Adult Heart Transplant Patients Research Articles

Alleviating Chaos Utilizing A Multidisciplinary Approach To Incorporate Heart Molecular Microscope Diagnostic System® Into Practice

Background A new technology known as Molecular Microscope Diagnostic System® (MMDx) uses microarrays to analyze RNA transcripts of transplanted heart tissue and provides sophisticated differentiation amongst cellular mediated rejection (TCMR), antibody mediated rejection (ABMR), injury and healthy tissue. Yet, incorporation of this new data into practice can be challenging. We report the results from our single center experience. Methods Endomyocardial biopsies (EMB) and corresponding MMDx results from 65 adult heart transplant patients from our single center were retrospectively reviewed. Rejection by EMB was defined as TCMR greater than 1R and/or ABMR greater than pAMR0 utilizing ISHLT grading schematics. Results A total of 97 specimen results were reviewed. There was concordant findings between the EMB and MMDx in 83.5% (81/97) of the specimens. Of the 81 specimens, 76 of those were negative for rejection on both tests and 5 had positive EMB for ABMR/TCMR with correlating MMDx suggestive of rejection. There was a discordance in 16.5% (16/97) of specimens reviewed. Of the 16 specimens, 15 had negative EMB with the MMDx concerning for rejection. One of the 16 patients had a positive EMB however the MMDX was consistent with healthy tissue. These complex cases with discordant data were reviewed during our multi-disciplinary meeting which includes transplant cardiologists, coordinators, APPs, pharmacists, pathologists and immunology partners to adjudicate further management. The team approached each case individually, reviewing other factors such clinical symptoms, graft function by TTE, hemodynamics, cell-free DNA and donor specific antibodies when available. For five discordant patients with negative EMB and concerning MMDx, the team favored treatment for rejection if there were other corresponding factors present such as high cell-free DNA or clinical symptoms. For one patient admitted with clinic concerns for rejection aggressive treatment had already been initiated prior to positive EMB and negative MMDx being available. For the remaining patients with negative EMB and positive MMDx we advocated for a second round of data, including repeat biopsy and continued surveillance, before deciding on course of treatment for rejection. Conclusion MMDx is an additional tool to provide potentially more accuracy in patient diagnoses but should be utilized in combination with all other diagnostic data. In the cases of conflicting findings, a multi-disciplinary approach should be used to discuss further steps. Larger studies are needed to validate these preliminary findings.

Differential Impact of Class I and Class II Panel Reactive Antibodies on Post-Heart Transplant Outcomes

Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically. Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05). Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear.

Comparison of Sirolimus and Everolimus on Hematologic Parameters in Pediatric Heart Transplant Recipients

Mammalian target of rapamycin inhibitors (mTORi) such as sirolimus (SRL) and everolimus (EVL) may lead to myelosuppression. Hematologic effects of SRL and EVL have been compared in adult heart transplant patients, but data in pediatric heart transplant patients remain limited. We performed a retrospective analysis of pediatric heart transplant patients transplanted at Loma Linda Children's Hospital between 2000 - 2017 who received a calcineurin inhibitor (CNI) and either SRL or EVL who had at least 1 year follow-up . White blood cell count (WBC), hemoglobin (Hgb), and platelet (PLT) median values and changes from baseline were compared at 1 week, 6 months, and 12 months. There were 41 and 13 patients in the SRL and EVL cohort, respectively. There was no difference in baseline WBC between the EVL and SRL cohort with a median WBC of 5.5 and 5.8, respectively (p =0.47). At 1 week, median WBC was significantly lower in the EVL group compared to the SRL group at 4.8 (95% CI 3.6-6.9) and 5.8 (95% CI 5.2-7.1), respectively (p=0.05) (Figure 1). There was no difference in median WBC at 6 months (EVL = 5.8, and SRL = 6.1, p =0.3) or 1 year (EVL = 6.1 and SRL= 6.4, p = 0.6). There was no difference in median Hgb or PLT at each interval. Percent change in all hematologic parameters at 1 week, 6 months, and 12 months were no different. There was no statistically significant difference in treatable biopsy proven rejection. As compared to SRL, EVL's effect on WBC was observed early at 1 week and was only transient as there was no difference at 6 and 12 months. Effects on Hgb and PLT were similar between EVL and SRL.

