tbuckley/cabot-search huggingface dataset:
Abstract 14665: Cybrid Analysis Delineates Nuclear and Mitochondrial Contributions to Oxidative Stress in Pulmonary Arterial Hypertension
Authors: Srimmitha Balachandar, Thomas M OConnell, Micheala A Aldred
Journal: Circulation (2023)

Rationale : Heritable pulmonary arterial hypertension (HPAH) is a serious vasculopathy caused by remodeling of pulmonary arterioles. It is inherited in an autosomal dominant pattern with reduced penetrance, suggesting additional triggers are needed for disease development. Past study shows increased DNA damage and total reactive oxygen species (ROS) in lymphoblastoid cells (LCL) from PAH patients and unaffected relatives, indicating a potential genetic component. Hypothesis: Increased oxidative stress is an independent genetically-determined modifier of PAH susceptibility. Methods: LCL from patients, relatives and unrelated controls were analyzed for total and mitochondrial (mt) ROS and mt function (Seahorse). Untargeted metabolomics were performed by Metabolon. Nuclear vs mt gene contribution was studied using cybrids created by transferring the mitochondria from high (HC) and low ROS LCL (LC) to mt negative 143B Rho0 cells. Results: Metabolomics revealed significant differences between PAH and control LCL in the TCA cycle and glutathione metabolism relating to oxidative stress. HPAH LCL showed significant upregulation of both ROS species compared to controls. LCL from relatives clustered into two groups, one with increased mtROS, the other comparable to controls . Like PAH lung vascular cells, LCL with increased mtROS had reduced spare respiratory capacity (SRC) suggesting dysfunctional mitochondria, but no glycolytic switch. Cybrid analysis revealed that HCs had significantly higher basal respiration (p=0.02), with SRC trending higher compared to LCs, indicating a functional electron transport chain. These cells also had elevated mtROS (p=0.04), suggesting reduced antioxidants. Conclusions: HPAH is a complex disease, and mutation status alone doesn’t determine its susceptibility. Patient LCL recapitulate some of the metabolomic pathways dysregulated in lung vascular cells. Oxidative stress in LCL extends to some unaffected relatives, suggesting this is an independent genetic trait that modifies PAH risk. Our cybrid analysis, novel in PAH highlights the importance of nuclear-mt crosstalk. WGS is underway to identify nuclear variants that could affect the mt, and act as potential modifiers and second hits in PAH pathogenesis.
Abstract 13017: National Characteristics and Outcomes of Adults With Pulmonary Embolism Undergoing Catheter Directed Thrombolysis Compared to Systemic Tissue Plasminogen Activator
Authors: Jasninder Dhaliwal, Rahat A Memon, Shruti Aggarwal, Kamleshun Ramphul, Shaheen Sombans, Hemamalini Sakthivel
Journal: Circulation (2023)

Introduction: Catheter Directed Thrombolysis (CDT) and systemic tissue plasminogen activator (tPA) are commonly used interventions for pulmonary embolism (PE). We aim to compare these two procedures. Methods: Cases of pulmonary embolism in adults were used for our study from the National Inpatient Sample (2016-2020). We compared the characteristics and outcomes of patients undergoing CDT vs. systemic tPA &lt;24 hours after hospitalization. Results: We found 16675 cases of PE, with 9130 (54.8%) patients undergoing tPA and 7545 (45.2%) needing CDT. Compared to tPA cases, a lower rate of weekend admission was seen in patients undergoing CDT. Both groups consisted of Whites and were covered primarily by Medicare. Most admissions took place in urban teaching centers, with large bed sizes and in the southern regions of the US. Furthermore, CDT patients were older (mean age 56.2 vs. 52.1 years), involving more patients with hypertension and obesity. However, CDT cases had fewer patients with diabetes, peripheral vascular disease, chronic kidney disease, prior stroke, and drug abuse and reported a lower mean Charlson Comorbidity Index(CCI) score(table 1). tPA patients also had higher rates of atrial fibrillation, ventricular fibrillation, and atrial flutter. Overall, 5.9% of patients undergoing tPA died, while 1.8% died in the CDT cohort (aOR death in tPA 2.604 vs. CDT, 95% CI 2.033-3.335, p&lt;0.01). A higher mortality rate within the first week of hospitalization was also seen in the tPA group (figure 1). tPA cohort also reported higher odds of acute kidney injury(AKI) (aOR 1.484, 95% CI 1.364-1.615, p&lt;0.01) and cardiogenic shock (aOR 3.588, 95% CI 2.990-4.304, p&lt;0.01). Finally, tPa patients had a lengthier stay. Conclusions: CDT cases showed lower mortality during the first week of the procedure. Differences in comorbidities exist between the two groups. Further research exploring additional factors may help address current protocols to improve long-term outcomes.
Abstract 14654: Contemporary Gender Differences in Clinical Outcomes of Patients With Takotsubo Cardiomyopathy - A United States National Inpatient Sample Database Analysis
Authors: Muhammad U Almani, Rasha Khan, Muhammad Qudrat Ullah, Anum Fatima, Audry Chacin Suarez, Raphael bonita, Behnam Bozorgnia
Journal: Circulation (2023)

