The Journal of Heart and Lung Transplantation

BACKGROUND: Machine learning (ML) models have been used to evaluate one-year post-transplant mortality in donor-recipient pairs. Previous modeling utilizing noninterpretable ML methods (deep neural networks [DNN] and XGBoost) showed modest gains in area under the receiver operating curve (AUC) beyond logistic regression, but suffered a significant drop in predictive AUC applied to the subsequent years' data and lacked statistical significance in validating previously identified risk factors. METHODS: Using balanced SRTR datasets, we evaluated non-interpretable models against interpretable ML models (adaptive logistic regression with interaction terms [aLR], Classification and Regression tree [CART], and conditional inference tree [CIT]) for one-year mortality, including comprehensive clinician-supervised data curation and inclusion of variables describing pre- and post-2018 listing status changes. Models were trained/tested using rolling-window validation across years and further analyzed with repeated ten-fold crossvalidation. Interaction terms were obtained via Adaptive Best-Subset Selection (ABESS). RESULTS: Predictive validation before the listing policy change in 2018 showed similar AUCs between DNN (0.579), aLR (0.642), CART (0.579), and CIT (0.584), with XGBoost having a higher (0.763) AUC. However, in the post-2018 predictive analysis, aLR outperformed XGBoost (AUC 0.613 vs. 0.586). The interpretable ML models confirm the significance of previously reported risk factors (recipient bilirubin and creatinine) and identify risk factors not previously reported (donor pH, potential recipient distance, and recipient transfusion), as well as clinically relevant interaction terms. CONCLUSIONS: Carefully developed interpretable ML models of one-year transplant mortality have similar predictive performance to black-box models, while identifying novel risk factors, and showing improved performance after recent listing policy changes. With appropriate validation and additional data, interpretable ML modeling may allow real-time data-driven donor selection.

Background: Gut injury after pediatric cardiac surgery remains an ongoing challenge, resulting in increased morbidity and mortality for children with congenital heart disease (CHD) and a significant burden on the healthcare system. It remains unclear what the driving forces are that result in this pro-inflammatory state following pediatric cardiac surgery with cardiopulmonary bypass. Understanding key components involved in the gut composition, gut barrier function, and systemic inflammation in children with CHD after cardiac surgery is critical to improve outcomes. Methods: A prospective study of patients aged 0-5 years with CHD undergoing cardiac surgery (CPB group) or non-CHD undergoing non-cardiac surgery (Comparison group). We collected pre-operative and post-operative stool and plasma to evaluate the microbiome, metabolites, markers of gut barrier function, and inflammatory cytokines. Clinical variables were collected to evaluate markers of inflammation. These variables were compared between the two groups to evaluate signatures and develop unique biomarker profiles. Results: We enrolled 62 patients (CPB, n=46; Comp, n=16). CPB patients had increased pro-inflammatory microbiota and reduced diversity metrics pre-operatively, which were exacerbated post-operatively. The CPB group also had increased pro-inflammatory eicosanoids and reduced gut and heart protective short-chain fatty acids versus the Comparison group. The CPB group had increased pro-inflammatory and reduced anti-inflammatory cytokines post-operatively. The CPB group also had increased markers of gut barrier dysfunction versus the Comparison group. Mediation analysis showed the microbial functional shift was associated with increased PGE2 and reduced butyric acid in the CPB group, associated with increased cytokines and clinical markers of inflammation post-operatively. Conclusion: We demonstrate unique gut microbial and metabolites profiles associated with gut permeability and systemic inflammation in children with CHD undergoing cardiac surgery highlighting a unique microbiome-inflammation axis in this patient population. Further studies to evaluate causal links with these profiles will identify potential targets to improve outcomes for these patients.

