Surveillance with dual noninvasive testing for acute cellular rejection after heart transplantation: Outcomes from the Surveillance HeartCare Outcomes Registry.

BACKGROUND: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated. METHODS: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed. RESULTS: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction. CONCLUSIONS: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction.

Variants in mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and leukopenia in heart transplant recipients.

BACKGROUND: The objective was to assess the relationship between single nucleotide polymorphisms in mycophenolate and cytomegalovirus antiviral drug pharmacokinetic and pharmacodynamic genes and drug-induced leukopenia in adult heart transplant recipients. METHODS: This retrospective analysis included n = 148 patients receiving mycophenolate and a cytomegalovirus antiviral drug. In total, 81 single nucleotide polymorphisms in 21 pharmacokinetic and 23 pharmacodynamic genes were selected for investigation. The primary and secondary outcomes were mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia, defined as a white blood cell count <3.0 × 109/L, in the first six and 12 months post-heart transplant, respectively. RESULTS: Mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia occurred in 20.3% of patients. HNF1A rs1169288 A>C (p.I27L) was associated with drug-induced leukopenia (unadjusted p = 0.002; false discovery rate <20%) in the first six months post-transplant. After adjusting for covariates, HNF1A rs1169288 variant C allele carriers had significantly higher odds of leukopenia compared to A/A homozygotes (odds ratio 6.19; 95% CI 1.97-19.43; p = 0.002). Single nucleotide polymorphisms in HNF1A, SLC13A1, and MBOAT1 were suggestively associated (p < 0.05) with the secondary outcome but were not significant after adjusting for multiple comparisons. CONCLUSION: Our data suggest genetic variation may play a role in the development of leukopenia in patients receiving mycophenolate and cytomegalovirus antiviral drugs after heart transplantation. Following replication, pharmacogenetic markers, such as HNF1A rs1169288, could help identify patients at higher risk of drug-induced leukopenia, allowing for more personalized immunosuppressant therapy and cytomegalovirus prophylaxis following heart transplantation.

Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients.

Background: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients. Methods: This retrospective analysis included N = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2. Results: Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (TGFB1) rs4803455 C > A and phospholipase C beta 1 (PLCB1) rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of TGFB1 rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12-0.62; p = 0.002], whereas PLCB1 rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21-5.84, p = 0.015). Conclusion: Our data suggest that genetic variation in TGFB1 and PLCB1 may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as TGFB1 rs4803455 and PLCB1 rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.

Bariatric Surgery Is Associated With Decreased Calcineurin Inhibitor Time in Therapeutic Range After Heart Transplantation.

Bariatric surgery (BSg) is an effective treatment for morbid obesity, but little is known about the outcomes of BSg patients who undergo orthotopic heart transplantation (OHT). The aim of this study was to determine if BSg alters calcineurin inhibitor (CNI) level variability after OHT. Data were collected from 58 consecutive patients who underwent OHT at a single center from 1/2018 to 4/2019: 4 with BSg prior to OHT (BSg + OHT) and 54 without prior BSg (OHT). CNI level, cardiac biopsy, and left ventricular ejection fraction (LVEF) data were collected during the first 6 months post-OHT. Comparisons were made for 3 measures of CNI variability: coefficient of variation, time in therapeutic range (TTR), and TTR by the Rosendaal method. A Pearson's correlation coefficient was calculated to assess the relationship between CNI TTR, episodes of rejection, and LVEF. The results show TTR was lower in BSg + OHT compared to OHT (12.5% vs 31.3%, P < .05). For the entire cohort, greater TTR correlated with fewer episodes of rejection (r = 0.31, P < .05). In conclusion, these findings suggest BSg + OHT patients may warrant closer monitoring of CNI levels post-OHT. Furthermore, episodes of rejection and LVEF were similar for BSg + OHT patients, indicating that BSg should not be a contraindication to transplant.

Relationship between nocturnal blood pressure patterns and end organ damage and diastolic dysfunction in heart transplant recipients.

BACKGROUND: We assessed the relationship between circadian blood pressure (BP) patterns and clinical outcomes in a contemporary cohort of adult heart transplant recipients. METHODS: This retrospective, cross-sectional study included adult heart transplant recipients at least 6 months post-transplant. Ambulatory BP measurements were recorded over 24 hours. Nondippers were defined as a decline in average nighttime BP ≤ 10% compared with daytime. Primary outcomes were the presence of end organ damage, that is, microalbuminuria, chronic kidney disease, and/or left ventricular hypertrophy. Secondary outcomes were measures of diastolic dysfunction (ie, mitral valve deceleration time, e/e', E/A, and isovolumetric relaxation time), microalbumin/creatinine ratio, eGFR, interventricular septal thickness, and left ventricular posterior wall thickness. RESULTS: Of 30 patients, 53.3% (n = 16) were systolic nondippers and 40% (n = 12) were diastolic nondippers. Diastolic nondippers had three times higher urine microalbumin/creatinine ratios than diastolic dippers (P = .03). Systolic nondippers had 16.3% lower mitral valve deceleration time (P = .05) than systolic dippers, while diastolic nondippers had 20.4% higher e/e' (P = .05) than diastolic dippers. There were no significant relationships between BP dipping status and any of the primary outcomes. CONCLUSIONS: These data suggest that systolic and diastolic nondipping BP patterns are associated with subclinical kidney damage and diastolic dysfunction in heart transplant recipients.

