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The severity of aortic stenosis (AS) has traditionally been graded by measuring hemodynamic parameters of transvalvular pressure gradient, ejection jet velocity, or estimating valve orifice area. Recent research has highlighted limitations of these criteria at effectively grading AS in presence of left ventricle (LV) dysfunction. We hypothesized that simulations coupling the aorta and LV could provide meaningful insight into myocardial biomechanical derangements that accompany AS. A realistic finite element model of the human heart with a coupled lumped-parameter circulatory system was used to simulate AS. Finite element analysis was performed with Abaqus FEA. An anisotropic hyperelastic model was assigned to LV passive properties, and a time-varying elastance function governed the LV active response. Global LV myofiber peak systolic stress (mean ± standard deviation) was 9.31 ± 10.33 kPa at baseline, 13.13 ± 10.29 kPa for moderate AS, and 16.18 ± 10.59 kPa for severe AS. Mean LV myofiber peak systolic strains were −22.40 ± 8.73%, −22.24 ± 8.91%, and −21.97 ± 9.18%, respectively. Stress was significantly elevated compared to baseline for moderate (p < 0.01) and severe AS (p < 0.001), and when compared to each other (p < 0.01). Ventricular regions that experienced the greatest systolic stress were (severe AS vs. baseline) basal inferior (39.87 vs. 30.02 kPa; p < 0.01), mid-anteroseptal (32.29 vs. 24.79 kPa; p < 0.001), and apex (27.99 vs. 23.52 kPa; p < 0.001). This data serves as a reference for future studies that will incorporate patient-specific ventricular geometries and material parameters, aiming to correlate LV biomechanics to AS severity.

Objective Atrial fibrillation (AF) is a significant cause of thromboembolism and stroke. Left atrial appendage (LAA) occlusion is associated with a decreased risk of stroke in patients with AF. Percutaneous implantation of the percutaneous LAA transcatheter occlusion (PLAATO) device has shown reduction in stroke risk and decreased need for anticoagulation. A surgical method of PLAATO implantation is proposed for its utility and efficacy in cardiac surgical procedures, where LAA occlusion is indicated as a primary procedure or as an adjunct. We describe a surgical method for PLAATO deployment in an experimental model that simulates various operative scenarios including right minithoracotomy, right video-assisted thoracoscopic, or median sternotomy. Methods The PLAATO LAA occlusion device was deployed into the LAA in six dogs using a right minithoracotomy incision and catheter deployment via direct left atrial access. Intracardiac echocardiography and left atrial angiography were used to size, position, and verify proper deployment of the device. Results Successful PLAATO deployment was achieved in six of the six dogs. One dog required replacement of an undersized device. One dog required replacement of an oversized device. Four dogs required minor repositioning for optimal positioning. Complete flush occlusion of the LAA was achieved in three dogs; the other three dogs had trace leak by LAA angiography. Conclusions Experimental surgical implantation of the PLAATO device produces stable and complete occlusion of the LAA. Potential surgical indications for PLAATO implantation include patients with AF where a percutaneous approach to LAA occlusion is contraindicated or in patients with AF who require concurrent cardiac surgery.

The integrin αvβ8 is a cell surface receptor for the latent domain (LAP) of the multifunctional cytokine TGF-β. Through its association with LAP, TGF-β is maintained in a latent form that must be activated to function. Binding to the integrin αvβ8 with subsequent metalloproteolytic cleavage of LAP represents a major mechanism of TGF-β activation in vivo. Altered expression of the integrin β8 subunit (ITGB8) is found in human chronic obstructive pulmonary disease, cancers, and brain vascular malformations. We have previously shown that the proinflammatory cytokine interleukin-1β (IL-1β) increases ITGB8 expression on lung fibroblasts, which increases αvβ8-mediated TGF-β activation in fibrosis and pathologic inflammation. Here we report the mechanism of increased ITGB8 expression by IL-1β. Our data support a model where the chromatin architecture of the ITGB8 core promoter is altered by nucleosomal repositioning that enhances the interaction of an AP1 complex (containing c-Jun and ATF2). This repositioning is caused by the dissociation of HDAC2 with the ITGB8 core promoter, leading to increased histone H4 acetylation and a loosening of nucleosomal-DNA interactions allowing "opening" of the chromatin structure and increased association of c-Jun and ATF-2. These changes are mediated through NFκB- and p38-dependent pathways. Ultimately, these events culminate in increasing ITGB8 transcription, αvβ8 surface expression, and αvβ8-mediated TGFβ activation.

