The Journal of Heart and Lung Transplantation

BackgroundIron metabolism disorder is highly prevalent before and after heart transplantation (HTx). The impact of pretransplant and posttransplant iron disorder on posttransplant outcomes is unclear. ObjectivePretransplant serum levels of key regulator proteins of iron metabolism (hepcidin, interleukin-6, erythroferrone) were tested for prediction of the composite outcome 1-year posttransplant all-cause mortality (ACM) or [≥]moderate acute cellular rejection (ACR). Furthermore, serum levels of these proteins were measured at 1-year posttransplant to explore their posttransplant course and association with ACR. ResultsIn a multicenter cohort including 276 consecutive HTx recipients, patients with or without outcome (n=118/158, respectively) did not differ for pretransplant demographics, mismatch of donor/recipient sex, mismatch of HLA epitopes, and hepcidin or interleukin-6 levels. However, pretransplant erythroferrone levels were higher (1.40 vs. 1.19 ng/mL; p=0.013) and hemoglobin levels were lower (124.5 vs. 127 g/L; p=0.004) among patients with the composite outcome. Pretransplant erythroferrone levels >2.25 ng/ml (4th-quartile) were significantly associated with the composite outcome in multivariable analysis (OR 2.17; 95% CI 1.19-3.94, p=0.011; reference: 1st-3rd quartiles). In adjusted predicted proportions analysis, the incidence of the composite outcome was higher in 4th-quartile patients when compared to 1-3rd -quartiles patients (58.0 vs. 37.7%; p=0.003). At 1-year posttransplant, 80.4% of patients with pretransplant erythroferrone levels >2.25 ng/ml remained high; 88.4% of patients with pretransplant erythroferrone levels [≤]2.25 ng/ml had high levels posttransplant. In 1-year survivors with high erythroferrone levels and [≥]moderate ACR during the first postoperative year, the ratio of the opponent regulators of hepcidin gene expression, erythroferrone to interleukin-6, was higher when compared to those without ACR (1.18 vs. 0.41; p=0.016). Hepcidin levels were not different between these two subgroups indicating disproportionate ERFE increase. ConclusionHigh pretransplant erythroferrone levels predict the composite posttransplant outcome 1-year ACM and ACR. Disproportionately high posttransplant erythroferrone levels are related with [≥]moderate acute cellular rejection.

ObjectiveTo analyze the experience of the last six years with ECMO in Uncontrolled Donation after Circulatory Death (uDCD), assessing the clinical and logistical factors that determine donation effectiveness and the viability of retrieved organs, with the nurse perfusionist as the central figure in organ perfusion. MethodsRetrospective observational study of uDCD procedures performed at Hospital Clinic de Barcelona between June 2019 and October 2025. ResultsOf 184 out-of-hospital ECMO-CPR activations, 108 (58.7%) underwent perfusion; 72 donor cases (66.7%) were generated, and 109 kidneys (75.7%) and 3 livers (4.15%) were retrieved. The annual number of uDCD donors was heterogeneous. Compared with non-effective donors, effective donors were significantly younger (48.1 {+/-} 12.4 vs 53.0 {+/-} 10.7 years, p=0.03) and had fewer comorbidities such as hypertension (13.8% vs 33.0%, p=0.018) and diabetes (4.1% vs 16.6%, p=0.027). Although effective donors had a shorter cannulation time (25.6 {+/-} 13.9 vs 29.1 {+/-} 11.9 min, p=0.09), the difference was not statistically significant; however, cardiocompressor time did show a significant difference (58.9 {+/-} 17.7 vs 65.8 {+/-} 18.2 min, p=0.03). ConclusionsuDCD was a useful source of transplantable organs, mainly kidneys (two out of every three perfused patients became donors), in the current context of scarcity of brain-dead donors. Shorter warm ischemia times (cardiocompressor and cannulation times) were significantly associated with more effective organ donation. The multidisciplinary transplant team may benefit from perfusion professionals with expertise in extracorporeal oxygenation therapy.

