David W. Bearl

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current diagnostic approaches rely on histology, which exhibits wide diagnostic variability and lacks clinically relevant molecular phenotyping. Here we leverage image-based spatial transcriptomics at subcellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant recipients during and following histologically diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in immune and parenchymal cells across different classes of rejection. We observed broad overlap in transcriptional states across rejection severity and significant heterogeneity within rejection grades. Responders and nonresponders to augmented therapies had distinct transcriptomic profiles, with nonresponders exhibiting baseline T cell hyperactivation and tissue remodeling genes. We also identified cell-specific genes linked to long-term outcomes after heart transplant. These results underscore the importance of subtyping cellular states during rejection to stratify immune–cardiac interactions relevant to short- and long-term outcomes.

Purpose of review: Heart failure is a final common pathway for many patients with adult congenital heart disease (ACHD). As such, ACHD heart transplantation is increasingly being considered and performed. Ethical considerations exist at each step in the transplantation process. Recent findings: ACHD patients face many challenges to successful heart transplantation. A dearth of ACHD cardiologists and many barriers to transplant consideration highlight inequities related to recognition of end-stage disease and timely referral for advanced therapies. Certain vulnerable ACHD sub-groups may more easily elude heart transplant consideration emphasizing injustices for patients such as those transitioning from pediatric to adult care, patients that are under- or uninsured, and those with chronic disabilities. Increased short-term transplant morbidity and mortality requires ACHD cardiologists and heart transplant teams to balance aspects of both beneficence and nonmaleficence when considering who, when, and where to transplant these complex patients. Summary: Given the rising incidence of ACHD transplantation, centers around the globe are tasked with how to best manage this patient cohort through successful heart transplantation. This review highlights multiple ethical issues in an effort to identify opportunities to provide more accessible, equitable, and standardized advanced cardiac therapies to this unique patient population.

Background: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care.Methods: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as “too late” (death or declined for transplant due to being too sick) and/or “care escalation” (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. “Late referral” was defined as those referred too late and/or had care escalation.Results: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8–21.5, p=0.004).Conclusions: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Background: Atrial and ventricular filling pressures are routinely used in pediatric heart transplant (PHTx) recipients to assess graft function. We hypothesized that cardiac magnetic resonance (CMR) diastolic indices correlate with filling pressures, providing a noninvasive method of hemodynamic assessment.Methods: Pediatric heart transplant recipients were prospectively enrolled at the time of cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured. CMR included standard volumetric analysis. Filling curves were calculated by contouring every phase in the short‐axis stack. Global longitudinal and circumferential strain (GLS, GCS) were calculated using feature tracking. Atrial volumes and ejection fraction were calculated from 4‐chamber and 2‐chamber cine images. Correlations were analyzed using Spearman's Rho; modeling was performed with multivariable logistic regression.Results: A total of 35 patients with a mean age of 15.5 years were included, 12 with acute rejection. The median time post‐transplant was 6.2 years. Peak filling rate (PFR) and peak LV ejection rate/end‐diastolic volume (PER/EDV) correlated with PCWP (rho = 0.48 p = .005, and rho = −0.35 p = .046, respectively) as did GLS and GCS (rho = 0.52 p = .002, and 0.40 p = .01). Indexed maximum and minimum left atrial (LA) volume correlated with PCWP (rho = 0.41, p = .01, rho = 0.41 p = .01), and LA ejection fraction inversely correlated with PCWP (rho = −0.40, p = .02). GLS and GCS correlated with RAP (rho = 0.55, p = .001 and rho = 0.43, p = .01). A model including LV GLS and PFR estimated PCWP ≥12 mmHg with an area under the curve of 0.84.Conclusions: Cardiac magnetic resonance can be a useful noninvasive modality to assess for signs of diastolic dysfunction after PHTx.