De novo sirolimus with low-dose tacrolimus versus full-dose tacrolimus with mycophenolate mofetil after heart transplantation--8-year results.

BACKGROUND: Although acute cellular rejection after heart transplantation (HTX) can be controlled by full-dose calcineurin inhibitor (CNI)-based immunosuppressive regimens, cardiac allograft vasculopathy (CAV), nephrotoxicity, and malignancy remain ongoing problems. To evaluate the potential beneficial effects of sirolimus and CNI reduction, we compared de novo low-dose tacrolimus and sirolimus with standard tacrolimus and mycophenolate mofetil (MMF)-based immunosuppression after HTX. METHODS: We analyzed a long-term follow-up cohort of 126 patients who underwent HTX during the period 1998-2005 and received either de novo low-dose tacrolimus/sirolimus (lowTAC/SIR; n = 61) or full-dose tacrolimus/MMF (TAC/MMF; n = 64). RESULTS: Freedom from treatment switch was less in the low TAC/SIR group than in the TAC/MMF group (51.7% vs 73.0%, p = 0.038) 8 years after HTX. Freedom from acute rejection was 90.6% in the low TAC/SIR group vs 80.3% in the TAC/MMF group (p = 0.100). There was no difference in freedom from International Society for Heart and Lung Transplantation CAV grade ≥ 1 (55.4% vs 60.0%, p = 0.922), time until CAV diagnosis (4.2 ± 2.0 years vs 3.2 ± 2.4 years, p = 0.087), and CAV severity (p = 0.618). The benefit of reduced early maximum creatinine for low TAC/SIR treatment (1.8 ± 0.9 mg/dl vs 2.4 ± 1.1 mg/dl in TAC/MMF group, p < 0.001) did not continue 5 years and 8 years after HTX (1.4 ± 0.4 mg/dl vs 1.7 ± 1.2 mg/dl, p = 0.333, and 1.6 ± 1.1 mg/dl vs 1.6 ± 0.8 mg/dl, p = 0.957). The trend for superior survival at 5 years with low TAC/SIR treatment (93.1% vs 81.3% in TAC/MMF group, p = 0.051) could not be confirmed after 8 years (84.7% vs 75.0%, p = 0.138). Multivariate analysis at 8 years did not reveal any benefit of low TAC/SIR treatment. CONCLUSIONS: Reduction of de novo CNI did not result in superior long-term renal function. Low-dose mechanistic target of rapamycin inhibition did not achieve any benefit in CAV prevention compared with full-dose TAC/MMF after HTX.

Applying the Gender Lens to Risk Factors and Outcome after Adult Cardiac Surgery.

BACKGROUND: Applying the gender lens to risk factors and outcome after adult cardiac surgery is of major clinical interest, as the inclusion of sex and gender in research design and analysis may guarantee more comprehensive cardiovascular science and may consecutively result in a more effective surgical treatment as well as cost savings in cardiac surgery. METHODS: We have reviewed classical cardiovascular risk factors (diabetes, arterial hypertension, hyperlipidemia, smoking) according to a gender-based approach. Furthermore, we have examined comorbidities such as depression, renal insufficiency, and hormonal influences in regard to gender. Gender-sensitive economic aspects have been evaluated, surgical outcome has been analyzed, and cardiovascular research has been considered from a gender perspective. RESULTS: The influence of typical risk factors and outcome after cardiac surgery has been evaluated from a gender perspective, and the gender-specific distribution of these risk factors is reported on. The named comorbidities are listed. Economic aspects demonstrated a gender gap. Outcome after coronary and valvular surgeries as well as after heart transplantation are displayed in this regard. Results after postoperative use of intra-aortic balloon pump are shown. Gender-related aspects of clinical and biomedical cardiosurgical research are reported. CONCLUSIONS: Female gender has become an independent risk factor of survival after the majority of cardiosurgical procedures. Severely impaired left ventricular ejection fraction independently predicts survival in men, whereas age does in females.

Preconditioning with levosimendan before implantation of left ventricular assist devices.

