Although the valved homograft is widely used to establish a connection between the right ventricle (RV) and the pulmonary artery (PA), its durability remains controversial. In the present study, the data on 141 valved homograft implantations in 107 consecutive patients performed from January 1990 to June 2000 were analyzed. The mean follow-up period was 4.6 years (range, 0.2-9.4 years). The clinical data, including clinic records, operative notes, follow-up visits, and letters from referring physicians, were analyzed with particular reference to variables associated with early and late mortality, deterioration of the homograft, and risk factors for patient survival and homograft failure. Early death occurred in 7.5% (n=8) of the cases, and each of these patients died without leaving the hospital. Late death occurred in 2 patients, for whom the cause of death was suggested to be related to arrhythmia. Thirteen patients underwent catheter intervention (ie, balloon dilatation and/or stenting) and 8 of these did not require homograft replacement following catheterization. The overall survival rate at both 3 years and 5 years was 88.9+/-3.4%. Cumulative freedom from total homograft failure was 82.5+/-3.6% at 1 year; 61.6+/-5.0% at 3 years; and 42.4+/-6.2% at 5 years. In comparison with 2 criteria of homograft failure (ie, total homograft failure and homograft failure including catheter intervention), the incidence of freedom from homograft failure including catheter intervention was lower than that of total homograft failure, although the difference was not statistically significant. In the multivariate analysis, significant risk factors with respect to patient survival were homograft replacement and the use of expanded polytetrafluoroethylene (ePTFE); those judged to be significant with respect to homograft failure were total repair with first homograft implantation and diagnosis of truncus arteriosus. The valved homograft was thus considered an appropriate choice of conduit between the RV and the PA, and it provided excellent patient survival. However, this type of homograft did not provide a completely permanent solution for the repair of complex cardiac anomalies. Therefore, the use of ePTFE for homograft extensions should be avoided. Finally, the results suggest that catheter intervention plays an important role in the longevity of the implanted homograft.

Kovacich, J. Craig BS; Boyle, Edward M. Jr., MD; Needle, David MD; Maier, Ronald V. MD Author Information

NephrologyVolume 5, Issue 3 p. A105-A105 INHIBITION OF TISSUE FACTOR EXPRESSED BY ISCHAEMIC CARDIOMYOCYTES REDUCES INFARCT SIZE AFTER MYOCARDIAL ISCHEMIA/REPERFUSION INJURY Erlich Jh, Erlich Jh The Scripps Research Institute, La Jolla, CA 92037 USA, Dept of Nephrology, Prince of Wales Hospital, Randwick, NSW 2031, Australia,Search for more papers by this authorBoyle Em, Boyle Em The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorSantucci Ra, Santucci Ra The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorKovacich Jc, Kovacich Jc The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorLabriola J, Labriola J The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorFearns C, Fearns C The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorMorgan En, Morgan En The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorYun W, Yun W The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorLuther T, Luther T Technical University of Dresden, Dresden, Germany D-01307.Search for more papers by this authorPohlman Th, Pohlman Th The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorVerrier Ed, Verrier Ed The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorMackman N, Mackman N The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this author Erlich Jh, Erlich Jh The Scripps Research Institute, La Jolla, CA 92037 USA, Dept of Nephrology, Prince of Wales Hospital, Randwick, NSW 2031, Australia,Search for more papers by this authorBoyle Em, Boyle Em The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorSantucci Ra, Santucci Ra The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorKovacich Jc, Kovacich Jc The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorLabriola J, Labriola J The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorFearns C, Fearns C The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this authorMorgan En, Morgan En The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorYun W, Yun W The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorLuther T, Luther T Technical University of Dresden, Dresden, Germany D-01307.Search for more papers by this authorPohlman Th, Pohlman Th The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorVerrier Ed, Verrier Ed The University of Washington, Seattle, WA 98195 USA,Search for more papers by this authorMackman N, Mackman N The Scripps Research Institute, La Jolla, CA 92037 USA,Search for more papers by this author First published: 09 October 2008 https://doi.org/10.1046/j.1440-1797.2000.005003a105.xCitations: 1Read the full textAbout ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume5, Issue3October 2000Pages A105-A105 RelatedInformation

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