Introduction: Takotsubo cardiomyopathy (TCM) is classically more prevalent in females, however whether gender differences exist in clinical outcomes of patients with TCM need further clarification. Given the lower prevalence of TCM in males, limitations of previous research included small sample size and demographic disproportion between groups. The purpose of our study is to analyze gender differences in clinical outcomes of TCM hospitalizations using national inpatient sample (NIS). Methods: We searched the 2020 NIS for TCM hospitalizations using ICD 10 code I51.81. Multivariable logistic regression model adjusted for patient and hospital level confounders was used to compare the clinical outcomes between genders. Results: We identified 41,290 TCM hospitalizations in 2020. Of these 19.9% were males (mean age = 63 years, mean charlson comorbidity index = 3.2) and 80.1% were females (mean age = 68 years, mean charlson comorbidity index = 2.7). Females had a lower risk of inpatient mortality (OR: 0.49, 95% CI 0.41-0.58, p &lt; 0.001), cardiac arrest (OR: 0.58, 95% CI 0.43-0.79, p = 0.001) and cardiogenic shock (OR: 0.67, 95% CI 0.55-0.82, p &lt; 0.001). There was no gender difference in the use of intra-aortic balloon pump (IABP), Impella assist system, or extra-corporeal membrane oxygenation (ECMO) Figure 1. Conclusion: Our findings indicate that despite a higher prevalence of TCM in females, clinical outcomes were worse in males. In our analysis, there was no gender difference in the use of IABP, Impella or ECMO. Future research is needed to better understand clinical predictors of adverse cardiac events in male patients hospitalized with TCM to improve outcomes.
Abstract 18388: Hypertension Identification and Management in the USA: Adherence of the 2017 ACC/AHA High Blood Pressure Guidelines
Authors: Joseph Heaton, Abbas Alshami, Ndausung Udongwo, Sowmya Dandu, Anton Mararenko, Steven Imburgio, Hira Akhlaq, Anmol Johal, Jesus Almendral, Brett Sealove
Journal: Circulation (2023)

Background: The 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults changed the criteria for a diagnosis of hypertension and provided new recommendations goals and management. We aimed to investigate the prevalence of hypertension identification, treatment, and adherence in the US population. Methods: We analyzed the 2017-2020 pre-pandemic National Health and Nutrition Examination Survey for participants between 18 and 79 years of age. Participant data was used to assess for a hypertension diagnosis and eligibility for AHA/ACC’s primary or secondary prevention hypertension strategies. Current hypertension medication usage was stratified if prescribed for hypertension management or a non-hypertension indication. Participants with a current hypertension-indicated medication were identified as “Undergoing Treatment”; all other participants were stratified into “No Indication”, “Primary Prevention”, or “Secondary Prevention”, based on the AHA/ACC guideline. Complex survey methodology with weighting was utilized for national estimates. Results: Our study included 236,621,712 participants, of which 22.4% (n=53,064,773) were undergoing treatment for hypertension, 67.0% (n=158,613,605) had no indication for management, 8.9% (n=21,158,544) qualified for primary prevention, and 1.6% (n=3,784,790) qualified for secondary prevention. A known hypertension diagnosis was reported in 26.0% of the primary prevention group, 45.0% of secondary prevention, and 94.8% of those undergoing treatment. In patients undergoing treatment, 57.9% of participants had mean blood pressure readings above goal. Conclusion: One in ten adults under 80 qualify for hypertension management but may not be undergoing treatment. Of patients qualifying without current treatment, most did not know they would qualify for a hypertension diagnosis. More than half of treated patients did not meet blood pressure goals.
Abstract 13015: Sex Disparities in Outcomes of Adults With Cardiogenic Shock Using Impella; a Propensity-Matched Analysis
Authors: Kamleshun Ramphul, Rahat A Memon, Jasninder S Dhaliwal, Shaheen Sombans, Abhimanyu Ravalani, Petras Lohana
Journal: Circulation (2023)

