Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients.

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [*1B (rs2740574), *1 G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This retrospective cohort study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Heart transplanted patients (n = 177, between 2008 and 2020) were included and median age was 54 years old. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*1B or *1 G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

Early Assessment of Cardiac Allograft Vasculopathy Risk Among Recipients of Hepatitis C Virus-infected Donors in the Current Era.

BACKGROUND: Transplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre-direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test-positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear. METHODS AND RESULTS: We performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT- donors. Additionally, in a subsample of 149 patients (including 55 in the NAT+ cohort and 94 in the NAT- cohort) who had serial adjunctive intravascular ultrasound examination performed, we compared development of rapidly progressive CAV, defined as an increase in maximal intimal thickening of ≥0.5 mm in matched vessel segments during the first year post-transplant. In an unadjusted analysis, recipients of HCV NAT+ hearts had reduced survival free of CAV ≥1 over the first year after heart transplant compared with recipients of HCV NAT- hearts. After adjustment for known CAV risk factors, however, there was no significant difference between cohorts in the likelihood of the primary outcome, nor was there a difference in development of rapidly progressive CAV. CONCLUSIONS: These findings support larger, longer-term follow-up studies to better elucidate CAV outcomes in recipients of HCV NAT+ hearts and to inform post-transplant management strategies.

Extracorporeal Life Support for Cardiogenic Shock in Adult Congenital Heart Disease-An ELSO Registry Analysis.

There are minimal data on the use of venoarterial extracorporeal membrane life support (VA-ECLS) in adult congenital heart disease (ACHD) patients presenting with cardiogenic shock (CS). This study sought to describe the population of ACHD patients with CS who received VA-ECLS in the Extracorporeal Life Support Organization (ELSO) Registry. This was a retrospective analysis of adult patients with diagnoses of ACHD and CS in ELSO from 2009-2021. Anatomic complexity was categorized using the American College of Cardiology/American Heart Association 2018 guidelines. We described patient characteristics, complications, and outcomes, as well as trends in mortality and VA-ECLS utilization. Of 528 patients who met inclusion criteria, there were 32 patients with high-complexity anatomy, 196 with moderate-complexity anatomy, and 300 with low-complexity anatomy. The median age was 59.6 years (interquartile range, 45.8-68.2). The number of VA-ECLS implants increased from five implants in 2010 to 81 implants in 2021. Overall mortality was 58.3% and decreased year-by-year (ß= -2.03 [95% confidence interval, -3.36 to -0.70], p = 0.007). Six patients (1.1%) were bridged to heart transplantation and 21 (4.0%) to durable ventricular assist device. Complications included cardiac arrhythmia/tamponade (21.6%), surgical site bleeding (17.6%), cannula site bleeding (11.4%), limb ischemia (7.4%), and stroke (8.7%). Utilization of VA-ECLS for CS in ACHD patients has increased over time with a trend toward improvement in survival to discharge.

Clonal hematopoiesis of indeterminate potential and outcomes after heart transplantation: A multicenter study.

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality.

Impact of Donor Hemodynamics on Recipient Survival in Heart Transplantation.

BACKGROUND: Heart transplantation is the gold-standard therapy for end-stage heart failure, but rates of donor-heart use remain low due to various factors that are often not evidence based. The impact of donor hemodynamics obtained via right-heart catheterization on recipient survival remains unclear. METHODS: The United Network for Organ Sharing registry was used to identify donors and recipients from September 1999-December 2019. Donor hemodynamics data were obtained and analyzed using univariate and multivariable logistical regression, with the primary endpoints being 1- and 5-year post-transplant survival. RESULTS: Of the 85,333 donors who consented to heart transplantation during the study period, 6573 (7.7%) underwent right-heart catheterization, of whom 5531 eventually underwent procurement and transplantation. Donors were more likely to undergo right-heart catheterization if they had high-risk criteria. Recipients who had donor hemodynamic assessment had 1- and 5-year survival rates similar to those without donor hemodynamic assessment (87% vs 86%, 1 year). Abnormal hemodynamics were common in donor hearts but did not impact recipient survival rates, even when risk-adjusted in multivariable analysis. CONCLUSIONS: Donors with abnormal hemodynamics may represent an opportunity to expand the pool of viable donor hearts.