In the process of harvesting an organ for transplantation, flushing the organ with various perfusates, and, ultimately, implanting the organ into the recipient, a number of abnormal hemodynamic forces have an impact on the microvasculature of the graft. First, the microvasculature can be acutely overdistended by the preservation solution infused at the time of organ harvest from the donor. Second, there is a loss of the usual pulsatile blood flow when the organs lie flaccid on ice during the transport period. At this point, the microvasculature is sensing a minimal intravascular pressure. Finally, when the graft is implanted, the conditions of reperfusion may have an impact on graft function as well. It is increasingly appreciated that extremes in perfusion pressure may ultimately affect graft function both in the short and long term. Inasmuch as these are variables that can be controlled, it is important to define the optimal hemodynamic conditions for organ preservation and reperfusion. Recently, a great deal has been learned about how the mechanical forces of flowing blood on the vessel wall interact with other endogenous and exogenous factors to regulate microvascular behavior [1Gotlieb A.I. Langille B.L. The role of rheology in atherosclerotic coronary artery disease.in: Fuster V. Ross R. Topol E.J. Atherosclerosis and coronary artery disease. vol. 2. Lippincott-Raven Publishers, Philadelphia1996: 595-606Google Scholar]. These forces can be in the form of pressure, tension (or stretch), and shear. Pressure is the force acting inward on the surface of the tissue elements. Tension pulls tissue along one axis, normally without constraining the tissue in the other directions. Shear stresses are small forces that cause very modest deformation of the full thickness of the arterial wall, but are the most physiologically significant in terms of cellular activation [1Gotlieb A.I. Langille B.L. The role of rheology in atherosclerotic coronary artery disease.in: Fuster V. Ross R. Topol E.J. Atherosclerosis and coronary artery disease. vol. 2. Lippincott-Raven Publishers, Philadelphia1996: 595-606Google Scholar]. What is clear is that many of these mechanical forces are transduced to biologic activity, particularly at the endothelial cell level. Because of their location at the interface between the blood and the body’s tissues, endothelial cells are uniquely situated to respond to alterations in hemodynamic forces. Specifically, evidence suggests that endothelial cells serve as mechanoreceptors by which changes in blood flow or tissue stress and strain are recognized by the endothelial cellular membranes [2Ando J. Kamiya A. Blood flow and vascular endothelial cell function.Front Med Biol Eng. 1993; 5: 245-264PubMed Google Scholar]. At the cellular level, when endothelial cells are exposed to abnormal hemodynamic forces, they undergo conformational changes, redistribution of cytoskeleton and organelles, cell proliferation, production of extracellular matrix, and transport of macromolecules [1Gotlieb A.I. Langille B.L. The role of rheology in atherosclerotic coronary artery disease.in: Fuster V. Ross R. Topol E.J. Atherosclerosis and coronary artery disease. vol. 2. Lippincott-Raven Publishers, Philadelphia1996: 595-606Google Scholar]. In addition to alterations in the physical properties of the endothelial cell layer, when the endothelium senses different flow environments, there are marked changes in cell signaling, resulting in the activation of ion channels and G proteins and the induction of oscillations in intracellular calcium concentration [3Barakat A.I. Responsiveness of vascular endothelium to shear stress potential role of ion channels and cellular cytoskeleton.Int J Mol Med. 1999; 4: 323-332PubMed Google Scholar, 4Topper J.N. Gimbrone Jr, M.A. Blood flow and vascular gene expression fluid shear stress as a modulator of endothelial phenotype.Mol Med Today. 1999; 5: 40-46Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 5Ishida T. Takahashi M. Corson M.A. Berk B.C. Fluid shear stress-mediated signal transduction how do endothelial cells transduce mechanical force into biological responses?.Ann N Y Acad Sci. 1997; 811: 12-23Crossref PubMed Scopus (119) Google Scholar]. These changes ultimately promote long-term alterations in endothelial properties through the induction of specific genes that encode new proteins [5Ishida T. Takahashi M. Corson M.A. Berk B.C. Fluid shear stress-mediated signal transduction how do endothelial cells transduce mechanical force into biological responses?.Ann N Y Acad Sci. 1997; 811: 12-23Crossref PubMed Scopus (119) Google Scholar]. Genes that are transcriptionally activated in this manner include a number of growth factors, cytokines, inflammatory adhesion molecules, and procoagulant proteins [6Schwachtgen J.L. Houston P. Campbell C. et al.Fluid shear stress activation of egr-1 transcription in cultured human endothelial and epithelial cells is mediated via the extracellular signal-related kinase 1/2 mitogen-activated protein kinase pathway.J Clin Invest. 1998; 101: 2540-2549Crossref PubMed Scopus (174) Google Scholar, 7Morigi M. Zoja C. Figliuzzi M. et al.Fluid shear stress modulates surface expression of adhesion molecules by endothelial cells.Blood. 