Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients.

CONTEXT: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring. OBJECTIVE: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL). MATERIALS AND METHODS: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis. RESULTS: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed. CONCLUSION: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.

Extracorporeal membrane oxygenation: experience in acute graft failure after heart transplantation.

INTRODUCTION: Acute graft failure is the leading cause of early mortality after heart transplantation (HTx). Extracorporeal membrane oxygenation (ECMO) is an efficient therapeutic option to treat various pathologies, unburden the left and right ventricle, and allow for functional recovery of the transplanted heart. We reviewed our ECMO experience and outcomes in HTx patients. METHODS: Retrospectively, we analyzed all patients who received an orthotopic HTx (n = 298) in our department over a 15-yr period (1997 through 2011) to assess the incidence of post-HTx ECMO implantation, perioperative complications, early and one-yr mortality as well as causes of death. RESULTS: ECMO therapy was utilized to treat graft failure in 28 patients (10.6%) with a mean duration of ECMO support of 4.2 d (six h to 9.4 d). Multivariate analysis revealed as independent predictors for mortality low cardiac output (p = 0.028; odds ratio (OR) = 11.3) and stroke (p = 0.008; OR = 19.7). Cumulative survival rates were 46.4 ± 9.4% within 30 d and 25.0 ± 8.2% at one yr. Causes of death were multiorgan failure (n = 9), sepsis (n = 9), lung failure (n = 2), and intracerebral bleeding (n = 2). ECMO was implanted due to primary graft failure (PGF, n = 16), sepsis (n = 4), and right heart failure (n = 6). CONCLUSION: Temporary ECMO support for postoperative output failure is an acceptable option as a last resort for otherwise doomed patients with fatal graft failure after HTx. The small fraction of patients surviving appear to have a decent long-term prognosis.

A randomized, placebo-controlled trial of aprotinin to reduce primary graft dysfunction following lung transplantation.

PURPOSE: Severe primary graft dysfunction (PGD) is the major early problem following lung transplantation. Aprotinin, a serine protease inhibitor, has many anti-inflammatory properties that might reduce or prevent lung injury. Our hypothesis was that the incidence of PGD could be reduced by a combination of donor lung perfusion and systemic administration of aprotinin to recipients. METHODS AND MATERIALS: The study was randomized and placebo controlled. Donor lungs were perfused during procurement with 4 L Perfadex containing aprotinin (280 mg load + 70 mg/hL) or placebo. Aprotinin or placebo was also administered peri-operatively to the recipients. The study was powered to detect a 10% improvement in the primary endpoint of developing ISHLT grade III PGD anytime within 48 hr following the transplant procedure. RESULTS: There were 48 patients randomized. Diagnosis and the use of bypass were different between groups. The study was stopped prematurely at the planned interim analysis point because of published concerns about renal toxicity of aprotinin. There was no difference in the occurrence of the primary endpoint between groups of patients. The median change from the baseline creatinine level at 24, 48, 72 hr; 7 and 30 d following the transplant was not associated with the administration of aprotinin. CONCLUSIONS: There was no statistically significant difference in the incidence of the primary endpoint between groups in the study. Excess renal failure related to aprotinin administration in a patient population at high risk for the event was not observed.

Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations.

OBJECTIVE: Cardiopulmonary bypass (CPB) support is required in some lung transplantation (LTX) operations. CPB support and full-dose heparin increases the risks of bleeding and early graft dysfunction. We report our experiences of replacing CPB with heparin-bonded low-dose heparin extracorporeal membrane oxygenation (ECMO) support in LTX surgery. METHODS: From 2003 to 2005 forty-seven patients were transplanted. Thirty-seven LTX patients were retrospectively evaluated for this study (10 patients were excluded due to heart-lung-, lung-kidney transplantation, LTX with bypass grafting, and ASD closure or emergency CPB support). Extracorporeal circulation support was necessary in 40% of the 37 LTX patients due to severe primary or secondary pulmonary hypertension (P or SPHTN), right heart dysfunction, or hemodynamic instability. There were seven LTX procedures with CPB and eight implantations with ECMO support. CPB (high-dose heparin) and ECMO support (ACT 160-220 s) was always set up through femoral veno-arterial canulation. All patients had limited access thoracotomies without transsection of the sternum. Normothermia was maintained in all patients. CPB patients: PPH 15%, COPD 15%, IPF with mean PAP>40 mmHg 70%. ECMO patients: PPH 13%, COPD 13%, IPF with severe PAP pressure elevation 74%. RESULTS: In patients undergoing LTX for PPH, the ECMO support was directly extended into the post-operative period. Packed red blood cell (PRBC) transfusion requirements during the operation and the first 24h were 13.25+/-1.6 PRBC units versus 5.1+/-2.8 PRBC units on CBP (p=0.02). Operative time was longer (p=0.11) in the ECMO LTX (451 min+/-76 vs 346+/-140). The increased 90-day mortality rate of the ECMO patients showed a trend toward significance (p=0.056), which was related to infectious complications (3 vs 1 patient). Severe graft ischemia/reperfusion injury occurred in 9% in the CPB versus 13% in the ECMO group. The 1-year survival was significantly reduced in ECMO patients (p=0.004, log-rank test). CONCLUSIONS: The advantages of femoral canulation rather than conventional central connections in lung transplantation procedures led to an undisturbed operative field. A significantly higher blood product amount was required in ECMO patients, which might lead to increased infection and mortality rates. CPB, obviously, should remain the standard support technique if extracorporeal circulation is required in lung transplantation surgery.

Pharmacodynamic monitoring of the immunosuppressive therapy in patients after heart transplantation: whole blood flow cytometric analysis of lymphocyte function.

Despite therapeutic monitoring and daily measurements of blood concentrations (pharmacokinetics) of immunosuppressive medications, immunosuppressive therapy remains still a challenge after heart transplantation (HTx) due to drug interactions, toxicities and individual responses to drug effects. We established whole blood flow cytometric assays of lymphocyte function to assess the pharmacodynamics of immunosuppressive therapy and investigated both pharmacokinetic and pharmacodynamic approaches after HTx. Our results showed that pharmacodynamic measurements provide a more direct assessment of the functional activity of immunosuppressants on immune cells compared to drug level monitoring alone. The information from both pharmacokinetic and pharmacodynamic monitoring has the potential to increase the efficacy and safety of individual immunosuppressive therapy after HTx.

Tuberculous Empyema Post Bilateral Lung Transplant.

Tuberculous empyema in lung transplantation recipients is a rare entity, with only a handful of cases reported in the English-language literature. We are reporting a case of tuberculous empyema 3 months after uncomplicated bilateral lung transplantation. The recipient underwent video-assisted thoracic surgery for diagnosis and decortication. Both the recipient and donor lacked a history of tuberculosis or tuberculosis exposure.

Affects of immunosuppression on circulating dendritic cells: an adjunct to therapeutic drug monitoring after heart transplantation.

OBJECTIVES: Recent evidence emerges dendritic cells (DCs) as pharmacological targets of immunosuppressive drugs. Therefore, in this study we monitored DCs in peripheral blood to compare the effects of calcineurin inhibitors (CNI: cyclosporine, tacrolimus) and mammalian target of rapamycin inhibitors (sirolimus, SRL, everolimus, ERL) basis-immunosuppressive therapies in human heart transplanted (HTx) recipients. METHODS: We compared HTx recipients which were converted from either CNI to ERL (severe renal dysfunction, n=8), or from SRL to ERL (approval of ERL for HTx, n=8) with 20 healthy human controls. Twenty four after the last CNI or SRL dose recipients were treated with ERL/BID on days 1-3. Peripheral blood was collected at trough in the morning before and on day 4 after conversion. Percentages of positive myeloid and plasmacytoid DC (m and pDC) subsets in peripheral blood were analysed by flow cytometry. The status of maturation was further characterised by flow cytometry analysis of % expression of CD83 and % expression of various intracellular cytokines (IL-1beta, TNF-alpha, IL-8, IL-12), respectively. RESULTS: HTx recipients had higher % positive mDCs regardless the immunosuppressive therapy compared to controls (p<0.05). Whereas, % positive pDCs were only significantly lower in recipients converted from CNI to ERL compared to controls (p<0.05). The data consolidate the finding that the subset ratio pDCs/mDCs was lower in recipients compared to controls. But after conversion from CNI or SRL to ERL the ratio increased towards pDCs. Percentages of expression of CD83 on mDCs were not different among the recipient groups and controls. Recipients with CNI and SRL had higher % expression of IL-12 and lower % expression of IL-1beta compared to controls (p<0.05). However, after conversion to ERL % expression of both IL-12 and IL-1beta returned to control values in both groups. CONCLUSIONS: The results showed that analysis of immunosuppression of circulating DCs in peripheral blood may be an adjunct to therapeutic drug monitoring to optimize immunosuppressive therapy after HTx.

Aprotinin decreases reperfusion injury and allograft dysfunction in clinical lung transplantation.

OBJECTIVE: Primary graft dysfunction caused by ischemia-reperfusion injury is one of the most frequent causes of early morbidity and death after lung transplantation. We hypothesized that the perioperative management with aprotinin decreases the incidence of allograft reperfusion injury and dysfunction after clinical lung transplantation. METHODS: Lung transplant databases of two transplant centers were used to investigate the incidence of severe post-transplant reperfusion injury (PTRI). We examined data of 142 patients who underwent either single lung (81) or bilateral sequential lung (61) transplantation for COPD, idiopathic pulmonary fibrosis, cystic fibrosis, and miscellaneous lung disorders between 1997 and 2000. Thirty patients were excluded due to heart-lung transplantation or lung transplantation for Eisenmenger's disease, re-transplantation, rejection, or deviation from the standardized triple immunosuppression protocol. The data of remaining 112 patients (control group, 64% single lung, 36% sequential bilateral lung transplants) were compared to the prospectively collected data of 59 lung transplant patients over the last 5 years. All of these 59 patients were managed perioperatively with aprotinin infusion. In addition, Euro-Collins-aprotinin procurement solution (Apt-EC group) was used for 50 donor lungs (58% single lung, 42% sequential bilateral lung transplants). Aprotinin in combination with low-potassium dextran (LPD) flush solution (Apt-LPD group) was used for the procurement of 34 lungs (59% single lung, 41% sequential bilateral lung transplants). The International Society of Heart and Lung Transplantation (ISHLT) grade III injury score was used for the diagnosis of severe PTRI, which is based on a PaO(2)-FIO(2) ratio of less than 200 mmHg. RESULTS: Severe reperfusion injury grade III was observed in 18% of the control group. ECMO support was required in 25% of these patients. The associated mortality rate was 40%. Correlating factors for PTRI were donor age greater than 35 years (45%, p=0.01, mean age 38+/-8) and recipient pulmonary artery systolic pressure greater than 60 mmHg (48%, p<0.05). Lung graft ischemic times (231+/-14 min) and intraoperative techniques (cardiopulmonary bypass in 12%) were not associated with negative outcomes. Despite longer ischemic times (258+/-36 min and 317+/-85 min, respectively) and older donors (42+/-12 years and 46+/-12 years, respectively) in the aprotinin patient groups (Apt-EC and Apt-LPD group), the incidence of PTRI was markedly lower (6% and 9%, respectively). There was no mortality in the Apt-EC group and one patient died in the Apt-LPD group due to PTRI-induced graft failure. CONCLUSIONS: Severe PTRI increased short-term morbidity and mortality. The incidence of reperfusion injury was not dependent upon the duration of donor organ ischemia. The use of aprotinin in the perioperative patient management in lung transplantation had strong beneficial effects on the patient outcomes and decreased the incidence of post-transplant ischemia-reperfusion injury significantly.

Assessment of Immunological Biomarkers in the First Year after Heart Transplantation.

BACKGROUND: Pharmacodynamic biomarkers that detect changes of immunological functions have been recognized as a helpful tool to increase the efficacy of immunosuppressive drug therapies. However, physiological changes of immunological biomarkers following transplantation are not investigated. Therefore, we assessed frequently used immunological biomarkers of the circulating blood in the first year following heart transplantation (HTx). METHODS: Activation markers CD25 and CD95, intracellular cytokines IL-2 and IFNγ, chemokines IP10 and MIG, and subsets of dendritic cells as well as antibodies against human leukocyte antigens (HLA) and major histocompatibility complex class I-related chain A (MICA) antigens were analyzed at different time points using flow cytometry and Luminex xMAP technology. RESULTS: Expression of IL-2, IFNγ, and plasmacytoid dendritic cells (pDCs) significantly increased (p < 0.01) during the first year. Anti-HLA antibodies decreased continuously, while anti-MICA antibodies showed minor increase within the first year. An association between percentage of pDCs and anti-MICA antibody positivity was proven. pDCs, IFNγ-producing T cells, and IP10 concentration were associated in a stronger way with age and gender of HTx recipients than with antibodies against HLA or MICA. CONCLUSIONS: We conclude that certain immunological biomarkers of the circulating blood change during the first year after HTx. These changes should be considered for interpretation of biomarkers after transplantation.

Assessment of immunosuppressive drug interactions: inhibition of lymphocyte function in peripheral human blood.

Cyclosporin (CsA) or tacrolimus (TRL) is routinely combined with either sirolimus (SRL) or mycophenolate mofetil (MMF) in immunosuppressive regimes in organ transplantation. The aim of our study was to establish a specific human blood assay of lymphocyte function in order to assess interactions of these drug combinations. Different concentrations (10(6)-10(9) nM) of CsA, TRL, SRL or mycophenolic acid (MPA, the active metabolite of MMF) was added to whole blood of five human volunteers. Drug combinations were studied by adding 250, 500 or 1000 nM of MPA to different concentrations of CsA, TRL, or SRL or by adding 1, 10 or 25 nM of SRL to different concentrations of CsA or TRL. After concanavalin-A stimulation, whole blood cultures were analyzed by flow cytometry detecting lymphocyte proliferation and activation by bivariate expression of proliferating cell nuclear antigen (PCNA)/DNA content and T cell-surface activation antigens (e.g. CD25, CD95, and CD154). We found an order of potency inhibiting lymphocyte function with SRL>TRL>CsA>MPA. In addition, we observed enhanced inhibition of PCNA, CD25, CD95 or CD154, if either CsA or TRL was combined with low concentrations of MPA, or SRL alone or if SRL was combined with low concentrations of MPA. Data analysis revealed an independent functional synergism or partial agonism in most combinations. This human blood assay is able to assess lymphocyte function and to monitor immunosuppressive therapy. The assay also permits pharmacological analysis of drug interactions, which will lead to improved safety and therapeutic efficacy in transplanted patients.

Coronary artery spasm and ventricular fibrillation after off-pump coronary surgery.

Native coronary artery or bypass graft spasm is a rare cause of acute myocardial infarction after coronary artery bypass grafting. This report presents angiographic documentation of native coronary artery spasm following successful multivessel off-pump coronary revascularization, which caused myocardial ischemia leading to inferior wall myocardial infarction and ventricular fibrillatory arrest.

Off-pump coronary artery bypass grafting decreases morbidity and mortality in a selected group of high-risk patients.

BACKGROUND: The ideal indication for off-pump coronary artery bypass grafting (OPCABG) has yet to be defined. High-risk surgical patients may benefit the most when cardiopulmonary bypass (CPB), aortic cross clamping, and cardioplegic arrest are avoided. The aim of this study was to determine whether off-pump coronary artery bypass grafting might decrease the operative morbidity and mortality in a select group of high-risk patients with multivessel coronary artery disease. METHODS: Utilizing a Parsonnet risk stratification model we analyzed prospectively collected data on a cohort of high-risk coronary artery disease patients, which were operated on with beating-heart technology by the same group of surgeons in a tertiary care university medical center. High-risk patients were defined as those with a Parsonnet score of 15 or greater. RESULTS: Fifty-seven multivessel disease OPCABG patients (over a period of 2 years) had markedly increased Parsonnet scores (24.3 +/- 10.6). The average ejection fraction of the patients was 42% (+/-12.3) and their age ranged from 52 to 85 years (mean 70.6 +/- 10.4, 26% women). Unstable angina was present in 42 patients (74%) and 10 patients underwent OPCABG within 24 hours of the occurrence of acute myocardial infarction. In addition to severe coronary artery disease 32% of the patients presented with congestive heart failure, insulin-dependent diabetes (18%), renal failure (22%), peripheral vascular disease (31%), pulmonary disease (18%), and neurologic disorders (14%). An average of 2.6 +/- 0.9 grafts/patient were performed and the posterior descending artery or marginal branches of the circumflex artery or both were grafted in 90%. The 30-day mortality rate was 3.5% (n = 2). CONCLUSIONS: OPCABG can be performed with a reasonable low morbidity and mortality in this select group of high-risk patients. OPCABG is a reasonable, and might even be preferable, operative strategy in this high-risk group of patients.

Timing of transesophageal echocardiography in diagnosing patent foramen ovale in patients supported with left ventricular assist device.

Left ventricular assist devices unload the left ventricle and decrease left atrial pressure. This hemodynamic change may cause a right to left atrial shunt and hypoxemia in patients with patent foramen ovale. We prospectively studied the best time for performing diagnostic transesophageal echocardiography in left ventricular assist device patients. Intraoperative transesophageal echocardiography was performed in 14 patients before cardiopulmonary bypass was initiated and after left ventricular assist device was implanted. No patent foramen ovale was detected when transesophageal echocardiography was done before bypass, but a patent foramen ovale was found in 3 patients when transesophageal echocardiography was performed after left ventricular assist device was activated. Patent foramen ovale was confirmed by inspection in all three patients and surgically closed during the same procedure. There were no patent foramen ovale closure-related complications.

Myocardial contractile performance, preload recruitable stroke work relationships, and histomorphometric changes following off-pump and on-pump coronary bypass grafting of the left internal thoracic artery to the left anterior descending artery.

BACKGROUND: It has been shown that coronary artery bypass grafting without cardiopulmonary bypass (off-pump or OPCABG) preserves better cerebrocognitive, pulmonary, hepatorenal, and blood cell functions compared with onpump surgery because of an attenuated inflammatory response. The degrees of ischemia/reperfusion injury, myocardial protection, and quantitative changes in myocardial contractile performance following OPCABG have not been well documented. METHODS: A canine myocardial ischemic injury model (60-minute occlusion of the left anterior descending artery [LAD];; n = 30, 27-35 kg body weight) was used to quantitatively assess postoperative regional left ventricular function (sonomicrometry, micromanometry, preload recruitable stroke work [PRSW]). The left internal thoracic artery (LITA) was anastomosed to the distal LAD in off-pump and on-pump CABG with antegrade/retrograde cold blood cardioplegic arrest (cardiopulmonary bypass time, 58 +/- 2 minutes; cross-clamp time, 28 +/- 3 minutes). Anastomosis patency and endothelial changes at the anastomoses were analyzed with light microscopy and histopathologic techniques. RESULTS: LAD occlusion resulted in ischemia/infarction (creatine kinase-MB levels on-pump and off-pump versus the baselines were, respectively, 17.5 +/- 1.4 mg/L versus 1.5 +/- 0.3 mg/L [P <.05 by analysis of variance and t test]; and 19.5 +/- 1.8 mg/L versus 2.1 +/- 0.4 mg/L [P < .05]) and a significant decrease in regional myocardial function in both groups (50% decrease of PRSW). Revascularization led to reestablishment of myocardial function to baseline (on-pump and off-pump PRSW were, respectively, 57-196 10(3) erg.cm-2; [mean, 127 x10(3) +/- 25 x 10(3) erg . cm-2] and 81-98 10(3) erg.cm-2; [mean, 90 x 10(3) +/- 15 x 10(3) erg .cm-2]). All anastomoses were widely patent in all animals 14 days after surgery. There was a significantly increased intimal thickening at the 8-0 monofilament suture line in the off-pump LITA-to-LAD anastomoses. CONCLUSIONS: Compared with most commonly applied myocardial preservation techniques (cardiopulmonary bypass, hypothermic blood cardioplegic arrest), OPCABG provides at least equal myocardial protection, because there were no significant quantitative differences between off-pump and onpump CABG in myocardial contractile performance following LITA-to-LAD revascularization. The more prominent intimal thickening observed in OPCABG procedures is worrisome and deserves further investigation.