Background: Primary graft dysfunction (PGD) remains one of the leading causes of early mortality after pediatric heart transplant (HT). While neurodevelopmental impacts of congenital heart disease (CHD) are well-characterized, the effect of PGD on long-term neurodevelopmental outcomes in pediatric HT recipients remains unknown. We sought to determine the association between PGD and neurodevelopmental outcomes in this population. Methods: We performed a retrospective cohort study using the United Network for Organ Sharing (UNOS) database. All pediatric (age <18 years) isolated heart transplant recipients from 2010-2025 were included. The most recent pre- and post-transplant neurodevelopmental outcomes including cognitive delay, motor development, academic progress, and function status (stratified by age) were compared between PGD (n=434) and non- PGD groups (n=6956). Results: PGD patients had significantly worse pre-transplant functional status and motor development. Post-transplant, PGD was associated with worse motor development (18.8% vs. 13.0% definite motor delay; p=0.01) and functional status in younger children (39.5% vs. 57.8% able to keep up with peers; p<0.001). Post-transplant stroke occurred 3.5 times more frequently in PGD patients (11.5% vs. 3.3%; p<0.001). Cognitive development (p=0.94) and academic progress (p=0.096) did not differ significantly. Thirty-day (7.8% vs. 1.9%) and 1-year mortality (20.3% vs. 6.4%) were significantly higher in PGD patients (both p<0.001). Conclusions: This is the first study to characterize neurodevelopmental outcomes in pediatric patients undergoing HT with PGD. PGD is associated with significantly worse motor development and functional status independent of pre-transplant baseline. There is a 3.5-fold higher stroke rate providing a plausible neurological mechanism. The findings support targeted developmental surveillance recommendations and early intervention for this high-risk population.

BackgroundIn 2018, the United Network for Organ Sharing (UNOS) revised the donor heart allocation policy, replacing the single urgency status for left ventricular assist device (LVAD)-related complications with three distinct categories. We evaluated the impact of this policy modification on transplant access and outcomes. MethodsThe UNOS Standard Transplant Analysis and Research File was queried to identify adult patients listed for heart transplantation with a LVAD-related complication in the United States between 2018 and 2023. The cumulative incidence of heart transplantation, mortality on device, and overall mortality following complication were assessed. ResultsDuring the study period, 792 patients experienced an LVAD complication that led to an initial listing or change in urgency status. Device infection was the most frequent complication (n=472, 59.6%), followed by device malfunction (n=80, 10.1%), aortic regurgitation (n=73, 9.2%), ventricular arrhythmias (n=46, 5.8%), thrombosis/hemolysis (n=43, 5.4%), bleeding (n=42, 5.3%), and right heart failure (n=36, 4.5%). At 1 year, transplantation incidence was 71.5% (95% CI, 67.9-74.8%), mortality on device was 3.8% (95% CI, 2.5-5.4%), and overall mortality was 12.3% (95% CI, 9.9-15.1%). Right heart failure was associated with increased 1-year mortality (34.1%, 95% CI, 18.2-50.8%; adjusted HR 2.0, 95% CI, 1.1-3.8). ConclusionsThe revised allocation system provides LVAD patients with complications timely access to transplantation, reflected in high transplant rates and low mortality. Right heart failure remains a distinct subgroup, with one-third of patients not surviving to one year, suggesting this complication may warrant consideration for higher urgency status.

BackgroundCardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality following heart transplantation, with limited therapeutic options. Endothelial cells (ECs), at the interface between the donor graft and host immune system, play a central role in CAV development. However, the molecular mechanisms driving endothelial dysfunction and vascular remodeling in chronic heart transplant rejection remain poorly understood. MethodsTo characterize endothelial alterations associated with CAV, we isolated nuclei from cardiac tissues of four human donor groups: (1) early post-transplant CAV-negative surveillance biopsies, (2) CAV-negative explanted grafts with acute cellular rejection (ACR), (3) late-stage CAV-positive explanted grafts, and (4) naive non-transplanted control hearts. We applied intranuclear cellular indexing of transcriptomes and epitopes (inCITE-seq) to profile endothelial gene expression together with nuclear protein levels of splice factor polypyrimidine tract-binding protein 1 (PTBP1), a key post-transcriptional regulator of endothelial inflammatory responses. Functional relevance of PTBP1 was assessed using endothelial-specific deletion of Ptbp1 in an F1 hybrid murine model of CAV. ResultsIn human CAV, endothelial cells exhibited increased transforming growth factor-{beta} (TGF-{beta}) signaling and reduced oxidative phosphorylation (OxPhos) transcripts. Nuclear PTBP1 protein levels were markedly elevated in CAV endothelium and were associated with TGF-{beta}-responsive transcriptional programs and correlated with clinical indices of cardiac dysfunction. In murine heart transplants, endothelial-specific deletion of Ptbp1 markedly reduced hallmarks of CAV, including neointimal hyperplasia, fibrosis, and lymphocyte activation. At the molecular level, endothelial Ptbp1 deletion prevented suppression of mitochondrial transcripts and preserved mitochondrial content and integrity under hypoxic stress, attenuating interferon signaling in endothelial cells. ConclusionThese findings identify PTBP1 as a central endothelial regulator linking pro-fibrotic stress to mitochondrial dysfunction and immune activation in chronic cardiac allograft rejection. Targeting endothelial PTBP1 may represent a strategy to limit chronic graft injury while minimizing systemic immunosuppression.

