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Background The ability to express genes with potential immunoregulatory capacity could reduce allograft rejection (AR). We examined the feasibility of transferring the viral interleukin-10 (vIL-10) gene into rat lungs by intra-bronchial instillation and the subsequent effects of delivered vIL-10 on acute lung AR. Methods First, the adenoviral β-galactosidase vector (adv-β-gal) particles were instilled into the airway of the rat lung and protein synthesis of β-gal was examined by histochemical staining. Next, the ability of the adenoviral vIL-10 vector (adv-vIL-10) transfection to modify AR was examined in a highly histoincompatible rat lung transplant model (BN → Lew). Donor left lungs were transfected with 3 × 108 pfu/0.3 mL of adv-vIL-10 (vIL-10 group) or adv-β-gal (control group) 3 days before transplantation. On day 6 post-transplant, lung allografts were harvested and AR was graded histologically (stage 0–4). Several pathological categories of inflammation (perivascular, peribronchial, or peribronchiolar mononuclear infiltrates, edema, vasculitis, intraalveolar hemorrhage, and necrosis) were also examined and scored on a scale of 0–4 as previously described. Results A successful transgene protein synthesis by adv-β-gal in alveolar epithelial cells and alveolar macrophages was confirmed by histochemical staining with X-gal. The vIL-10 group showed a trend toward an improved stage of AR (3.75 ± 0.5 vs. 4.0 ± 0), and also a decreased pathological scores for edema (3.5 ± 0.6 vs. 4.0 ± 0), intraalveolar hemorrhage (2.3 ± 1.0 vs. 2.5 ± 0.6) and necrosis (1.5 ± 0.5 vs. 1.75 ± 1.3) compared with the control group, however, the differences in any pathological scores between the two groups did not reach a statistical significance. Conclusions 1. A successful transgene protein synthesis in alveolar epithelial cells was ensured by intra-bronchial instillation of an adenoviral vector encoding β-galactosidase gene. 2. Transferring the vIL-10 gene into rat lungs by intra-bronchial instillation did not seem to reduce lung AR significantly, as opposed to the results of our previous experiments in a rat cardiac allograft model. This discrepancy may be explained by several potential factors including the immunogenecity of adenoviral vectors in conjunction with the nature of the lung more susceptible to immune response and inflammation.

My family joins me in thanking the membership for the extraordinary privilege and honor of having served as the 35th President of The Society of Thoracic Surgeons (STS). I include my family in this “thank you” because they have always supported me in every adventure I have embarked upon, and have accepted the consequences with dignity. I especially thank my wife, Martha, who has kept us all together these past 2 years. She, our daughter Lori, Lori’s fiance Brian Goler, our son Stephen, and my brother Ken, have been my equivalent of the STS Chicago and Washington staff, dedicated to our common commitment to the patients who have entrusted their lives to our care.

Objective: We sought to compare outcomes with tissue and St Jude Medical mechanical valves over a 20-year period. Methods: Valve-related events and overall survival were analyzed in 2533 patients 18 years of age or older undergoing initial aortic, mitral, or combined aortic and mitral (double) valve replacement with a tissue valve (Hancock, Carpentier-Edwards porcine, or Carpentier-Edwards pericardial) or a St Jude Medical mechanical valve. Total follow-up was 13,390 patient-years. There were 666 St Jude Medical aortic valve replacements, 723 tissue aortic valve replacements, 513 St Jude Medical mitral valve replacements, 402 tissue mitral valve replacements, 161 St Jude Medical double valve replacements, and 68 tissue double valve replacements. The mean age was 68 ± 13.3 years (St Jude Medical valve, 64.5 ± 12.9; tissue valve, 72.0 ± 12.6). Results: There were no overall differences in survival between tissue and mechanical valves. Multivariable analysis indicated that the type of valve did not affect survival. Analysis by age less than 65 years or 65 years or older and presence or absence of coronary disease revealed similar long-term survival in all subgroups. The risk of hemorrhage was lower in patients receiving tissue aortic valve replacements but was not significantly different in patients receiving mitral valve or double valve replacements. Thromboembolism rates were similar for tissue and mechanical valve recipients. However, reoperation rates were significantly higher in patients receiving both aortic and mitral tissue valves. The reoperation hazard increased progressively with time both in patients receiving aortic and in those receiving mitral tissue valves. Overall valve complications were initially higher with mechanical aortic valves but not with mechanical mitral valves. However, valve complication rates later crossed over, with higher rates in tissue valve recipients after 7 years in patients undergoing mitral valve replacement and 10 years in those undergoing aortic valve replacement. Conclusions: Tissue and mechanical valve recipients have similar survival over 20 years of follow-up. The primary tradeoff is an increased risk of hemorrhage in patients receiving mechanical aortic valve replacements and an increased risk of late reoperation in all patients receiving tissue valve replacements. The risk of tissue valve reoperation increases progressively with time. J Thorac Cardiovasc Surg 2001;122:257-69

BACKGROUND We have reported previously that F344 rats develop a spontaneous tolerance to WKY lung allografts and show long-term retention of donor-specific skin grafts placed 35 days after lung transplantation. In this study, we investigated the immunologic mechanisms that may be responsible for the prolonged skin graft survival in animals tolerized with lung allografts. METHODS In the rejection group, WKY skin grafts were placed on normal F344 rats, whereas, in the tolerance group, the skin grafts were placed on F344 rats that had received a WKY lung transplant 35 days before skin grafting. Th1 (interleukin [IL]-2 and interferon-gamma [IFN-gamma]) and Th2 (IL-4 and IL-10) cytokine as well as transforming growth factor-beta1 mRNA expression in skin grafts and in draining lymph nodes were determined by reverse transcription-polymerase chain reaction. Macrophage and lymphocyte infiltration in skin grafts and the number of Langerhans cells in epidermal sheets of the grafts were examined by immunohistochemistry. RESULTS IL-2 and IFN-gamma mRNA expression was significantly decreased in both the skin grafts and the draining lymph nodes of the tolerance group, compared to the rejection group, whereas IL-10 and transforming growth factor-beta1 mRNA expression was similar in both groups and IL-4 mRNA was rarely detected. Decreased and delayed CD8+, macrophage, and natural killer cell infiltration in the skin grafts from the tolerance group was also detected. Similar reduction in the number of Langerhans cells in the epidermis of the grafts from both groups was seen on day 1 after skin grafting, and thereafter the number remained stable in both groups. CONCLUSIONS Reduced expression of Th1 cytokines and decreased infiltration of CD8+ cells, macrophages, and natural killer cells in the skin grafts may be responsible for prolongation of skin graft survival in the tolerance group.