Introduction: Impella use is one of the mechanical circulatory support options in patients with cardiogenic shock (CS). While recent studies have associated a 47.3% short-term mortality in Impella support for CS, there is a lack of data on sex disparities in its use. We, therefore, conducted a retrospective analysis to analyze its impact. Hypothesis: We assessed the hypothesis that females and males have different outcomes following the use of Impella for CS. Methods: We explored the 2016-2020 National Inpatient sample for adults with CS and Impella use. Propensity matching was conducted for multiple patient and hospital characteristics. The differences in males and females for various complications were analyzed. Results: Our study initially found 57630 cases that matched our selection, with 41455(71.9%) males and 16175(28.1%) females. After propensity matching, Females showed a higher mean age (64.31 vs. 62.82 years, p&lt;0.01), with a higher mean Charlson Comorbidity Index (CCI) score (4.50 vs. 4.25, p&lt;0.01), but a shorter hospitalization ( 15.31 vs. 16.64 days). In addition, females showed higher odds of central line-associated bloodstream infection (CLABSI) (aOR 2.576, 95% CI 1.147-5.788, p=0.022), pulmonary embolism (PE) (aOR 1.544, 95% CI 1.077-2.213, p=0.018), respiratory failure/arrest (aOR 1.124, 95% CI 1.001-1.262, p=0.048) than males, while having lower odds of acute kidney injury (AKI) (aOR 0.727, 95% CI 0.648-0.815, p&lt;0.01). No differences in stroke, sepsis, or death events were found between them. Conclusions: In conclusion, there are differences in outcomes between males and females following use of Impella for CS, as females expressed higher odds of CLABSI, PE, respiratory failure/arrest, and lower odds of AKI than males. Future randomized studies in clinical settings and addressing for limitations of our study (such as drug use and duration of various comorbidities) are warranted to improve outcomes between the two cohorts.
Abstract 257: VIGAB-STAT- A Phase IIa Feasibility Trial of Irreversible GABA-Transaminase Inhibition as Adjunct Treatment of Status Epilepticus After Cardiac Arrest
Authors: Bakhtawar Ahmad, Nicole F Maranchick, Daniela P Forero, Katharina M Busl, Lawrence Hirsch, Maria Bruzzone, Stephan Eisenschenk, Charles A Peloquin, Carolina Maciel
Journal: Circulation (2023)

Background: Effective therapeutic interventions for post-anoxic status epilepticus (PASE) are lacking. Vigabatrin (VGB) could be an attractive adjunct drug in PASE by increasing GABA availability in inhibitory synapses; however, enteral malabsorption in the post-cardiac arrest (CA) period and difficulty enrolling in the FDA mandatory registry could hinder its use in this setting. We hypothesize that CA survivors absorb VGB despite vasopressor use, concurrent enteral feeding, and regardless of gastric or post-pyloric drug delivery. Goals: Prove feasibility and study pharmacokinetics of a single enteric VGB load within 48 hours of PASE onset. Methods: We administered a single load 1125-4500 mg VGB (based on creatinine clearance; CrCl) in adults with non-traumatic CA, with electrographic SE and gastric or duodenal access. Plasma samples were collected at 0, 0.5, 1, 2, 3, 6, 12, 24, 48, 72 and 168 hours. Results: Interim results from a cohort of 6 subjects comprised of 67% male (4 of 6), 83% White (5 of 6), with a median age 62 years 22-68), median BMI 30 Kg/m 2 (20-53), and median CrCl 44cc/min (22-186) are presented. All subjects received VGB within 48h window; median VGB dose was 2250 mg (1125-4500). The median time to peak (Tmax) was 2 h (1-3); median peak concentration (Cmax) was 38.1 mcg/ml (16.7 -91.8). Median 24h VGB concentration (C24) was 9.4 mcg/ml (3.4-14.2) and half-life (T1/2) was 16 h (10-24). The AUC 0-24 value was 318 mcg*h/ml (262-1012). No significant association was found between sex or BMI and Cmax. Three out of six patients achieved EEG response following VGB load; no association with dose or concentration was noted. Conclusions: All patients achieved detectable VGB levels with peak occurring between 1-3 hours post-administration. Enteric administration of VGB does not preclude phase IIb clinical trials of VGB in PASE. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT04772547
Abstract 13022: Myocardial Restoration and Functional Recovery Through Transplantation of Vascularized Cardiac Microtissues Derived From Human Induced Pluripotent Stem Cells in a Rat Model of Myocardial Infarction
Authors: Keisuke Hakamada, Kozue Murata, Kenji Minatoya, Hidetoshi Masumoto
Journal: Circulation (2023)