BackgroundTraditional heart transplant registries often lack the granularity required for deep phenotyping and rely on labor-intensive manual abstraction. We describe the methodology and validation of a next-generation, automated, multi-source registry designed to address these limitations. MethodsUtilizing a High-Performance Computing environment, we integrated structured data from Epic data warehouses (Clarity and Caboodle), external molecular diagnostics, and verified UNOS survival records. A custom deterministic rule-based Natural Language Processing (NLP) engine was developed to extract echocardiographic measures, rejection grades, and vasculopathy scores from over 21,000 unstructured clinical reports. ResultsThe Houston Methodist J.C. Walter Jr. Transplant Center Precision Registry and Platform-Heart (TCPR-Heart) captures 1,687 heart transplants (1,636 patients) spanning the years 1984-2025. The TCPR-Heart comprises 1,054 transplants with active clinical follow-up: 555 transplants were extracted and abstracted from our modern electronic health record (EHR) in the decade since deployment, providing access to data throughout the patients course of heart transplant; 427 were legacy active transplants (transplanted pre-2016 with continued follow-up), and 72 were external transplants (transplanted elsewhere but followed at Methodist). Additionally, the registry houses a historic cohort of 633 transplants (last follow-up < June 2016) with limited variables. Automated deep phenotyping successfully generated longitudinal data trends across clinical domains, including immunosuppression strategies, rejection, immunologic HLA data, renal function, metabolic profiles, vasculopathy, graft function, hospitalization burden and survival information. ConclusionThis automated framework unifies clinical, administrative, and molecular data streams. By leveraging an automated, regularly updated registry, we established a scalable, high-fidelity data source as a foundation for further innovations and novel applications based on an expertly curated and validated data source.

Solid-organ transplantation in aging recipients represents a unique opportunity to study how age-related immunity in the context of non-specific immunosuppression strategies balances infection, malignancy, and rejection. Heart transplantation is an exemplar platform, as routine endomyocardial biopsy for rejection surveillance is the clinical "gold standard" regardless of clinical status. Here, we undertook the largest granular study to date to characterize the association between increasing recipient age at heart transplantation with acute allograft rejection and age-related cell-specific transcriptomic changes in circulating immune cells. This single-center retrospective cohort study evaluated individuals undergoing heart transplantation between July 2013 and December 2023 at Vanderbilt University Medical Center. Eligible participants were aged [&ge;]18 years. A subset of individuals underwent single-cell RNA-sequencing of circulating immune cells. Among 799 adults, each one standard deviation increase in recipient age was associated with a [~]17% lower odds of allograft rejection (adjusted OR 0.83, 95% CI 0.71-0.98). In 40 individuals who underwent single-cell RNA-sequencing of circulating immune cells, increasing recipient age was associated with increases in CD4+ and CD8+ memory T cell subsets, monocytes, and NK cells. Furthermore, genes upregulated with increasing recipient age were associated with enrichment for pathways involved in immunosenescence and chronic low-grade inflammation while downregulated genes suggested decreased protein synthesis. These findings have clinical implications for an aging transplant population and support a more personalized approach to immunosuppression.

BackgroundIn lung transplantation, de novo immunodominant donor-specific anti-HLA antibodies recognizing HLA-DQ antigens (dn-iDSA-DQ) are predominant and can induce chronic lung allograft dysfunction (CLAD). We previously developed a method to measure the active concentration of dn-iDSA-DQ. We aimed to determine whether this new quantitative biomarker is associated with transplantation outcomes. MethodsThis retrospective multicentre cohort study included 90 lung transplant recipients (LTRs) developing dn-iDSA-DQ, evidenced through single antigen flow beads (SAFB) follow-up. We measured the active concentration of dn-iDSA-DQ at the time of their first detection (T0) for all LTRs, and within the 2 years after DSA detection, whenever possible. SAFB dn-iDSA-DQ characteristics and clinical data were retrieved up to 5 years after DSA detection. ResultsWe tested 184 sera with SPR (n=90 at T0, n=94 within the 2 years after DSA detection), among which 63 (34.4%) had a quantifiable concentration of the dn-iDSA-DQ ([&ge;]0.3 nM). The median SAFB mean fluorescence intensity (MFI) of the dn-iDSA-DQ with a concentration [&ge;]0.3 nM was higher (p<0.0001), yet the correlation between SAFB MFI and active concentration was low (r=0.758, p<0.0001). In multivariate analysis, a concentration of the dn-iDSA-DQ [&ge;]0.3 nM at T0 was independently associated with a lower 2-year CLAD-free survival (HR 2.06, p=0.02). A concentration of the dn-iDSA-DQ [&ge;]0.3 nM within the 2 years from DSA detection was associated with a lower graft survival in univariate analysis. ConclusionsActive concentration of dn-iDSA-DQ appears as a valuable biomarker to identify pathogenic DSA at their first detection because of its association with CLAD.

