Biology subjects

Stauffer, B. L.

Publications and source records attributed to Stauffer, B. L..

5 recordsLinked to original sources

bioRxiv2026

Endothelium-Dependent Vasodilation is Impaired in Chronic Spinal Cord Injury and is Associated with Oxidative Stress

BackgroundIndividuals with spinal cord injury (SCI) experience accelerated atherosclerotic cardiovascular disease that is not fully explained by traditional risk factors. Endothelial dysfunction is a key mechanism in atherosclerosis. We tested the hypothesis that endothelium-dependent vasodilation is impaired in adults with SCI and is due, at least in part, to oxidative stress. MethodsTwenty-four adults (age:19-58 yr) free of overt cardiometabolic disease were studied: 12 non-injured adults (9 M/3 F) and 12 adults with chronic SCI (8 M/4 F; time since injury 1.5 - 25 years). Forearm blood flow was determined (FBF; via strain-gauge plethysmography) in response to intra-arterial infusion of acetylcholine and isoproterenol in the absence and presence of the antioxidant vitamin C as well as the FBF response to sodium nitroprusside. ResultsAdults with SCI demonstrated significantly lower vasodilator response to acetylcholine (from 4.1{+/-}0.6 to 10.7{+/-}2.6 mL/100 mL tissue/min vs 4.1{+/-}1.1 to 15.7{+/-}3.4 mL/100 mL tissue/min) and isoproterenol (4.0{+/-}0.6 to 11.2{+/-}2.2 mL/100 mL tissue/min vs 4.3{+/-}1.0 to 15.0{+/-}2.6 mL/100 mL tissue/min) compared with non-injured adults. FBF response to sodium nitroprusside was not significantly different between the groups. Co-infusion of vitamin C significantly increased the vasodilator response to acetylcholine (~45%) and isoproterenol (~25%) in the adults with SCI to levels comparable with non-injured adults. ConclusionsChronic SCI is associated with endothelial-dependent vasodilator dysfunction. Impaired vasodilation across two distinct endothelial agonists suggests that chronic SCI is associated with endothelial dysfunction not confined to a specific receptor or intracellular signaling pathway. Moreover, oxidative stress is a contributing factor underlying SCI-related endothelial vasodilator dysfunction. NCT06443151 CLINICAL PERSPECTIVEO_LIThe novel finding of this study is that individuals with SCI demonstrate impaired endothelial vasodilator function in absence of traditional cardiovascular risk factors. C_LIO_LIOxidative stress is a contributing factor to SCI-related endothelial vasodilator dysfunction. C_LIO_LIFuture studies are needed to determine the efficacy of therapeutic interventions, either lifestyle or pharmacologic, in improving endothelial function in order to mitigate the elevated ASCVD risk after SCI. C_LI

physiology↗

bioRxiv2026

Mitochondrial and Cardiolipin Adaptations to Ventricular Assist Device Support in Pediatric Versus Adult Failing Myocardium

BackgroundVentricular assist devices (VADs) are used as treatment for end-stage heart failure in children and adults. We previously demonstrated decreased mitochondrial function and changes in cardiolipin, a mitochondrial phospholipid, in explanted pediatric and adult failing hearts. In this study, we tested the hypothesis that VAD unloading of failing hearts leads to positive changes in myocardial cardiolipin in both pediatric and adult hearts. MethodsVentricular tissue was collected from the same patient at time of VAD implantation and at transplant. Ejection fraction (EF), left ventricular internal diameter at end-diastole (LVIDd) and brain natriuretic peptide (BNP) were assessed pre- and post-VAD. Cardiolipin species from paired VAD core and explants were quantified using liquid chromatography mass spectrometry. Mitochondrial respiration was measured in ventricular tissue pre- and post-VAD in paired pediatric samples using the Oroboros Oxygraph-2k. ResultsVAD support led to increased EF and decreased LVIDd and BNP. The predominant cardiolipin species in cardiac mitochondria, tetralinoleoylcardiolipin, was positively remodeled in pediatric post-VAD myocardium, while adult post-VAD myocardium demonstrated significantly increased total cardiolipin and decreased oxidized cardiolipin but did not demonstrate the tetralinoleoylcardiolipin remodeling seen in pediatric hearts. In pediatric patients, VAD support resulted in significant increases in Complex I+II activity, and a trend toward increases in Complex I activity. ConclusionOur data demonstrate age-related differences in VAD-associated cardiolipin remodeling and suggest that improved mitochondrial function in pediatric VAD-supported hearts could be related to increased tetralinoleoylcardiolipin.

physiology↗

bioRxiv2026

Circulating miRNA-Protein Signatures Predict Outcomes in Pediatric Dilated Cardiomyopathy

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

systems biology↗

bioRxiv2025

A novel Notch and WNT signaling mechanism contribute to pediatric DCM: a pathway to new therapeutics.

