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Background . Optimal clinical stimulation for skeletal muscle cardiac assist systems (such as dynamic cardiomyoplasty) is not clearly defined. The pressure-generating capacity of canine skeletal muscle ventricles (SMVs) at a variety of preloads and stimulation frequencies was examined as was time for SMVs to develop peak pressure. Methods . SMVs were analyzed just after construction and after 3 months of electrical conditioning. Pressure generation and time to develop peak pressure were determined using a distensible mandrel. Results . Higher preloads resulted in increased pressure generation; conditioned SMVs generated significantly less pressure than unconditioned SMVs. Increasing stimulation frequency from 20 to 50 Hz increased pressure-generating capacity; increases beyond 50 Hz did not result in further increases. Time to 90% peak pressure was least at 10 HZ and 65 Hz. Conclusions . Higher stimulation frequencies and preloads result in a more quickly contracting muscle, which generates more pressure. Midrange stimulation frequencies of 30 Hz provide optimal muscle strength and minimize time to develop peak pressure. Initiation of contraction should begin before the time maximal pressure is desired.

To determine whether the contractile work history of cardiac muscle influences its responsiveness to insulin, we examined the effect of insulin infusion on glycogen metabolism in the rat heart 1 wk after transplantation into a nonworking heterotopic infrarenal position. Nonworking heterografts had higher basal glycogen concentrations than did in situ working hearts of the same animals (29.9 +/- 2.7 vs. 23.3 +/- 0.8 mumol/g; P < 0.05), and a smaller fraction of their glycogen synthase enzyme activity was in the physiologically active glycogen synthase I form (8 +/- 2 vs. 22 +/- 3%; P < 0.02). During a 25-min infusion of insulin (1 U/min) and glucose (30 mg.kg-1.min-1), the fractional glycogen synthase I activity of heterografts remained lower than that of in situ hearts (29 +/- 5 vs. 56 +/- 7%; P < 0.02) and heterografts synthesized glycogen more slowly (0.126 +/- 0.07 vs. 0.352 +/- 0.06 mumol.g-1.min-1; P < 0.02). These effects could be duplicated by a 24-h fast, which similarly increased myocardial glycogen concentration (to 32.9 +/- 5.6 mumol/g). These observations suggest that the performance of repetitive contractile work is necessary to maintain the myocardium maximally responsive to insulin. Mechanical unloading increases myocardial glycogen concentration, thereby reducing the magnitude of insulin's stimulation of glycogen synthase and consequently the rate of incorporation of circulating glucose into glycogen.

The therapeutic mechanism of transmyocardial revascularization (TMR) is not yet fully understood, and continues to be a subject of controversy and active research. Immediate direct laser channel flow, gradual angiogenesis, denervation, and perioperative infarction of the ischemic area have been all discussed, without clear evidence indicating superiority of individual factors.We utilized a prospective noninvasive physiologic dynamic method to assess laser-related myocardial injury. The study protocol included EKGs and echocardiograms, including intraoperative transesophageal echocardiograms (TEE) on consecutive TMR patients. CPK-MB was measured postoperatively, with 5 samples at 6-hour intervals.Fifty male patients averaging 62 years old were enrolled in the study. Two patients experienced postoperative myocardial infarctions, from which 1 died. The average CPK-MB values were 12.8+/-1.28 immediately after surgery, 19.2+/-2.4 at 6 h, 15.2+/-2.3 at 12 h, 12.2+/-6.3 at 18 h, and 11.7+/-1.3 at 24 h. In only 5 patients were the CPK-MB values over 30 units at their peak. The intraoperative wall motion remained unchanged in the patients studied, both using TEE and transthoracic echography.Significant myocardial injury after TMR appears unlikely, as indicated by CPK-MB and myocardial wall dynamics. Furthermore, TMR does not seem to aggravate baseline myocardial ischemia. We found no evidence to support a hypothesis that surgical myocardial injury constitutes the mechanism of therapeutic action in TMR.

Transmyocardial revascularization (TMR) is an emerging therapy for coronary artery disease, with 7 years of published clinical research and nearly three years of clinical application. Every report thus far has confirmed that TMR relieves severe angina pectoris. It is primarily an alternative therapy for angina which has been refractory to conventional medical and surgical treatment. Operative mortality of 3% to 10% has been reported.Seventy-seven patients were treated with TMR using a Holmium: YAG laser. Admission criteria included severe angina despite high doses of at least two anti-angina medications and nitroglycerin, reversible ischemia by thallium scan, and unsuitability for CABG or angioplasty. Patients had end-stage ischemic heart disease and multiple previous conventional procedures. TMR was performed through small left anterior thoracotomies using a 10.16 cm or less incision.Seventy-five patients recovered from surgery without major complications. One patient (1.3%) died of an autopsy-proven myocardial infarction in the treated region, and two additional patients had a myocardial infarction (4.3%). Four patients had paresis of the left phrenic nerve, as determined by an elevated left hemi-diaphragm on chest X-ray, from which three recovered fully. Patients had no bleeding or wound infections. Patients were intubated for an average of 1.5 hours and remained in ICU an average 0.8 days. Mean hospitalization was 3.4 days.Technically well-done TMR through a small anterior thoracotomy can have good therapeutic results and low morbidity and mortality. We will describe operative techniques which minimize pain and stress and help to insure surgical success.

