Histocompatibility studies in a closely bred colony of dogs. II. Influence of the DL-A system of canine histocompatibility upon the survival of cardiac allografts.

The DL-A system of histocompatibility plays an important role in conditioning the survival of cardiac allografts in the unmodified canine host. The mean survival time of six cardiac allografts performed in DL-A-compatible littermate dogs obtained from a closely bred colony of beagles was 53.2 days, while the MST of transplants performed in seven DL-A-incompatible animals was 7.3 days. The MST of cardiac allografts performed in nine DL-A-compatible nonlittermate beagles was 26.3 days, as compared with 6.3 days in six DL-A-incompatible nonlittermate transplants. The results did not appear to be affected by Swisher erythrocyte-group incompatibilities. The MST of 28 cardiac allografts performed in randomly selected mongrel dogs was 10.0 days. Incompatibilities for DL-A antigens e, f, g, l, and m may constitute major barriers to transplantation, but antigens b, c, d, and k appeared to act as weak histocompatibility antigens. Under controlled conditions of donor-recipient DL-A compatibility, cardiac allografts may be less immunogenic than renal transplants. Heart transplants performed across major donor-recipient DL-A incompatibilities appeared, however, to be more vulnerable to the events of allograft rejection than renal allografts performed under similar conditions. The selection of optimally compatible donor-recipient combinations for organ transplantation may be aided materially by genetic studies of the transmission of DL-A antigens to the animals under consideration.

Afferent reinnervation of the autotransplanted heart in dogs.

Patients have been observed with a chest pain syndrome after cardiac transplantation. For this pain to be cardiac in origin the afferent nerves carrying sensory information from the heart would have to reinnervate the heart. A previous study in dogs indicated that afferent reinnervation is uncommon during the first 2 years after transplantation. The purpose of this study was to determine whether afferent reinnervation of the heart occurs in the long term. The decreases in arterial pressure and renal nerve activity resulting from chemical stimulation of left ventricular sensory receptors with vagal afferents with cryptenamine (veratrum alkaloid) were assessed in three dogs 8 to 12 years and in four dogs 6 to 8 weeks after cardiac autotransplantation and in six sham-operated dogs (thoracotomy-pericardiotomy 6 to 8 weeks before study). Responses of renal nerve activity to physiologic stimulation of cardiac receptors by volume expansion were also determined. Left ventricular cryptenamine inhibited renal nerve activity by 72 +/- 8% in dogs with long-term and by 10 +/- 6% in dogs with short-term autotransplantation and by 92 +/- 5% in sham-operated dogs. Decreases in mean arterial pressure in these groups were 34 +/- 4, 11 +/- 3 and 67 +/- 16 mm Hg, respectively. Volume expansion inhibited renal nerve activity in long-term autotransplant (43%) and sham-operated (48%) groups but less in the short-term transplant group (33%) for comparable increases in cardiac filling pressure. It is concluded that in dogs there is extensive afferent reinnervation of the long-term autotransplanted heart that results in relatively normal cardiopulmonary baroreflex responses to volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial norepinephrine, epinephrine and dopamine concentrations after cardiac autotransplantation in dogs.

Myocardial norepinephrine is markedly reduced after cardiac transplantation because of interruption of postganglionic cardiac sympathetic nerves. There are also substantial stores of dopamine in the myocardium, but the influence of cardiac denervation on dopamine remains unknown. The effect of cardiac transplantation was determined and, thus, the effect of denervation on myocardial norepinephrine, dopamine and epinephrine. Myocardial catecholamines were measured with high-performance liquid chromatography with electrochemical detection in five dogs 6 to 8 weeks and in four dogs 8 to 12 years after cardiac autotransplantation and in six sham-operated dogs with intact cardiac innervation. Norepinephrine, dopamine and epinephrine levels were determined from samples obtained from the right and left atria and ventricles. Samples from the left ventricular apex and base were analyzed separately. There was a striking depletion of norepinephrine in all cardiac chambers after short-term autotransplantation. The norepinephrine content of the left atrium in sham-operated dogs (1,659 +/- 219 ng/g) was significantly higher than that of dogs with long-term autotransplanted hearts (754 +/- 372 ng/g). Sham-operated dogs and dogs with long-term autotransplanted hearts had statistically significant (p less than 0.05) differences in norepinephrine content in the left ventricular apex (480 +/- 197 versus 294 +/- 198 ng/g), left ventricular base (876 +/- 2204 versus 654 +/- 156 ng/g) and right ventricle (766 +/- 133 versus 247 +/- 29 ng/g). In contrast to norepinephrine, dopamine concentrations were relatively preserved in the short-term group despite the virtual depletion of myocardial norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocarditis due to accidental penetrating foreign bodies.