Background. Recent studies have shown that the extent of platelet accumulation in the vasculature of transplanted organs correlates with the degree of preservation-reperfusion injury. In this study, we examined the effect of a stable prostacyclin analog, beraprost sodium, which possesses potent antiplatelet activity, on parameters of platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation. Methods. The heart-lung blocks of donor rats were flushed with and preserved in modified Euro-Collins solution at 4°C for 6 hr or 24 hr. The left lung was transplanted into recipient rats and reperfused for 1 hr. Lung injury was evaluated by the pulmonary blood flow ratios to the lung isografts, the weight gain of the isografts, and histological examination. Small portions of the lung isografts were excised and stained with an antibody specific for rat platelets. A scoring system was developed to semiquantitate the intensity of antibody staining (score 0-4). The recipient rats received oral administration of beraprost sodium (0.3 mg/kg) before lung transplantation. Control animals received no beraprost sodium. Results. In the 6-hr preservation study, administration of beraprost sodium significantly reduced the score for platelet accumulation (1.8±0.4 vs. 3.3±0.5, P

Our previous studies have shown that a spontaneous functional tolerance develops in a rat model of lung transplantation (WKY--F344). The tolerance observed in this model may be due to the minor histocompatible differences in this combination, however, the possibility of a tolerogenic effect related specifically to the lung allograft must be considered. To further examine this model, the effect of pre-transplant donor-specific spleen cell transfusions (DSTs) was examined on the functional tolerance state seen in this model. F344 rats received WKY spleen cells on days -45 and -30 before lung transplantations. Control F344 rats received lung transplants without DSTs. Recipients in both groups were killed on day 7, 14, 21 and 49 post-transplant, and allograft rejection (AR) was graded histologically (stage 0-IV). Intragraft cytokine gene transcripts were examined on day 7 and 14 post-transplant using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques to investigate the underlying immunological events occurring in each group. In addition, allogeneic (WKY) and third party (BN) skin grafts were placed on lung recipients at day 35 post-transplant to evaluate the development of systemic tolerance. It was seen that control animals showed moderate to severe lymphocytic infiltrations (stage II-III AR) in the first 3 weeks followed by spontaneous recovery with stage I-II AR on day 49. In marked contrast, DST-treated animals showed more aggressive AR with severe lymphocytic infiltration and haemorrhagic infarction (stage III-IV AR) by day 14-21, without any evidence of recovery on day 49. WKY skin grafts showed prolonged survival in control animals, but were promptly rejected in DST-treated animals. Intragraft cytokine gene expression in control animals was characterized by no or weak expression of IL-2 and high IL-10, while DST-treated animals showed high levels of IL-2 transcripts. IL-2:IL-10 and IL-2:IL-4 ratios were significantly increased in DST-treated animals compared with controls on day 7 post-transplant. It was concluded that pre-transplant DSTs did not enhance allograft survival, but actually induced AR and ablated any immunological benefit of the lung allograft on induction of tolerance in the WKY--F344 lung transplant model. It was found that the DST-induced AR was associated with a deviation of cytokine immune responses from a predominant Th2 to Th1 profile characterized by increased IL-2 gene expression in the allografts. We also conclude that factors other than the degree of histocompatibility matching, such as the route and timing of alloantigen exposure, and the amount or nature of alloantigens associated specifically with lung allografts, are involved in deviating native immune responses toward acceptance or rejection of lung allografts in this model of lung transplantation.

Background. Platelets are known to play an important role in the pathogenesis of adult respiratory distress syndrome as well as preservation-reperfusion injury of liver allografts. However, the role of platelets in pulmonary preservation-reperfusion injury is unknown. In this study, we examined whether the extent of platelet accumulation in the preserved and subsequently reperfused lungs correlated with the degree of preservation-reperfusion injury in a rat lung isotransplant model. Methods. Heart-lung blocks from donor rats were flushed with and preserved in modified Euro-Collins solution at 4°C for 0 hr (n=5), 6 hr (n=6), and 24 hr (n=6). The left lung was divided from the heart-lung block, transplanted into the recipient rat, and reperfused for 1 hr. Lung injury was evaluated by the left-to-right pulmonary blood flow ratio, the weight gain of the isograft, and the scores for histological categories of lung injury (intra-alveolar edema, intra-alveolar hemorrhage, and capillary congestion). Small portions of the lung isograft were excised and stained with an antibody specific for rat platelets. A scoring system was developed to semiquantitate the intensity of antibody staining in isografts. Results. Lung isografts were injured and platelets accumulated in the capillaries in proportion to the length of preservation endured before transplantation. The extent of platelet accumulation evaluated by our morphological scoring system correlated significantly with the degree of lung injury assessed by the blood flow ratio (P

Background . Heart transplantation has become a highly successful therapeutic option for patients with end-stage cardiomyopathy. Consequently, the criteria for patient selection, particularly regarding recipients' upper age limits, have been expanded, with an increasing number of people older than 60 years of age now undergoing transplantation. Methods . A retrospective analysis of 6 patients 70 years of age and older who underwent heart transplantation was done; their clinical courses and outcomes were compared with those of younger patients, with a special emphasis on their posttransplantation quality of life. Results . All 6 patients are alive and clinically well at a mean follow-up of 12 months. No age-related complications have been observed, and their quality of life is excellent. There has been a very low incidence of rejection, as well as few episodes of rejection. Conclusions . Heart transplantation in selected people 70 years of age and older can be performed successfully with a morbidity comparable to that seen in younger patients and excellent short-term survival. This initial experience is encouraging, but further studies and long-term follow-up are needed to validate the more routine application of this therapy.