A rare case of sinus of valsalva-right atrial fistula secondary to an abscess perforation from underlying aortic valve endocarditis.

Sinus of Valsalva-right atrial fistulas are abnormal connections between the aorta and the right atrium, and present challenging surgical conditions. An extremely rare etiology of aorto-right atrial fistula is infective endocarditis. This case report presents a 21 year old Caucasian female patient who had native aortic valve Staphylococcus aureus endocarditis complicated by sinus of Valsalva abscess perforation associated with an acute heart block, an aorto-right atrial fistula, severe heart failure, and cardiogenic shock. She underwent emergent aortic valve replacement and complex sinus of Valsalva fistula pericardial patch reconstruction and repair. This case report further explores the advantages and disadvantages of different valves for different patient populations, and evaluates the patient's prosthesis mismatch and effective orifice area.

Flow cytometric evaluation of T cell activation markers after cardiopulmonary bypass.

Background. Cardiopulmonary bypass surgery (CPBS) is associated with an increased risk for infections or with subsequent organ dysfunction. As T cell activation is a central mechanism during inflammatory processes, we developed an assay to evaluate T cell activation pathways in patients undergoing CPBS. Methods. Blood was obtained from eleven patients undergoing CPBS preoperatively, on postoperative day (POD)-3, and on POD-7 and was stimulated with different concentrations of Concanavalin A (ConA). Cyclosporine and sirolimus, inhibiting different pathways of the T cell cycle, were added to blood ex vivo. Expression of T cell activation markers CD25 and CD95 was analyzed by flow cytometry. Results. In untreated blood, expression of CD25 and CD95 significantly increased with higher ConA concentrations (P < 0.05) and decreased for all ConA concentrations for both antigens over the study time (P < 0.05). Independently from the ConA concentration, inhibition of CD25 and CD95 expression was highest preoperatively for sirolimus and on POD-3 for cyclosporine. At all time points, inhibition of CD25 and CD95 expression was significantly higher after cyclosporine compared to sirolimus treatment (P < 0.001). Conclusion. Our results showed that different pathways of T cell activation are impaired after CPBS. Such knowledge may offer the opportunity to identify patients at risk for postoperative complications.

Bilateral versus single lung transplant for idiopathic pulmonary fibrosis.

