The Journal of Heart and Lung Transplantation

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.

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: 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: 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: Adult congenital heart disease (ACHD) patients are prone to HLA-antibody formation from multiple surgeries, transfusions, and prosthetic surgical material. Females with ACHD may accrue additional, non-surgical alloantigen exposure. Whether sex modifies the impact of allosensitization on heart transplant (HT) access and outcomes in ACHD remains unknown. Methods: We retrospectively analyzed the OPTN/UNOS registry of adults with ACHD listed for first-time HT (2018-2025). Sensitization was defined by calculated panel reactive antibodies (cPRA) at listing. We tested the sex x sensitization (highly sensitized, cPRA >50%) interaction on transplant access using Fine-Gray competing-risks regression, treating transplantation as the event of interest and death or removal from the waitlist as competing events, and on post-transplant survival using multivariable Cox proportional-hazards regression, both adjusted for age at listing, mechanical support at listing, and the number of distinct prior cardiac surgery categories. Results: Among 856 candidates (38% female), females were more often highly sensitized than males (23% vs 14%; age-adjusted OR 1.81, 95% CI 1.26-2.61), even after adjusting for surgical burden. Sensitization reduced transplant access in females (84% to 71%; median wait 60 to 110 days, p < 0.001) but not males (79% vs 79%, median wait 88 vs 98 days). In adjusted Fine-Gray models, the subdistribution hazard for transplant was reduced in sensitized females (sHR 0.54, 95% CI 0.41-0.72) with no effect in males (sHR 0.96, 95% CI 0.73-1.26), and the sex x sensitization interaction was significant (interaction sHR 0.64, 95% CI 0.44-0.94, p = 0.02). Post-transplant mortality was numerically higher in sensitized than non-sensitized candidates in both sexes and the sex x sensitization interaction on 1-year mortality was not significant. The sex-asymmetric effect persisted and was more pronounced in the multiorgan candidates. Conclusions: Allosensitization is not a sex-neutral barrier to transplant in HT candidates with ACHD. Females are more sensitized and have reduced transplant access without differences in 1-year mortality. The female excess in sensitization is not accounted for by surgical burden, and the exposures responsible remain to be defined. These findings warrant a sex-aware listing strategy and further studies.

Background Exercise intolerance is common in adults with repaired tetralogy of Fallot (rTOF) despite preserved left ventricular ejection fraction (LVEF [&ge;]50%). Whether reduced exercise capacity is associated with early cardiac remodeling remains unclear. Objectives To determine whether reduced exercise capacity in rTOF with preserved LVEF is associated with diastolic dysfunction, atrial remodeling, right ventricular (RV) dysfunction, and myocardial fibrosis. Methods We retrospectively studied adults with rTOF and preserved LVEF who underwent cardiopulmonary exercise testing (CPET) and transthoracic echocardiography (TTE) and/or cardiac MRI (CMR) within 18 months. Exercise capacity was assessed by percent-predicted peak VO2 (ppVO2). Diastolic function and atrial remodeling were evaluated by TTE, and CMR assessed RV function and myocardial fibrosis. Results Reduced exercise capacity was associated with larger left atrial volume index (LAVI; p < 0.001), elevated E/e' and reduced e' velocity (both p < 0.05), and reduced RV systolic function (p < 0.001). LAVI correlated inversely with ppVO2 ({rho} = -0.27, p = 0.003). A composite diastolic dysfunction score showed a graded relationship with exercise capacity, with patients exhibiting [&ge;]2 abnormalities having lower ppVO2 than those with [&le;]1 abnormality (both p < 0.01). In contrast, pulmonary regurgitation (PR) severity and myocardial fibrosis by late gadolinium enhancement (LGE) were not associated with exercise capacity. Conclusions In adults with rTOF and preserved LVEF, reduced exercise capacity is associated with atrial remodeling, diastolic dysfunction, and RV dysfunction despite the absence of overt myocardial fibrosis. This suggests that multimodal imaging identifies an imaging-defined cardiac remodeling phenotype associated with early functional impairment.