Integrin alphavbeta8 is a critical regulator of transforming growth factor beta activation in vasculogenesis during development, immune regulation, and endothelial/epithelial-mesenchymal homeostasis. Recent studies have suggested roles for integrin beta8 in the pathogenesis of chronic obstructive pulmonary disease, brain arteriovenous malformations, and select cancers (Araya, J., Cambier, S., Markovics, J. A., Wolters, P., Jablons, D., Hill, A., Finkbeiner, W., Jones, K., Broaddus, V. C., Sheppard, D., Barzcak, A., Xiao, Y., Erle, D. J., and Nishimura, S. L. (2007) J. Clin. Invest. 117, 3551-3562; Su, H., Kim, H., Pawlikowska, L., Kitamura, H., Shen, F., Cambier, S., Markovics, J., Lawton, M. T., Sidney, S., Bollen, A. W., Kwok, P. Y., Reichardt, L., Young, W. L., Yang, G. Y., and Nishimura, S. L. (2010) Am. J. Pathol. 176, 1018-1027; Culhane, A. C., and Quackenbush, J. (2009) Cancer Res. 69, 7480-7485; Cambier, S., Mu, D. Z., O'Connell, D., Boylen, K., Travis, W., Liu, W. H., Broaddus, V. C., and Nishimura, S. L. (2000) Cancer Res. 60, 7084-7093). Here we report the first identification and characterization of the promoter for ITGB8. We show that a SP binding site and a cyclic AMP response element (CRE) in the ITGB8 core promoter are required for its expression and that Sp1, Sp3, and several AP-1 transcription factors form a complex that binds to these sites in a p38-dependent manner. Furthermore, we demonstrate the requirement for Sp3, ATF-2, and p38 for the transcription and protein expression of integrin beta8. Additionally, reduction of SP3 or inhibition of p38 blocks alphavbeta8-mediated transforming growth factor beta activation. These results place integrin beta8 expression and activity under the control of ubiquitous transcription factors in a stress-activated and pro-inflammatory pathway.

Congestive heart failure (CHF) has become an international heath care problem and it is one of the world’s leading causes of hospitalization and mortality. In the United States alone, 4.9 million people (2.3 % of total population) are suffering from heart failure with 550,000 new cases diagnosed each year. Hospital discharge for CHF increased from 377,000 in 1979 to 970,000 in 2002, an increase of 157 %. Estimated health expenditures amount to $ 25.3 billion in 2005 [1]. In spite of these, only 2,100 of the 53,000 patients who die annually are offered transplantation, which many consider to be the standard treatment for selected patients with severe CHF and end-stage heart disease. Transplantation is severely limited by the paucity of donor availability and enormous cost. The inapplicability in the older patient or those with comorbid medical conditions as well as relatively fixed donor pool suggest that transplantation will likely never have a major epidemiological impact [2]. Treatment with mechanical circulatory support devices dances on the horns of the same dilemma. Consequently, despite improvements with medical management, 1 year, 3 year and 5-year survival after hospitalization from CHF have been reported at approximately 80–60 %, 50 % and 40–20 % respectively, which is worse than that of most cancers [3–7].

