Diminished lymphocyte growth from endomyocardial biopsies from cardiac transplant patients on FK 506 immunosuppression.
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Biopsy↗
Biomedical subjects
R L Kormos
Publications and source records attributed to R L Kormos.
The clinical trial of FK 506 as primary and rescue immunosuppression in adult cardiac transplantation.
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Adult↗
Cardiac transplantation at the University of Pittsburgh: 1980 to 1991.
When examining survival rates following cardiac transplantation, it is important to examine the risk factors for both early (30-day) and late (greater than 30-day) survival as they may well be different. Factors affecting early survival appear related more to the preoperative condition of the patient (including degree of pulmonary hypertension) as well as advances that have been made in postoperative care. It is not immediately obvious why gender has such a profound effect on early survival and why primary graft failure rates appear higher in this group. Donor organ factors did not appear to relate to this difference. On the other hand, late survival appears to be influenced mainly by immunologic factors such as panel reactive antibody level and immunosuppressive protocol. A less dramatic effect of transpulmonary gradient appears to have a lasting effect on recipients even when they survive the initial 30-day period. Thus, pulmonary hypertension may have prolonged effects on the cardiac allograft which as yet we do not understand completely. The majority of late mortality is still due to graft atherosclerosis, infection, and acute cellular rejection, the latter 2 occurring most frequently within the first year after transplantation whereas death from graft atherosclerosis becomes most prominent beyond 5 years. Despite persistent improvements in 30-day survival, late survival following cardiac transplantation will only improve with the advent of better tissue matching and improved immunosuppression. The results with FK506, for example, are promising.
Adult↗
Evolution of human cardiac myocyte dimension during prolonged mechanical support.
In animal models using left ventricular assist systems over long time periods, myocardial cellular atrophy has been reported, raising concern that prolonged clinical use of such systems might lead to deterioration in left ventricular function. At the University of Pittsburgh, long-term clinical use of the Novacor (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.) left ventricular support system for patients awaiting heart transplants has allowed study of the effects of long-term mechanical support on human subjects. This study determined that cardiac myocyte dimension is initially greater in patients with end-stage cardiac disease who require support rather than in patients with the same disease who do not require such support. Although myocyte dimension does decrease within a few days of the inception of support, this decrease merely brings cell size closer to the values usual in patients with chronic end-stage cardiac disease, and no further shrinkage is observed. Thus the Novacor left ventricular assist system does not appear associated with left ventricular atrophy, and its long-term use may not be detrimental to left ventricular function.
Cardiomyopathies↗
Experience with univentricular support in mortally ill cardiac transplant candidates.
Between July 1987 and March 1989, 11 patients underwent left ventricular support with the Novacor left ventricular assist system irrespective of apparent degree of right ventricular failure. The first 2 patients died of multisystem organ failure while on support. All the remaining patients survived the support period, and actuarial survival after transplantation was 100% at 6 months and 89% at 1 year. In no patient did bacterial infection develop during support or after transplantation. Right ventricular ejection fraction before implantation of the left ventricular assist system was lower than 15% in 6 of 8 patients, yet it increased twofold during left ventricular support. The need for excessive inotropic support (2 patients) or temporary (four days) mechanical right ventricular support (2 patients) while on the left ventricular support system appeared to be related to elevated pulmonary vascular resistance during support in association with large preimplantation ventricular volumes. It appears that even patients with compromised right ventricular performance can be supported long term with a left ventricular assist device. Patients with elevated pulmonary vascular resistance may require temporary right ventricular support.
Adult↗
Disruption of the aortic anastomosis after heart-lung transplantation.