A 15 year old boy had an eight month history of recurrent fever, malaise and poor appetite. Chest roentgenogram revealed a foreign object overlying the right ventricle. Multiple blood cultures grew Enterobacter cloacae. The patients condition improved and blood cultures became negative following gentamicin and carbenicillin therapy. E. cloacae was isolated from the foreign body (a finishing nail) at surgery. Antimicrobial therapy was continued for a total of 30 days, and the patient made an uneventful recovery.

Urinary thromboxane excretion in cardiac allograft rejection in immunosuppressed rats.

Increased urinary excretion of immunoreactive thromboxane B2 (iTxB2) was found to have a high predictive value, with high sensitivity as an indicator of cardiac allograft rejection in both the immunosuppressed and nonimmunosuppressed rat. In the animals receiving an allograft, urinary iTxB2 excretion significantly increased prior to the onset of rejection, remained elevated, and returned to basal values following completion of the episode. Urinary iTxB2 remained at baseline values in the control animals. The association between rejection and iTxB2 excretion was preserved regardless of the presence or nature of immunosuppression. Urinary iTxB2 excretion increased significantly prior to the reduction of graft beat or histological evidence of rejection. Evaluation of urinary iTxB2 monitoring as a noninvasive indicator for surveillance of clinical cardiac allograft rejection appears to be warranted.

Clinical significance of in situ detection of T lymphocyte subsets and monocyte/macrophage lineages in heart allografts.

Seventy fresh frozen biopsies of 22 human heart allografts were stained with mouse antihuman monoclonal antibodies (OKT-4, OKT-8, and OKM-1) using the immunoperoxidase method. The numbers of infiltrating cell phenotypes were correlated with patients' clinical status and histopathological diagnoses of the biopsies. At the clinically stable stage the number of OKT-4-positive cells (T-4 cells, helper/inducer), OKT-8-positive cells (T-8 cells, suppressor/cytotoxic), OKM-1-positive cells (M-1 cells, monocyte/macrophage) and T4/T8 ratio were lowest. During the early stage of rejection T-4 cells increased to the highest values. T-8 cells also increased significantly and T4/T8 ratio increased to the peak level as well. During the later stage of rejection, T-8 and M-1 cells increased to the highest values and T-4 cells and T4/T8 ratio decreased. After the treatment of rejection T-4 cells continued to decrease and T-8 cells and M-1 cells decreased to intermediate levels, but T4/T8 ratio still remained level. The numbers of T-4 cells, T-8, cells and M-1 cells were closely associated with the histopathologic severity of rejection. These results were also correlated with the allografts' prognoses. Interestingly, high T4/8 ratios with high number of T-4 cells in biopsies during the quiescent period were often followed by rejection episodes within 7 days, even though the pathological diagnoses were mild rejection. Another important finding was that after the treatment of rejection, persistent M-1 cells and low T4/T8 ratios in situ were frequently accompanied by recurrent rejections. Thus, monitoring of infiltrating cell phenotypes may be beneficial in the management of clinical cardiac transplantations.

Pretransplant transfusions in cardiac allograft recipients.

The role of pretransplant transfusion in cardiac allograft recipients was determined retrospectively in 68 patients. Three groups were studied: group 1 (n = 29) received no pretransplant transfusion, group 2 (n = 15) received transfusion over one year prior to transplantation, and Group 3 (n = 24) received 5 or 10 50-100 ml units of random donor red blood cells or buffy coat 2-4 weeks prior to transplantation. Data were analyzed for survival, number of rejection episodes, and number of infections. Immunosuppression included azathioprine, prednisone, and antithymocyte globulin. Survival in transfused patients (groups 2 and 3) was 68% and 51% at 1 and 5 years, respectively, while in the nontransfused population (group 1) it was 35% and 16%. The incidence of rejection episodes per year of survival was similar in the three groups (group 1: 1.3, group 2: 1.1, group 3: 1.3; P greater than 0.05). The number of infections per year of survival were greater in the transfused patients but this did not achieve statistical significance (group 1: 1.0, group 2: 1.2, group 3: 1.7; P greater than 0.05). Thus, we conclude that cardiac transplant recipients who have received blood transfusions prior to transplantation may have enhanced survival over patients who have not received preoperative transfusions.

Congenital tricuspid insufficiency. Definition and review.

Simple congenital tricuspid insufficiency (CTI) has, up to now, been loosely included with the larger Ebstein's anomaly (EA) group. Certain pathologic and clinical features of CTI deserve definition and a place apart from EA. A review of the literature has produced 20 clinical cases for analysis to which we add two cases successfully treated surgically. The high mortality in the neonatal age group (14 of 14) continues to be a formidable challenge, but the older survivors (2 of 8) would appear to have better prospects, based on our limited experience.

Complete repair of tetralogy associated with sickle cell anemia and G-6-PD deficiency.