Background Donation after circulatory death (DCD) is an increasingly accepted strategy to expand the adult heart donor pool, but its use in children remains limited and incompletely characterized. We compared national characteristics and post-transplant outcomes of pediatric DCD versus donation after brain death (DBD) heart transplantation. Methods We performed a retrospective cohort study of the Organ Procurement and Transplantation Network (OPTN) registry, including patients younger than 18 years who underwent primary isolated heart transplantation between January 1993 and March 2025. Recipients were stratified by donor type (DCD vs DBD). Continuous variables were compared with the Mann Whitney U test and categorical variables with the Fisher exact test. Survival was estimated by the Kaplan Meier method and compared using the log-rank test and Cox proportional hazards regression. Results Of 10,671 pediatric heart transplant recipients, 33 (approximately 0.3%) received DCD allografts. The first DCD transplant was recorded in 2004, with a marked increase in 2023 to 2024. Compared with DBD recipients, DCD recipients were more frequently infants (<1 year, 51.5% vs 28.4%) and more often had congenital heart disease (69.7% vs 47.6%; P=0.033); DCD donors were younger (median 0 vs 6 years; P=0.038) and more frequently died of anoxia (72.7% vs 37.0%; P<0.001). Donor and recipient left ventricular mass were lower in the DCD group (P<0.05), but predicted left ventricular mass matching was similar. DCD recipients had longer hospital stays (median 31.5 vs 19 days; P=0.023); rates of treated rejection, dialysis, stroke, and pacemaker implantation were comparable. Early survival did not differ (30-day, 90-day, and 1-year), and Kaplan Meier survival through 5 years was not significantly different (hazard ratio 1.17; 95% CI 0.49 to 2.81; log-rank P=0.73). More than 90% of DCD transplants were performed in four UNOS regions (11, 4, 5, and 8). Conclusions In this national analysis, pediatric DCD heart transplantation was uncommon but expanding rapidly, concentrated in a few regions, and used preferentially in infants and children with congenital heart disease. Early post-transplant outcomes were not significantly different from DBD, supporting cautious expansion of DCD as a means of enlarging the pediatric donor pool. The small number of DCD recipients and limited followup warrant confirmation in larger, longer-term studies. Keywords: pediatric heart transplantation; donation after circulatory death; donor pool; congenital heart disease; OPTN registry; organ allocation.

Background: Transplant arterial injury is an underlying feature of acute organ transplant rejection and is a main cause of late heart transplant failure. The role of the gut microbiota, and especially specific microbial components of this community, in controlling immune responses that cause this aspect of rejection is poorly understood. Methods: We utilized a murine aortic interposition model of transplant arterial injury to investigate the role of the gut commensal bacteria, Akkermansia muciniphila, in controlling immune responses in transplant arteries. Results: Early life treatment of female mice with broad spectrum antibiotics, which delayed colonization of the intestinal tract with bacteria until after weaning, led to the development of dysbiosis in adults that was characterized by the absence of A. muciniphila. This was related to an elevation in systemic levels of CCL2 and a reduction in the immunomodulatory short-chain fatty acid, propionate. When transplant arterial injury was examined, there was more arterial injury indicative of acute rejection and increased intimal thickening reflective of transplant arteriosclerosis in grafts from dysbiotic mice compared to controls. Dysbiosis also increased macrophage accumulation early after transplantation in dysbiotic mice. Notably, restoring A. muciniphila in the gut microbiota of dysbiotic mice through voluntary oral administration in infants ameliorated macrophage-mediated transplant arterial injury. Conclusions: A. muciniphila is an immunomodulatory component of the gut microbiota that protects against vascular injury and pathology in organ transplantation.

Residual congestion is the principal driver of heart failure readmission, and reliable serial assessment of volume status remains an unmet clinical need. This study asked whether a wrist-worn, machine-learning-based device for non-invasive venous waveform analysis in heart failure (the NIVAHF device), which produces an integer-scaled estimate of pulmonary capillary wedge pressure termed the NIVA Score, responds to acute changes in volume status. Agreement between the NIVA Score and invasively measured pulmonary capillary wedge pressure at single time points has been established in a separate prospective, multi-site study; however, such static agreement does not establish whether the measure tracks dynamic decongestion. We therefore evaluated the directional responsiveness of the locked NIVA Score in two prespecified cohorts: hospitalized adults with acute decompensated heart failure undergoing routine intravenous diuresis, and a controlled porcine model of volume overload followed by diuresis. In eleven patients contributing thirteen paired measurements (mean net fluid balance -2.1 {+/-} 1.0 L), NIVA Scores decreased significantly after diuresis (paired t-test, P = 0.04). In five pigs contributing twenty-four paired measurements, NIVA Scores decreased significantly after intravenous furosemide following crystalloid loading (P < 0.01), and the direction of change was concordant with measured urine output in every animal. Statistical significance was reached in both cohorts despite modest sample sizes, indicating a measurable NIVA Score reduction with volume removal. In an exploratory analysis, the discharge NIVA Score yielded an area under the receiver-operating-characteristic curve of 0.85 (95% confidence interval 0.575-1.00; P = 0.04) for thirty-day readmission. Together, the significant, directionally concordant NIVA Score reductions across independent clinical and preclinical cohorts demonstrate that the device tracks acute decongestion and support its use for serial, non-invasive congestion monitoring; an adequately powered prospective study is the planned next step.

