Expression of alpha isoforms of the Na,K-ATPase in human heart.

We studied expression of isoforms of Na,K-ATPase in normal and diseased human hearts. Na,K-ATPase alpha-isoform mRNA in samples from normal human left ventricle (LV) was composed of 62.5%, alpha 1, 15% alpha 2 and 22.5% alpha 3 on average. There was an increase in expression of the alpha 3 isoform in samples from failing hearts, but expression of all three isoforms decreased in pressure-overloaded right ventricle (RV).

Long-term cardiac and pulmonary histology in primates following combined heart and lung transplantation.

To investigate the long-term histologic consequences of combined heart and lung transplantation, heart and lung biopsies were obtained from six rhesus monkeys; two had undergone heart-lung autotransplantation 3.5 and 4.5 years previously, two were the recipients of heart-lung allografts 4.1 and 4.5 years previously, and the results were compared with two normal control animals. Cyclosporine had been used as maintenance immunosuppression in the allograft group. The heart and lung biopsies in the autograft animals were essentially normal. Dense adhesions were noted in the allografts, adn in one the visceral pleura was grossly thickened. Cardiac biopsies in the allografts were unimpressive, with a normal myocardium in one, and minimal interstitial fibrosis in the other. Intimal hyperplasia was present in the pulmonary arterioles of one of the allografted animals. Focal scarring was present in the lung of one allograft recipient, and the other animal showed severe thickening and fibrosis of the alveolar septae, as well as marked interstitial fibrosis such that large areas of the specimen were replaced by connective tissue. Histologic abnormalities in the allografted lungs correlated with the abnormal hemodynamics in these animals reported in a previous study. It is suggested that the histologic appearances in the lung are a consequence of chronic rejection, and that these findings may become a significant problem in human heart-lung transplant recipients.

An assessment of Nva2-cyclosporine in primate cardiac transplantation.

The immunosuppressive potency, hepatotoxicity, and nephrotoxicity of Norvaline2-cyclosporine (Nva2-CsA), an analog of cyclosporine (CsA), were tested in a primate cardiac transplant model. After orthotopic cardiac transplantation in cynomolgus monkeys, immunosuppression was maintained with 16 mg/kg/day of either CsA or Nva2-CsA given intramuscularly in two divided daily doses. Immunosuppression was augmented with i.m. methyl-prednisolone, 1.0 mg/kg/day, which was tapered weekly by .1 mg/kg/day to a maintenance dose of .1 mg/kg/day. A group of 6 untransplanted monkeys were treated for a year with this dose of either CsA or Nva2-CsA and steroids. Renal biopsies were performed at one year. Among the transplanted monkeys, mean survival was 77.3 +/- 73 days for the CsA group and 16 +/- 8 days for the Nva2-CsA group. All 11 animals in the Nva2-CsA group died of cardiac rejection, but only 7 of 10 treated with CsA died of rejection. There was mild hepatic and renal dysfunction in both treatment groups, but no significant difference between groups as judged by blood urea nitrogen, creatinine, total bilirubin, serum glutamic oxaloacetic transaminate, and alkaline phosphatase. Cyclosporine levels were significantly higher in the CsA group. There were important morphological changes in both groups on histological examination of the kidneys, with proximal tubular vacuolation and enlargement of the juxtaglomerular apparatus predominating. It is concluded that Nva2-CsA is a less effective immunosuppressant than CsA when given parenterally in equal doses.

Treatment of bronchopleural fistula after pneumonectomy.

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.

Bronchial responsiveness after human heart-lung transplantation.

We evaluated bronchial responsiveness to inhaled albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol in eight heart-lung transplant (HLT) recipients 2.3 +/- 1.5 months (mean +/- SD) (range, 1 to 4.5 months) after HLT. All patients had a restrictive ventilatory defect but none had airflow limitation (FEV1/FVC = 0.93 +/- 0.05) (range, 0.86 to 0.97). Specific airway conductance (sGaw) improved significantly with both albuterol (p less than 0.01) and ipratropium bromide (p less than 0.01) but FEV1 did not. Only one HLT patient had bronchoconstriction with propranolol, whereas all but one were hyperresponsive to methacholine. Prior inhalation of ipratropium bromide blocked the response to methacholine (p less than 0.005). Serial methacholine provocation tests performed in seven long-term survivors of HLT 24.6 +/- 16.0 months (range, 12 to 51 months) after HLT revealed no time-dependent evolution of bronchial hyperresponsiveness to methacholine. Limited maximal airway narrowing to methacholine was seen in five HLT recipients who showed a 29 +/- 4 percent (range, 23 to 35 percent) fall in FEV1 compared with two patients who did not achieve a plateau with a 47 percent and 63 percent fall in FEV1, respectively. These results further our understanding of bronchial responsiveness in the denervated transplanted lung. The findings of stable hyperresponsiveness to methacholine over a prolonged time interval, limited maximal airway narrowing to methacholine, and blockade of methacholine hyperresponsiveness by ipratropium bromide support the concept of denervation hypersensitivity of muscarinic receptors.

Long-term hemodynamic results after cardiac transplantation.

