Biomedical subjects
Publications and source records attributed to D H Adams.
Mitral valve repair techniques are now widely applied in patients with myxomatous valve disease. The use of artificial chords to achieve correct height adjustment of the prolapsing anterior leaflet segment can often be challenging. We describe a simple method of artificial chord reconstruction performed after annuloplasty, which allows for easy identification of functional prolapse and accurate chordal height adjustment.
BACKGROUND: Homograft valves are subject to calcification and structural degeneration in the long term. Blood group matching is performed in many centers, and it remains controversial whether immunologic responses associated with potential blood group incompatibility contribute to the degeneration of unmatched homografts. We studied the expression of carbohydrate blood group antigens on valve endothelium of thawed aortic homograft valves and freshly harvested human cardiac valves. METHODS: Cryopreserved human aortic homograft valves and freshly harvested human aortic, pulmonary, mitral, and tricuspid valves were incubated with antibodies to A, B, and O blood group antigens. RESULTS: Cardiac microvascular endothelium stained positively with antiendothelial CD31 antibody in both cryopreserved and fresh tissue. Cryopreserved valve endothelial lining rarely stained positively for CD31, in contrast to fresh valves, which always stained positive. Cryopreserved or fresh cardiac microvascular endothelium strongly expressed A, B, or H antigens. In contrast, ABH antigens were not detectable on homograft or fresh cardiac valve endothelium. CONCLUSIONS: The absence of expression of carbohydrate antigen on valvular endothelium suggests that blood group incompatibility does not play a significant role in homograft degeneration.
BACKGROUND: Porcine valvular prostheses may stimulate inflammation after implantation, with resultant accelerated structural degeneration. We investigated the expression of porcine major histocompatibility complex (MHC) class II molecules on valve leaflets and the possibility of decreasing valve antigenicity with in vitro culture. METHODS: Aortic and pulmonary valves were harvested from domestic pigs under sterile conditions and cultured in vitro with either porcine or baboon serum for 4 days. Valves were harvested daily and fixed in Carnoy's or formalin solution. Microtome sections of valves were examined by hematoxylin and eosin, and by immunohistochemistry for porcine MHC class II proteins and an endothelial marker, alpha-N-acetylgalactosaminyl glycoprotein (alpha-GalNac). RESULTS: Porcine aortic and pulmonary valves constitutively express alpha-GalNac proteins and porcine MHC class II antigens. Porcine valves continue to express both alpha-GalNac and MHC class II after 48 hours of culture in porcine serum. After 48-hour culture in baboon serum, however, MHC class II antigens became undetectable on valvular leaflets, although alpha-GalNac molecules were still detected. CONCLUSIONS: Porcine valvular endothelial cells remain viable after 2 days of in vitro culture. Porcine valves cultured with primate serum show decreased MHC class II antigenic expression. In vitro culture before glutaraldehyde fixation may decrease inflammation associated with implantation.
BACKGROUND: Glutaraldehyde fixation stiffens the structural integrity of porcine valves, although the solution also destroys tissue viability and accelerates calcification. Recently, we demonstrated that fresh cardiac valves from domestic pigs do not express the galactose alpha1, 3 galactose (alpha-Gal) antigen and may be immunologically unique. The absence of alpha-Gal explained why the valves remained pristine while the rest of the porcine heart was destroyed by primate immunoglobulin M (IgM) and complement membrane attack complex (MAC) within 60 minutes. We sought to clarify whether fresh porcine valves from transgenic pigs bearing human complement regulatory proteins (CD59/DAF) can survive longer in primates and whether porcine cardiac valves remained immunologically privileged after prolonged exposure. METHODS: Tissue sections from wild-type untransplanted (n = 6), wild-type transplanted (n = 3), and transgenic pigs expressing human CD59/DAF proteins transplanted (n = 3) porcine-to-primate cardiac grafts were examined by hematoxylin and eosin, and by immunohistochemistry for the porcine endothelial marker (GalNac), alpha-Gal, primate IgM and MAC. RESULTS: alpha-Gal antigens were highly expressed on the vascular, but not valvular, endothelium of transgenic pigs. Hearts from CD59/DAF transgenic pigs survived 5, 7, and 11 days, but showed increasing IgM and MAC deposition until failure. Valves remained morphologically intact at explant, and strong GalNac staining suggested an intact endothelial surface. However, the valves showed no signs of IgM- or MAC-mediated damage. CONCLUSIONS: Although hearts from transgenic pigs expressing human complement regulatory proteins can survive for days in the primate recipient, the xenografts eventually fail because of escalating attacks of primate IgM and MAC. The absence of the alpha-Gal antigens protects unfixed porcine valves from rejection.
