The Journal of Heart and Lung Transplantation

Background: Antibody-mediated rejection (AMR) after heart transplant (HT) is associated with increased risk of mortality and graft loss. Contemporary studies delineating AMR presentation, management, and response to treatment are lacking, especially for patients who do not have typical immunohistological evidence of rejection (biopsy-negative, BN-AMR). In this study, we sought to describe the prevalence and clinical course of BN-AMR compared to biopsy-positive (BP-AMR) patients in a multicenter HT population. Methods: We conducted a retrospective analysis of all adult HT recipients at 2 academic medical centers. AMR was further divided into BP-AMR and BN-AMR, depending on their endomyocardial biopsy findings. The primary outcome was death and secondary outcome was a composite of death, retransplant, and new International Society of Heart and Lung Transplant grade 2 or 3 coronary artery vasculopathy. Results: A total of 742 patients were included in this study. We found that AMR occurred in 10% of HT recipients and was associated with worse overall survival compared to those with only cellular rejection or no rejection. BN-AMR accounted for 33% of AMR cases. Compared to BP-AMR, BN-AMR was diagnosed later, less aggressively treated, and associated with high morbidity and mortality. The long-term outcomes between BP-AMR and BN-AMR were similarly poor, with 5-year mortality approaching 50% after diagnosis. Conclusions: AMR after HT is associated with poor clinical outcomes and BN-AMR is common. Future studies should focus on incorporating novel tools for earlier detection of AMR and investigating AMR sub-phenotypes and optimal modes of treatment.

Tricuspid regurgitation and pulmonary artery systolic pressure may contribute to post-operative morbidity and mortality in liver transplantation. Previous studies suggest that a high Model for End-Stage Liver Disease score may influence the relationship between tricuspid regurgitation and post-operative mortality. Adult patients undergoing liver transplantation workup between 2010 and 2023 were included in this retrospective observational cohort study. Patients with significant portopulmonary hypertension were excluded. Transthoracic echocardiograms were completed pre-transplant and patients were followed up for one year post-operatively. 1031 patients (median MELD score 17, IQR 12-23) underwent transthoracic echocardiography for liver transplantation workup, of whom 708 underwent successful transplantation. Mild or greater tricuspid regurgitation did not predict 1-year mortality in the overall population (HR 1.79 (95% CI 0.78-4.11), p=0.19). Among patients with MELD scores [≥]20, mild or greater tricuspid regurgitation was a significant predictor of 1-year mortality (7 (12.7%) vs 9 (3.8%), p=0.01) (HR 3.46 (1.30-10.32), p=0.02). Tricuspid regurgitation in patients with high MELD scores was associated with a trend towards an increased risk of 30-day major adverse cardiovascular events (9 (16.4)% vs 46 (8.1%), p=0.06), driven predominantly by rates of post-operative heart failure (12.7% vs 3.8%, HR 3.66 (95%CI 1.30-10.32), p=0.01). Elevated pulmonary artery systolic pressure was associated with prolonged hospital stay (30 days (14-46) vs 15 days (11-29), p=0.01). Our study confirms that mild or greater tricuspid regurgitation is a significant predictor of 1-year mortality in patients with high MELD scores undergoing liver transplantation. Tricuspid regurgitation severity should be considered during pre-liver transplantation risk stratification.

Donor derived cell free DNA (ddcfDNA) is increasingly used for post transplantation non invasive surveillance; however, its clinical interpretation remains inconsistent, with widely ranging thresholds and is typically applied as a single binary cutoff in literature. The optimal decision framework for rule out and rule in decisions, and whether a single threshold remains clinically meaningful, are currently uncertain. We performed a Bayesian hierarchical summary receiver operating characteristic (HSROC) meta analysis of 14 studies (1,763 patients) evaluating ddcfDNA against endomyocardial biopsy. To account for serial testing within individuals, we applied a cluster corrected design effect, reducing 6,103 observations to 2,518 effective tests. Threshold dependent sensitivity and specificity were modelled continuously. We compared a conventional single threshold approach (Youden index) with a data driven adaptive framework defining rule out and rule in thresholds. Clinical utility was evaluated using decision curve analysis across a range of rejection prevalences (10% to 30%), incorporating repeat testing strategies. The pooled area under the HSROC curve was 0.78 (95% CrI, 0.67 to 0.84). The Youden optimal threshold (0.20%) yielded balanced sensitivity (0.77) and specificity (0.77) but failed to support clinical objectives of diagnosis. An adaptive framework identified a rule out threshold of 0.16% (sensitivity 0.80) and a rule in threshold of 0.48% (specificity 0.90), defining a indeterminate / grey zone. Across all prevalence scenarios, ddcfDNA guided strategies provided positive net benefit compared with biopsy all and biopsy none approaches. A repeat if borderline strategy consistently achieved the highest net benefit, particularly in low and intermediate risk settings, by reducing false positive biopsies without materially compromising detection. A single threshold interpretation is not clinically adequate for post heart transplant surveillance. Our tri state, prevalence aware framework integrating rule out, indeterminate, and rule in zones with selective repeat testing, more accurately reflects biomarker behavior and improves clinical decision making. These findings support a shift away from binary thresholds toward dynamic, context dependent use of ddcfDNA in transplant surveillance.