Elderly surgical patients have higher operative morbidity and mortality than younger cohorts, particularly when the procedure is lengthy and complex. While use of bilateral internal thoracic arteries (BITA) is often associated with increased surgical risk, we nevertheless hypothesized that the use of BITA in elderly coronary artery bypass patients would not significantly increase their operative risk beyond that encountered using single internal thoracic arterial (SITA) or saphenous vein grafts (SVG). We maintained that arterial grafts remain essentially unaffected by arteriosclerosis, and that extension of a high-quality life is a desirable outcome regardless of age at operation.We studied myocardial revascularization in 673 patients over 65 years of age at the time of operation. All operations were conducted or supervised by a single surgeon during a ten-year period from January 1986 to January 1996. Preoperative and operative dates were recorded prospectively.All patients underwent coronary artery bypass grafting.The study compared outcomes in patients having all veins, SITA or BITA operations. For the first analysis, 673 patients were divided into three groups: 163 patients (Group 1) had saphenous vein used for all bypasses; 338 patients had a SITA with supplemental vein grafts (Group 2); and 172 patients (Group 3) had BITAs with additional vein grafts as needed. In the second analysis, Group 3 was subdivided and grouped by the coronary arteries which received the ITA grafts, and the analysis was repeated. One hundred and sixteen patients (Group 3A) underwent traditional placement of ITA bypasses (left ITA to the LAD, right ITA to the RCA); in Group 3B, 56 patients received revascularization of branches of the left coronary artery (left ITA to the circumflex system, right ITA to the LAD).We communicated directly with 90.5% of the patients, their families, or their physicians. The survival status of the remainder was determined through the National Social Security Death Index Network. This allowed us to obtain follow-up longevity data for 100% of the study sample at a mean observation period of 5.03+/-3.1 years with variation between 10.8 years to 2.4 years.A multivariate analysis showed that placement of both ITA grafts to left-sided arteries in older patients independently improved long-term survival (p=0.031).The BITA procedure does not have greater operative morbidity or mortality in the elderly despite the length or complexity of the surgery. To realize improved long-term survival rates, however, both ITAs must be grafted to the left coronary artery branches.

Despite many technological advances in cardiovascular surgery, some patients still experience postcardiotomy left ventricular (LV) failure that is refractory to both inotropic support and intra-aortic balloon pump (IABP) placement. The primary author (MJR) recently changed from inflow cannulation at the right superior pulmonary vein/left atrial junction to inflow cannulation at the dome of the left atrium. The purpose of this study was to compare data collected during placement of a left ventricular assist device (LVAD) at the junction of the right superior pulmonary vein with positioning the device in the dome of the left atrium. Experimental design, setting, and participants: the medical records of all patients undergoing cardiac surgery by one author (MJR) between 1994 and 1997 were retrospectively reviewed, and 4 patients requiring LVAD placement for short term postcardiotomy support were identified. Each patient's chart was reviewed for duration of LVAD support, average LVAD blood flows, pulmonary capillary wedge pressures (PCWP), preoperative characteristics, postoperative complications, and final outcome for the patients.Accessing the left atrium through the dome resulted in excellent blood flow through the LVAD and allowed for good LV decompression. Hemostasis remained the most common complication regardless of the technique employed; however, the enhanced visibility provided by accessing the left atrium via the dome made repairs less technically difficult. Three patients (75%) were able to be weaned from the LVAD and were discharged from the hospital to home. Two of these patients were cannulated via the left atrial dome making removal of the LVAD easier, thus exposing the patients to less additional operative time. One patient could not be weaned from LVAD support secondary to development of right ventricular failure requiring RVAD insertion and subsequent development of multiple organ failure syndrome.Patients requiring LV assistance following cardiopulmonary bypass surgery traditionally have high levels of morbidity and mortality. In spite of the complications associated with the placement of an assist device, we remain encouraged by the excellent LV decompression and systemic flows we achieved following implantation of the LVAD through the dome of the left atrium. The superior ease of implantation and decannulation provided better operative care and postoperative management for our patients.

During hypoxia, the heart consumes glycogen to generate ATP. Tolerance of repetitive hypoxia logically requires prompt replenishment of glycogen, a process whose regulation is not fully understood. To examine this, we imposed a defined hypoxic stimulus on the rat heart while varying its workload. In intact rats, hypoxia reduced myocardial glycogen approximately 30% and increased both the fraction of glycogen synthase in its physiologically active (GS I) form (from 0.24 +/- 0.06 to 0.82 +/- 0.07; P < 0.005) and glycogen synthesis (from 0.087 +/- 0.011 to 0.375 +/- 0.046 mumol.g-1.min-1; P < 0.005). Reducing cardiac work (with propranolol or heterotopic transplantation) reduced glycogen breakdown, glycogen synthase activation, and glycogen synthesis in parallel, stepwise fashion in intact rats. Correspondingly, hypoxia increased GS I activity in the perfused heart in vitro, but only under conditions where glycogen was consumed. This suggests myocardial glycogen synthase is activated by systemic hypoxia and catalyzes rapid posthypoxic glycogen synthesis. Hypoxic glycogen synthase activation appears to be a proportionate, wholly intrinsic response to local glycogenolysis, operating to preserve myocardial glycogen stores independent of any extracardiac mediator of carbohydrate metabolism.