This study employed in situ hybridization to directly compare the effects of cocaine and methamphetamine on neurotensin/neuromedin N and preprotachykinin messenger RNAs in distinct striatal regions. Male, Sprague-Dawley rats received a single administration of 15mg/kg methamphetamine (s.c.) or 30mg/kg cocaine (i.p.) and were killed 30min or 3h later. Methamphetamine and cocaine produced significant increases in preprotachykinin messenger RNA in the striatum after 3h, but often in different subregions. Both drugs produced similar effects on preprotachykinin messenger RNA in the rostral striatum. However, methamphetamine produced significant increases in all regions of the caudal striatum, whereas cocaine-induced preprotachykinin messenger RNA expression was limited to dorsal regions of this striatal area. Methamphetamine also produced a significant increase in preprotachykinin messenger RNA in the caudal striatum after 30min, whereas cocaine had no significant effect on preprotachykinin messenger RNA at this early time-point. The pattern of changes in neurotensin/neuromedin N messenger RNA caused by methamphetamine and cocaine after 3h was even more distinct. Cocaine produced significant increases in neurotensin/neuromedin N messenger RNA in all regions of the rostral striatum, whereas methamphetamine had no effect in these areas. Furthermore, in more caudal sections, cocaine predominantly affected neurotensin/neuromedin N expression in dorsal aspects of the striatum, whereas methamphetamine significantly increased neurotensin/neuromedin N messenger RNA in all regions. There was much less effect of either drug on neuropeptide expression in the nucleus accumbens. The only significant effect was an increase in neurotensin/neuromedin N messenger RNA in the core region 3h after methamphetamine administration. These results indicate that methamphetamine and cocaine increase preprotachykinin and neurotensin/neuromedin N messenger RNAs in distinct regions of the striatum. The ability of methamphetamine and cocaine to alter neuropeptide messenger RNA expression in unique regions of the striatum may be important for the long-term effects of these drugs, such as sensitization, since the striatum is not homogeneous in its connections and function.
A detailed anaesthetic technique for baboons (Papio anubis) undergoing heterotopic abdominal cardiac xenotransplantation is described. Twenty-two baboons served as transplant recipients. Donors were either crossbred farm pigs (Sus scrofa) (n = 4) or transgenic pigs (Sus scroefa) (n = 18) expressing human complement regulatory proteins on the endothelium. Intra-operative management was complicated by the physiological consequences of infrarenal. abdominal aortic cross-clamping, in addition to the immunological sequelae related to cross-species transplantation. In choosing anaesthetics for this procedure, we considered the need for maximal cardiac stability throughout a long surgical procedure that required abdominal aortic cross-clamping to facilitate the implantation of an oversized porcine cardiac graft. Baboons received a balanced anaesthetic consisting of inhaled isoflurane in oxygen, intravenous fentanyl and intravenous pancuronium. The pharmacological techniques employed were found to be safe and reliable and were well tolerated by our recipients without any significant side-effects.
Recently, we and others have shown the prolongation of xenograft survival with the use of transgenic pigs bearing human CD 59 and DAF complement regulatory proteins (CRP). We now report heart transplantation using a new line of transgenic pigs bearing a different human CRP, membrane cofactor protein (MCP, CD 46). We transplanted three MCP transgenic and three wild-type porcine hearts into baboons suppressed with cyclosporine, methylprednisone, and rapamycin or cyclophosphamide. In addition, recipients were treated with extracorporeal plasma perfusion to remove alpha-Gal reactivity. The wild-type grafts were rapidly rejected at 60 to 80 min. Two functioning MCP hearts were removed after 5 and 46 h for histological examination. One MCP heart showed vigorous function until postoperative day 16. Immunohistochemistry of both wild-type and MCP-transgenic hearts showed strong deposition of IgM. In contrast, there was less MAC deposition in the transgenic graft as compared to the wild-type control. MCP is another CRP capable of decreasing the features of hyperacute rejection of cardiac xenografts in baboon recipients.
Mucosal addressin cell adhesion molecule (MAdCAM-1) plays a pivotal role in T-lymphocyte homing to the gut. Given the strong association between the autoimmune liver diseases primary sclerosing cholangitis and autoimmune hepatitis and inflammatory bowel disease, we investigated the role of MAdCAM-1 in recruiting mucosal lymphocytes to the liver. MAdCAM-1 was strongly expressed on inflamed portal vein/sinusoidal endothelium in autoimmune mediated liver disease. In modified Stamper-Woodruff assays, MAdCAM-1 on hepatic vessels supported adhesion of alpha4beta7+ lymphocytes (i.e., gut-derived T cells) from patients with inflammatory bowel disease and primary sclerosing cholangitis. This adhesion was inhibited by pretreatment with blocking antibodies to MAdCAM-1, alpha4beta7, or the integrin alpha4 chain indicating that MAdCAM-1 in inflamed liver is functionally active. Circulating lymphocytes from patients with primary sclerosing cholangitis showed rolling adhesion on MAdCAM-1 transfectants in a flow-based adhesion assay that could be blocked by anti-MAdCAM-1 or anti-alpha4beta7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of alpha4beta7+ mucosal lymphocytes via binding to aberrantly expressed MAdCAM-1 on liver endothelium. This provides a mechanism to explain the hepatic recruitment of mucosal lymphocytes in inflammatory liver disease complicating inflammatory bowel disease.
Fas-mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas-mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40-induced apoptosis of BEC is mediated through Fas/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF-kappaB and AP-1 were both activated after CD40 ligation. Increased functional NF-kappaB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up-regulation of AP-1 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas/FasL-dependent apoptosis of liver epithelial cells supporting the importance of cross-talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP-1 in the absence of NF-kappaB signaling may be a critical factor in determining the outcome of CD40 engagement.
For more than three decades, conventional coronary artery bypass grafting (full sternotomy, cardiopulmonary bypass, and cardioplegic arrest) has been the treatment of choice for patients with multi-vessel coronary artery disease. However, neurologic injury secondary to ascending aortic manipulation and systemic inflammatory reaction related to cardiopulmonary bypass are major causes of morbidity. During the past decade research efforts have been focused on the development of innovative revascularization techniques to minimize these deleterious effects. Minimally invasive direct coronary artery bypass surgery was developed to reduce chest trauma and to accelerate patient recovery. The relatively recent introduction of mechanical stabilizers and positioning devices has allowed for the safe performance of off-pump coronary artery bypass for patients with multi-vessel disease. Robotic technology has offered the possibility of myocardial revascularization through limited access using endoscopic principles. Recently, emphasis has been placed on the development of new sutureless anastomotic devices that may revolutionize the field of myocardial revascularization and allow a broader acceptance of minimally invasive CABG. Despite the increasing availability of new technologies, the validity of these procedures must be evaluated carefully. Prospective randomized studies and longitudinal follow-up will be required.
Perioperative graft failure after coronary artery bypass graft (CABG) can result in acute myocardial infarction with dire clinical consequences. We report a case of rescue percutaneous coronary intervention immediately after unsuccessful CABG. This approach salvaged the patient from cardiogenic shock and should be recognized as a viable alternative to immediate reoperation for certain patients.
BACKGROUND AND AIM OF THE STUDY: With increasing use of homograft and autograft aortic valves for aortic valve replacement (AVR), more patients will be presenting for aortic valve reoperation due to structural degeneration of the homograft or autograft valve. Management options include homograft re-replacement, which may require extensive surgery, versus AVR with a mechanical valve or a stented xenograft. Here, results are reported in 18 consecutive patients who underwent aortic valve re-replacement (AVreR) after previous homograft or autograft insertion. METHODS: Between May 1976 and March 2001, 18 patients underwent AVR after previous homograft (n = 16) or autograft (n = 2) insertion. The homograft or autograft had been implanted as a full root in eight patients (44%), as a mini-root in one (6%), and in the subcoronary position in nine (50%). Indication for the reoperation was structural valve degeneration (n = 14; 72%) in one occasion combined with aneurysm of the homograft, or endocarditis (n = 4; 22%), and seven (39%) presented as a non-elective procedure. The median interval between the two operations was 5.4 years (range: 0.3-10.8 years). RESULTS: Fourteen patients (78%) received either a mechanical valve (n = 12; 67%) or a stented xenograft valve (n = 2; 11%). Four others (22%) required root re-replacement with either another homograft (n = 3) or a mechanical valved conduit (n = 1) for endocarditis (n = 2) or an associated aneurysm (n = 2). Overall hospital mortality was 11% (n = 2) due to stroke (n = 1) or respiratory failure (n = 1). Two patients died 3.1 and 7.0 years after the procedure. CONCLUSION: Aortic valve reoperation after previous homograft or autograft implantation is a rare operation and presents a high-risk group. A simplified approach was preferred by utilizing mechanical or stented xenograft valves at reoperation, while homograft re-replacement was reserved for endocarditis or an associated aneurysm.