OBJECTIVES: It is unknown if uni- or bilateral lung transplant is best for treatment of usual idiopathic pulmonary fibrosis. We reviewed our single-center experience comparing both treatments. MATERIALS AND METHODS: Between 2002 and 2011, one hundred thirty-eight patients at our institution underwent a lung transplant. Of these, 58 patients presented with idiopathic pulmonary fibrosis (56.9%) and were the focus of this study. RESULTS: Thirty-nine patients received a single lung transplant and 19 patients a bilateral sequential lung transplant. The mean patient age was 54 ± 10 years, and 69% were male. The intraoperative course was uneventful, save for 7 patients who needed extracorporeal membrane oxygenation support. Three patients had respiratory failure before the lung transplant that required mechanical ventilation and was supported by extracorporeal membrane oxygenation. Elevated pulmonary artery pressure > 40 mm Hg was identified as an independent predictor of early mortality by uni- and multivariate analysis (P = .01; OR 9.7). Using a Cox regression analysis, postoperative extracorporeal membrane oxyge-nation therapy (P = .01; OR 10.2) and the need for > 10 red blood cell concentrate during the first 72 hours after lung transplant (P = .01; OR 5.6) were independent predictors of long-term survival. Actuarial survival at 1 and 5 years was 65.6% and 55.3%, with no significant between-group differences (70.6% and 54.3%). CONCLUSIONS: Lung transplant is a safe and curative treatment for idiopathic pulmonary fibrosis. According to our results, unilateral lung transplant for idiopathic pulmonary fibrosis is an alternative to bilateral lung transplant and may affect the allocation process.

Role of dendritic cells in the context of acute cellular rejection: comparison between tacrolimus- or cyclosporine A-treated heart transplanted recipients.

BACKGROUND: In the last years many studies have been designed to predict risk of acute rejection and to adapt the immunosuppressive therapy. The importance of dendritic cells (DCs) in the immune response, especially their role in tolerance is known. Thus, we investigated the influence of tacrolimus (TAC)-based and of cyclosporine A (CsA)-based immunosuppressive therapies on dendritic cells and the incidence of rejection in heart transplant recipients. METHODS: Groups consisted of 14 CsA treated and 15 TAC treated patients. At different study time points (0, 3 and 6 months after study begin) peripheral blood from the patients was drawn to analyse (1) blood concentration of CsA or TAC (trough value) and (2) percentages of plasmacytoid and myeloid DC (p and mDC) subsets using flow cytometry. Histological rejection grading was performed of endomyocardial biopsies. RESULTS: TAC treated patients had significantly higher values of pDCs (CsA group 53.9%±13.0%; TAC group 67.5%±8.4%; p<0.05) and significantly lower values of mDCs than CsA treated patients (CsA group 58%±19.0%; TAC group 45.2%±10.7%; p<0.05). In general, HTx patients with rejection grade of ≥2 had significant lower values of pDCs (55.1%±16.2%) compared to patients without rejection (63.6%±10.5%; p<0.05). TAC-treated patients had significantly less rejections CsA-treated patients (CsA group 0.86±0.95; TAC group 0.2±0.4; p<0.05). CONCLUSIONS: Our results showed that HTx patients with high pDCs had a lower risk for rejection and that TAC-treated patients had higher pDCs values compared to CsA-treated patients. Future studies need to define individual pDC values to predict acute cellular rejection.

Heart transplantation and left ventricular assist device therapy: two comparable options in end-stage heart failure?

Heart transplantation is the only curative therapy for chronic heart failure, and it plays an important role in the treatment of chronic heart failure with a survival rate of approximately 50% of all patients after 10 years. This has to be kept in mind when alternative therapies enter into our daily routine in treating this patient population. However, the shortage of appropriate donor organs and the expanding pool of patients waiting for heart transplantation have led to growing interest in alternative strategies, particularly in left ventricular assist device (LVAD) therapy. With growing clinical experience and continued technical advances, continuous-flow pumps are evolving as a bridge to transplantation or as a destination therapy for advanced heart failure. Nevertheless, the importance of this new indication of chronic cardiac support compared to heart transplantation is still completely open and the object of controversial ongoing discussion. This review (1) describes the clinical use and long-term outcome of a currently available miniaturized LVAD in the context to the standard of care-heart transplantation, (2) provides an outlook of the ongoing process of further optimization of LVADs, and (3) comments on the challenges with assist devices as alternatives to transplantation with a 5-year outlook.