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. CCL20 is the only chemokine ligand for the chemokine receptor CCR6, which is expressed by the critical antigen presenting cells, dendritic cells. Increased expression of CCL20 is likely involved in the increased recruitment of dendritic cells observed in fibroinflammatory diseases such as chronic obstructive pulmonary disease (COPD). CCL20 expression is increased by the proinflammatory cytokine IL-1β. We have determined that IL-1β-dependent CCL20 expression is also dependent on the multifunctional cytokine TGF-β. TGF-β is expressed in a latent form that must be activated to function, and activation is achieved through binding to the integrin αvβ8 (itgb8). Here we confirm correlative increases in αvβ8 and IL-1β with CCL20 protein in lung parenchymal lysates of a large cohort of COPD patients. How IL-1β- and αvβ8-mediated TGF-β activation conspire to increase fibroblast CCL20 expression remains unknown, because these pathways have not been shown to directly interact. We evaluate the 5′-flanking region of CCL20 to determine that IL-1β-driven CCL20 expression is dependent on αvβ8-mediated activation of TGF-β. We identify a TGF-β-responsive element (i.e. SMAD) located on an upstream enhancer of the human CCL20 promoter required for efficient IL-1β-dependent CCL20 expression. By chromatin immunoprecipitation, this upstream enhancer complexes with the p50 subunit of NF-κB on a NF-κB-binding element close to the transcriptional start site of CCL20. These interactions are confirmed by electromobility shift assays in nuclear extracts from human lung fibroblasts. These data define a mechanism by which αvβ8-dependent activation of TGF-β regulates IL-1β-dependent CCL20 expression in COPD.

Objective A project is now underway to implement a novel percutaneous mitral repair system for severe mitral regurgitation (MR). The initial phase of the project consists of proof-of-concept by testing device characteristics using open surgical implantation. When surgical proof-of-concept of the intended percutaneous design is completed, a second phase of the project will consist of in vivo testing of the percutaneous transseptal system. The device is currently being designed to fold into a 17F catheter system and to unfold within the left atrium where attachment is accomplished using a reversible anchoring system. The purpose of this study was to show functionality of the device in elimination of MR using the open surgical method. Methods We have performed surgical prototype device implantation in 5 acute and 7 chronic sheep preparations. We created a P2-flail model of severe (4+) MR in the 12 sheep. Via a minimally invasive left thoracotomy incision and open repair on cardiopulmonary bypass, the device was implanted to determine efficacy of elimination of severe MR. Implantation was considered successful if 4+ regurgitation was converted to 1+ MR or lower. Left ventriculography and epicardial 2-dimensional/3-dimensional echocardiography were used to assess repair; serial 2-dimensional/3-dimensional transthoracic echocardiography was used to assess long-term mitral repair status. Results Twelve sheep had surgical creation of severe (4+) MR by cutting all chordae to the P2 scallop of the mitral valve; this preparation was tested and was found to produce 100% acute fatality without repair of the mitral valve. Five sheep had acute implantation of the device with elimination of regurgitation in 5/5 sheep. Seven sheep had chronic (1–7 month) implantation of the device. The device was tested in the chronic model for clinical status, residual regurgitation, thrombosis, and histopathology. All sheep had mitigation of MR and survived to the intended date of death. Conclusions Proof-of-concept of a novel percutaneous mitral repair device has been completed using an ovine P2-flail severe MR model. The device has characteristics that will allow its use in posterior leaflet degenerative disease and functional/secondary MR. Open, minimally invasive, and robotic surgical implantation of the device can also be developed as an alternative to the percutaneous approach.

Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor–β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases.

Background . There is a paucity of literature regarding iatrogenic aortic valve perforation after cardiac operations performed in the vicinity of the aortic valve. This report describes the echocardiographic recognition of iatrogenic aortic valve perforation. Methods . Among 6 patients who had previously undergone non–aortic valve cardiac operations, a diagnosis of iatrogenic aortic regurgitation was made by transthoracic two-dimensional echocardiography and Doppler color flow imaging. Results . The location of the aortic valve leaflet perforation varied and depended on the site of the previous intracardiac lesion repair. Repeat operations in 5 patients confirmed the echocardiographic findings. Aortic valve repair was confirmed in 2 patients by transesophageal echocardiography, whereas aortic valve replacement became necessary in 2 other patients. A fifth patient with acquired cardiomyopathy underwent orthotopic heart transplantation. Conclusions . A detailed two-dimensional echocardiographic examination, along with color flow imaging, should be done to evaluate iatrogenic aortic valve perforation in patients with a new murmur of aortic regurgitation after cardiac operations in proximity to the aortic valve. Precise preoperative diagnosis of this lesion allows optimal surgical planning and treatment.