Heart Transplant Outcomes in Obese Patients BMI 35-39.9

The 2016 ISHLT revised cardiac transplantation listing criteria has recommended patients to achieve a body mass index (BMI) <35 kg/m² prior to listing. Although some studies show that patients with pre-transplant BMI>35 show poorer outcome post-transplant, there is limited data on the BMI group of 35-39.9. This study aims to determine the relationship between post-transplant outcomes and a pre-transplant listing BMI of 35-39.9 as compared to a BMI <35. A retrospective cohort analysis of patients stratified by BMI subgroup was performed of 23,009 adult heart transplant patients from 2009-2018 using the United Network for Organ sharing database. Patients with BMI of 35-39.9 post-transplant outcomes were compared to patients with BMI <35. Kaplan-Meier analysis univariate and multivariate Cox proportional-hazards models were used to determine the prognostic factors associated with mortality at 90 days, 1 year and 5 year after transplantation. Patients with a BMI 35.0-39.9 had post-transplant survival of 92.4% at 90 days, 89.3% at 1 year and 74.5% at 5 years, compared to patients with a BMI < 35.0 whose post-transplant survival were 94.6% at 90 days, 91.3% at 1 year, and 79.3% at 5 years. The proportion of stroke events was 2.7%, 2.1%, and 2.2% for BMI <35, 35-39.9, and ≥40, respectively, with no statistically significant difference among the BMI groups for stroke events before discharge. There was a statistically significant difference in the proportion of dialysis events between the BMI < 35 and BMI 35-39.9, and BMI ≥40 group, with rates of 10.5%, 14.0%, and 16.2% for the BMI <35, 35-39.99, and ≥40 groups respectively. There was no statistically significant differences in the proportion of acute rejection events prior to discharge, with rates of 19.6%, 21.2% and 24.5% for BMI<35, 35-39.9, and ≥ 40, respectively. Although a statistically significant increase in mortality was observed between the BMI < 35 and BMI 35-39.9 groups, this difference may not be clinically significant, with acceptable survival rates observed in the high risk group. There were no significant differences in stroke rate and acute rejection, although there was an observed difference in dialysis events. Given the acceptable overall outcomes in the higher BMI cohort, the benefits of heart transplantation in this group may outweigh the risks, and these patients should be considered as candidates for heart transplantation.

Induction Therapy in Patients with Prolonged Ischemic Times May Be Protective for Early Graft Failure

Primary graft dysfunction (PGD) in heart transplantation (HTx) patients is the leading cause of death within the first 30 days of HTx. Ischemic time >4 hours has been associated with a significant increase in mortality at 30 days post-transplant and up to 6 years post-transplant. The optimal immunosuppression regimen including induction therapy to prevent allograft failure is unclear. Induction therapy may have a protective effect against ischemia-reperfusion injury, a main mechanism of allograft injury after HTx. We sought to evaluate the effect of induction therapy in heart transplant recipients with longer ischemic times in both early and long-term graft failure. This retrospective cohort study used the United Network for Organ Sharing (UNOS) and included adult (>21yr) heart transplant patients from Jun 30, 2004 to Mar 2015. The effect of induction therapy, either basiliximab (IL-2Rab) or ATG/ALG/thymoglobulin, on all-cause early and late graft failure was estimated by a logistic regression adjusted for the covariates ischemic time, age, African American race, serum creatinine >2.5, HLA mismatch > 4, and acute rejection episodes. The Inverse Probability Treatment Weighting (IPTW) was used to control for imbalanced propensity of receiving induction given the covariates. At 30 days, induction was shown to reduce graft failure OR 0.69 (95% CI, 0.57-0.82) in all comers with no additional benefit for patients with prolonged ischemic time OR 1.08 (95% CI 0.87-1.36). Induction had no effect on long term graft failure up to 5.6 years OR 0.96 (95% CI 0.88 -1.04), except in patients with prolonged ischemic time OR 0.88 (95%CI 0.79-0.98). Our results suggest that induction therapy may be protective against graft failure at 30 days, and late graft failure up to five years in a subset of patients with prolonged ischemic times.

