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Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center's DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs.
BACKGROUND - Mechanical circulatory support is an accepted strategy to bridge patients to heart transplantation (HTx). Among mechanical circulatory support patients who go on to HTx, factors associated with improved graft survival have not been fully elucidated.
METHODS - Using the Scientific Registry for Transplant Recipients, we identified adults who were treated with a left ventricular assist device (LVAD) or total artificial heart (TAH) before HTx. Kaplan-Meier and multivariate Cox regression models were used to identify patient, donor, and device characteristics associated with graft survival.
RESULTS - Between January 1997 and February 2012, 2,785 adults underwent HTx. Before HTx, 2,674 patients were treated with a LVAD (HeartMate XVE, 724; HeartMate II, 1,882; HeartWare, 68), and 111 were treated with a TAH. Follow-up averaged 25 ± 24 months. Gender mismatch occurred in 23%. Graft survival did not differ between LVAD groups (all p > 0.168), but TAH was associated with reduced graft survival compared with LVADs (p < 0.001). After controlling for device type (LVAD vs TAH), lower recipient pulmonary vascular resistance, shorter ischemic time, younger donor age, donor-to-recipient gender match, and higher donor-to-recipient body mass index ratio were independent predictors of longer graft survival (all p < 0.05).
CONCLUSIONS - TAH was associated with reduced graft survival after transplant, and survival did not differ between the LVAD device groups. Additional variables that were independently associated with graft survival were donor age, recipient peripheral vascular resistance, ischemic time, gender match, and donor-to-recipient body mass index ratio. Recognition of these factors may inform decisions regarding device support and donor suitability.
Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Outcomes in cases of adult accidental ABO incompatible cardiac transplantation are highly variable, with some patients suffering nearly immediate catastrophic antibody-mediated rejection while others (~37%-45%) survive. We hypothesize that these disparate outcomes could be influenced by variations in blood group antigen expression on allograft endothelium.
METHODOLOGY - Immunohistochemical stains for blood Group A antigen were performed on cardiac tissue from 18 blood Type A cadavers. Staining was evaluated by two distinct modalities: semiquantitative light microscopy, which measured the intensity of antigen expression on endothelium, and quantitative digital analysis, which determined the percentage of the total tissue section area staining positive for blood Group A antigen. These data were used to compute a Comprehensive Expression Index (CEI) of blood Group A antigen expression for each specimen.
RESULTS - Semiquantitative light microscopic examination determined that endothelium was stained with low intensity in four (22%) myocardial samples, intermediate intensity in five (28%) samples, and high intensity in nine (50%) samples. Quantitative digital analysis revealed a range in the percentage of total cross sectional area composed of blood Group A-positive signal (median, 2.69%; interquartile range, 1.68%-2.94%). Increased percentage of total cross sectional area composed of blood Group A-positive signal was positively associated with patient age (P=.0037). The CEI showed a broad range, with a median of 5.27 and an interquartile range of 2.92-8.22.
CONCLUSIONS - There are little data available regarding interindividual differences in blood Group A antigen expression in cardiac endothelium. Here, we report interindividual variation in endothelial expression of blood Group A antigen in 18 specimens. These variations may help to explain disparate outcomes in cases of accidental ABO incompatible cardiac transplantation in adults.
Published by Elsevier Inc.
In 2015, there will be an estimated 11.3 million cancer survivors. With an increasing population of cancer survivors, it is imperative to understand the treatment options available and outcomes for chemotherapy-related cardiomyopathy. Anthracycline-based chemotherapy causes heart failure in approximately 5% of patients. Orthotopic heart transplantation (OHT) is an option for cancer survivors in complete remission who develop end-stage heart failure. We examined retrospective OHT data collected from the United Network of Organ Sharing from 1987 to 2011. The primary aim was to characterize the survival in patients with either the primary diagnosis of "dilated cardiomyopathy: Adriamycin" (DCA) versus "all other" causes of cardiomyopathy. The secondary aim was to define the differences in the primary cause of death and to describe the temporal relationship of DCA OHT. The United Network of Organ Sharing database identified 453 OHTs for the diagnosis of DCA and 51,312 OHTs for all other causes of cardiomyopathy. The DCA group was significantly younger with a greater percentage of women. After adjusting for age, gender, and history of malignancy, the 10-year survival curves showed that patients with DCA have an improved survival compared to those with all other causes of cardiomyopathy (hazard ratio 1.28, p = 0.026). No difference was found in the primary cause of death between the 2 groups. A statistically significant increasing temporal trend was seen in the number of OHTs for the diagnosis DCA. In conclusion, patients who undergo OHT for DCA have favorable 10-year survival, making OHT a good therapeutic option for end-stage heart failure due to anthracyclines. Additionally, no increased risk of cancer-related deaths was found in the DCA group, demonstrating that recurrent malignancy does not affect long-term survival. The temporal trends demonstrated that DCA remains a significant problem for cancer survivors.
Copyright © 2013 Elsevier Inc. All rights reserved.
OBJECTIVE - Axillary intra-aortic balloon pump therapy has been described as a bridge to transplant. Advantages over femoral intra-aortic balloon pump therapy include reduced incidence of infection and enhanced patient mobility. We identified the patients who would benefit most from this therapy while awaiting heart transplantation.
