Combination prophylaxis in CMV high risk heart transplant recipients: A single center experience.

INTRODUCTION: Cytomegalovirus (CMV) is the most clinically relevant infectious agent following heart transplantation (HTX). Data on the beneficial effects of prophylactic use of CMV immunoglobulins (CMVIG) are scarce. METHODS: In this single-center, retrospective study, we reported patient outcomes following cardiac transplantation using prophylactic CMV treatment, including CMVIG. Distinct clinically relevant outcomes were compared across different CMV risk groups (CMV D-/R-, CMV D-/R+, CMV D+/R+, and CMV D+/R- or CMV high risk group). RESULTS: We included 272 heart transplant procedures, performed between 1/1/2009 and 1/11/2020. Sixty-one (22%) procedures belonged to the CMV high risk group, while 96 (35%), 50 (18%), and 65 (24%) were CMV D-/R-, CMV D-/R+, and CMV D+/R+, respectively. Baseline donor and recipient characteristics (sex, age, body mass index, cause of death, indication for HTX), ischemia times and baseline immunosuppressive regimens were similar across the different CMV risk groups, yet fewer patients were bridged with a mechanical circulatory support in the CMV D+/R- group. CMV disease following cardiac transplantation was more common in the CMV D+/R- risk group (n = 40 or 66.7%; p < .001), yet mortality and re-transplantation rates, cardiac allograft vasculopathy (CAV) severity, rejection episodes, and development of donor-specific antibodies (DSA), post-transplant lymphoproliferative diseases (PTLD), and EBV infections were similar across all four CMV risk groups. CONCLUSION: High risk CMV D+/R- patients had a similar survival compared to low and intermediate CMV risk groups using a prophylactic strategy combining CMVIG and viral DNA polymerase inhibitors. This may be related to a number of factors unrelated to prophylaxis strategy as two out of three CMV D+/R- recipients developed CMV primary infection after prophylaxis was discontinued.

Successful heart transplantation from donation after euthanasia with distant procurement using normothermic regional perfusion and cold storage.

While euthanasia has been legalized in a growing number of countries, organ donation after euthanasia is only performed in Belgium, the Netherlands, Spain, and Canada. Moreover, the clinical practice of heart donation after euthanasia has never been reported before. We describe the first case of a heart donated after euthanasia, reconditioned with thoraco-abdominal normothermic regional perfusion, preserved using cold storage while being transported to a neighboring transplant center, and then successfully transplanted following a procurement warm ischemic time of 17 min. Heart donation after euthanasia using thoraco-abdominal normothermic regional perfusion is feasible, it could expand the heart donor pool and reduce waiting lists in countries where organ donation after euthanasia can be performed.

The role of transesophageal echocardiography in guiding heart donation after circulatory death.

Heart donation after circulatory death (DCD) can significantly expand the heart donor pool, helping to overcome the problem of organ shortage and the increase in waiting list mortality and morbidity. To improve the outcome of DCD heart transplantation, thoraco-abdominal normothermic regional perfusion (TA-NRP) can be performed by selectively restoring circulation followed by in vivo functional heart assessment. Here, we report on the use of periprocedural transoesophageal echocardiography (TOE) as a minimally invasive cardiac assessment tool during different stages of a DCD heart procurement procedure using TA-NRP. We conclude that TOE is a valuable method to assess the donor heart for transplantation eligibility before and after withdrawal of life-sustaining therapy and during subsequent TA-NRP.

Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.

Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV).

BACKGROUND: The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant. METHODS: This is a phase III investigator-initiated study in 100 persons living with HIV (age 18-45 years) and 171 SOT recipients (age 18-55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs). RESULTS: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study. CONCLUSIONS: Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.

The effect of universal infant vaccination on the prevalence of hepatitis B immunity in adult solid organ transplant candidates.

BACKGROUND: Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region. METHODS: Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986. RESULTS: The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18-2.66, P = .006) were associated with increased HBV immunity. CONCLUSION: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.

How to screen for at-risk alcohol use in transplant patients? From instrument selection to implementation of the AUDIT-C.

