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Biomedical subjects

D G Renlund

Publications and source records attributed to D G Renlund.

At least 19 recordsLinked to original sources
PubMed1992

A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.

BACKGROUND: Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. METHODS: This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. RESULTS: Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. CONCLUSIONS: The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

Adolescent↗
PubMed1992

Mediastinitis in heart transplantation.

Between March 1985 and December 1991, mediastinitis developed in 12 of 420 cardiac transplantation patients (2.8%). The mortality rate in this group of patients was 8.3% (1/12). Actuarial survival (1 year, 75%; and 5 years, 65%) was not significantly different from that of the group without mediastinitis (1 year, 88%; and 5 years, 75%). A higher percentage of the patients in the group with mediastinitis were listed as UNOS status 1 (50% versus 35%) and had a history of previous sternotomies (58% versus 44%). The presentation of mediastinitis was typical. Computed tomographic scanning with or without aspiration was a valuable adjunct in the diagnosis of mediastinitis. Induction immunotherapy with minimal steroids in the perioperative period was used in all patients. This may contribute to the patients' ability to mount an appropriate and effective response to infection, permitting earlier diagnosis. The debridement irrigation technique used in 8 of 12 patients had a low success rate of 33%, whereas the debridement muscle flap technique used in 4 of 12 was 100% successful in eliminating infection.

Actuarial Analysis↗
PubMed1992

Cardiac retransplantation: a viable option? The Registry of the International Society for Heart and Lung Transplantation.

To evaluate cardiac retransplantation as an appropriate utilization of scarce donor organs we analyzed data from the registry of the International Society for Heart and Lung Transplantation (ISHLT) (n = 449) and the Utah Cardiac Transplant Program (n = 20). Actuarial survival among retransplants was lower than in patients who received only one transplant in both the ISHLT registry patients (1 year survival, 48% versus 78%; p = 0.001) and the Utah series (1 year survival, 74% versus 88%; p = 0.06). Uncontrolled rejection, short interval (< 6 months) between transplantations, and the need for mechanical circulatory support were identified as risk factors for retransplantation. The incidence of rejection and infection was similar in first and second transplant recipients. Second transplant recipients had a higher level of sensitization, a greater incidence of donor-specific positive crossmatches, and an increased early mortality. Repetition in the second donor of mismatched HLA antigens present in the first donor did not adversely affect survival. If patients who underwent retransplantation within 6 months of their initial transplantation, those receiving transplants for uncontrolled rejection, and those requiring mechanical assistance were eliminated from the study, the short-term and long-term survival after cardiac retransplantation does not differ from that in patients having a single transplant.

Actuarial Analysis↗
PubMed1992

Outcome of cardiac transplant recipients with a positive donor-specific crossmatch--preliminary results with plasmapheresis.

To assess the influence of a positive T or B cell IgG crossmatch on the development of rejection and mortality following cardiac transplantation, we reviewed all cardiac transplants performed in Utah between March 1985 and October 1990. Of the 328 cardiac allograft recipients, 11 (3.4%) had an IgG positive crossmatch. Actuarial survival at 24 months in the positive crossmatch group was 57.3% +/- 0.02 while that of the controls was 86.1% +/- 2.1 (P < 0.05). Allograft rejection occurred earlier in recipients with a positive crossmatch (10.0 +/- 5.8 days versus 34.0 +/- 2.3 days, P < 0.001). The first allograft rejection episode in patients with a positive crossmatch was characterized by immunoglobulin and complement deposition in small blood vessels and interstitial edema and endothelial cell activation in the absence of a lymphocytic infiltrate. Furthermore, the allograft rejection in the positive crossmatch group was accompanied by hemodynamic compromise in a large proportion of the patients (73%). In addition to augmentation of immunosuppression, plasma exchange therapy was performed within the first week following transplantation in 8 of the 11 positive crossmatch patients. Survival in the patients treated with plasma exchange (75%) appears to be better than in those not receiving plasma exchange (33%) within one week of transplantation. While immunosuppressive therapy aimed at the humoral arm of the immune system and plasma exchange therapy may improve survival in recipients with a positive donor-specific crossmatch, survival is worse in patients with a positive crossmatch than in patients with a negative crossmatch. Thus, it would appear prudent to prospectively crossmatch cardiac transplant candidates with a greater risk of developing a positive crossmatch, such as those potential recipients with an elevated level of panel-reactive antibodies.