Modifiable Mechanical Ventilation Targets Are Associated With Improved Survival in Ventilated VA-ECLS Patients.

BACKGROUND: In acute respiratory distress syndrome (ARDS), lung protective ventilation (LPV) improves patient outcomes by minimizing ventilator-induced lung injury. The value of LPV in ventilated patients with cardiogenic shock (CS) requiring venoarterial extracorporeal life support (VA-ECLS) is not known, but the extracorporeal circuit provides a unique opportunity to modify ventilatory parameters to improve outcomes. OBJECTIVES: The authors hypothesized that CS patients on VA-ECLS who require mechanical ventilation (MV) may benefit from low intrapulmonary pressure ventilation (LPPV), which has the same end goals as LPV. METHODS: The authors queried the ELSO (Extracorporeal Life Support Organization) registry for hospital admissions between 2009 and 2019 for CS patients on VA-ECLS and MV. They defined LPPV as peak inspiratory pressure at 24 hours on ECLS of <30 cm H2O. Positive end-expiration pressure and dynamic driving pressure (DDP) at 24 hours were also studied as continuous variables. Their primary outcome was survival to discharge. Multivariable analyses were performed that adjusted for baseline Survival After Venoarterial Extracorporeal Membrane Oxygenation score, chronic lung conditions, and center extracorporeal membrane oxygenation volume. RESULTS: A total of 2,226 CS patients on VA-ECLS were included: 1,904 received LPPV. The primary outcome was higher in the LPPV group vs the no-LPPV group (47.4% vs 32.6%; P < 0.001). Median peak inspiratory pressure (22 vs 24 cm H2O; P < 0.001) as well as DDP (14.5 vs 16 cm H2O; P < 0.001) were also significantly lower in those surviving to discharge. The adjusted OR for the primary outcome with LPPV was 1.69 (95% CI: 1.21-2.37; P = 0.0021). CONCLUSIONS: LPPV is associated with improved outcomes in CS patients on VA-ECLS requiring MV.

Beyond Stage C: Considerations in the Management of Patients With Heart Failure Progression and Gaps in Evidence.

Despite treatment with contemporary medical therapies for chronic heart failure (HF), there has been an increase in the prevalence of patients progressing to more advanced disease. Patients progressing to and living at the interface of severe stage C and stage D HF are underrepresented in clinical trials, and there is a lack of high-quality evidence to guide clinical decision making. For patients with severe HF phenotypes, the medical therapies used for patients with less advanced stages of illness are often no longer tolerated or provide inadequate clinical stability. The limited data on these patients highlights the need to increase formal research characterizing this high-risk population. This review summarizes existing clinical trial data and incorporates our considerations for approaches to the medical management of patients advanced "beyond stage C" HF.

Efficacy of bortezomib desensitization among heart transplant candidates.

Allosensitization is prevalent in heart transplant candidates and is associated with prolonged waiting times and poor outcomes following transplantation. We analyzed the efficacy of a desensitization regimen consisting of plasma exchange, intravenous immunoglobulin, and bortezomib among 25 consecutive sensitized waitlisted candidates at our center from 2016 to 2021. Following desensitization therapies, all C1q negative antibodies were removed from a candidate's unacceptable antigen list. There was a significant decrease in the median number of human leukocyte antigen (HLA) class I (21-15, p = .001) but not class II antibodies (7-6.5, p = .07). There was a significant corresponding decrease in median calculated panel reactive antibodies for class I (90%-74%, p = .004) but not class II (74.5%-75.5%, p = .30). Following desensitization, 76% of patients were transplanted at a median of 91 days. One-year survival following transplant was 89% with a 33% rate of antibody-mediated rejection (AMR). In conclusion, a bortezomib desensitization protocol was modestly effective for class I antibodies and allowed successful transplant in most cases when combined with selective crossing of C1q negative antigens.