Left ventricular rupture following mitral valve replacement is an unusual and often lethal complication. Despite being well described since the initial description in 1967 by Roberts, this catastrophic complication still occurs. A recent case of a delayed Type III rupture is presented. The pathology and repair of the three recognized types of rupture are reviewed and the preventive measures discussed.

Extended ischemia results in organ infarction which limits the availability of donor hearts. Hypothermic storage extends heart preservation by effectively stopping cellular metabolism, thereby preventing toxic accumulations of metabolic wastes and depletion of energy stores. However, cell swelling as a result of ion concentration changes and cell laceration due to ice crystal growth are consequences of hypothermic ischemia. Supercooling successfully preserves hearts for an extended time without associated myocardial necrosis. The efficacies of four supercooling preservative solutions, containing hypertonic glucose, polyethylene glycol, and or winter flounder antifreeze protein, are assessed using the Langendorff isolated organ perfusion apparatus and transmission electron microscopy. Polyethylene glycol seems the most effective in preventing myocardial necrosis possibly by dehydrating, minimizing cellular ice formation, protecting against cell swelling, and functioning as an antioxidant. Hypertonic glucose seems the most effective in reducing cell swelling; it may also depress solution freezing points, bind water, adjust both intra- and extracellular osmolarities, stabilize proteins, and assist in adenosine triphosphate (ATP) production. Antifreeze protein seems to bind effectively to ice and inhibit its growth; it may also reduce membrane permeabilities to Ca2+ and K+ ions.

Palliation of acute airway obstruction using the neodymium yttrium aluminum garnet (Nd-YAG) laser was studied in 54 patients who presented over a 42-month period to the Yale cardiothoracic surgery service. Thirty-seven patients had bronchogenic carcinoma; 27 had stage IIIB or IV disease. Nine patients had endobronchial metastases from a primary nonbronchogenic carcinoma. Eight patients had benign disease. A total of 109 Nd-YAG laser tumor ablations were performed. In addition, 32 patients underwent postoperative brachytherapy. Median survival for all patients was 12 months. Patients with bronchogenic carcinoma had a median survival of five months. Fifteen of 20 patients (75%) alive at the time of follow-up reported continued palliation as shown by an improved postoperative Karnofsky score. There was no survival benefit from Nd-YAG laser ablation of endobronchial bronchogenic carcinoma; however, the Nd-YAG laser provided good to excellent palliation in the majority of patients on long-term follow-up.

Between May 1988 and June 1989, five combined heart-lung transplants were performed. There were two males, age 16 and 19 years, and three females age 33, 34, and 19 years. Three patients had primary pulmonary hypertension, one had cystic fibrosis, and the fifth had doxorubicin-induced cardiomyopathy with associated pulmonary hypertension. All patients were severely restricted in functional capacity and were oxygen-dependent. Four grafts were distantly procured (ischemic times 1:15, 2:35, 2:45, 3:45); one was procured on-site (ischemic time 0:58). Four of five grafts functioned well (PO2 on FIO2 30% postoperatively: 102, 120, 180, and 129 torr). One graft (distantly procured with an ischemic time of 1:15) showed total failure of oxygenation secondary to fluid overload during donor surgery; the recipient could not be weaned from cardiopulmonary bypass. All patients were extubated 24 to 30 hours postoperatively. Rejection episodes have been infrequent and all have been successfully treated with pulse steroids. Four of the five patients are alive and well with normal cardiopulmonary function and normal functional capacity 15, 12, 8, and 6 months after surgery. Heart-lung transplantation is an effective therapy for properly selected patients with end-stage cardiopulmonary disease resulting from a variety of primary disorders.

Implantation response has been a critical problem following heart-lung and lung transplantation. While the precise etiology of this problem remains unclear, improvements in organ preservation would be expected to have a beneficial effect on implantation response. The time-related profile of the implantation response was studied in 20 patients who underwent heart-lung transplantation between March 1984-March 1987. In 10 operations the donors had intravenous prostaglandin E-1 pretreatment while 10 had no vasodilatation before explantation of the organs. Otherwise lung preservation and early (2 weeks) immunotherapy were similar in both groups. The implantation response was evaluated by chest films and postoperative lung functions and mechanics. Roentgenographic implantation response was evident from the first postoperative day, was less evident at the seventh postoperative day and then gradually increased during the second postoperative week. There was a tendency towards less implantation response in the PGE-1 group than in the control group, but no statistical difference was observed. Patients with severe operative bleeding problems were excluded from the study. Only peak inspiratory pressures were significantly higher in the control group than in the PGE-1 group (p less than 0.01). Other lung function studies (alveolar-capillary pO2 difference, extubation time) were not different in the groups. This study supported the hypothesis that prostaglandin E-1 may have salutary effects on graft preservation and implantation response in heart-lung transplantation. Since 1986, we have performed 16 heart-lung transplantations using graft preservation with PGE-1 and flush perfusion. Thirty-day mortality is 0% and 13 of 16 patients are surviving.