Disruption of the aorta at the anastomotic site occurred in 4 of 66 consecutive heart-lung transplant recipients and was associated with a 100% mortality. In 3 of these patients, Candida either was cultured from the suture line or was seen in the wall of the aorta at postmortem examination. In 2 of these 3 patients, cultures of material from the donor trachea taken at the time of explanation grew Candida species. Two patients were seen with sudden massive hemorrhage on postoperative day 26 and postoperative day 28. One patient experienced acute decompensation due to right ventricular outflow tract obstruction on postoperative day 30, and the remaining patient was seen 7 months postoperatively with obstruction of both the left main bronchus and the right pulmonary artery caused by extrinsic compression by an aortic pseudoaneurysm. A high index of suspicion should be maintained when transplanting lungs containing Candida species, as we believe there is substantial evidence of donor transmission of the fungal agents. We now include amphotericin B in our antibiotic prophylactic regimen in an attempt to prevent fungal infection because previous treatment has been uniformly unsuccessful. Furthermore, we wrap both the trachea and the aorta with omentum to lessen the likelihood of mediastinal spread of infection to the aortic suture line.
Adolescent↗
Propagation of infiltrating lymphocytes and graft coronary disease in cardiac transplant recipients.
The pattern of lymphocyte growth from endomyocardial biopsies in 55 heart transplant recipients was shown to be correlated with the subsequent development of graft coronary disease. Persistent lymphocyte growth was observed in 39 patients, and 15 of these growers (or 41%) developed graft coronary disease. In contrast, only 1 of 15 patients (or 6%) with nongrower biopsies showed subsequent graft coronary disease. Thus, biopsy growth was associated with a higher incidence of subsequent GCD (p = 0.02). A comparison between the group of 15 growers with subsequent graft coronary disease and the 24 growers without subsequent graft coronary disease did not show any differences with respect to patient age, presence of coronary artery disease in the native heart, biopsy histology, donor alloreactivity of biopsy grown lymphocytes, and immunosuppressive drug regimen. On the other hand, the number of treated rejection episodes was significantly lower in the grower group with subsequent graft coronary disease (p = 0.04). These data support the concept that graft coronary disease may involve rejection and that more immunosuppression may lower its incidence. This concept is strengthened by findings showing that alloreactive T cells can be propagated from coronary arteries of cardiac allografts with graft coronary disease.
Biopsy↗
The scalar electrocardiogram of the orthotopic heart transplant recipient.
The 12-lead scalar electrocardiograms of heart transplant recipients were examined prior to hospital discharge (N = 191), and at 1 (N = 162), 2 (N = 97), and 3 years (N = 46) after transplantation. At the pre-discharge point, 46% had right bundle branch block (RBBB) QRS morphology (QRS duration greater than or equal to 120 msec: 20 patients, less than 120 msec: 67 patients). This finding tended to be manifest on the first day following transplantation; its prevalence remained constant over 3 years of follow up. Rejection, ischemic time, preoperative pulmonary vascular resistance, and donor age were not associated with the presence of RBBB morphology. A subgroup of 46 consecutive patients (21 with RBBB morphology) underwent right-sided heart catheterization and radionuclide angiography prior to discharge. RBBB morphology was not associated with any hemodynamic abnormality at catheterization. Based on the radionuclide study, RBBB morphology was associated with a greater left anterior oblique angle required for the best visual separation of the ventricles during acquisition of the study (angle of interventricular septal plane to sagittal plane: 69 +/- 11 versus 59 +/- 9 degrees; p = 0.019), and with the presence of right ventricular dysfunction (13 of 21 versus 6 of 25 patients; p = 0.009). The high prevalence of RBBB morphology in heart transplant recipients appears to be related to posterior rotation of the long axis of the heart in the transverse plane, probably resulting from the surgical technique, and to right ventricular dysfunction.
Adult↗
Heart transplantation in diabetic recipients.