In recent years, there has been a nationwide trend toward performing percutaneous transluminal coronary angioplasty in patients with multivessel coronary artery disease. The clinical course of 57 consecutive patients who required emergency first-time coronary artery bypass grafting operations were reviewed to assess for difference in outcome between the 28 patients (49%) with single-vessel disease and the 29 patients (51%) with multivessel disease. The two groups were similar in preoperative characteristics except for a higher proportion of chronic obstructive pulmonary disease in the patients with multivessel disease ( p =0.03). Twice as many patients with multivessel disease were in shock (single-vessel disease=4 [14%], multivessel disease=8 [28%], p =not significant) en route to the operating room and significantly more patients with multivessel disease required on-going cardiopulmonary resuscitation (single-vessel disease=0 [0%], multivessel disease=5 [17%], p =0.03). Significantly more coronary artery bypass grafts were placed in the patients with multivessel disease (single-vessel disease=1.5±0.6, multivessel disease=2.9±0.7, p p =0.02) and cardiopulmonary bypass time ( p p =0.05). According to multivariate analysis, incremental risk factors of mortality were preoperative shock ( p p =0.06), and multivessel disease ( p =0.12). Despite a similar incidence of myocardial infarction (single-vessel disease=8 [29%], multivessel disease=12 [41%], p = not significant), patients with multivessel disease had a higher incidence of cardiac morbidity (single-vessel disease=4 [14%], multivessel disease=11 [38%], p =0.04) and noncardiac morbidity (single-vessel disease=4 [14%], multivessel disease=12 [41%], p =0.02). By multivariate analysis, incremental risk factors of morbidity were preoperative shock ( p p =0.02), and ejection fraction p =0.07). In the subset of patients with multivessel disease, preoperative shock, ejection fraction

Mitral valve prolapse is defined as abnormal bulging of the mitral valve leaflets into the left atrium during ventricular systole. Mitral valve prolapse is a common condition that is a risk factor for mitral regurgitation, congestive heart failure, arrhythmia, and endocarditis. Myxomatous degeneration is the most common cause of mitral prolapse in the United States and Europe, and progression of myxomatous mitral prolapse is the most common cause of mitral regurgitation that requires surgical treatment. Myxomatous degeneration appears to have genetic etiology. The genetics of myxomatous degeneration is complex and not fully worked out; it appears to be heterogeneous with multi-gene, multi-chromosomal autosomal dominance with incomplete penetrance. The molecular disorder of myxomatous degeneration appears to consist of a connective tissue disorder with altered extracellular matrix status and involves the action of matrix metalloproteinase, cysteine endoproteases, and tenomodulin. Treatment of mitral prolapse with regurgitation is complex, and the technological advances that are currently in development will be challenging and controversial.