METHODS - We conducted a single-center, retrospective observational study to evaluate outcomes from axillary intra-aortic balloon pump therapy. These included hemodynamic parameters, duration of support, and success in bridging to transplant. We selected patients on the basis of history of sternotomy, elevated panel-reactive antibody, and small body habitus. Patients were made to ambulate aggressively beginning on postoperative day 1.
RESULTS - Between September 2007 and September 2010, 18 patients underwent axillary intra-aortic balloon pump therapy. All patients had the devices placed through the left axillary artery with a Hemashield side graft (Boston Scientific, Natick, Mass). Before axillary placement, patients underwent femoral placement to demonstrate hemodynamic benefit. Duration of support ranged from 5 to 63 days (median = 19 days). There was marked improvement in ambulatory potential and hemodynamic parameters, with minimal blood transfusion requirements. There were no device-related infections. Some 72% of the patients (13/18) were successfully bridged to transplantation.
CONCLUSIONS - Axillary intra-aortic balloon pump therapy provides excellent support for selected patients as a bridge to transplant. The majority of the patients were successfully bridged to transplant and discharged. Although this therapy has been described in previous studies, this is the largest series to incorporate a regimen of aggressive ambulation with daily measurements of distances walked.
Copyright © 2012. Published by Mosby, Inc.
The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.
Acute renal failure (ARF) is common after cardiac surgery and more frequent after complex cardiac surgery. While the incidence of ARF is increasing after coronary artery bypass graft (CABG) surgery, trends in other forms of cardiac surgery remain unclear. We investigated the trend of ARF in various cardiac procedures and compared patterns using CABG surgery as a reference group. The study population consisted of discharges from the Nationwide Inpatient Sample from 1988 to 2003, grouped according to surgery as: CABG, CABG with mitral valve, CABG with other valve, valve alone, and heart transplant. Standard diagnostic codes were used to identify ARF among discharges. Multivariable regression was used to determine trends in ARF among various procedures with CABG as a reference group. The incidence of ARF increased in all five groups (p < 0.001) over the 16-year period. The ARF incidence was highest in the heart transplant group (17%). Compared to the CABG population, patients following heart transplantation developed ARF at higher rates during the study period. In contrast, while ARF increased over time in other groups, the rates of rise were slower than in CABG patients. Among heart surgery procedures, ARF incidence is highest in heart transplantation. The incidence of ARF is also increasing at a faster rate in this group of patients in contrast to other procedure groups when compared to CABG surgery. The disproportionate increase in ARF burden after heart transplantation is a concern due to its strong association with chronic kidney disease and mortality.
BACKGROUND - Neuregulin-1 (NRG-1) is a paracrine factor released by microvascular endothelial cells that has cardioprotective effects in animal models of heart failure. However, circulating NRG-1 has not been studied in human heart disease. We used a novel immunoassay to test whether circulating NRG-1beta is associated with disease severity and clinical outcomes in chronic heart failure.
METHODS AND RESULTS - Serum NRG-1beta was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1beta was significantly elevated in patients with worse disease severity (median, 6.2 ng/mL for New York Heart Association class IV versus 4.4 ng/mL for class I; P=0.002). In adjusted models, NRG-1beta was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted hazard ratio, 1.58; 95% confidence interval, 1.04 to 2.39; P=0.03 comparing fourth versus first NRG-1beta quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction P=0.008) and New York Heart Association class III/IV symptoms (interaction P=0.01). These findings were all independent of brain natriuretic peptide, and assessment of NRG-1beta and brain natriuretic peptide jointly provided better risk stratification than each biomarker individually in patients with ischemic or New York Heart Association class III/IV heart failure.
CONCLUSIONS - Circulating NRG-1beta is independently associated with heart failure severity and risk of death or cardiac transplantation. These findings support a role for NRG-1/ErbB signaling in human heart failure and identify serum NRG-1beta as a novel biomarker that may have clinical applications.
We present a patient who was found to have constrictive pericarditis 6 months after cardiac allograft transplantation. The many invasive and non-invasive diagnostic procedures that were undertaken are reviewed, as is the gross pathology seen during surgery. In addition, the entity of constriction in the transplant patient is placed in context by an examination of the previous literature.
Protein kinase C (PKC)-theta mediates the critical TCR signals required for T cell activation. Previously, we have shown that in response to TCR stimulation, PKC-theta-/- T cells undergo apoptosis due to greatly reduced levels of the anti-apoptotic molecule, Bcl-xL. In this study, we demonstrate that PKC-theta-regulated expression of Bcl-xL is essential for T cell-mediated cardiac allograft rejection. Rag1-/- mice reconstituted with wild-type T cells readily rejected fully mismatched cardiac allografts, whereas Rag1-/- mice reconstituted with PKC-theta-/- T cells failed to promote rejection. Transgenic expression of Bcl-xL in PKC-theta-/- T cells was sufficient to restore cardiac allograft rejection, suggesting that PKC-theta-regulated survival is required for T cell-mediated cardiac allograft rejection in this adoptive transfer model. In contrast to adoptive transfer experiments, intact PKC-theta-/- mice displayed delayed, but successful cardiac allograft rejection, suggesting the potential compensation for PKC-theta function. Finally, a subtherapeutic dose of anti-CD154 Ab or CTLA4-Ig, which was not sufficient to prevent cardiac allograft rejection in the wild-type mice, prevented heart rejection in the PKC-theta-/- mice. Thus, in combination with other treatments, inhibition of PKC-theta may facilitate achieving long-term survival of allografts.