Preexisting diabetes mellitus (DM) has been regarded as a contraindication to heart transplantation (HT). This prejudice has been based upon concern over increased infection rates and worsening DM with the initiation of prednisone immunosuppression. To better evaluate these suppositions, we reviewed our experience with diabetic patients who underwent HT. Between 6/80 and 1/88, 367 nondiabetics (NDs) and 19 diabetics underwent HT at our institution. Of the 19 diabetic recipients (DRs), two were black and four were female. Six DRs were on insulin (average daily dose: 46 U) prior to HT, and the remainder required oral hypoglycemic agents. Following HT, five DRs had insulin substituted for oral hypoglycemics. The 11 insulin-dependent DRs now require an average daily dose of 48 U. The average duration of follow-up for the 19 DRs was 17 months (range 1-67 months). During this time, 5 hospitalizations were required for complications of diabetes. The rejection rate was not higher for the DRs than the NDs (0.37 events/100 pt. days vs. 0.51 events/100 pt. days). The DRs who have undergone coronary angiography up to 4 years following HT have had no evidence of coronary atherosclerosis. Three-year survival for DRs and NDs is similar. DRs have a slightly higher incidence of lethal infections than NDs, which is not statistically significant (16% at 17 months vs. 10% (p greater than 0.4). We conclude that carefully selected diabetics can undergo HT with minimal consequent worsening of their DM. Diabetic HT recipients do not suffer a higher incidence of graft atherosclerosis, rejection, or lethal infection.
Coronary Disease↗
Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin.
A randomized trial of RATG (polyclonal) vs. OKT3 (monoclonal) antibody prophylaxis was carried out in 82 cardiac transplant recipients who, in addition, received baseline immunosuppression with cyclosporine, azathioprine and prednisone. One-year actuarial survival was comparable between groups (95% and 98%). The incidence of moderate or severe rejection within the first 30 days of transplant was over 7 times greater in patients receiving OKT3 vs. those receiving RATG. Patients receiving OKT3 were more likely to have repeated episodes of rejection and the mean time to rejection for patients receiving OKT3 was shorter (33 days) than for RATG patients (67 days). At 120 days, 52% of RATG patients were free of rejection while only 37% of the OKT3 patients were rejection-free. There was no difference in the incidence of major or minor bacterial or viral infection between groups. Patients receiving OKT3 showed a less-prolonged depression of the CD3 and CD4 T cell subsets than did those receiving RATG. Significant hemodynamic side-effects were seen after the first dose of OKT3 and there was a 5% incidence of aseptic meningitis associated with its use.
Antibodies, Monoclonal↗
Cyclosporine nephrotoxicity in cardiac allograft patients--a seven-year follow-up.
Renal function was observed retrospectively in a population of 228 adults who underwent a cardiac allograft at the University of Pittsburgh from June 1980 through June 1987, survived a minimum of one year, and received cyclosporine. Renal function was determined by serial measurement of serum creatinine concentration. Serum creatinine rose from 1.2 +/- 0.0 mg/dl at time of hospital discharge to 2.0 +/- 0.0 mg/dl at two and four years and 3.3 +/- 0.1 mg/dl at seven years. The fall in renal function was biphasic, with a rapid decline (reciprocal creatinine slope -0.018 dl/mg-mo) through 24 months and a slower decline thereafter -0.0036 dl/mg/month). This occurred despite a progressive decrease in cyclosporine levels from 668 +/- 23 ng/ml (whole blood RIA) to 380 +/- 12 ng/ml at seven years. Three of 222 patients (1.6%) developed end-stage renal disease within 18 months of initiation of cyclosporine therapy. Only one additional patient of 26 followed through 54 months (3.8%) developed end-stage disease thereafter. The decline in renal function seen with cyclosporine is rapid in the first 18 months, with a slower but continuing decline seen with later follow up. At least in heart transplantation, the risk of end-stage renal disease is significant, but not prohibitive.
Adult↗
Hemodynamic parameters influencing clinical performance of Novacor left ventricular assist system.
