Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

The HCA National Disease Management Program for coronary disease detection and treatment in women.

The diagnosis and treatment of heart disease in women continues to be one of the greatest challenges facing cardiovascular medicine today. Marked reductions in mortality rates during the past 2 decades did not result in improved outcomes for women. A major rate-limiting step to improving mortality rates for women is early diagnosis and initiation of effective lifesaving therapies for women. In 1999, HCA Healthcare Systems, Inc, Nashville, TN, initiated a coordinated effort among 208 hospitals in 26 states to improve the diagnosis of coronary disease and to target women who should receive aggressive risk factor modification and referral to cardiologists. We describe the initial phases of program development, including employee risk factor screening; citywide health risk assessment; nationwide educational programs for clinicians, staff, and consumers; and a dedicated outcomes assessment program for tracking women at risk for coronary disease. We believe that these efforts provide a venue for optimal care and improved outcomes for women served by HCA facilities.

Guidelines for the referral and management of patients eligible for solid organ transplantation.

Members of the Clinical Practice Committee, American Society of Transplantation, have attempted to define referral criteria for solid organ transplantation. Work done by the Clinical Practice Committee does not represent the official position of the American Society of Transplantation. Recipients for solid organ transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral practice and, therefore, inequity may exist in terms of access to transplantation, there needs to be uniformity about who should be referred to transplant centers so the system is fair for all patients. A review of the literature that is both generic and organ specific has been conducted so referring physicians can understand the criteria that make the patient a suitable potential transplant candidate. The psychosocial milieu that needs to be addressed is part of the transplant evaluation. Early intervention and evaluation appear to play a positive role in maximizing quality of life for the transplant recipient. There is evidence, especially in nephrology, that the majority of patients with progressive failure are referred to transplant centers at a late stage of disease. Evidence-based medicine forms the basis for medical decision-making about accepting the patient as a transplant candidate. The exact criteria for each organ are detailed. These guidelines reflect consensus opinions, synthesized by the authors after extensive literature review and reflecting the experience at their major transplant centers. These guidelines can be distributed by transplant centers to referring physicians, to aid them in understanding who is potentially an acceptable candidate for transplantation. The more familiar physicians are with the exact criteria for specific organ transplantation, the more likely they are to refer patients at an appropriate stage. Individual transplant centers will make final decisions on acceptability for transplantation based on specific patient factors. It is hoped that this overview will assist insurers/payors in reimbursing transplant centers for solid organ transplantation, based on criteria for acceptability by the transplant community. The selection and management of patients with end-stage organ failure are constantly changing, and future advances may make obsolete some of the criteria mentioned in the guidelines. Most importantly, these are intended to be guidelines, not rules.

Recent developments in microvascular angina.

Microvascular angina (Syndrome X) is an extremely heterogeneous clinical entity that is the product of genetic, coronary microvascular, metabolic, and clinical factors, which combine together to produce distinct cardiac manifestations and complications. The interactions of these abnormalities remain poorly understood. The diagnosis is considered in patients with anginal symptoms and no epicardial coronary narrowing. Therapy is also problematic, with beta-blockers as first-line pharmacotherapy followed by angiotensin-converting enzyme inhibitors and calcium channel blockers.

Regulation of dendritic spine stability.

Dendritic spines undergo several types of transformations, ranging from growth to collapse, and from elongation to shortening, and they experience dynamic morphological activity on a rapid time scale. Changes in spine number and morphology occur under pathological conditions like excitotoxicity, but also during normal central nervous system development, during hormonal fluctuations, and in response to neural activity under physiological circumstances. We briefly review evidence for various types of alterations in spines, and discuss the possible molecular basis for changes in spine stability. Filamentous actin appears to be the most important cytoskeletal component of spines, and a growing list of actin-associated and actin-regulatory proteins has been reported to reside within spines. We conclude that spines contain two distinct pools of actin filaments (one stable, the other unstable) that provide the spine with both a stable core structure and a dynamic, complex shape. Finally, we review the current state of knowledge of actin filament regulation, based on studies in nonneuronal cells.

Inhibition of interleukin 7 receptor signaling by antigen receptor assembly.

After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7-dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a mu heavy chain with a D-proximal V(H)7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the mu(1), kappa(1) stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged lambda light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rbeta chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.

Difficult cases in heart failure: Bridge to beta blockade in severe heart failure: the use of phosphodiesterase inhibitors.