Objective: Our objective was to assess survival, need for pacemaker insertion, and rejection frequency with a new surgical technique of orthotopic heart transplantation using bicaval and pulmonary venous anastomoses. Methods: We retrospectively reviewed 100 consecutive patients who had orthotopic heart transplantation with this technique between July 1991 and September 1995. Results: The mean age was 57.0 ± 11.1 years, with 51 patients being 60 years or older. The mean donor/recipient weight ratio was 0.92, and in 28 patients the ratio was less than 0.8. The early (30-day) survival was 100% and the 1- and 2-year survivals were 98% ± 2% and 96% ± 2%, respectively. Survival was not affected by age or by the duration of the OKT3 therapy ( p > 0.2 for each of these parameters). The seven late deaths were due to infection ( n = 2), graft atherosclerosis ( n = 3), acute rejection ( n = 1), and nonspecific graft failure ( n = 1). No permanent pacemaker was required in the first 6 months after the operation, and all the patients were discharged in normal sinus rhythm. Freedom from treated rejection was significantly greater in patients with 7 days of OKT3 therapy than in patients with 14 days of therapy ( p Conclusions: Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses offers an improved alternative to the standard biatrial technique, with a 30-day mortality of 0% in 100 consecutive patients, excellent intermediate-term survival, and elimination of the need for pacemaker insertion. More normal anatomic configuration and synchronous function of the atria may have contributed to these results. (J T horac C ardiovasc S urg 1996;112:1496-503)

Coronary saphenous vein grafts in human beings have a more limited long-term patency rate than internal thoracic artery grafts, primarily because of more rapid development of arteriosclerosis. The factors responsible for this increased susceptibility are not completely understood. To test the hypothesis that vein valves may influence this process, we studied 48 hypercholesterolemic rabbits with jugular vein grafts interposed into the carotid arterial circulation. In 24 animals (group A), the vein segments did not contain a vein valve. In the other 24 animals (group B), a vein valve was present. Both groups were further divided in four subgroups of six to be put to death at 2, 4, 6, and 8 weeks after the operation. All animals were fed a 2% cholesterol diet. At postmortem examination, alternate 2 mm sections were either stained with hematoxylin and eosin for histologic and morphometric studies or frozen in liquid nitrogen for immunohistochemistry and in situ hybridization studies. Proliferating cell nuclear antigen immunostaining was used to study cell proliferation. Wall thickness of vein grafts increased with time. During the first 2 weeks intimal and medial thickening was primarily due to an increase in numbers of cells. Between 2 and 6 weeks further intimal and medial thickening occurred, but without additional increase in cell numbers. After 6 weeks, foam cells and lipid deposits started to appear. By 8 weeks, changes identical to those seen in arteriosclerotic plaques in human beings were evident. These changes developed sooner and with more intensity in group B animals ( p < 0.01 to 0.001), and they developed faster and with more severity in segments of vein located distal to the valve than in the segments located proximal to the valve ( p < 0.001). This is the first controlled experiment demonstrating that the presence of valves in the vein segments is associated with augmented and accelerated intimal changes leading to vein atheromatosis. (J THORAC CARDIOVASC SURG 1995;110:1381-90)

If we are going to reform our healthcare system, we will have to start by providing access to basic care for everyone. This can be done through embracing a strategy that is built around integrated healthcare delivery systems. Payment should be via a universal tax for the basic plan, and there should be ways in which to pursue options beyond the basic plan, to be paid for by individuals. What is provided by way of care will need to be evaluated through a central technology assessment institute. The system will have to slow the rate of growth of spending in an intelligent way, not using price controls, caps, or repressive methodologies. The trick will be to still preserve a certain amount of freedom and flexibility, and include the capacity for change. There will have to be a significant reorientation of what has been our traditional approach to malpractice. Through the course of this symposium there has not been a great deal to be positive about. There are many physicians today who are well described by the English poet A. E. Housman's line, "A stranger and afraid in a world I never made." Change is inevitable; it is here and more is coming. The great medical historian Henry Sigerist noted that: "The physician's position in society, the task assigned to him, and the rules of conduct imposed on him changed in every period. They were determined primarily by the social and economic structure of society and by the technical and scientific means available to medicine at the time."(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine gene expression is a critical component of the lung allograft rejection (AR) response and tolerance development in rat models. In order to determine the specificity of cytokine gene expression for AR and tolerance, we examined cytokine (interleukin-2) (IL-2), (gamma-interferon) (γ-IFN), IL-4, IL-10 and tumor necrosis factor-α (TNF-α) and control (cyclophilin) mRNA levels in two models of rat lung allograft rejection by RT-PCR (reverse transcriptase polymerase chain reaction), Southern blotting. The first model (WKY→F344) develops a mild to moderate lymphocytic infiltrate on days 14–21 post-transplant (stage II–III AR), which spontaneously resolves by day 35 post-transplant with subsequent development of allograft tolerance (grafts surviving without evidence of AR for > 140 days). Conversely, F344→WKY develops a similar lymphocytic infiltrate by day 14 post-transplant, but by day 21 post-transplant the graft shows severe AR (stage III–IV) and has haemorrhagic infarction with alveolar haemorrhage. Methods: RNA was extracted from allografts removed on days 3, 7, 13, 21, 35 and 42 post-transplant. Five animals for each group (WKY→F344) and F344→WKY) were examined at each time point, except that no animals in the F344→WKY were examined on day 42. cDNA was synthesized from total extracted RNA and primers specific for rat TNF-α, rat IL-2, rat γ-IFN, rat IL-4, rat-IL-10 and rat cyclophilin were used for gene-specific amplification. (TNF-α, γ-IFN, IL-10, 20 cycles; IL-2, IL-4, 30 cycles; cyclophilin, 20 cycles). The cycles numbers chosen for comparison were found to be optimal during preliminary experiments and occurred during the exponential phase of amplification. PCR products were electrophoresed on a polyacrylamide gel and silver-stained. Gels were subsequently electrotransferred to nylon membranes which were probed with murine cDNAs specific for IL-2, γ-IFN IL-4, IL-10 and TNF-γ. Results: Cyclophilin gene expression was similar for both models at all time points tested; this also served as an internal standard for RT-PCR. In the WKY→F344 tolerance model, TNF-α mRNA levels were not detectable on days 3 and 7 post-transplant, were at very low levels on day 14 and were undetectable on day 21 post-transplant. In marked contrast, the F344→WKY rejection model showed TNF-α mRNA present on day 3 which increased markedly on day 7 and peaked on day 14 post-transplant. TNF-α mRNA levels decreased on days 21 and 35 post-transplant, a time when the lung was undergoing AR. The pattern of IL-2 and γ-IFN mRNA expression was similar to that for TNF-α. However, IL-2 mRNA was clearly detectable in the WKY→F344 tolerance model on day 7 and γ-IFN was not present until day 14 post-transplant. The F344→WKY rejection model showed very high levels of IL-2 and γ-IFN on day 3 which peaked on day 14. The ratio of IL-2/IL 10 in the F344→WKY rejection model was more than five times that seen in the WKY→F344 tolerance model on day 3 (p Conclusions: 1) The WKY→F344 tolerance model develops mild to moderate lymphocytic infiltrates on day 14 which is associated with low level IL-2, γ-IFN and TNF-α gene expression. IL-10 and IL-4 are present at day 3; however, by day 14, IL-10 is the predominantly expressed Th2 cytokine and IL-4 is not expressed. The infiltrates ultimately resolve and the animals develop a functional tolerance to their grafts. 2) The F344→WKY rejection model shows similar lymphocytic infiltrates on day 14, but diverges to a severe rejection which is associated with very early and high levels of IL-2, IL-4, γ-IFN and TNF-α mRNA expression. IL-10 is not expressed on day 3, and only poorly expressed on day 14. 3) These data suggest that delayed and low level expression of cytokines can be seen in animals developing tolerance to their grafts while early and abundant expression of cytokines (IL-2, IL-4, γ-IFN and TNF-α) is associated with AR and ultimate graft loss. It also appears that, in this system, IL-10 expression is critical for development of tolerance while IL-4 expression occurs early in both the rejection and tolerant models, but it expressed poorly in the tolerant models on day 14.