BACKGROUND: Given that drinking >2-3 units of alcohol daily might already have adverse health effects, regular screening of at-risk drinking is warranted. We aimed to select and pilot a short instrument to accurately screen for at-risk drinking in transplant patients. METHODOLOGY AND RESULTS: Five consecutive steps were completed: A comprehensive literature review identified 24 possible self-report instruments (step 1). These instruments were scored on six yes/no criteria (ie, length, concept measured, diagnostic accuracy, population, manual available, cost) (step 2). Four nurses piloted three instruments with the highest score and were interviewed on their experiences with using the AUDIT-C, TWEAK, and Five Shot. The AUDIT-C was the easiest to use and score, and items were clear. Cognitive debriefings with 16 patients were conducted to verify clarity of instructions and items, and suggestions were incorporated into a modified version of the AUDIT-C (step 4). A convenience sample of 130 Dutch-speaking heart transplant patients completed the modified AUDIT-C during a scheduled visit (Step 5), revealing that 27.6% of patients showed at-risk drinking. CONCLUSION: The AUDIT-C might be a suitable instrument to identify at-risk drinking in routine post-transplant follow-up. Further validation, however, is indicated.

Exercise capacity, muscle strength and objectively measured physical activity in patients after heart transplantation.

Maximal exercise capacity of patients after heart transplantation (HTX) remains limited, affecting their quality of life. Evidence on the evolution of muscle strength and physical activity (PA) post-HTX is lacking, but a prerequisite to tailor cardiac rehabilitation programmes. Forty-five consecutive patients were evaluated every 3 months during the first year post-HTX. Functional exercise capacity (Six minutes walking distance test (6MWD)), peripheral (Quadriceps strength (QF)) and respiratory (Maximal inspiratory strength (MIP)) muscle strength were evaluated. PA (number of steps (PAsteps), active time (PAactive) and sedentary time (PAsed)) was objectively measured. 6MWD, QF, MIP, PAsteps and PAactive significantly improved over time (P < 0.001). No change in PAsed was noticed (P = 0.129). Despite improvements in 6MWD and QF, results remained substantially below those of age-and gender-matched healthy subjects. One year post-HTX, 30% of patients presented with peripheral muscle weakness. Baseline levels of 6MWD and QF were significantly higher in patients with pretransplant LVAD-implantation and this difference was maintained during follow-up. cardiac rehabilitation, combining aerobic exercise training and peripheral muscle strength training, is mandatory in patients post-HTX. Inspiratory muscle training should be implemented when respiratory muscle weakness is present. Programmes improving physical activity and reducing sedentary time post-HTX are essential.

Prognostic value of cardiovascular magnetic resonance in patients with biopsy-proven systemic sarcoidosis.

OBJECTIVES: As prognosis in sarcoidosis is determined by cardiac involvement, the objective was to study the added value of cardiovascular magnetic resonance (CMR) in risk stratification. METHODS: In 114 patients (48 ± 12 years/52% male) with biopsy-proven sarcoidosis, we studied the value of clinical and CMR-derived parameters to predict future events, using sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac death, implantable cardioverter-defibrillator (ICD) placement with appropriate shocks, hospitalization for heart failure, and death as composite endpoint. Median follow-up after CMR was 3.1 years (1.1-5.7 years). RESULTS: The ejection fraction (EF) was 58.2 ± 9.1% and 54.7 ± 10.8% for left ventricle (LV) and right ventricle (RV), respectively. LV late gadolinium enhancement (LGE) was present in 40 patients (35%) involving 5.1% of the LV mass (IQR, 3.0-12.0%), with concomitant RV involvement in 12 patients (11%). T2-weighting imaging and/or T2 mapping showed active disease in 14 patients. The composite endpoint was reached in 34 patients, with 7 deaths in the LGE-positive group (17.5%), versus two deaths in the LGE-negative group (2.7%) (p = 0.015). At univariate analysis, RVEF (p = 0.009), pulmonary arterial pressure (p = 0.002), and presence of LGE (p < 0.001) and LGE (% of LV) (p < 0.001) were significant. At multivariate analysis, only presence of LGE and LGE (% of LV) was significant (both p = 0.03). At Kaplan-Meier, presence of LGE and an LGE of 3% predicted event-free survival and patient survival. We found no difference in active versus inactive disease with regard to patient survival. CONCLUSION: Myocardial enhancement at LGE-CMR adds independent prognostic value in risk stratification sarcoidosis patients. In contrast, clinical as well as functional cardiac parameters lack discriminative power. KEY POINTS: • Sarcoidosis often affects the heart. • Comprehensive CMR, including T2 imaging and LGE enhancement CMR, allows to depict both active and inactive myocardial damage. • Patient prognosis in sarcoidosis is determined by the presence and severity of myocardial involvement at LGE CMR.