The authors describe the use of milrinone as a bridge to beta blockade in a patient with severe heart failure. This case is clinically important because in patients with severe heart failure phosphodiesterase inhibitors, unlike beta agonists, will retain their positive inotropic and vasodilator effects in the presence of beta blockade and, in addition, these agents will attenuate the negative inotropic side effects of beta blockers. Conversely, a beta blocker associated with a phosphodiesterase inhibitor will protect against myocyte loss and arrhythmias, may prevent sudden death, and will improve long-term symptoms and exercise tolerance. This combination is being investigated in a large, multicenter, double-blind, randomized trial of intravenous milrinone vs. placebo as a therapeutic tool to allow the initiation of carvedilol orally in patients hospitalized with class III/IV heart failure. (c)2000 by CHF, Inc.

Impedance cardiography: a bridge between research and clinical practice in the treatment of heart failure.

This paper proposes that impedance cardiography could narrow the gap between heart failure clinical research and the appropriate and timely application of new knowledge and technology in the care of patients with heart failure. Research variables and measurement strategies, identified in the heart failure scientific literature between 1994-1999, are compared to measures that can be obtained through a cost effective, noninvasive technology--impedance cardiography. Emphasis is placed on case reports that illustrate how "real time" evaluation and trending of key hemodynamic variables through impedance cardiography monitoring has been used to apply state of the science knowledge and technology to improve the inpatient and outpatient management of care for patients with severe heart failure. (c)2000 by CHF, Inc.

Difficult cases in heart failure: beneficial effects of aldosterone blockade in heart failure.

The authors describe the use of spironolactone, an aldosterone receptor blocker, in a patient with heart failure refractory to conventional therapy. The clinical importance of this case is that not only does spironolactone improve symptoms, but its use also improves survival in patients with severe heart failure. Clinicians should be aware that this therapy has to be added to the medical armamentarium for patients with severe heart failure. In addition, it is important to point out that the use of the aldosterone receptor blockers and their beneficial effects in morbidity and mortality in heart failure has helped to understand more clearly the relationship between aldosterone and its importance in the pathophysiology of heart failure. (c)2000 by CHF, Inc.

Difficult cases in heart failure: Ventricular resynchronization in refractory heart failure.

The use of a multisite transvenous pacemaker in a patient with refractory heart failure who experienced short-term symptomatic improvement is described. The improvement in heart failure symptoms was most likely related to resynchronization of atrioventricular and interventricular asynchrony. Large, multicenter, randomized trials of this technology are being performed to evaluate the importance of this therapeutic modality in the treatment of heart failure. (c)2000 by CHF, Inc.

Treatment of the hypertensive patient with microvascular angina.

Syndrome X and microvascular angina are a heterogenous group of diseases. Several medications, including angiotensin-converting enzyme inhibitors, beta-blockers, and calcium-channel blockers, have been reported to be successful in the treatment of microvascular angina. Control of hypertension and regression of left ventricular hypertrophy are important in controlling symptoms associated with this intriguing problem. The role of nitric oxide and the effects of L-arginine in the pathogenesis and treatment of hypertension and microvascular angina need to be elucidated. Optimal treatment will depend on the appropriate classification and diagnosis of chest pain in patients with hypertension and normal coronary angiograms.

Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors.

Here, we define the IL-7R-activated signal that promotes survival and proliferation of T cell progenitors and demonstrate that it is distinct from the signals that induce differentiation. We show that IL-7 activates PKB and STAT5 in human thymocytes. Into T cell precursors we introduced chimeric receptors with a cytoplasmic domain of the IL-7R that is no longer able to activate PI-3K/PKB and STAT5 and tested the transduced cells in a fetal thymic organ culture. We also examined the T cell precursor activity of progenitors expressing dominant-negative forms of PI-3K or STAT5B. These experiments revealed that PI-3K/PKB activation is essential for the survival and proliferation of T cell precursors and suggest that STAT5 activated by IL-7 mediates T cell differentiation.

A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus.