1995; 85: 1696-1703PubMed Google Scholar, 8Nagel T. Resnick N. Atkinson W.J. et al.Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells.J Clin Invest. 1994; 94: 885-891Crossref PubMed Google Scholar, 9Grabowski E.F. Zuckerman D.B. Nemerson Y. The functional expression of tissue factor by fibroblasts and endothelial cells under flow conditions.Blood. 1993; 81: 3265-3270PubMed Google Scholar, 10Grabowski E.F. Lam F.P. Endothelial cell function, including tissue factor expression, under flow conditions.Thromb Haemost. 1995; 74: 123-128Crossref PubMed Scopus (47) Google Scholar, 11Lin M.C. Almus-Jacobs F. Chen H.H. et al.Shear stress induction of the tissue factor gene.J Clin Invest. 1997; 99: 737-744Crossref PubMed Scopus (209) Google Scholar]. In this way, fluctuations in hemodynamic force sensed at the microvascular level can contribute to a dysfunctional, activated endothelial cell layer that promotes vasomotor dysfunction, neutrophil adhesion, and increased microvascular thrombogenicity on reperfusion. Coupled with the oxidative stress-induced endothelial cell activation that is inherent in the organ preservation process, one can appreciate how organ function can be drastically impaired on reperfusion [12Soler H.M. Watkins M.T. Albadawi H. et al.Effects of oxygen tension and shear stress on human endothelial cell prostacyclin production.J Surg Res. 1997; 67: 46-53Abstract Full Text PDF PubMed Scopus (14) Google Scholar]. Although a great deal has been learned about how abnormal hemodynamic stresses have an impact on endothelial cell activation in vitro, comparatively little is known about how this affects pathophysiology in vivo. Specifically, little is known about how these forces alter clinically significant events, such as organ preservation for transplantation. In the present study, Halldrosson and colleagues [13Halldorsson A.O. Kronon M.T. Allen B.S. Rahman S. Wang T. Lowering reperfusion pressure reduces the injury after pulmonary ischemia.Ann Thorac Surg. 2000; 69: 198-204Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] have nicely illustrated that the perfusion pressure of the initial reperfusate contributes to the degree of tissue injury seen on lung reperfusion. The premise of the paper is that by controlling the conditions of reperfusion at a lower pressure, they demonstrate improved pulmonary graft preservation. This line of inquiry complements the shear stress–related endothelial biology literature, where it has been demonstrated that high, low, and fluctuating shear forces are actively involved in the well-characterized endothelial injury patterns that contribute to the development of atherosclerosis [14Boyle Jr, E.M. Lille S.T. Allaire E. et al.Endothelial cell injury in cardiovascular surgery atherosclerosis.Ann Thorac Surg. 1997; 63: 885-894Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Although the role of high or low shear stress as an inciting factor in the development of atherosclerosis is still being uncovered, what is clear is that at many sites at which advanced lesions are predictably found, such as at branch and bend points in the vasculature, there are marked abnormalities in flow with wide, complex fluctuations in the degree of shear stress [1Gotlieb A.I. Langille B.L. The role of rheology in atherosclerotic coronary artery disease.in: Fuster V. Ross R. Topol E.J. Atherosclerosis and coronary artery disease. vol. 2. Lippincott-Raven Publishers, Philadelphia1996: 595-606Google Scholar]. Comparatively little is known about the acute microvascular responses to abnormal hemodynamic forces in vivo. Because a transplant graft undergoes complex fluctuations in the degree of hemodynamic stress throughout the preservation process, it is likely vulnerable to endothelial cell injury acutely just as the vasculature is to atherosclerosis chronically. Judging from what is known, it is a reasonable hypothesis that avoiding high, low, and fluctuating degrees of hemodynamic stress at the endothelial cell layer is important in organ preservation. In vivo, organs are known to tightly autoregulate blood flow to avoid either too high or too low a pressure. The teleologic importance of microvascular autoregulation is lost in the transplanted graft when the graft is flushed, left flaccid on ice, and then uncontrollably reperfused after implantation. Because the organ is no longer able to autoregulate, it is perhaps up to the transplant surgeon to determine these conditions. Early in the history of transplantation, surgeons used continuous organ perfusion to prevent the long period of time when the organs sat on ice. A number of studies demonstrated far superior preservation with continuous perfusion devices compared with storing organs on ice alone [15Rao V. Feindel C.M. Weisel R.D. et al.Donor blood perfusion improves myocardial recovery after heart transplantation.J Heart Lung Transplant. 