Deterioration of lung function is a major cause of long-term morbidity after hematopoietic stem cell transplantation (HSCT) and lung transplantation (LT). In both settings, obliterative bronchiolitis represents the most common final pathway, with bronchiolitis obliterans syndrome (BOS), representing its clinical correlate. Understanding of the pathophysiological mechanisms leading to BOS is limited by restricted access to human lung tissue and the imperfect relevance of animal models. We hypothesize that transplantation procedures cause bronchial epithelial damage that promotes the development of BOS. To investigate this, we established ex vivo human airway epithelia (HAE) cultures from bronchial biopsies of HSCT and LT recipients, collected prior to the development of BOS, and compared them with non-transplant controls. HAE from HSCT recipients exhibited reduced tissue differentiation ability, associated with defect in mucociliary clearance and impaired barrier integrity, most markedly in one patient who subsequently developed BOS. In contrast, LT-derived HAE showed normal mucociliary clearance and barrier integrity but displayed increased mucin secretion. Donor and recipient-derived cells were detected in both paraffin-embedded biopsies and reconstructed HAE derived from transplant recipients, demonstrating epithelial chimerism. Our data highlight specific modifications of the airway epithelium after LT and HSCT that may represent a first trigger for subsequent BOS development.

BACKGROUND: Increased left ventricular mass (LVM) at a single time point after heart transplantation (HT) predicts future adverse outcomes. However, dynamic changes in LVM could have better biological relevance and reflect adverse graft remodeling (AGR). The prognostic significance of such serial changes has not been studied. METHODS: Using an automated, electronic health record-based institutional data infrastructure, we studied 439 HT recipients with 5,563 LVM measurements. Separate Bayesian joint models estimated the simultaneous associations of current LVM and its instantaneous rate of change with graft dysfunction (GD) and mortality. A joint-model-derived remodeling score combining patient-specific deviations in LVM and slope was dichotomized to define AGR and non-AGR groups. A mixed-effects analysis of all clinical variables was performed to assess associations with LVM both between and within patients. An independent cohort of 35 patients with 79 surveillance-biopsy RNA-sequencing samples was used to examine early stress-responsive pathways associated with the remodeling score. RESULTS: LVM declined by approximately 7 g/year after transplantation, with regression attenuating over time. Sixty patients (13.7%) had GD, and 75 (17.1%) died. Higher LVM was associated with subsequent GD (hazard ratio [HR] per 10 g, 1.14; 95% credible interval [CrI], 1.02-1.28) and mortality (HR, 1.10; 95% CrI, 1.02-1.19). A more positive LVM slope was associated with GD (HR per 1 g/year, 1.21; 95% CrI, 1.06-1.42) and with cardiac allograft vasculopathy (CAV) grade 2 or 3 (HR, 1.39; 95% Crl, 1.02-1.96). LVM regressed more slowly in the AGR group (-5.8 vs -8.4 g/year), with higher GD (21.0% vs 6.4%) and mortality (24.2% vs 10.0%). Time-updated GD was associated with subsequent death (HR, 8.12; 95% Confidence Interval [CI], 4.67-14.14). Transcriptomic analysis showed enrichment of interferon-mediated signaling and vascular endothelial activation with higher remodeling scores, whereas lower scores were associated with mitochondrial and metabolic processes, ribosome biogenesis, and pathways related to tissue repair and stress responses. CONCLUSIONS: AGR is an easily accessible imaging biomarker that reflects the changes in the allograft in response to various stressors and predicts future adverse outcomes. Discovery of molecular mechanisms of AGR could lead to novel therapies to protect the allograft from chronic rejection.