Neonatal pulmonary hypoplasia resulting from a congenital diaphragmatic hernia (CDH) produces hemodynamic changes and morphologic abnormalities of the pulmonary vasculature. To characterize the myocardial and pulmonary vascular status of the fetus with pulmonary hypoplasia, we studied four chronically instrumented, near-term fetal lambs with pulmonary hypoplasia, induced by producing a diaphragmatic hernia. We found an elevation in the pulmonary arterial pressure (control, 43.8 +/- 5.9 mmHg; CDH, 58.8 +/- 9.1 mmHg; p < 0.05), an elevation in the systemic arterial pressure (control, 43.8 +/- 0.48 mmHg; CDH, 58.6 +/- 6.7 mmHg; p < 0.05), and an elevation in the pulmonary vascular resistance (control, 0.47 +/- 0.11; CDH, 3.87 +/- 1.9; p < 0.05). In addition, though the total pulmonary blood flow was reduced (control, 83.5 +/- 32.9 mL/min; CDH, 22.2 +/- 17.6 mL/min; p < 0.05), the blood flow reduction was proportional to the reduction in the lung mass (control, 79.8 +/- 28.1 [in flow per 100-g lung weight]; CDH, 85.4 +/- 71.7). The increase in the pulmonary vascular resistance in relation to the unit lung mass (control, 0.55 +/- 0.33; CDH, 0.99 +/- 0.5) was not as pronounced as its increase in relation to the total pulmonary blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The purpose of this study was to evaluate the amount of neo-intimal tissue in-growth present at the arterial and venous sides of the anastomosis and the degree of endothelial cell lining of the graft lumen in sheep using commercial vascular grafts coated with the P15 cell-binding peptide. Methods: ePTFE vascular grafts were coated with the cell-binding P15 peptide using a newly developed plasma surface treatment method. 4 P15-treated grafts and 2 control grafts were implanted as arterio-venous fistulas between the femoral artery and vein and between the carotid artery and jugular vein in 2 sheep. 1 animal was euthanized after 14 days and the other animal after 28 days. The grafts along with the connecting arteries and veins were explanted and evaluated for the length of tissue in-growth along the luminal surface of the ePTFE graft from the anastomosis at the arterial and venous sides. Intimal thickness was carefully measured. Scanning electronic microscopy (SEM) was used to confirm the endothelial cell lining. Results: The study showed a significant difference (p

vealed a residual bidirectional flow disturbance across one site of the repair, with subsequent resolution over a 2-month period. The clinical importance of such a residual flow abnormality rests on the differentiation between inadequate or incomplete surgical repair and a transient postoperative shunting across suture lines that will eventually obliterate or endothelialize. In that respect, this residual flow abnormality appears analogous to flow disturbances described after ventricular septal defect patch repair, where it has been postulated to occur along the suture line and not through the patch material itself.gr lo This study illustrates the usefulness of serial postoperative echocardiographic and color Doppler evaluation in ascertaining the true nature of post-repair residual shunting. We conclude that the diagnosis of a pseudoaneurysm and the detection of shunting flow through its communication with the left ventricle can be significantly facilitated by colorflow Doppler imaging. Early residual shunting after surgical repair may indicate a transient flow disturbance along suture lines, with subsequent obliteration or endothelialization.

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD.

Transforming growth factor (TGF)-beta is a potent multifunctional cytokine that is an essential regulator of epithelial proliferation. Because TGF-beta is expressed almost entirely in a latent state in vivo, a major source of regulation of TGF-beta function is its activation. A subset of integrins, alphavbeta8 and alphavbeta6, which are expressed in the human airway, has recently been shown to activate latent TGF-beta in vitro, suggesting a regulatory role for integrins in TGF-beta function in vivo. Here we have developed a novel, biologically relevant experimental model of human airway epithelium using intact human bronchial tissue. We have used this model to determine the function of integrin-mediated activation of TGF-beta in the airway. In human bronchial fragments cultured in vitro, authentic epithelial-stromal interactions were maintained and integrin and TGF-beta expression profiles correlated with profiles found in normal lung. In addition, in this model, we found that either the integrin alphavbeta8 or TGF-beta could inhibit airway epithelial cell proliferation. Furthermore, we found that one mechanism of integrin-alphavbeta8-dependent inhibition of cell proliferation was through activation of TGF-beta because anti-beta8 antibody blocked the majority (76%) of active TGF-beta released from bronchial fragments. These data provide compelling evidence for a functional role for integrin-mediated activation of TGF-beta in control of human airway epithelial proliferation in vivo.