In this retrospective study, we investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before left ventricular assist device (LVAD) implantation on outcome and survival. Nine consecutive LVAD patients (seven suffering from dilative cardiomyopathy and two from ischemic cardiomyopathy) with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 µg/kg body weight/min for 24 h before implantation of the assist device (seven HeartWare and two Jarvik 2000). Administration of levosimendan was safe and had not to be discontinued in any patient. We observed no relevant side effects. Twelve-month survival after implantation of the LVAD was 89% representing a superior outcome compared with the fifth INTERMACS registry data with 75% survival. Two temporary extracorporeal membrane-oxygenation implantations were necessary due to intraoperative right ventricular dysfunction. Only one patient died 5 weeks after LVAD implantation of multiorgan failure, five patients were successfully transplanted, and three patients underwent LVAD implantation for destination therapy. Levosimendan might improve clinical outcome and survival when used as pretreatment in patients with right heart insufficiency prior to LVAD implantation. However, we recommend a larger controlled trial in the future to confirm our preliminary results.

Extracorporeal life support and left ventricular unloading in a non-intubated patient as bridge to heart transplantation.

INTRODUCTION: Veno-arterial extracorporeal life support (ECLS) is a well-established bridging therapy in patients with cardiac or pulmonary failure to maintain organ function and is frequently performed in patients who are not intubated. However, severly impaired cardiac function can occur pulmonary edemy in these patients, necessitating left ventricular unloading. METHODS AND RESULTS: In this study we report a 37-year old female patient with familiar dilated cardiomyopathy suffering from acute biventricular heart failure. After implantation of a peripheral ECLS, the decreased ventricular led to refractory pulmonary edema. To unload the left ventricle, an percutaneous balloon atrioseptostomy was performed without intubating the patient. The left ventricle was vented by the venous cannula resting inside the atrioseptostomy. After twelve days on ECLS, the patient underwent orthotopic heart transplantation. The postoperative course was uneventful and the patient discharged from intensive care unit four days after surgery. CONCLUSIONS: In this report we present a patient in which the hybrid technique of ECLS with secondary left ventricular unloading was successfully used as a bridge to transplant therapy. This procedure may offer an alternative bridge-to-decision options in selected patients, including those that were not intubated or anaesthetized.

Local expression of myocardial galectin-3 does not correlate with its serum levels in patients undergoing heart transplantation.

BACKGROUND: Galectins are a family of soluble lectins expressed in a variety of tissues, which play many important regulatory roles in inflammation, immunity, and cancer. The up-regulation of galectin-3 in hypertrophied hearts and the development of fibrosis have been shown in experimental studies. Increased galectin-3 levels are associated with poor long-term survival in end-stage heart failure (HF). We examined the relationship between plasma galectin-3 levels and the myocardial tissue expression of galectin-3 in patients with end-stage HF. MATERIAL AND METHODS: Expression of galectin-3 was assessed by real-time PCR and immunohistochemistry in left ventricle and atrial myocardium of patients (n=12) with end-stage HF undergoing heart transplantation. All patients gave informed consent. Serum expression of galectin-3 was assessed by ELISA in serum from 20 patients with end-stage HF and in 20 healthy volunteers who served as controls. RESULTS: Expression of galectin-3 was similar in the myocardium of patients in comparison to the control group, independently of the anatomical area (HF vs. healthy ventricle: 1.73E-02 vs. 1.50 E-02; HF vs. healthy atrium: 1.32E-02 vs. 1.16E-02). However, serum expression of galectin-3 was significantly higher in the end-stage HF patients compared to the healthy controls (13.02±10.6 vs. 3.7±1.3 ng/ml; p<0.05). CONCLUSIONS: Plasma galectin-3 levels correlate with the ejection fraction and are elevated in patients with HF. However, the myocardial expression of galectin-3 does not correlate with the ventricular ejection fraction. Our data support the use of galectin-3 as a marker of heart insufficiency.

Renal recovery after conversion to an everolimus-based immunosuppression in early and late heart transplant recipients: a 12-month analysis.

