tbuckley/cabot-search huggingface dataset:
Abstract 16786: Integrative Omics in Failing Myocardium Highlights Metabolic Substrate Utilization Defects in Human Heart Failure
Authors: Lydia C Kwee, Lauren K Truby, Stephani Page, Dawn E Bowles, Carmelo Milano, Olga Ilkayeva, Christopher Newgard, Michael Felker, Michael Bristow, Christopher L Holley, Robert W McGarrah, Svati H Shah
Journal: Circulation (2023)

Introduction: Changes in substrate utilization may be a biomarker of, or a contributor to, heart failure with reduced ejection fraction (HFrEF). Previous work has described circulating metabolites, proteins and transcripts that reflect myocardial bioenergetics, but direct assessment in relevant tissues is lacking. Here, we leverage integrative omics to identify tissue-level biomarkers and pathways of HFrEF that may play a role in pathogenesis. Methods: Myocardial tissue was obtained from 27 HFrEF donors and 21 non-failing hearts (noHF) from Duke University and the University of Colorado Medical Centers. Targeted (n=139 metabolites) and nontargeted (Metabolon, n=817) metabolic profiling was performed; in addition, 496 proteins were assayed (Olink) and ~31,000 transcripts were quantified via RNA sequencing. Individual metabolites were tested for association with HFrEF in models adjusted for age, sex and diabetes. Metabolomics, proteomics and RNA-seq data were integrated using block sparse partial least squares discriminant analysis (sPLS-DA) to identify correlated biomarkers that discriminate HFrEF from noHF hearts. Results: The targeted metabolomics platform primarily assayed metabolic fuel substrate pathways; 71 analytes (51%) were associated with HFrEF after controlling the false discovery rate (FDR) at 5%. Medium- and long-chain acylcarnitines (C10s-C18s) were significantly lower in tissue from failing hearts, while branched-chain amino acids (BCAA) and ketoacids were higher. In the nontargeted set, 293 metabolites (36%) differed between HFrEF and noHF. BCAA and acylcarnitine associations were recapitulated along with a decrease in malonylcarnitine. The sPLS-DA model selected 25 targeted and 50 nontargeted metabolites, 35 proteins and 35 transcripts, and successfully discriminated HFrEF from no HF (balanced error rate = 3.2%). 39/186 tested KEGG pathways were overrepresented in these analytes, including fatty acid metabolism (FDR q=0.002). Conclusions: Analysis of tissue-level metabolites suggests both decreased use of fatty acids as a fuel and disrupted enzymatic breakdown of BCAAs in the failing heart, while integrative omics pathway analysis also supports the association of disrupted fatty acid metabolism with HF.
Abstract 211: Targeting the Mitochondrial Fission Protein Dynamin Related Protein 1 to Mitigate Oxygen Toxicity Following Cardiac Arrest
Authors: Lin Piao, Yong-hu Fang, Rongxue Rosie Wu, Robert Hamanaka, Gokhan Mutlu, Alfredo J Garcia, Stephen L Archer, Willard Sharp
Journal: Circulation (2023)

Introduction: Oxygen administration following cardiac arrest (CA) is associated with cardiac dysfunction, brain injury, and poor survival. These injuries are driven in part by mitochondrial injury, but the specific mechanisms underlying oxygen-induced mitochondrial injury are unclear. Here we hypothesized that oxygen-mediated injury following CA is influenced by the mitochondrial fission protein Dynamin Related Protein 1 (Drp1) and that targeting Drp1 could mitigate the effects of post-CA oxygen toxicity. Methods and Results: Mice underwent brief asystole CA (12 min) followed by cardiopulmonary resuscitation (CPR). One hour following successful CPR, mice were randomized to receive hyperoxia (33% O 2 ), normoxia (21% O 2 ), or hypoxia (10% O 2 ) in an environmental chamber for 6 hours. After exposure, the mice were returned to room air. Hyperoxia and normoxia groups exhibited lower 10-day survival rate compared to mice exposed to hypoxia (15% and 67% vs. 92%, n=13/group, P&lt;0.05, respectively). The hyperoxia group also showed decreased myocardial fractional shortening (30.1±3.0% vs 45.0±1.4%) and neurological scores (5.8±0.8 vs 9.8±0.3) 48 hours post CA compared to the hypoxia group (n=13, P&lt;0.05, respectively). Hyperoxia increased the expression of the activated form of Drp1 (Drp1-S616) to 134% in the heart (n=4, P&lt;0.05) and decreased cardiomyocyte mitochondrial size to 75% (n=30, P&lt;0.05) compared to hypoxia-treated CA mice. The hypoxia-dependent decrease in Drp1 activity was associated with a 46% increase in myocardial mitochondrial respiration (n=5, P&lt;0.01) and a 32% reduction in ROS production vs hyperoxia-treated CA mice (n=6, P&lt;0.05). Administration of the Drp1 GTPase inhibitor Drpitor1a to hyperoxia-exposed post-CA mice increased survival (40% vs 20%), myocardial function (31.5±4.4% vs 42.0±1.3%) and neurological scores (4.1±0.7 vs 9.0±0.0) compared to untreated hyperoxia-exposed post-CA mice (n=10, P&lt;0.05, respectively). Conclusions: Oxygen dependent post-CA injury is partly dependent on the mitochondrial fission factor Drp1. Targeting Drp1 is a promising strategy to limit post-CA oxygen toxicity.
Abstract 17639: Association of Retinal Microvascular Changes With Incidence and Progression of Coronary Artery Calcium Score in Individuals With vs Without Diabetes Mellitus; Data From the Multi-Ethnic Study of Atherosclerosis
Authors: bahram khazai, Fatemeh Adabifirouzjaei, Mengye Guo, Eli Ipp, Ronald Klein, Barbara Klein, Mary Frances Cotch, Tien Y Wong, Ronald Swerdloff, Christina Wang, Prasanth Surampudi, Joel D Kaufman, Claire Park, Robert C. C Hendel, Matthew J Budoff
Journal: Circulation (2023)