The transplantation of organ xenografts from pigs could readily address the severe and growing shortage of human organ donors. Xenotransplantation of vascular organs is not feasible with current technology, however, due to severe acute rejection. In particular, acute vascular rejection (AVR), caused by induced antibodies to porcine endothelial cells, has consistently resisted efforts to prevent rejection. 1 Although the use of transgenic pigs expressing human complement inhibitors has proved effective in preventing hyperacute rejection, these grafts are usually rejected by AVR. 2 Drugs that are effective in preventing allograft rejection are not effective in preventing AVR. 3 Immune tolerance to pig cells could reduce the need for immune suppression. However, the induction of tolerance through bone marrow transplantation subjects the recipient to a period of severe immune deficiency. Furthermore, tolerance to donor hematopoietic cells following bone marrow transplantation of the recipient does not prevent AVR of vascular grafts. 4 If graft rejection by antibodies can be prevented, the graft eventually may become accommodated or resistant to injury. Accommodation has been studied extensively and proposed as a pathway to prolonged xenograft acceptance and prevention of AVR. 5–8 Engraftment of recipient lymphocytes within donor pigs could reduce the severity of xenograft rejection and the need for severe immune suppression. The lymphocytes would become tolerant to the donor tissue antigens as well as the hematopoietic cells. The specific suppressor cells could then be transferred back to the recipient. The porcine tissues could also become accommodated within the chimeric donor, before the transplantation. They would then resist injury by formed and developing antibodies following transplantation. Billingham et al. demonstrated that the environment during early immune ontogeny is conducive to immune tolerance. 9 The fetus or newborn develops specific tolerance to exposed antigens, including injected cells. In our previous studies with fetal pigs, tolerance of the injected lymphocytes to the pig was also demonstrated. 10 Tissue accommodation develops within chimeric pigs, before transplantation. 11,12 In two recipients with preformed antibodies, pig heart xenografts developed neither hyperacute rejection nor AVR. Heart explants from chimeric pigs functioned for a prolonged period when perfused with plasma from sensitized sheep. The feasibility of clinical xenotransplantation will depend on the prevention of rejection with acceptable levels of immune suppression. For the pig heart xenotransplants described here, immune suppression was limited to levels administered to allograft recipients. In this large animal study using chimeric donor pigs, AVR of pig xenografts was prevented without severe immune deficiency or toxicity.

Background. Animal models have suggested that retrograde cardioplegia may be poorly distributed to septal and right ventricular regions of the heart; if true, this may have dangerous implications for warm continuous retrograde cardioplegia in humans. We have previously shown that blood gases from coronary arteries during warm continuous retrograde cardioplegia represent postcapillary "venous" gases and are reflective of myocardial perfusion. Methods. To determine regional differences in perfusion during warm continuous retrograde cardioplegia we obtained blood gases from three regions of the heart in 141 consecutive patients undergoing coronary artery bypass grafting, aortic valve replacement, or both. Right heart perfusion was determined by blood gases from the right coronary artery orifice, acute marginal, or posterior descending coronary arteries; circumflex or lateral wall perfusion was determined by samples from obtuse marginal or intermediate coronary arteries; and anterior wall/septal perfusion was determined by left anterior descending and diagonal coronary artery blood gases. Warm continuous retrograde cardioplegia flow ranged from 150 to 300 mL/min depending on heart size. A mean of 4 ± 1 samples/patient were obtained. Results. There were no regional differences in postcapillary pH, carbon dioxide tension, or CO 2 production during warm continuous retrograde cardioplegia. Oxygen tensions were lower in the right and anterior/septal regions of the heart, implying more O 2 uptake. No regional acidosis, consistent with poor perfusion, could be detected. Conclusions. We conclude that, unlike experimental models, regional myocardial perfusion, including the right heart, is uniform during "high-flow" warm continuous retrograde cardioplegia in humans.

