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W H Frist

Publications and source records attributed to W H Frist.

At least 37 records · Page 2Linked to original sources
PubMed1993

Noninvasive detection of acute rejection in a new experimental model of heart transplantation.

We have shown that positron emission scintigraphy detects changes in the uptake of 18-F 2-deoxyglucose and 13-N ammonia by the acutely rejecting myocardium in a nonworking model of heterotopic heart transplantation in the rat. We developed a new working model of heterotopic heart transplantation to determine the possible relevance of these changes to clinical transplantation. Moderate aortic valvular regurgitation was produced allowing the heterotopic left ventricle to fill and eject. Rejecting allografts and nonrejecting isografts (controls) were studied 4 days after transplantation. Histologically, isografts were normal and all allografts showed mild acute rejection. Decay-corrected uptakes of 18-F 2-deoxyglucose and 13-N ammonia reflect glucose metabolism and blood flow, respectively. Values are presented as percent of injected dose per gram of tissue. Uptake of 18-F 2-deoxyglucose was higher in rejecting allografts compared with nonrejecting isografts (3.0 +/- 1.8 versus 1.1 +/- 0.4; p = 0.024). Ammonia uptake was elevated in allografts compared with isografts (2.2 +/- 0.5 versus 1.3 +/- 0.5; p = 0.023). Uptakes of 18-F 2-deoxyglucose and 13-N ammonia are higher in mildly rejecting allografts, implying increased glucose utilization and blood flow during acute rejection. These data support our earlier findings of changes in myocardial metabolism in the absence of diminishing blood flow in acutely rejecting hearts. This model may lead to a better understanding of the physiology and metabolism of acute rejection.

Animals↗
PubMed1993

Immunosuppressive therapy as a determinant of transplantation outcomes.

Although surgical proficiency is essential to the immediate outcome of transplantation, long-term success depends upon how adequately the transplantation recipient is managed. Immunosuppression, the most critical aspect of after care, is subject to wide variation. In January 1990, a survey was sent to the directors of all transplant programs in the United States performing one or more kidney, heart, liver, heart-lung, or pancreas transplant in 1988. Detailed data were obtained on both the drugs and methods used for induction and maintenance immunosuppression, as well as the treatment of rejection. Each program director was asked to rank each immunosuppressive approach according to its perceived impact on patient outcomes. Over 85% of all eligible program directors completed the survey. There is no evidence of survey respondent bias. The use of polyclonal and monoclonal agents for induction immunosuppression was favored most by pancreas program directors (72-76%). These agents were least preferred by liver transplant programs (35-37%). About half of kidney, heart, and heart-lung program directors preferred these agents. Triple-drug therapy consisting of CsA, PRED, and AZA was considered the most preferable maintenance protocol for all transplants (i.e., kidney, 89%; heart, 94%; liver, 88%; heart-lung, 86%; pancreas, 96%). Either i.v. steroids or OKT3 were regarded as the preferred approaches for the treatment of acute or resistant rejection. Finally, the acceptability of outpatient treatment of rejection varied by transplant type (i.e., kidney, 9%; heart, 58%; liver, 5%; heart-lung, 29%; pancreas, 8%). Although there are similarities in the ratings of various aspects of immunosuppressive therapy, there are important differences. This information is critical to anticipate the implications of new immunosuppressive agents and to evaluate changes in the use of existing drugs and therapeutic approaches.

Data Collection↗
PubMed1993

The expression of acidic fibroblast growth factor (heparin-binding growth factor-1) and cytokine genes in human cardiac allografts and T cells.

The purpose of this study was to investigate the role of cytokines and growth factors in cardiac allograft rejection and vasculopathy (CAV). The polymerase chain reaction (PCR) was used to detect the expression of IL-1, IL-2, IL-4, IL-5, IL-6, TNF-alpha, IFN-gamma, TGF-beta, TCR-beta chain and aFGF genes in 21 myocardial biopsies obtained from 9 heart transplant patients. There was no statistically significant correlation between cytokine gene expression and rejection, although a trend toward increased IL-6 and TGF-beta expression was noted with rejection (6 of 10 biopsies with vs. 1 of 7 without rejection, and 4 of 9 biopsies with vs. none of 7 without rejection, respectively). IL-2 gene expression was detected in only 2 of 21 biopsies, both positive for rejection. IL-1, IL-4, IL-5, CD8, IFN-gamma, and TNF-alpha were not detected in any of the biopsies. TCR-beta chain mRNA was found in all biopsies, indicating the invariable presence of T cells regardless of histologic diagnosis of rejection. The aFGF gene was expressed in the majority (18 of 21) of biopsies, and its presence was not correlated with rejection. In addition to mRNA for the complete coding sequence of aFGF, two alternatively spliced mRNAs for aFGF were present in myocardial biopsies. Because aFGF and TCR beta genes were expressed in most biopsies, we determined whether aFGF mRNA was expressed in T cells; aFGF transcripts were found in 2 of 5 T-cell clones examined. Thus, aFGF mRNA in cardiac allografts may have been induced within the myocardium or elaborated by infiltrating T cells. The presence of mRNA for aFGF, a potent endothelial and smooth muscle cell mitogen, in allograft myocardium suggests that aFGF may play a role in the pathogenesis of CAV.