(1957). A Rorschach Experiment with Six, Seven, and Eight Year Old Children. Journal of Projective Techniques: Vol. 21, No. 2, pp. 166-171.

The heats of hydrolysis, in aqueous 1 M-hydrochloric acid, of one silicon, five germanium, and eight tin(IV) compounds of type (Me3M)nX (where M = Si, Ge, or Sn, n= 1–3, and X is a univalent ligand in which the donor atom adjacent to M is N, O, S, Cl, Br, or I) to give (Me3Si)2O, (Me3Ge)2O, and (Me3SnOH)2 have been measured. From these, standard heats of formation have been calculated as follows: ΔHf°(Me3Si·OEt), I =–126·4 ± 0·7; ΔHf°[(Me3Ge)2O], I =–136·0 ± 4·0; ΔHf°(Me3GeCl), I =–71·6 ± 2·1; ΔHf°(Me3GeBr), I =–62·1 ± 2·1; ΔHf°(Me3Ge·OEt), I =–95·8 ± 2·2; ΔHf°(Me3Ge·SBun), I =–64·7 ± 2·1; ΔHf°(Me3Ge·NMe2), I =–37·1 ± 2·2; ΔHf°(Me3SnCl), c =–58·4 ± 1·2; ΔHf°(Me3SnBr), c =–48·8 ± 1·3; ΔHf°(Me3SnI), I =–31·2 ± 1·1; ΔHf°(Me3SnOH), c =–90·8 ± 1·2; ΔHf°(Me3Sn·OEt), I =–73·1 ± 1·5; ΔHf°(Me3Sn·SBun), I =–47·1 ± 1·6; ΔHf°(Me3Sn·NMe2), I =–13·3 ± 1·4; ΔHf°[(Me3Sn)2NMe], I =–31·5 ± 2·5; ΔHf°[(Me3Sn)3N], c =–29·2 ± 3·6 kcal mol–1. Gas-phase enthalpies of formation of these compounds and thermochemical bond energy terms E(M–X) have been calculated. Group trends show that, for constant X, E(C–X) E(Ge–X) > E(Sn–X), whereas E(C–Y) > E(Si–Y)(Y = H or Me). Another conclusion is that the ‘softness’(in terms of ΔH of reactions) of the acid Me3M+ increase in the order C < Si < Ge < Sn; several chemical reaction types are examined in this light.

With rare exception, the bulk of out knowledge concerning the performance of any particular valve substitute originates from one institution; thus, if valve-related complications are more a function of the patient substrate undergoing operation than the prosthesis per se, the usefulness of inter-institutional comparisons would be severely limited. To address this question, the outcome of 2,719 patients after mitral or aortic valve replacement over 12,955 patient-years of follow-up was analyzed by time-dependent multivariate statistical methods with respect to thromboembolic events, anticoagulant-related hemorrhage, valve failure, fatal valve failure, all valve-related morbidity and mortality, necessity for reoperation, and late survival. Many patient-related factors were significant predictors of the probability of certain patient groups for sustaining these valve-related complications. Hence, comparisons of results of valve performance from different institutions may be misleading unless patient populations are comparable.

Lymphoma remains an important complication after heart transplantation in the era of cyclosporine immunosuppression. It has been generally assumed that the occurrence of lymphoma related to quantitative degree of immunosuppression, and this assumption is exemplified in the treatment of some such lymphomas with reduction of immunosuppression. Seventy-five consecutive survivors of heart and heart-lung transplantation between December 1980 and July 1983 were treated with cyclosporine and steroids; some received rabbit anti-thymocyte globulin for prophylaxis or treatment of rejection. Measured quantitative parameters of immunosuppression during the first three months after transplantation included mean cyclosporine level, total rabbit anti-thymocyte globulin dosage, number of days of T-cell suppression, and mean cyclosporine level during T-cell suppression. Serial Epstein-Barr virus antibody titers were measured. Lymphoma was diagnosed in six patients. The mean number of episodes of rejection did not differ between the lymphoma and the non-lymphoma groups. All quantitative measures of immunosuppression were higher in the lymphoma group, but this difference achieved statistical significance only in the case of total dosage of rabbit anti-thymocyte globulin (p less than 0.02). Four of the six lymphoma patients received some or all of their rabbit anti-thymocyte globulin dosage as prophylaxis against rejection; one received rabbit anti-thymocyte globulin solely for rejection; and the sixth received no rabbit anti-thymocyte globulin. Ebstein-Barr virus titer conversion (four-fold rise in titer) alone was not significantly associated with occurrence of lymphoma. However, logistic regression analysis suggested that Epstein-Barr virus conversion in concurrence with high mean cyclosporine levels predicted a higher risk of lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Transplantation for end-stage pulmonary disease is now established as an effective therapy for selected patients. Initially, combined heart and lung transplantation was the only therapeutic option for these patients. Recent developments that include improved immunosuppression, preservation of grafts and technical advances and markedly decreasing bronchial anastomotic complications have made unilateral pulmonary transplantation a clinical reality.