The management of intrathoracic esophageal perforation with delayed diagnosis is a subject of controversy. Because of the obvious advantages of primary repair as a simple single-stage operation, this technique was preferentially used to treat 18 of 22 consecutive patients with esophageal perforation. These patients were stratified into three groups according to the time interval between perforation and repair: group A, less than 6 hours, five patients (28%); group B, 6 to 24 hours, six patients (33%); and group C, more than 24 hours, seven patients (39%). Group A patients were older (p < 0.05) and group B had fewer iatrogenic perforations (B, 17%; A, 80%; C, 57%, p < 0.1). Additional tissue was used to buttress the repair site in all three groups (A, 3/5 patients, 60%; B, 4/6 patients, 67%; C, 6/7 patients, 86%; p = not significant). In seven patients (39%), a fundic wrap was used to reinforce the site of primary repair. The outcomes of the three groups were analyzed. Group A had the lowest proportion of postoperative leaks (A, 0/4 patients, 0%; B, 4/6 patients, 67%; C, 5/6 patients, 83%; p < 0.05) and postoperative morbidity (A, 2/5 patients, 40%; B, 6/6 patients, 100%; C, 6/7 patients, 86%; p < 0.1). However the increased incidence of leak and morbidity did not lead to an increase in mortality. One death occurred in each group, with an overall mortality of 17% (A, 1/5 patients, 20%; B, 1/6 patients, 17%; C, 1/7 patients, 14%; p = not significant). We conclude that in the era of advanced intensive care capabilities, primary repair of intrathoracic esophageal perforation can be safely accomplished in most patients regardless of the time interval between perforation and operation. Leakage at the suture site is common unless primary repair is carried out without delay. Postoperative leakage, however, is usually inconsequential and does not necessarily result in an adverse outcome. (J THORAC CARDIOVASC SURG 1996;111:114-22)

A paucity of donor organs is the principal limitation in human heart transplantation. Prompted by our short-term studies of reanimating "dead" donor hearts in sheep, we applied the same reperfusion modifications in juvenile baboons to determine human applications in an anoxic arrest model (as occurs when non-brain-dead patients are extubated and allowed to die). Ten juvenile baboons (mean weight 3.6 kg) were studied. Five baboons were used as donors. After being anesthetized, donors were pretreated with methylprednisolone (Solu-Medrol), 50% dextrose, nifedipine, and prostaglandin E 1 and then paralyzed and extubated. Donors became pulseless at 7 ± 1 minutes and had electric arrest 9 to 18 minutes after paralysis. The five donors were left undisturbed and warm for 15, 22, 30, 30, and 31 minutes, respectively, after asystole. They were then given 250 ml of 4° C Roe's crystalloid cardioplegic solution via the aortic root and the hearts were explanted into iced Euro-Collins solution. Five baboons served as recipients. After donor harvest, recipients were placed on cardiopulmonary bypass, given prostaglandin E 1 , and cooled to 18° C; circulatory arrest was instituted and the recipient's heart excised. The donor heart was transplanted in an orthotopic position. Before reinstitution of bypass, 250 ml of terminal leukocyte-depleted blood cardioplegic solution was given, then bypass was restarted and the hearts were reperfused for 60 minutes. All animals were weaned from bypass without the use of inotropic agents. All animals were extubated within 2 to 4 hours after bypass and received standard immunosuppression. Peak creatine kinase MB/total creatine kinase ratio was 0.2% ± 0.2%. Postoperative ejection fractions by echocardiography were 75% to 80% (mean 76%). Animals survived 1, 9, 13, 16, and 34 days, with three deaths caused by acute rejection and one each by stroke and diarrhea/dehydration. Pathologic findings showed no areas of fibrosis or ischemic damage. We conclude that successful reanimation and engraftment can be achieved with the use of the asystolic primate heart; this work suggests that human application is realistic and could greatly expand the donor pool. (J T HORAC C ARDIOVASC S URG 1995;109:1097-102)

Urbanism and technology brought profound and far-reaching changes in the manner in which black people in the rural South prepare for and celebrate the funeral ritual. The moment of death, the funeral rituals, and the period of mourning afterwards have all been affected by urbanism. Hard-surfaced roads and the telephone have accelerated the spread of the “bad news.” The automobile has made possible much larger attendance at funerals, and the airplane has dramatically reduced the period of “mourning” for the dead. Perhaps nowhere else have these changes been more evident than in an obscure community in the Cumberland Mountains of middle Tennessee.