B-Lymphocytes↗
PubMed1991

Detection of allograft endothelial cells of recipient origin following ABO-compatible, nonidentical cardiac transplantation.

Endothelial cells serve an important role in augmenting immune responses through enhanced expression of MHC class II antigens. Immune-mediated vascular injury associated with rejection requires reendothelialization to restore vascular integrity. The origin of the reparative endothelial cells can be determined when ABO antigens expressed on these cells differ in the donor and recipient. To assess the frequency and significance of reendothelialization by recipient endothelial cells, we stained serial endomyocardial biopsies for ABO antigens in 34 (13%) compatible, nonidentical cardiac allograft recipients of 268 cardiac transplant procedures. In ten (30%) the allograft endothelial cells expressed the characteristics of the recipient (five partial and five complete) within 7.5 +/- 1.0 months (mean +/- SEM) after transplantation. Over 26.3 +/- 2.5 months follow-up no differences could be detected in pretransplant characteristics, allograft survival, survivor rejection morbidity, long-term allograft function, and presence of coronary vasculopathy between those whose endothelial cells expressed recipient blood group antigens and those who did not, which may merely be a reflection of the small sample size. This study indicates that recipient reendothelialization occurs frequently following cardiac transplantation and may result from immune-mediated vascular injury. The effect of recipient reendothelialization on allograft tolerance requires further investigation.

ABO Blood-Group System↗
PubMed1991

Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy.

BACKGROUND: We measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC). METHODS AND RESULTS: The results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles, IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast, compared with IDC right ventricles, isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol, indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition, relative to IDC left ventricles, preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation, indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles, ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right ventricles exhibited a "selective" (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC: CONCLUSIONS: These data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC, differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.

Adenylyl Cyclases↗
PubMed1991

Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy.

BACKGROUND: We investigated the effects of bucindolol, a nonselective, non-ISA beta-blocker with mild-vasodilatory properties, in patients with congestive heart failure from ischemic dilated cardiomyopathy (ISCDC, n = 27) and compared the results with those in subjects with heart failure from idiopathic dilated cardiomyopathy (IDC, n = 22). METHODS AND RESULTS: Patients were randomized in a double-blind fashion to receive 12 weeks' treatment with either bucindolol or placebo, with randomization stratified for IDC or ISCDC: Invasive (right heart catheterization) and noninvasive (echo, MUGA, central venous norepinephrine, exercise treadmill studies, and symptom scores) tests of heart failure severity were determined at baseline and end of the study. For all subjects (ISCDC plus IDC), relative to placebo treatment, bucindolol-treated patients had significant improvement in ejection fraction, left ventricular size and filling pressure, stroke work index, symptom score, and central venous norepinephrine. However, most of these differences could be attributed to improvement in the IDC subgroup, as the only parameter with a statistically significant degree of improvement in the bucindolol-treated ISCDC subgroup was left ventricular size. CONCLUSIONS: We conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.

Adrenergic beta-Antagonists↗
PubMed1991

Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors.

During a 3-year period we administered enoximone, a phosphodiesterase inhibitor with positive inotropic and vasodilator properties, to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects, all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone, whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-, 3-, and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%, 82.5%, and 82.5% compared with 92.1%, 83.8%, and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone, ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists, total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists, but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally, patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher, p less than 0.01) or with (65% higher, p less than 0.01) intravenous beta-adrenergic agonists. Finally, isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists, suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.

Adult↗
PubMed1990

Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo.