The efficacy of CTLA4Ig in blocking immune activation and allograft rejection (AR) was tested in an aggressive and rapid model of rat lung AR (Brown Norway [BN]→Lewis [LEW]). CTLA4Ig is a recombinant soluble protein that binds with high affinity to rat B7/BB1 and other surface molecules on APCs, subsequently blocking the binding of B7/BB1 to CD28/CTLA4 on T cells. This interrupts the costimulatory pathway critical for complete T cell activation and completion of the AR process. Left single-lung transplants were performed between BN→Lew. Five allograft recipients were examined in each group. At transplantation, animals received 250 μg of CTLA4Ig or 250 μg of control Ig intraperitoneally daily until sacrifice. Animals were sacrificed on days 2, 4, and 7 after transplant. Control (BN→Lew) grafts show irreversible rejection by day 7. Syngeneic (Lew→Lew) grafts show no AR on day 7. AR episodes were graded histologically (stages 0-IV and pathologic intensity of inflammation was graded on percentage of involvement. Cytokine transcript levels were measured in control and CTLA4Ig-treated animals (n=5 in each group) on day 7 using reverse transcriptase polymerase chain reaction techniques. The most profound differences were found on day 7 after transplant. The degree of lymphocytic infiltration was greater in the CTLA4Ig group (perivascular: 4±0 vs. 2.6±0.6, peribronchial: 4±0 vs. 2.2±0.4, and peribronchiolar: 3.6±0.5 vs. 2±0.3, P

Within the first year, 15-20% of coronary artery saphenous bypass vein grafts (SVGs) occlude because of thrombosis or progressive intimal hyperplasia. One potential new strategy to reduce this complication would be to introduce antithrombotic or antiproliferative genes in vein grafts before implantation. The success of this approach requires an efficient DNA delivery system. In the present study we tested the feasibility of using adenovirus-transferrin/polylysine-DNA complexes (TfAdpl/DNA) to achieve high-efficiency gene transfer into vascular interposition vein grafts. All studies used the Escherichia coli LacZ (beta-galactosidase [beta-Gal]) reporter gene under the control of the cytomegalovirus (CMV) earlier promoter and enhancer (pCMV/LacZ). Autologous rabbit jugular vein segments were incubated ex vivo for 60 min in a solution of TfAdpl/DNA complexes (1.2 x 10(10) biotinylated adenovirus particles, 2,430 ng of streptavindylated polylysine. 10 micrograms of plasmid DNA, and 9 micrograms of transferrin-polylysine per ml), and then reimplanted across the ligated right carotid artery. Control veins were incubated in TfAdpl solution in which DNA was omitted. A total of six grafts were treated with TfAdpl/DNA, and two grafts were treated with TfAdpl. Veins were harvested 3 (n = 3) and 7 (n = 3) days later and beta-Gal activity was determined by X-Gal chromogen staining. All six TfAdpl/DNA-treated grafts stained intensely blue, whereas control grafts were negative. Microscopic examination of serial sections revealed intracellular blue granules consistent with beta-Gal activity to be present in all of the endothelial cells and in numerous medial and advential cells.(ABSTRACT TRUNCATED AT 250 WORDS)

We analyzed the long-term results of valve replacement with the St. Jude Medical bileaflet valve (St. Jude Medical, Inc., St. Paul, Minn.) in our first 1000 implantations between 1978 and 1992. A total of 399 patients had mitral valve replacement, 471 aortic valve, and 130 double (mitral and aortic) valve replacement. The average patient age was 64 ± 15 years and the majority of patients (52 %) had concomitant coronary disease. With 4328 patient-years of follow-up, 83% of the mitral group, 76% of the aortic group, and 77% of the double valve group were free of thromboembolism at 10 years after operation, and 87% of the mitral group, 82% of the aortic group, and 85% of the double valve group were free of valve-related hemorrhage. At 10 years, 91 % of the mitral group, 84 % of the aortic group, and 84 % of the double valve group were free of valve-related death. However, overall survival at 10 years was only 42 % ± 4 % for the mitral group, 43 % ± 4 % for the aortic group, and 43% ± 6 % for the double valve group. For all three groups, age was a highly significant factor stratifying survival (p