Association of Donors With US Public Health Service Risk Criteria and Outcomes After Adult vs Pediatric Cardiac Transplant.

Importance: The United Network for Organ Sharing (UNOS) evaluates donor risk for acute transmission of HIV, hepatitis B, or hepatitis C based on US Public Health Services (PHS)-specific criteria. However, recent data regarding use and outcomes of those donors with PHS risk criteria among pediatric and adult heart transplant recipients are lacking. Objective: To compare use and outcomes of graft from donors with PHS risk criteria vs those with a standard-risk donor (SRD) in children vs adults in a contemporary cohort. Design, Setting, and Participants: This cohort was a nationwide analysis of heart transplants in the US that used data from the UNOS database. Participants were children (<18 years old) and adults (≥18 years old) who received a heart transplant from January 1, 2010, to December 31, 2021. Exposures: UNOS-defined donor risk status. Main Outcomes and Measures: Trend analysis compared changes in PHS risk criteria use among children and adults. Patient survival was analyzed using Kaplan-Meier curves with log rank and Cox proportional hazards to compare PHS risk-criteria outcomes vs SRD-criteria outcomes in children and adult heart transplant recipients. Additional analysis was performed among adults who received a PHS-risk criteria graft that was previously declined for pediatric recipients. Results: Of 5115 pediatric transplant recipients (donor without PHS risk median [IQR] age, 5 [0-13] years and donor with PHS risk median [IQR] age, 8 [0-14] years) and 30 289 adult heart transplant recipients (donor without PHS risk median [IQR] age, 56 [46-63] years and donor with PHS risk median [IQR] age, 57 [47-63] years), PHS risk criteria comprised 8% in children vs 25% in adults. PHS criteria are being increasingly used over the past decade with the proportion of recipients transplanted with PHS risk-criteria donors being approximately 3 times greater among adult recipients than children recipients. Pediatric recipients of a PHS risk-criteria donor had greater pretransplant ventilatory support, whereas adult recipients of a PHS risk-criteria donor had greater pretransplant extracorporeal membrane oxygenation use. Patient survival was similar between pediatric recipients of PHS risk-criteria grafts vs SRD-criteria grafts and slightly higher among adult recipients of PHS risk-criteria grafts vs SRD-criteria grafts. The 1778 adult recipients who received a PHS criteria-risk donor that was previously declined for pediatric recipients had similar patient survival recipients compared with SRD-criteria donors (HR, 0.92; 95% CI, 0.81-1.03; P = .18). Conclusions and Relevance: In the current era, a 3-fold greater proportion of adult recipients receive a PHS risk-criteria graft compared with children despite similar posttransplant patient survival. The ongoing organ donor shortage underscores the need for consideration of PHS risk criteria where these donors remain underused.

Post-transplant diabetes mellitus following heart transplantation.

Post-transplant diabetes mellitus (PTDM) is common following heart transplant, impacting greater than 20% of patients with most cases occurring in the first year after transplant. PTDM is associated with multiple negative sequelae including increased post-operative infections, a higher rate of renal failure, and increased mortality. Compared with pre-transplant diabetes mellitus, PTDM has several unique risk factors and immunosuppressive medications play an important role in disease pathophysiology. Newer treatments for hyperglycemia, including glucagon like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, may counter the mechanisms of immunosuppression-related hyperglycemia making them an appealing treatment option for patients with PTDM. Here, we review the definitions, incidence, risk factors, pathophysiology, clinical outcomes, treatment options, pharmacologic considerations, and future directions in PTDM.

Early Blood Pressure Variables Associated With Improved Outcomes in VA-ECLS: The ELSO Registry Analysis.