BACKGROUND: Tacrolimus-based immunosuppression seems safe and effective in liver and kidney transplantation. To assess the safety and efficacy of tacrolimus (TAC)-based immunosuppression after cardiac transplantation as well as the relative impact of tacrolimus on immunosuppression-related side effects such as hypertension and hyperlipidemia, we conducted a prospective, randomized, open-label, multicenter study of otherwise identical tacrolimus- and cyclosporine-based immunosuppressive regimens in adult patients undergoing cardiac transplantation. METHODS: Eighty-five adult patients (pts) at six United States cardiac transplant centers, undergoing their first cardiac transplant procedure, were prospectively randomized to receive either TAC-based (n = 39) or cyclosporine (CYA)-based (n = 46) immunosuppression. All pts received a triple-drug protocol with 15 pts (18%) receiving peri-operative OKT3 to delay TAC/CYA due to pre-transplant renal dysfunction. Endomyocardial biopsies were performed at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 24, and 52. The study duration was 12 months. RESULTS: Patients were mostly male (87%) Caucasian (90%) with a mean age of 54 years and primary diagnoses of coronary artery disease (55%) and idiopathic dilated cardiomyopathy (41%). There were no significant demographic differences between groups. Patient and allograft survival were not different in the two groups. The probability and overall incidence of each grade of rejection, whether treated or not, and the types of treatment required did not differ between the groups. At baseline and through 12 months of follow-up, chemistry and hematology values were similar between the groups except serum cholesterol was higher in the CYA group at 3, 6, and 12 months (239 vs 205 mg/dL, 246 vs 191 mg/dL, 212 vs 186 mg/dL, respectively, p < 0.001). Likewise, LDL-cholesterol, HDL-cholesterol and triglycerides were significantly higher in the CYA group. More CYA patients received therapy for hypercholesterolemia (71% vs 41% at 12 months, p = 0.01). There were no significant differences in renal function, hyperglycemia, hypomagnesemia, or hyperkalemia during the first 12 months. More CYA patients developed new-onset hypertension requiring pharmacologic treatment (71% vs 48%, p = 0.05). The incidence of infection was the same for the two groups (2.6 episodes/pt/12 month follow-up). CONCLUSION: Tacrolimus-based immunosuppression seems effective for rejection prophylaxis during the first year after cardiac transplantation and is associated with less hypertension and hyperlipidemia and no difference in renal function, hyperglycemia or infection incidence when compared to cyclosporine-based immunosuppression.

Effect of hypoxia and hypoxia/reoxygenation on proteoglycan metabolism by vascular smooth muscle cells.

Hypoxia and hypoxia/reoxygenation are known to affect vascular smooth muscle cell physiology. In this study, we first investigated proteoglycan synthesis by human aortic smooth muscle cells exposed to normoxia, hypoxia, or hypoxia/reoxygenation. We then compared the newly synthesized proteoglycans from normoxic and hypoxic-reoxygenation cultures for their ability to bind low density lipoprotein (LDL). Confluent smooth muscle cells under normoxia, hypoxia, or hypoxia/reoxygenation were pulsed with [35S]sulfate, and secreted and cell-associated proteoglycans were analyzed. Secreted proteoglycans in cultures exposed to hypoxia (4 h)/reoxygenation (19 h) increased 28% over those of cells continuously exposed to normoxia. Cell-associated proteoglycans did not differ significantly between the two groups. In contrast, hypoxia (4 h) followed by a 30-min reoxygenation produced a 37% decrease in newly synthesized proteoglycans. Hypoxia alone also resulted in a 24% decrease in secreted proteoglycans and a 20% decrease in cell-associated proteoglycans. Proteoglycans newly synthesized by smooth muscle cells exposed to normoxia and hypoxia/reoxygenation did not differ in their charge densities and molecular size but did differ in glycosaminoglycan composition. Exposure of smooth muscle cells to hypoxia/reoxygenation produced a 60% increase in a proteoglycan subfraction that bound LDL with very high affinity. The incorporation of [3H]leucine into total cellular protein decreased significantly following exposure of smooth muscle cells to hypoxia as well as hypoxia/reoxygenation. These results indicate that hypoxia and hypoxia/reoxygenation cause major alterations in proteoglycan metabolism by vascular smooth muscle cells.

The independent effects of left ventricular ejection fraction on short-term outcomes and resource utilization following hospitalization for heart failure.