BackgroundTherapies for pediatric idiopathic dilated cardiomyopathy (iDCM) are extrapolated from adult heart failure despite limited efficacy, suggesting fundamental biological differences. Our prior transcriptomic studies indicate activation of developmental signaling pathways, including Notch and WNT, in pediatric iDCM; however, their mechanistic contribution remains unknown. We tested whether reactivation of Notch and WNT/{beta}-catenin signaling drives pathological remodeling in postnatal hearts and whether pathway inhibition improves cardiac function. MethodsWe developed a juvenile rat model to reproduce age-dependent molecular features of pediatric iDCM using {beta}-adrenergic stimulation (isoproterenol, ISO) and secreted frizzled-related protein-1 (sFRP1), a circulating WNT modulator elevated in children with DCM. Cardiac function was assessed by echocardiography; pathway activation by immunoblotting and transcriptomics; myocardial stiffness by atomic force microscopy. Findings were compared with explanted pediatric and adult human myocardium. ResultsExplanted pediatric, but not adult iDCM hearts exhibited increased nuclear and cytoplasmic Notch intracellular domain (NICD) and {beta}-catenin. Combined ISO and sFRP1 treatment recapitulated key features of pediatric disease, including ventricular dilation, reduced ejection fraction, reactivation of the fetal gene program, and increased myocardial stiffness in the absence of fibrosis or hypertrophy. Bulk and single-nucleus RNA sequencing identified cardiomyocyte-specific activation of Notch and WNT pathways and reduced intercellular signaling diversity. Mechanistically, {beta}-catenin silencing attenuated Notch target gene activation and pathological remodeling in vitro. Pharmacologic Notch inhibition reduced NICD and {beta}-catenin accumulation, improved ventricular function, and normalized myocardial stiffness in vivo. ConclusionPediatric iDCM is characterized by pathological co-activation of developmental Notch-WNT signaling pathways that are not observed in adult disease. Reactivation of this axis promotes maladaptive remodeling and myocardial stiffening, and its inhibition improves cardiac function. These findings establish developmental signaling reactivation as a central mechanism of pediatric iDCM and support age-specific therapeutic strategies.

molecular biology↗

bioRxiv2025

Impact of Serum Circulating Factors and PDE5 Inhibitor Therapy on Cardiomyocyte Metabolism in Single Ventricle Heart Disease

BackgroundWhile operative and perioperative care continues to improve for single ventricle congenital heart disease (SV), long-term morbidities and mortality remain high. Importantly, phosphodiesterase-5 inhibitor therapies (PDE5i) are increasingly used, however, little is known regarding the direct myocardial effects of PDE5i therapy in the SV population. ObjectivesOur group has previously demonstrated that the failing SV myocardium is characterized by increased PDE5 activity and impaired mitochondrial bioenergetics. Here we sought to determine whether serum circulating factors contribute to pathological metabolic remodeling in SV, and whether PDE5i therapy abrogates these changes. MethodsUsing an established in vitro model whereby primary cardiomyocytes are treated with patient sera +/- PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry-based lipidomics and metabolomics were performed to identify phospholipid and metabolite changes. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer and a stable isotope based mitochondrial enzyme activity assay. Relative mitochondrial copy number was quantified using RT-qPCR. ResultsOur data suggest that serum circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, increased reactive oxygen species (ROS) generation, and altered metabolite milieu. Treatment with PDE5i therapy was sufficient to abrogate a number of these metabolic changes, including a rescue of phosphatidylglycerol levels, a reduction in ROS, improved energy production, and normalization of several key metabolic intermediates. ConclusionsTogether, these data suggest PDE5i therapy has direct cardiomyocyte effects and contributes to beneficial cardiomyocyte metabolic remodeling in SV failure.

cell biology↗