The case of a 5-year-old black girl with sickle cell anemia and G-6-PD deficiency is described. The child underwent successful repair of tetralogy of Fallot. Open-heart surgery can be safely performed on these patients if certain guidelines are observed, particularly the avoidance of hypoxia, hypothermia, acidosis, and dehydration. The patients should be prepared for the operation with transfusion of normal red cells. Routine preoperative testing for the above hemoglobinopathologic conditions is urged. The pertinent literature is reviewed.

Successful orthotopic canine heart transplantation after 24 hours of in vitro preservation.

A protocol was developed to provide continuous, hypothermic, low-pressure perfusion for 24 hours' preservation of the isolated canine heart prior to orthotopic transplantation. Donor cardiectomy included coronary vasodilatation with diltiazem, potassium arrest, and rapid cooling of the heart. The graft was perfused at a pressure of 18 to 22 cm H2O and at an average flow of 0.743 cc/min/gm of tissue. The septal temperature was 5 degrees to 7 degrees C and perfusate pH was 7.25 to 7.4. Two groups of mongrel dogs were studied after orthotopic transplantation: Group I (n = 15) received hearts perfused for 24 hours. Group II (n = 9) received hearts removed by the same cardiectomy technique, but transplanted immediately. All grafts were able to support the recipient circulation after cardiopulmonary bypass. These was no significant difference in survival or in graft function when hemodynamic studies were done in five animals of each group, between 5 and 10 days after operation. We conclude that a reliable and reproducible method of 24 hours' in vitro perfusion of the canine heart has been obtained and should be applicable in clinical cardiac transplantation when prolonged periods of preservation are required.

Heart and unilateral lung transplantation in the dog.

A technique is presented for transplantation of the heart and left lung en bloc in the dog. In contrast to the erratic respiratory pattern that occurs in subprimate animals after total cardiopulmonary denervation, preservation of innervation to the native right lung results in a normal respiratory pattern in the dog and has allowed survival of one animal for 68 days. This model is proposed as potentially suitable for physiologic and immunologic studies of cardiopulmonary transplantation in the dog.

Anatomic correction of transposition of the great arteries without significant ventricular septal defect or patent ductus arteriosus.

A case of transposition of the great arteries without a significant ventricular septal defect or patent ductus arteriosus was treated when the patient was 5 months of age by retransposition of the great arteries and coronary arterial supply to the appropriate ventricle. The patient has done well for 13 months, despite the late occurrence of aortic regurgitation.

Advantages of open mind commissurotomy using a triple-orifice technique.

Our experience over an eight-year period with the operative relief of mitral stenosis is reviewed and detailed. Of the 106 patients in the series, 80% had minimal or no calcification, 17% had moderate calcification, and 4% had severe calcium deposits in the valve. Four patients have required reoperation for recurrent stenosis, with valve replacement in 3 and a second commissurotomy in the fourth. Left atrial thrombus was encountered in 16%, and no patient with thrombus experienced embolization in the postoperative period. One postoperative death occurred within 30 days, and a single late death occured 35 days after operation. For the scarred, retracted mitral valve we have utilized a multiple-orifice technique that provides maximal flow without the risk of inducing significant mitral insufficiency.

Pull-through esophagectomy without thoracotomy for esophageal carcinoma.

Seventeen consecutive patients underwent pull-through esophagectomy using blunt dissection from laparotomy and cervical incisions for carcinoma of the esophagus. Fifteen patients had a middle-third lesion while 2 patients had a distal-third lesion. The gastrointestinal tract was reconstructed using primary gastroesophagostomy in 15 patients and colon interposition in 2. Both the colon and stomach were placed through the posterior mediastinum. The surgical technique and results are described in detail. There were two major complications. One patient died of massive gastric hemorrhage on the eighth postoperative day in spite of emergency operation. Another patient sustained a tear of the membranous trachea at the time of blunt dissection. This was repaired through a right thoracotomy without difficulty. Esophagectomy using blunt dissection offered excellent palliation and resulted in little morbidity in our series. The shortened operating time, minimal blood loss, total lack of postoperative chest pain, minimal pulmonary complications, and the benefit of a cervical anastomosis are several advantages compared with the present surgical approaches.

Circulatory assistance with a cardiac allograft after exclusion of the canine left ventricle.

Cardiogenic shock after myocardial infarction still carries a high mortality despite use of intraaortic counterpulsation and early surgical revascularization. An experimental canine model of left ventricular exclusion and circulation support was developed by closing the mitral valve and by interposing "in series" a cardiac allograft between pulmonary and systemic circulations. This preparation was able to support the recipient circulation after cardiopulmonary bypass in 25 animals. In 16 dogs the graft sustained life for from 1 to 32 days. It is hypothesized that such left ventricular assistance could be used to maintain the life of patients in cardiogenic shock after myocardial infarction. By providing maximal left ventricular decompression and improvement of the native coronary perfusion, this method may reverse the metabolic imbalance responsible for extension of the infarction, thereby salvaging muscle that is in jeopardy but still viable.