Introduction: Cardiac regenerative therapy is acknowledged as a promising strategy for treating individuals suffering from severe heart failure. To address the current constraints of stem cell therapy, which primarily relies on indirect paracrine effects for functional improvement, the ideal goal would be to restore the damaged myocardium in the diseased heart. To achieve this, the transplantation of biomimetic heart tissues that closely resemble the natural structure of the heart is highly anticipated. Methods: We successfully generated 3-dimensional vascularized cardiac microtissues (VCMs) using human induced pluripotent stem cells (hiPSCs) through dynamic culture on thin cardiac tissue sheets (CTSs) composed of hiPSC-derived cardiomyocytes and vascular cells. These VCMs exhibited a robust vascular network comprising human vascular cells. Subsequently, we transplanted CTSs (n=6) or VCMs (n=6) onto an athymic rat model of myocardial infarction (MI), while a sham operation was performed on another group (n=6). To assess cardiac function, we employed cardiac magnetic resonance imaging. The survival of grafts, extension of fibrotic scars, neovascularization in the MI border zone, and the formation of a human vascular network within the engrafted region were evaluated through histopathology and light sheet fluorescence microscopy with tissue clearing techniques. Results: Functional analyses demonstrated that the VCM group exhibited the highest left ventricular ejection fraction (Sham: 36.5±0.9%, CTS: 43.5±2.9%, VCM: 55.2±2.5%, p &lt; 0.01). Histopathological evaluation revealed that the VCM group had a larger engraftment area, along with the smallest scar extension and the highest vascular density in the myocardial infarction border zone. Furthermore, LSFM revealed the presence of vascular networks originating from human cells within the engrafted VCMs. Conclusions: The transplantation of hiPSC-derived VCMs demonstrated remarkable therapeutic potential in a rat model of MI, leading to the formation of a vascular network by human cells. This approach might hold great promise as an effective strategy for efficiently restoring the damaged myocardium in hearts afflicted with disease.
Abstract 14659: Muscle Oxygenation Responses to Acute Exercise and Cellular Biomarkers of Vascular Health in Veterans With Chronic Kidney Disease
Authors: Jared M Gollie, Seshagiri R Nandula, David J Kim, Arad Jain, Abel Argaw, Tharangini Singarapu, samir patel, Scott D Cohen, Peter F Kokkinos, Marc R Blackman, Sabyasachi Sen
Journal: Circulation (2023)