Influence of Genetic Variants on Steady-State Etonogestrel Concentrations Among Contraceptive Implant Users.

OBJECTIVE: To identify genetic variants that influence steady-state etonogestrel concentrations among contraceptive implant users. METHODS: We enrolled healthy, reproductive-age women in our pharmacogenomic study using etonogestrel implants for 12-36 months without concomitant use of hepatic enzyme inducers or inhibitors. We collected participant characteristics, measured serum etonogestrel concentrations, and genotyped each participant for 120 single nucleotide variants in 14 genes encoding proteins involved in steroid hormone (ie, estrogens, progestins) metabolism, regulation, or function. We performed generalized linear modeling to identify genetic variants associated with steady-state etonogestrel concentrations. RESULTS: We enrolled 350 women, who had a median serum etonogestrel concentration of 137.4 pg/mL (range 55.8-695.1). Our final generalized linear model contained three genetic variants associated with serum etonogestrel concentrations: NR1I2(PXR) rs2461817 (ß=13.36, P=.005), PGR rs537681 (ß=-29.77, P=.007), and CYP3A7*1C (ß=-35.06, P=.025). Variant allele frequencies were 69.4%, 84.9%, and 5.1%, respectively. Our linear model also contained two nongenetic factors associated with etonogestrel concentrations: body mass index (BMI) (ß=-3.08, P=7.0×10) and duration of implant use (ß=-1.60, P=5.8×10); R for the model =0.17. CONCLUSION: Only BMI and duration of implant use remained significantly associated with steady-state etonogestrel concentrations. Of the three novel genetic associations found, one variant associated with increased etonogestrel metabolism (CYP3A7*1C) causes adult expression of fetal CYP3A7 proteins and can consequently alter steroid hormone metabolism. Women with this variant may potentially have increased metabolism of all steroid hormones, as 27.8% (5/18) of CYP3A7*1C carriers had serum etonogestrel concentrations that fell below the threshold for consistent ovulatory suppression (less than 90 pg/mL). More pharmacogenomic investigations are needed to advance our understanding of how genetic variation can influence the effectiveness and safety of hormonal contraception, and lay the groundwork for personalized medicine approaches in women's health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03092037.

Non-interventional cardiologists' perspectives on the role of pharmacogenomic testing in cardiovascular medicine.

AIM: To evaluate factors influencing cardiologists' perspectives about pharmacogenomic (PGx) testing in clinical practice. PATIENTS & METHODS: Semistructured interviews with practicing cardiologists were qualitatively analyzed to identify common themes. RESULTS: Five themes were identified among 16 cardiologists from four specialties (n = 5 general cardiology, n = 3 electrophysiology, n = 2 adult congenital and n = 6 heart failure/transplant): cardiologists' knowledge and needs, perceived clinical validity and utility of PGx testing, dissemination and management of PGx results, patient-related considerations and incidental findings. CONCLUSION: Lack of evidence was considered by many cardiologists to be a major barrier hindering the use of PGx testing. However, they would consider adopting PGx if they were provided additional education, ongoing support and evidence supporting the clinical utility of PGx testing in cardiovascular medicine.

Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in zebrafish.

Zebrafish (Danio rerio) have emerged as a popular model for studying the pharmacology and behavior of anxiety. While there have been numerous studies documenting the anxiolytic and anxiogenic effects of common drugs in zebrafish, many do not report or test for behavioral differences between the sexes. Previous studies have indicated that males and females differ in their baseline level of anxiety. In this study, we test for a sex interaction with fluoxetine and nicotine. We exposed fish to system water (control), 10 mg/L fluoxetine, or 1 mg/L nicotine for three minutes prior to being subjected to four minutes in an open-field drop test. Video recordings were tracked using ProAnalyst. Fish from both drug treatments reduced swimming speed, increased vertical position, and increased use of the top half of the open field when compared with the control, though fluoxetine had a larger effect on depth related behaviors while nicotine mostly affected swimming speed. A significant sex effect was observed where females swam at a slower and more constant speed than males, however neither drug produced a sex-dependent response.