We present our experience with an alternative technique for orthotopic heart transplantation. It consists of total excision of the recipient's atria, with the donor's heart implantation performed using bicaval end-to-end anastomoses as well as pulmonary venous anastomoses. Forty consecutive patients receiving transplants in this fashion were compared with 64 patients who underwent orthotopic transplantation with the standard technique. The incidence of postoperative tricuspid regurgitation was reduced in patients receiving transplants with the new surgical approach (p = 0.003). In addition, the need for pacemaker implantation for severe bradyarrhythmia in the early (0 to 6 weeks) posttransplantation period (p = 0.003) was eliminated. Although not statistically significant, there was a trend in the reduction of postoperative mitral regurgitation in patients who received transplants by the modified technique. Based on this experience, we believe this modified technique for orthotopic heart transplantation has an anatomic and physiologic advantage that may improve long-term hemodynamic results.

A 10-year experience with early operation for postinfarction ventricular septal defect is reviewed. Twenty-two patients underwent surgical repair; operative mortality was 36% ( horac C ardiovasc S urg 1992;104:961-5)

Multiple studies have shown that coronary bypass surgery in women clearly has a higher risk of operative death. The reason for this higher risk remain less clear, however. Although earlier studies suggested that women were at higher risk due to their smaller body size, several recent studies have suggested that a significant component of the higher mortality of women may be late referral for bypass surgery. Complication rates and hospital stay also appear to be higher in women. Although operative mortality is higher, women have similar long-term results from bypass surgery. Thus, coronary bypass surgery is a valuable treatment option for women with advanced coronary disease with excellent long-term outcomes. The short-term outcomes of women referred for bypass surgery may be improved with earlier referral of women for revascularization.

Allogeneic lung transplantation was performed using a rat model in order to assess the pathologic changes that developed during the process of rejection. The left lungs of 38 BN rats (RT-1n) were orthotopically transplanted into LEW rats (RT-11). The allografts developed the well-known changes of perivascular, peribronchial, and interstitial lymphocytic infiltrates resulting in necrosis of the pulmonary parenchyma at 7–8 days after transplantation. In addition, we document two findings that have not been reported previously in lung transplantation: vasculitis and eosinophilic infiltrates. Vasculitis with swelling and vacuolization of the endothelial cells was observed in transplants as early as 3 days following transplantation. Vasculitis with fibrinoid necrosis of the vessel wall was prominent at 7–8 days after grafting. The allografts also exhibited eosinophilia at 2 to 4 days following transplantation. The density of eosinophils in the inflammatory infiltrate reached a peak of 20% on Day 3 post-transplantation. These findings suggest an important role of humoral immunity and a possible involvement of eosinophils in lung allograft rejection.

One hundred fifty seven consecutive octogenarians (mean age +/- standard deviation, 82.4 +/- 1.9 years) underwent coronary artery bypass grafting with hypothermia (mean temperature, 21.8 degrees +/- 1.8 degrees C), hyperkalemic cardioplegia, and cardiopulmonary bypass in a 9-year period. Sixty-six percent were male. Preoperatively, 115 patients (73%) were in New York Heart Association functional class IV, with the remainder being in either class III (23%) or class II (4%). Twenty percent of the patients had major complications including postoperative hemorrhage (15), sepsis (9), cerebrovascular accident (6), third-degree heart block (5), renal failure requiring dialysis (1), and pulmonary embolism (1). The 30-day or in-hospital mortality rate was 7.0%. Mean total hospital stay was 26.1 +/- 17.9 days. One-year and 5-year actuarial survival rates were 85% and 62%, respectively. Higher mortality was seen to be associated with New York Heart Association class IV, left ventricular ejection fraction less than 0.40, and lesser values for cardiac output and cardiac index. At the 6-month postoperative follow-up, 73% of the survivors reported that their general health had improved as compared with before operation. This experience demonstrates that for select octogenarians with unmanageable angina pectoris, coronary artery bypass grafting is an effective therapeutic option.

Background. Antithrombin III (AT-III) is an antithrombotic agent with known anti-inflammatory properties that is also known to attenuate acute inflammation, prevent ischemia-reperfusion injury, and disseminated intravascular coagulation (DIC) associated with sepsis and endotoxemia. Here, we examined the ability of AT-III to modify parameters of acute inflammation in a highly histoincompatible model of rat lung allograft rejection (AR) . Methods. After left single lung transplantations (BN→Lew), recipient animals were treated i.v. with 50 U/kg of human AT-III (low dose group), 500 U/kg of human AT-III (high dose group), or normal saline (control group) on days 2 and 4 posttransplant. All animals were sacrificed on day 6, and several pathological categories of acute inflammation related to AR were scored (0-4). The effect of AT-III on concanavalin A (Con A)-stimulated rat spleen cell proliferation was also examined. Results. The stage of AR, and the degrees of edema, hemorrhage, and necrosis were significantly reduced in the high dose group compared with the control group. AT-III significantly inhibited rat spleen cell proliferation in response to Con A, in a dose-dependent manner. Maximal inhibition was seen at 15 U/ml in culture. Identical inhibition of Con-A-stimulated cultures occurred in both serum free and serum-containing media, indicating that AT-III inhibition of Con-A-stimulated rat spleen cell proliferation is independent of its actions on thrombin. Conclusions. 1) AT-III treatment significantly improves parameters of acute inflammation seen in a highly histoincompatible model of rat lung AR. 2) AT-III inhibits in vitro T cell proliferation to the potent mitogen Con A, suggesting that protease inhibition may inhibit T cell activation in vitro. 3). The beneficial effects of AT-III on parameters of lung AR relate to the anti-coagulant, anti-inflammatory, and possibly immunoregulatory actions of AT-III.

In summary, we have shown that although nonagenarians are at higher risk from cardiac surgical procedures, they can derive significant benefit from these same procedures. This fact has important implications in the present health care debate on the use of limited resources in the elderly.