Mid-Term Effectiveness of Everolimus on Heart Transplant Recipients with Renal Dysfunction or Transplant Coronary Artery Atherosclerosis

Everolimus (EVL) can be utilized after heart reduce calcineurin inhibitor (CNI) associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection and cardiac allograft vasculopathy (TCAV). Since 2007, we have primarily considered converting from mycophenolate mofetil with standard-dose CNIs to EVL with low-dose CNIs for the following recipients: 1) recipients with impaired renal function; 2) those with increases in or an initially large maximal intimal thickness (MIT) on routine intravascular ultrasound (IVUS) examinations; 3) donor derived TCAV; and 4) those with MMF-related leukopenia. In the present study, mid-term safety and effectiveness of EVL on heart transplant recipients with renal dysfunction or TCAV. A single-center, retrospective cohort study was conducted including 116 adult heart transplant patients between 1999 and 2018. Sixty nine of 116 patients was started EVL and patients who was initiated EVL due to renal dysfunction (n=21) with longer than 1 year follow-up of serum creatine and TCAV (n=22) with longer than 3 years follow-up of annual MIT measurement by IVUS were enrolled in this study. The trough levels of EVL were evaluated at 1 week after initiation. Once target trough levels of EVL (6-8 ng/mL) were achieved, the CNI dose was reduced to obtain target trough levels. EVL efficacy on renal dysfunction and TCAV and safety were assessed. In 21 patients given EVL due to renal dysfunction, serum creatinine was significantly decreased from initiation of EVL to 1 year after initiation (1.44 +/- 0.32 vs 1.23 +/- 0.36 mg/dL; p=0.0004), but that did not significantly changed since then. In 22 patients given EVL due to TCAV, MIT was significantly decreased from initiation of EVL to 3 years after initiation (1.20 +/- 0.38 mm vs 1.00 +/- 0.40 mm, p<0.001), but that did not significantly changed since then. EVL with low-dose CNI might play a role in short-term improvement in renal function and TCAV in heart transplant patients. However, immunosuppressive regimen to furtherly improve renal function or TCAV mid-term after initiation of EVL should be investigated.

Incidence of end‐stage renal disease after heart transplantation and effect of its treatment on survival

AimsMany heart transplant recipients will develop end‐stage renal disease in the post‐operative course. The aim of this study was to identify the long‐term incidence of end‐stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival.Methods and resultsA retrospective, single‐centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end‐stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re‐transplantations. During a median follow‐up of 8.6 years, 121 (19.7%) patients developed end‐stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end‐stage renal disease (examined as a time‐dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus‐based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end‐stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end‐stage renal disease development.ConclusionsEnd‐stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end‐stage renal disease.

Cell-free DNA donor fraction analysis in pediatric and adult heart transplant patients by multiplexed allele-specific quantitative PCR: Validation of a rapid and highly sensitive clinical test for stratification of rejection probability.

Lifelong noninvasive rejection monitoring in heart transplant patients is a critical clinical need historically poorly met in adults and unavailable for children and infants. Cell-free DNA (cfDNA) donor-specific fraction (DF), a direct marker of selective donor organ injury, is a promising analytical target. Methodological differences in sample processing and DF determination profoundly affect quality and sensitivity of cfDNA analyses, requiring specialized optimization for low cfDNA levels typical of transplant patients. Using next-generation sequencing, we previously correlated elevated DF with acute cellular and antibody-mediated rejection (ACR and AMR) in pediatric and adult heart transplant patients. However, next-generation sequencing is limited by cost, TAT, and sensitivity, leading us to clinically validate a rapid, highly sensitive, quantitative genotyping test, myTAIHEART®, addressing these limitations. To assure pre-analytical quality and consider interrelated cfDNA measures, plasma preparation was optimized and total cfDNA (TCF) concentration, DNA fragmentation, and DF quantification were validated in parallel for integration into myTAIHEART reporting. Analytical validations employed individual and reconstructed mixtures of human blood-derived genomic DNA (gDNA), cfDNA, and gDNA sheared to apoptotic length. Precision, linearity, and limits of blank/detection/quantification were established for TCF concentration, DNA fragmentation ratio, and DF determinations. For DF, multiplexed high-fidelity amplification followed by quantitative genotyping of 94 SNP targets was applied to 1168 samples to evaluate donor options in staged simulations, demonstrating DF call equivalency with/without donor genotype. Clinical validation studies using 158 matched endomyocardial biopsy-plasma pairs from 76 pediatric and adult heart transplant recipients selected a DF cutoff (0.32%) producing 100% NPV for ≥2R ACR. This supports the assay’s conservative intended use of stratifying low versus increased probability of ≥2R ACR. myTAIHEART is clinically validated for heart transplant recipients ≥2 months old and ≥8 days post-transplant, expanding opportunity for noninvasive transplant rejection assessment to infants and children and to all recipients >1 week post-transplant.

