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Biomedical subjects

D G Renlund

Publications and source records attributed to D G Renlund.

At least 37 records · Page 2Linked to original sources
PubMed1996

Improved long-term survival after heart transplantation predicted by successful early withdrawal from maintenance corticosteroid therapy.

BACKGROUND: Short-term studies suggest that cardiac transplant immunosuppression without maintenance corticosteroids is feasible in selected patients. However, concern exists as to the long-term effects, specifically the possibility of increased morbidity and mortality because of late allograft rejection and allograft coronary artery disease. METHODS: We retrospectively reviewed the records from 441 consecutive heart transplantation procedures done in 416 patients with use of an immunosuppressive protocol that attempted corticosteroid withdrawal within 2 months of transplantation. forty-two patients died or underwent retransplantation during the first 3 months and were excluded from further analysis. Analysis focused on demographic and long-term outcome variables (including death, rejection, retransplantation, and infection). RESULTS: Thirty percent (111) of eligible patients (374) met the definition of successful early steroid withdrawal. Only male gender independently predicted successful withdrawal. Mortality, both short and long term, was significantly lower in patients in whom successful early withdrawal from corticosteroids was achieved than in patients in whom the early attempts failed (1.7% per year versus 4.7% per year; p < 0.0001). The prevalence of late acute allograft rejection (more than 1 year after transplantation) was lower in patients successfully withdrawn from steroid therapy early after transplantation (0.07 pt-yr of follow-up versus 0.15 pt-yr; p = 0.002). Multivariate analysis of the entire group identified incidence of infection (p = 0.001), older age (p = 0.001), failed early steroid withdrawal (p = 0.006), and female gender (p = 0.016) as independent predictors of mortality. CONCLUSIONS: Successful early corticosteroid withdrawal identifies a subgroup of "immunologically privileged" patients with a low risk for long-term mortality and is not associated with an increased prevalence of late rejection or clinically significant coronary artery disease.

Case-Control Studies↗
PubMed1996

Cyclophosphamide in cardiac transplant recipients with frequent rejection: a six-year retrospective review.

Allograft rejection remains a major cause of morbidity and mortality. Cyclophosphamide, a nitrogen mustard, is a potent immunosuppressive agent with effects on both T- and B-lymphocytes, and thus may be effective in preventing further cellular and/or humoral rejection in cardiac transplant recipients with recurrent or recalcitrant rejection. We retrospectively reviewed the records of 320 surviving cardiac transplant recipients. Cyclophosphamide was substituted for azathioprine in 28 patients because of frequent allograft rejection. We then reviewed the rejection history of these 28 patients, specifically looking at rejection frequency, type (cellular, vascular or mixed), and treatment. Cyclophosphamide was substituted for azathioprine at an average of 8.4 +/- 2.8 months after transplantation. Despite a 56.0% reduction in prednisone dose (p < 0.001), at least a threefold reduction in rejection frequency (p < 0.001) was observed, while cyclosporine levels were unchanged. Twenty-eight percent of the patients did not experience even mild rejection after beginning therapy with cyclophosphamide, 55% had 1 or 2 subsequent mild or moderate rejection episodes, and only 17% had more than two subsequent episodes of mild or moderate rejection. Overall, the number of treated rejection episodes decreased from 0.37 episodes per patient month with azathioprine to 0.10 episodes per patient month on therapy with cyclophosphamide. Separating the patients into two groups based on the predominant rejection type (cellular vs. vascular) occurring at the time of cyclophosphamide substitution revealed a similar reduction in cellular and vascular rejection in each respective group. While white blood cell count decreased by 16%, cyclophosphamide was not discontinued in any patient due to leukopenia, and no change was noted in hematocrit. Cyclophosphamide appears to be safe and effective in maintenance immunosuppression and may reduce rejection frequency in some patients with frequently occurring allograft rejection without necessitating the augmentation of either corticosteroids or cyclosporine.

Azathioprine↗
PubMed1995

Left ventricular mass increases during cardiac allograft vascular rejection.

OBJECTIVES: This study evaluated whether left ventricular mass increases during cellular or vascular (humoral) cardiac allograft rejection. BACKGROUND: An increase in left ventricular mass during cellular cardiac allograft rejection has been described by other investigators, although controversy has existed over the validity of these findings. Left ventricular mass changes have not been evaluated in the setting of vascular (humoral) cardiac allograft rejection. METHODS: To determine the effect of allograft rejection on left ventricular mass, we retrospectively reviewed endomyocardial biopsy results and corresponding echocardiograms in 41 cardiac transplant recipients undergoing treatment for allograft rejection. Left ventricular mass was assessed by two-dimensional echocardiography using the method of Schiller. Maintenance immunosuppression included cyclosporine in all patients. RESULTS: Although significant changes in left ventricular wall thickness, mass and dimensions were not observed in patients experiencing moderate or severe cellular allograft rejection (International Society for Heart and Lung Transplantation grades III and IV, n = 27), marked changes were noted in patients with vascular (humoral) rejection (n = 14). Patients with vascular rejection demonstrated an echocardiographic mean (+/- SEM) increase in left ventricular wall mass (from 109 +/- 17 to 151 +/- 17 g), and left ventricular wall thickness (from 1.3 +/- 0.1 to 1.6 +/- 0.1 cm) during the rejection episode. Additionally, vascular rejection was associated with a trend toward an increase in left ventricular systolic dimension (from 2.6 +/- 0.1 to 3.0 +/- 0.2 cm) and a decrease in left ventricular fractional shortening and increased incidence of hemodynamic compromise with rejection (50% for vascular vs. 11% for cellular rejection). CONCLUSIONS: Left ventricular mass increases during episodes of vascular (humoral) rejection, but there is no significant change in left ventricular mass during cellular cardiac allograft rejection.

Adult↗
PubMed1995

Evidence that human cardiac allograft acceptance is associated with a decrease in donor-reactive helper T lymphocytes.

We have reported that acute cardiac allograft rejection is associated with increased numbers of donor-reactive helper T lymphocytes (HTL) in the peripheral blood of patients. Further, increased frequencies of circulating donor-reactive HTL may predict allograft rejection episodes diagnosed by endomyocardial biopsy. The present study evaluates the relationship between donor-reactive HTL and allograft "acceptance" in cardiac transplant recipients bearing long-term allografts (> 1 year). Patients were categorized as either long-term acceptors or persistent rejecters based on the number of rejection episodes and the ability to withdraw steroid therapy. Limiting dilution analysis for IL-2-producing HTL was utilized, with cadaver donor splenocytes as a source of donor alloantigens. Donor-reactive HTL frequencies were determined from peripheral blood samples obtained before transplant, and at 1 month and 1 year after transplant. Individuals who accommodated their allografts and were withdrawn from steroid therapy had reduced numbers of donor-reactive HTL at 1 year after transplant as compared with earlier time points. Further, PBMC obtained from these individuals at 1 year after transplant responded weakly to donor alloantigens in a mixed lymphocyte response (MLR). This relationship between donor-reactive HTL and allograft accommodation was exemplified in a cardiac/liver transplant patient who was diagnosed with progressive multifocal leukoencephalopathy and removed from all immunosuppression. No subsequent rejection episodes were diagnosed. Donor-reactive HTL were not detectable and this individual failed to mount an MLR to donor alloantigens. However, a vigorous donor-reactive response was observed when MLR cultures were supplemented with exogenous IL-2. Therefore, nonresponsiveness to the allograft appeared to be due to a deficit in IL-2 production. In contrast, patients who experienced persistent rejection episodes and required continued steroid therapy maintained large numbers of donor-reactive HTL at 1 year after transplant. PBMC from these individuals responded vigorously to donor alloantigens in an MLR. Hence, monitoring donor-reactive HTL may identify individuals who have accommodated their graft and may tolerate a reduction in immunosuppression.

Graft Rejection↗
PubMed1995

Tricuspid valve dysfunction in the transplanted heart.

Mild degrees of tricuspid regurgitation are common in the orthotopically transplanted heart, probably secondary to the geometry of the right atrial anastomosis. At the University of Utah, 5 (0.95%) of 526 patients with transplantations performed from March 1985 to December 1993 have presented with severe tricuspid regurgitation requiring operative intervention. Echocardiographic findings confirmed at the time of operation consisted of ruptured chordae to the tricuspid valve. Standard tricuspid valve repair and replacement techniques were used with good results. We postulate the chordal disruption found in these patients is secondary to injuries incurred at the time of endomyocardial biopsy.

Adult↗
PubMed1995

Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study.

OBJECTIVES: This study assessed the safety and efficacy of carvedilol in patients with heart failure caused by idiopathic or ischemic cardiomyopathy. BACKGROUND: Carvedilol is a mildly beta 1-selective beta-adrenergic blocking agent with vasodilator properties. Beta-blockade may be beneficial in patients with heart failure, but the effects of carvedilol are not known. METHODS: Sixty patients with heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction < or = 0.35 were enrolled in the study. All patients tolerated challenge with carvedilol, 3.125 mg twice a day, and were randomized to receive carvedilol (n = 36) versus placebo (n = 24). Study medication was titrated over 1 month from 6.25 to 25 mg twice a day (< 75 kg) or 50 mg twice a day (> 75 kg) and continued for 3 months. One placebo-treated and two carvedilol-treated patients did not complete the study. RESULTS: Carvedilol therapy resulted in a significant reduction in heart rate and mean pulmonary artery and pulmonary capillary wedge pressures and a significant increase in stroke volume and left ventricular stroke work. Left ventricular ejection fraction increased 52% in the carvedilol group (from 0.21 to 0.32, p < 0.0001 vs. placebo group). Carvedilol-treated patients also reported a significant lessening of heart failure symptoms (p < 0.05 vs. placebo group). Submaximal exercise duration tended to increase with carvedilol therapy (from 688 +/- 31 s to 871 +/- 32 s), but this change was not significantly different from that with placebo therapy by between-group analysis. Peak oxygen consumption during maximal exercise did not change. CONCLUSIONS: Long-term carvedilol therapy improves rest cardiac function and lessens symptoms in patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed1995

Method for isolation of human ventricular myocytes from single endocardial and epicardial biopsies.

The study of adult human ventricular cells has been limited by tissue availability. In this study we describe techniques for the isolation of Ca(2+)-tolerant adult human ventricular cells from both transvenous endomyocardial and epicardial biopsies. Ca(2+)-tolerant cells were obtained from 80% of the biopsies processed. Although the yield of Ca(2+)-tolerant myocytes from either type of biopsy was low (1-5%), myocytes with normal resting potentials and action potentials can be obtained from single biopsy specimens, providing a source of normal human myocytes for electrophysiological study. Resting potentials (Vrest) were recorded in 41 isolated right ventricular endomyocardial cells at 37 degrees C. Sixteen cells were depolarized (Vrest = -26 +/- 13 mV), and 25 cells had normal resting potentials (Vrest = -84 +/- 6 mV). Action potentials were recorded in 16 cells. At a pacing cycle length of 1 s, 4 cells had prolonged action potential duration at 90% (APD90, 718 +/- 26 ms) and 10 cells had normal APD90 (381 +/- 94 ms) compared with those recorded from intact right ventricular septal trabeculae from explanted hearts. Voltage-clamp studies of isolated human ventricular myocytes obtained from these biopsies document the presence of currents previously reported from cells isolated from explanted hearts.

Animals↗
PubMed1994

Cardiac transplantation: 2. Life with a new heart.

Most postoperative needs can be handled by the primary care physician. In particular, attention should be given to signs of allograft rejection, opportunistic infection, side effects from immunosuppressive agents, interactions between newly prescribed and established drugs, and immune-induced coronary artery disease.

Adult↗
PubMed1994

Cardiac transplantation: 1. From CHF to surgery.

Patients are often referred for transplantation prematurely, without a thorough workup or a trial of optimal medical therapy. The cause of heart failure symptoms may be as easy to correct as excessive salt or water intake. Moreover, careful drug manipulation can defer transplantation for up to 10 years in some cases.

Algorithms↗
PubMed1994

A prospective, randomized comparison of cyclophosphamide and azathioprine for early rejection prophylaxis after cardiac transplantation. Decreased sensitization to OKT3.

Humoral immune responses have been implicated in the pathogenesis of vascular rejection, allograft coronary artery disease, and sensitization to OKT3. Because cyclophosphamide (CP) is a potent suppressor of humoral immunity, we postulated that substituting cyclophosphamide for azathioprine (AZA) would be associated with a decrease in acute vascular rejection and sensitization to OKT3 in cardiac transplant recipients also receiving cyclosporine, corticosteroids, and perioperative OKT3. We prospectively randomized 119 patients to receive azathioprine (n = 61) or cyclophosphamide (n = 58) from the time of transplantation. Dosage was adjusted to target white blood cell (WBC) counts. At six weeks posttransplantation, cyclophosphamide was converted to azathioprine. Patients were followed for a mean of 321 +/- 16 days. At four weeks WBC (1000/mm3) was 9.2 +/- 0.4 (SEM) in the AZA group and 9.7 +/- 0.6 for the CP group (P = 0.4). No differences were noted between the CP and AZA groups in mean cellular grades of rejection (1.8 +/- 0.1 vs. 1.7 +/- 0.1), mean vascular grades of rejection (2.0 +/- 0.1 vs. 1.8 +/- 0.1), early treated rejection episodes (1.9 +/- 0.1 vs. 2.2 +/- 0.1) days to first treated cellular rejection (38 +/- 3 vs. 41 +/- 3), or the number of patients manifesting primarily vascular rejection (18 vs. 19). Major infections and survival did not differ between the two groups. Eight patients in the AZA group developed anti-OKT3 antibodies, whereas only one patient in the CP group did (P = 0.04). In the early posttransplant period cyclophosphamide decreases the incidence of sensitization to OKT3 and appears to be as effective as azathioprine in preventing both cellular and vascular rejection.

Antibody Formation↗
PubMed1994

Paternity by cardiac transplant recipients.

To assess whether children fathered by cardiac transplant recipients are at high risk of teratogenicity, cardiac transplant centers listed with the International Society for Heart and Lung Transplantation were surveyed. Paternities after transplantation by heart (n = 35) and heart-lung (n = 1) allograft recipients have resulted in 42 pregnancies (children's age 3.3 +/- 0.3 years). The fathers' age at conception was < 45 years in 40 (95%) and > 45 years in 2 (5%). Most fathers (86%) were enjoying an active and healthy lifestyle at the time of conception; one (2%) was on dialysis and listed for kidney transplantation due to nephrotic syndrome, 1 (2%) had asthma, 4 (10%) had allograft coronary disease (1 died while waiting for second heart transplant when the child was 2 months old), and 2 (5%) were retransplanted after the pregnancies. Immunosuppressive regimens were reported for 37 paternities; drug protocols at the time of conception were as follows: 25 (60%) CsA/prednisone/AZA, 6 (14%) CsA/prednisone, 4 (10%) CsA/AZA, and 2 (5%) AZA/prednisone. Twenty-six (62%) had received treatment for rejection episodes before conception; seven (17%) had received treatment for rejections since conception. Of the 42 children fathered by these recipients, 3 (7%) were preterm, 1 (2%) had a cleft palate and lip that have subsequently been corrected, 1 (2%) died from interruption of umbilical cord circulation at 24 weeks, and 1 (2%) whose father had familial cardiomyopathy was born with a cardiomyopathy that improved with time. Although the numbers are small, the available data suggest that paternity by cardiac transplant recipients may be safe.

Adult↗
PubMed1994

Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise.

The cardiovascular response to beta-adrenergic stimulation is markedly blunted with advancing age, and this blunting may underlie some of the prominent age-associated changes in the hemodynamic profile during dynamic exercise. To examine this hypothesis, we administered the nonselective beta-adrenergic receptor blocker propranolol (0.15 mg/kg IV) to 25 healthy normotensive men ages 28 to 72 years from the Baltimore Longitudinal Study of Aging (BLSA) immediately before maximal upright cycle ergometry with 99mTc gated cardiac blood pool scintigraphy. Their hemodynamic responses to exercise were compared with those of 70 age-matched healthy unmedicated male BLSA control subjects. The maximal cycle work rate achieved was similar in propranolol-treated men (158 +/- 32 W) and control subjects (148 +/- 32 W) and declined similarly with age in both groups. Hemodynamics at seated rest were not age-related in either group; however, propranolol-treated men had lower heart rates (HR), systolic blood pressure (SBP), ejection fraction, and cardiac index than control subjects but higher end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) by covariance analysis. At maximal effort, several striking age-drug interactions were evident: Propranolol caused a greater reduction in HR and greater increases in EDVI and stroke volume index (SVI) in younger than in older men. Hence, at maximal work rate, HR declined less with age in the propranolol group (0.46 versus 1.09 beats per minute per year, P < .05 by covariance analysis); EDVI and SVI decreased with age (0.27 and 0.48 mL/m2 per year, respectively) after propranolol compared with increases of 0.47 and 0.16 mL/m2 per year in control subjects, respectively, each P < or = .05 by covariance analysis. The left ventricular contractility index, SBP/ESVI, at exhaustion was reduced by propranolol to a greater extent in younger than older men. Thus, acute beta-adrenergic blockade reverses the age-associated ventricular dilation at end diastole and end systole observed during upright cycle exercise and blunts the decline in maximal HR and myocardial contractility. These data suggest that the age-associated declines in maximal HR and left ventricular contractility during vigorous exercise are manifestations of reduced beta-adrenergic responsivity with advancing age which is partially offset by exercise-induced ventricular dilation.

Adrenergic beta-Antagonists↗
PubMed1993

beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy.

Alterations in the myocardial receptor-G protein-adenylate cyclase (RGC) complex and cardiac adrenergic neurons in the failing human heart result in subsensitivity to beta-adrenergic stimulation. Pharmacologic interventions such as beta blockade may modify critical components of the RGC complex and partially restore the sensitivity of the beta-adrenergic pathway. Among the receptors coupled to the stimulatory (Gs) protein are the beta 1 and beta 2 receptors. Because of differences in receptor population and agonist (i.e., norepinephrine) affinity, the beta 1-receptor is the predominate adrenergic subtype regulating contractility in the nonfailing myocardium. Down-regulation occurs in the myocardial beta-receptor component of the RGC complex with mild-to-moderate and severe left ventricular dysfunction. However, abnormalities of the RGC complex vary with the etiology of heart failure; beta 1-receptor down-regulation is greater in idiopathic dilated cardiomyopathy than in post-infarction cardiomyopathy, while beta-receptor uncoupling is greater in post-infarction disease. In chronic heart failure, the adrenergic nervous system is activated in the heart and kidney. There is evidence that an increased cardiac norepinephrine concentration contributes to the decrease in beta 1-receptor density in heart failure. However, norepinephrine exposure is not the only factor responsible for regulating beta-adrenergic receptors in heart failure. Chronic beta blockade may improve hemodynamic and clinical response in patients with idiopathic dilated cardiomyopathy by protecting the myocardium from the cardiotoxic effects of increased catecholamines and by up-regulating the beta 1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1993

Up-regulation of beta 2-adrenergic receptors in previously transplanted, denervated nonfailing human hearts.

OBJECTIVES: The purpose of this study was to examine beta-adrenergic receptor signal transduction in denervated, previously transplanted human ventricular myocardium. BACKGROUND: In model systems, surgical denervation typically results in both presynaptic and postsynaptic supersensitivity in beta-adrenergic receptor pathways and alteration in G protein-mediated signal transduction. METHODS: We examined beta-adrenergic receptor signal transduction in the left and right ventricles removed from nine subjects with a previous transplant and surgical denervation 25 +/- 4 months after their first transplantation. Twenty-six hearts removed from organ donors served as control hearts. RESULTS: Total beta-adrenergic receptor density and stimulation of muscle contraction in isolated right ventricular trabeculae by the nonselective agonist isoproterenol were similar in the transplant and donor groups. Beta 1-receptor density was not different in the left ventricles of the two groups but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast, beta 2-receptor density was higher in transplant left and right ventricles relative to the respective values in donor ventricles by 33% in left ventricles and 97% in right ventricles (both p < 0.05). Isoproterenol, which in particulate fractions of human heart stimulates adenylyl cyclase primarily via beta 2-receptors, produced a greater increase in cyclic adenosine monophosphate generation in membranes prepared from transplant left ventricles and right ventricles compared with donors. In contrast, guanosine 5'-[beta,gamma-imido]triphosphate, sodium fluoride and forskolin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded similar degrees of adenylyl cyclase stimulation in the two groups, and both pertussis toxin- and cholera toxin-catalyzed adenosine diphosphate ribosylation were not altered in transplanted left ventricles. CONCLUSIONS: These data indicate that the transplanted human heart exhibits an up-regulation of functional beta 2-adrenergic receptors.

Adenylyl Cyclases↗
PubMed1993

Prevention of Pneumocystis carinii pneumonia in cardiac transplant recipients by trimethoprim sulfamethoxazole.

Pneumocystis carinii pneumonia (PCP) continues to cause significant morbidity in recipients of solid-organ transplants. While some programs administer trimethoprim-sulfamethoxazole (TMP-SMX) prophylactically following transplantation, a prospective determination of the safety and efficacy of TMP-SMX in cardiac transplant recipients has not previously been reported. We therefore prospectively randomized 58 cardiac transplant recipients to receive TMP (160 mg)-SMX (800 mg) twice daily either three days per week (group B), or seven days per week (group C), or to receive no treatment (group A). Treatment began 14 days after transplantation and continued for four months. Age, sex, preexisting pulmonary pathology and immunosuppressive protocols did not differ among the groups. Of 17 patients in the control group (A), 7 developed a clinical syndrome compatible with PCP, with the diagnosis histologically confirmed by bronchoalveolar lavage during the first four months following transplantation. In contrast, no patients in either the daily or intermittent therapy groups developed PCP during the study period (P < 0.005). Both doses of TMP-SMX were well tolerated, and discontinuation of therapy was not necessary in any patient. Total white blood cell count, azathioprine dose, and number of treated episodes of rejection per patient did not differ among the three groups. We conclude that TMP-SMX can safely and effectively be administered to prevent the occurrence of P carinii pneumonia during the first four months following cardiac transplantation.

Adult↗