Background: Severe aortic stenosis is associated with systemic and splanchnic hemodynamic disturbances that may alter gut microbial metabolism and host inflammatory responses. Objectives: We aimed to determine whether TAVI remodels the gut microbiome-derived metabolome and whether post-procedural SCFA dynamics are associated with the inflammatory cytokine response. Methods: We conducted a prospective paired single-center study of patients undergoing elective TAVI at Bern University Hospital. Stool and blood samples were collected before and three months after the procedure. Gut microbial composition was profiled by full-length 16S rRNA sequencing, circulating short-chain fatty acids (SCFAs) by targeted metabolomics, and inflammatory mediators by multiplex cytokine analysis, and integrated with hemodynamic and clinical data. Results: Forty patients were enrolled. Following TAVI, microbial richness declined without significant restructuring of overall community composition. In contrast, circulating SCFA profiles were significantly remodeled, driven by selective reductions in butyrate and isovalerate. A greater decline in circulating butyrate was inversely associated with IL-18 elevation (rho=0.668, p<0.001, n=36), independent of aortic valve calcification burden, hemodynamic improvement, and cardiovascular medications. Baseline isovalerate was nominally associated with 1-month adjudicated adverse events (AUC 0.77; exploratory). Conclusions: TAVI is associated with selective changes in gut microbiome-derived metabolic output rather than broad alterations in microbial community structure. Declining circulating butyrate identifies a gut-metabolite-immune axis linked to IL-18 dynamics and represents a potential biomarker of inflammatory recovery following valve intervention.

Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 phenotype was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio [&ge;]0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.

Background: Digoxin use after the Norwood procedure has been associated with improved interstage survival in hypoplastic left heart syndrome and related conditions. Whether this benefit translates into improved longer-term outcomes through staged palliation remains unknown. We aimed to determine the association of digoxin use at Norwood discharge with transplant-free survival and Fontan completion. Methods: We conducted a retrospective cohort study using the Pediatric Heart Network (PHN) Single Ventricle Reconstruction trial public dataset, including 549 infants enrolled at 15 North American centers between 2005 and 2008. Competing risk analysis was used to evaluate Fontan completion and Cox regression to assess death or transplantation within 6 years after the Norwood procedure. Mixed-effects models compared pre-Fontan hemodynamic and echocardiographic right ventricular indices between patients treated with and without digoxin after accounting for center clustering and adjustment for sex, shunt type, heart failure medications at Norwood discharge, and census block poverty level. Results: The 6-year cumulative incidence of Fontan completion was higher among patients discharged on digoxin than among those not receiving digoxin (82% vs 71%; p = 0.013). Competing-risk analysis accounting for death and transplant demonstrated a greater likelihood of Fontan completion among digoxin users (aHR 1.31; 95%CI 1.09-1.58; p = 0.005), without significant difference in the hazard of death or transplant (aHR 0.78; 95%CI 0.53-1.15; p = 0.208). No significant differences in pre-Fontan hemodynamic or echocardiographic indices were observed between groups. Initiation of digoxin post Stage II procedure was not associated with improved survival or likelihood to complete Fontan. Conclusion: Digoxin use at the time of Norwood discharge was associated with a 30% greater likelihood of Fontan completion by 6 years, without accompanying improvement in transplant-free survival. These findings extend prior observations of improved interstage outcomes associated with digoxin use and suggest that treatment may facilitate progression through staged palliation.