Cardiogenic shock (CS) is associated with high short-term mortality and the use of temporary mechanical circulatory support (tMCS) devices, especially left-sided microaxial flow pumps (Impella, Abiomed), has increased in recent years. However, few studies have investigated tMCS's effect on right ventricular-pulmonary artery (RV-PA) hemodynamics and its impact on clinical outcomes. We retrospectively analyzed all adult patients implanted with Impella 5.5 at our institution with acute myocardial infarction or acute decompensated heart failure-induced CS between 2019 to 2023. We found that Impella 5.5 led to an early improvement in RV-PA hemodynamics, even in patients with poor baseline RV function. In addition, we found that RV function itself did not predict death, post-heart transplant right ventricular-primary graft dysfunction, or post-left ventricular assist device severe RV failure. However, an increase in right atrial:pulmonary capillary wedge pressure ratio (RA/PCWP) despite tMCS support was a powerful prognosticator. Our study sheds important insight into anticipated hemodynamic changes after Impella 5.5 placement, supports the use of early tMCS even in patients with marginal RV function in the setting of left heart disease, and highlights the importance of serial assessment of RA/PCWP as a key determinant of CS outcomes.

Background: The importance of lactate trajectory during the first day of cardiogenic shock is increasingly recognized. We aimed to assess the association between admission-day lactate trajectory and in-hospital mortality, and to identify same-day interventions predictive of lactate clearance. Methods: We analyzed adult patients admitted with cardiogenic shock between October 2015 and June 2023, using the Vizient(R) Clinical Data Base. Early lactate clearance was defined as lactate <2.5 mmol/L by the end of the admission day. We used multivariable logistic regression to assess the association between lactate change and in-hospital mortality, and to identify interventions associated with lactate clearance. Results: Among 40,434 patients with cardiogenic shock, 30.1% achieved same-day lactate normalization, which was associated with lower in-hospital mortality (aOR 0.51; 95% CI 0.48-0.54). Lactate change showed the greatest prognostic importance, with observed mortality exceeding 80% among those with lactate increase >5 mmol/L regardless of baseline values. After adjustment, lactate change showed a positive exponential relationship with mortality, with aORs ranging from 0.25 (95% CI 0.23-0.27) for a -10 mmol/L change to 3.99 (95% CI 3.58-4.40) for a +10 mmol/L change. The intervention most strongly associated with early lactate clearance was pulmonary artery catheter (PAC; aOR 1.28 [95% CI 1.19-1.37]). Conclusions: Nearly 1 in 3 patients with cardiogenic shock achieved early lactate clearance, which was associated with lower mortality. The magnitude of lactate change had profound prognostic implications regardless of the initial value. Among day 1 interventions, PAC use had the strongest association with lactate clearance.

BackgroundAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are frequently associated with cardiac complications, including myocardial injury and right ventricular dysfunction. However, the mechanisms linking pulmonary injury to cardiac dysfunction remain incompletely understood. In this study, we investigated ventricular mitochondrial respiratory function during the acute phase of bleomycin-induced ALI. MethodsALI was induced in male and female rats by intratracheal bleomycin (2.5 mg/kg); saline served as a control. Circulating cardiac troponin I (cTnI) was measured as an indicator of myocardial injury. Mitochondrial respiration was assessed in permeabilized ventricular fibers using high-resolution respirometry (HRR). The mitochondrial respiration rate of the H9C2 cardiomyoblast cell line was performed using Seahorse Xfe96 Cell Mitochondrial Stress Test. Cells were treated with pro-inflammatory cytokine cocktails (PRO; IL1{beta} plus TNF plus IL6), anti-inflammatory cytokine cocktails (ANTI; IL4 plus IL10), a mixture of PRO and ANTI (BOTH), and (-)-norepinephrine (NE) in either hypoxic (1% oxygen) or normoxic conditions. ResultsBleomycin-induced ALI increased circulating cTnI levels in male rats, indicating early cardiac stress following lung injury. Mitochondrial respiration in the LV appeared to show modest alterations, with preserved oxidative phosphorylation (OXPHOS) and electron transport (ET) capacity. In contrast, the RV of male animals demonstrated marked reductions in absolute respiratory flux and substrate-supported OXPHOS capacity, indicating impaired mitochondrial oxidative capacity. Female animals exhibited greater preservation of mitochondrial respiratory function, particularly in the RV, with higher OXPHOS capacity and greater Complex I gain than males. H9C2 cells treated with PRO showed a significant increase in uncoupled respiration following 6- and 24-hour incubation periods, under normoxic conditions. Maximal respiration and spare respiratory capacity were increased following 24-hours under hypoxia. No significant changes were observed following treatment with NE alone and in combination with PRO under normoxia or hypoxia for 24 hours. ConclusionsALI induces ventricle-specific and sex-dependent alterations in cardiac mitochondrial bioenergetics, with pronounced impairment in males and relative mitochondrial resilience in females. In H9C2 cardiomyoblasts, short-term exposure (6-24 hours) to pro-inflammatory cytokines enhances uncoupled mitochondrial respiration under normoxic conditions, while short-term hypoxic exposure independently increases maximal respiration and spare respiratory capacity.

Objective: To compare RNA-sequencing-derived transcriptomic profiles of thoracic aortic aneurysm tissue from individuals with bicuspid versus trileaflet aortic valves. Methods: Human ascending aortic tissue was collected from patients undergoing cardiac surgery at a single institution between January 2021 and December 2022 with bicuspid aortic valves (BAV) and trileaflet aortic valves (TAV) with (-A) and without (-N) thoracic aortic aneurysm. TAV-N tissue was collected from heart transplant donors. The decision to perform ascending aortic replacement was at surgeon discretion following ACC/AHA guidelines. Bulk RNA was extracted from the aortic wall, and Illumina RNA Sequencing performed. Differential gene expression analysis, enrichment analyses, network analysis, and deconvolution single cell-mapping were performed in R. Cell-type specificity of differentially expressed genes was determined using an established Aorta single cell RNA sequencing matrix. Results: Tissue samples from 60 patients were included: 4 TAV-N, 16 BAV-N, 28 BAV-A, and 12 TAV-A. Average absolute aortic diameter was 5.1 +/- 0.38 cm for BAV-A and 5.3 +/- 0.44 cm for TAV-A, as measured on pre-operative CT. Gene ontology analyses of differentially expressed genes revealed enrichment of genes associated with extracellular matrix (ECM) organization, cellular receptor interactions and vascular smooth muscle cell (VSMC) function in BAV-A and BAV-N. In contrast, analysis of TAV-A versus TAV-N showed enrichment in genes associated with immune and inflammatory processes. Cell-type specificity analysis revealed a downregulation of genes associated with ECM components, cell signaling, and ECM remodeling in mesenchymal cells, VSMCs, and matrix fibroblasts specifically in BAV-A versus BAV-N. Conclusions: The transcriptome changes observed in aneurysmal aortas of BAV and TAV patients are distinct, suggesting mechanistic differences contributing to aneurysm development and progression. The observed differences in gene expression between the non-aneurysmal aortas may signify a predisposition to aneurysm development unique to BAV aortopathy.