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.

Operative technique for heart-lung transplantation.

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.

Steroid-responsive bronchiolitis after human heart-lung transplantation.

This report describes the clinical course of a patient who developed obliterative bronchiolitis after viral infection on three separate occasions. Long-term follow-up is given. It is suggested that the syndrome of late pulmonary deterioration after transplantation may be steroid responsive if treatment is initiated early in the natural history of the syndrome. In addition, it is suggested that increased emphasis should be placed on the documentation of viral infection in transplant recipients to define a possible interaction between infection and rejection.

Significant patient-related determinants of prosthetic valve performance.

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.

Improved ultrastructural lung preservation with prostaglandin E1 as donor pretreatment in a primate model of heart-lung transplantation.

Donor pretreatment with prostaglandin E1 as a pulmonary vasodilator has developed as a simple, effective means to provide excellent preservation in heart-lung transplantation. This study was undertaken to investigate the degree of ultrastructural preservation of the lung with prostaglandin E1 and other pulmonary vasodilators in a primate heart-lung transplantation model. Heart-lung transplantation was performed in 14 African green monkeys. Donor cardiac preservation was achieved with cold crystalloid cardioplegic solution (10 ml/kg). Lung preservation was achieved with cold, modified Euro-Collins solution delivered into the main pulmonary artery (60 ml/kg total). Vasodilator agents were administered intravenously 15 minutes before aortic crossclamping. The heart-lung grafts were stored at 4 degrees C for 6 hours. Three groups of animals were studied: five donors with prostaglandin E1 (0.1 to 4.0 micrograms/kg per minute), five donors with prostacyclin (0.1 to 0.35 micrograms/kg per minute), and four donors with nitroprusside (0.8 to 5.0 micrograms/kg per minute). After transplantation, arterial blood gas measurements and lung biopsies were performed at 1- and 3-hour intervals. Five formalin blocks per specimen were sectioned for hematoxylin and eosin staining. Cellular preservation and endothelial cell swelling were evaluated with electron microscopy. The specimens were graded for alveolar hemorrhage, endothelial cell swelling, and cellular preservation (grade 0, minimal, to grade 3, severe) and a mean score was obtained for each preservative agent. Prostaglandin E1-treated specimens demonstrated the least amount of endothelial swelling (mean score of 1.0) compared with prostacyclin- and nitroprusside-treated specimens (mean scores of 1.4 and 2.7, respectively). All nitroprusside-treated specimens demonstrated moderate to severe endothelial cell swelling. Interstitial and alveolar hemorrhage was noted in poorly preserved specimens, but there were no significant differences between groups. We conclude that prostaglandin E1 provides improved cellular preservation by decreasing the extent of endothelial cell swelling as observed on electron microscopy.

Bronchoscopy after cardiopulmonary transplantation.

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.

Proper donor selection for heart-lung transplantation. The Stanford experience.

Clinical cardiopulmonary transplantation is currently limited by the availability of suitable heart-lung donors. Distant graft procurement, with pretreatment, of the donor by intravenous prostaglandin E1 and cooling of the graft with pulmonary artery perfusion, is now clinically established and should increase the number of available donors. Between March 1981 and September 1986, 40 heart-lung transplantations were performed. The characteristics of the donor pool were analyzed. Gram stain of the donor tracheal aspirate revealed gram-positive bacteria in 80% and gram-negative organisms in 35%. Yeast was present on stain in 25% of the patients. Donor arterial oxygen tension was less than 100 torr inspired oxygen concentration 40%) repeatedly in one patient; this recipient died of lung failure at operation. Severe deterioration of allograft lung function was seen in 11 (27.5%) recipients. The causes of deterioration were substantial postoperative bleeding in six patients, sepsis in two, and acute rejection, poor lung function, and allograft heart failure in one patient each. HLA-A locus mismatch, poor donor alveolar-capillary gas exchange, tracheal colonization with heavy polymorphonuclear cells, and heavy bacteria and fungus resulted in increased operative mortality. Donor pretreatment with prostaglandin E1 was associated with improved survival. Recipient selection, emphasizing adequate liver function and absence of previous thoracic operation, careful surgical technique with minimal bleeding, and brief perfusion time were factors associated with improved survival. Early morbidity and mortality were principally related to recipient risk factors, and the strict criteria observed for selection of heart-lung donors were valid. The importance of appropriate recipient selection is underscored.

Cardiopulmonary function at maximum tolerable constant work rate exercise following human heart-lung transplantation.

Studies were performed measuring parameters of respiratory and circulatory function at rest and during maximum tolerable constant work rate treadmill exercise in 16 clinically well patients who had undergone heart-lung transplantation for end stage pulmonary hypertension. Ten patients were studied before and within eight weeks following transplantation. Long-term function with exercise was further evaluated with follow up studies at one year (n = 10) and two years (n = 6), posttransplantation. Posttransplant gas exchange and ventilation during exercise are essentially normal with neither being limiting to maximal exercise. Exercise capacity is significantly improved posttransplant, primarily as a result of improvement in the circulation over that found pretransplant in uncorrected pulmonary hypertension. Although improved, circulatory limitations of maximal exercise may still persist. Cardiorespiratory function at maximum tolerable exercise is well maintained following heart-lung transplantation for at least two years, providing no complications occur. This suggests that denervation of the heart and lungs, disruption of the bronchial circulation and pulmonary lymphatics, and the graft ischemia encountered at the time of transplantation impose no serious limitations on long-term cardiopulmonary function. The overall functional capacities of the transplanted heart and lungs are more than adequate for meeting the activities of normal life.