The interrelationships between hemodynamic variables including right ventricular (RV) performance with filling/ejection dynamics of the Novacor left ventricular assist system (LVAS) were determined in 10 of 11 patients who received LVAS as a bridge to heart transplant. Nine were successfully transplanted. Data were obtained intraoperatively, at periodic intervals up to 48 h postimplant and at explant. The hypotheses investigated included (a) RV performance influences LVAS filling characteristics and (b) LVAS pump output is influenced by systemic vascular resistance (SVR). During the period of LVAS support (2-126 days), pumping characteristics included a mean filling volume of 51 ml (range, 24-70), residual volume of 4.9 ml (range, 1-18), pump rate of 113/min (range, 63-175), and pump output of 5.81/min (range, 2.8-8.2). Multiple regression analysis identified pulmonary vascular resistance (PVR), RV stroke work index (RVSWI), and pulmonary capillary wedge pressure, but not RV ejection fraction, pulmonary artery pressure, or central venous pressure (CVP) as the most important correlates with LVAS filling volume (p less than 0.001, R2 = 0.6). In addition, LVAS pump output was influenced mainly by RVSWI, PVR, and SVR (p less than 0.001, R2 = 0.7). It was concluded that LVAS performance is highly dependent on RV function and systemic/pulmonary vascular resistances.
Equipment Design↗
Biomedical engineering management of Novacor left ventricular assist system (LVAS) patients.
As the number of cardiac transplant centres increases, there is an associated decrease in the availability of donor organs per centre. Subsequently, hospitals are utilizing cardiac assist systems (total artificial heart and ventricular assist devices) as a bridge to cardiac transplantation. Because of the engineering complexities related to the clinical implantation and follow up of these devices, a successful centre should have a well co-ordinated biomedical engineering programme. These engineers are responsible for the calibration, monitoring, and continued operation of these units. This paper is intended to serve as a guide to any centre interested in utilizing total artificial heart and ventricular assist systems, in particular the Novacor left ventricular assist system, and focuses on the management and function of the biomedical engineering component of our cardiac assist programme.
Biomedical Engineering↗
Hypertension, creatinine, and plasma renin activity in heart transplant recipients.
Development of de novo hypertension in a large proportion of orthotopic heart transplant recipients receiving cyclosporine has previously been reported. This hypertension is characterized by a persistence of increased peripheral resistance, sodium retention, and loss of nocturnal decline in BP. Vascular nephropathy with plasma renin activity (PRA) elevation from cyclosporine (CsA) may also be major factor in the progress of hypertension. To investigate this hypothesis, observations of BP, creatinine (Cr), and PRA were made in 144 heart transplant recipients followed for up to four and a half years. Median Cr was 133 mumol/l. Average diastolic BP and mean PRA values were significantly higher in patients with Cr greater than or equal to the median. Cr and PRA were significantly correlated (r = 0.4; P less than 0.001) in recipients with Cr greater than or equal to 133 mumols/l but not in those with Cr less than 133 mumols/l. In a selected subsample of heart transplant recipients with repeated Cr and PRA values, Cr and PRA appeared to increase longitudinally after transplant. These data are derived from a case series of patients managed on a variety of antihypertensive agents (excluding ACE inhibitors) needed to control the persistent hypertension.
Antihypertensive Agents↗
Bradyarrhythmia after heart transplantation. Incidence, time course, and outcome.
From June 1980 to April 1989, 72 of 401 (18%) adult recipients of orthotopic heart transplantation developed prolonged (greater than 24 hours) bradyarrhythmias (less than 60 beats/min) within 5 days after transplantation. Junctional bradycardia occurred in 50 (69%) recipients, sinus bradycardia in 18 (25%), and slow ventricular response during atrial fibrillation in four (6%). Fifty-five of 72 (76%) patients had bradyarrhythmias of less than 20 days' duration (less than 7 days, 50 patients; 7-20 days, five patients). Fifty patients returned to sinus rhythm (greater than 60 beats/min) by the time of discharge. Five patients expired within 20 days. Seventeen of 72 (24%) patients had bradyarrhythmia for more than 20 days, which was symptomatic in 11. All 17 patients (junctional bradycardia, 13 patients; sinus bradycardia, four patients) received a permanent pacemaker within 40 days after transplantation. Between 1 and 12 months (mean, 4 +/- 3 months) after pacemaker implantation, 12 patients recovered sinus rhythm (greater than 70 beats/min). The other five patients had intrinsic rates of 32-57 beats/min (mean, 48 +/- 10 beats/min) during 1-9 months (mean, 4 +/- 3 months) of follow-up. The donor ischemic time in bradyarrhythmia patients was 202 +/- 34 minutes, which was significantly longer (p less than 0.01) than the 173 +/- 43 minutes for those patients without bradyarrhythmia. Conclusively, the incidence of posttransplantation bradyarrhythmia is relatively high. It is usually temporary, however, even in patients with a prolonged duration of bradyarrhythmia. A relation appears to exist between donor ischemic time and the incidence of bradyarrhythmia.