BackgroundDelirium, a common and multifactorial complication after cardiac surgery, is influenced by several factors including inflammation, metabolic disturbances, and cerebral hypoperfusion. Because these factors can be reflected in an elevated anion gap (AG), we hypothesized that a higher preoperative albumin corrected anion gap (ACAG) is associated with increased risk of delirium and 1-year mortality after cardiac surgery. MethodsWe examined a retrospective cohort of adult patients within our healthcare system who underwent cardiac surgery between 2014 and 2022 and had a recorded Confusion Assessment Method for the ICU (CAM-ICU) evaluation. Patients were excluded if they had documented preoperative delirium during the index hospital admission or a history of dementia. The final cohort included 4,482 patients. Preoperative laboratory values were collected, using the most recent results obtained within 48 hours prior to surgery. The primary outcome was delirium after cardiac surgery (DACS), defined as delirium occurring within postoperative days 1 through 5. The secondary outcome was all-cause 1-year mortality. ResultsThe incidence of DACS and 1-year mortality were 9.5% and 4.8%, respectively. A multivariable logistic regression model adjusting for baseline characteristics showed that higher ACAG was significantly associated with higher risk of DACS (adjusted odds ratio (AOR) = 1.56, 95% Confidence Interval (CI) = 1.40-1.74, p < 0.001). Other predictors of DACS included increasing age (AOR = 1.31, CI = 1.16-1.48, p < 0.001), surgery duration (AOR = 1.35, CI = 1.22-1.49, p < 0.001), and history of delirium (AOR = 1.70, CI = 1.29-2.24, p < 0.001). Moreover, increasing ACAG was also associated with 1-year mortality (AOR = 1.35, CI = 1.16-1.56, p < 0.001). Finally, receiver operating characteristic (ROC) analysis demonstrated that ACAG exhibited superior predictive performance compared with AG and anion gap to bicarbonate ratio (AGBR) for both DACS and 1-year mortality outcomes. ConclusionsHigher preoperative ACAG was associated with elevated risk for DACS and 1-year mortality. Preoperative ACAG is an accessible and cost-efficient biomarker that may improve risk stratification for cardiac surgery patients.

BackgroundPatients with systemic lupus erythematosus (SLE) face markedly increased cardiovascular disease (CVD) risk driven by mechanisms beyond traditional risk factors. Thoracic aortic perivascular adipose tissue (tPVAT) is dysfunctional in lupus and exacerbates endothelial dysfunction, yet the molecular basis of this dysfunction remains poorly defined. MethodsIntegrated multi-omics profiling, including bulk RNA-seq, untargeted proteomics, lipidomics, and high-dimensional spectral flow cytometry, was performed on tPVAT from 15-week-old MRL/lpr mice (active lupus, n = 4-6) and MRL control mice (n = 5-6). Adipogenic differentiation capacity of tPVAT adipose stromal and progenitor cells (ASPCs) from MRL/lpr was assessed by Oil Red O staining at 5 (pre-dieasea) and 15 weeks (active disease), with subcutaneous ASPCs used as depot controls. ResultsTranscriptomic profiling of tPVAT from MRL/lpr mice identified 2,742 upregulated and 1,494 downregulated genes (adjusted p < 0.001, |log2FC| > 1), with strong activation of interferon, IL6-JAK-STAT3, and TNFA signaling pathways together with suppression of fatty acid metabolism, oxidative phosphorylation, and adipogenic pathways. Proteomic and lipidomic analyses were concordant, revealing broad downregulation of mitochondrial bioenergetic machinery, depletion of cardiolipin and acylcarnitines, and enrichment of ceramide phosphoinositols and lysophosphatidylcholines. Cardiolipin strongly correlated with the mitochondrial/metabolic protein module (r = 0.95) and inversely with the immune/inflammatory protein module (r = -0.92). Spectral flow cytometry confirmed marked CD45+ leukocyte infiltration dominated by T cells, together with a significantly reduced Treg/CD4+ ratio indicating loss of local immunoregulatory balance. ASPCs derived from PVAT of 15-week-old MRL/lpr mice exhibited impaired white and beige adipogenic differentiation, while APCs from PVAT of 5-week-old MRL/lpr mice, and from subcutaneous adipose tissues of 15-week-old MRL/lpr mice, had normal white and beige differentiation, consistent with an acquired, depot-specific, disease-stage-dependent progenitor defect in PVAT of MRL/lpr mice. ConclusionsLupus tPVAT undergoes a concordant cross-platform molecular reprogramming of mitochondrial bioenergetic genes coupled with establishment of an interferon-dominant immune niche and acquired loss of ASPC adipogenic capacity. These findings provide a molecular framework for lupus PVAT dysfunction and identify restoration of mitochondrial function, suppression of interferon-driven inflammation, and renewal of progenitor differentiation as potential therapeutic strategies for lupus vasculopathy.