Association Between Time-in-Therapeutic Tacrolimus Range and Early Rejection After Heart Transplant.

Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30days following HT. This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4weeks. Outcomes included the effect of time to and time-in-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. We reviewed 67 HT patients (median age 58.8yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30days of HT.

Retrospective Nested Case Control Study of the Impact of Immunosuppression on Post Transplant Malignancy among Adult Heart Transplant Patients

Purpose Post-transplant malignancy is diagnosed in approximately 18% of heart transplant (HTx) recipients and is a leading long-term cause of death among these patients. The association between exposure to rabbit anti-thymocyte globulin (rATG), a polyclonal depleting antibody used for its immunomodulatory activity, and incidence of malignancy in HTx is unclear. Methods This is a single-center, retrospective chart review of all HTx recipients who received rATG induction between October 1, 2008 and December 31, 2015. ICD-9 codes were used to identify HTx patients who were diagnosed with any malignancy post-transplant (cases). A nested, case-control study design was used to determine the relative risk of rATG exposure with the incidence of malignancy post-transplant. Cancer cases were matched to controls in a 1:2 method based on age, sex, Epstein Barr Virus donor/recipient status, and year of transplant. Secondary analyses amongst 1:2 matches examined the impact of maintenance immunosuppression exposure on cancer risk using a weighted equation composed of the drug dose, duration, and trough values when applicable. Results Of the 126 patients included in the study, 25 developed malignancy. These 25 patient cases were matched to 50 control patients. The primary endpoint was to evaluate the association of rATG on the risk of malignancy. The median cumulative rATG dose in milligrams (mg) between groups was 365mg in cases and 465mg in controls (OR 0.94, 95% CI 0.79 - 1.11, p=0.46). The cumulative dose of rATG in mg/kg was 4.7 mg/kg in cases vs. 5.7 mg/kg in controls (OR 0.96, 95% CI 0.82 - 1.12, p=0.59). By both univariate and multivariate analyses, there were no statistically significant differences in malignancyassociated with the usage of or quantified exposure to tacrolimus, sirolimus, cyclosporine, or mycophenolate mofetil, although sirolimus showed anti-oncotic trends. Conclusion The results of this study demonstrate current rATG dosing strategies may not singularly be associated with malignancy development as previous dosing strategies suggested. Additional investigations are needed to explore the multiple factors associated with post-transplant malignancy as well as the possible modulating effect of sirolimus.

Slowed Progression of Maximal Intimal Thickening by Intravascular Ultrasound after Initiation of Sirolimus

Purpose Evidence in adult heart transplant (HT) patients (pt) shows that initiating sirolimus (SRL) slows progression of cardiac allograft vasculopathy (CAV) measured by intravascular ultrasound (IVUS). However, no data exist in children. We evaluated changes in maximal intimal thickness (MIT) using serial IVUS measurements in children who initiated SRL for increased MIT post-HT. Methods A single center retrospective review of all pt who underwent pediatric HT and initiated SRL after diagnosis (dx) of increased MIT. We included pt with at least one IVUS before and after starting SRL and excluded re-HT. Repeated measures were analyzed with a univariable linear mixed model with a breakpoint at the time of SRL initiation to account for differing numbers of IVUS studies between pt. The F test compared the difference in slopes before vs. after starting SRL. Results Twenty-eight pt met inclusion criteria and had HT between 1991 - 2007 with IVUS performed between 1995 - 2018. Mean age at HT was 4.1 ± 5.2 yr and 68% were male. Pre-HT dx was cardiomyopathy in 12 and congenital in 16. Mean number of rejection episodes was 1.9 ± 1.7 before SRL and 0.5 ± 0.9 after SRL (p Conclusion SRL initiation slowed the increase in MIT by IVUS in pediatric HT pt. This suggests that intimal thickening after pediatric HT may be mitigated by incorporating SRL into maintenance immunosuppression.

Prediction of tacrolimus dosage in the early period after heart transplantation: a population pharmacokinetic approach.