BACKGROUND AND AIM OF THE STUDY: An alternative to avoid redo sternotomy in patients with patent left internal mammary artery-left anterior descending coronary artery (LIMA-LAD) grafts undergoing mitral valve surgery is right thoracotomy with moderate-deep hypothermia (approximately 20 degrees C) and fibrillatory arrest without aortic cross-clamping. Few reports exist which directly compare re-sternotomy and right thoracotomy. METHODS: Between July 1992 and February 2000, 47 patients (39 males, eight females; median age 66 years; range: 41-83 years; 41 in NYHA class III or IV) with patent LIMA-LAD grafts underwent mitral valve surgery. Thirty-seven patients were approached through a right thoracotomy with moderate-deep hypothermia (median 20 degrees C) and fibrillatory arrest (right thoracotomy group), and 10 were approached through a re-sternotomy, with aortic cross-clamping and cardioplegic arrest. The median ejection fraction was 42% (range: 20-71%). Univariate analysis was used to determine predictors of outcome, as well as to evaluate differences in characteristics between groups. RESULTS: Operative mortality (OM) and perioperative myocardial infarction for the entire cohort was 11% and 10%, respectively, and there were no inter-group differences. No preoperative characteristics were associated with OM. Two LIMA-LAD graft injuries occurred in the re-sternotomy group compared with none in the right thoracotomy group (20% versus 0%, p = 0.04). Transfusion requirements were also greater in the redo sternotomy group (median 7 versus 2 packed red blood cell units, p = 0.04). CONCLUSION: Right thoracotomy with moderate-deep hypothermia and fibrillatory arrest is the preferred approach for reoperative mitral valve surgery after coronary artery bypass grafting in the presence of patent LIMA-LAD grafts. These data suggest that this approach is associated with decreased incidence of LIMA-LAD graft injury, as well as reduced transfusion requirements.
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BACKGROUND: Pig-to-primate cardiac xenografts undergo hyperacute rejection (HAR), in which primate IgM bind to porcine endothelial alpha-Gal molecules and activate membrane attack complex (MAC) deposition. Prolonged graft survival can be achieved by using transgenic pig donors, which express human complement regulatory proteins (hCRP) to inhibit MAC. However, these xenografts invariably fail from delayed xenograft rejection (DXR). We sought to investigate the poorly understood DXR process. MATERIALS AND METHODS: Wild-type (n = 3) and transgenic (n = 3) porcine hearts were heterotopically transplanted into baboons. Biopsies were analyzed by histology and by immunohistochemistry for porcine endothelial markers (vWF, alpha-Gal, and beta-Gal) and primate IgM and MAC deposition. RESULTS: Wild-type xenografts survived 60-80 min but succumbed to rapid IgM/MAC deposition and microvascular thrombosis. Transgenic xenografts avoided HAR but showed increasing IgM/MAC deposition before rejection on days 5, 7, and 11. Serum from baboons after transgenic xenograft rejection showed increased activity against porcine endothelial cells, and in vitro incubation of untransplanted porcine cardiac sections with sensitized baboon serum showed elevated microvascular IgM binding. Increased IgM deposition appeared specific to alpha-Gal, since it competes specifically with alpha-Gal-specific GS-4 lectin, but not with beta-Gal-specific RCA-1 lectin. Competition with GS-4 was not seen if naïve baboon serum was used. CONCLUSION: DXR may be mediated by increasing baboon IgM binding on porcine microvascular endothelial alpha-Gal molecules.
We report our entire experience with minimal access aortic root, valve, and complex ascending aortic surgery. A total of 290 consecutive patients underwent aortic root, valve, and ascending aortic surgery between July 1996 and February 2000. Four groups were identified: isolated aortic valve replacement (AV group, n = 227), aortic root replacement (AR group, n = 44), aortic valve replacement with concomitant replacement of the supracoronary ascending aorta (V/A group, n = 9), and isolated ascending aortic replacement (AA group, n = 10). The procedures were performed through a partial upper hemisternotomy (87%) or a right parasternal approach (13%). Overall mortality was 3.1% (n = 7) for the AV group, 2.3% (n = 1) for the AR group, 0% for the V/A group, and 10.0% (n = 1) for the AA group. Complications included reoperation for bleeding in 10 (4.5%), two (4.7%), one (11.1%), and one (11.1%) for the four groups respectively; and sternal wound infection in eight (3.6%) patients of the AV group and one (2.3%) patient of the AR group. Five (2.3%) patients of the AV group suffered stroke. Isolated or more complicated aortic valve, root and ascending aortic surgery is feasible and safe through a minimally invasive approach with acceptable incidence of complications and mortality, without compromising the efficacy of the procedure.