Alternative Splicing↗
PubMed1993

Expression of cytokine genes in human cardiac allografts: correlation of IL-6 and transforming growth factor-beta (TGF-beta) with histological rejection.

Cytokines may play critical roles in allograft rejection. Currently, a clear pattern of cytokine production that correlates with rejection has not emerged. Our preliminary studies suggested a trend toward increased IL-6 and TGF-beta gene expression in cardiac allografts during rejection. We have extended these studies using reverse transcriptase/polymerase chain reaction (RT/PCR) to detect the expression of IL-6, TGF-beta, and T cell receptor beta chain constant region (TCR-beta) genes in 21 additional consecutive myocardial biopsies obtained from six heart transplant patients and from five pre-transplant donor hearts. Cytokine gene expression was compared with histological diagnosis of rejection. There was strong correlation between IL-6 as well as TGF-beta gene expression, and histological rejection (6/8 biopsies with versus 0/7 without rejection (P = 0.006) and 7/9 biopsies with versus 0/7 without rejection (P = 0.003) respectively). Neither IL-6 nor TGF-beta transcripts were detected in any pre-transplant donor heart. TCR-beta chain mRNA was found in all allograft biopsies regardless of the presence of rejection, but was absent in pre-transplant donor hearts. Our results indicate that expression of IL-6 and TGF-beta is highly correlated with allograft rejection and thus may play an important role in regulation of cardiac allograft rejection. T cell infiltration of allografted myocardium is invariably detected by PCR regardless of histological rejection. The long-term functional significance of these cells in transplanted hearts needs further investigation.

Base Sequence↗
PubMed1993

Molecular forms of atrial natriuretic factor in normal and failing human myocardium.

BACKGROUND: Atrial natriuretic factor (ANF) is produced by myocardial tissue, and the plasma ANF concentration is known to be elevated in congestive heart failure (CHF). Data from animal models indicate that myocardial concentrations of ANF are depleted in CHF, and this has given rise to the hypothesis that CHF is characterized by depletion of stored ANF. To date, the molecular forms of ANF and their concentrations in atrial and ventricular myocardium remain poorly characterized in the normal and the failing human heart. METHODS AND RESULTS: We measured ANF concentrations in fresh tissue from failing human hearts explanted at the time of cardiac transplantation and from organ donors whose normal hearts could not be used for transplantation. We determined total ANF and alpha, beta, and gamma ANF concentrations in the right and left atrial appendages, atrial free walls, and ventricles. In normal hearts, ANF concentration in the atrial appendages was 40-fold higher than ANF in the rest of the atrial free wall and in the ventricles. In the failing hearts, atrial appendage ANF concentrations increased 5- to 10-fold, and atrial free wall ANF concentrations increased 200-fold. Analysis of molecular forms of ANF demonstrated significant increases in the gamma and beta forms in the left atrial appendage of failing hearts. alpha, beta, and gamma ANF forms were also significantly increased in right and left atrial free wall tissue from failing hearts. In addition, failing hearts were characterized by absolute and relative increases in the precursor form gamma ANF. CONCLUSIONS: These data from fresh tissues suggest that cardiac ANF stores are not decreased in severe CHF in humans; rather, chronic CHF is characterized by marked increases in atrial ANF tissue concentrations, particularly the beta and gamma ANF forms. These findings are consistent with intracellular accumulation of precursor ANF forms in severe chronic human CHF.

Adolescent↗
PubMed1993

Infection in the transplanted and native lung after single lung transplantation.