BackgroundPulmonary artery (PA) wave reflection is a key determinant of right ventricular (RV) afterload. RV function is the most important factor determining long-term prognosis in patients with surgically repaired tetralogy of Fallot (rTOF). This study aimed to evaluate PA wave reflection in rTOF using RV pressure phase plane (PPP) analysis, and to identify the clinical, morphological, and hemodynamic characteristics associated with increased PA wave reflection in patients with rTOF. MethodsAugmentation pressure (AugPr) during late systole was quantified using the inflection point of systolic dP/dt on the PPP. The ratio of AugPr to RV systolic pressure (RVSP) was defined as the AugPr index. The study included 87 patients with rTOF (mean age, 15.9 {+/-} 10.0 years), 17 control subjects (13.3 {+/-} 6.3 years), and seven patients with pulmonary arterial hypertension (PAH) (16.4 {+/-} 11.7 years). The rTOF cohort was categorized according to surgical procedure: pulmonary valve-sparing repair (PVS, n = 5), transannular patch repair (TAP, n = 34), and the Rastelli procedure (n = 48). ResultsThe prevalence of AugPr was 0% in the control group, 100% in the PAH group, and 26.4% in the rTOF group (p < 0.0001). Among the surgical subgroups, the prevalence was 0% in PVS, 14.7% in TAP, and 41.7% in the Rastelli group (p < 0.0027). AugPr and the AugPr index were significantly higher in the Rastelli group than in the other two groups (p = 0.0447 and 0.0433, respectively). In addition, AugPr showed significant correlations with RVSP, RV outflow tract obstruction, maximal dP/dt, and pulmonary regurgitation grade (all p < 0.05). ConclusionsPA wave reflection can be clearly visualized using PPP. The Rastelli group demonstrated a higher prevalence and magnitude of PA wave reflection, suggesting a greater increase in RV afterload compared with other surgical repair types.

Background Cardioplegic arrest during complex aortic arch repair imposes prolonged global myocardial ischaemia, which may contribute to postoperative low cardiac output syndrome (LCOS) and mortality. Whether cardioplegic arrest can be entirely avoided -- performing the complete procedure on a continuously perfused, beating heart -- has not previously been evaluated in a clinical series. Methods and Results Between November 2017 and January 2026, 29 consecutive patients underwent total beating-heart aortic arch repair without any cardioplegic arrest at a single centre. Continuous antegrade myocardial perfusion (warm blood, 34{degrees}C, 300-400 mL/min, perfusion pressure 60-80 mmHg) was delivered via an aortic root needle vent throughout each procedure. Two variants were employed: axillary cannulation with selective antegrade cerebral perfusion (n = 24, 82.8%), and direct aortic cannulation with extra-anatomical left carotid bypass for distal Zone 2 pathology (n = 5, 17.2%). Mean age was 55.4 {+/-} 13.6 years; 41.4% presented with aortic dissection (B/non-A-non-B). No patient required conversion to cardioplegic arrest. Perioperative myocardial infarction and LCOS occurred in none of the patients. Median peak CK-MB was 44.0 U/L. Thirty-day mortality was 10.3% (n = 3); all deaths were due to respiratory failure or visceral ischaemia complicating acute type B dissection. Conclusions Total beating-heart aortic arch repair without cardioplegic arrest is technically feasible and clinically safe in appropriately selected patients and is associated with the complete absence of perioperative myocardial infarction and LCOS across a heterogeneous, high-risk cohort. These findings support prospective, multicentre evaluation of no-arrest myocardial protection as a strategy to reduce the cardiac morbidity of complex arch surgery.