Background: Blood volume (BV) in patients with chronic heart failure (HF) is characterized by heterogeneity in volume profiles; one profile being "normal BV". While overall intravascular volume may be considered normal clinically, the relative contributions of red blood cell (RBC) mass and plasma volume (PV) may not be. Objective: Assess how normal is a "normal BV" based on quantitative measures of RBC mass and PV. Methods: Retrospective analysis was undertaken in 395 patients with Class II-III HF. BV was quantitated using indicator-dilution methodology. Cohort was stratified by normal and hypervolemic BV. Results: Of the cohort, 31% (123/395) demonstrated normal total BV and 62% (244/395) hypervolemic BV. Of patients with "normal BV", 36% (44/123) demonstrated normal RBC mass and 60% normal PV (74/123). Importantly, 60% (74/123) demonstrated a deficit in RBC mass (true anemia), while a low hemoglobin (<12 g/dL) was present in just 29% (36/123). An excess in RBC mass (erythrocytosis) in 4% (5/123). Notably, true normal BV (i.e., normal RBC mass and normal PV) was observed in only 30% (37/123) of patients with an overall "normal" intravascular volume. Conclusions: Findings reveal that "normal BV" can be misleading by concealing substantial variability in RBC mass (including unrecognized anemia and erythrocytosis) as well as different degrees of PV expansion and contraction. An actual normal BV was identified in a minority of "normal BV" patients. This underscores the importance of looking beyond overall "normal BV" to the contributing elements of RBC mass and PV with significant implications for patient management and outcomes.

Background: Risk stratification in pericarditis relies mainly on clinical presentation, suspected etiology, imaging findings, and conventional inflammatory biomarkers. Whether complete blood count-derived inflammatory indices are associated with mortality in pericarditis and whether these associations are directionally consistent across independent real-world datasets remain unclear. Methods: We conducted a retrospective dual-cohort study of hospitalized adults with pericarditis using a Hong Kong cohort from the Clinical Data Analysis and Reporting System (CDARS) as the primary analysis cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) cohort as an independent reproducibility cohort. Baseline neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were analyzed as continuous variables and cohort-specific tertiles. The primary outcome was long-term all-cause mortality in the Hong Kong cohort. Secondary and reproducibility outcomes included 90-day mortality in the Hong Kong cohort and 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Cox models were adjusted for age, sex, renal disease, diabetes mellitus, hypertension, ischemic heart disease, and malignancy. Results: Among 504 patients in the Hong Kong cohort and 464 patients in MIMIC-IV, all-cause mortality occurred in 241 and 113 patients during cohort-specific follow-up, respectively. In the Hong Kong cohort, higher NLR was associated with long-term all-cause mortality after full adjustment. Compared with NLR tertile 1, the adjusted hazard ratio was 1.60 for tertile 3. Higher SII was also associated with long-term mortality, with an adjusted hazard ratio of 1.55 for tertile 3 versus tertile 1. NLR and SII showed directionally consistent associations with 90-day mortality in the Hong Kong cohort and with 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Sensitivity analyses yielded broadly consistent findings. Conclusions: In two independent real-world cohorts of hospitalized patients with pericarditis, higher baseline NLR and SII were associated with increased all-cause mortality, with NLR showing the more consistent prognostic signal. These complete blood count-derived indices may provide simple adjunctive information for mortality risk stratification, although prospective validation is needed before incorporation into formal management algorithms.

Background Totally endoscopic aortic root (AR) surgery via right anterior minithoracotomy (RAMT) may reduce surgical trauma and accelerate recovery compared with full sternotomy (FS). However, the approach is technically demanding due to limited access and anatomical complexity. This study compares early clinical outcomes and quality of life (QoL) after RAMT versus FS to evaluate the feasibility and safety of the totally endoscopic approach. Methods This single-center, retrospective study included 149 patients underwent AR surgery via RAMT (n=74) or FS (n=75) between January 2021 and March 2026. Patients with aortic dissection, infective endocarditis, redo surgery, concomitant procedures, or arch replacement were excluded. Operative outcomes, postoperative recovery, 30-day and 1-year mortality were analyzed. QoL was assessed using the Short Form-8 (SF-8) questionnaire. Results The median age was 60.0 years, and 79.9% of patients were male. Bentall procedure was performed in 84.6% of patients, 15.4% underwent a David procedure. Compared with FS-AR, RAMT-AR was associated with shorter median operative time (147.0 vs. 178.0 min; p<0.001), lower median chest drainage volume (650.0 vs. 850.0 mL; p<0.001), and shorter median ICU stay (24.0 vs. 25.0 h; p=0.008) and hospital stay (6.0 vs. 8.0 days; p=0.028). Overall, 30-day and 1-year mortality was 0.7%. SF-8 analysis demonstrated significantly higher physical and mental component scores in RAMT-AR patients. Conclusion In specialized centers, totally endoscopic AR surgery via RAMT is a safe and feasible minimally invasive approach associated with favorable early outcomes and a potential benefit in postoperative physical and mental QoL by reducing surgical trauma.