OBJECTIVES: Calcineurin inhibitor-induced nephrotoxicity reduces long-term patient survival after heart transplant. Proliferation signal inhibitors, in combination with or replacing calcineurin inhibitors, may preserve or improve renal function. We evaluated the effect of calcineurin inhibitor-reduction and withdrawal in everolimus-based immunosuppression on renal function after a heart transplant. MATERIALS AND METHODS: Twenty-four patients with creatinine clearance < 1 mL/s (60 mL/min) were switched from tacrolimus and mycophenolate mofetil to low-dose tacrolimus/everolimus if their heart transplant was ≤ 1 year ago (group 1, n=13) and to everolimus/mycophenolate mofetil if their heart transplant was > 1 year ago (group 2, n=11). Serum creatinine levels and calculated creatinine clearance were analyzed up to 12 months after conversion. RESULTS: The switch in immunosuppression was associated with a significant decrease/increase of serum creatinine/creatinine clearance in both groups between baseline and month 12 (group 1, creatinine, 221.0 ± 70.7 to 159.1 ± 44.2 µmol/L (2.5 ± 0.8 to 1.8 ± 0.5 mg/dL); creatinine clearance, 0.75 ± 0.45 to 1.01 ± 0.50 mL/s (45.1 ± 26.7 to 60.5 ± 29.7 mL/min) (P < .01 each); group 2, creatinine, 247.5 ± 79.6 to 159.1 ± 44.2 µmol/L (2.8 ± 0.9 to 1.8 ± 0.5 mg/dL), creatinine clearance, 0.57 ± 0.23 to 0.93 ± 0.33 mL/s (34.1 ± 13.8 to 55.7 ± 19.6 mL/min) [P < .05 each]) with no significant group difference in the creatinine and the creatinine clearance levels after switching. No acute rejections or deaths occurred during the 12-month follow-up. Four patients (36.4%) from group 2 and 1 patient (7.7%) from group 1 discontinued everolimus because of adverse events. CONCLUSIONS: Everolimus allows calcineurin inhibitor-reduction and withdrawal after a heart transplant, resulting in improved renal function. However, adverse effects are common and lead to a high reconversion rate.

Norepinephrine versus dopamine pretreatment of potential heart donors - impact on long-term outcome.

BACKGROUND: Current guidelines advocate administration of inotropic agents to stabilize potential deceased heart-beating donors. A consensus on the specific agent or combination therapy is lacking. We thus initiated a retrospective analysis of patients being transplanted at our center in a matched-pair study design focusing on survival after donor pre-treatment either with norepinephrine or dopamine. MATERIAL AND METHODS: 936 patients (759 male; 177 female; mean age: 47.5 ± 15.4 years) were transplanted at our center between 8/1981 and 12/2010. An overall of 22 patient pairs (all male; mean age 55.4 ± 7.5 years; range 23-67 years) were matched according to our strict criteria. During follow-up (5037 ± 1791 days) 11 deaths occurred. Overall survival in both groups was not different (p=0.1438). RESULTS: In a sub-population analysis of all patient-pairs that completed 5-year follow-up (n=19), Kaplan-Meier analysis revealed significant superior survival of recipients that received hearts pre-treated with norepinephrine vs. dopamine pre-treatment (p=0.0368). CONCLUSIONS: Neither norepinephrine nor dopamine pre-treatment of potential heart donors showed superior overall survival. In a sub-population of long-term survivors norepinephrine pre-treatment was associated with better survival in a rather small cohort of heart transplant recipients. These findings underscore the urgent need of further prospective multicenter randomized trials to recommend a preferable adrenergic therapy.

Ten-year results of a randomized trial comparing tacrolimus versus cyclosporine a in combination with mycophenolate mofetil after heart transplantation.

BACKGROUND: Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization. METHODS: Ten-year follow-up data of 60 patients included in a prospective, randomized trial between 1998 and 2000 were analyzed as intention-to-treat (TAC-MMF n=30; CsA-MMF n=30). Baseline characteristics were well balanced. Cardiac allograft vasculopathy (CAV) was graduated in accordance with the new ISHLT classification. RESULTS: Survival at 1, 5, and 10 years was 96.7%, 80.0%, and 66.7% for TAC-MMF and 90.0%, 83.3%, and 80.0% for CsA-MMF (P=ns). Freedom from acute rejection (AR) was significantly higher in TAC-MMF versus CsA-MMF (65.5% vs. 21.7%, log-rank 8.3, P=0.004). Freedom from ISHLT≥CAV1 after 5 and 10 years was in TAC-MMF 64.0% and 45.8%, and in CsA-MMF 36.0% (log-rank 3.0, P=0.085) and 8.0% (log-rank 9.0, P=0.003). No difference in long-term results for freedom from coronary angioplasty or stenting, renal dysfunction, diabetes mellitus, CMV infection, or malignancy was detected. CONCLUSION: Cross-over effects because of treatment switch may result in impairment of significance between the groups. The long-term analysis resulted in a significant difference in manifestation of CAV between the groups after 10 years. Less rejection in the TAC-group might have contributed to the lower incidence of CAV. Superior freedom from AR and CAV in the TAC-MMF group did not result in better long-term survival.