Objective: Nitric oxide has been reported to reduce intimal hyperplasia as a response to arterial injury. This study was designed to assess the possible effect of perivascular application of a nitric oxide donor on neointimal proliferation occurring in veins exposed to the dynamics of the arterial circulation in a hypercholesterolemic rabbit model. Methods: Autologous jugular vein grafts were implanted in the carotid circulation of 20 hypercholesterolemic rabbits. A mixture of a biodegradable polymer and the nitric oxide donor, spermine/nitric oxide, which releases nitric oxide with a half-life of 39 minutes, was applied periadventitially at the time of implantation. Controls were veins bathed in saline solution, polymer alone, and polymer plus the carrier vehicle spermine without nitric oxide. Animals ( n = 5 in each group) were put to death on day 28 for morphometric analysis, cell count, and immunohistochemical staining. Results: Treatment with perivascular nitric oxide donor significantly decreased wall thickness (126 ± 24 μm vs 208 ± 45 μm, p = 0.0017) and area (124 ± 22 μm 2 /μm vs 211 ± 37 μm 2 /μm, p = 0.005). With the carrier vehicle spermine alone, there was a trend toward reduced intimal thickness, but the change was not statistically significant. In the grafts treated with nitric oxide donor, expression of insulin-like growth factor, fibroblast growth factor, thrombospondins, fibronectin, and tenascin was reduced. Conclusion: The periadventitial delivery of nitric oxide donor produces a reduction of neointimal hyperplasia in veins implanted in the arterial circulation. The mechanism of action is not entirely clear, but the reduction cannot be explained on the basis of decreased cell proliferation alone. Other possibilities are modulation of protein synthesis of vascular smooth muscle cells and production of extracellular matrix components. (J Thorac Cardiovasc Surg 1998;115:604-14)

Background . Growth of the elderly population worldwide, and specifically in the United States, will continue to accelerate and will have a profound impact on the cost and delivery of health care resources in the future. A medical strategy that allows the elderly to live independently is essential to most cost-effective use of our resources. The question remains as to what will be the future of surgical therapy for this increasing population. Methods . We retrospectively studied the cases of 30 consecutive nonagenarians (mean age, 92.3 ± 1.8 years) who underwent a cardiac operation within a 9-year period. All patients were in New York Heart Association class III or IV and underwent operation urgently or emergently. Results . The 30-day mortality rate was 10%, and the actuarial survival rates were 81% ± 8% and 75% ± 9% at 1 year and 2 years, respectively. Seventy-eight percent of survivors were in New York Heart Association class I or II within 2 years after operation and had an improved quality of life. The cost of providing care in this age group was 24% higher than in octogenarians. Conclusions . Advanced age in and of itself (>90 years) should not be a contraindication to an open-heart operation, although morbidity, mortality, and cost may be higher. However, selective criteria identifying risks and benefits for individual patients should be applied. The aging of our population will have a profound impact on the cost and delivery of health care resources in the future. This issue must be addressed in the current debate on the provision of expensive procedures under a realigned national health-care system. (Ann Thorac Surg 1997;63:1685–90)

The format for future cardiothoracic surgical practices includes the option of a hospital-based group where provider groups and the hospital share the responsibilities and obligations of clinical care and the cost of that care. Based on personal experience at the Cedars-Sinai Medical Center, Los Angeles, three separate contract relationships during our tenure have reflected the evolution of cardiothoracic surgeons' relationship to our patients and the hospital in which we work. Although other organizational modes may prove equally successful, the hospital-based group practice is a viable structure that supports the preservation of quality in the work performed. This relationship helps to maintain a steady volume of patients enabling research endeavors, which are primarily funded through practice incomes, to continue and it also provides a platform for networking with defined patient referrals, shared services, and bench-marking with other centers.

The rapid change occurring in American healthcare is a direct response to rising costs. Managed care is the fastest growing model that attempts to control escalating costs through limitations in patient choice, the active use of guidelines, and placing providers at risk. Managed care is an information intensive system, and those providers who use information effectively will be at an advantage in the competitive healthcare marketplace. There are five classes of information that providers must collect to be competitive in a managed care environment: patient satisfaction, medical outcomes, continuous quality improvement, quality of the decision, and financial data. Each of these should be actively used in marketing, assuring the quality of patient care, and maintaining financial stability. Although changes in our healthcare system are occurring rapidly, we need to respond to the marketplace to maintain our viability, but as physicians, we have the singular obligation to maintain the supremacy of the individual patient and the physician-patient relationship.

The United States health care system is under tremendous pressure to cut costs while maintaining quality. One mechanism to reduce costs is managed care--a system with both risks and benefits for patients, providers, and payors, and one that requires large volumes of data to ensure optimal medical and financial decision-making. In this review, we describe the types of information needed by managed care systems, including medical outcome data (satisfaction, survival, quality of life, and complications) and financial data (costs and long-term resource utilization). From a provider's point of view, the customers for these data range from individual patients to large self-insured corporations, and we describe the data required for each potential customer. Finally, as a concrete example of how data can be collected and analyzed to improve a provider's competitiveness, we describe the Cedars-Sinai Medical Center cardiothoracic surgery database from a managed care perspective. The concepts presented are generalizable to other subspecialties, and will become more important in the increasingly competitive milieu of American health care.

Contract pricing among providers is being used as a method to control the costs of health care. To estimate a contract price. providers must take into account not only the direct costs of uncomplicated procedures. but the incremental costs of complications. Accordingly, we determined the incremental costs of postoperative complications in a series of 722 consecutive patients (3/12/90 to 3/22/94) undergoing routine CABG (DRG 107–CABG without catheterization). We identified 31 prospectively collected candidate variables from the perioperative period and 15 routinely collected complications. Total direct costs were obtained from the hospital central financial system. Only patients who survived to discharge were included in the analysis. Forward, stepwise, multiple linear regression was used to determine the incremental costs of complications above the cost of an uncomplicated procedure. Of the candidate variables. 6 perioperative variables (age, angina CHA class, non-use of internal thoracic artery, widow(er), peripheral vascular disease, hypercholesterolemia), and 6 complications contributed to the direct costs of CABG. The following table shows the incremental cost of each postoperative complication and its percent of the average direct cost of CABG ($27,400). New dialysis $36,436 133% Any neuro compl $13,333 49% Intubated g48 hrs $24,535 90% Leg infection $ 5.055 18% Pneumonia $20,847 76% SVT $ 2,670 10% Conclusion Postoperative complications add large, incremental costs to CABG surgery, and can be more expensive than the basic direct costs of the procedure itself. By knowing the incidence and costs of complications, contract prices can be adjusted to more accurately reflect true direct costs.

