Strategies for routine biopsies in heart transplantation based on 8-year results with more than 13,000 biopsies

The endomyocardial biopsy (EMB) in heart transplant recipients has been considered the "gold standard" for diagnosis of graft rejection (REJ). The purpose of this retrospective study is to develop long-term strategies (frequency and postoperative duration of EMB) for REJ monitoring. Between 1985 and 1992, 346 patients (mean age 44.5 years, female patients = 14%) received 382 heart grafts. For graft surveillance EMBs were performed according to a fixed schedule depending on postoperative day and the results of previous biopsies. In the first year the average number (no.) of EMBs/patient was 20 with 19% positive for REJ in the first quarter, dropping to 7% REJ/EMB by the end of the first year. The percentage of REJ/EMB declined annually from 4.7% to 4.5%, 2.2% and less than 1% after the fifth year. Individual biopsy results in the first 3 postoperative months had little predictive value. Patients with fewer than two REJ (group 1), vs patients with two or more REJ in the first 6 postoperative months (group 2), were significantly less likely to reject in the second half of the first year (group 1: 0.29 +/- 0.6 REJ/patient; group 2:0.83 +/- 1.3 REJ/patient; P < 0.001) and third postoperative year (group 1:0.12 +/- 0.33 REJ/patients; group 2:0.46 +/- 0.93 REJ/patient; P < 0.05). In conclusion, routine EMBs in the first 3 postoperative months have only limited predictive value, however the number of routine EMBs can be drastically reduced later depending on the intermediate postoperative REJ pattern.

Myocardial preservation with the UW solution. First European results in clinical heart transplantation

In recent years, there is a growing body of evidence that the University of Wisconsin (UW) solution offers many advantages in organ preservation with regard to preservation quality and time. We, therefore, conducted the first European prospective, randomized, clinical trial comparing myocardial performance after preservation with UW and St. Thomas Hospital (ST) solution. Preliminary results indicated superior heart function after preservation with UW solution.

Heart rate response determines long term exercise capacity after heart transplantation

BACKGROUND: Exercise capacity after heart transplantation (HTx) remains limited despite normal left ventricular systolic function of the allograft. Various clinical and haemodynamic parameters are predictive of exercise capacity following HTx. However, the predictive significance of chronotropic competence has not been demonstrated unequivocally despite its immediate relevance for cardiac output. AIMS: This study assesses the predictive value of various clinical and haemodynamic parameters for exercise capacity in HTx recipients with complete chronotropic competence evolving within the first 6 postoperative months. METHODS: 51 patients were enrolled in this exercise study. Patients were included when at least >6 months after HTx and without negative chronotropic medication or factors limiting exercise capacity such as significant transplant vasculopathy or allograft rejection. Clinical parameters were obtained by chart review, haemodynamic parameters from current cardiac catheterisation, and exercise capacity was assessed by treadmill stress testing. A stepwise multiple regression model analysed the proportion of the variance explained by the predictive parameters. RESULTS: The mean age of these 51 HTx recipients was 55.4 +/- 13.2 yrs on inclusion, 42 pts were male and the mean time interval after cardiac transplantation was 5.1 +/- 2.8 yrs. Five independent predictors explained 47.5% of the variance observed for peak exercise capacity (adjusted R2 = 0.475). In detail, heart rate response explained 31.6%, male gender 5.2%, age 4.1%, pulmonary vascular resistance 3.7%, and body-mass index 2.9%. CONCLUSION: Heart rate response is one of the most important predictors of exercise capacity in HTx recipients with complete chronotropic competence and without relevant transplant vasculopathy or acute allograft rejection.

Experimental heart transplantation: effect of cyclosporine on expression and activity of metzincins