1997; 16: 667-673PubMed Google Scholar, 16Sellke F.W. Richter H.W. Dunphy G. et al.Twenty-four-hour heart preservation using continuous cold perfusion and copper (II) complexes.J Surg Res. 1998; 80: 171-176Abstract Full Text PDF PubMed Scopus (5) Google Scholar]. In this study, the authors’ work demonstrates that once the organ is reperfused, the conditions of reperfusion can still affect organ function, and that a sudden uncontrolled increase in pressure may in fact be damaging. Taken together, these studies demonstrate the importance of the perfusion conditions in all phases of the preservation process. It is tempting to speculate from what is available in the literature that avoiding overdistention of the organ on the initial infusion of the perfusate, continuously perfusing the organ during transport, and, ultimately, controlling the perfusion pressure on reperfusion to allow a more gradual increase in pressure will lead to maximal recovery of a preserved organ. Simply put, avoiding too high, too low, and, perhaps, too quick a change in perfusion pressure may be maximally beneficial. On a broader scale, it is important to recognize that abnormal forces imposed on vascular endothelial cells may have implications beyond organ preservation. This may be particularly true in the setting of myocardial protection during ischemic cardiac arrest, the role of pulseless flow on the systemic inflammatory response to cardiopulmonary bypass, and the influence of bypass conduit harvest and handling on outcomes in coronary artery surgical procedures. It is only with studies such as these, in which investigators model clinically significant events in whole-organ preparations, that we will be able to better bridge the gap between the growing basic rheology literature and the clinical acute organ dysfunction seen in the setting of cardiovascular surgery.

Dissection of the thoracic aorta presents some of the greatest challenges in cardiovascular disease. The diagnosis often requires clinical suspicion. Patients present with a spectrum of symptoms, which can include acute myocardial ischemia or failure, neurologic events, visceral ischemia, and/or peripheral vascular insufficiency. Chest radiographs may suggest the diagnosis. Echocardiography (transthoracic and transesophageal), CT scan, MRI, and angiography are all applicable and have sensitivity of 80 to 100%. Angiography is particularly useful if there is clinical evidence of" malperfusion" of a critical branch vessel.1Coselli JS Koksoy C Aortic dissections.in: Franko KL Verrier ED Advanced therapy in cardiac surgery. BC Decker, Hamilton, Ontario1999: 296-310Google Scholar Once the diagnosis is made, or if there is a suspicion of a diagnosis in an otherwise stable patient, the initial therapy includes antihypertensive therapy with β-blockers, maintaining systolic blood pressures of 110 to 120 mm Hg (or mean of 70 to 80 mm Hg). The subsequent management of aortic dissection is determined by the anatomic extent and the chronicity of presentation. The DeBakey classification includes the following: type I, the dissection involves the ascending aorta, arch, and the various lengths of the descending and abdominal aorta; type II, limited to the ascending aorta and proximal arch; type III, involving the aorta distal to the left subclavian artery, with IIIa being limited to the thoracic aorta, and IIIb involving various degrees of the thoracic abdominal aorta.2DeBakey ME McCollum CH Crawford ES et al.Dissection and dissecting aneurysms of the aorta: twenty-year follow-up of five hundred twenty-seven patients treated surgically.Surgery. 1982; 92: 118-134Google Scholar In the Stanford classification, type A dissections are those that involve the ascending aorta regardless of the site and distal extent to the process, and type B are those that involve the aorta distal to the left subclavian artery.3Daily PO Trueblood HW Stinson EB et al.Management of acute aortic dissections.Ann Thorac Surg. 1970; 10: 237-247Abstract Full Text PDF PubMed Scopus (889) Google Scholar Dissections are further categorized as being acute or chronic, depending on whether or not the duration of symptoms prior to diagnosis is < 2 weeks. The proximal (type A Stanford type and DeBakey types I and II) represent up to 70% of dissections. These patients tend to present with anterior substernal pain, vascular instability, and/or asymmetric upper extremity pulses. Aortic insufficiency is present in up to three fourths of patients. Five percent may have an acute myocardial infarction. The risk of rupture is immediate, with 36% of patients presenting with free rupture or tamponade.1Coselli JS Koksoy C Aortic dissections.in: Franko KL Verrier ED Advanced therapy in cardiac surgery. BC Decker, Hamilton, Ontario1999: 296-310Google Scholar In patients presenting with acute ascending aortic dissections who are not treated surgically, ≥ 50% die within 48 h, and as many as 90% die by 3 months. Thus, the majority of patients are treated as surgical emergencies. Operative mortality ranges from 5 to 30%. Chronic dissections complicated by aortic insufficiency, aneurysmal dilation (> 5 cm), and/or organ ischemia are also managed operatively. Currently, most acute type III (Stanford type B) dissections are initially managed medically, as the mortality of surgical management acutely is at best the same as with medical management (5 to 20%). The friability of the tissues, coagulopathy, and the risk of spinal cord ischemia as well as of distal embolization complicate surgery. A complication specific approach is taken.4Elfteriades JA Lovoulos CJ Coady