Background. Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is characterized by substantial clinical and biological heterogeneity. Sex differences are central to HFpEF pathophysiology, yet current phenotyping approaches often aggregate women and men, potentially obscuring distinct molecular mechanisms of disease progression. Molecularly resolved, sex-specific stratification is therefore needed to identify divergent risk pathways and improve biological understanding of HFpEF heterogeneity. Methods. In 698 HFpEF participants from the prospective MyoVasc cohort (379 females, 319 males), we run separate analyses on sex-specific cohorts. For each cohort, we integrated 92 circulating proteins (Olink Inflammation panel) and 49 clinical variables using Similarity Network Fusion to construct sex-stratified patient-patient similarity networks. Spectral clustering identified sex-specific prognostic subgroups related to the primary endpoint, i.e. worsening of Heart Failure (WHF). XGBoost models characterizing cluster-defining features were validated in an independent cohort of 342 HFpEF patients from the Gutenberg Health Study (GHS; 194 females, 148 males). Results. Two clusters emerged in each sex, with high-risk and low-risk clusters, showing the difference in WHF risk (MyoVasc females: HR 2.45, 95% CI 1.32-4.54, p=0.005; males: HR 2.77, 95% CI 1.27-6.04, p=0.011; C-index 0.62-0.63). Kaplan-Meier analyses confirmed separation (p<0.02 females, p<0.01 males). Clusters were reproduced in GHS using MyoVasc-trained XGBoost (females p=0.0082, males p=0.037). Shared top-ranking features included VEGF-A, TNFRSF9, and TGF-. Females were characterized by inflammatory (CD40, HGF, TNF) and glycemic signatures, whereas males showed prominence of immune-regulatory markers (IL-10RB, PD-L1) and renal function indicators (eGFR, creatinine). Conclusions. Sex-stratified molecular-clinical networks define prognostically distinct HFpEF subgroups with robust external validation. Shared protein biomarkers alongside sex-specific drivers reveal complementary progression mechanisms, supporting precision medicine strategies targeting high-risk cluster patients in sex-specific manner.

BACKGROUND: The revised 2018 AHA/ACC guidelines introduced the Adult Congenital Heart Disease Anatomic and Physiologic classification (ACHD-AP) to better categorize disease severity and prognosis in the ACHD population. The ACHD-AP has not been rigorously studied as a perioperative prediction tool. OBJECTIVE: We aimed to assess the accuracy of the ACHD-AP classification in predicting perioperative morbidity and mortality. METHODS: This retrospective cohort study included 295 ACHD patients at a single academic institution between 2018 to 2022. Patients were identified by the STS congenital surgery registry and had undergone a congenital surgical procedure. The primary outcome was overall mortality. Secondary outcomes included short-term post-operative morbidity and comparison of the ACHD-AP score to other existing surgical mortality risk scores. Kaplan-Meier and area under the curve (AUC) of Receiver Operating Characteristic curves were used to evaluate mortality. Logistic regression was used to compare short-term morbidity. RESULTS: A total of 295 patients were included with a median age of 30 years (interquartile range 21-41 years) and 52% were female. There was a total of 14 deaths with 5 (2%) early post-operative deaths and 9 (3%) long-term deaths. By increasing anatomy complexity, overall mortality was 0%, 4% (n=10), and 8% (n=4), respectively. By increasing physiologic severity, overall mortality was 0%, 3% (n=2), 4% (n=7), and 14% (n=5). Moderate and complex anatomy trended towards increased mortality but were not statistically significant (p-value > 0.9). More severe physiology scores predicted increased mortality (p-value = 0.02). Higher physiologic or anatomic complexity scores were associated with longer post-operative length of stay (>5 days). The ACHD-AP AUC was 0.711 for mortality, which was comparable to the Adult Congenital Heart Surgery (ACHS) score (AUC 0.798) and better than the PEACH score (AUC 0.575). CONCLUSION: The ACHD-AP score revealed comparable or better predictive power to existing risk models. Worsening physiologic and anatomy scores were associated with worse post-operative outcomes. Further prospective studies are needed to validate the ACHD-AP score as a prognostic factor for patients undergoing ACHD surgery.

