Renal graft outcome in combined heart-kidney transplantation compared to kidney transplantation alone: a single-center, matched-control study.

BACKGROUND: Renal allograft outcome in heart-kidney transplantation (HKTx) might be affected by hemodynamic instability and high levels of calcineurin inhibitor-dependent immunosuppression. METHODS: From November 1999 to March 2008, 13 patients who received HKTx were compared with a matched control group of 13 kidney transplantation (KTx) recipients with similar cardiovascular risk factors. Graft function, rejection periods, and patient survival were analyzed. RESULTS: Renal allograft rejection was noted in three patients (23%) after HKTx and in four patients (31%) after KTx. Serum creatinine levels were comparable at 1 week, 1 month, 1, 2, and 3 years after transplantation. Patient survival rates at 1, 2, and 3 years were 100% for HKTx recipients and 100, 92, and 92% for isolated KTx patients. Graft survival was 92% at 1, 2, and 3 years after HKTx and 100% at 1 year and 92% at 2 and 3 years after isolated KTx. CONCLUSIONS: Our results with excellent long-term graft function and survival after combined HKTx indicate that this procedure is a valuable option for a growing number of patients suffering from coexistent cardiac and renal failure.

Drug treatment for chronic systolic heart failure.

Drug treatment of chronic systolic heart failure usually includes angiotensin-converting enzyme inhibitor, or an angiotensin II receptor blocker, and a beta blocker, as prognostic benefit of these agents has been demonstrated in a large body of clinical trials. Depending on the stage of the disease and concomitant factors, an aldosterone antagonist and/or a digitalis glycoside may provide additional benefit. Most patients also receive a diuretic for symptomatic relief. Conversely, some drugs may precipitate or aggravate chronic systolic heart failure.

Pulmonary Palacos embolism: a case report.

Instrumentation with cement-augmented pedicle screws has expanded the therapeutic spectrum. This technique is useful for the palliation of bone metastases and in generalized osteoporosis. Serious complications such as pulmonary embolism have been described following percutaneous vertebroplasty, a frequently used technique. We report the case of a 55-year-old patient with a large central Palacos embolism of the right pulmonary artery after corporectomy of the lumbar vertebrae 3 and 4 and reconstruction using autologous pelvic bone. The large Palacos embolism was removed successfully from the right pulmonary artery with extracorporeal circulation.

German disease management guidelines: surgical therapies for chronic heart failure.

The German Disease Management Guideline "Chronic Heart Failure" intends to guide physicians working in the field of diagnosis and treatment of heart failure. The guideline provides a tool on the background of evidence based medicine. The following short review wants to give insights into the role of some surgical treatment options to improve heart failure, such as revascularization, ventricular reconstruction and aneurysmectomy, mitral valve reconstruction, ventricular assist devices and heart transplantation.

Limitations of high urgency listing--ventricular assist device support in a neonate for 452 days.

The Eurotransplant International Foundation in Leiden, the Netherlands, is responsible for mediation and allocation of organ donation procedures to its member countries Austria, Belgium, Croatia, Germany, Luxembourg, the Netherlands and Slovenia. To provide organs for the patients who require urgent transplantation, the "high urgent (HU)" status was introduced in 2001 in Germany . This new HU allocation system is applicable to neonates as well as adults. However, waiting times on HU status exceed several weeks to months. Therefore an increasing number of pediatric patients has to undergo implantation of a ventricular assist device (VAD). In the present report we discuss the current Eurotransplant heart allocation system for pediatric heart transplantation in the light of a neonate with 452 days on mechanical support. We compare the average waiting time of patients on HU status at our center and their outcome in 2007 and 2008 (Data obtained from Eurotransplant International Foundation). Waiting time on HU status in our center increased significantly from 2007 to 2008. Therefore more patients require VAD support as bridging to transplantation. The case of a neonate under long-term VAD support is an outstanding example of the negative effects of this development.

Successful management of MRSA sepsis in a patient with left ventricular assist device.

Left ventricular assist devices (LVADs) offer the opportunity to substantially improve the clinical conditions and to interrupt hospitalization of patients suffering from end-stage heart failure awaiting heart transplantation. The authors report a case of a 66-year old patient suffering from end-stage idiopathic dilative cardiomyopathy who needed the implantation of a LVAD and later developed a sepsis with a methicillin resistant Staphylococcus aureus (MRSA) which could be recovered by a differentiated antibiotic regimen.

Investigations of the lymphokine system in elderly individuals.

Elderly people are at risk from an increased incidence of infections. Therefore we have studied the correlation between the production of several immunological parameters such as interferon-gamma (IFN-gamma), interferon-alpha-2 (IFN-alpha-2), interleukin-2 (IL-2), soluble interleukin-2 receptors (sIL-2R) and interleukin-6 (IL-6) in young controls of 25-34 years old and old individuals with a minimum age of 65 years. All persons were selected according to the basic concept of the 'Senieur protocol'. Heparinized blood was taken and cultured in the whole-blood assay. The determination of all cytokines in the supernatants of stimulated cultures was done by the ELISA technique. We found significantly decreased levels of sIL-2R and IFN-alpha-2 after stimulation, whereas the values of IFN-gamma and IL-2 showed no significant difference between elderly and young persons. The values of IL-6 showed a distinct trend towards an increased synthesis for the elderly. We also studied the lymphocyte subpopulations T4 and T8 by flow cytometry. Elderly individuals showed a significantly increased T4/T8 ratio, caused by a slightly but not significantly decreased level of T8 cells. These results show that the elderly have decreased values of some immunological parameters such as IFN-alpha-2 and sIL-2R, which might explain an increased susceptibility of elderly individuals to bacterial and viral infections.

Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture.

We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.

A simple method for the flow cytometric analysis of intracellular antigens in whole smooth muscle cells: quantification of cyclin-dependent kinase 2.

Flow cytometry has become a widely used technique for the quantitative analysis of antigens at the single cell level. In the past, several protocols have been published for the detection of cytoplasmic and nuclear antigens in various cell lines, especially blood cells or cells growing in fluid culture. The applicability of these protocols to cells growing in a monolayer, such as smooth muscle cells (SMC) is often restricted, although flow cytometry is of great interest in the fields of arteriosclerosis and cancer research. We here describe a simple and reproducible method for the flow cytometric analysis of intracellular antigens such as cyclin-dependent kinase 2 (Cdk2) in rat aortic SMC. The sensitivity of the method was analyzed under growth and growth-inhibitory conditions using lovastatin, a cholesterol-lowering compound with antiproliferative capacity. Various antigens (Ras-protein, protein kinase C-alpha (PKC-alpha), Ki-67/MIB-1) in rat and bovine SMC were detectable using this methodology which should have a wide range of applications.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years' follow-up from the University Hospital Münster.

BACKGROUND: Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus. METHODS: After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. RESULTS: After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)]. CONCLUSION: CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.

Switch from assist device to total artificial heart to improve cardiac output.

Left ventricular assist devices (LVADs) offer the opportunity to substantially improve the clinical condition and to interrupt the hospitalization of patients suffering from end-stage heart failure awaiting heart transplantation.We report a case of a 30-year-old patient (body surface area 2.49 m2) suffering from idiopathic dilative cardiomyopathy who was primarily given an LVAD with a free floating impeller pump and was finally switched to a total artificial heart due to the demand for a higher cardiac output.

Vascular remodeling in ApoE-deficient mice: diet dependent modulation after carotid ligation.

Vascular remodeling is influenced by trauma and proatherogenic factors such as cholesterol. It has been shown that cholesterol exerts a direct effect on vessel wall structure. In this study we evaluated the effects of vascular trauma and cholesterol treatment on vascular remodeling and plaque integrity in carotid ligated ApoE-deficient mice. The right carotid artery was ligated in mice fed regular chow or cholesterol and fat containing diet. After 4 weeks left (non-ligated) and right (ligated) carotids were prepared. For studying vascular remodeling the vascular areas were evaluated morphometrically by calculating the areas from circumference measurements on Verhoff-van Gieson stains. The cellular and structural features of the plaque were analyzed by histological staining and immunohistochemistry. Under regular chow total vessel area decreased by 35% (p<0.001); cholesterol-rich diet led to an increase by 20% (p<0.05). In both feeding groups ligated carotids presented neointima development. The medial area increased only in mice fed regular chow. The luminal area was reduced by 80% (regular chow: p<0.001) and by 90% (cholesterol-rich diet: p<0.01). Regular chow led to structured plaques showing the typical features of stable plaques. Under cholesterol diet well defined plaque structures were missing. These lesions were characterized by numerous macrophages, few mostly PCNA positive smooth muscle cell (SMC) and less collagen particularly in the shoulder region. Our data indicate that in ApoE-deficient mice both direction of the remodeling response and lesion integrity are due to the diet applied: regular chow led to constrictive remodeling, whereas cholesterol and fat containing diet was associated with an adaptive response. Our data further indicate that the direction of response is not only related to the macrophage content but also to a proliferative intimal SMC-phenotype. Our data implicate that high serum cholesterol levels are not only inducers of plaque instability but also of the so far "positively recorded" compensatory remodeling.

[Off-label use in cardiac surgery]. / "Off-label use" in der Herzchirurgie.

In the view of off-label use, special concern should be granted to obtaining informed consent from the patient. It is important to point out the test character of the treatment. The patient has to be informed about the risks that exist with the treatment. The patient has to know that a drug not yet approved for this treatment is being used and the risks linked with its use have to be addressed. In addition, informed consent has to be documented and the differences compared with the standard treatment have to be pointed out.

Lovastatin controls signal transduction in vascular smooth muscle cells by modulating phosphorylation levels of mevalonate-independent pathways.