The most quoted long-term outcome studies from the coronary artery bypass surgery literature were performed in the 1970s, and these trials--the Coronary Artery Surgery Study, the Veterans Administration Study, and the European Cooperative Study--added significantly to our knowledge of the efficacy of bypass surgery. However, important studies are still being performed and are refining our knowledge of long-term outcomes. This review covers early factors that affect long-term outcome, and recent information concerning particular subgroups of patients undergoing bypass surgery. In addition, new information is becoming available about the relative roles of percutaneous transluminal coronary angioplasty and coronary artery bypass grafting, and these studies are also discussed.

Five hundred twenty-eight consecutive patients aged 80 years and over (mean age, 83.1 +/- 2.7 years) underwent cardiac operations with hypothermia (mean, 21.9 degrees +/- 2.2 degrees C), hyperkalemic cardioplegia, and cardiopulmonary bypass in a 10-year period. Fifty-six percent of the patients were male. Preoperatively, 68% of the patients were in New York Heart Association functional class IV, and 31% were in class III. Among them, 303 patients had isolated coronary artery bypass grafting (CABG) (group I), 132 had aortic valve replacement only or combined with CABG (group II), 42 had mitral valve replacement only or combined with CABG (group III), 31 had mitral valve repair and CABG (group IV), and 20 had double-valve procedure only or combined with CABG (group V). The 30-day or in-hospital mortality was 8.3% in group I, 4.5% in group II, 29% in group III, 23% in group IV, and 30% in group V. Total 30-day or in-hospital mortality was 10.6%. One-year and 5-year actuarial survival rates were as follows: group I, 82% and 62%; group II, 85% and 58%; group III, 61% and 37%; group IV, 56% and 19%; and group V, 63% and 15%. Total 1-year and 5-year actuarial survival were 79% and 54%. At follow-up (mean, 2 years), 70% of overall survivors reported that their general health had improved. Our experience demonstrates that for select patients aged 80 years and over with unmanageable cardiac symptoms, CABG and aortic valve replacement groups had better results in improving quality of life as compared with patients having mitral or combined procedures.

Fifteen elderly patients (age more than 70 years) underwent surgical repair of postinfarction ventricular septal defects during the years 1980 through 1992. The operative (to discharge or30 days) mortality rate was 47%, and the complication rate among survivors was 63%. The probability of survival at 1 year was 47% +/- 13%. Because of the small sample size of our patient population, predictive preoperative risk factors associated with early mortality could not be identified with certainty. However, there is a trend suggesting that high right atrial pressures (p = 0.15) and the need of an intraaortic balloon pump preoperatively (p = 0.12) influence 30-day mortality, as previously described in larger series. Of 5 long-term survivors, 3 are in New York Heart Association functional class I and 2 are in class II. Our experience in this group of patients suggests that in the elderly, a very aggressive approach should be taken in recommending early surgical intervention for postinfarction ventricular septal defect before hemodynamic deterioration ensues and severely compromises chances for survival.

Left lung transplantation (n = 30) between BN rat (RT1n) and LEW rat (RT11) was performed to examine serial changes in the inflammatory cell profile and T-cell subsets occurring in bronchoalveolar lavage (BAL) obtained after transplantation. Transplanted animals were sacrificed on Days 1 to 7 post-transplantation. Previous studies show that lung allografts between these rat strains were strongly rejected within 7 days. The serial change in the cell profile of BAL showed a marked initial predominance of polymorphonuclear leukocytes, a decrease in macrophages, and a temporary increase in number of eosinophils on Day 2 posttransplantation. A gradual increase in lymphocytes coincident with progression of rejection was also noted. Immunocytologic studies using monoclonal antibodies specific for rat T-cell subsets and interleukin-2 receptor (IL-2R) showed significant increase in pan-T-cells on Days 3, 4, and 5 and T-suppressor/cytotoxic (CD8 positive) fraction on Days 4 and 5, whereas the T-helper (CD4 positive) fraction peaked on Day 2. The frequency of T-cells expressing IL-2R (55 kDa), indicating activated T-cells, significantly increased as early as Day 2 and maintained its high value thereafter. mRNA levels for IL-2R were detectable in the allografts on Day 2 and peaked on Day 5 post-transplantation. The value of CD4/CD8 T-cell ratios rose initially and then dropped below 1.0 on Days 4 and 5. These values differed markedly from those of syngeneic transplants (Lew → Lew) examined on Day 5 post-transplantation. First, no significant changes in BAL cytology were seen when syngeneic transplants were compared with normal (Lew) lung. However, there were significant differences between syngeneic and allogeneic transplants preformed on Days 1-5 (P < 0.01). All immunocytology parameters (CD4-, CD8-, and IL-2R-positive T-cells) were significantly (P < 0.01) different between syngeneic and allogeneic transplants at each time point examined. No IL-2R mRNA was detectable in syngeneic transplants on Day 5, and none was detected in normal lungs. In summary, the following cellular events in BAL were felt to correlate closely with the histological diagnosis of rat lung allograft rejection: (i) An increase infiltration of T-cells bearing the pan-T-cell marker, OX-19, (ii) an increase in T-cells hearing the CD8 phenotype with a progressive decrease in the CD4/CD8 ratio, (iii) a progressive increased accumulation of mRNA specific for IL-2R and increased expression of IL-2R on graft-infiltrating T cells, (iv) an increase in the number of eosinophils infiltrating the graft.