Background: Outpatient chronic heart failure (HF) assessment relies on NYHA class and distance-based testing that can obscure physiological heterogeneity. Near-infrared spectroscopy (NIRS) enables tissue oxygenation phenotyping but is underexplored during standardized stressors in outpatient HF. We tested whether wearable NIRS-derived oxygenation kinetics during a vascular occlusion test (VOT) and six-minute walk test (6MWT) differ across NYHA classes. Methods: In this prospective, single-center pilot study, 44 chronic HF outpatients (mean age 70.9 {+/-} 8.7 years, 75% male; NYHA I [n=19], II [n=12], III [n=13]) were monitored with a novel wearable NIRS device (NIRSense Envello Core) during a VOT and 6MWT. Primary endpoints were the post-occlusion net area under the curve (net AUC; VOT) and post-walk recovery net AUC (modified 6MWT). Secondary endpoints included the exertional tissue oxygenation (Oxy) nadir, VOT reperfusion kinetics, gait metrics, and tolerability. Results: Despite NYHA I and II walking identical median distances (420 m), post-walk recovery net AUC was lower in NYHA II (-16.3 a.u.xs) and III (-12.8 a.u.xs) than NYHA I (46.1 a.u.xs, p=0.004). The exertional Oxy nadir did not differ (p=0.722), but NYHA III walked 27% and 38% slower than NYHA II and I (p<0.001). NYHA II had higher VOT net AUC (134.2 a.u.xs) than NYHA I (71.9; p=0.018) and III (61.1; p=0.011). Post-walk recovery net AUC correlated with gait velocity (rs=0.44) and distance (rs=0.39; both p<0.05). VOT net AUC did not correlate with functional metrics, but resting reperfusion kinetics correlated with 6MWT performance (rs=0.41-0.46, p<0.05). The sensor was well tolerated. Conclusions: Wearable NIRS-derived recovery kinetics differentiated NYHA I from NYHA II despite these classes walking identical median distances. Coupled with distinct resting VOT hyperemic differences, these preliminary findings indicate wearable NIRS may capture physiological heterogeneity in outpatient HF not reflected by NYHA class and standard functional metrics.

Background: Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective: To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods: We performed a retrospective cohort study of adults (?18 years) first evaluated at Mayo Clinic from 2002?2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results: A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9?5.3) and Fontan physiology (HR 3.2, 95% CI 2.3?4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions: In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.

Background Cardiac magnetic resonance imaging (CMR) T1 and T2 mapping accurately detect acute heart transplant rejection, but the diagnostic value of CMR-derived strain imaging remains uncertain, particularly for right ventricular strain. Data incorporating donor-derived cell-free DNA (dd-cfDNA) into a composite reference standard are limited. We evaluated the diagnostic accuracy of CMR-derived left and right ventricular strain and ejection fraction for detecting acute rejection in pediatric and adult heart transplant recipients. Methods Blinded analysis of 1.5T CMR studies was performed in pediatric and adult heart transplant recipients 1-24 months post-transplant, as well as during five additional episodes of acute rejection occurring 3-14 years post-transplant. Left and right ventricular strain and ejection fraction were quantified using semi-automated post-processing. Acute rejection was defined using a composite reference standard comprising endomyocardial biopsy (EMB), clinical assessment, and dd-cfDNA. Diagnostic performance was assessed using cut-off values derived from receiver operator characteristic (ROC) analysis. Results Among 214 CMR studies in 58 patients, 13 cases of acute rejection were identified. Diagnostic performance for detecting acute rejection was moderate for pediatric right ventricular longitudinal strain (AUC 0.782, 95% CI 0.565-0.999), whereas all other cardiac functional parameters demonstrated limited discrimination in both pediatric and adult patients (AUC 0.536-0.739). Models based on individual rejection indicators (EMB, clinical assessment, and dd-cfDNA) also showed poor diagnostic accuracy. Conclusion CMR-derived left and right ventricular strain and ejection fraction demonstrated limited ability to independently detect acute rejection. However, strain abnormalities, particularly RVLS in pediatric patients, may reflect downstream functional effects in more advanced rejection and may complement T1 and T2 mapping in assessing rejection severity.