Despite immunosuppressive regimens targeting adaptive immunity, chronic lung allograft dysfunction (CLAD) remains the major obstacle to durable lung allograft survival. Here, we identify colony-stimulating factor 1 receptor (CSF1R)-expressing interstitial macrophages as critical orchestrators of CLAD. Using lung tissue from patients with CLAD and a mouse model of mismatched lung transplantation, we show that both donor-derived tissue-resident and recipient- monocyte-derived interstitial macrophages spatially co-localize within peribronchial immune aggregates in patients with CLAD. These interstitial macrophages express distinct cytokine programs that include those implicated in the recruitment of T and B cells. Pharmacological inhibition of CSF1R after lung transplantation in mice reduced interstitial macrophage abundance and attenuated CLAD pathology. Our findings identify donor- and recipient-derived interstitial macrophages as upstream regulators of CLAD and suggest CSF1R as a therapeutic target for its prevention and treatment.

Background: Right ventricular (RV) function predicts survival in pulmonary hypertension (PH) and other cardiovascular diseases, yet echocardiographic AI has largely focused on the left ventricle (LV). Objectives: To develop and evaluate PH-ECHO-AI, a unified deep learning model performing four-chamber segmentation, landmark localisation, biventricular ejection fraction (EF) estimation, deformation analysis, and PH prediction from a single apical four-chamber (A4C) clip. Methods: We developed the model using 8,416 clips from four public datasets and no institutional data: EchoNet-Dynamic, CAMUS, RVENet (apical four-chamber clips paired with 3D-echocardiographic right ventricular ejection fraction, RVEF), and MIMIC-IV-ECHO. Evaluation used held-out, training-excluded data with expert-reviewed reference standards and a per-cohort audit of patient-level separation: 1,416 clips for segmentation; 600 clips for function and deformation (350 referenced to 3D-echocardiographic RVEF, 250 to the EchoNet LVEF); and 1,076 MIMIC-IV patients for PH prediction, with five-fold cross-validation. Performance measures were Dice, correlation, mean absolute error (MAE), Bland-Altman agreement, and area under the receiver operating characteristic curve (AUC). Results: Four-chamber segmentation generalised robustly across all datasets (pooled Dice: LV 0.925, RV 0.836, LA 0.910, RA 0.904). Left ventricular ejection fraction (LVEF) was estimated with r=0.845 (95% CI 0.786 to 0.886) and MAE 4.67%. RVEF, regressed directly from the clip by a supervised head trained on 3D-echocardiographic labels with no geometric assumption, reached r=0.754 (95% CI 0.690 to 0.806) and MAE 4.98%, matching published single-view RVEF ceilings and exceeding geometric RV fractional area change (RVFAC; r=0.278). Deformation and excursion metrics, namely RV free-wall and LV A4C longitudinal strain and tricuspid and mitral annular plane systolic excursion (TAPSE, MAPSE), proved physiologically coherent. Segmentation generalised to the external MIMIC-IV cohort, and PH prediction was developed and evaluated entirely within it; RVEF evaluation was clip-disjoint and same-source, so cross-centre RVEF validation remains outstanding. Using echocardiographic geometry alone, confirmed PH was detected with an AUC of 0.697 and strong calibration (Brier 0.061). Conclusions: A single, reproducible model provides comprehensive right-heart-focused interpretation from one A4C view. It achieves RVEF accuracy competitive with dedicated RV models while simultaneously delivering segmentation, deformation, annular excursion (TAPSE and MAPSE), and PH prediction. Registration: This retrospective study used existing datasets. Code is openly released, and trained model weights are available to credentialed investigators, for independent evaluation.

Rationale: Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives: To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods: Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements: NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results: We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61{+/-}15 years, female/male ratio 2.5, BMI 26 {+/-}7 kg/m2, mPAP 41{+/-}16 mmHg, PAWP 8.8{+/-}3.2 mmHg, PVR 8.0{+/-}4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite2. Conclusion: PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