OBJECTIVE: To analyze a single-center experience with infectious complications of single lung transplantation (SLT) with special emphasis on risk factors for infection in the transplanted and native lung. DESIGN: Consecutive case series. SETTING: University teaching hospital. PATIENTS: Fifteen consecutive SLT recipients (mean age, 43 years; 9 men and 6 women). Mean follow-up was 337 days. RESULTS: Fifteen patients had 24 infectious episodes (1.6 per patient) of which 83 percent were life-threatening, 79 percent involved the lung, airway, or pleural space, and 79 percent occurred in the first 4 months after transplantation. Despite this high infectious morbidity, there were no infectious deaths. The most important infections were bacterial pneumonia (n = 10), cytomegalovirus (CMV) pneumonia (n = 5), and bronchial anastomotic infections (n = 3). Significant risk factors for bacterial pneumonia were a diagnosis of primary or secondary pulmonary hypertension (p < 0.05) and the presence of airway complications of stenosis or dehiscence (p < 0.05). No risk factors for overall lung infections were identified. The native lung was involved in 6 of 16 lung infections and was the exclusive site of infection in 4 cases. Underlying disease in the native lung may have predisposed to infection at that site by a mechanism of inadequate blood flow or impaired ventilation. Three bronchial anastomotic infections (Pseudomonas, Candida, Aspergillus) occurred, all with dehiscence of the anastomosis. These were highly morbid but resolved with antibiotics, stent placement, and surgical retention in two of the three cases. The five episodes of CMV pneumonia caused mild (four patients) or moderate (one patient) dysfunction and responded to antiviral agents without relapse. CONCLUSION: The frequency, complexity, and morbidity of infections after SLT were great, but most infections were manageable and good outcomes were achieved. A pretransplant diagnosis of pulmonary hypertension or posttransplant occurrence of bronchial stenosis or dehiscence were associated with a higher rate of bacterial pneumonia. The underlying disease in the native lung may predispose to infection at that site.

Adolescent↗
PubMed1993

Estimation of left ventricular mass and infarct size from nitrogen-13-ammonia PET images based on pathological examination of explanted human hearts.

The purpose of this study was to develop a technique to quantify left ventricular mass and infarct size in chronic ischemic heart disease from PET images based on correlation with pathological examination of explanted human hearts. Fourteen hearts from patients with cardiomyopathy who had 13N-ammonia scans prior to orthoptic heart transplantation were studied. Accurate estimation of the relative infarct size was possible in patients with a well-delineated, nearly transmural infarct (r = 0.93, y = 1.1x - 0.7, n = 11). Both absolute and relative infarct mass measurements on PET images correlated well with pathological measurements. We identified a population of patients with patchy interstitial or subendocardial scarring with globally reduced perfusion, for which the infarct size could not be estimated using the criteria derived for the patients with well-delineated infarcts.

Adult↗
PubMed1992

Noninvasive detection of heart transplant rejection with positron emission scintigraphy.

Positron emission tomography has recently been used to evaluate ischemic heart disease through changes in myocardial blood flow and carbohydrate metabolism. Positron-emitting tracers were evaluated for their ability to detect acute allograft rejection after heterotopic cardiac transplantation in the rat. Sham-operated controls, nonrejecting isografts, and rejecting allografts were evaluated. Decay-corrected uptake of 13NH3 and 18F 2-fluoro 2-deoxyglucose (FDG) reflects blood flow and glucose flux, respectively. Histologic examination of rejecting allografts documented mild rejection at 4 days and severe acute rejection by 8 days. All isografts were free from rejection. Uptake of FDG is greater in rejecting allografts than in nonrejecting isografts during both severe rejection (2.4% +/- 0.8% versus 0.7% +/- 0.4%; p less than 0.02) and mild rejection (2.1% +/- 0.6% versus 0.4% +/- 0.1%; p less than 0.02). Uptake of NH3 in severely rejected grafts is reduced compared with nonrejecting grafts (0.6% +/- 0.3% versus 1.7% +/- 1.1%; p less than 0.02). There is no difference in NH3 uptake during mild rejection (1.8% +/- 0.7% versus 1.3% +/- 0.3%; p greater than 0.05). Uptake of FDG and NH3 in native hearts of animals from all experimental groups is not significantly different from that in sham-operated controls. Glucose may be a preferred metabolic substrate during rejection. Our data support a humoral mechanism for substrate preference during transplant rejection and a potential diagnostic role for positron emission tomography.

Ammonia↗
PubMed1992

Staging lung carcinoma with a Tc-99m labeled monoclonal antibody.