Tacrolimus with mycophenolate mofetil or sirolimus compared with calcineurin inhibitor-free immunosuppression (sirolimus/mycophenolate mofetil) after heart transplantation: 5-year results.

BACKGROUND: Despite improvements in immunosuppressive therapy, the most advantageous combination for cardiac transplant recipients has not been established. This randomized controlled trial was performed to evaluate the efficacy and safety of 3 immunosuppressive protocols. METHODS: Between 2003 and 2005, 78 de novo cardiac transplant recipients were randomized 2:2:1 to receive steroids and tacrolimus plus mycophenolate mofetil (TAC/MMF; n = 34), TAC and sirolimus (TAC/SRL; n = 29), or SRL and MMF (SRL/MMF) plus anti-thymocyte globulin (ATG; n = 15). Steroids were withdrawn after 6 months. RESULTS: The 5-year survival was 85.3% for TAC/MMF, 93.1% for TAC/SRL, and 86.7% for SRL/MMF (p = 0.31 for TAC/MMF vs TAC/SIR; p = 0.47 for TAC/MMF vs SIR/MMF and p = 0.86 for TAC/SIR vs SIR/MMF). Despite the use of ATG, patients in the SRL/MMF group revealed numerically fewer freedom from acute rejection episodes: TAC/MMF, 82.4%; TAC/SRL, 85.2%; SRL/MMF, 73.3% (p = 0.33). Mean creatinine at 5 years revealed preservation of renal function in the SRL/MMF vs the TAC/MMF group (p = 0.045): TAC/MMF, 1.70±0.91 mg/dl; TAC/SRL, 1.44±0.65 mg/dl; and SRL/MMF, 1.25±0.46 mg/dl. Freedom from cardiac allograft vasculopathy was improved in the SRL/MMF group (93.3%) compared with TAC/MMF (73.5%) and TAC/SRL (80.8%) groups, reaching no statistical significance. Freedom from cytomegalovirus infection was TAC/MMF, 72.2%; TAC/SRL, 89.7%; and SRL/MMF, 86.7%. There was a trend toward improved freedom from cytomegalovirus infection with TAC/SRL vs TAC/MMF (p = 0.076). More frequent discontinuations of study medication occurred in SRL-based immunosuppression protocols (TAC/SRL vs TAC/MMF, p = 0.034; SRL/MMF vs TAC/MMF, p = 0.003). CONCLUSIONS: The 3 strategies yield no survival advantage at 5 years, with higher numeric rates of rejection and adverse effects in the calcineurin inhibitor-free arm. A trend was observed in favor of freedom from cardiac allograft vasculopathy and preservation of renal function in the calcineurin inhibitor-free arm. However, the clinical relevance on outcomes is unclear because only few patients were receiving the assigned treatment protocols.

Gender does matter: gender-specific outcome analysis of 67,855 heart transplants.

BACKGROUND: Gender differences between donor and recipient might have an impact on the outcome after heart transplantation (HT). Data of more than 67,000 patients registered at the International Society of Heart Lung Transplantation (ISHLT) were reviewed focusing on the influence of gender differences on short- and long-term outcome after HT. METHODS: We performed a retrospective analysis of 67,855 cardiac allograft recipients. They received orthotopic HT between January 1, 1980 and June 30, 2009. In contrast to other studies the data for gender differences (donor gender and recipient gender) were calculated with respect to actuarial and conditional survival (without 30-day mortality). RESULTS: One-year survival was highest in male recipients of male donor hearts (mR/mD: 83.74%). The lowest 1-year outcome showed male recipients of female donor organs (mR/fD: 78.95%). Best 5-year survival rates were shown by male recipients with male donor organs (70.75%, p < 0.0001). These differences disappeared in survival conditional to 1 year, indicating that gender predominantly influences short-term outcome. CONCLUSIONS: The combination male recipient/female donor carries a higher risk for early mortality, whereas female recipients/male donor reveals favorable short-term results. Gender-matched HT would be ideal, but not suitable in practice because of the shortage of organs.