Adult↗
Resolution of severe pulmonary hypertension after heterotopic cardiac transplantation.
In patients with severe congestive heart failure, a marked elevation in pulmonary vascular resistance limits the success of orthotopic cardiac transplantation, thus providing the rationale for heterotopic transplantation. To determine the changes in pulmonary hemodynamics after heterotopic cardiac transplantation, postoperative right heart pressures were serially measured in five patients who underwent this operation for end-stage congestive heart failure accompanied by severe secondary pulmonary hypertension and elevation in calculated pulmonary vascular resistance. Hemodynamics were compared with those of a matched group of 10 orthotopic cardiac transplant recipients. Preoperatively, pulmonary artery mean and wedge pressures, pulmonary vascular resistance and transpulmonary pressure gradient (pulmonary artery mean minus wedge pressure) were significantly higher in the heterotopic group. Postoperatively, significant improvement in pulmonary hemodynamics occurred in both groups and, by 12 months, the pulmonary artery mean pressure, wedge pressure, pulmonary vascular resistance and transpulmonary pressure gradient were similar in the two groups. These findings suggest that pulmonary hypertension secondary to congestive heart failure, even when severe and associated with a high pulmonary vascular resistance, is to a great extent reversible.
Adult↗
The value of protective isolation procedures in cardiac allograft recipients.
The impact of protective isolation on the incidence of infection in 60 cardiac transplant recipients (mean age, 49.2 years) was studied in a prospective randomized trial. Thirty patients were randomized to protective isolation, which consisted of private room, hat, mask, sterile gown, and handwashing. Thirty patients were randomized to no isolation, which meant they recovered in a crowded, open intensive care unit and were adjacent to recipients of liver transplants or patients who were on the trauma, neurosurgical, and general surgical services, many of whom had an infection of the incision or a pulmonary infection. There was no difference between groups in the proportion of patients in whom infection developed (chi 2[1] = 0.27; p = 0.6), the number of infection-related deaths (2 in each group), the types of infection (bacterial, viral, fungal, or protozoal), or the overall outcome. Because protective isolation offered no benefit over standard care in protecting these patients from infections or the associated complications, we have discontinued its routine use after cardiac transplantation.
Adolescent↗
Organ procurement for pulmonary transplantation.
Selection of suitable donors is critical to the success of clinical pulmonary transplantation. Requirements for lung donors, management before explantation, and methods of preservation were reviewed for the 70 heart-lung, eight double-lung, and two single-lung transplantations performed at the University of Pittsburgh since 1982. Careful observation of trends of hyperoxygenation studies, chest roentgenograms, and Gram stain and culture results of tracheal secretions, as well as findings on bronchoscopy, can help identify which lungs not only have adequate function but are acceptable for transplantation. In spite of the rigid criteria used, 76% of tracheal cultures from donors deemed acceptable grew organisms. The presence of oropharyngeal flora has been shown to correlate with the development of early intrathoracic infections in the recipient. Prophylactic broad-spectrum antibiotic treatment of the donor is desirable to treat microbial contamination that could cause focal injury to the donor lung and predispose to infection in the recipient. Acceptance of less than ideal donors is ill-advised even though rejection of such donors conflicts with the current shortage of organs.
Graft Survival↗