MA et al.Management of descending aortic dissection.Ann Thorac Surg. 1999; 65: 2002-2005Abstract Full Text Full Text PDF Scopus (202) Google Scholar Patients who fail medical management (usually indicated by persistent pain) or who experience complications (malperfusion, leak, and impending or frank rupture) undergo surgery. There are multiple technical issues that need to be considered on an individual basis with any dissection. A variety of strategies have been employed to reduce the risk of CNS and spinal insult, including hypothermic circulatory arrest, bypass, and CSF drainage. In acute dissections, the major effort is directed at eliminating the proximal false lumen, and in the case of proximal dissections, resuspending the aortic valve as well as addressing any coronary insufficiency that has resulted from the dissection. Persistence of the distal false lumen is not uncommon and may be associated with the risk of subsequent aneurysmal formation and rupture. The adaptation of the gelatin-resorcinol-formal glue has allowed easier approximation of the intimal flap back to the media, thereby obliterating the false lumen, and allowing simpler anastomotic technique.1Coselli JS Koksoy C Aortic dissections.in: Franko KL Verrier ED Advanced therapy in cardiac surgery. BC Decker, Hamilton, Ontario1999: 296-310Google Scholar Performing the distal anastomosis in an "open" fashion, allowing maximum visualization, may be associated with decreased incidence of false lumen persistence, but must be weighed against the neurologic and hemostatic consequences of circulatory arrest.5Nguyen B Muller M Kipfer B et al.Different techniques of distal aortic repair in accute type A dissection: impact on late aortic morphology and reoperation.Eur J Cardiothorac Surg. 1999; 15: 500-501Crossref Scopus (51) Google Scholar In chronic dissections, as opposed to the acute setting, the false lumen is often more substantial and directly supplies a branch vessel. In this situation, the distal anastomosis is combined with a fenestration procedure, in which a wedge is cut out of the membrane between the two lumens and flow is maintained to both. There is preliminary experience that suggests a potential role for intervention techniques, including fenestration, and endovascular stent placement.6Nienaber CA Fattori R Lund G et al.Nonsurgical reconstruction of thoracic aortic dissection by stent-graft placement.N Engl J Med. 1999; 340: 1539-1545Crossref PubMed Scopus (923) Google Scholar, 7Dake MD Kato N Mitchell RS et al.Endovascular stent-graft placement for the treatment of acute aortic dissections.N Engl J Med. 1999; 340: 1546-1552Crossref PubMed Scopus (1130) Google Scholar Malperfusion is associated with as high as 50% mortality, and affects 30 to 50% of patients. Fenestration of the membrane distally allows equalization of pressures and can restore flow to the affected branch vessel. This, in conjunction with stent grafts, has been used in selected patients as preliminary or definitive therapy, with perioperative mortality rates as low as 16%.8Slonim SM Miller DC Mitchell RS et al.Percutaneous balloon fenestration and stenting for life-threatening ischemic complications in patients with acute aortic dissection.J Thorac Cardiovasc Surg. 1999; 117: 1118-1126Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar In this episode of CHEST (see page 1271), Mèszàros and associates describe the results of a population-based study over a 27-year period, including 18 patients who died from aortic dissection prehospitalization and 66 patients who were admitted. They describe an incidence of 2.9 in 100,000, largely in patients with atherosclerosis. They note that in 85% of cases, the diagnosis was initially not recognized, resulting in a critical delay in treatment. The overall mortality of those admitted alive within 48 h was approximately 50%. All of these point to the importance of having clinical pathways for acute chest pain. The authors also noted that up to 41% of patients who experienced rupture had a pain window, which implies that this is not a reliable end point for gauging success of medical management. Rather, more aggressive radiologic follow-up may be required. They also describe that 11 of 14 patients with descending aortic dissections experienced rupture (7 patients within 24 h), which would tend to support more aggressive early intervention. Their data are consistent with other reports noting a high rate of branch artery occlusion (41%) and associated increased mortality. Interestingly, they documented in five cases spontaneous healing of the false lumen, an event that is generally considered uncommon. The importance of this article, given the continuing evolution in the management of aortic dissection, is that it refocuses attention on the fact that there are possibly significantly older and more fragile patients who present with this complex process. Survival is linked critically with the early diagnosis and an appropriate decision between surgical and medical management. Surgical outcomes may be improved by newer intervention techniques. As the population gets older, the prevalence of aortic dissection will increase, and with it so will the need for more creative and specific strategies.