Urinary peptidomic biomarkers of renal function in heart transplant recipients.

BACKGROUND: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). METHODS: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. RESULTS: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. CONCLUSIONS: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction.

Double-lung versus heart-lung transplantation for precapillary pulmonary arterial hypertension: a 24-year single-center retrospective study.

Transplant type for end-stage pulmonary vascular disease remains debatable. We compared recipient outcome after heart-lung (HLT) versus double-lung (DLT) transplantation. Single-center analysis (38 HLT-30 DLT; 1991-2014) for different causes of precapillary pulmonary hypertension (PH): idiopathic (22); heritable (two); drug-induced (nine); hepato-portal (one); connective tissue disease (four); congenital heart disease (CHD) (24); chronic thromboembolic PH (six). HLT decreased from 91.7% [1991-1995] to 21.4% [2010-2014]. Re-intervention for bleeding was higher after HLT; (P = 0.06) while primary graft dysfunction grades 2 and 3 occurred more after DLT; (P < 0.0001). Graft survival at 90 days, 1, 5, 10, and 15 years was 93%, 83%, 70%, 47%, and 35% for DLT vs. 82%, 74%, 61%, 48%, and 30% for HLT, respectively (log-rank P = 0.89). Graft survival improved over time: 100%, 93%, 87%, 72%, and 72% in [2010-2014] vs. 75%, 58%, 42%, 33%, and 33% in [1991-1995], respectively; P = 0.03. No difference in chronic lung allograft dysfunction (CLAD)-free survival was observed: 80% & 28% for DLT vs. 75% & 28% for HLT after 5 and 10 years, respectively; P = 0.49. Primary graft dysfunction in PH patients was lower after HLT compared to DLT. Nonetheless, overall graft and CLAD-free survival were comparable and improved over time with growing experience. DLT remains our preferred procedure for all forms of precapillary PH, except in patients with complex CHD.

The international prevalence and variability of nonadherence to the nonpharmacologic treatment regimen after heart transplantation: Findings from the cross-sectional BRIGHT study.

INTRODUCTION: Heart transplant (HTx) recipients need to follow a complex therapeutic regimen. We assessed the international prevalence and variability in nonadherence to six nonpharmacologic treatment components (physical activity, sun protection, diet, alcohol use, nonsmoking, and outpatient follow-up visits). METHODS: We used self-report data of 1397 adult HTx recipients from the 36-HTx-center, 11-country, 4-continent, cross-sectional BRIGHT study (ClinicalTrials.gov ID: NCT01608477). The nonadherence definitions used were as follows: Physical activity: <3 times/wk 20 minutes' vigorous activity, <5 times/wk 30 minutes' moderate activity, or <5 times/wk a combination of either intensity; Sun protection: not "always" applying any sun protection; Diet: not "often" or "always" following recommended diet(s); Alcohol use: >1 alcoholic drink/d (women) or >2 drinks/d (men); Smoking: current smokers or stopped <1 year before; Follow-up visits: missing ≥1 of the last 5 outpatient follow-up visits. Overall prevalence figures were adjusted to avoid over- or underrepresentation of countries. Between-country variability was assessed within each treatment component via chi-square testing. RESULTS: The adjusted study-wide nonadherence prevalence figures were as follows: 47.8% for physical activity (95% CI [45.2-50.5]), 39.9% for sun protection (95% CI [37.3-42.5]), 38.2% for diet recommendations (95% CI [35.1-41.3]), 22.9% for alcohol consumption (95% CI [20.8-25.1]), 7.4% for smoking cessation (95% CI [6.1-8.7]), and 5.7% for follow-up visits (95% CI [4.6-6.9]). Significant variability was observed between countries in all treatment components except follow-up visits. CONCLUSION: Nonadherence to the post-HTx nonpharmacologic treatment regimen is prevalent and shows significant variability internationally, suggesting a need for tailored adherence-enhancing interventions.

Heart re-transplantation in Eurotransplant.