BACKGROUND: As utilization of veno-arterial extracorporeal life support (VA-ECLS) in treatment of cardiogenic shock (CS) continues to expand, clinical variables that guide clinicians in early recognition of myocardial recovery and therefore, improved survival, after VA-ECLS are critical. There remains a paucity of literature on early postinitiation blood pressure measurements that predict improved outcomes. OBJECTIVES: The objective of this study is to help identify early blood pressure variables associated with improved outcomes in VA-ECLS. METHODS: The authors queried the ELSO (Extracorporeal Life Support Organization) registry for cardiogenic shock patients treated with VA-ECLS or venovenous arterial ECLS between 2009 and 2020. Their inclusion criteria included treatment with VA-ECLS or venovenous arterial ECLS; absence of pre-existing durable right, left, or biventricular assist devices; no pre-ECLS cardiac arrest; and no surgical or percutaneously placed left ventricular venting devices during their ECLS runs. Their primary outcome of interest was the survival to discharge during index hospitalization. RESULTS: A total of 2,400 CS patients met the authors' inclusion criteria and had complete documentation of blood pressures. Actual mortality during index hospitalization in their cohort was 49.5% and survivors were younger and more likely to be Caucasian, intubated for >30 hours pre-ECLS initiation, and had a favorable baseline SAVE (Survival After Veno-arterial ECMO) score (P < 0.05 for all). Multivariable regression analyses adjusting for SAVE score, age, ECLS flow at 4 hours, and race showed that every 10-mm Hg increase in baseline systolic blood pressure (HR: 0.92 [95% CI: 0.89-0.95]; P < 0.001), and baseline pulse pressure (HR: 0.88 [95% CI: 0.84-0.91]; P < 0.001) at 24 hours was associated with a statistically significant reduction in mortality. CONCLUSIONS: Early (within 24 hours) improvements in pulse pressure and systolic blood pressure from baseline are associated with improved survival to discharge among CS patients treated with VA-ECLS.

Transcatheter Aortic Valve Replacement and Surgical Aortic Valve Replacement Outcomes in Left Ventricular Assist Device Patients with Aortic Insufficiency.

Background: Worsening aortic insufficiency (AI) is a known sequela of prolonged continuous-flow left ventricular assist device (LVAD) support with a significant impact on patient outcomes. While medical treatment may relieve symptoms, it is unlikely to halt progression. Surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) are among non-medical interventions available to address post-LVAD AI. Limited data are available on outcomes with either SAVR or TAVR for the management of post-LVAD AI. Methods: The National Inpatient Sample data collected for hospital admissions between the years 2015 and 2018 for patients with pre-existing continuous-flow LVAD undergoing TAVR or SAVR for AI were queried. The primary outcome of interest was a composite of in-hospital mortality, stroke, transient ischaemic attack, MI, pacemaker implantation, need for open aortic valve surgery, vascular complications and cardiac tamponade. Results: Patients undergoing TAVR were more likely to receive their procedure during an elective admission (57.1 versus 30%, p=0.002), and a significantly higher prevalence of comorbidities, as assessed by the Elixhauser Comorbidity Index, was observed in the SAVR group (29 versus 18; p=0.0001). We observed a significantly higher prevalence of the primary composite outcome in patients undergoing SAVR (30%) compared with TAVR (14.3%; p=0.001). Upon multivariable analysis adjusting for the type of admission and Elixhauser Comorbidity Index, TAVR was associated with significantly lower odds of the composite outcome (odds ratio 0.243; 95% CI [0.06-0.97]; p=0.045). Conclusion: In this nationally representative cohort of LVAD patients with post-implant AI, it was observed that TAVR was associated with a lower risk of adverse short-term outcomes compared with SAVR.

Hepatitis C Positive Organ Donation in Heart Transplantation.

PURPOSE OF REVIEW: To summarize outcomes to date, as well as important considerations and unanswered questions related to the use of hepatitis C virus (HCV) positive donors for heart transplantation. RECENT FINDINGS: Outcomes from single-center studies and registry data to date suggest that among patients who develop donor-transmitted HCV after heart transplantation, direct-acting antiviral therapies (DAAT) are effective and well-tolerated, and that short-term survival is similar to that of patients transplanted with HCV - donors. SUMMARY: In an era marked by increasing numbers of HCV positive deceased donors and a growing imbalance between the demand and supply of donor hearts, utilization of HCV + donors is a feasible strategy to expand the donor pool and reduce waitlist times. Ongoing work is needed to clarify longer-term outcomes with the use of this strategy.