The authors hypothesized that augmenting skeletal muscle adenosine 3',5'-cyclic monophosphate (cAMP) levels could reduce tissue inflammation and improve muscle survival in response to ischemia/ reperfusion (I/R) injury. Gracilis muscle flaps in male Wistar rats were subject to 4 hr of ischemia followed by 3 hr of reperfusion, to assess neutrophil accumulation and microvessel tone, or by 24 hr to evaluate percentage of muscle survival. Animals were grouped as follows: positive (saline) or negative (sham) control, or with infused cAMP elevating agents (8 Bromo-cAMP (8 Br-cAMP) or forskolin). Radioimmunoassay demonstrated significant increases in tissue cAMP levels throughout 3 hr of reperfusion with forskolin, while the 8 Br-cAMP-treated group showed only a temporary increase. Compared with vehicle-infused controls, forskolin administered 5 min prior to reperfusion and repeated as an infusion during the first 45 min of reperfusion, resulted in reduced neutrophil adherence and transmigration, and muscle edema with sustained vasodilatation. The percentage of muscle survival using nitro-blue tetrazolium staining demonstrated enhanced muscle-flap preservation with forskolin. There was no beneficial change in the presence of 8 Br-cAMP These observations suggested that sustained elevation of the cAMP pathway may reduce ischemia-reperfusion injury by decreasing neutrophil-mediated injury and improving vessel tone. Elucidation of the cAMP pathway may provide novel opportunities to modulate ischemia/ reperfusion injury.

BACKGROUND:Platelet-activating factor (PAF) is one of the most potent biological mediators of tissue injury. PAF acetylhydrolase (PAF-AH) is a recently isolated naturally occurring enzyme that hydrolyzes PAF and renders it inactive. We hypothesize that inhibition of PAF with PAF-AH will reduce myocardial ischemia-reperfusion (I/R) injury in vivo.METHODS AND RESULTS:The coronary ligation model was used in New Zealand white rabbits. The large branch of the marginal coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given either 2 mg/kg of vehicle or of PAF-AH. At the completion of 120 minutes of reperfusion, percentage of necrosis, degree of neutrophil infiltration, and measurements of regional contractility were assessed. Data are expressed as the mean+/-SEM and compared by Student's t test or Mann-Whitney ANOVA. Both groups of animals showed an equivalent area at risk; however, 46.7+/-11% was necrotic in the animal treated with vehicle. In contrast, 20.9+/-7.0% was necrotic in the animals treated with PAF-AH (P<0.05). Systolic shortening and wall thickness were significantly greater in those animals treated with PAF-AH at 15, 30, 60, and 120 minutes of reperfusion (P<0.05). Quantification of neutrophil infiltration showed a 62% reduction in the PAF-AH treated animals compared with those treated with vehicle alone.CONCLUSIONS:PAF-AH is a potent cardioprotective agent in an in vivo model of I/R injury.

Cardiopulmonary bypass can result in proinflammatory and procoagulant changes that can contribute to morbidity and mortality in heart surgery patients. These responses, many of which are mediated by activation of endothelial cells, normally serve to repair damaged tissue or as defenses against infection. Once activated in the setting of surgery and trauma, these responses may cause unwarranted tissue destruction if they occur inappropriately or too diffusely. The proinflammatory response results in the release of cytokines and subsequent localization of neutrophils, which can disrupt the endothelial barrier and damage underlying tissue. The procoagulant response is characterized by the transcriptional activation of tissue factor, subsequent thrombin generation with subsequent microvascular thrombosis. Techniques to inhibit endothelial cell activation while attempting to preserve the body's anti-infectious and repair mechanisms are being investigated. These include hypothermia, blockade of adhesion molecules, blocking of chemotactic factors such as interleukin-8, and prevention of transcriptional activation by inhibiting the action of nuclear factor kappa-B, which activates genes involved in this process.