Objectives To evaluate the safety and effectiveness of a self-closing surgical clip with an interrupted technique in left internal thoracic artery to left anterior descending artery bypass grafting. Methods Eighty-two patients were enrolled and treated (February 2000 through August 2001) in a prospective, nonrandomized, multicenter trial. Left internal thoracic artery to left anterior descending artery anastomoses were performed in 60 off-pump coronary artery bypasses (73%), 12 conventional coronary artery bypass grafting (15%), and 10 minimally invasive direct coronary artery bypass (12%) procedures. Angiograms (64 to 383 days, mean 200 days) were obtained on 63 patients (77%). Qualitative and quantitative angiographic assessment was performed by an independent core laboratory. Results The self-closing surgical clip was used for 82 left internal thoracic artery to left anterior descending artery interrupted anastomoses without the requirement for knot tying or primary suture management. Minimum left internal thoracic artery to left anterior descending artery anastomosis time was 3 minutes. There was one perioperative and one late death (both not heart related) and one reexploration for bleeding unrelated to the anastomotic site. FitzGibbon grades were as follows: A (n = 60, 95.2%), B (n = 3, 4.8%) including one kinked left internal thoracic artery, and O (n = 0, 0%). Quantitative analysis (n = 57) showed mean lumen diameters of left internal thoracic artery proximal to the anastomosis of 2.1 mm, at anastomosis of 2.0 mm, and in the left anterior descending artery distal to the anastomosis of 1.9 mm. The average ratio of the anastomosis to the left anterior descending artery diameter was 1.14 (0.45 to 1.93). Anastomotic stenosis as a percentage of average left internal thoracic artery to left anterior descending artery diameter was −2.3%, comparing favorably with results (23% to 24%) reported from the Patency, Outcomes, Economics, Minimally invasive direct coronary artery (POEM) bypass study. Conclusions The interrupted technique, facilitated by a self-closing anastomotic clip, yields favorable 6-month angiographic results when compared with other published studies.

Current methods of orthotopic liver transplantation are expensive, entail high morbidity and mortality, and are limited by a serious shortage of donor organs for the pediatric recipient. Auxiliary transplantation of livers from anencephalics is a potential solution to the problems of size discrepancy and organ availability for the pediatric patient. To investigate the feasibility of auxiliary fetal liver transplantation, we have developed a sheep model of auxiliary transplantation of the fetal liver into the adult neck. We report here the results of the transplantation of 32 fetal lamb livers ranging in age from 100 to 140 days gestation (term 145 days). We conclude that (1) fetal organ harvest can be effectively accomplished by surface cooling followed by umbilical cold perfusion; (2) auxiliary transplantation of the fetal lamb liver is technically feasible; (3) the fetal liver can survive on umbilical inflow alone but function is improved by hepatic arterial inflow; and (4) the fetal liver is sensitive to excessive flow or pressure and is best transplanted in a parallel vascular arrangement. Auxiliary transplantation of the fetal liver is a promising alternative to current methods of liver transplantation.

CoSeal mark surgical sealant (CoSeal) was evaluated for inhibiting suture line bleeding using a canine iliac PTFE graft model. Both iliac arteries of 12 heparinized canines were grafted with PTFE. CoSeal was applied to the suture lines of one graft in each animal. The contra-lateral graft served as a control and bleeding was controlled with gauze and pressure (tamponade). The cross-clamps were removed 30 s following application of CoSeal. Times to hemostasis and volume of blood loss at each graft site were determined. Compared to tamponade control, CoSeal significantly reduced the time to hemostasis (average of 5 min vs. greater than 15 min, p < 0.05) and blood loss (19 g vs. 284 g, p < 0.05). Small amounts of CoSeal were visible grossly or histologically at day 7. Histology showed moderate to marked inflammation in CoSeal sites and moderate inflammation in control sites at day 7. At 30 and 60 days, no CoSeal was visible grossly or histologically. Histology showed moderate inflammation in both CoSeal treated sites and in control sites at day 30 and mild to moderate inflammation in both CoSeal and control sites at day 60. CoSeal significantly reduced the time to hemostasis and blood loss in comparison to tamponade.