BackgroundPediatric dilated cardiomyopathy (DCM) is a rare, progressive heart disease with variable outcomes that range from recovery to heart transplantation. To date, there are no prognostic biomarkers for children with DCM. Identifying circulating biomarkers that are associated with clinical outcomes is critical for personalized management. MethodsmiRNAs were identified by RNA-seq, whereas proteins were identified by SomaScan(R). Machine learning methodologies were used to explore the predictive ability of circulating factors identified from serum samples collected at the time of presentation with acute heart failure. ResultsThirty patients experienced poor outcomes (cardiac transplantation, mechanical circulatory support, or death) and 19 patients recovered left ventricular function. Distinct miRNA and protein signatures differentiated outcomes groups. Top candidate proteins (COL2A1, CXCL12, and ADGRF5) and miRNAs (miR-874-3p, miR-335-3p, miR-323a-3p) demonstrated strong discriminatory performance within the study cohort (recovered vs poor outcomes; Area Under the Curve of 0.92). Ingenuity Pathway Analysis implicates cardiac remodeling, fibrosis, and inflammatory signaling as central pathways differentiating patient outcomes. ConclusionsCirculating miRNA and protein signatures at presentation identify a circulating molecular signature associated with divergent clinical trajectories in pediatric DCM. These findings support the potential utility of multi-omic biomarkers for early risk stratification and provide insight into mechanisms underlying divergent outcomes. CLINICAL PERSPECTIVEWhat Is New? O_LICirculating miRNA and protein profiles measured at presentation distinguish children with pediatric DCM who recover from those who progress to advanced heart failure. C_LIO_LIA combined multi-omic biomarker demonstrated strong discriminatory performance in this cohort (AUC 0.92). C_LIO_LIPathway analysis implicates extracellular matrix remodeling, fibrosis, and inflammatory signaling in children with adverse clinical trajectories. C_LI What Are the Clinical Implications? O_LISerum-based molecular biomarkers may enable earlier risk stratification in children presenting with dilated cardiomyopathy. C_LIO_LIMulti-omic integration may improve identification of pediatric patients at risk for transplantation, mechanical circulatory support, or death. C_LIO_LIThese findings support further validation of circulating biomarker panels to guide personalized management in this rare disease. C_LI RESEARCH PERSPECTIVEWhat New Question Does This Study Raise? O_LICan integrated circulating miRNA-protein signatures identify biologically distinct trajectories of recovery versus progression in children with dilated cardiomyopathy? C_LIO_LIDo circulating molecular profiles reflect underlying disease mechanisms that determine divergent clinical outcomes in pediatric DCM? C_LI What Question Should Be Addressed Next? O_LIDo the pathways identified by integrated miRNA-protein analysis (fibrosis, remodeling, and inflammation) play causal roles in determining recovery versus progression? C_LIO_LICan multi-omic biomarkers be incorporated into prospective studies to improve early risk stratification and guide clinical management? C_LI

Background and Aims: Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods: Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results: Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions: These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM.

Background: Anemia is nearly ubiquitous in hospitalized patients with congestive heart failure (CHF), yet little data informs the decision to transfuse blood in this population. Objectives: To determine average and heterogenous effects of blood transfusion in hospitalized patients with CHF. Methods: We performed a multicenter retrospective cohort study with individual treatment effect analysis using the Premier Healthcare Database (2022-2024). Adult patients with CHF hemoglobin concentrations between 6.5-7.4 g/dL were included. The exposure was blood transfusion based on hemoglobin concentration threshold of <7.0 g/dL. The primary outcome was hospital free days by day 28 (HFDs). We determined the average effect of transfusion using instrumental variable analysis based on a hemoglobin threshold of 7.0 g/dL and estimated the predicted effects of transfusions on HFDs (i.e., conditional average treatment effects) for individual patients using causal forest machine learning models. Results: We included 31,408 patients in a derivation cohort and 30,677 in a validation cohort, of which 13,437 (42.8%) and 13,334 (43.5%) received transfusions, respectively. The average association between transfusion and HFDs suggested harm (derivation mean difference -1.8 [95% CI -2.3, -1.3] days; validation mean difference -1.5 [95% CI -2.0, -1.0] days). However, the effects of transfusion were heterogenous (p=0.001) with the strongest drivers of transfusion benefit being transfusion on hospital day 1 and low serum bicarbonate concentration. Conclusions: The average association between transfusion and HFDs in hospitalized patients with CHF suggested harm; however, there were potential small benefits early in hospitalization and in those with low serum bicarbonate concentrations.