Exacerbation of, rather than improvement in, a hypoxic injury after reperfusion of ischemic tissues is recognized as the specific clinicopathologic entity referred to as ischemia/reperfusion (I/R) injury. Arguably, one of the most common forms of I/R injury occurs during cardiac surgery, which has a mandatory period of myocardial ischemia required to allow surgery in a bloodless, motionless field, followed by coronary artery reperfusion after removal of the aortic cross-clamp. In this review, we examine the endothelial cell activation phenotype that initiates and propagates myocardial I/R injury. Emphasis is given to the biology of one transcription factor, NF-κB, that has the principal role in the regulation of many endothelial cell genes expressed in activated endothelium. NF-κB-dependent transcription of endothelial cell genes that are transcribed in response to I/R injury may be a favorable approach to preventing tissue injury in the setting of I/R. Elucidating safe and effective therapy to inhibit transcription of endothelial cell genes involved in promoting injury after I/R injury may have wide applicability to the patients with heart disease and other forms of I/R injury.

Background. Ischemic preconditioning (IP) is the phenomenon whereby brief episodes of ischemia protect the heart against a subsequent ischemic stress. We hypothesize that activation of the transcription factor NF-kappa B mediates IF.Methods. Rabbits were randomly allocated to one of three groups: (1) 45 minutes of myocardial ischemia followed by 2 hours of reperfusion (I/R); (2) three cycles of 5-minute ischemia and 5 minutes of reperfusion followed by I/R (IP + I/R); or (3) IP in the presence of ProDTC, a specific NF-kappa B inhibitor, followed by I/R (IPProDTC + I/R). Infarct size, indices of regional contractility, and NF-kappa B activation were determined.Results. In preconditioned rabbits (IP + I/R), infarct size was reduced 83% compared with both I/R alone and IPProDTC + I/R groups (p < 0.05). Throughout reperfusion, preconditioned myocardium showed enhanced regional contractile function compared with I/R and IPProDTC + I/R groups (p < 0.05). Gel shift analysis showed NF-kappa B activation with IP that was blocked by ProDTC. I/R and IPProDTC + I/R groups showed NF-kappa B activation with I/R that was absent in preconditioned animals.Conclusions. The cytoprotective effects induced by IP require activation of NF-kappa B. (C) 1999 by The Society of Thoracic Surgeons.

BACKGROUND E-selectin transcription requires binding of transcription factors, NF-kappaB, ATF-2, and HMG-I(Y). Here we characterize the mechanism responsible for the transcriptional downregulation of E-selectin expression. MATERIALS AND METHODS Human umbilical vein endothelial cells (HUVECs) were treated with TNF-alpha for 24 h. HUVEC E-selectin expression was measured by enzyme-linked immunosorbent assay, Northern blotting, and nuclear run-on assays, and NF-kappa B was assessed by electrophoretic gel mobility shift assays (EMSAs). RESULTS (1) E-selectin surface expression peaked at 4 h and then diminished over the next 20 h. (2) Transcription of E-selectin began within 1 h of TNF-alpha exposure and ceased by 8 h, despite continuous stimulation of HUVECs with TNF-alpha. (3) EMSAs revealed persistent binding activity of NF-kappa B proteins to two NF-kappa B-binding sites during 24 h of continuous stimulation with TNF-alpha. However, binding activity of proteins that recognize a third NF-kappa B element, -126 to -116 bp from the transcription start site, was lost after 4 h during 24 h of continuous stimulation with TNF-alpha; ATF-2 binding was unchanged over 24 h stimulation with TNF-alpha. CONCLUSION The termination of E-selectin expression is controlled at the level of transcription, with loss of protein-DNA interactions at only one of three NF-kappa B-binding sites in the E-selectin promoter.