BACKGROUNDChronic thromboembolic pulmonary hypertension (CTEPH) is a severe and progressive condition characterized by dyspnea and fatigue. Our previous study reported cognitive impairment in pulmonary hypertension (PH) patients. However, balloon pulmonary angioplasty (BPA) capable of alleviating cognitive impairment in patients with CTEPH is largely unknown. METHODSThis was a prospective study involving a total of 131 patients with CTEPH who underwent BPA at the Shanghai Pulmonary Hospital. We collected Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) questionnaires and examined plasma A{beta} and phosphorylated-tau217 (p-tau217) levels to assess the cognitive function of patients with CTEPH between the pre-BPA and post-BPA stages. RESULTSFollowing BPA, patients exhibited improved cognitive performance, accompanied by reduced plasma levels of A{beta}1-42 and p-tau217. After the third BPA session, patients with a mean pulmonary arterial pressure (mPAP) of[&ge;]25 mmHg had significantly lower MMSE and MoCA scores compared to those with an mPAP of <25 mmHg. Linear regression analyses revealed that baseline and post-intervention MMSE or MoCA total scores were significant predictors of cardiac output (CO) levels measured after the last BPA procedure. Logistic regression analyses incorporating pre- and post-BPA clinical parameters identified three independent predictors of baseline cognitive dysfunction: lower educational attainment, higher baseline A{beta}1-42 levels, and elevated baseline p-tau217 concentrations. CONCLUSIONSOur findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH. NOVELTY AND RELEVANCEO_ST_ABSWhat Is New?C_ST_ABSThis is the first study to demonstrate that balloon pulmonary angioplasty (BPA) improves cognitive function (MMSE/MoCA scores) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). And the first report that BPA reduces plasma levels of A{beta}1-42 and p-tau217-- key Alzheimers disease-related proteins--in CTEPH patients, establishing a peripheral biomarker for CTEPH-associated cognitive impairment. What Is Relevance?Cognitive impairment is common but underrecognized in CTEPH, BPA now addresses both cardiopulmonary and cognitive dysfunction, improving quality of life beyond hemodynamic recovery. Findings support the cardiopulmonary-brain axis in CTEPH: improved pulmonary hemodynamics and oxygenation reduce systemic pathological protein release, benefiting brain function. Clinical/Pathophysiological Implications?Our findings suggest promising therapeutic effects of BPA, associated with improvements in cognitive dysfunction and reductions in plasma A{beta}1-42 and p-tau217 levels in patients with CTEPH.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Patients with Fontan circulation face evolving risk for cardiovascular morbidity and mortality, yet the interplay between cardiac function, vascular properties, and circulating proteins is incompletely defined. We hypothesized that biochemical biomarkers and multimodal cardiovascular profile differ significantly between Fontan patients and controls, and that selected markers may serve as predictors of reduced single ventricle function. We conducted a prospective observational study at a tertiary pediatric heart center including 31 individuals with Fontan circulation and 52 matched controls. Cardiac function was assessed by echocardiography; vascular phenotyping included carotid intima-media thickness, central and peripheral blood pressure, augmentation index corrected for heart rate, carotid-femoral pulse wave velocity, aging index, and reactive hyperemia index. Compared to controls, the Fontan group had increased pulse wave reflection and central systolic pressure as well as decreased echocardiographic markers of systolic and diastolic function, while pulse wave velocity and other vascular parameters were not significantly different between the groups. Levels of 92 circulating cardiovascular biomarkers were quantified in a subset of 25 of the Fontan cohort and 81 controls using a proximity extension assay. Twenty-two biomarkers differed significantly in the Fontan group compared to controls, including FGF23, REN, HAOX1, and IL17D. Levels of several of these biomarkers correlated with patient age. Most importantly, HAOX1 (a peroxisomal oxidase linked to redox metabolism) and FGF23 (a bone-derived hormone regulating phosphate and vitamin D homeostasis) correlated negatively with ejection fraction within the Fontan group. By contrast, BNP was not associated with cardiac function in the Fontan group. None of the biomarkers correlated with central arterial parameters. In summary, central arterial hemodynamics and biomarkers such as FGF23 and HOAX1 may improve monitoring of cardiovascular function in single ventricle patients with Fontan circulation.

Tuberculosis screening is not mandatory for prospective tissue donors. In 2021 and 2023, two different bone allograft products caused nationwide tuberculosis outbreaks. We assessed the morbidity and mortality of the second outbreak and reviewed donor and tissue screening to identify deficiencies. Thirty-six people residing in nine states received the product during spinal and dental procedures. Twenty-seven recipients had tuberculosis infection, 11 had microbiologic or imaging evidence of tuberculosis disease, and two died from tuberculosis within 12 months of outbreak detection. Another recipient died from tuberculosis nearly 3 years after product implantation. The bone donor died of pneumonia and septic shock. Polymerase chain reaction testing of the product before and after distribution did not detect Mycobacterium tuberculosis. Mycobacterial culture was not performed until after outbreak detection, when M. tuberculosis was isolated from 2 of 6 unused product units. This outbreak demonstrates persistent gaps in tissue transplant safety. Appropriate selection of donors and mycobacterial culture of donated tissues could reduce but not eliminate the risk of M. tuberculosis transmission. Therefore, it is important that clinicians monitor tissue recipients and promptly report adverse events to tissue establishments and health authorities.