Background Adults with a systemic right ventricle (sRV) due to congenitally corrected transposition of the great arteries (ccTGA) or atrial switch repair for d-transposition of the great arteries (d-TGA) experience substantial physiologic and psychosocial morbidity. Relationships among exercise capacity, sRV function, and mental health remain incompletely characterized. Objectives To characterize relationships among anatomic subtype, exercise capacity, sRV function, and mental health in adults with sRV physiology. Methods We performed a retrospective cohort study of adults with ccTGA or d-TGA (Mustard/Senning) followed at a tertiary Adult Congenital Heart Disease program from 2000 to 2025. Clinical, imaging, cardiopulmonary exercise testing, and patient-reported data were obtained from electronic health records. Mental health diagnoses were identified from clinical documentation. Functional status was assessed using NYHA class and the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results Among 137 adults (ccTGA, n = 51; d-TGA, n = 86), percent-predicted peak VO2 was lower in d-TGA than ccTGA (60% vs 74%, p < 0.001), as was sRV systolic function (41 +/- 11% vs 47 +/- 10%, p < 0.01). Anxiety or depression was more common in d-TGA (46% vs 25%, p < 0.05). Across the cohort, anxiety or depression was associated with lower exercise capacity, worse NYHA functional class, and lower KCCQ scores. Conclusions Adults with d-TGA following atrial switch have lower exercise capacity, reduced sRV systolic function, and greater mental health burden than adults with ccTGA. These findings support integrated assessment of physiologic performance, functional status, and mental health in adults with sRV physiology.

Objective(s)Tricuspid valve (TV) remodeling and functional tricuspid regurgitation (FTR) progression during right ventricular (RV) pressure overload and reverse remodeling after resolution of RV afterload is poorly understood. We set out to investigate tricuspid leaflet tissue response to induction and subsequent alleviation of pressure overload in a large animal model of RV failure with FTR. MethodsFifteen healthy adult male Dorset sheep (72{+/-}4 kg) underwent pulmonary artery banding (PAB) to induce RV failure and FTR. After 8 weeks, 7 sheep (PAB, n=7) were terminated, and remaining 8 had the PAB removed (rPAB, n=8) and were followed for another 8 weeks before termination. Both groups underwent epicardial echocardiography and hemodynamic assessment during banding surgery and at terminal operation. Ten healthy sheep served as a control group (CTL, n=10) and underwent terminal procedure only. In all animals, TV leaflets and right ventricular (RV) tissue were harvested at terminal procedure and analyzed histologically and transcriptionally. ResultsTV leaflets in PAB animals showed increased cross-sectional area and ECM alterations, some of which persisted after resolution of RV pressure overload. rPAB valves exhibited distinct ECM composition, with notably altered mucin and fibrin content, suggesting a shift toward matrix stabilization, dissimilar to control and PAB. RNA sequencing uncovered a unique molecular state in rPAB valves, with persistent changes in PRG4, PDE3A, CXCL8, and HLA transcripts. RV tissue also demonstrated a separate remodeling trajectory, with sustained expression of stress-related genes including PDE3A, NAV2, ANFB, and ACTS. These findings indicate that both valve and ventricular tissues retain a persistent remodeled phenotype post-unloading. ConclusionsTV leaflets actively remodel in response to hemodynamic stress and do not fully revert to a normal state after relief of pressure overload. This persistent altered phenotype may represent a biological contribution of the TV leaflets to recurrent TR with implications for long-term outcomes following treatment of FTR. Clinical Perspective What is new?O_LIRelief of right ventricular pressure overload, in a large animal model, resulted in substantial reverse remodeling of the right heart and reduction of tricuspid regurgitation severity, but tricuspid valve leaflets did not return to a normal state. C_LIO_LIReverse remodeled leaflets remained enlarged despite normalization of hemodynamics with an altered extracellular matrix. C_LIO_LICellular proliferation and immune cell infiltration observed during pressure overload resolved after unloading, yet transcriptomic analysis identified a distinct molecular phenotype that differed from both healthy and diseased valves. C_LIO_LITricuspid valve leaflets are active biological participants in the remodeling process and exhibit persistent adaptation or maladaptation after resolution of the initiating hemodynamic stress. C_LI What Are the Clinical Implications?O_LISecondary tricuspid regurgitation should be considered a disease involving both right heart geometry and leaflet biology. C_LIO_LIResolution of the underlying cause of tricuspid regurgitation may not restore leaflet structure and molecular homeostasis. C_LIO_LIPersistent leaflet remodeling may contribute to residual or recurrent tricuspid regurgitation despite successful treatment of pulmonary hypertension or other inciting conditions. C_LIO_LITherapies directed at leaflet remodeling may ultimately complement surgical and transcatheter strategies currently focused on annular and ventricular geometry. C_LI