Everolimus in heart transplantation: an update.

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

Arterial chimney graft cannulation for interventional lung assist.

An interventional lung assist membrane ventilator (iLA) for arteriovenous extracorporeal CO2 removal was connected to a small-diameter femoral artery by use of a chimney graft in an underweight patient with acute respiratory failure and a previous history of heart-lung transplantation. This concept offers additional therapeutic options in underweight patients requiring extracorporeal CO2 removal with arterial vessels that are too small for percutaneous arterial cannulation with standard-sized percutaneous insertable iLA cannulae.

Gender-based analysis of outcome after heart transplantation.

OBJECTIVES: Gender differences between donors and recipients might have an effect on outcome after heart transplantation. Literature and registries reveal controversial results. We reviewed 1000 heart transplantations at our center focusing on the influence of gender differences on short- and long-term outcome after heart transplantation. MATERIALS AND METHODS: We performed a retrospective analysis of 1000 (960 primary and 40 redo-heart transplantations) between August 1981 and July 2008. In contrast to other studies, the data for gender differences (donor gender and recipient gender) were evaluated for recipient survival and survival conditional to early mortality. RESULTS: Female donors are significantly older than male donors (females, 36.5 ± 14.5 years; males, 31.2 ± 13.8 years). One-year survival was significantly inferior in male recipients receiving female donor hearts (mR/fD: 73.7%) compared to females receiving male donor organs (fR/mD: 90.9%) (P = .045). Univariate analysis revealed that, for recipients who survived > 1 year, survival at 10 years was significantly greater for female donors and female recipients (90%) than it was for male donors and male recipients (72%; P = .034). Multivariate analysis showed that the gender combination with female donors and female recipients was an independent indicator for greater long-term survival (P = .04). CONCLUSIONS: The gender combination of female donors and male recipients had a greater risk for early mortality after heart transplantation, and the combination of male donors and female recipients resulted in favorable short-term outcomes. In long-term follow-up, recipients of hearts from female donors had better survival, especially female recipients.

Detection of significant coronary artery stenosis with cardiac dual-source computed tomography angiography in heart transplant recipients.

Present study evaluates clinical feasibility of cardiac dual-source computed tomography angiography (DSCTA) to detect significant coronary stenosis because of chronic allograft vasculopathy (CAV) after heart transplantation (HTX). An overall of 51 consecutive heart transplant recipients (43 men, 8 women, mean age: 52.3 ± 13.6 years) underwent DSCTA 1 ± 2 days before annual routine invasive coronary angiography (ICA). Three patients were excluded from further analysis. Total 714/717 (99.6%) segments in remaining 48 patients were depicted in diagnostic image quality by DSCTA with three vessel segments in two patients being additionally excluded because of motion artefacts. On a segment-based analysis, sensitivity, specificity, and diagnostic accuracy (DA) for detection of significant stenosis were calculated as 100%, 98.9% and 98.9% respectively. On a patient-based evaluation, sensitivity, specificity and DA were 100%, 86.0% and 93.0% respectively for remaining 46 patients. Negative predictive value (NPV) was 100%. DSCTA enables diagnosis and especially the exclusion of significant coronary artery stenosis in patients after HTX with a high NPV. The low rate of excluded vessel segments compared with former studies indicates improvement in image acquisition and robustness of latest scanner technology and thus may make subsequent annual invasive coronary angiography unnecessary.

Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases.

Vasodilatory shock frequently occurs after cardiac surgery, particularly after cardiac assist device implantation. This complication is often associated with high mortality, especially if refractory to conventional vasoconstrictor treatment. Methylene blue, a guanylate cyclase inhibitor, has been successfully used in the management of vasodilatory shock associated with cardiopulmonary bypass. We present four successive cases after implantation of cardiac assist devices suffering from norepinephrine and vasopressin refractory severe vasodilatory shock. In all patients, administration of a single dose of methylene blue (2 mg/kg body weight) resulted in an immediate and persistent decrease in vasoconstrictor dosages and serum lactate concentrations. Despite of this benefit, all patients deceased during hospital stay, however, this was not related to the methylene blue treatment. Methylene blue seems to be a promising therapeutical option in patients with otherwise resistant vasodilatory shock after cardiac assist device implantation. However, controlled clinical trials are necessary to substantiate safety and efficacy.