Thirty-three patients with biopsy-proven lung cancer and a total of 150 lesions diagnosed by conventional staging procedures were imaged using a Tc-99m labeled monoclonal Fab fragment of an IgG2B murine monoclonal antibody (MoAb) (NR-LU-10, NeoRx Corporation). Immunoscintigraphy demonstrated 100% of primary and 78% of metastatic lesions. MoAb imaging detected 88% of lesions in 12 small cell lung cancer (SCLC) patients and 77% of lesions in 21 non-small cell lung cancer (NSCLC) patients. Based on initial evaluation by other methods, 29 sites of MoAb activity were not associated with evidence of disease. Eleven of these were subsequently shown to represent sites of metastases; 18 remain unconfirmed. Four of ten patients studied with limited NSCLC had eight unsuspected lesions on MoAb imaging. Confirmation of unsuspected lesions in two patients altered initial clinical staging, and surgical therapy was abandoned. This study demonstrates that Tc-99m labeled NR-LU-10 can accurately stage patients with lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

Effects of the pericardium on left ventricular diastolic filling and systolic performance early after cardiac operations.

To determine whether closure of the pericardium after cardiac operations affects the filling characteristics and systolic performance of the left ventricle, we measured left ventricular volume, pressure, cardiac index, and stroke work index in 10 patients between 11 and 15 hours after cardiac operations, with the pericardium first closed and then open. At the time of operation, radiopaque tantalum markers were inserted in the left ventricular myocardium to outline the chamber in the 30-degree right anterior oblique projection, and the pericardium was closed by a continuous polypropylene suture exteriorized at both ends of the sternotomy. The patient was then transferred to the surgical intensive care unit, where left atrial pressure was measured via a fluid-filled catheter, left ventricular pressure with a micromanometer-tipped catheter, and myocardial oxygen consumption via a coronary sinus catheter. Left ventricular volume was measured by computer-aided analysis of fluoroscopic images (recorded at 30 frames per second) of the implanted myocardial markers. Left atrial pressure was maintained at target values of 10, 15, and 20 mm Hg by intravenous augmentation of blood volume. Left ventricular and left atrial pressures and volumes were measured with the pericardium closed; the pericardium was then opened by withdrawal of the pericardial suture. Radiopaque clips on the pericardial edges confirmed opening of the pericardium seconds after withdrawal of the suture. Repeated measurements of left ventricular pressures and volumes were then made at the target left atrial pressures with the pericardium open. End-diastolic volume index, peak positive time derivative of pressure, stroke work index, and cardiac index all increased significantly when the pericardium was opened (p < 0.001). Thus we found the following: (1) At physiologic pressures, the pericardium had a significant constraining effect on diastolic filling of the left ventricle, and (2) opening of the pericardium resulted in increased cardiac index and stroke work index. These increases may be attributed to the Frank-Starling response to increased left ventricular preload. The demonstrated improvement in left ventricular systolic performance should be considered when contemplating closure of the pericardium after cardiac operations, especially in patients with preoperative left ventricular dysfunction.

Adult↗
PubMed1992

Clinical significance of mild rejection of the cardiac allograft.

BACKGROUND: The clinical status of heart transplant patients during mild rejection (lymphocytic infiltrate without myocyte necrosis) has not been previously reported. This study examined the frequency and outcome of mild rejection associated with allograft dysfunction sufficient in magnitude to be evident on clinical exam (two or more abnormal findings) and/or two-dimensional echocardiography. METHODS AND RESULTS: The study population consisted of 59 patients, 50 men and nine women 14-61 years old (mean, 1.7 +/- 0.8 years) with a mean follow-up of 1.7 +/- 0.8 years after transplant. All were receiving cyclosporine, azathioprine, and prednisone. A total of 108 episodes of mild rejection were detected (frequency, 1.8 episodes per patient). Detailed records of clinical findings were available for 94 episodes. Thirty-five (37%) of these 94 mild rejections were associated with allograft dysfunction: hypotension, n = 4; elevated jugular venous pressure, n = 14; S3, n = 13; rales, n = 10; sinus rate > or = 110 beats per minute, n = 25; atrial fibrillation, n = 5; bradycardia < 60, n = 1; and systolic dysfunction on echo, n = 14. Treatment with high-dose steroids was clinically indicated in eight mild rejection episodes (9%) with allograft dysfunction. Of the remaining 86 untreated episodes, eight (30%) of 27 with allograft dysfunction versus six (10%) of 53 without allograft dysfunction progressed to moderate rejection on subsequent biopsy (chi 2 = 5.15, p = 0.02). Episodes with allograft dysfunction occurred earlier than those without dysfunction (15.4 +/- 2.8 weeks versus 34.4 +/- 5.5 weeks, p = 0.01) when baseline immunosuppression was higher. CONCLUSIONS: Our findings indicate that 1) mild rejection is frequently associated with cardiac allograft dysfunction; 2) nine percent of mild rejection episodes may be accompanied by severe allograft dysfunction or arrhythmias, requiring aggressive treatment; 3) mild rejection associated with allograft dysfunction occurs earlier than that without allograft rejection; 4) untreated, mild rejection episodes with allograft dysfunction progress to moderate rejection more frequently than those without allograft dysfunction. These episodes require increased surveillance for progression.