Despite extensive pretransplant serological screening and HLA matching, 10-15% of kidney allografts experience acute rejection within the first year. Currently, risk stratification for transplantation relies primarily on antibody reactivity to HLA molecules, with no assessment of the T cell compartment before or after transplantation. In our previously established longitudinal cohort of 54 patients, T cell receptor {beta} (TCR{beta}) sequencing was performed on paired kidney biopsy and peripheral blood samples. Here, we further analyzed the data to construct a comprehensive set of sequence-similarity networks and quantify over 30 network metrics. After adjusting for repertoire size, graft status was the strongest signal for the underlying differences in network metrics. Individuals who rejected the kidney graft generally exhibited more fragmented and less connected networks at baseline, with fewer interconnect T cell clones and more isolated sequences. Notably, pre-transplant peripheral blood mononuclear cell (PBMC) network topology alone predicted non-stable outcomes with an area under the curve (AUC) of 0.81, sensitivity of 76%, and specificity of 76%. The performance of this prediction model was independent of HLA mismatch, while changes in network topology at three months post-transplantation further improved prediction to an AUC of 0.88 (permutation p = 0.009). Collectively, TCR sequencing and network analysis represent a potential novel, non-invasive approach for pre-transplant risk stratification and immune monitoring, capturing functional immunological risk that may not be accessible through HLA genotyping or serology.

Background: Pediatric dilated cardiomyopathy (DCM) is a leading cause of heart failure and transplantation, with variable prognosis and high early mortality. This study developed and validated a nomogram predicting short-term mortality risk to guide clinical decisions. Methods: The data were sourced from the Pediatric Cardiomyopathy Database at Shandong Provincial Hospital. Cox regression analysis was conducted to determine outcome-associated factors, and a nomogram was developed to estimate 1, 3, and 5year mortality risks for children with DCM. Model effectiveness was assessed through the concordance index (C-index) and area under the receiver operating characteristic curve (AUC). Additionally, calibration curves and decision curve analysis (DCA) were employed to evaluate the model's predictive accuracy and clinical relevance. Results: A cohort of 106 children diagnosed with primary DCM and who underwent genetic analysis was studied, with a median diagnostic age of 10 months (ranging from 5 to 84 months), comprising 50 girls (47.2%). The rate of detecting genetic mutations was 28.3%, uncovering 14 gene variants linked to DCM, with TTN mutations being the most common. Both univariate and multivariate Cox regression analyses indicated that both sex and NT-proBNP levels had a significant impact on survival rates among pediatric DCM patients.The model exhibited strong discriminative performance, calibration, and clinical net benefit, as assessed by the C-index, calibration plots, and decision curve analysis (DCA). Conclusions: The prediction model created in this research shows strong accuracy in forecasting survival rates at 1, 3, and 5 years for children with DCM, highlighting its significant relevance in clinical settings.

BACKGROUNDPatients with severe aortic stenosis (AS) exhibit heterogeneous flow-gradient hemodynamics and ventricular remodeling, which may influence symptomatic, functional, and structural responses to transcatheter aortic valve implantation (TAVI). Thus, we evaluated differences in functional recovery and reverse remodeling after transfemoral TAVI across flow-gradient phenotypes. METHODSIn this sub-study of the COMPARE-TAVI 1 trial, 975 patients undergoing transfemoral TAVI were classified as classical low-flow low-gradient (cLFLG, 9.1%), paradoxical low-flow low-gradient (pLFLG, 7.7%), low-flow high-gradient (24.7%), normal-flow low-gradient (NFLG, 13.0%), and normal-flow high-gradient (45.4%). The primary functional outcome was longitudinal change in six-minute walk test distance (6MWTD) from baseline to 1 year follow-up. Secondary endpoints included changes in NYHA functional class and reverse remodeling from baseline to 1 year follow-up along with the incidence and risk of all-cause death and a composite MACE-endpoint. RESULTSMean 6MWTD increased by 59{+/-}4 meters at 1-month (p=0.000) with no additional improvement at 1-year, but with heterogeneity between groups (p=0.000). Improvements among NFLG, cLFLG and low-flow high-gradient AS were comparable with normal-flow high-gradient AS, while pLFLG AS exhibited significantly increments at 1-year (-28{+/-}15 meters, p=0.007). Patients with NFLG, cLFLG and pLFLG were more symptomatic at baseline (NYHA [&ge;]III: 40.5%, 57.3% and 50.6%, respectively, p=0.000). NYHA improved in all groups at 1-year follow-up (p=0.000), although persistent symptoms at 1-year were most frequent in pLFLG (NYHA [&ge;]II; 38.7%, p=0.012). Reverse remodeling was also comparable between normal-flow high-gradient AS and NFLG, cLFLG, and low-flow high-gradient AS, respectively, but attenuated in pLFLG AS in both unadjusted and adjusted analyses. No differences were observed in the incidence and risk of all-cause death or the composite MACE-endpoint. CONCLUSIONTAVI associates with functional recovery across all flow-gradient phenotypes, although with heterogeneous responses. Patients with NFLG showed comparable functional recovery and reverse remodeling at 1-year follow-up compared with normal-flow high-gradient AS, whereas pLFLG demonstrated attenuated benefits across all parameters.