Background: Cardiogenic shock (CS) remains associated with high short-term mortality despite contemporary advances in care. The association between institutional cardiac capability and outcomes?particularly among transferred patients and after accounting for clinical instability?remains incompletely defined. Objectives: To evaluate the association between hierarchical hospital cardiac capability and in-hospital mortality using a latent measure of acute physiologic severity. Methods: Using the National Inpatient Sample (2016?2022), hospitals were classified into five hierarchical tiers ranging from non-PCI (Tier 1) to heart transplant/durable LVAD centers (Tier 5). Generalized structural equation modeling (GSEM) assessed the relationship between hospital tier and mortality. A latent "Acute Severity" construct?comprising cardiac arrest, acute kidney and liver injury, and mechanical ventilation?was incorporated to model the effects of clinical instability Results: Among an estimated 1,177,180 CS hospitalizations, most occurred at cardiac surgical and transplant/LVAD centers. Crude mortality declined stepwise from non-PCI hospitals (64.5%) to transplant/LVAD centers (36.5%). After adjustment, higher hospital tier was independently associated with lower mortality (Tier 2 OR 0.43 [95% CI 0.38?0.48]; Tier 3 OR 0.37 [0.32?0.43]; Tier 4 OR 0.33 [0.30?0.38]; Tier 5 OR 0.35 [0.31?0.40]). Although transfer-in status was associated with increased mortality (OR 1.39 [1.33?1.46]), this association was attenuated at cardiac surgical and transplant/LVAD centers, consistent with a mitigation of transfer associated risk. Conclusions: Higher hospital cardiac capability is independently associated with lower mortality in CS. Advanced centers are associated with mitigation transfer-associated risk, supporting regionalized hub-and-spoke systems with early referral to high-capability centers.

BackgroundAnthracyclines are central to childhood cancer therapy but predispose patients to cardiotoxicity leading to long-term cardiovascular risk. Endothelial injury and impaired repair contribute to this, yet pediatric data remain limited. ObjectiveTo longitudinally assess endothelial injury and repair in childhood cancer patients treated with anthracyclines by quantifying circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs). MethodsIn a single-centre retrospective cohort, children (<18 years) diagnosed with leukemia (n=35) or lymphoma (n=13) were studied at four timepoints: pre-treatment ("Pre"), [~]1-month- ("End"), 3 months- (3M), and 1 year- (1Y) post-treatment. Peripheral blood mononuclear cells were analyzed by flow cytometry to quantify CECs and EPCs, and EPC fate was assessed by p16 (senescence) and Annexin V (apoptosis). Cardiac injury biomarkers and left ventricular function were assessed at each timepoint. ResultsLongitudinal trends of CEC and EPC counts were similar between leukemia and lymphoma participants. CECs were highest at pre-treatment and declined significantly thereafter, though they remained marginally elevated during remission compared with healthy controls, indicating that endothelial damage had largely subsided following treatment. EPCs were also highest at pre-treatment and decreased to levels below healthy controls during remission, suggesting impaired baseline endothelial maintenance and repair. Furthermore, EPCs were predominantly senescent up to 1-year post-treatment. ConclusionsEndothelial injury resolves by treatment completion, but repair remains impaired during remission with EPC pools dominated by senescent cells. This suggests defective endothelial regeneration, rather than persistent injury, drives long-term cardiovascular complications and underscores the need to restore EPC viability and function in childhood cancer survivors.