Arrhythmias, Cardiac↗
PubMed1992

Single lung transplantation: replacement therapy for end-stage lung disease.

Advances in immunosuppression and operative techniques have allowed single lung transplantation to become a viable treatment option at selected medical centers. We describe eight patients, all from the southeastern United States, who had single lung transplantation at Vanderbilt University Medical Center from March 1990 to June 1991. Their diagnoses represent a diverse set of diseases including idiopathic pulmonary fibrosis, primary pulmonary hypertension, emphysema, and pulmonary veno-occlusive disease. After thorough evaluation, the average waiting period to transplantation was 165 days. The posttransplantation periods were conspicuous for rejection, infection, and other complications. All of these recipients have either returned to an active life or are actively recuperating; this center's first single lung recipient has now survived 15 months. Our initial experience with single lung transplantation is encouraging, yet broader application requires that the paucity of donor organ availability be rectified.

Adult↗
PubMed1992

Twenty years' experience with pulmonary metastasectomy.

From January 1969 through December 1989, 63 patients had 69 operations for pulmonary metastases. Patients ranged in age from 1 to 75 years; there were 36 men and 27 women. Metastasectomy was accomplished through a thoracotomy incision in 59 cases (5 staged, bilateral), and median sternotomy was used in 10 instances. Wedge resection was performed in 54 patients, with segmentectomy in 2, lobectomy in 12, and pneumonectomy in 1. There were no operative deaths. Multiple metastases were present in 29 patients, and a single metastasis in 34. Follow-up ranges from 2 to 204 months (mean = 42 months). Thirty-eight patients remain alive; thirty are free of disease and eight have developed other metastases. Actuarial survival at 5, 10, and 15 years is 40 (CL [confidence limits] 49,31), 36 (CL 44,26), and 24 (CL 35,13) per cent, respectively. Mean actuarial survival is 84 months, and median survival is 58 months. There is no difference in survival whether metastases were single or multiple. Survival is significantly less in groups with primary sarcoma and melanoma (P = .012). While pulmonary metastases may be a manifestation of terminal disease, metastasectomy has an important role in the multidisciplinary management of selected patients when metastatic disease is confined to the lung. Prolonged survival may be achieved in many patients.

Actuarial Analysis↗
PubMed1992

Pediatric organ donation: the paradox of organ shortage despite the remarkable willingness of families to donate.

The 105 pediatric deaths (ages 1 to 16 years) that occurred at Vanderbilt University Medical Center during a 31-month period were reviewed to define the size of the donor pool in the pediatric population and to assess the role of physicians in the procurement of these much-needed organs. Computerized discharge abstracts showed that 57 pediatric patients died without contraindications to organ donation. Manual review of these 57 medical records yielded 46 records suitable for review by Tennessee Donor Services. From this group, 19 eligible donors were identified. All eligible donors died from trauma, intracerebral hemorrhage, anoxic events, or hydrocephalus. Physicians failed to ask one family for permission to donate. All 18 of the families who were asked agreed to donate and organs were successfully procured from all 18 patients. These data suggest that families of pediatric patients are much more willing to agree to donation than the families of adult patients. As a result of this study, a simplified audit process has been developed for hospitals to use in evaluating compliance with required-request legislation.

Adolescent↗
PubMed1991

Heart transplantation in children.

Orthotopic cardiac transplantation has been performed in 15 consecutive neonates and children since 1987. Diagnoses include hypoplastic left heart syndrome (5 patients), critical aortic stenosis with small left ventricle (1 patient), complex cyanotic heart disease (6 patients), and cardiomyopathy (3 patients). Twelve patients survived operation and have been followed from 1 to 45 months. Patients less than 6 years of age are managed with cyclosporine +/- azathioprine; in older patients steroid weaning is attempted. Monitoring for rejection is performed with serial echocardiography in patients under 6 years of age; older patients undergo serial biopsies. Actuarial freedom from rejection was 26% 3 months after operation; 47% were free of infection 6 months after operation. There have been no late deaths. Actuarial survival at 3 years is 79%. Nine patients have undergone postoperative catheterization. Resting hemodynamics were normal in every patient. All long-term survivors are asymptomatic and fully active. It is concluded that cardiac transplantation in neonates and children is an effective treatment option for end-stage cardiomyopathy or otherwise incurable congenital heart disease. Long-term survivors have excellent potential for full rehabilitation.

Actuarial Analysis↗