Background: Unstructured biomedical data, such as echocardiography reports, are rich in information but time consuming to analyze at scale. Rule-based, regular expression-driven terminology mapping can only extract individual variables while large language models (LLMs) offer scalable and clinically meaningful interpretations of heterogeneous disease processes. Right ventricular dysfunction (RVD) is an example of a multifactorial disease state in which key structural and physiologic features are captured both narratively and in structured fields, making it an ideal test case for evaluating whether LLMs can recover complex phenotypes that rules based methods routinely miss. Purpose: To compare an LLM-based extraction method to a conventional rules-based schema for identifying and phenotyping echocardiographic features associated with RVD in a large TTE dataset. Methods: MIMIC-III NOTE2NUM echocardiography reports (n = 45,794) were analyzed using GPT-4o-based LLM extraction deployed within a secure health system enclave and were benchmarked against echocardiographic measurements defined in the MIMIC-III dictionary schema. In MIMIC-III, PH was recorded qualitatively (mild/moderate/severe) based on tricuspid regurgitant (TR) jet velocity and then re-coded as present vs. absent. LLM based extraction defined RVD as (1) RV structural abnormality (>= 1 of hypertrophy, dilation, or wall hypo-/akinesis) or (2) RV pressure/volume overload (>= 2 of the following: estimated right atrial pressure > 8 mmHg, TR jet velocity > 2.8 m/s, fractional area change < 35%, tricuspid annular planar systolic excursion < 17 mm, S' < 9.5 cm/s, or E/e' > 14), with PH defined as estimated pulmonary artery systolic pressure > 35 mmHg or qualitative documentation of PH. Results: LLM extraction identified PH in 15,394 (33.6%), RV pressure/volume overload in 14,449 (31.6%), and RV structural abnormalities in 11,955 (26.1%). Co-occurrence was common: overload + structural changes in 9,380 (20.5%), overload + PH in 9,756 (21.3%), structural changes + PH in 6,183 (13.5%), and all three in 5,620 (12.3%). Using the MIMIC-III dictionary schema, PH prevalence was similar (15,371; 33.6%), but RV overload fields were captured less often (pressure overload 1,357 [3.0%], volume overload 1,128 [2.5%], pressure + volume overload 1,093 [2.4%]; any overload field 3,578 [7.8%]), and RV pressure/volume overload with PH was identified in only 731 (1.6%). Conclusions: LLM-based extraction outperforms rules-based schemas for identifying complex disease states not defined by any single variable. By synthesizing multifactorial signals, LLMs can phenotype RVD with higher fidelity and support population-level assessment. Further validation using multimodality imaging, invasive hemodynamics, and clinical outcome data is needed.

Background: Preoperative risk assessment in vascular surgery relies on clinical scores and lipids that do not capture atherosclerotic disease activity. Circulating fatty acid synthase (cFAS) is a liver-derived enzyme whose concentration correlates with arterial plaque FAS content independent of LDL. The 5-item modified frailty index (mFI-5) is a validated predictor of postoperative mortality. Whether cFAS predicts outcomes after vascular surgery, and whether combining it with the mFI-5 improves risk discrimination, have not been examined. Methods: We studied 657 patients undergoing elective vascular surgery at a single center (2014 to 2023). cFAS was classified as non-detectable (n = 306) or, among detectable values, by tertiles (n = 117 each). Multivariable Cox models assessed associations with major adverse events (MAE), major adverse cardiovascular events (MACE), major adverse limb events (MALE), reintervention, and mortality, and Harrell's C-statistic quantified the incremental discrimination gained by adding cFAS and the mFI-5 to standard clinical covariates. Results: High serum cFAS was independently associated with 5-year MAE (adjusted hazard ratio [aHR] 1.94; 95% CI 1.31- 2.85), mortality (aHR 1.77; 1.05 to 3.00), MALE (aHR 4.53; 2.04 to 10.05), and reintervention (aHR 2.50; 1.37 to 4.57), but not MACE. Severe frailty (mFI-5 of 3 or higher) was associated with MACE (aHR 2.69; 1.29 to 5.58) and MAE (aHR 2.46; 1.30 to 4.65) but not limb endpoints at 1 year. Adding cFAS raised the 1-year MALE C-statistic from 0.649 to 0.764; the combined model yielded the highest discrimination. Conclusions: cFAS and mFI-5 were independently and additively associated with adverse outcomes after elective vascular surgery. cFAS was associated with limb events and mortality, the mFI-5 with cardiovascular events. Combining them improved discrimination over standard covariates.