BackgroundMyocardial 18fluorodeoxyglucose (18FDG)-avidity is frequently seen in patients with genetic cardiomyopathy (CMP), as well as a growing "idiopathic 18FDG-avidity" group of genotype-negative patients who do not clearly have cardiac sarcoidosis (CS). ObjectivesTo determine the prognostic implications of 18FDG-avidity in patients with and without genetic CMP, and the effects of immunosuppression in the latter. MethodsThis multicenter, retrospective study included all patients who were referred for both 18FDG-PET and CMP genetic testing. Patients with acute myocarditis, biopsy-proven sarcoidosis or extracardiac 18FDG-avidity were excluded. We investigated heart failure (HF) composite (left ventricular assist device, heart transplant, HF hospitalization, death) and arrhythmia composite (sustained ventricular arrhythmias (VT/VF), atrio-ventricular block, death) outcomes using survival analysis including Cox proportional hazards modeling and inverse probability of treatment weighting (IPWT). ResultsAmong 372 patients, 142 (38%) were 18FDG-avid. Prevalence of genetic CMP among 18FDG-avid patients (12%) was similar to that of 18FDG-negative patients (19%, p=0.07). 18FDG-avidity was associated with increased risk of HF composite (HR 1.69 (1.04-2.75), p=0.034) and arrhythmia composite (HR 1.63 (1.1-2.4), p=0.014) outcomes compared to 18FDG-negative patients. However, these associations were present only in genotype-negative patients, and not in genetic CMP. After IPWT, immunosuppression of 18FDG-avid patients (n=49) was not associated with a reduction in HF (HR 3.31 (1.25, 8.77), p=0.016) or arrhythmia composite outcomes (HR 1.61 (0.79, 3.25), p=0.19) compared with those who were not immunosuppressed (n=93). ConclusionsMyocardial-only 18FDG-avidity is only associated with adverse HF and arrhythmia outcomes in genotype-negative patients who do not clearly have CS. IST does not seem to modify the disease course, suggesting that not all myocardial 18FDG uptake reflects clinically significant inflammation.

Severe forms of inflammation-induced acute and chronic myocarditis have a poor prognosis. Promising therapeutic efforts focused on monoclonal antibodies (mAbs) inhibiting inflammation-inducing molecules. However, most mAbs target only one or a limited number of such molecules. Since inflammation involves multiple redundant pathways, we postulated that an mAb inhibiting multiple inflammatory pathways would be a potent therapeutic agent. We initially tested the commercially available anti-natural killer (NK) cell mAb (anti-NK1.1), which binds a receptor expressed on NK cells and depletes them. Since NK cells are key cellular orchestrators of inflammation, by reducing their number, we aimed to inhibit multiple inflammatory pathways. Our initial studies demonstrated that administration of this antibody significantly improved myocardial outcomes in mouse models of acute myocardial infarction and of heart failure. Since NK1.1 is not expressed in human cells, we built on these promising preclinical results by developing a novel mAb targeting CD160 on human NK cells for evaluation as an immunosuppressive therapy. We found that the anti-CD160 mAb depletes both murine and human NK cells. We also found that, while CD160+ cells were largely present in the NK population, they also occurred among CD8+ and {gamma}/{delta} T cell subsets in human cells. Anti-CD160 therapy entirely prevented the deterioration of the myocardial function of mice with autoimmune-induced acute myocarditis. This outcome suggests our novel approach for inhibiting multiple inflammatory pathways may provide a potent strategy for improving outcomes of inflammation-driven myocarditis, as well as of other inflammation-driven diseases. Key PointsO_ST_ABSQuestionC_ST_ABSCan the depletion of CD160+ cells prevent autoimmune-induced myocarditis? FindingsIn this study we found that CD160 is expressed by mouse and human natural killer cells and other subtypes of cytotoxic T cells, and that a monoclonal antibody targeting CD160 depletes NK cells. In a preclinical model of experimental autoimmune myocarditis, administration of the anti-CD160 monoclonal antibody prevented myocardial dysfunction and systemic inflammation. MeaningOur results are compatible with the hypothesis that early autoimmune-induced myocardial dysfunction is promoted by CD160+ cells, which elevate inflammation-induced circulating factors (or factors released by tissue-resident cytotoxic immune cells) that cause myocardial dysfunction in the absence of myocardial necrosis or fibrosis, and further, that targeting CD160+cells with a mAb that depletes NK cells (and probably CD160 expressing cytotoxic T cells) entirely prevents the deterioration of myocardial function in such mice. This outcome suggests our novel approach for inhibiting multiple inflammatory pathways may provide a potent strategy for improving outcomes of inflammation-driven myocarditis, as well as of other inflammation-driven diseases.