Lovastatin has been proven to effectively lower circulating LDL cholesterol and to exert antiproliferative effects on various cell lines, the latter effect being only incompletely understood. We found that lovastatin modulates the signal transducing phosphorylation cascade in vascular smooth muscle cells in a mevalonate-independent manner. Lovastatin was found to distinctively increase total phosphotyrosine levels in smooth muscle cells, an effect which could not be restored by mevalonate. At a concentration of 5 micromol/L lovastatin had a highly specific effect on the mitogen-activated protein kinase pathway. The expression of p42/44 mitogen-activated protein kinase (MAPK) was clearly reduced, but could be restored by addition of mevalonate, while the phosphorylation of p44 was mildly suppressed and the phosphorylation of p42 MAPK was reduced to non-detectable levels. While the phosphorylation of p44 MAPK could partially be restored by addition of mevalonate, the reduced phosphorylation of p42 MAPK could not be restored by addition of excessive doses of mevalonate or stimulation of the cells with basic fibroblast growth factor. Concurrently the expression of the GTP-binding Ras protein was significantly elevated at 5 and 20 micromol/L lovastatin, this effect being attenuated by addition of mevalonate to cell cultures. The data indicate that lovastatin is capable of modulating cellular signaling independently of the cholesterol synthesis pathway.

Macrophage colony-stimulating factor (CSF-1) is expressed by spontaneously outgrown EBV-B cell lines and activated normal B lymphocytes.

Human B lymphocytes activated by mitogens or infected by Epstein Barr virus (EBV) have previously been shown to release colony-stimulating activity (CSA) supporting the growth of normal human bone marrow progenitors. We established five different human EBV-B cell lines spontaneously outgrown from nonmalignant peripheral blood cells and long-term bone marrow cultures. CSA derived from all of these lines induces the growth of murine macrophage colonies, whereas virtually no human bone marrow cell progenitors were stimulated. As observed in the tumor cell line MIA PaCa-2, a 4.3-kilobase (kb) transcript was detected in all cases using a human colony-stimulating factor (CSF)-1 probe. Expression of this transcript can be further stimulated within three hours upon addition of phorbol myristate acetate (PMA). The highly purified native protein exerting macrophage colony-stimulating activity (M-CSA) exhibits a molecular size of approximately 75 to 97 Kd in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The identity of EBV-B cell derived M-CSA with human urinary CSF-1 was confirmed by a complete neutralization of macrophage CSA by an antihuman urinary CSF-1 antiserum. Normal human B lymphocytes purified from tonsils or from mononuclear blood cells also express CSF-1 upon stimulation with Staphylococcus aureus Cowan I. No CSF-1 expression, however, could be detected in normal resting B lymphocytes or in the Burkitt lymphoma cell line RAJI.

Radiofrequency energy modification of the atrioventricular junction in patients with atrial fibrillation: modes of ventricular response under autonomic blockade and long-term effect.

The short- and long-term effect of radiofrequency (RF) modification of the AV junction on ventricular rate and left ventricular function and the different types of ventricular response during energy application under autonomic nervous blockade were assessed in 28 patients with medically refractory atrial fibrillation. During the successful RF application, ventricular rate slowed progressively (type I response, ten patients) or accelerated at first and then slowed (type II response, 11 patients). Type II response was associated with a more anterior ablation site compared to Type I response. A primary successful outcome was achieved in 21 patients. Inadvertent complete AV block developed in three patients, while in four patients AV nodal ablation was performed after an unsuccessful modification attempt. During 6-month follow-up, the ventricular rate was adequately controlled in only four patients. Among the 16 patients with a recurrence of uncontrolled AF were all 10 patients with type I response and 6 of 11 patients with type II response. One patient died suddenly 10 weeks after the procedure.

Sequence-specific antiproliferative effects of antisense and end-capping-modified antisense oligodeoxynucleotides targeted against the 5'-terminus of basic-fibroblast-growth-factor mRNA in coronary smooth muscle cells.

Basic fibroblast growth factor (bFGF), a potent mitogen for arterial smooth muscle cells, has been shown to play a fundamental role in the pathogenesis of arteriosclerosis and restenosis by stimulating the proliferation of vascular smooth muscle cells. We found that partially phosphorothioate-modified 15-residue antisense oligodeoxynucleotides complementary to bFGF mRNA at 0.1-2.0 microM block growth and division of cultured human and bovine coronary smooth muscle cells in a dose-dependent manner. The effect is sequence specific at low (0.1-0.5 microM) nontoxic concentrations. It is associated with inhibition of expression of pericellular and intracellular bFGF, with a decreased de novo synthesis of bFGF and is partly reversible by the addition of exogenous (recombinant) bFGF. The antisense effect lasts 48-72 h and diminishes thereafter. If the antisense oligodeoxynucleotide medium is replaced by an oligonucleotide-free medium after 24 h, the [3H]thymidine incorporation rate returns to control levels. Under the same conditions, the corresponding sense oligodeoxynucleotide exerts negligible nonspecific inhibitory actions. The antiproliferative potency of the 15-residue antisense oligodeoxynucleotide is markedly enhanced by adding 3-4 nonbase-pairing guanosine residues at the 5'- and 3'-termini of the 15-residue antisense oligonucleotide. The data implicate bFGF in the process of smooth muscle cell proliferation and an effective and specific antiproliferative potency of bFGF-specific antisense oligonucleotides. The results point to possible new therapeutic strategies for the use of antisense methodology in the suppression of post-angioplasty restenosis.