Forty-two patients underwent resection of primary cardiac neoplasms at Stanford University Medical Center and the Palo Alto Veterans Administration Medical Center between 1961 and 1986. A total of 27 atrial myxomas, seven benign nonmyxomatous tumors, and eight malignant tumors were resected. The mean age was 47 years (range 8 to 79) in 27 female and 15 male patients. The clinical presentations included congestive heart failure in 24 patients, palpitations in nine, neurologic symptoms in six, recurrent cardiac tamponade in three, vasculitis in two, and chest pain in two. Thirty-one of 34 benign lesions were completely resected, although one patient required cardiac transplantation to resect completely an "inoperable" benign tumor. All gross tumor was resected in four of eight patients with malignant lesions. All patients survived operation, but three with malignant disease died within 30 days. Late outcome was known for 41 of 42 (98%) patients. Total follow-up for the series was 200.1 patient-years, for an average of 4.7 years (range 1 month to 18 years). Excellent early and late results were obtained in patients with benign lesions, as there was no known tumor recurrence even if resection was incomplete. Effective palliation and local control of disease is possible with extensive resection of malignant primary tumors, but more effective adjuvant therapy will be necessary to improve long-term prognosis.

Data were analyzed from 19 long-term survivors of cardiopulmonary transplantation in this institution, including nine patients with normal pulmonary function and 10 recipients with posttransplant obliterative bronchiolitis. In all cases, donor cytomegalovirus titers (IgG), preoperative recipient titers (IgG), and serial postoperative recipient titers (IgM, IgG, and complement fixation) were available. In addition, surveillance cytomegalovirus cultures and pulmonary function tests were obtained prospectively after surgery in all 19 patients. A total of 12 patients developed active cytomegalovirus infection (serologic conversion confirmed by positive cultures) after transplantation, six of whom subsequently developed obliterative bronchiolitis. However, infection was clinically associated with pulmonary deterioration in only four of these patients, three of whom had cytomegalovirus pneumonitis. With the exception of obliterative bronchiolitis, no other permanent sequelae of cytomegalovirus infection were evident in this small group. Progressive obliterative bronchiolitis was also seen in four of the seven recipients who had no evidence of cytomegalovirus infection at any time. Although viral causes have been associated with obliterative bronchiolitis, the current data suggest that cytomegalovirus infection in the absence of pneumonitis does not appear to be a significant risk factor for obliterative bronchiolitis in cardiopulmonary transplant recipients. A larger group of patients will be required to ultimately establish the role of cytomegalovirus infection in this setting.

Between May, 1981, and December, 1984, thirteen combined heart-lung transplants were performed in 12 patients for the treatment of Eisenmenger's syndrome. The age range of the recipients was 22 to 42 years. Two patients had undergone previous open cardiac operations; in addition, one had had closure of a persistent ductus arteriosus, one an open lung biopsy, one a pulmonary artery banding, and one patient received a second heart-lung transplant after 3 years. Four recipients died before hospital discharge, one at operation and three at 4, 10, and 33 days after operation. Early symptomatic results and cardiopulmonary function were excellent in all of the survivors. Two patients died 14 and 15 months after transplantation of accelerated graft arteriosclerosis and respiratory failure, respectively, and six remain alive 7 to 44 months after transplantation. Four of these surviving patients and the two patients who died late subsequently had major pulmonary complications. Symptoms included progressive breathlessness, cough (often productive), and fever with physical signs of diffuse crepitations and expiratory rhonchi. Serial pulmonary function tests showed progressive obstructive physiology in all six patients with superimposed restrictive defects in four. Histologic examination of tissue from open lung biopsy or autopsy displayed bronchiolitis obliterans in five of these patients, one of whom required retransplantation. It is possible that these late changes are the result of rejection, since similar changes in one other patient have now been reversed with augmented immunosuppression. Further understanding of the causes and manifestations of late pulmonary deterioration should improve the late functional results of this operation for Eisenmenger's syndrome.

Cardiac transplantation represents an expanding therapeutic modality for end-stage heart disease in children and adolescents. During the past 5 years, 27 patients (15 boys; 12 girls) between the ages of 2 and 18 have undergone cardiac transplantation. The preoperative diagnosis was cardiomyopathy in 24 (six familial), congenital heart disease in two, and endocardial fibroelastosis in one. Immunosuppression included cyclosporine, azathioprine, and prednisone. There were 22 survivors, with four hospital deaths (three infection, one pulmonary hypertension), and one death at 4.5 years from graft atherosclerosis. The actuarial survival at 4 years was 83 +/- 7.4% and that at 5 years was 69 +/- 14.2%. Renal function was stable at 4 years, with an average creatinine clearance of 69.75 +/- 27.0 ml/min/m2. Hypertension was present in 21 of 22 patients, who require multiple drug therapy. Rehabilitation is 100% among discharged patients, with 14 in school, six employed, and two toddlers.