Background: Manual abstraction of complex percutaneous coronary intervention (PCI) variables from cardiac catheterization reports is labor-intensive and limits scalable cardiovascular research. Large language models (LLMs) may enable automated extraction of procedural data, but their performance remains uncertain. Methods: We evaluated three open-source LLMs (Llama 3.3 70B, Meditron-7B, and BioMistral-7B) using manually annotated cardiac catheterization reports from three hospitals within Yale New Haven Health system. Models were tasked to identify if a procedure note was a PCI procedure, and extract variables used to classify PCI as complex using predefined criteria, including 3 vessels treated, [&ge;]3 treated lesions, bifurcation PCI with two stents, chronic total occlusion, [&ge;]3 stents, and total stent length [&ge;]60 mm. Results: The evaluation cohort included 1,412 clinical notes of which 596 were PCI procedures. Llama 3.3 70B consistently outperformed both domain-specific models across nearly all extraction tasks. For PCI identification, Llama 3 70B had 100.0% sensitivity, 93.8% specificity, 92.1% positive predictive value, 100.0% negative predictive value, 96.4% accuracy, and an F1 score of 95.9%. For complex PCI classification, among 590 evaluable PCI reports, sensitivity was 97.7%, specificity was 80.1%, positive predictive value was 57.6%, negative predictive value was 99.2%, accuracy was 83.9%, and the F1 score was 72.5%. Variables that were explicitly documented, including stent number, stent length, and adjunctive device use, were extracted with high accuracy, whereas performance was lower for variables requiring contextual reasoning, including lesion counting, bifurcation PCI, and chronic total occlusion. Conclusion: High-capacity open-source LLMs can accurately extract complex PCI variables from free-text catheterization reports, supporting LLM-enabled automated phenotyping to reduce manual abstraction and facilitate scalable cardiovascular research.

Background Idiopathic Pulmonary Fibrosis (IPF) is a fatal chronic lung disease with limited therapeutic options. While alveolar epithelial injury and fibroblast activation are well-studied, endothelial-mesenchymal transition (EndoMT) is emerging as a critical pathogenic mechanism. The regulatory role of exosomal miRNAs in pulmonary fibrosis remains unclear. This study investigates serum exosomal miRNAs, particularly let-7a-5p, in modulating EndoMT during the onset of pulmonary fibrosis. Methods Clinical cohorts of IPF patients and healthy controls were enrolled. Serum exosomal miRNAs were profiled, followed by differential expression and functional enrichment analyses. In vitro experiments involved human pulmonary artery endothelial cells (HPAECs) transfected with let-7a-5p mimic or inhibitor. Dual-luciferase reporter assays confirmed the binding between let-7a-5p and TGFBR1. HPAECs were co-cultured with lung epithelial cells to examine paracrine signaling. In vivo studies used a bleomycin-induced mouse model with let-7a-5p agomir administration. Assessments included histopathological staining, hydroxyproline content, Western blot, qPCR, micro-CT, and pulmonary function tests. Results Let-7a-5p was significantly downregulated in serum exosomes from IPF patients, correlating with clinical indicators. Mechanistically, let-7a-5p directly bound the TGFBR1 3'UTR to inhibit its expression. Inhibition of let-7a-5p upregulated -SMA, FN1, smad2/3 phosphorylation, and collagen I, while downregulating CD31 and VE-cadherin. Therapeutically, let-7a-5p mimic reversed bleomycin-induced EndoMT and suppressed epithelial-mesenchymal transition (EMT) via paracrine signaling. Mice administered agomir showed reduced fibrosis, improved lung function, and suppressed TGF-{beta}/Smad signaling. Conclusion Serum exosomal let-7a-5p suppresses pulmonary fibrosis by targeting TGFBR1 to inhibit EndoMT. Its downregulation in IPF patients correlates with disease progression, highlighting its biomarker potential.