Tumor necrosis factor alpha and beta are polypeptide cytokines with a wide range of metabolic, immunologic, and inflammatory activities. TNF is known to participate in immune mediated injury of native lungs, but a role for TNF in mediating lung allograft rejection (AR) has not been established. In experiments reported here, we assessed the role of TNF in mediating lung AR in a rat model of lung transplantation (BN-->Lew) (RT1n-->RT1l). This model shows florid AR with all grafts completely destroyed by day 6 posttransplant. Graft pathology is characterized by massive lymphocytic infiltrates and hemorrhagic necrosis. Initially, 5 lung allograft recipients in each group were sacrificed on days 1 to 6 posttransplant. Allografts were removed, mRNA isolated, and Northern blotting or RT-PCR performed with blots probed with cDNAs or oligos specific for rat TNF-alpha cyclophylin and gamma-actin. Data were compared with syngeneic transplants (Lew-->Lew) and with normal controls. In addition, frozen lung allograft tissue was examined by indirect immunofluorescence, using antibodies specific for TNF. TNF-alpha mRNA levels were detectable on day 2 posttransplant, and peaked on days 6-7 posttransplant. IF studies showed TNF protein expression in mononuclear cells of rejecting allografts on day 3, peaking on day 6. Both TNF-alpha mRNA and protein levels correlated with maximal AR and hemorrhagic necrosis of grafts. Minimal TNF-alpha mRNA or protein was detected in syngeneic grafts or in contralateral native lungs. We then examined the ability of a rabbit polyclonal anti-TNF-alpha (7000 U/day) and anti-TNF-beta (5000 U/day) with 30% crossreactivity with rat TNF to modify the AR response. For each group, 4-5 left lung transplants were performed as described, and animals treated with anti-TNF-alpha, anti-TNF-beta, (anti-TNF-alpha+anti-TNF-beta) or with preimmune rabbit sera. All animals were sacrificed on day 6 posttransplant. Several pathological categories of inflammation were examined and scored (0-4), with a score of 0 = 0% involvement; 1 = 1-25% involvement; 2 = 26-50% involvement; 3 = 51-75% involvement; and 4 = 76-100% involvement. The mean and SD scores were obtained for all animals in the treatment categories mentioned above, and compared with preimmune-treated controls. Briefly, no differences in perivascular, peribronchial, or peribronchiolar cell infiltrates or edema were seen in treatment groups compared with controls.(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND Thrombolytic therapy is a promising alternative to valve replacement in the management of prosthetic valve thrombosis. We sought to determine the short- and long-term results of treating thrombosed St. Jude heart valves with thrombolytic therapy as the primary treatment modality. METHODS AND RESULTS Between March 1978 and December 1991, 988 patients underwent implantation of St. Jude prosthetic valves at our medical center, and all patients with thrombosed valves were identified prospectively. During this period, 17 patients (13 women; mean age, 66.8 +/- 19.0 years) developed prosthetic valve thrombosis (11 aortic, six mitral). In six patients, Coumadin was stopped in preparation for elective surgery. The clinical presentation was congestive heart failure in 13, syncope and fatigue in two, and a cerebrovascular accident in one; one patient was asymptomatic. The average duration of symptoms was 11.7 +/- 12.0 days (range, 1-45 days). Anticoagulation was subtherapeutic in all but one patient at the time of presentation. Cinefluoroscopy was the primary method used for diagnosis and was also used to follow the response to therapy. Twelve patients were treated medically (10 with thrombolytic therapy and two with heparin), three were treated surgically, and two were diagnosed at autopsy. Of the 12 medically treated patients, 10 had marked improvement in leaflet movement and symptoms within 12 hours. Thus, 10 of 12 patients (83%) had a satisfactory response to medical therapy alone. No medically treated patient died or had a major complication resulting in permanent damage. However, four of the 12 medically treated patients had minor complications, including a transient episode of facial weakness in one patient, hematomas in two, and epistaxis in one. Late rethrombosis recurred in two patients in the medically treated group and was successfully retreated with thrombolytic therapy. At 3 months, all patients were alive and well. CONCLUSIONS Thrombolytic therapy can be used as the first line of therapy for thrombosed St. Jude valves with a low risk of permanent side effects and excellent chances of success. In most cases, surgery can be reserved for patients who do not respond to thrombolytic therapy.

The development of color Doppler echocardiography flow mapping (CDFM) represented a major technological breakthrough in the noninvasive investigation of flow fields in the heart. CDFM displays the spatial distribution of abnormal blood velocities in the heart and has been primarily used for evaluation of valvular regurgitation [1]. However, quantitation of regurgitation by CDFM remains difficult [2].

Laser coronary angioplasty using the 308-nm Excimer laser was successfully performed intraoperatively during coronary artery bypass grafting. It achieved a reduction of the left anterior descending artery stenosis from 99% to 25% as seen on angioscopy, without evidence of vascular perforation or intimai disruption. The Excimer laser offers the opportunity for intraoperative endovascular remodeling and recanalization and has a potential role as an adjunct to existing standard coronary artery bypass grafting protocol.

To determine whether differences in referral reasons explain the higher operative mortality of women in coronary artery bypass surgery.Case series.A tertiary care, private teaching hospital.Consecutive patients who had isolated coronary artery bypass surgery between 1982 and 1987 (total, 2297; 79% male and 21% female).The inhospital mortality rate was significantly higher for women than for men (4.6% compared with 2.6%; P = 0.036; 95% CI for difference in mortality, 0% to 4.0%). Women were older than men (mean, 68.2 and 64.0 years, respectively; P less than 0.001), and a higher percentage of women were referred with unstable angina (P = 0.007), postmyocardial infarction angina (P = 0.029), congestive heart failure (P less than 0.001), and New York Heart Association class IV symptoms (66% compared with 45%, P less than 0.001). More men were referred with a history of an abnormal exercise test (P less than 0.001), and patients referred because of a positive exercise test had a lower mortality (P less than 0.001). Using multivariate analysis, adjustment for the higher preoperative functional class of women and for age accounted for all of the difference in mortality between men and women (odds ratio, 1.04; CI, 0.60 to 1.79; P = 0.89). After correction for functional class alone, there continued to be no significant difference in mortality between men and women (P = 0.40).Differences in functional class and age account for the higher operative mortality of women in coronary bypass surgery. Women are referred for coronary bypass surgery later in the course of their disease than men, and later referral may increase their changes of operative death.