protein kinases are activated in saphenous veins during preparation for coronary artery bypass grafting. METHODS: Saphenous veins were harvested from 10 patients undergoing coronary artery bypass grafting. A specimen from each vein was placed in ice-cold lysis buffer immediately after harvesting (t = 0). The remaining tissue was incubated at room temperature in normal saline, 0.1% dimethylsulfoxide (vehicle), or 50 mmol/L PD98059 (mitogen-activated protein kinase kinase-1/2 inhibitor) until the vein was grafted (mean 50 minutes). To study kinetics of intracellular signaling pathways, canine saphenous veins were harvested, and mitogen-activated protein kinases and PI-3 kinase pathways were studied after different incubation time intervals. Extracted proteins were analyzed by Western blotting or in vitro kinase assay. RESULTS: The human saphenous veins showed elevated levels of active extracellular signal-regulated kinase after harvesting (t = 0) and prior to implant (t = 1). Incubation with PD98059 resulted in decreased activation of extracellular signal-regulated kinase. Kinetics of canine saphenous veins showed extracellular signal-regulated kinase and c-jun N-terminal kinase activation, in a time-dependent manner, along with activation of the growth factor-regulated PI3 kinase pathway. CONCLUSIONS: This study characterizes activation of extracellular signal-regulated kinases and c-jun N-terminal kinases during vein graft preparation and demonstrates the ability to inhibit extracellular signal-regulated kinase activation by simple incubation with a specific inhibitor. Further studies are needed to evaluate the significance of these findings with respect to graft durability.

BACKGROUND: Patients after cardiac operation pose a challenge to the treating physician-these patients may become critically ill and are among the most difficult to image using transthoracic echocardiography. Several factors contribute to this, including difficulties in positioning the patient, inability of the patient to cooperate with instructions, surgical dressings, and hyperinflated lungs. Transesophageal echocardiography may be performed when transthoracic echocardiography is not diagnostic; however, transesophageal echocardiography is semi-invasive and does not lend itself to prolonged or repeated monitoring. METHODS: Recently, a new approach to echocardiography for use in the patient after operation has been introduced with the modification of the standard mediastinal drainage tube to allow for substernal epicardial echocardiography (SEE). The SEE tube has 2 lumens. The first allows for routine mediastinal drainage and the second has a blind end that permits the insertion of a standard transesophageal echocardiographic probe for high-resolution imaging as often as is desired over the period during which the mediastinal tube is in place. CONCLUSION: This article reviews the technique of SEE including a description of the method of performance of SEE (with representative images), a review of the published literature on this new modality, examples of clinical use, and a discussion of the advantages, indications, and limitations of SEE with an eye toward future directions for research

BACKGROUND: Patients with severe atheromatous aortic disease (AAD) who undergo coronary artery bypass (CABG) have an increased risk of death and stroke. We hypothesized that in these high risk patients, off-pump coronary artery bypass (OPCAB) technique is associated with lower morbidity and mortality. METHODS AND RESULTS: Between June 1993 and January 2002, 5737 patients undergoing CABG had routine intra-operative TEE with 913 (15.9%) found to have severe AAD in the aortic arch or ascending aorta. Of these, 211 patients who underwent OPCAB were matched with 211 on-pump CABG patients by age, ejection fraction, history of stroke, cerebrovascular disease, diabetes, renal disease, nonelective operation, and previous cardiac surgery. Hospital mortality was 11.4% (24/211) for on-pump CABG and 3.8% (8/211) for OPCAB (P=0.003). Multivariate analysis revealed that increased mortality was associated with on-pump CABG (P=0.001), acute MI (P=0.03), number of grafts (P=0.01), age (P=0.01), history of stroke or cerebrovascular disease (P=0.04), CHF (P=0.02), and peripheral vascular disease (P=0.03). Multivariate analysis showed that OPCAB technique was associated with decreased stroke (P=0.05). Freedom from any complication was 78.7% for on-pump CABG and 91.9% for OPCAB (P<0.001). At 36 month follow-up multivariate analysis revealed that increased mortality was associated with age (P=0.001), previous MI (P=0.03), and renal disease (P=0.04), whereas increased survival was associated with increased number of grafts (P=0.001) and OPCAB (P=0.01). CONCLUSIONS: OPCAB surgery in patients with severe AAD is associated with lower risk of death, stroke and complications and improved mid-term survival. Routine intra-operative TEE allows identification of these patients and directs choice of appropriate surgical technique

OBJECTIVE: The development of intimal hyperplasia involves smooth muscle cell (SMC) migration into the intima and proliferation. Matrix metalloproteinases and their tissue inhibitors play important roles in this process. In this study, we describe a novel in vitro model for studying SMC migration through the vessel wall. METHODS AND RESULTS: Human aortic SMCs (hASMCs) labeled with 125I-iododeoxyuridine or unlabeled were grown on the stromal aspect of the human amniotic membrane. Mechanical damage to endothelial cells grown on the basement membrane and addition of growth factors or platelets were characterized for their effect on SMC migration into the stroma both by histological methods and by measuring the radioactivity associated with the membrane after removal of noninvasive SMCs. To assess the reliability of the model, the cells were infected with a recombinant adenovirus encoding the tissue inhibitor of metalloproteinase-1 (TIMP-1). Addition of a platelet-derived growth factor gradient stimulated hASMC infiltration into the stroma. This effect was abolished with TIMP-1-transduced hASMC, confirming that TIMP-1 overexpression blocks SMC invasion of the stroma. CONCLUSIONS: This in vitro model of SMC migration in the vessel wall provides an inexpensive, quantitative, and reliable tool to study the molecular and cellular mechanisms of intimal hyperplasia

Basic fibroblast growth factor (FGF-2) and matrix metalloproteinases (MMPs) play key roles in vascular remodeling. Because FGF-2 controls a number of proteolytic activities in various cell types, we tested its effect on vascular endothelial cell expression of MMP-3 (stromelysin-1), a broad-spectrum proteinase implicated in coronary atherosclerosis. Endothelial cells (EC) from FGF-2-/- mice are highly responsive to exogenous FGF-2 and were therefore used for this study. The results showed that treatment of microvascular EC with human recombinant FGF-2 results in strong induction of MMP-3 mRNA and protein expression. Upregulation of MMP-3 mRNA by FGF-2 requires de novo protein synthesis and activation of the ERK-1/2 pathway. FGF-2 concentrations (5-10 ng/ml) that induce rapid and prolonged (24 h) activation of ERK-1/2 upregulate MMP-3 expression. In contrast, lower concentrations (1-2 ng/ml) that induce robust but transient (<8 h) ERK-1/2 activation are ineffective. Inhibition of ERK-1/2 activation at different times (-0.5 h to +8 h) of EC treatment with effective FGF-2 concentrations blocks MMP-3 upregulation. Thus, FGF-2 induces EC expression of MMP-3 with a threshold dose effect that requires sustained activation of the ERK-1/2 pathway. Because FGF-2 controls other EC functions with a linear dose effect, these features indicate a unique role of MMP-3 in vascular remodeling