Martin Memorial Lecture: Operating outside the theater: new challenges for leadership.
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Health Policy↗
Biomedical subjects
W H Frist
Publications and source records attributed to W H Frist.
Association of acidic fibroblast growth factor and untreated low grade rejection with cardiac allograft vasculopathy.
Acidic fibroblast growth factor (aFGF) is a potent growth factor for vascular smooth muscle cells and may mediate vasculopathy in cardiac allografts subjected to chronic immunological injury. Therefore, we examined cardiac expression of aFGF, the number of rejection episodes, and other potential risk factors in 32 heart transplant patients who underwent intravascular ultrasound (IVUS) for detection of cardiac allograft vasculopathy (CAV). As defined by IVUS, CAV was present in 21 patients and absent in 11 patients (follow-up time: 52 +/- 21 vs. 51 +/- 12 months, respectively, P = NS). The level of aFGF in myocardial biopsies obtained at the time of IVUS was measured by semiquantitative reverse transcriptase polymerase chain reaction and expressed as the aFGF:GAPDH ratio. Higher level of aFGF were associated with CAV (mean aFGF:GAPDH ratio was 1.45 +/- 0.99 in patients with vs. 0.18 +/- 0.12 in patients without CAV [P < 0.001]). A strong association was found between high levels of cardiac aFGF and CAV, as 18 of 19 patients (95%) with high levels of aFGF (aFGF:GAPDH > 1) but only 3 of 13 patients with low levels of aFGF had CAV (P < 0.001). The relative risk of high level of aFGF for CAV was 4.1. Untreated low grade rejection (ISHLT I), but not treated high grade rejection (ISHLT > 2), was also associated with CAV (average number of untreated low grade rejection episodes was 3.5 +/- 1.8 in patients with vs. 2.1 +/- 1.0 in patients without CAV [P = 0.04]). Among other risk factors examined (age, sex, serum cholesterol, blood pressure, CMV infection, dose of immunosuppressants, and ischemic time), only triglycerides were higher in patients with than those without CAV (P = 0.003). We conclude that increased cardiac production of aFGF is significantly associated with CAV, which suggests that aFGF may serve as an important mediator in CAV. Untreated low grade rejection also poses an increased risk for CAV.
Adult↗
Confirmation of alternatively spliced platelet-derived growth factor-A chain and correlation with expression of PDGF receptor-alpha in human cardiac allografts.
PDGF is a potent mitogen for vascular smooth muscle cells (SMC) and may play an important role in the pathogenesis of cardiac allograft vasculopathy (CAV). Two isoforms of PDGF-A chain exist as a result of alternative mRNA splicing that either includes (long-form) or excludes (short-form) exon 6. Short-form PDGF-A is expressed in both resting and activated cells, while the long-form is present predominantly in activated cells. Using RT/PCR, we have found previously that long-form PDGF-A chain was expressed in human cardiac allografts but not in normal human hearts. In the experiments reported here, we studied the cellular distribution of PDGF-A chain isoforms and expression of PDGF receptor-alpha in cardiac allografts. In situ hybridization and immunohistochemistry confirmed the PCR data and demonstrated that expression of long-form PDGF-A chain was diffusely increased in cardiac allografts, predominantly in myocytes and vascular structures. Expression of PDGF receptor alpha also was induced in cardiac allografts and was not detected in any of the normal hearts. Induction of PDGF receptor alpha in cardiac allografts was associated with the presence of long-form PDGF-A chain. In vitro experiments with human endothelial cells demonstrated that aFGF, IL-6, and TGF-beta, which are produced in cardiac allografts in vivo, induced expression of long-form PDGF-A chain. Expression of long-form PDGF-A chain and its receptor was markedly increased in cardiac allografts, predominantly in vascular structures and myocytes. Alterative splicing of PDGF-A chain variants may be mediated by growth factors and cytokines produced in vivo.
Adult↗
MRI complements standard assessment of right ventricular function after lung transplantation.
BACKGROUND: Changes in right ventricular mass and ejection fraction after single-lung transplantation for pulmonary hypertension are poorly understood. METHODS: To complement functional data provided by echocardiography, radionuclide ventriculography, and right heart catheterization, magnetic resonance imaging was used to assess right ventricular function in 5 single-lung transplant recipients with preoperative pulmonary hypertension and right ventricular dysfunction (right ventricular ejection fraction, 0.21 +/- 0.09). The right and left ventricular mass, ejection fraction, and mass ratio (left ventricular mass/right ventricular mass) were calculated from the magnetic resonance images. RESULTS: The mean pulmonary artery pressure fell from 72 +/- 18 to 21 +/- 8 mm Hg after transplantation. At 3 months after transplantation both the left ventricular and right ventricular ejection fractions approached normal values, as shown by both radionuclide ventriculography and magnetic resonance imaging, but the right ventricular mass remained abnormally high with slightly low mass ratios. By 1 year both the left ventricular and right ventricular masses had regressed to normal with near-normal mass ratios. CONCLUSIONS: Right ventricular performance returns to nearly normal early after transplantation, but the right ventricular mass regresses over a more prolonged time. Cine magnetic resonance imaging provides a noninvasive means of assessing changes in right ventricular function and mass after lung transplantation.