PURPOSE: Bucindolol is a potent nonselective beta-blocking agent with vasodilatory properties. In this study, we evaluated the effects of long-term bucindolol therapy in the treatment of heart failure from idiopathic dilated cardiomyopathy. PATIENTS AND METHODS: Patients were eligible for enrollment if they had symptomatic heart failure, idiopathic dilated cardiomyopathy, and left ventricular ejection fraction less than 0.40. All patients received an initial test dose of 12.5 mg bucindolol orally every 12 hours for two or three doses. Patients tolerating the test dose were randomly assigned (double-blind) to receive bucindolol or placebo in a 3:2 ratio. Study medication was begun at a dose of 12.5 mg orally every 12 hours and gradually increased over a 1-month period until either a maximum tolerated dose or a target dose of 100 mg every 12 hours was reached. Study medication was then continued for an additional 2 months. RESULTS: A total of 24 patients were enrolled into the study. Twenty-three patients tolerated bucindolol test challenge; 14 were randomized to receive bucindolol, and nine were randomly assigned to receive placebo. The placebo group (age 56 +/- 2 years) was significantly older than the bucindolol group (46 +/- 3 years), but by all other clinical and hemodynamic parameters the two groups were comparable. Twenty-two of 23 patients completed the study. Patients treated with bucindolol had significant improvements in clinical heart failure symptoms and in resting hemodynamic function, including an increase of left ventricular ejection fraction (0.26 +/- 0.02 to 0.35 +/- 0.09, p = 0.003), cardiac index (2.2 +/- 0.1 to 2.5 +/- 0.4 L/minute/m2, p = 0.014), and left ventricular stroke work index (25 +/- 3 to 35 +/- 7 g.m/m2, p = 0.002) and a decrease in pulmonary artery wedge pressure (17 +/- 3 to 10 +/- 5 mm Hg, p = 0.005) and heart rate (86 +/- 3 to 75 +/- 9 beats/minute, p = 0.012). Patients treated with bucindolol also had a significant increase in exercise left ventricular ejection fraction (0.26 +/- 0.03 to 0.32 +/- 0.14, p = 0.015) and reduction in questionnaire-measured symptoms (p = 0.007) and New York Heart Association functional class (p less than 0.001). However, total treadmill exercise duration and maximal oxygen consumption with exercise did not change. No changes in rest or exercise parameters were observed in the placebo-treated group. Central venous plasma norepinephrine concentration decreased significantly in the bucindolol-treated group (423 +/- 79 to 212 +/- 101 pg/mL, p = 0.010), but was unchanged in the placebo-treated group. CONCLUSION: Bucindolol is well tolerated in patients with idiopathic dilated cardiomyopathy and congestive heart failure, and therapy for 3 months is associated with improved resting cardiac function, improved heart failure symptoms, and a reduction in venous norepinephrine concentration.

Adrenergic beta-Antagonists↗
PubMed1990

A randomized trial of the immunosuppressive efficacy of vincristine in cardiac transplantation.

We evaluated the efficacy of the addition of the lymphoblasticidal agent vincristine to standard immunosuppression in heart transplantation in a prospective randomized study of 92 patients (46 to receive and 46 to not receive vincristine) with a follow-up period of 12 months. Patients received either equine antithymocyte globulin for the first week or OKT3 monoclonal antibody (OKT3) for the first 10 or 14 days after transplantation. Six to eight doses of vincristine were given over 9-12 weeks, beginning 2 days after completion of ATG or OKT3. The number of rejection episodes in the first six months posttransplantation, the percentage of patients corticosteroid maintenance-free at one year, cumulative immunosuppressive drug doses, deaths, infections, and neuropathy were followed. The addition of vincristine resulted in more patients achieving corticosteroid maintenance-free status at one year (vincristine 68%, no vincristine 38%, P = 0.01). In comparing patients at relatively high risk for rejection (those younger than 55 years and all females) with those at relatively low risk (males older than 55 years), only the high-risk vincristine-treated patients showed significantly fewer rejection episodes and a higher corticosteroid maintenance status at one year (66% vs. 32%, P = 0.01). There were no significant differences in survival (vincristine 96%, no vincristine 98%), infection, or amounts of other immunosuppressive agents used. The major side effect was neuropathy, which occurred more frequently in the vincristine-treated group (43% vs. 18%, P less than .001). We conclude that vincristine acts as an immunosuppressive agent in cardiac transplantation, particularly in patients at higher risk for rejection.

Cyclosporins↗
PubMed1990

Methotrexate as an adjunct in the treatment of persistent mild cardiac allograft rejection.

Because methotrexate arrests inflammation in autoimmune disease, we studied its efficacy in persistent low-grade cardiac allograft rejection. Seventeen patients aged 39.5 +/- 0.9 years (mean +/- SE) had persistent rejection despite previous therapy with high dose corticosteroids. Maintenance immunosuppression consisted of prednisone, azathioprine, and cyclosporine. The rejection episode treated with methotrexate occurred 180 +/- 55.4 days posttransplantation. Patients had incurred 2.7 +/- 0.3 previous episodes of rejection with the first episode occurring 30.6 +/- 6.2 days post transplant. Methotrexate was administered orally in 3 doses to an average weekly dose of 12.8 +/- 0.8 mg. The duration of methotrexate therapy was 9.0 +/- 1.1 weeks. Sixteen of the seventeen persistent rejection episodes resolved by 22.8 +/- 3.2 days of methotrexate therapy. Using methotrexate, the prednisone dose was decreased from 22.4 +/- 4.8 mg/day at initiation of methotrexate to 9.7 +/- 1.4 mg/day at the completion of methotrexate therapy (P less than 0.01). Over a 306 +/- 35-day follow-up, 9 of 17 patients (53%) have remained rejection-free. Leukopenia, necessitating reduction in azathioprine occurred in 10 patients. One patient developed herpes zoster during therapy. These data indicate that methotrexate is effective in resolving persistent cardiac allograft rejection with minimal morbidity. In addition, the use of methotrexate for treatment of rejection allows reduction in maintenance corticosteroid doses.