Introduction: Increased susceptibility of endothelial dysfunction and skeletal muscle impairments suggest peripheral limitations as an explanation for diminished aerobic capacity in chronic kidney disease (CKD) patients. However, data on peripheral limitations in CKD patients is limited. Hypothesis: We hypothesized CKD patients would experience reduced muscle oxygenation responses to acute exercise and cellular evidence of declines in vascular health compared to those without CKD. Methods: Sixteen male Veterans (CKD: n=9, age 74±6 yrs, eGFR, 41.7±10 mL/min/1.73 m 2 ; non-CKD controls (CON): n=7, age, 67±8 yrs, eGFR, 75±10.6 mL/min/1.73 m 2 ) completed treadmill cardiopulmonary exercise testing via the Modified Bruce protocol. Oxygenation responses were obtained from the medial gastrocnemius using near-infrared spectroscopy. Blood samples were collected at rest and analyzed for colony-forming units (CFU), flow-cytometry of mononuclear cells (MNCs) focusing on endothelial lineage cells and gene expression of MNCs. Effect sizes between groups were determined using Hedge’s g (g). Results: At peak exercise, oxygen consumption (VO 2peak 19±5 vs 25.8±5.2 ml/kg/min -1 , g=1.2), heart rate (HR peak 132±21 vs 160±9 bpm, g=1.6), oxygen extraction (Δ[HHb] 14.8±10.8 vs 24.9±6.8 a.u., g=1.0), and change in total hemoglobin concentration (Δ[tHb] 8.9±5.1 vs 22.5±12.8 a.u., g=1.4) were lower in CKD compared to CON. At an exercise intensity of 3.4 METs, Δ[HHb] and Δ[tHb] were 42% and 54% lower (8.0±7.8 vs 13.8±8.8 a.u., g=0.6 and 4.9±4.1 vs 10.7±4.5 a.u., g=1.2) in CKD vs CON, despite no differences in oxygen consumption or heart rate. CD34 + 184 expression was 47% lower in CKD vs CON (0.2±0.04 vs 0.38±0.48 %, g=0.5). CFU was significantly inversely correlated with body mass index and waist circumference (r=-0.67, p=0.034; r=-0.65, p=0.041). Conclusions: Preliminary data from this ongoing study suggest oxygen extraction and capillary blood volume expansion are impaired during exercise in CKD patients when compared to those without CKD. CD34 + 184 expression was lower in CKD patients versus those without CKD, indicating poor hematopoietic stem cell migratory function in the CKD group. In addition, an inverse association between CFU and body habitus was observed.
Abstract 15422: Diffuse Myocardial Fibrosis Predicts Outcome in Moderate and Asymptomatic Severe Aortic Stenosis
Authors: Hyun-Jung Lee, Anvesha Singh, Jaehyun Lim, Rong Bing, Lionel Tastet, Jun-bean Park, Hyung-kwan Kim, Yong-Jin Kim, Marie-Annick A Clavel, Bernhard L Gerber, Gerry McCann, MARC DWECK, Philippe Pibarot, Seung-Pyo Lee
Journal: Circulation (2023)

Introduction: Patients with moderate or asymptomatic severe aortic stenosis (AS) are at increased risk of cardiovascular events, but markers to guide intervention are lacking. We investigated the use of cardiovascular magnetic resonance (CMR) to identify drivers of outcome. Methods: Moderate (aortic valve area [AVA] 1.0-1.5 cm2) or asymptomatic severe AS patients (AVA≤1.0 cm2 and NYHA functional class I-II) (n=457) were prospectively enrolled from five international sites and parameters including extracellular volume fraction (ECV%) and late gadolinium enhancement were analyzed on CMR. Clinical events were defined as all-cause mortality and admission for heart failure. Results: Moderate AS patients had smaller left ventricular (LV) mass and less diastolic dysfunction compared to asymptomatic severe AS patients, but showed no difference in the extent of myocardial fibrosis and scar. During median 5.7-years follow-up, 83 clinical events occurred. Patients with clinical events had smaller AVA, greater diastolic dysfunction, and higher ECV% (median [interquartile range] ECV% 26.3% [24.3-29.8] vs 28.2% [25.5-30.8], P=0.003). There was a stepwise increase of clinical events across ECV tertiles. ECV% was associated with clinical outcome (adjusted HR 1.05, 95% CI 1.00–1.09, P=0.035), independent of AVA and aortic valve replacement as a time-dependent covariate. The prognostic significance of ECV% was consistent when AS severity was alternatively defined using aortic peak velocity and mean pressure gradient, and also across subgroups by AS severity and symptoms, AVA, aortic peak velocity, mean pressure gradient, and left ventricular ejection fraction (Figure). Conclusions: Increased diffuse myocardial fibrosis is associated with poor outcomes in moderate and asymptomatic severe AS patients and can help identify those who require closer surveillance and possibly earlier intervention.
Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice
Authors: Brenda J. Seymour, Brandon Trent, Brendan E. Allen, Adam J. Berlinberg, Jimmy Tangchittsumran, Widian K. Jubair, Meagan E. Chriswell, Sucai Liu, Alfredo Ornelas, Andrew Stahly, Erica E. Alexeev, Alexander S. Dowdell, Sunny L. Sneed, Sabrina Fechtner, Jennifer M. Kofonow, Charles E. Robertson, Stephanie M. Dillon, Cara C. Wilson, Robert M. Anthony, Daniel N. Frank, Sean P. Colgan, Kristine A. Kuhn
Journal: Journal of Clinical Investigation (2023)

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colonic lymphocytes to indole increased the expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA.