Effect of barium and tetraethylammonium on membrane circulation in frog retinal photoreceptors.

We studied the influence of altered ionic conditions on the recycling of synaptic vesicle membrane in frog retinal photoreceptors using horseradish peroxidase to monitor synaptic activity and trace the fate of internalized membrane. The addition of 1.2 mM barium or 20 mM tetraethylammonium to isolated retinas maintained in Ringer's solution, changes the usual balance of membrane circulation in the rod cells; the cone cells are much less affected. Retrieval of synaptic vesicle membrane in the rods, which normally regenerates small vesicles, becomes mediated predominantly by large sacs and vacuoles ("cisternae"). Because these cisternae can be labeled with peroxidase, they appear to arise from endocytized membrane. Morphometric analysis suggests strongly that the cisternae are formed of circulating synaptic vesicle membrane. The effects of barium and tetraethylammonium can be inhibited by high extracellular potassium, by high intensity light, and by 5 mM cobalt. They seem likely to depend on potassium channels, though additional more complex mediation may also be involved. The alterations in membrane retrieval that we find are of interest in terms of the multiple pathways of membrane cycling now being uncovered. They open potential experimental approaches to the controls of this circulation. In addition, the findings extend our previous ones demonstrating that rod cells and cone cells differ in their responses to divalent cations in ways that seem likely to be of physiological importance.

Pericardial effusions after cardiac transplantation.

OBJECTIVES: The aim of this study was to determine the etiologic factors in the formation of significant pericardial effusion after orthotopic heart transplantation and to determine the association of pericardial effusion with survival. BACKGROUND: The formation of pericardial effusions has been well described after orthotopic heart transplantation, but the risk factors for development of effusions remain unclear. Rejection and cyclosporine have been cited as possible causes, but anatomic factors have not been studied. METHODS: We conducted a retrospective review of medical records and echocardiograms of 203 consecutive patients at one center, including ischemic time, incidence and severity of rejection, weight difference between donor and recipient and previous cardiac surgical history. Multivariate analysis was performed, and actuarial survival rate curves were calculated according to the Kaplan-Meier method. RESULTS: Eighteen (8.9%) of 203 transplant recipients developed moderate to large pericardial effusions. Forty-four percent of patients required pericardiocentesis, and 28% subsequently required pericardiectomy for management of the effusions. Multivariate analysis identified the presence of a positive weight difference between recipient and donor (recipient weight > donor weight) and the lack of previous median sternotomy as the most powerful predictors of effusion formation. No significant association was found with rejection. There was no difference in actuarial survival rate between patients with and without effusions. CONCLUSIONS: A positive mismatch in weight between recipient and donor and the absence of previous cardiac surgery are associated with the formation of significant pericardial effusions. Closer monitoring of these patients at risk may be warranted.

Angiography of potential cardiac donors.

OBJECTIVES: This retrospective review of organ donor records was designed to evaluate the practice of donor angiography in one organ procurement organization and determine the outcomes of angiography and its impact on the timing of the organ donation process. BACKGROUND: Concerns about transmission of atherosclerosis from donor to recipient have been heightened by the increasing prevalence of older donors. Guidelines that advocate the use of angiography in specific settings have been published, but no formal large-scale review has been performed. METHODS: For the period January 1993 through June 1997, we reviewed all New England Organ Bank records of donors between the ages of 40 and 65 including any from whom at least one solid organ was procured. Data abstracted included the presence of risk factors, timing of the evaluation process and angiographic findings. RESULTS: Coronary angiography was performed in 119 donors aged 40 and older; 64.7% of these hearts were transplanted. Thirty-eight hearts were transplanted from donors not subjected to angiography and outcomes were poorer compared with donors who underwent angiography. Advanced donor age was the only significant predictor of coronary artery disease. The duration of the procurement process was not prolonged by the performance of angiography. CONCLUSIONS: Donor coronary angiography does not complicate the donation process. Older donor age is the most powerful predictor of coronary artery disease and may explain prior observations of poorer outcome with older donor hearts. These factors should be considered when angiography is performed as part of the heart donor evaluation.

Adherence to national guidelines for drug treatment of suspected acute myocardial infarction: evidence for undertreatment in women and the elderly.

BACKGROUND: Evidence-based guidelines for the treatment of patients with acute myocardial infarction (AMI) have been published and disseminated by the American College of Cardiology and the American Heart Association. Few studies have examined the rates of adherence to these guidelines in eligible populations and the influence of age and gender on highly effective AMI treatments in community hospital settings. METHODS: Medical records of 2409 individuals admitted to 37 Minnesota hospitals between October 1992 and July 1993 for AMI, suspected AMI, or rule-out AMI, and meeting electrocardiographic, laboratory, and clinical criteria suggestive of AMI were reviewed to determine the proportion of eligible patients who received thrombolytic, beta-blocker, aspirin, and lidocaine hydrochloride therapy. The effects of patient age, gender, and hospital teaching status on the use of these treatments were estimated using logistic regression models. RESULTS: Eligibility for treatment ranged from 68% (n=1627) for aspirin therapy, 38% (n=906) for lidocaine therapy, and 30% (n=734) for thrombolytic therapy to 19% (n=447) for beta-blocker therapy. Seventy-two percent of patients eligible to receive a thrombolytic agent received this therapy; 53% received beta-blockers; 81% received aspirin; and 88% received lidocaine. Among patients ineligible for lidocaine therapy (n=1503), 20% received this agent. Use of study drugs was lower among eligible elderly patients, especially those older than 74 years (thrombolytic agent: odds ratio, 0.2; 95% confidence interval, 0.1 to 0.4; aspirin: odds ratio, 0.4, 95% confidence interval, 0.3 to 0.6; beta-blocker: odds ratio, 0.4; 95% confidence interval, 0.2 to 0.8). Female gender was associated with lower levels of aspirin use among eligible patients (odds ratio, 0.7; 95% confidence interval, 0.6 to 0.9); and there was a trend toward lower levels of beta-blocker and thrombolytic use among eligible women. CONCLUSIONS: Use of lifesaving therapies for eligible patients with AMI is higher than previously reported, particularly for aspirin and thrombolytic use in nonelderly patients. Lidocaine is still used inappropriately in a substantial proportion of patients with AMI. Increased adherence to AMI treatment guidelines is required for elderly patients and women.

Pitfalls in assessing the quality of care for patients with cardiovascular disease.

PURPOSE: There are no clinical performance measures for cardiovascular diseases that span the continuum of hospital through postdischarge ambulatory care. We tested the feasibility of developing and implementing such measures for patients with acute myocardial infarction, congestive heart failure, or hypertension. SUBJECTS AND METHODS: After reviewing practice guidelines and the medical literature, we developed potential measures related to therapy, diagnostic evaluation, and communication. We tested the feasibility of implementing the selected measures for 518 patients with myocardial infarction, 396 with heart failure, and 601 with hypertension who were enrolled in four major U.S. managed care plans at six geographic sites, using data from administrative claims, medical records, and patient surveys. RESULTS: Difficulties in obtaining timely data and small numbers of cases adversely affected measurement. We encountered 6- to 12-month delays, disagreement between principal discharge diagnosis as coded in administrative and records data (for 9% of myocardial infarction and 21% of heart failure patients), missing medical records (20% for both myocardial infarction and heart failure patients), and problems in identifying physicians accountable for care. Low rates of performing key diagnostic tests (e.g., ejection fraction) excluded many cases from measures of appropriate therapy that were conditional on test results. Patient survey response rates were low. CONCLUSIONS: Constructing meaningful clinical performance measures is straightforward, but implementing them on a large scale will require improved data systems. Lack of standardized data captured at the point of clinical care and low rates of eligibility for key measures hamper measurement of quality of care.

The direct effect of injectable cyclosporine and its vehicle, cremophor, on endothelial vascular cell adhesion molecule-1 expression. Ricinoleic acid inhibits coronary artery endothelial activation.

As in humans, rabbit coronary artery endothelium basally expresses vascular cell adhesion molecule-1 (VCAM-1). Treatment with parenteral cyclosporine (CsA) to prevent graft rejection in rabbits receiving heterotopic heart transplantation reduced VCAM-1 expression in coronary arteries not only in transplanted, but also in native rabbit hearts. To explore the mechanism of this effect, we co-incubated cultured human saphenous vein endothelial cells for 24 hr with CsA or its vehicle (containing polyoxyethylated castor oil, or Cremophor, and ethanol), at concentrations compatible with those achievable in plasma during administration of parenteral preparations of CsA. Cells were then stimulated with TNF alpha or IL-4 to induce VCAM-1 expression, assessed by a cell-surface enzyme immunoassay. Both CsA and vehicle inhibited IL-4-stimulated VCAM-1 expression in a dose-dependent manner (from [OD mU, mean +/- SEM] 230 +/- 5 to 165 +/- 3 for CsA 50 ng/ml, and to 181 +/- 6 for the corresponding vehicle concentration; P < 0.05 for both comparisons). To investigate whether this vehicle effect also occurs in vivo, we treated 9 New Zealand White rabbits with saline (n = 3), CsA (10 mg/kg/day, n = 3), or vehicle at corresponding doses (n = 3) for 6 weeks. Profiles of coronary arteries (> or = 48 for each group) were semiquantitatively scored (0-5) for VCAM-1 in immunostained heart cross-sections. Administration of both CsA and vehicle significantly reduced VCAM-1 expression compared with saline. Two vehicle components, ethanol and ricinoleic acid, were further evaluated directly on endothelial cells in vitro. While ethanol was ineffective, the monounsaturated fatty acid ricinoleic acid inhibited IL-4-stimulated VCAM-1 expression in a dose-dependent manner (IC50 between 10 and 100 microM). Thus, a fatty acid component of CsA vehicle exerts direct endothelial effects, potentially limiting arterial leukocyte recruitment during parenteral CsA treatment. This observation reveals a novel mechanism for CsA as an inhibitor of leukocyte-endothelial interactions, and furnishes a new potential rationale for the therapeutic action of unsaturated fatty acids in graft coronary disease.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Bradycardia: a late complication following cardiac transplantation.

Symptomatic bradycardia occurred in 11 of 213 patients (5.2%) surviving > 1 year after orthotopic heart transplantation, most of whom were managed with permanent pacemakers. Evidence for sinus and/or atrioventricular node dysfunction was present in many cases, but patients at risk for this complication could not be predicted from baseline clinical characteristics.

Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Fatal hyperthyroidism after amiodarone treatment and total lymphoid irradiation in a heart transplant recipient.

Recurrent severe allograft rejection is an uncommon but difficult management problem in heart transplantation. Total lymphoid irradiation is now a recognized treatment modality when conventional therapy has failed. We describe an unusual complication of total lymphoid irradiation in a patient who had been treated with amiodarone for malignant arrhythmias before transplantation.

Changing patterns in donor and recipient risk: a 10-year evolution in one heart transplant center.

BACKGROUND: Expansion of the donor pool and liberalization of recipient criteria have occurred since the introduction of cyclosporine for heart transplantation. METHODS: We sought to evaluate the impact of these changes on outcome during a 10-year period in one program. A total of 251 transplantations were retrospectively reviewed and divided into two periods (1984 to 1989 and 1990 to 1994). RESULTS: In the latter period, there were increases in donor and recipient age, degree of weight mismatch, ischemic time, bypass time, and severity of illness in the recipient before transplantation as judged by status at the time of transplantation and preoperative requirements for pharmacologic or mechanical support. Despite these changes, time to hospital discharge decreased and a trend to improved survival was seen with the use of Kaplan-Meier analysis. CONCLUSIONS: These findings suggest that improvements in perioperative and posttransplantation care have permitted a safe expansion of both the donor pool and recipient criteria for transplantation.

The role of echocardiography in heart transplantation.

Echocardiography has gained increasing importance as an imaging modality in the care of the cardiac transplant recipient. Its utility in detecting the complications of transplantation, with special reference to the diagnosis of rejection and graft arteriosclerosis, is discussed. On the basis of a review of the current literature, an outline for serial echocardiographic studies is proposed.

Electrocardiographic artifact with a transcutaneous electrical nerve stimulation unit.

We describe an unusual electrocardiographic artifact in a patient with a transcutaneous electrical nerve stimulation unit. The artifact, consisting of low amplitude high frequency deflections, can be misinterpreted as a runaway pacemaker.

Update on recent clinical trials in congestive heart failure.

Understanding of the pathophysiology of heart failure has advanced over the last decade, resulting in new therapeutic advances. Convincing data exist that angiotensin-converting enzyme (ACE) inhibition and adrenergic blockade are the most important therapies and have the capacity to improve survival and lower morbidity. Higher doses of both ACE inhibitors and beta-blockers appear to provide additional benefits. The aldosterone antagonist spironolactone, when used in severe heart failure, provides additional survival advantage when added to standard triple therapy. Angiotensin receptor blockers have not been shown to be superior to ACE inhibitors, and their role in heart failure treatment requires further investigation. No trial's data support the use of inotropic agents or calcium channel blockers in heart failure. A number of new therapeutic agents, including vasopressin antagonists and tumor necrosis factor-alpha receptor antibody are in phase II and III clinical trials. If proved beneficial, they may provide new treatment options for patients with heart failure. Nevertheless, the current challenge is to increase the use of proven therapies, namely ACE inhibitors and beta-blockers, to improve outcomes in the rapidly growing population of patients with congestive heart failure.

Digitalis.

Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.