Adult↗
PubMed1990

Relationship of OKT3 sensitization and vascular rejection in cardiac transplant patients receiving OKT3 rejection prophylaxis.

We prospectively and serially monitored plasma levels of OKT3 in 20 patients who were receiving 14- or 21-day rejection prophylaxis with OKT3. We retrospectively compared plasma OKT3 levels with biopsy scores assessed by light microscopy and immunofluorescence, clinical findings, human antimouse antibody (HAMA) production assessed by a blocking assay and by ELISA, and circulating immune complex levels assessed by a flow cytometric Raji cell assay. Using these methods, we evaluated the relationship of OKT3 sensitization, a humorally mediated immune response, to the development of vascular rejection in these patients. We found that 6 of 20 patients had declines in plasma OKT3 levels to less than 50% of their steady-state value before the conclusion of therapy (OKT3 consumption). This fall in plasma OKT3 preceded a significant rise in the CD 3 lymphocyte level by up to 3 days. All 6 patients showed HAMA production by either blocking or ELISA assay (P = less than 0.02) and developed vascular rather than cellular rejection (P = less than 0.01). OKT3 sensitization was significantly more common in patients treated with 21-day rejection prophylaxis (4 of 6 patients, P = less than 0.01). Only 4 of 14 other patients showed vascular rejection; 2 of these 4 also developed HAMA without OKT3 consumption and both had been treated with 21-day rejection prophylaxis with OKT3. None of the 20 patients showed significant levels of circulating immune complexes. This study demonstrates that OKT3 sensitization is strongly associated with vascular rejection. Vascular rejection was usually demonstrated 7 days after OKT3 consumption was seen and was coincident with HAMA production. By contrast, 4 patients without OKT3 sensitization had vascular rejection demonstrable in the early posttransplant period; in such patients, prospective immunofluorescence of biopsies was the only reliable indicator of this rejection type. The higher incidence of vascular rejection in these 20 patients was definitely related to the use of 21-day OKT3 rejection prophylaxis. Overall, 7 of the 12 patients treated with this regimen developed vascular rejection. Allograft and patient survival among patients with vascular rejection was significantly worse than in patients with cellular rejection (P = less than 0.01). Prospective monitoring of patients treated with OKT3 by serial plasma levels and by biopsy immunofluorescence will identify patients at risk for these types of humoral rejection.

Antibodies, Anti-Idiotypic↗
PubMed1990

Interaction between left ventricular end-diastolic and end-systolic volumes in normal humans.

The extent to which the end-systolic volume (ESV) "follows" the end-diastolic volume (EDV) when the latter changes in response to various perturbations is a major determinant of the cardiac ejection fraction (EF) and has not been studied in humans. We measured EDV, ESV, and EF, determined by gated blood pool scans, during a change in posture from the supine to the upright seated position and during graded upright bicycle exercise. The experimental group consisted of 119 healthy individuals (79 males and 40 females) ranging in age from 21 to 81 yr and in physical-conditioning status (75-225 W maximum work load); rigorous screening excluded cardiac disease. Multiple regression analysis showed that the change in ESV (delta ESV) during a postural shift or during graded exercise was highly statistically correlated with the change in EDV (delta EDV) that occurred (r2 ranged from 0.34 to 0.49, correlation is positive) regardless of age, sex, or exercise work load. The correlation of delta ESV with delta EDV observed in this large sample, heterogeneous with respect to age, sex, and physical fitness, was also present in additional 31 subjects who exercised during beta-adrenergic blockade (propranolol 0.15 mg/kg). The delta EF with posture change and exercise in all subjects under all conditions was highly and inversely correlated with the delta ESV (r2 ranged from 0.38 to 0.81). Thus the delta ESV during the circulatory adaptive response to orthostatic and exercise stresses in humans is related to the delta EDV, and this relationship modulates the delta EF in response to these stresses.

Adult↗