Background Hospitalizations and mortality due to heart failure (HF) are rising in rural areas. However, inpatient outcomes for young adults with HF are not well understood. We aimed to compare in-hospital mortality, advanced procedure utilization, length of stay, and total charges among rural and urban HF patients ages 18-45. Methods We analyzed hospitalizations from the National Inpatient Sample (2016-2022), categorizing discharges as rural (National Center for Health Statistics [NCHS] 5-6), small and medium metropolitan (NCHS 3-4), and urban (NCHS 1-2). Generalized estimating equations were used to model outcomes and adjust for demographics, comorbidities, and hospital characteristics. Outcomes are reported as adjusted rate (aIRRs) or risk ratios (aRRs) with 95% confidence intervals. Results Among 79,258 HF hospitalizations among young adults, 45,075 and 10,722 were for patients from urban and rural areas, respectively. Rural patients had higher rates of in-hospital mortality (1.6% vs. 1.2%; aIRR = 1.28, 95% CI = 1.05, 1.56, p = 0.043), advanced cardiac procedure utilization (15.0% vs. 14.8%; aIRR = 1.19, 95% CI = 1.11, 1.28, p < 0.001), and longer hospital stays (aIRR = 1.10, 95% CI = 1.05, 1.14, p = 0.003). Small and medium metropolitan residents had similar outcomes to urban residents. In interaction analyses, the association between rural-urban residence and mortality differed by race (pint = 0.003) and payer type (pint < 0.001). Conclusions Young adults in rural areas may be prone to poor outcomes following hospitalization for HF. Strategies to identify rural adults at risk for HF and provide affordable and timely care may improve disparities.

Objectives: Mitral regurgitation (MR) evolution after transcatheter aortic valve replacement (TAVR) in low-flow aortic stenosis (LFAS) is poorly characterized. We evaluated MR trajectories across LFAS phenotypes, predictors of MR worsening, and associations with clinical outcomes. Methods: We retrospectively studied 614 LFAS patients undergoing TAVR: low-flow high-gradient (LFHG; n=153, 24.9%), classical low-flow low-gradient (cLFLG; n=155, 25.2%), and paradoxical low-flow low-gradient (pLFLG; n=306, 49.8%). MR severity was abstracted from clinical echocardiography reports using a 6-level ordinal scale. MR worsening was defined as a [&ge;]1-grade increase from baseline MR at ~30 days or ~1 year. Multivariable logistic models identified predictors of MR worsening. Kaplan-Meier and Cox models evaluated associations of MR trajectory and LFAS subtype with all-cause death, heart failure hospitalization (HFH), and their composite. Results: Among 614 LFAS patients, 443 had 30-day and 290 had 1-year echocardiographic follow up. At 30 days, MR trajectory differed significantly across LFAS phenotypes, with the highest rate of worsening in cLFLG and the lowest in LFHG. At 1 year, unadjusted MR trajectory distributions did not differ significantly across phenotypes. In adjusted logistic models, cLFLG remained independently associated with MR worsening at both timepoints. MR worsening was associated with worse unadjusted outcomes at 30 days but was not independently associated with the composite endpoint after multivariable adjustment. LFAS phenotype, particularly cLFLG, remained the dominant predictor of adverse clinical outcomes. Conclusions: MR evolution after TAVR is phenotype-specific: cLFLG patients have the highest risk of MR worsening and lowest event-free survival, supporting phenotype-informed post-TAVR surveillance.

BACKGROUND Children receiving extracorporeal membrane oxygenation (ECMO) are at high risk for focal cerebral injury (FCI). There is emerging evidence that electroencephalography (EEG) may aid FCI detection. The EEG Correlate of Injury to the Nervous System (COIN) index quantifies and displays focal background asymmetries. We evaluated whether COIN is associated with FCI in pediatric ECMO. METHODS Retrospective, cross-sectional study of patients age 28 days to 21 years, on venoarterial ECMO at a tertiary children's hospital, who received EEG monitoring and neuroimaging during ECMO. COIN was calculated from all available EEG data. COIN of 0 implies a symmetric EEG and negative COIN values are observed with FCI. Median COIN values near FCI recognition time were compared to median COIN values from randomly selected control EEG batches using logistic regression. A receiver operator characteristic curve was used to identify multilevel FCI test ranges. Likelihood ratios were calculated to estimate the posttest FCI probability for each COIN range. RESULTS During the 8-year study period (2015-2023), 33 of 142 ECMO runs met study criteria for COIN analysis. Twelve patients (36%) had FCI. The COIN cutoff of -13.3 had 92% sensitivity and 67% specificity for FCI. The COIN cutoff of -27.7 had 67% sensitivity and 90% specificity. Likelihood ratios were 0.13 for COIN (0 to -13.3), 1.1 for COIN (-13.3 to -27.7), and 7.0 for COIN (< -27.7). Posttest probability was 0.02, 0.13, 0.49 in each respective range. CONCLUSION FCI on ECMO is associated with COIN-measured EEG asymmetry. COIN may support FCI risk-stratification during ECMO.