Adult↗
Positive expectations predict health after heart transplantation.
We explored the relations between positive expectations and adjustment, adherence, and health in cardiac transplant patients. Thirty-one patients and their nurse completed questionnaires before transplantation and at 3 times after surgery. As predicted, patients' self-reported positive expectations were generally associated with good mood, adjustment to the illness, and quality of life, even in patients who experienced health setbacks. High preoperative expectations predicted later adherence to a complex medical regimen. Positive expectations measured before the transplant predicted a substantial amount of the variance in the nurse's ratings of physical health 6 months after surgery, covarying for adherence behavior and preoperative health.
Adaptation, Psychological↗
Politics: a surgeon's road to the Senate.
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General Surgery↗
Nitrogen-13-ammonia and PET to detect allograft coronary artery disease after heart transplantation: comparison with coronary angiography.
UNLABELLED: The diffuse nature of allograft coronary artery disease (CAD) suggests that global myocardial blood flow (MBF) may decrease with time after transplantation; therefore the diagnosis of this disease remains problematic. METHODS: To investigate whether PET detects a fall in allograft MBF over time, PET scans (108) were obtained from 43 heart transplant recipients. Thirty-five patients underwent two serial PET scans 1 yr apart. MBF was measured by PET using 13N-ammonia as a tracer. Coronary angiography was performed parallel with PET imaging and compared with perfusion rates measured by PET scans. RESULTS: MBF measured by PET decreased sequentially with time. The mean MBF was 73 +/- 21, 56 +/- 13, 51 +/- 11 and 51 +/- 27 ml/min/100 g of tissue in patients surviving 3 mo, 1, 2 and 3 yr after transplantation, respectively. Significant MBF decrease occurred within 1 yr after transplantation. Sequential PET studies showed a decrease in MBF in 22 of 35 patients (63%). Mean MBF for the first and second scans was 65 +/- 18 and 54 +/- 16, respectively. MBF decrease was more profound in patients (n = 11) angiographic evidence of CAD. There was a trend towards increased rejection and CMV infection rates in patients with decreased MBF. CONCLUSION: With time, PET detects a decrease in MBF in cardiac allografts. The frequency of MBF decrease detected by PET is concordant with the true incidence of allograft CAD, suggesting that sequential PET is a more sensitive modality for monitoring allograft CAD than angiography.
Ammonia↗
Chronic myelogenous leukemia after lymphoid irradiation and heart transplantation.
We have previously reported a case of recurrent cardiac rejection in a heart transplant recipient successfully treated with total lymphoid irradiation. Five years after transplantation chronic myelogenous leukemia was diagnosed in this patient. The long-term effects of total lymphoid irradiation in the heart transplant population have not been reported. Based on the known relationships among irradiation, gene translocations, and leukemia, we postulate that this patient's chronic myelogenous leukemia may be a long-term sequela of previous total lymphoid irradiation.
Adult↗
Thymectomy for the myasthenia gravis patient: factors influencing outcome.
Thymectomy is a therapeutic option for patients with myasthenia gravis with moderate to severe disability. To document the efficacy of thymectomy coupled with medical therapy to treat this disease and to identify clinical factors that influence outcome, the clinical courses of all 46 patients (12 male and 34 female; mean age, 30 +/- 16 years) with myasthenia gravis who underwent thymectomy through a median sternotomy at a single institution over a 21-year period were reviewed. Clinical staging was determined preoperatively, at 1 month, 6 months, and 12 months postoperatively, and at last follow-up (mean time, 75 months postoperatively) using the Oosterhuis classification. Changes in severity of illness were graded as "deteriorated," "unchanged," "improved," or "much improved." Preoperative Oosterhuis classification was 3.3 +/- 1.1 and at last follow-up, 1.4 +/- 1.2 (p = 0.022). At last follow-up, 40 patients (87%) were in the improved or much improved category, and 6 patients were in the deteriorated or unchanged category. Status at 1 month, 6 months, and 12 months after operation predicted outcome at last follow-up visit (p = 0.007, p = 0.005, and p = 0.001, respectively). Clinical factors that positively influenced outcome were age less than 45 years (p = 0.004), female sex (p = 0.0309), and preoperative stage (p = 0.021).
Acetylcholine↗
Successful treatment of invasive bronchial aspergillosis after single-lung transplantation.
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Adult↗
Induction of acidic fibroblast growth factor and full-length platelet-derived growth factor expression in human cardiac allografts. Analysis by PCR, in situ hybridization, and immunohistochemistry.
BACKGROUND: Further understanding of cardiac allograft vasculopathy (CAV) is needed to improve long-term survival after cardiac transplantation. The diffuse hyperplasia of coronary intima characteristic of CAV suggests that growth factors may play a role in the development of CAV. Fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are potent mitogens for smooth muscle cells (SMCs), and PDGF is an important cofactor in the pathogenesis of native coronary atherosclerosis. METHODS AND RESULTS: Reverse transcriptase/polymerase chain reaction (RT/PCR), in situ hybridization, and immunohistochemistry were used to determine whether transplantation results in increased cardiac expression of acidic (a) FGF, basic (b) FGF, and PDGF-A and -B chains. Sixty-eight myocardial biopsies from 36 heart transplant recipients and 7 normal hearts were analyzed by PCR. aFGF mRNA was present in 54 of 61 allograft biopsies and was not found in any normal heart. In situ hybridization and immunohistochemistry demonstrated diffuse, intense expression of a FGF mRNA and protein in allograft biopsies, predominantly in myocytes and vascular walls. Only scattered aFGF expression was observed in normal hearts. mRNA for the full-length isoform of PDGF-A chain was found in 43 of 61 allograft biopsies and was not detected in any normal heart. In situ hybridization and immunohistochemistry confirmed that full-length PDGF-A chain mRNA and PDGF protein were present in myocytes and vascular walls. CONCLUSIONS: Expression of aFGF and PDGF-A chain is significantly increased in cardiac allografts. Cardiac myocytes and vascular walls are the predominant sources of aFGF and PDGF. Diffuse expression of these growth factors in cardiac allografts may be important in the pathogenesis of CAV.
Adult↗
Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection.
Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV.
Adolescent↗
Analysis of blunt and penetrating injury of the innominate and subclavian arteries.
Injury to the innominate or subclavian artery is an uncommon but difficult management problem. Review of trauma admissions from August 1983 to August 1992 revealed 21 patients who sustained injury to the innominate or subclavian artery. Eight patients sustained blunt trauma, while 13 patients sustained penetrating injuries. The mechanism of injury was variable, and associated injuries were common in both blunt and penetrating trauma. Injuries involved the right innominate or subclavian artery in 10 patients and the left subclavian artery in 11 patients. Twenty patients were managed operatively. Primary repair was preferred for penetrating injuries, whereas a bypass graft was more common for blunt injuries (P = 0.41). Patients with penetrating injury were more unstable at presentation (admission systolic blood pressure 73 mm Hg vs 119 mm Hg, P = 0.006; preoperative evaluation time 66 min vs 319 min, P = 0.002) and required more blood transfusions (5 units vs 26 units, P = 0.007) than patients with blunt injuries. Mortality for the entire series was 24 per cent (0% blunt vs 38% penetrating, P = 0.047). Hospital days (28 vs 48) and ICU days (8 vs 14) were longer for survivors of penetrating injuries (P = NS). Complications were common in both groups. Innominate/subclavian artery injury remains a significant cause of mortality and morbidity.
Adolescent↗
Single lung transplantation: a temporal look at rejection, infection, and survival.
Single lung transplantation (SLT) has emerged as routine therapy for selected patients with end-stage lung disease. This study examines the incidence of rejection, infection, and survival during the first posttransplant year. Twenty-one patients (12 male, 9 female; mean age 46 +/- 13 years) underwent 23 SLT procedures (12 left, 11 right lung). Indications were pulmonary fibrosis in six, emphysema in seven, primary pulmonary hypertension in three, Eisenmenger's syndrome in one, pulmonary veno-occlusive disease in one, a-1 antitrypsin deficiency in two, CREST syndrome in one, and retransplantation (graft failure and bronchiolitis obliterans) in two. All were maintained on triple immunotherapy. Survival at 1 year was 100%. The five patients with preoperative pulmonary hypertension had normal hemodynamics at follow up. Freedom from event at 1 year was rejection 23 per cent, all infections 6 per cent, viral 40 per cent, bacterial 55 per cent, fungal 74 per cent. At 1 year, cumulative incidence (events/patient-year) was rejection 1.61, all infections 2.18, viral 0.78, bacterial 1.12, fungal 0.28. Two of 21 patients have developed bronchiolitis obliterans at 1 and 2 years posttransplant. SLT provided safe, effective treatment for a wide variety of end-stage lung diseases. Rejection and infection, although common, may be safely treated with resolution.
Actuarial Analysis↗
Third-time coronary artery bypass grafting: midterm results.
Minimal data are available regarding the results of patients who have undergone myocardial revascularization more than twice. The records of 13 consecutive patients who underwent a coronary artery bypass procedure for the third time were reviewed. The indication for operation was unstable angina in all patients. All patients were placed on cardiopulmonary bypass through a median sternotomy. The mean number of bypass grafts placed at the third operation was 1.9 (range, 1 to 3 grafts). A new internal mammary artery graft was placed in 6 patients (2 had prior internal mammary artery grafts). Hospital mortality was 7.7% (1/13). The single death was due to incomplete revascularization in a patient with poor distal vessels. Three patients required intraaortic balloon pump support postoperatively, and 2 patients had prolonged ventilatory insufficiency. There have been no late deaths. The 12 survivors have been followed up a mean of 44 months (range, 6 to 90 months). Four remain asymptomatic; 5 have mild angina easily controlled with medication. All except 1 are in improved condition compared with their preoperative status. We conclude that a third myocardial revascularization can be performed with low mortality and morbidity and with the expectation of long-lasting symptomatic improvement.
Aged↗
Cytomegalovirus disease after heart transplantation: is acyclovir prophylaxis indicated?
To determine the efficacy of acyclovir prophylaxis in preventing cytomegalovirus (CMV) disease after heart transplantation, the clinical course of 103 patients (ages, 0.1 to 62 years; mean age, 41.8 years; 87 males, 16 females) was analyzed. Active CMV infection (defined as a positive culture from any site or a fourfold increase in immunoglobulin G antibody titers) occurred in 64% (66/103) and clinical CMV disease (defined as pathologic evidence of CMV in tissue biopsy or a typical CMV syndrome with fever and two of the following: leukopenia, thrombocytopenia, atypical lymphocytes, and elevated liver function test results in a patient with CMV infection) occurred in 25% (26/103). Independent variables studied included acyclovir prophylaxis, duration of acyclovir use, duration and type of induction therapy, donor and recipient CMV status, total steroid dose at 3 and 6 months, azathioprine dose and cyclosporine level at 3 months, age, and sex. In a multivariate regression analysis, acyclovir prophylaxis was independently associated with freedom from CMV disease (p = 0.029). Positive donor CMV status (p = 0.025), higher total steroid dose at 3 months (p = 0.036), and lower azathioprine dose at 3 months (p = 0.047) were associated with higher occurrence of CMV disease. The use of antilymphocyte induction therapy was associated with an increased occurrence of active CMV infection (p = 0.022) but not CMV disease. The prophylactic administration of acyclovir reduced the occurrence of CMV disease after heart transplantation.
Acyclovir↗
Aortobronchial fistula after unilateral lung transplantation.
An aortobronchial fistula resulting in massive hemoptysis developed in a 48-year-old man 13 months after unilateral lung transplantation. His posttransplantation recovery was complicated by bronchial dehiscence requiring revision and subsequent stricture formation treated by granulation tissue excision, placement of endobronchial stents, dilation, and laser photoablation. Early and aggressive treatment using these modalities is necessary in the successful management of airway complications after pulmonary transplantation.
Aorta, Thoracic↗
Determinants of heart-lung transplantation outcomes: results of a consensus survey.
Substantial progress has been made in clinical heart-lung transplantation. Although outcomes vary across centers, 1-year patient survival is now 59%. This study was an attempt to assess consensus among transplant program directors regarding the major determinants of patient outcome. In the National Cooperative Transplantation Study we evaluated consensus through a survey of all heart-lung transplant programs active in 1988. Of the eligible programs, 23 (85%) returned completed surveys. Data on the medical and surgical determinants of outcome were analyzed. There was considerable consensus among program directors as to the importance of several factors. The three most critical predictors of favorable outcomes were periodic pulmonary function tests to detect rejection (85.7%), avoidance of use of prednisone during the first 14 days after transplantation (76.2%), and annual left and right heart catheterization with coronary arteriography (76.2%). Several approaches were considered undesirable or unnecessary. These included electrocardiogram as standard rejection monitoring technique (71.4%), cytoimmunological monitoring as standard rejection monitoring technique (66.7%), and routine steroid discontinuation after transplantation (66.7%). On various other treatment approaches there was little evidence of consensus. These included prophylaxis with acyclovir and severe bronchiolitis as a criterion for retransplantation. Although controversial, consensus conferences are one means by which to evaluate technological innovations. Based on their results, practice guidelines can be developed to better inform third-party payers on issues related to transplantation.
Data Collection↗