BackgroundConventional definitions of vasoplegia and cardiogenic shock rely on fixed thresholds for mean arterial pressure (MAP), cardiac index (CI), and systemic vascular resistance (SVR), failing to account for the physiologic interdependence between cardiac output and vascular tone. We propose the Resistance:Flow Ratio (RFR = SVRI/CI) as a continuous, physiologically anchored measure to differentiate vascular versus cardiac dysfunction and to unify compensated, decompensated, and mixed shock states. MethodsSingle-center retrospective study of adult cardiac surgery cases, 2014-2024. Hemodynamic data for the first 72h post-operatively were analyzed. RFR thresholds were derived by modeling the relative efficiency of an increase in CI versus SVRI in improving perfusion pressure (PP: calculated as MAP minus central venous pressure) by 25%, identifying inflection points corresponding to vasoplegic, mixed, and cardiac-dominant physiology. Patients were categorized into six states by combining RFR-defined etiology with perfusion status (PP [&ge;]50 vs <50 mmHg). Transition dynamics were analyzed using Markov chain modeling. Agreement with conventional definitions of vasoplegia and cardiogenic shock was assessed using sensitivity, specificity, predictive values, and accuracy relative to RFR-PP defined states. ResultsOut of 10,338 cases, 3,378 met inclusion criteria. RFR thresholds of <400, 400-900, and >900 corresponded to vasoplegic, mixed, and cardiogenic shock, respectively. Conventional (decompensated) vasoplegia occurred in 19.4% of patients, versus 22.8% by RFR-PP criteria, while 39.9% met criteria for compensated vasoplegia. Decompensations occurred within the same RFR category in 65% of cases, validating physiologic separation of etiology from compensation. Markov chain modeling revealed a postoperative drift from pump-failure to vasoplegic states during the postoperative course. RFR-PP definitions showed greater sensitivity than conventional criteria while maintaining high specificity. ConclusionsThe RFR-PP framework quantitatively separates cardiac from vascular dysfunction, captures compensated precursor states, and links directly to therapeutic logic. RFR-PP could provide a scalable platform for real-time, physiology-based hemodynamic assessment and shock management.

Background Exercise capacity varies among individuals with a Fontan circulation. Percent predicted peak oxygen consumption (%pVO2) may be influenced by ventricular morphology, Fontan subtype, and conduit characteristics, but data explaining variability in exercise capacity are limited. This study examined whether anatomical and surgical factors are associated with %pVO2 later in life. Methods Participants enrolled in the multicenter Single Ventricle Outcomes Network (SV-ONE) database who had cardiopulmonary exercise testing (CPET) data were included. Published reference equations were used to estimate %pVO2. Multivariable regression models evaluated associations between anthropometric, anatomical (diagnosis and dominant ventricle), and surgical (Fontan subtype, conduit size, and surgical era) factors and %pVO2. Restricted spline analyses assessed nonlinearity. Results 561 individuals with a Fontan circulation were included in the analysis; age 20 {+/-} 8 years, 54% male, mean %pVO2 was 63 {+/-} 16%. Sex and exercise modality were the strongest predictors of %pVO2, with females being 12% higher than males and treadmill 4.6% higher than a cycle. Age at CPET was a predictor of exercise capacity with %pVO2 decreasing by 0.8% per year. Ventricular morphology, diagnosis, and Fontan subtype did not have a statistical association with the primary outcome. In models restricted to patients with an extracardiac conduit (n = 330), conduit diameter and area were not associated with %pVO2, even after indexing to body surface area. Univariable nonlinear spline analyses suggested an optimal conduit size of 18 mm for %pVO2, but this was not significant after body size adjustments. Conclusion In this large multicenter cohort, surgical and anatomical features were not as important as sex, age, and body size as determinants of exercise performance in patients with a Fontan circulation. Reduced exercise capacity in this population appears to reflect progressive pathophysiological changes of the Fontan circulation rather than specific characteristics such as conduit size, ventricular morphology, or anatomy.

Abstract Background: ST-elevation myocardial infarction (STEMI) is reported to be a leading cause of mortality worldwide. While cardiac troponins are the gold standard for myocardial injury detection but creatine kinase-MB (CK-MB) and total creatine phosphokinase (CPK) retain prognostic use in resource-limited settings. Objective: To evaluate the prognostic significance of admission CK-MB and CPK levels in STEMI patients and to assess their association with hematological parameters for integrated risk stratification. Methods: This cross-sectional study enrolled 15 consecutive STEMI patients from the Punjab Institute of Cardiology, Lahore, during January 2024. Comprehensive laboratory analysis including cardiac biomarkers (CK-MB, CPK, troponin-I, LDH), complete blood count, renal function, serum electrolytes, and metabolic parameters, was performed on admission. Pearson correlation and comparative statistical analyses were also conducted to assess the relationships between cardiac biomarkers and hematological indices. Results: The cohort includes 15 patients (mean age 50.1 +/- 12.2 years; 73.3% male). Cardiac biomarker elevation was prevalent: CK-MB was elevated in 12/15 (80%), CPK was elevated in 12/15 (80%), with concordant elevation in 11/15 (73.3%), which indicates extensive myocardial necrosis. Troponin-I showed the highest elevation rate at 13/15 (86.7%). Hematological abnormalities included anemia (60%), WBC elevation (53.3%), and RBC reduction (40%). Random glucose averaged 150.80 +/- 63.55 mg/dL, with 66.7% highlighted the hyperglycemia. Remarkably, electrolyte balance was preserved in all of the patients (0% sodium, potassium, and bicarbonate abnormalities), indicating maintained homeostasis. Pearson correlation analysis revealed a significant correlation between CK-MB and CPK (r = 0.615, p = 0.0126), while correlations between cardiac biomarkers and hematological parameters were weak (p > 0.05). Risk stratification identified 53.3% of patients as high-risk who required intensive management. Conclusions: CK-MB and CPK demonstrate significant concordance and retain prognostic value in STEMI patients, particularly in resource-limited settings where troponin access may be constrained. While troponin-I remains the most sensitive biomarker, combined assessment of conventional cardiac enzymes supports reliable evaluation of myocardial injury. Hematological parameters reflect systemic response but show limited correlation with cardiac biomarkers.