Cyclosporin A-associated nephrotoxicity has precipitated the need to develop new immunosuppressive protocols or agents that have a higher therapeutic index than cyclosporin A. A new immunosuppressive agent, cyclosporin G or norvaline (Nva-2) cyclosporine, has been shown to be potent. The rat heterotopic transplant model (ACI to Lewis) and Lewis rats that had no operation were used to compare cyclosporin G with cyclosporin A (5 mg/kg/day per gavage) with and without azathioprine (5 to 10 mg/kg/day, intraperitoneally) in terms of immunosuppressive efficacy (graft survival), toxicity (mortality, renal histopathology, and serum creatinine and blood urea nitrogen values), and pharmacokinetics (trough whole blood cyclosporine levels as measured by radioimmunoassay on days 14 and 28 of treatment). In this model no statistically significant difference in immunosuppression was shown between the two cyclosporins both with and without azathioprine. Cyclosporin G, however, was associated with significantly less mortality when combination therapy with azathioprine was used. Both cyclosporins were associated with normal serum creatinine values and little histopathologic evidence of nephrotoxicity, except juxtaglomerular apparatus hyperplasia. Comparable cyclosporine levels were achieved when cyclosporin A or G was used as the sole immunosuppressive agent, but significantly higher cyclosporine levels were shown with cyclosporin A than with cyclosporin G when combination therapy with azathioprine was used. Further studies in humans are needed to evaluate whether cyclosporin G will be a clinically useful immunosuppressive agent either alone or combined with other immunosuppressive modalities.

The relationship of heart-lung allograft-related death and obliterative bronchiolitis (OB) to human leukocyte antigen (HLA) matching was studied in 40 consecutive heart-lung transplant patients operated on between March 1981 and September 1986. Mismatch was defined as an antigen present in the donor but not in the recipient. Patients with only one antigen identified at a given locus were presumed to be homozygous for that antigen. The results were obtained from the patients who survived more than 3 months after surgery. The patients with zero to one mismatches in the HLA locus A (10 patients) had a tendency toward less OB, less severe OB, and fewer deaths from OB than the patients (15) with two mismatches in HLA locus A. However, only graded OB (1, mild; 2, moderate; 3, severe) was significantly different (p = 0.05) in these groups. There was one patient with no A locus mismatches; she survived 62 months, and no OB was found at her autopsy. This limited experience suggests that HLA-A locus match may have a salutary effect on long-term results and that OB may be at least partly a result of chronic rejection.

Cardiac biopsy remains the principal tool for diagnosis of rejection in heart and heart-lung transplantation. In rare instances pulmonary rejection may occur without cardiac rejection, but the overall incidence of cardiac rejection may be less with heart-lung transplantation than with heart transplantation. During the 6 months from March to September 1986, 40 heart transplantations and nine heart-lung transplantations were performed. Heart transplant patients received cyclosporine (8 to 10 mg/kg/day), azathioprine (1 to 2 mg/kg/day), and prednisone (0.8 mg/kg/day, with tapering). Heart-lung transplant patients received cyclosporine and azathioprine in the same dosages, but steroids were withheld for 3 weeks. Heart-lung transplant patients received three postoperative dosages of rabbit antithymocyte globulin (200 mg intramuscularly). There were five early deaths in the heart transplant group, four from infection and one from cerebrovascular accident. Since the initial rejection analysis presented here, one additional heart transplant patient died from rejection (241 days), and one heart-lung transplant patient died from infection (99 days). Cyclosporine levels were determined by radioimmunoassay, and cardiac rejection was diagnosed by serial endomyocardial biopsy. Early cardiac rejection is notably less common after heart-lung transplantation than after heart transplantation. Although the prophylactic antithymocyte globulin given in heart-lung transplantation may be important in this regard, rejection is probably inherently less common after heart-lung transplantation.

For no organ is the need more acute than for the lung or heart-lung block. The new improved "freezing" technique with simultaneous use of intravenous prostaglandin E1 will result in reliable and adequate heart-lung block preservation. The lungs are flushed with high-volume (60 ml/kg), low-pressure (less than 20 mmHg), low-flow (15 ml/kg/min), using modified Euro-Collins solution (added 12 Meq/L of MgSO4 and 65 ml/L of 50% Dextrose). Additional topical cooling has been achieved by cold Physiosol and the excised graft is then placed in a plastic bag filled with Physiosol. This static hypothermia has been successfully used with extended ischemia times of more than six hours in primates and almost four hours in man. Forty heart-lung transplantations have been done from March 1981 to September 1986 and nine of them have been performed using this "freezing" technique with prostaglandin E1. Distant graft procurement has been used twice for heart-lung transplantation. All nine most recent patients who have received the graft harvested with this new "freezing" technique are doing well.