Abstract Background Cardiogenic shock (CS) is a heterogeneous syndrome with diverse etiologies, treatment pathways, and outcomes. Prior studies of sex differences in CS have largely focused on acute myocardial infarction-related CS or evaluated CS as a single entity. Whether sex-based differences in outcomes and treatment utilization vary across distinct CS phenotypes remains incompletely defined. Methods We performed a retrospective cohort study using the National Inpatient Sample, a nationally representative all-payer database of United States hospitalizations. Adult hospitalizations with CS were identified using ICD-10-CM code R57.0 and categorized into clinically relevant phenotypes, including acute myocardial infarction (AMI), heart failure (HF), arrhythmia-related shock, myocarditis/Takotsubo, valvular disease, and other etiologies. Survey-weighted analyses accounting for the complex sampling design were used for primary analyses. The primary outcome was in-hospital mortality. Secondary outcomes included use of mechanical circulatory support (MCS) and mechanical ventilation. Propensity score-matched analyses were performed as sensitivity analyses. Results Among 254,691 weighted CS hospitalizations, 158,747 (62.3%) occurred in men and 95,896 (37.7%) in women. In survey-weighted analyses, women had higher in-hospital mortality in AMI-related CS (36.1% versus 31.3%; OR, 1.24; 95% CI, 1.19-1.28), HF-related CS (30.5% versus 25.8%; OR, 1.27; 95% CI, 1.23-1.30), and arrhythmia-related CS (37.3% versus 31.6%; OR, 1.28; 95% CI, 1.20-1.38). Women were less likely to receive ECMO (2.4% versus 2.9%), IABP/Impella (13.1% versus 18.9%), or any MCS (14.6% versus 20.4%), but were more likely to receive mechanical ventilation (44.9% versus 42.9%). In propensity-matched analyses, mortality differences were attenuated but persisted in AMI-related, HF-related, and valvular CS. Conclusions Sex differences in CS outcomes and treatment utilization are strongly phenotype dependent. Women experienced higher mortality in major CS phenotypes while receiving less advanced mechanical circulatory support. These findings support early recognition, rapid phenotype classification, and sex-conscious but non-delayed escalation strategies for women with CS.

Background: Heart failure (HF) is a major contributor to inpatient hospital utilization, with persistently high 30-day readmission rates. Existing prediction tools are frequently restricted to primary-diagnosis HF admissions, potentially excluding clinically relevant HF-related hospitalizations. Objectives: To develop and validate risk prediction models using machine learning (ML)-based risk prediction models to predict 30-day readmissions among patients with HF using the Kansas Health Information Network, a statewide health information exchange. Methods: This retrospective cohort study analyzed HF hospitalizations using predictors including demographics, comorbidities, laboratory results, medications, clinical quality metrics for diabetes and kidney disease management, and prior healthcare utilization. Five ML models, including regularized logistic regression, random forest, extreme gradient boosting, categorical boosting, and deep neural network, were trained using stratified 5-fold cross-validation. Model performance was evaluated on an independent test set using the area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), misclassification rate (MCR), and Brier score. Results: Among 2,734 HF patients, the 30-day readmission rate was 27%. The XGBoost model achieved the best discrimination (AUROC=0.75; AUPRC=0.58; MCR=0.21). Patients in the highest-risk decile had a positive predictive value of 76%, accounted for approximately one-third of all 30-day readmissions, and had a 3.3-fold enrichment compared with baseline risk. The key predictors included prior hospital utilization, diabetes and kidney disease management indicators, and comorbidity burden. Conclusions: Risk stratification using routinely collected clinical data identified a subgroup at elevated risk for 30-day readmission. These findings support the potential role of data-driven risk prediction to inform targeted transitional care.