Metzincins, such as matrix metalloproteases (MMP), and extracellular matrix (ECM) proteins are differentially regulated in inflammation. We hypothesised that metzincins are also dysregulated in experimental acute cardiac allograft rejection. We investigated the Dark Agouti-to-Lewis (DA-to-Lew) rat model of acute cardiac allograft rejection. Cyclosporine (CsA) (7.5 mg/kg/d) was given from transplantation to sacrifice (day +5). At that time, mRNA levels were analysed by Affymetrix genechip and quantitative reverse transcription polymerase chain reaction (qRTPCR). MMP protein and activities were analysed by immunohistology, fluorometry, zymography and Western blots. In untreated rejected DA allografts, mRNA levels of MMP-2/-7/-9/-/12-/14, a disintegrin and metalloprotease (ADAM)-17, tissue inhibitor of metalloprotease (TIMP)-1/-3 were increased, whereas MMP-11/-16/-24 and TIMP-2/-4 were lowered compared to native DA hearts. With respect to these untreated allografts, CsA lowered mRNA levels of MMP-7, TIMP-1/-3 (TIMP-2/-4 remained relatively low) and ADAM17, but augmented mRNA levels of MMP-11/-16/-23 and of many ECM genes. Immunohistology showed increased staining of MMP-2 in acute rejection (AR). Overall MMP activity was augmented in both transplanted groups, but CsA reduced MMP-9 activity and MMP-14 production. Taken together, MMP and TIMP were upregulated during acute AR. CsA ameliorated histology of rejection but showed potential pro-fibrotic effects. Thus, MMP and TIMP may play a role in acute cardiac allograft rejection, and beneficial modification of the MMP-ECM balance requires interventions beyond CsA.

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival

BACKGROUND: Restrictive lung defects are associated with higher mortality in patients with acquired chronic heart failure. We investigated the prevalence of abnormal lung function, its relation to severity of underlying cardiac defect, its surgical history, and its impact on outcome across the spectrum of adult congenital heart disease. METHODS AND RESULTS: A total of 1188 patients with adult congenital heart disease (age, 33.1+/-13.1 years) undergoing lung function testing between 2000 and 2009 were included. Patients were classified according to the severity of lung dysfunction based on predicted values of forced vital capacity. Lung function was normal in 53% of patients with adult congenital heart disease, mildly impaired in 17%, and moderately to severely impaired in the remainder (30%). Moderate to severe impairment of lung function related to complexity of underlying cardiac defect, enlarged cardiothoracic ratio, previous thoracotomy/ies, body mass index, scoliosis, and diaphragm palsy. Over a median follow-up period of 6.7 years, 106 patients died. Moderate to severe impairment of lung function was an independent predictor of survival in this cohort. Patients with reduced force vital capacity of at least moderate severity had a 1.6-fold increased risk of death compared with patients with normal lung function (P=0.04). CONCLUSIONS: A reduced forced vital capacity is prevalent in patients with adult congenital heart disease; its severity relates to the complexity of the underlying heart defect, surgical history, and scoliosis. Moderate to severe impairment of lung function is an independent predictor of mortality in contemporary patients with adult congenital heart disease.

Lactic acidosis following heart transplantation: a common phenomenon?

BACKGROUND Lactic acidosis (LAc) is a common form of metabolic acidosis early after heart transplantation (HTX). The mechanism remains unclear. This study analyzed 13 patients who developed severe LAc after HTX. METHODS From a series of 60 consecutive heart transplant patients, we identified 13 patients with LAc in the first hours following HTX. Nine patients with normal or mildly elevated lactate levels (<5.0 mmol/l) were investigated as controls. RESULTS Thirteen patients developed a moderate or severe LAc (up to 14.6 mmol/l) after HTX. Serum lactate levels increased immediately following surgery with a peak after 6.3+/-1.4 h, spontaneously returning to normal values within 24 h. In contrast to the control group, a significant correlation was found between the maximal serum lactate level and the maximal dosage of inotropic drugs (r=0.93, P<0.02), administered during the reperfusion phase and continued for 12-24 h postoperatively. No correlation was found between LAc and blood gas analysis during extracorporeal perfusion period. CONCLUSION LAc can occur after HTX and seems to be related to the inotropic support of the graft. In contrast to other forms, LAc after HTX has an excellent prognosis and resolves rapidly and spontaneously without treatment. The fact that inotropic support during and immediately after cardiac transplantation can enhance preexisting severe peripheral metabolic cellular dysfunction remains hypothetical.

Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice.