BACKGROUND: While depressed left ventricular ejection fraction is clearly associated with poor long-term outcome in heart failure (HF), the effect of ejection fraction on short-term outcomes and resource utilization following hospitalization for HF remains unclear. HYPOTHESIS: We evaluated the independent effect of depressed ejection fraction (< or = 40%) on short-term outcomes and resource utilization following hospitalization for HF. METHODS: The study population included 443 consecutive patients hospitalized for DRG 127 (HF and shock) with known ejection fraction. For each patient, we assessed the hospitalization cost (1995 US$), length of stay, in-hospital mortality, 30-day mortality, and 30-day readmission rates. RESULTS: Despite similar disease severity at admission, patients with ejection fraction < or = 40% (Group 1) had longer length of stay (4.0 vs. 3.7 days; p = 0.03), a tendency toward higher hospitalization cost ($3,054 vs. $2,770; p = 0.08), more readmissions for any cause (0.4 vs. 0.3; p = 0.05) and for HF (0.2 vs. 0.1; p = 0.01), but similar in-hospital (2.5 vs. 2.6%) and 30-day mortality (4.0 vs. 4.6%) compared with patients with ejection fraction > 40% (Group 2). In multivariate analyses, Group 1 patients were more likely to have higher than median hospitalization cost [odds ratio (OR) = 1.98; 95% confidence intervals (CI) = 1.02-3.91] and longer than median hospital stay (OR = 1.68; CI = 1.08-3.91); they were also more likely to be readmitted for any cause (OR = 2.07; CI = 1.15-3.78) or for HF (OR = 5.71; CI = 1.64-21.94), and they tended to have a higher 30-day incidence of death or readmission (OR = 1.65; CI = 0.96-2.84). CONCLUSIONS: Depressed left ventricular ejection fraction is associated with higher resource utilization and readmission rates following hospitalization for HF. Greater focus on patients with depressed ejection fraction may increase cost savings from HF disease management programs.

Difficult cases in heart failure: Atrioventricular interval optimization utilizing thoracic electrical bioimpedance.

The authors describe the use of thoracic electrical bioimpedance, a noninvasive, simple, low risk technique to optimize atrioventricular delay in a patient with a dual chamber pacemaker, right ventricular infarct, and symptoms NYHA functional class III-IV. Optimization of the atrioventricular interval was associated with improvement of hemodynamic parameters and resolution of the symptoms of heart failure. The application of noninvasive hemodynamic parameters might have a great deal of impact in the management of patients with several cardiovascular diseases. Multicenter studies are underway. (c)1999 by CHF, Inc.

Difficult cases in heart failure: Left ventricular assist device implantation for the treatment of recurrent ventricular tachycardia in end stage heart failure.

The authors describe the surgical implantation of a left ventricular assist device (LVAD) in a patient with ischemic cardiomyopathy and recurring episodes of ventricular tachycardia with associated sudden death, as a therapeutic intervention for the recurrent ventricular arrhythmias. The clinical inference of this report demonstrates that these devices are useful as a bridge to heart transplantation, not only improving the symptoms of heart failure but also suppressing malignant ventricular arrhythmias. (c) 1999 by CHF, Inc.

Difficult cases in heart failure: Bilateral renal artery fibrous dysplasia and heart failure.

The clinical characteristics as well as treatment of a patient with renal artery stenosis associated with uncontrolled hypertension and heart failure is described. Patients with similar findings should alert clinicians of this entity, since rapid diagnosis and treatment will assure a prompt relief not only of the increased blood pressure but also of the symptoms of heart failure. (c)1999 by CHF, Inc.

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators.

BACKGROUND: After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS: In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS: Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS: Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Cardiomyocyte transplantation in a porcine myocardial infarction model.

Transplantation of cardiomyocytes into the heart is a potential treatment for replacing damaged cardiac muscle. To investigate the feasibility and efficiency of this technique, either a cardiac-derived cell line (HL-1 cells), or normal fetal or neonatal pig cardiomyocytes were grafted into a porcine model of myocardial infarction. The myocardial infarction was created by the placement of an embolization coil in the distal portion of the left anterior descending artery in Yorkshire pigs (n = 9). Four to 5 wk after creation of an infarct, the three preparations of cardiomyocytes were grafted, at 1 x 10(6) cells/20 microL into normal and into the middle of the infarcted myocardium. The hearts were harvested and processed for histologic examinations 4 to 5 wk after the cell grafts. Histologic evaluation of the graft sites demonstrated that HL-1 cells and fetal pig cardiomyocytes formed stable grafts within the normal myocardium without any detrimental effect including arrhythmia. In addition, a marked increase in angiogenesis was observed both within the grafts and adjacent host myocardium. Electron microscopy studies demonstrated that fetal pig cardiomyocytes and the host myocardial cells were coupled with adherens-type junctions and gap junctions. Histologic examination of graft sites from infarct tissue failed to show the presence of grafted HL-1 cells, fetal, or neonatal pig cardiomyocytes. Cardiomyocyte transplantation may provide the potential means for cell-mediated gene therapy for introduction of therapeutic molecules into the heart.