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Item A Challenging Combination: Anomalous Left Anterior Descending Coronary Artery, Myocardial Bridging, and Endothelial Dysfunction(Frontiers Media, 2020) El-Am, Edward A.; Corban, Michel T.; Pollak, Amy W.; Lerman, Amir; Ammash, Naser M.; Medicine, School of Medicine50 years old female patient with a medical history of hypertension presented to the clinic with chest pain, palpitations, and dyspnea on exertion of 2 years duration. Extensive workup in search of the culprit etiology of her chest pain revealed a challenging combination of an anomalous left anterior descending artery with myocardial bridging and endothelial dysfunction. She was treated medically with long acting nitrates, L-arginine and calcium channel blockers, and remains asymptomatic after 12 months of follow up.Item Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort(Research Square, 2023-12-06) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of MedicineBackground: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.Item Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1(BMC, 2023-06-26) Atreya, Mihir R.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Weiss, Scott L.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Allen, Geoffrey L.; Thomas, Neal J.; Grunwell, Jocelyn R.; Baines, Torrey; Quasney, Michael; Haileselassie, Bereketeab; Alder, Matthew N.; Lahni, Patrick; Ripberger, Scarlett; Ekunwe, Adesuwa; Campbell, Kyle R.; Walley, Keith R.; Standage, Stephen W.; Pediatrics, School of MedicineBackground: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction. Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. Results: A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. Conclusions: We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.Item Effect of Modernized Collaborative Care for Depression on Depressive Symptoms and Cardiovascular Disease Risk Biomarkers: eIMPACT Randomized Controlled Trial(Elsevier, 2023) Stewart, Jesse C.; Patel, Jay S.; Polanka, Brittanny M.; Gao, Sujuan; Nurnberger, John I., Jr.; MacDonald, Krysha L.; Gupta, Samir K.; Considine, Robert V.; Kovacs, Richard J.; Vrany, Elizabeth A.; Berntson, Jessica; Hsueh, Loretta; Shell, Aubrey L.; Rollman, Bruce L.; Callahan, Christopher M.; Psychology, School of ScienceAlthough depression is a risk and prognostic factor for cardiovascular disease (CVD), clinical trials treating depression in patients with CVD have not demonstrated cardiovascular benefits. We proposed a novel explanation for the null results for CVD-related outcomes: the late timing of depression treatment in the natural history of CVD. Our objective was to determine whether successful depression treatment before, versus after, clinical CVD onset reduces CVD risk in depression. We conducted a single-center, parallel-group, assessor-blinded randomized controlled trial. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). Outcomes were depressive symptoms and CVD risk biomarkers at 12 months. Intervention participants, versus usual care participants, exhibited moderate-to-large (Hedges' g = -0.65, p < 0.01) improvements in depressive symptoms. Clinical response data yielded similar results - 43% of intervention participants, versus 17% of usual care participants, had a ≥ 50% reduction in depressive symptoms (OR = 3.73, 95% CI: 1.93-7.21, p < 0.01). However, no treatment group differences were observed for the CVD risk biomarkers - i.e., brachial flow-mediated dilation, high-frequency heart rate variability, interleukin-6, high-sensitivity C-reactive protein, β-thromboglobulin, and platelet factor 4 (Hedges' gs = -0.23 to 0.02, ps ≥ 0.09). Our modernized collaborative care intervention - which harnessed technology to maximize access and minimize resources - produced clinically meaningful improvements in depressive symptoms. However, successful depression treatment did not lower CVD risk biomarkers. Our findings indicate that depression treatment alone may not be sufficient to reduce the excess CVD risk of people with depression and that alternative approaches are needed. In addition, our effective intervention highlights the utility of eHealth interventions and centralized, remote treatment delivery in safety net clinical settings and could inform contemporary integrated care approaches.Item Endothelial dysfunction in pathological processes of chronic liver disease during aging(Wiley, 2022) Wan, Ying; Li, Xuedong; Slevin, Elise; Harrison, Kelly; Li, Tian; Zhang, Yudian; Klaunig, James E.; Wu, Chaodong; Shetty, Ashok K.; Dong, X. Charlie; Meng, Fanyin; Medicine, School of MedicineAging is associated with gradual changes in liver structure and physiological/pathological functions in hepatic cells including hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). LSECs are specialized hepatic endothelial cells that regulate liver homeostasis. These cells actively impact the hepatic microenvironment as they have fenestrations and a thin morphology to allow substance exchange between circulating blood and the liver tissue. As aging occurs, LSECs have a reduction in both the number and size of fenestrations, which is referred to as pseudocapillarization. This along with the aging of the liver leads to increased oxidative stress, decreased availability of nitric oxide, decreased hepatic blood flow, and increased inflammatory cytokines in LSECs. Vascular aging can also lead to hepatic hypoxia, HSC activation, and liver fibrosis. In this review, we described the basic structure of LSECs, and the effect of LSECs on hepatic inflammation and fibrosis during aging process. We briefly summarized the changes of hepatic microcirculation during liver inflammation, the effect of aging on the clearance function of LSECs, the interactions between LSECs and immunity, hepatocytes or other hepatic nonparenchymal cells, and the therapeutic intervention of liver diseases by targeting LSECs and vascular system. Since LSECs play an important role in the development of liver fibrosis and the changes of LSEC phenotype occur in the early stage of liver fibrosis, the study of LSECs in the fibrotic liver is valuable for the detection of early liver fibrosis and the early intervention of fibrotic response.Item Experimental animal models of coronary microvascular dysfunction(Oxford Academic, 2020-03) Sorop, Oana; van deWouw, Jens; Chandler, Selena; Ohanyan, Vahagn; Tune, Johnathan D.; Chilian, William M.; Merkus, Daphne; Bender, Shawn B.; Duncker, Dirk J.; Anatomy and Cell Biology, School of MedicineCoronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed 'ischaemia and no obstructive coronary artery disease' (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive. Although to date there is no animal model for INOCA, animal models of CMD, one of the hallmarks of INOCA, offer excellent test models for enhancing our understanding of the pathophysiology of CMD and for investigating novel therapies. This article presents an overview of currently available experimental models of CMD-with an emphasis on metabolic derangements as risk factors-in dogs, swine, rabbits, rats, and mice. In all available animal models, metabolic derangements are most often induced by a high-fat diet (HFD) and/or diabetes mellitus via injection of alloxan or streptozotocin, but there is also a wide variety of spontaneous as well as transgenic animal models which develop metabolic derangements. Depending on the number, severity, and duration of exposure to risk factors-all these animal models show perturbations in coronary microvascular (endothelial) function and structure, similar to what has been observed in patients with INOCA and comorbid conditions. The use of these animal models will be instrumental in identifying novel therapeutic targets and for the subsequent development and testing of novel therapeutic interventions to combat ischaemic heart disease, the number one cause of death worldwide.Item External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock(Research Square, 2023-08-02) Atreya, Mihir R.; Bennett, Tellen D.; Geva, Alon; Faustino, E. Vincent S.; Rogerson, Colin M.; Lutfi, Riad; Cvijanovich, Natalie Z.; Bigham, Michael T.; Nowak, Jeffrey; Schwarz, Adam J.; Baines, Torrey; Haileselassie, Bereketeab; Thomas, Neal J.; Luo, Yuan; Sanchez-Pinto, L. Nelson; Novel Data-Driven Sepsis Phenotypes in Children Study and the Genomics of Pediatric Septic Shock Investigators; Pediatrics, School of MedicineObjective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata. Design: We trained and validated a random forest classifier using organ dysfunction subscores in the EHR dataset used to derive the PHES phenotype. We used the classifier to assign phenotype membership in a test set consisting of prospectively enrolled pediatric septic shock patients. We compared biomarker profiles of those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk-strata. Setting: 25 pediatric intensive care units (PICU) across the U.S. Patients: EHR data from 15,246 critically ill patients sepsis-associated MODS and 1,270 pediatric septic shock patients in the test cohort of whom 615 had biomarker data. Interventions: None. Measurements and main results: The area under the receiver operator characteristic curve (AUROC) of the new classifier to predict PHES phenotype membership was 0.91(95%CI, 0.90-0.92) in the EHR validation set. In the test set, patients with the PHES phenotype were independently associated with both increased odds of complicated course (adjusted odds ratio [aOR] of 4.1, 95%CI: 3.2-5.4) and 28-day mortality (aOR of 4.8, 95%CI: 3.11-7.25) after controlling for age, severity of illness, and immuno-compromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and overlapped with high risk-strata based on PERSEVERE biomarkers predictive of death and persistent MODS. Conclusions: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlap with higher risk-strata based on validated biomarker approaches.Item Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study(BMC, 2022-07-11) Atreya, Mihir R.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Weiss, Scott L.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Allen, Geoffrey L.; Thomas, Neal J.; Grunwell, Jocelyn R.; Baines, Torrey; Quasney, Michael; Haileselassie, Bereketeab; Lindsell, Christopher J.; Alder, Matthew N.; Wong, Hector R.; Pediatrics, School of MedicineBackground: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. Methods: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. Results: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. Conclusions: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.Item Potential health effects of dietary nitrate supplementation in aging and chronic degenerative disease(Elsevier, 2020-08) Carter, Stephen J.; Gruber, Allison H.; Raglin, John S.; Baranauskas, Marissa N.; Coggan, Andrew R.; Kinesiology, School of Health and Human SciencesIn the United States, latest projections indicate the number of adults 65 years of age and older is expected to double by 2050. Given that increased oxidative stress is a hallmark of aging, it is understandable that waning nitric oxide and chronic degenerative disease arise in tandem. To this end, translational evidence-based strategies are needed to mitigate the impending toll on personal and public health. Dietary nitrate supplementation, particularly in the form of beetroot juice, is an active area of inquiry that has gained considerable attention in recent years. Compelling evidence has revealed beetroot juice can elicit potent physiological responses that may offer associated health benefits for multiple clinical disorders including hypertension, dementia, and sarcopenia. Even in the absence of overt disease, age-related impairments in cardiovascular and skeletal muscle function may uniquely benefit from beetroot juice supplementation as evidence has shown blood pressure lowering effects and improved muscle function/contractility – presumably from increased nitric oxide bioavailability. This, in turn, presents a practical opportunity for susceptible populations to support ease of movement and exercise tolerance, both of which may promote free-living physical activity. A theoretical rationale details the potential health effects of dietary nitrate supplementation, wherein a working framework hypothesizes beetroot juice consumption prior to structured exercise training may offer synergistic benefits to aid healthy aging and independent-living among older adults.Item Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock(BMC, 2023-07-03) Atreya, Mihir R.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Weiss, Scott L.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Allen, Geoffrey L.; Thomas, Neal J.; Grunwell, Jocelyn R.; Baines, Torrey; Quasney, Michael; Haileselassie, Bereketeab; Alder, Matthew N.; Goldstein, Stuart L.; Stanski, Natalja L.; Pediatrics, School of MedicineBackground: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI. Methods: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk. Results: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr. Conclusions: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.