Background: The saphenous vein (SV) remains the most widely used graft in coronary artery bypass grafting (CABG). However, graft failure over the years has compromised long-term outcomes. Preservation of the vascular endothelium is fundamental for vein graft patency, and hydrogen sulfide (H2S) a protective gasotransmitter, plays a significant role in vascular homeostasis. This study evaluated how different intraoperative preservation solutions modulate H2S-synthesizing enzymes and endothelial integrity. Methods: SV segments from 20 CABG patients were subdivided into five groups: Control (immediate fixation), normal saline (NS; 0.9% NaCl), autologous heparinized arterial blood (AHB), histidine-tryptophan-ketoglutarate (HTK) solution, and a damage group (no solution for 30 minutes). Structural integrity was evaluated by measuring endothelial coverage using light microscopy, and the expression of eNOS, CD31, and H2S pathway enzymes (CSE, CBS, and 3-MPST) was assessed by immunofluorescence (IF) and confocal microscopy to determine mean fluorescence intensity (MFI). Results: LM analysis revealed that AHB (89.66% {+/-} 3.02) and HTK (88.72% {+/-} 3.07) preserved endothelial coverage significantly better than NS (78.06% {+/-} 4.48) and the Damage Group (76.82% {+/-} 4.90; p < 0.001). In IF, all interventions reduced eNOS and CD31 expression compared to the control, but AHB and HTK maintained significantly higher levels than NS (p < 0.001). All three H2S-producing enzymes were detected in the GSV endothelium, with CSE being the most expressed isoform. The use of NS caused a marked depletion of these enzymes, while AHB and HTK showed specific superiority in preserving H2S synthesizing enzymes. Conclusions: The choice of preservation solution significantly affects endothelial integrity and the modulation of enzymatic H2S synthesis. NS proved to be deleterious to the endothelium, whereas AHB and HTK better preserved vascular structure and function, suggesting their clinical superiority for the preparation of venous grafts during CABG.

Aims: Prognostic stratification and individual management are essential in the heterogeneous population of non-ischemic dilated cardiomyopathy (NIDCM). We applied unsupervised machine learning (ML) clustering in NIDCM cohorts, using semi-automated artificial intelligence (AI)-based cardiac magnetic resonance imaging (CMR) measurements with multimodal data to identify distinct phenotypes, characterize echocardiographic remodeling trajectories, and evaluate prognostic significance. Methods and results: We analyzed 347 patients with NIDCM from two tertiary centers who underwent CMR and echocardiography at baseline, with follow-up echocardiography at a median 12 months. The cohort was randomly divided into derivation (n=242) and validation (n=105) sets using stratification by the composite outcome. Remodeling trajectories were evaluated using follow-up echocardiographic changes, and associations with outcomes were assessed by multivariable Cox regression adjusted for age and sex. Using eleven comprehensive clinical, laboratory, echocardiographic, and CMR-derived variables, partitioning around medoids clustering identified three phenotypes: (i) a younger, male-predominant preserved phenotype; (ii) a metabolic, fibrotic-remodeling phenotype; and (iii) an atrial fibrillation-predominant biventricular dysfunction phenotype. Cluster 1 showed the most favorable prognosis, whereas Cluster 3 had the highest risk of the composite outcome. Although LV reverse remodeling occurred across all clusters, Cluster 3 was characterized by attenuated LA reverse remodeling, suggesting persistent LA dysfunction. Conclusion: Unsupervised ML-based clustering of NIDCM patients, integrating AI-derived CMR parameters with multimodal data, identified three clusters exhibiting distinct patterns in longitudinal echocardiographic trajectories and outcomes. This strategy may enable more individualized management in heterogeneous NIDCM.