T-lymphocyte analysis in cardiac allograft recipients treated with cyclosporine.

To assess the usefulness of circulating T-lymphocyte analysis in cardiac transplantation, T helper (Th) and T suppressor-cytotoxic (Ts-c) subsets were serially monitored in 33 cardiac allograft recipients treated with cyclosporine. The short-term prognosis of their 47 treated rejection episodes were retrospectively correlated with the changes in T-cell subpopulations. The data indicate three main findings. Reversed Th to Ts-c ratio (less than 1) was associated with a reduced incidence of rejection onset and a benign clinical course after treatment for rejection. Reversed Th:Ts-c ratio caused by antirejection therapy was associated with less chance of recurrence during the rest of hospitalization, regardless of the mode of therapy and irrespective of whether the rejection was primary or recurrent. These changes were mainly mediated by a reduction in T helper cells rather than changes in the T suppressor-cytotoxic subset or total T cells. Titration of antirejection therapy based on these T-cell dynamics may reduce either overtreatment or undertreatment. A prospective randomized study seems warranted to evaluate this approach as an alternative to a predetermined antirejection protocol.

Apparent coexistent valvular and subvalvular left ventricular outflow tract obstruction.

A patient is presented in whom coexisting bicuspid valvular aortic stenosis and asymmetrical septal hypertrophy were suggested by echocardiography. A focal area of hypertrophy noted at operation was excised. Subsequent histological examination did not reveal evidence to support the echographic and surgical observations. The necessity for careful intraoperative assessment of the degree and nature of subvalvular muscular hypertrophy is stressed. The absence of classic echographic findings in these patients is noted.

Successful intracardiac repair of the Taussig-Bing malformation in 2 children.

Surgical repair of the Taussig-Bing deformity has been successful in 2 children weighting 7.7 and 11.1 kg, respectively. In the first case the right ventricular patch divered left ventricular blood to the pulmonary arter, thus creating a physiologically complete transposition which was then corrected by an interatrial Mustard baffle. In the second case a right ventricular tunnel diverted left ventricular blood to the aorta, and right ventricular blood was directed to the distal pulmonary artery by means of an external conduit bypassing a subpulmonic stenosis. These patients represent the seventh and eighth successful corrections of the Taussig-Bing anomaly. One case (Patient 2) is the youngest to undergo repair and the first to receive an external conduit for bypass of an associated subpulmonic stenosis.

Improved immunosuppression for cardiac transplantation: immune monitoring and individualized modulation of recipient immunity by in vitro testing.

These studies demonstrate that immune monitoring and individualized modulation of recipient immune reactivity using a quality-controlled preparation of rabbit antithymocyte globulin can improve results of cardiac transplantation. The most valuable assay in individualizing drug doses was the serial measurement of T-cell levels using a complete lymphocyte profile technique and monitoring with phytohemagglutinin to rule out false low T-cell levels. Using this system, the incidence and severity of early rejections were markedly reduced and no grafts were lost to rejection in the first month. The recent first-year graft survival has been about 60%, an improvement largely related to a reduction in early rejection and infection. This technique of immunosuppression appears quite promising for improving the results of future cardiac transplantations.

Immunological monitoring as a guide to the management of transplant recipients.

Immunological monitoring assays are of current value in the management of transplant recipients. These assays allow the pre-transplant quantitation of both donor-recipient histocompatibility and recipient "responder status." In addition, these assays allow the individualization of immunosuppression, permitting a more uniform and effective immunosuppression in the difficult early post-transplant period. Individualized modulation of recipient immune reactivity avoids the documented pitfalls of conventional stereotyped suppression and permits better abrogation of acute rejection responses and lesser rates of serious infections consequent to excessive immune suppression. Immunological monitoring of long-surviving recipients permits early detection of immune reactivity which often culminates in clinical chronic rejection, as well as permits the quantitation of immune facilitory mechanisms (reduced capability to generate anti-donor cytotoxic T cells and/or cellular suppressor mechanisms) that indicate an immune milieu conductive to long-term graft survival. The primary limitations to the more widespread use of immunological monitoring assays at present are the need for more consensual validations of the utility of these assays in different laboratories, more standardization and better controls of techniques, and improvement in the technology of the assays to permit rapid, reproducible, and accurate results with a lesser expenditure of laboratory time and money and greater economy in demands for recipient blood and donor tissue. Finally, immunological monitoring assays are notable for the great promise they offer in terms of immunobiological probes to dissect mechanisms of rejection, mechanisms of graft facilitation, mechanisms of action of immunosuppressive agents, and mechanisms by which empirical technology of recipient pre-treatment may condition the host to better acceptance of an incompatible graft.