Eighteen combined heart and lung transplant operations were performed between March, 1981, and March, 1984. Six of these patients have undergone bronchoscopy, at varying intervals after transplantation. Five of these procedures were done for specific clinical indications; one was done incidentally, during another surgical procedure requiring general anesthesia. All patients had intact, healing tracheal anastomotic suture lines; there were no instances of tracheal stenosis. The distal tracheobronchial tree appeared endoscopically normal in the transplanted lungs, except in areas of known infiltrates. Four of the patients had endobronchial biopsies, and alveolar eosinophilic proteinaceous exudate and submucosal mononuclear infiltrate were consistent features. Two of the later biopsies suggest that squamous metaplasia of the respiratory epithelium may occur with long-term follow-up. Controversy exists as to the optimal technique for tracheal anastomosis, but in the case of the steroid-treated, immunosuppressed transplant patient, continuous anastomosis with polypropylene has yielded satisfactory results.

During the past 17 years, cardiac transplantation has evolved from experimentation to reliable clinical application. Advances in this field have paralleled progress in cardiovascular surgery and in other branches of medicine. Technical aspects of donor procurement and recipient operation are outlined. Introduction of cyclosporine has been associated with improved results, but adverse side effects associated with this drug have prompted introduction of lower-dose cyclosporine regimens. Infection and rejection remain the most common and difficult complications after cardiac transplantation. Current survival exceeds 80% at one year, and more than 80% of one year survivors can be expected to be fully rehabilitated. Continuing research will focus upon improved control of the immune response and wider application of transplantation techniques.

Twenty-seven years of laboratory experience in cardiac transplantation at Stanford have provided the necessary background for a moderately successful clinical program which now extends over a period of 17 years. Heart-lung transplantation, again entirely a product of intensive laboratory research, is now ready for clinical use. Certainly much work remains to be done in the area of donor tissue preservation, particularly with respect to the lungs. It appears that new and more specific immunosuppressing drugs are on the horizon, so tissue transplantation in general will be increasingly safer. Heart transplantation has come of age, and combined heart-lung transplantation is well under way.

Severe pulmonary rejection without cardiac rejection in a patient after combined heart-lung transplantation is presented with the clinical and pathological findings. Acute lung rejection after heart-lung transplantation cannot be excluded by normal cardiac biopsy results.

Cardiac transplantation has emerged as a standard mode of clinical therapy for end-stage heart failure. Since clinical application began in 1967, there has been continual improvement in donor management, surgical techniques, post-operative management, and the diagnosis and treatment of rejection. More than 350 cardiac transplant operations have been performed in our institution, and one-year survival currently exceeds 80%. Current immunosuppressive techniques involve the use of cyclosporine, and experience with this agent and its adverse side effects has prompted institution of low-dose cyclosporine regimens. Principal complications of cardiac transplantation include infection, rejection, malignancy related to immunosuppression, and graft atherosclerosis. During the past four years, clinical cardiopulmonary transplantation has emerged as a therapeutic alternative for patients with end-stage pulmonary vascular disease. Problems of donor identification and management, post-operative pulmonary failure due to rejection and infection, and long-term obstructive pulmonary changes are being addressed in both the clinical and laboratory efforts.

The electrically driven Novacor implantable left ventricular assist device has been implanted in six patients (four men and two women) since Sept. 7, 1984. In four of the six patients (67%) the device was a successful bridge to cardiac transplantation. One patient died of multiple organ failure and Candida sepsis after 16 days of support with the device. One patient died in the operating room of uncontrollable hemorrhage and biventricular failure caused by severe cardiac rejection. Three patients are alive with cardiac transplants 38, 17, and 10 months after transplantation. One patient died after cardiac transplantation of presumed sepsis. The Novacor left ventricular assist device performed in all cases without mechanical or electrical failure. Excluding the intraoperative death, assist duration ranged from 2 to 16 days. The cardiac index (synonymous with device output) ranged from 2.4 to 3.4 L/min/m2. No embolic events (cerebrovascular or systemic) occurred during assistance with the device. Minimal red cell hemolysis was documented during the period of support. The Novacor left ventricular assist device is a safe and effective bridge to cardiac transplantation in patients with refractory cardiogenic shock.

Combined heart and lung transplantation has now been carried out in 17 patients at Stanford University Hospital. The emphasis on the management of donors is upon thorough tracheobronchial toilet and ensuring an absence of significant cardiopulmonary disease. The most important aspects of the recipient operation are to remove the heart and lungs without injury to the phrenic, vagus, or recurrent laryngeal nerves and to ensure hemostasis. This is best effected if the heart and lungs are removed separately. The operative technique for both the donor and recipient is described.