Internationally 3% of the donor hearts are distributed to re-transplant patients. In Eurotransplant, only patients with a primary graft dysfunction (PGD) within 1 week after heart transplantation (HTX) are indicated for high urgency listing. The aim of this study is to provide evidence for the discussion on whether these patients should still be allocated with priority. All consecutive HTX performed in the period 1981-2015 were included. Multivariate Cox' model was built including: donor and recipient age and gender, ischaemia time, recipient diagnose, urgency status and era. The study population included 18 490 HTX, of these 463 (2.6%) were repeat transplants. The major indications for re-HTX were cardiac allograft vasculopathy (CAV) (50%), PGD (26%) and acute rejection (21%). In a multivariate model, compared with first HTX hazards ratio and 95% confidence interval for repeat HTX were 2.27 (1.83-2.82) for PGD, 2.24 (1.76-2.85) for acute rejection and 1.22 (1.00-1.48) for CAV (P < 0.0001). Outcome after cardiac re-HTX strongly depends on the indication for re-HTX with acceptable outcomes for CAV. In contrast, just 47.5% of all hearts transplanted in patients who were re-transplanted for PGD still functioned at 1-month post-transplant. Alternative options like VA-ECMO should be first offered before opting for acute re-transplantation.

Pregnancy Outcomes Following Cardiac Transplantation.

OBJECTIVE: This study sought to report pregnancy outcomes in women following cardiac transplantation. METHODS: This was a descriptive retrospective cohort study of women with pregnancies following cardiac transplantation managed at two large tertiary centres in Canada and Belgium between 2001 and 2017. RESULTS: Sixteen women had 17 singleton pregnancies following cardiac transplantation. The mean maternal age was 28 ± 5.8, and the transplant-to-pregnancy interval was 7.3 ± 4.0 years. There were two first trimester terminations, one for teratogenicity concerns and the other because of a maternal cardiac condition. There was one spontaneous miscarriage. All women had normal left ventricular function at the start of pregnancy. Graft rejection occurred in two women. Other maternal complications included anemia requiring blood transfusion (n = 5), renal failure or deterioration (n = 4), preeclampsia (n = 2), and urine infections (n = 2). The mean GA at delivery was 35 ± 3.5 weeks. Six infants were born preterm, and two were small-for-gestational-age. Fetal anomalies were identified in two pregnancies. Women were followed after pregnancy for a median of 5.6 years (range, 10 months to 15 years). Although there were no deaths during pregnancy, two women died at 10 and 18 months after delivery. CONCLUSION: With appropriate multidisciplinary care, women with cardiac transplants can have successful pregnancies. Although rates of fetal loss are low, these women continue to be at risk for graft rejection, preterm birth, other pregnancy-related complications, and cardiovascular death.

Prognostic value of electrocardiographic time intervals and QT rate dependence in hypertrophic cardiomyopathy.

INTRODUCTION: Preventing sudden cardiac death (SCD) is one of the main goals in hypertrophic cardiomyopathy (HCM). Many variables have been proposed, however the European and American guidelines do not incorporate any ECG or Holter monitoring derived variables other than the presence of ventricular arrhythmia in their risk stratification models. In the present study we evaluated electrocardiographic parameters in risk stratification of HCM. METHODS AND RESULTS: Novel electrocardiographic parameters including the index of cardio-electrophysiological balance (iCEB), individualized QT correction (QTi) and QT rate dependence were evaluated along with established risk factors. A composite endpoint of SCD was defined as out of hospital cardiac arrest, appropriate ICD shock and sustained ventricular tachycardia. Cox regression analysis was used to evaluate predictors of SCD. Out of the 466 HCM patients, 31 reached the composite endpoint during a follow up of 75 ±â€¯86 months. In a multivariate model, nor iCEB, QTi or QT rate dependence were predictors of SCD. Only male gender (p < 0.01; OR 13.1; CI 1.74-98.83), negative T waves in the inferior leads (p = 0.04; OR 2.51; CI 1.03-6.13) and familial sudden death (p < 0.01; OR 3.03; CI 1.39-6.59) were significant predictors. On top of either the ESC risk score or the 3 traditional 'American risk factors', only male gender was a significant predictor of SCD. CONCLUSION: No ECG or Holter monitoring parameters added in risk stratification for SCD in HCM. However, male gender and negative T waves in the inferior leads are promising novel markers to evaluate in larger cohorts.