Performance characteristics of the Starr-Edwards Model 1260 aortic valve prosthesis beyond ten years.

The Starr-Edwards non-cloth-covered silicone ball (Model 1260) aortic valve prosthesis has been widely used for over 15 years and remains a standard against which newer values are compared. To define more completely the performance characteristics of this prosthesis, this study (including 449 patients) analyzed the long-term function of this specific valve over a cumulative total of 2,896 patient-years (pt-yrs) of follow-up which extended beyond 13 years. Expressed in both actuarial (% [+/- standard error of the mean] free at 10 years) and linearized (%/pt-yr) terms, respectively, valve-related complications occurred at the following rates: thromboembolism, 76 +/- 3 and 2.7; anticoagulant-related hemorrhage, 74 +/- 3 and 3.1; prosthetic valve endocarditis, 92 +/- 2 and 0.9; reoperation, 90 +/- 2 and 1.1; valve failure, 82 +/- 2 and 2.2; all valve-related morbidity and mortality, 51 +/- 3 and 6.0; and valve-related death, 88 +/- 2 and 1.3. Thirteen percent of hospital and 18% of late deaths were due to valve-related causes. No case of structural failure was documented. This prosthesis has an admirable structural durability record out to 13 years, and its long-term performance is satisfactory, albeit not optimal. Despite the indestructable design and construction of this mechanical valve substitute, 12% +/- 2% of patients had died of valve-related complications by 10 years, and fully 49% +/- 3% had had some form of serious valve-related complication. The long-term data reported herein can be used for analytical comparison when follow-up of patients with newer mechanical prostheses and tissue bioprostheses reaches 10 years to elucidate whether or not these newer valves truly represent improvements and which type of valve substitute proffers the most possible net benefit to the patient.

Combined heart-lung transplantation for end-stage Eisenmenger's syndrome.

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.

Determinants of operative mortality for patients undergoing aortic valve replacement. Discriminant analysis of 1,479 operations.

The influence of 35 preoperative and intraoperative characteristics on operative mortality risk after 1,479 isolated aortic valve replacement procedures (1967 to 1981) was investigated utilizing univariate and multivariate logistic regression analyses. Mean age at operation was 58 +/- 13 years; 72% of patients were men. Physiology was classified as aortic stenosis (58%), regurgitation (30%), or both (9%). The overall operative mortality rate was 7% +/- 1%, but there were substantial differences in operative mortality rates among physiological subgroups (aortic regurgitation, 10% +/- 2%; aortic stenosis, 6% +/- 1%; stenosis/regurgitation, 5% +/- 2%). Independent determinants of operative mortality rate in the entire group were advanced New York Heart Association functional class, renal dysfunction, physiological subgroup, atrial fibrillation, and older age. In the aortic regurgitation subgroup, functional class, atrial fibrillation, and operative year were independent predictors. In the aortic stenosis subgroup, the significant determinants were functional class, renal dysfunction, age, prosthetic valve dysfunction, and absence of angina. Concomitant coronary bypass grafting, previous operation, endocarditis, and ascending aortic replacement had no independent predictive effect on operative mortality rate. Thus, the early results of aortic valve replacement can be related to several specific variables describing the functional and physiological status of the patient. Operative mortality rate is not independently related to previous operation or concomitant operative procedures. Specific differences in risk factors exist among the various physiological subgroups, probably reflecting the pathophysiology of the different hemodynamic lesions. This information should provide for a more rational approach to aortic valve replacement, at least in terms of early risk/benefit deliberations.

Isolated pulmonary rejection after combined heart-lung transplantation.

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.

Primary cardiac neoplasms. Early and late results of surgical treatment in 42 patients.

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.

Isolated left ventricular assist as bridge to cardiac transplantation.

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.

Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation.

Since March 1981, 19 patients have undergone heart-lung transplantation for end-stage pulmonary vascular disease, with 14 long-term survivors. In five of the survivors, obstructive airway disease has developed with the superimposition of a progressive restrictive ventilatory defect in three of them. None of these five patients showed a tendency for spontaneous improvement of flow rates. Biopsy and postmortem material was available in four of the five patients and showed obliterative bronchiolitis (OB) in three. A fourth patient showed clinical and physiologic data consistent with obliterative bronchitis, but histologic material was not available. Obstructive lung disease without restrictive features developed in a fifth patient, but no histologic evidence of OB was found at transbronchial biopsy. In addition to OB, recurrent lung infections were found in all patients, significant pleural fibrosis in two patients, and bronchiectasis in one patient. Despite these long-term sequelae of human heart-lung transplantation, ten of the 14 surviving patients are leading relatively normal lives.