The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients. A total of 707 tacrolimus concentrations from 107 adult heart transplant patients were included in model development. The effects of demographic, clinical factors and CYP3A5 genotype on tacrolimus clearance were evaluated using a nonlinear mixed-effects modeling. 24 patients with 106 tacrolimus concentrations were used for external validation. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution of tacrolimus were 13.7 l/h and 791 l, respectively. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). A predictive performance was further confirmed in an external validation by Bayesian estimation. Recommended dose regimens were obtained by simulations based on the established model. This is the first population pharmacokinetic study conducted in Chinese heart transplant recipients. These findings are of great importance with regards to tacrolimus dose optimization in heart transplantation patients.

Everolimus Use for Intolerance or Failure of Baseline Immunosuppression in Adult Heart and Lung Transplantation.

BackgroundEverolimus can be utilized after heart or lung transplantation to reduce calcineurin inhibitor associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection, cardiac allograft vasculopathy, and bronchiolitis obliterans syndrome.Material/MethodsA single-center, retrospective cohort study was conducted including 51 adult heart transplant patients (n=32) and lung transplant patients (n=19) started on everolimus due to immunosuppressive therapy intolerance or failure, between 2010 and 2017. Everolimus indication, response, efficacy, and tolerability were assessed.ResultsEverolimus was most commonly initiated due to leukopenia/neutropenia (n=17, 33%) or renal dysfunction (n=13, 25%). Leukopenia/neutropenia resolved in 76% of patients (13 out of 17 patients). Renal function (GFR) increased 7.4 mL/min from baseline to 3 months after everolimus initiation (P=0.011). The most common adverse effects were edema (n=23, 45%) and hyperlipidemia (n=25, 49%). A high discontinuation rate was observed (n=21, 41%), mostly from edema.ConclusionsEverolimus might be beneficial in heart and lung transplant patients with leukopenia or neutropenia and lead to modest, short-term renal function improvement. Patient selection is crucial because adverse effects frequently lead to everolimus discontinuation.

Shedding light on an unknown reality in solid organ transplant patients' self-management: A contextual inquiry study.

Traditional quantitative and qualitative research methods inadequately capture the complexity of patients' daily self-management. Contextual inquiry methodology, using home visits, allows a more in-depth understanding of how patients integrate immunosuppressive medication intake, physical activity, and healthy eating in their daily lives, and which difficulties they experience when doing so. This mixed-method study comprised 2 home visits in 19 purposively selected adult heart, lung, liver, and kidney transplant patients, asking them to demonstrate how they implement the aforementioned health behaviors. Meanwhile, conversations were audio-taped and photographs were taken. Audio-visual materials were coded using directed content analysis. Difficulties and supportive strategies were identified via inductive thematic analysis. We learned that few patients understood what "sufficiently active" means. Physical discomforts and poor motivation created variation across activity levels observed. Health benefits of dietary guidelines were insufficiently understood, and their implementation into everyday life considered difficult. Many underestimated the strictness of immunosuppressive medication intake, and instructions on handling late doses were unclear. Interruptions in routine and busyness contributed to nonadherence. We also learned that professionals often recommend supportive strategies, which patients not always like or need. This contextual inquiry study revealed unique insights, providing a basis for patient-tailored self-management interventions.

Preoperative Use of Amiodarone is Associated With Perioperative Morbidity, But Not Mortality in Pediatric Heart Transplant Recipients

Amiodarone use is common for pediatric arrhythmias and its preoperative use is associated with increased mortality in adult heart transplant patients at one year. We hypothesized that pre-transplant use of amiodarone would increase the one year morbidity and mortality in pediatric heart transplant recipients.

Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyte globulin.

Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P=.001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.

Association of Whole Blood Tacrolimus Concentrations with Kidney Injury in Heart Transplantation Patients.

Background and ObjectivesAcute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI.MethodsIn a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included. AKI was assessed in the first 2 weeks after transplantation as classified by the Kidney Disease Improving Global Outcomes Network (KDIGO). Whole-blood tacrolimus trough concentrations were determined from day 1 to day 14 and at 1, 3, 6 and 12 months post-transplantation. The therapeutic range was 9 to 15 ng/ml in the first 2 months and tapered to 5–8 ng/ml thereafter. The relationship between supratherapeutic tacrolimus trough concentrations and AKI was evaluated. The impact of various potentially confounding factors on tacrolimus concentrations and AKI was considered.ResultsWe included 110 patients. AKI occurred in 57% of patients in the first week. Recovery from AKI was seen in 24%. The occurrence of chronic kidney disease (CKD) was 19% at 1 year. Whole-blood tacrolimus trough concentrations were often supratherapeutic and, despite correction for confounding factors, independently associated with AKI (OR 1.66; 95% CI 1.20–2.31).ConclusionsSupratherapeutic whole-blood tacrolimus trough concentrations are independently associated with the development of AKI in adult heart transplantation patients. More stringent dosing of tacrolimus early after transplantation may be critical in preserving the kidney function.Electronic supplementary materialThe online version of this article (10.1007/s13318-017-0453-7) contains supplementary material, which is available to authorized users.