Respiratory diseases are a major cause of mortality and morbidity worldwide. Current treatments offer no prospect of cure or disease reversal. Transplantation of pulmonary progenitor cells derived from human embryonic stem cells (hESCs) may provide a novel approach to regenerate endogenous lung cells destroyed by injury and disease. Here, we examine the therapeutic potential of alveolar type II epithelial cells derived from hESCs (hES-ATIICs) in a mouse model of acute lung injury. When transplanted into lungs of mice subjected to bleomycin (BLM)-induced acute lung injury, hES-ATIICs behaved as normal primary ATIICs, differentiating into cells expressing phenotypic markers of alveolar type I epithelial cells. Without experiencing tumorigenic side effects, lung injury was abrogated in mice transplanted with hES-ATIICs, demonstrated by recovery of body weight and arterial blood oxygen saturation, decreased collagen deposition, and increased survival. Therefore, transplantation of hES-ATIICs shows promise as an effective therapeutic to treat acute lung injury.

Heart transplantation with donation after circulatory determination of death.

The constant shortage of available organs is a major obstacle and limiting factor in heart transplantation; the discrepancy between the number of donors and potential recipients leads to waiting-list mortality of 10-12% per year in Europe and the USA. If adopted for heart transplantation, donation after circulatory determination of death (DCDD) would be expected to improve the availability of organs substantially for both adults and children. With DCDD, however, hearts to be transplanted undergo a period of warm ischaemia before procurement, which is of particular concern because tissue damage occurs rapidly and might be sufficient to preclude transplantation. Nonetheless, the heart is able to withstand limited periods of warm ischaemia, which could provide a window of opportunity for DCDD. Development of clinical approaches specifically for DCDD is critical for the exploitation of these organs, because current practices for donor heart procurement, evaluation, and storage have been optimized for conventional donation after brain death, without consideration of warm ischaemia before organ procurement. Establishment of clinical protocols and ethical and legal frameworks for DCDD of other organs is underway. This Review provides a timely evaluation of the potential for DCDD in heart transplantation.

Favourable mid-term outcome after heart transplantation for late Fontan failure.

OBJECTIVES Fontan failure (FF) represents a growing and challenging indication for paediatric orthotopic heart transplantation (OHT). The aim of this study was to identify predictors of the best mid-term outcome in OHT after FF. METHODS Twenty-year multi-institutional retrospective analysis on OHT for FF. RESULTS Between 1991 and 2011, 61 patients, mean age 15.0 ± 9.7 years, underwent OHT for failing atriopulmonary connection (17 patients = 27.8%) or total cavopulmonary connection (44 patients = 72.2%). Modality of FF included arrhythmia (14.8%), complex obstructions in the Fontan circuit (16.4%), protein-losing enteropathy (PLE) (22.9%), impaired ventricular function (31.1%) or a combination of the above (14.8%). The mean time interval between Fontan completion and OHT was 10.7 ± 6.6 years. Early FF occurred in 18%, requiring OHT 0.8 ± 0.5 years after Fontan. The hospital mortality rate was 18.3%, mainly secondary to infection (36.4%) and graft failure (27.3%). The mean follow-up was 66.8 ± 54.2 months. The overall Kaplan-Meier survival estimate was 81.9 ± 1.8% at 1 year, 73 ± 2.7% at 5 years and 56.8 ± 4.3% at 10 years. The Kaplan-Meier 5-year survival estimate was 82.3 ± 5.9% in late FF and 32.7 ± 15.0% in early FF (P = 0.0007). Late FF with poor ventricular function exhibited a 91.5 ± 5.8% 5-year OHT survival. PLE was cured in 77.7% of hospital survivors, but the 5-year Kaplan-Meier survival estimate in PLE was 46.3 ± 14.4 vs 84.3 ± 5.5% in non-PLE (P = 0.0147). Cox proportional hazards identified early FF (P = 0.0005), complex Fontan pathway obstruction (P = 0.0043) and PLE (P = 0.0033) as independent predictors of 5-year mortality. CONCLUSIONS OHT is an excellent surgical option for late FF with impaired ventricular function. Protein dispersion improves with OHT, but PLE negatively affects the mid-term OHT outcome, mainly for early infective complications.

Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II.

AIMS A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. METHODS AND RESULTS Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. CONCLUSION For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.

Report of eighteenth conference of cardiovascular training grant program directors National Heart and Lung Institute.

Mode of access: Internet.

Somebody Else's heart inside me: A descriptive study of psychological problems after a heart transplantation

This Article does not have an abstract