BACKGROUND:Rel/NF-kappaB, an oxidative stress-responsive transcription factor, participates transiently in the control of gene expression. The cellular mechanisms that mediate NF-kappaB activation during ischemia (and during reperfusion in the course of treating ischemia) are not known.METHODS AND RESULTS:To investigate the NF-kappaB activation induced during oxidative stress, we examined human cardiac tissue obtained during surgical procedures requiring cardiopulmonary bypass. In vitro, we examined human umbilical vein endothelial cells (HUVECs) exposed to hypoxia, reoxygenation after hypoxia, or a reactive oxygen intermediate (H(2)O(2)). Electrophoretic mobility shift assays performed on right atrial tissue revealed prominent NF-kappaB activation after hearts had been exposed to ischemia and reperfusion. The assays also showed that NF-kappaB activation was observed in hypoxic HUVECs after reoxygenation and in cultures treated with H(2)O(2) (500 micromol/L). Pervanadate (200 micromol/L) also induced marked NF-kappaB activation in HUVECs, indicating that H(2)O(2)-induced NF-kappaB activation is potentiated by the inhibition of tyrosine phosphatases. Western blotting of cytoplasmic IkappaBalpha demonstrated that NF-kappaB activation induced by oxidative stress was not associated with IkappaBalpha degradation. In contrast, tumor necrosis factor-alpha-induced NF-kappaB activation occurred in concert with degradation of IkappaBalpha. Inhibition of IkappaBalpha degradation with a proteasome inhibitor, MG-115, blocked NF-kappaB activation induced by tumor necrosis factor-alpha; however, MG-115 had no effect on NF-kappaB activation during oxidative stress.CONCLUSIONS:This study demonstrated a stimulus-specific mechanism of NF-kappaB activation in endothelial cells that acts independently of IkappaBalpha degradation and may require tyrosine phosphorylation.

Introduction: Interleukin-8 is thought to play a role in neutrophil activation and transcapillary migration irate the interstitium. Because neutrophils are principal effector cells in acute myocardial ischemia-reperfusion injury, we postulated that the inhibition of interleukin-8 activity with a neutralizing monoclonal antibody directed against rabbit interleukin-8 (ARIL8.2) would attenuate the degree of myocardial injury encountered during reperfusion. Methods: In New Zealand White rabbits, the large branch of the marginal coronary artery supplying most of the left ventricle was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given an intravenous bolus of either 2 mg/kg of ARIL8.2 or 2 mg/kg anti-glycoprotein-120, an isotype control antibody that does not recognize interleukin-8. Al the completion of the 120-minute reperfusion period, infarct size was determined, Results: In the area at risk for infarction, 44.3% +/- 4% of the myocardium was infarcted in the anti-glycoprotein-120 group compared with 24.8% +/- 9% in the ARIL8.2 group (p < 0.005). In control animals, edema and diffuse infiltration of neutrophils were observed predominantly in the infarct zone and the surrounding area at risk, Tissue myeloperoxidase determinations did not differ significantly between groups, indicating that the cardioprotective effect of ARIL8.2 was independent of an effect on neutrophil infiltration. Conclusions: A specific monoclonal antibody that neutralizes interleukin-8 significantly reduces the degree of necrosis in a rabbit model of myocardial ischemia-reperfusion injury.

We studied the capacity of isolated Bacteriodes fragilis outer membrane, B. fragilis NCTC9343 lipopolysaccharide (LPS; endotoxin), and B. fragilis NCTC9343 capsular polysaccharides to activate human umbilical vein endothelial cell (HUVEC) monolayers. To assess HUVEC activation, E-selectin expression was measured by enzyme-linked immunosorbent assay (ELISA), Northern blot analysis for E-selectin-specific mRNA, and electrophoretic gel mobility shift assay (EMSA) for NF-kappa B, a transcription factor necessary for E-selectin gene activation. Exposure of HUVECs to B. fragilis outer membrane fractions, separated from other components of the B. fragilis cell wall by isopycnic, sucrose gradient centrifugation, significantly increased surface expression of E-selectin and induced functional endothelial cell-dependent leukocyte adhesion. B. fragilis outer membranes induced translocation of NF-kappa B to HUVEC nuclei and accumulation of E-selectin mRNA in HUVEC cytoplasm. E-selectin expression induced by B. fragilis outer membranes was not blocked by polymixin B. In contrast, E-selectin expression induced by outer membrane fractions purified from E. coli was competitively inhibited by polymixin B. Neither purified B. fragilis LPS, a prominent constituent of the outer membrane, nor purified B. fragilis capsular polysaccharides induced HUVEC activation. Two different monoclonal antibodies directed against human CD14 completely inhibited B. fragilis outer membrane-induced NF-kappa B activation, E-selectin transcription, and E-selectin surface expression. We conclude that the outer membrane component of the B. fragilis cell wall contains a proinflammatory factor(s), that is not LPS, which induces human endothelial cell activation by a soluble CD14-dependent mechanism.