ECG correlates of acute allograft rejection among heart transplant recipients in the NEW HEART study

Background Previous studies have suggested that acute allograft rejection is associated with increases in QT/QTc. Purpose This study sought to determine the relationship between acute allograft rejection and ECG changes in patients undergoing an orthotopic heart transplant. Methods The study population consisted of 220 adult heart transplant patients enrolled in the NEW HEART Study. ECGs performed within 72 h of endomyocardial biopsy were analyzed with ECGs obtained Results Among the 151 male and 69 female transplant recipients (age 54 ± 13), there were 969 biopsy/ECG pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate/severe rejection was associated with significant increases in QRS duration (p Conclusions Moderate/severe acute allograft rejection is associated with ECG changes following transplant surgery. Future studies are needed to assess the value of computerized ECG measurement algorithms for detecting acute allograph rejection.

Abstract 13424: Prospective Trial of Adenosine on Atrioventricular Nodal Conduction in the Pediatric Transplanted Heart

Introduction: Supraventricular tachycardia (SVT) is common after heart transplant. Adenosine is the standard of care for SVT treatment in children and adults, but is relatively contraindicated post-transplant due to presumed risk of prolonged atrioventricular (AV) block in denervated hearts. This is the first trial of adenosine use in pediatric and young adult heart transplant patients. Hypothesis: Adenosine use after heart transplant does not cause prolonged asystole and is effective in blocking AV nodal conduction. Methods: This was a single center prospective clinical trial including healthy heart transplant recipients ages 6 months - 25 years presenting for routine cardiac catheterization from July 2015 to April 2016. After catheterization, a pacing catheter was placed in the right ventricle and adenosine was given according to a stepwise protocol (12.5mcg/kg, 25mcg/kg, 50mcg/kg, 100mcg/kg and 200mcg/kg, with maximum doses of 0.8mg, 1.5mg, 3mg, 6mg and 12mg for patients ≥ 60kg) until AV block was achieved. The primary outcome was clinically significant asystole ≥ 12 seconds following adenosine that required rescue ventricular pacing. The effects of patient characteristics on adenosine dose and total adenosine effect were tested. Results: Eighty patients completed adenosine testing. No patient (0%, 95% CI 0-3%) required rescue ventricular pacing. AV block was observed in 77 patients (96%, 95% CI 89-99%) at different doses (Figure 1). The median longest AV block was 1.9 seconds (IQR 1.4-3.2) and the mean total adenosine effect was 4.3 seconds (±2.0). No patient characteristics were significant predictors of adenosine dose and total adenosine effect. Results were similar when patients were stratified by weight ≥60kg. Conclusion: Adenosine is a safe medical therapy for the induction of AV block in pediatric and young adult heart transplant patients when using low initial doses (25mcg/kg; 1.5mg if ≥60kg) and gradually escalating therapy.

Hypertension and arterial stiffness in heart transplantation patients

OBJECTIVES:Post-transplantation hypertension is prevalent and is associated with increased cardiovascular morbidity and subsequent graft dysfunction. The present study aimed to identify the factors associated with arterial stiffness as measured by the ambulatory arterial stiffness index.METHODS:The current study used a prospective, observational, analytical design to evaluate a group of adult heart transplantation patients. Arterial stiffness was obtained by monitoring ambulatory blood pressure and using the ambulatory arterial stiffness index as the surrogate outcome. Multivariate logistic regression analyses were performed to control confounding.RESULTS:In a group of 85 adult heart transplantation patients, hypertension was independently associated with arterial stiffness (OR 4.98, CI 95% 1.06-23.4) as well as systolic and diastolic blood pressure averages and nighttime descent.CONCLUSIONS:Measurement of ambulatory arterial stiffness index is a new, non-invasive method that is easy to perform, may contribute to better defining arterial stiffness prognosis and is associated with hypertension.