Effect of the Direct Oral Anticoagulants Rivaroxaban and Apixaban on the Disposition of Calcineurin Inhibitors in Transplant Recipients.

BACKGROUND: Calcineurin inhibitors (CNIs) and direct oral anticoagulants (DOACs) share certain metabolic pathways, but whether DOACs influence CNI exposure has not been assessed. METHODS: A single-center retrospective analysis was performed including 39 organ recipients treated with the combination of a CNI and rivaroxaban (n = 29) or apixaban (n = 10). Dose-corrected CNI trough concentrations (C0/D) during 200 days before and after DOAC initiation were recorded (n = 261), together with covariates known to influence CNI disposition such as steroid dose and hematocrit. The average C0/D before and during DOAC therapy was compared using paired samples t test. Multivariable mixed models were constructed to estimate the effect of DOAC and other predictors on C0/D at each time point. RESULTS: Group average C0/D was not significantly different before and during DOAC therapy for any CNI-DOAC combination (P = 0.089-0.761), although C0/D changed >20% in 19/39 patients (13 increases, 6 decreases). In multivariable analysis, independent predictors of tacrolimus C0/D were methylprednisolone dose (P = 0.039) and concomitant use of a CYP3A inhibitor (P = 0.007). The subgroup analysis per DOAC showed a limited but significant effect of rivaroxaban on tacrolimus C0/D (9.2% increase, P = 0.042). Independent predictors of ciclosporin C0/D were age (P = 0.018) and use of any DOAC (12.1% increase, P = 0.020). CONCLUSIONS: Apixaban, and particularly rivaroxaban, may cause a limited (<20%) increase in CNI trough concentration, an effect that is unlikely to trigger a dose change. It may be prudent to perform an additional CNI trough concentration measurement 5-7 days after DOAC initiation, but preemptive CNI dose changes are not warranted based on these observations.

Exercise-induced right ventricular dysfunction is associated with ventricular arrhythmias in endurance athletes.

AIMS: Intense exercise places disproportionate strain on the right ventricle (RV) which may promote pro-arrhythmic remodelling in some athletes. RV exercise imaging may enable early identification of athletes at risk of arrhythmias. METHODS AND RESULTS: Exercise imaging was performed in 17 athletes with RV ventricular arrhythmias (EA-VAs), of which eight (47%) had an implantable cardiac defibrillator (ICD), 10 healthy endurance athletes (EAs), and seven non-athletes (NAs). Echocardiographic measures included the RV end-systolic pressure-area ratio (ESPAR), RV fractional area change (RVFAC), and systolic tricuspid annular velocity (RV S'). Cardiac magnetic resonance (CMR) measures combined with invasive measurements of pulmonary and systemic artery pressures provided left-ventricular (LV) and RV end-systolic pressure-volume ratios (SP/ESV), biventricular volumes, and ejection fraction (EF) at rest and during intense exercise. Resting measures of cardiac function were similar in all groups, as was LV function during exercise. In contrast, exercise-induced increases in RVFAC, RV S', and RVESPAR were attenuated in EA-VAs during exercise when compared with EAs and NAs (P < 0.0001 for interaction group × workload). During exercise-CMR, decreases in RVESV and augmentation of both RVEF and RV SP/ESV were significantly less in EA-VAs relative to EAs and NAs (P < 0.01 for the respective interactions). Receiver-operator characteristic curves demonstrated that RV exercise measures could accurately differentiate EA-VAs from subjects without arrhythmias [AUC for ΔRVESPAR = 0.96 (0.89-1.00), P < 0.0001]. CONCLUSION: Among athletes with normal cardiac function at rest, exercise testing reveals RV contractile dysfunction among athletes with RV arrhythmias. RV stress testing shows promise as a non-invasive means of risk-stratifying athletes.

Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection.

AIMS: The cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown. METHODS AND RESULTS: Expression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-ß, and with infiltrating CD3⁺ T-cells and CD68⁺ monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-ß transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts. CONCLUSION: Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.

Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.

BACKGROUND AND OBJECTIVE: Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. METHODS: We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. RESULTS: We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. CONCLUSIONS: Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.