Immune reconstitution after allogeneic hematopoietic stem cell transplantation is influenced by graft-composition and viral reactivation, but the combined long-term impact on {beta} and {gamma}{delta}T cells remains unclear. We analyzed a cohort of 213 patients receiving either {beta}T cell-depleted grafts (n=146; graft engineering that removes donor {beta}T cells) or T cell-replete grafts (n=67; containing donor T cells). Longitudinal immune phenotyping was integrated with bulk and single-cell TCR repertoire and transcriptomic profiling. CMV reactivation was associated with expansion of CD8+ {beta}T cells across both transplant types and with numerical dominance of V{delta}2- {gamma}{delta}T cells specifically in {beta}T cell-depleted recipients. V{delta}2- {gamma}{delta}T cells underwent early polyclonal expansion followed by repertoire focusing, independent of CMV, whereas {beta}T cells remained clonally restricted. Reduced early V{delta}2+ {gamma}{delta}TCR diversity was associated with EBV reactivation. Single-cell and TCR tracking analyses revealed long-term persistence of donor-derived V{delta}2+ {gamma}{delta}TCRs, whereas V{delta}1+ {gamma}{delta} and {beta}T cell repertoires were predominantly rebuilt de novo. Despite de novo rebuilding, {beta}TCR repertoire diversity diverged by platform at one year: {beta}T cell-depleted recipients exhibited marked (hyper)expansion of {beta}TCR clonotypes and lower diversity than T cell-replete recipients, indicating a durable imprint of graft engineering on {beta}TCR-clonality. Transcriptomic profiling showed that post-transplant T cells predominantly adopted effector programs, with platform-dependent polarization toward cytotoxic signatures in {beta}T cell-depleted recipients and toward AREG-associated tissue-repair signatures in T cell-replete recipients, consistent with wound-healing functions. In conclusion, transplantation platforms imprint durable clonal and transcriptional remodeling of {beta} and {gamma}{delta}T cells, while viral reactivation primarily amplifies expansion without fundamentally reshaping repertoire architecture. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/704768v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@88f136org.highwire.dtl.DTLVardef@944f13org.highwire.dtl.DTLVardef@d3835corg.highwire.dtl.DTLVardef@5548ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundSubclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient". The diagnosis of SCR relies on surveillance biopsy. Positron emission tomography (PET/CT) after injection of F18-fluorodeoxyglucose ([18F]FDG) has been proposed as a non-invasive screening approach. In the present multicenter prospective study, we assess the diagnostic yield [18F]FDGPET/CT to rule out SCR in stable KTR at 3 months post KTx. MethodsFrom 01/2021 to 03/2025, we prospectively combined surveillance biopsy and [18F]FDGPET/CT at [~]3 months post transplantation in adult kidney transplant recipients from 4 independent imaging centers. The mean standardized uptake value (mSUV) was measured in kidney cortex and referenced as a ratio to psoas muscle mSUV (mSUVR). ResultsOur multicentric 185-patient cohort was categorized upon Banff-2022: normal (n=158); borderline (n=18); SCR (n=9, including 6 T-cell-mediated rejection and 3 microvascular inflammation). No significant correlation was observed between the mSUVR and ti score (R=0.032, p-value=0.67). The mSUVR reached 2.33 [1.97-2.93], 2.71 [2.50-3.33] and 2.42 [2.27-3.14] in normal, borderline and SCR groups, respectively. In multivariate models stratified by center, the risk of non-normal histology (n=27, including borderline and SCR) increased with donor age (OR=1.05 [1.01-1.1], p=0.02) but not with the mSUVR (OR=4.11 [0.91-18.48], p=0.07). The risk of biopsy-proven SCR (n=9) was not significantly associated with mSUVR. ConclusionsThe mSUVR of [18F]FDG PET/CT does not reliably rule out SCR on surveillance biopsy.