Although survival after cardiac transplantation has improved since the introduction of cyclosporine to clinical practice in 1980, the long-term hemodynamic results of transplantation in cyclosporine-treated recipients has not been reported. Annual cardiac catheterization data for 109 cyclosporine-treated recipients were analyzed and compared to those of a nonconcurrent group of 65 recipients treated with azathioprine and corticosteroids. Recipient age, donor age, sex, and human leukocyte antigen mismatch were comparable for the two groups. Satisfactory left ventricular function of the cyclosporine-treated heart was characterized on the first annual study by a normal ejection fraction (60% +/- 10%), cardiac index (3.0 +/- 0.8 L/min/m2) and stroke work index (53 +/- 15 gm-m/m2) associated with moderately increased left ventricular end-diastolic pressures (12 +/- 6 mm Hg) and significantly increased mean aortic pressures (116 +/- 8 mm Hg). With the exception of aortic diastolic pressure, which tended to increase with time, the mean values of each variable analyzed did not change significantly over the period of study. In comparison to the azathioprine group, the cyclosporine cohort displayed higher aortic, left ventricular end-diastolic, and pulmonary artery pressures and produced more stroke work at each annual study. Analysis of the azathioprine group over extended (8 year) follow-up suggested excellent preservation of graft function. In summary, the long-term hemodynamic function of the transplanted heart treated with cyclosporine was satisfactory, demonstrated no deterioration over 5 year follow-up, but manifested substantially greater hypertension than hearts from the pre-cyclosporine era.

At Stanford University Medical Center from January 1968 until January 1984, 288 patients received 313 heart transplants. The immunosuppressive regimen before December 1980 consisted of azathioprine and prednisone, with or without rabbit antithymocyte globulin. After that time cyclosporine replaced azathioprine. In 92 recipients of 95 heart allografts, the 1- and 3-year survival rates were 82% and 65% to 70% respectively. In the 3 years from March 1981 to March 1984, successful heart-lung transplantation was accomplished in 13 of 19 recipients, using cyclosporine-based immunosuppression. Survival ranged from 1 to 38 months. While it is true that cyclosporine has improved survival in heart transplant recipients, has allowed successful heart-lung transplantation to be performed, has shortened intensive care unit and total hospital stays and therefore hospital costs, and has allowed easier management of rejection and infection, several disconcerting problems have not yet been resolved. These include hypertension that is difficult to control and renal dysfunction in all patients, and the fact that cellular and humoral rejection still occurs, as manifested by graft atherosclerosis, bronchiolitis obliterans and classic acute rejection. Better understanding and application of cyclosporine immunosuppression will undoubtedly minimize both cyclosporine- and non-cyclosporine-related postoperative complications and will improve survival even further.

Nephrotoxicity has limited the effectiveness of cyclosporine in transplantation therapy and has precipitated the need to develop a new immunosuppressive agent that lacks this nephrotoxicity or has a higher therapeutic index. Prior studies have suggested that cyclosporin G may be equally effective immunosuppressively, but less nephrotoxic than cyclosporine. To compare the immunosuppressive effects of the two agents, graft survival was analyzed in Lewis-Brown Norway rats, which received heterotopic ACl heart allografts and were treated orally with cyclosporin G or cyclosporine at 5 and 10 mg/kg/day. To compare nephrotoxicity the group of rats that had transplantations and an additional group of surgically intact Lewis-Brown Norway rats, treated orally with cyclosporin G or cyclosporine at dosages ranging from 10 to 50 mg/kg/day and for durations ranging from 50 to 180 days, were analyzed in terms of kidney morphology (fibrosis, glomerular damage, interstitial infiltrate, and tubular dilation) and kidney function (blood urea nitrogen and serum creatinine levels) in this model cyclosporin G was significantly less effective than cyclosporine in prolonging graft survival at 5 mg/kg/day but equally effective at 10 mg/kg/day. In addition, cyclosporin G was substantially less nephrotoxic both morphologically and functionally at low (10 mg/kg/day) and high (50 mg/kg/day) dosages. Further studies are indicated to determine the therapeutic index of cyclosporin G and to evaluate its use in combination with other immunosuppressive agents.

Breakdown of the closure of the main-stem bronchus after pneumonectomy is a dreaded complication, and empyema and bronchopleural fistula frequently develop in patients who survive. Management of these fistulas remains a formidable therapeutic challenge, which has been approached with a variety of surgical techniques. We report our experience with anterior transpericardial closure, emphasizing the ability to expose either main-stem bronchus by this approach. The case histories of three patients who had bronchopleural fistula after pneumonectomy are presented. The first patient had left pneumonectomy for complicated tuberculosis; the second had right pneumonectomy for neoplasm; and the third had right pneumonectomy for trauma. All fistulas were treated surgically via a median sternotomy and transpericardial approach to the distal trachea. The posterior pericardium was divided between the superior vena cava and aorta. In-continuity staple closure (with two lines of staples) of the proximal main-stem bronchus was employed in all cases. Two patients remain clinically well 21 and 17 months after the operation. The third patients did well initially but developed a recurrent bronchopleural fistula 2 1/2 months after the operation and has required repeat closure with pedicled muscle flaps. In postpneumonectomy bronchopleural fistula, the anterior, transpericardial approach to bronchial closure has several advantages: the relatively well-tolerated median sternotomy, the avoidance of dealing directly with areas of postoperative scarring and the devascularized bronchial stump, the avoidance of areas of chronic sepsis, and the avoidance of thoracoplastic surgical deformity of the chest wall, with possible associated compromise in pulmonary function. Our experience also indicates that either main-stem bronchus is accessible through an approach between the superior vena cava and aorta, without division of either pulmonary artery.