Introduction: Retinopathy (RP) is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. Microvascular disease may play a prominent role in coronary heart disease (CHD) development. We performed this study to evaluate the association of grades of RP with incidence of CAC (Coronary Artery Calcium) among those with zero CAC at baseline. Hypothesis: We performed this study to evaluate the association of grades of RP with incidence of CAC among those with zero CAC at baseline and to Identify the association of grades of MA and RP with progression of CAC among those with positive CAC at baseline. Methods: We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis (MESA), who had retinal photos and CAC score available. We analyzed the association of grades of RP with incidence and progression of CAC among subjects with and without DM with zero CAC and positive CAC at baseline from robust regression models. The grades of RP were defined as: no retinopathy, minimal non-proliferative R (NPR) (level 14 -20), early to moderate NPR (level 31-41) and severe NPR or proliferative RP (level 51-80). Results: Among those with zero CAC, in the diabetic group, early to moderate (95% CI [1.2, 2]) and severe (95% CI [1.3, 3]) NPR had significantly higher incident CAC risk than the non-retinopathy group. Among those with positive CAC at baseline, in the diabetic group, the early to moderate NPR group had higher CAC progression than the non-retinopathy group. (95% CI [-146, 228]). In the non-diabetic group, the minimal NPR group had significantly higher CAC progression than the non-retinopathy group (95% CI [1.8, 52.7]). Conclusions: In conclusion, after adjustment for major CHD risk factors, RP with any severity was associated with incident CAC in DM individuals, however only early to moderate NPDR was associated with CAC progression in them.
Abstract 13189: Early Evolution of SCAI-Shock Stage and In-Hospital Mortality in a CICU Population From the Critical Care Cardiology Trials Network-CCCTN
Authors: Stephanie Skove, David Berg, Jianping Guo, Jason N Katz, Sean Van Diepen, David Morrow, Kevin S Shah
Journal: Circulation (2023)

Introduction: The SCAI shock staging system is a useful tool for categorizing cardiogenic shock (CS) severity. Presenting SCAI shock stage is known to be associated with in-hospital mortality. However, few studies have evaluated the prognostic significance of very early evolution in SCAI stage. Methods: The Critical Care Cardiology Trials Network (CCCTN) is a multicenter network of tertiary CICUs in the US and Canada coordinated by the TIMI Study Group (Boston, MA). Among consecutive CICU admissions with CS, we captured clinician assigned SCAI shock stage at 0-6 hours and 6-12 hours post-CICU admission. Cases were classified as having an improved (e.g., D to C), stable, or worsened SCAI stage between these time periods. The association between change in SCAI stage and in-hospital mortality was evaluated using logistic regression, adjusting for age and 0-6 hour SCAI stage. Results: Among 793 CS admissions between 10/2021 to 09/2022, 73% had a stable SCAI stage, 13% had an early worsening SCAI stage, and 14% had an improving SCAI stage during the initial 12 hours of CICU admission. Compared to cases with stable SCAI stage, cases with worsened SCAI stage had greater use of renal replacement therapy and mechanical circulatory support (Fig 1A) and a longer hospital stay (median 27.5 [IQR 13.6-36.7] vs. 14.7 [8.6-24.9] days, p=0.006). In-hospital mortality among cases with a worsened SCAI stage was 61%, compared to 31% with stable and 26% with improved SCAI stage (Fig 1B). Classification by both initial and 12h SCAI stage revealed a gradient of mortality risk (Fig 1C). Compared to cases with stable SCAI stage, those with worsened SCAI stage had higher adjusted risk of in-hospital mortality (OR: 5.1[95% CI 3.1-8.3]). Conclusion: Patients with early worsening of SCAI stage have a markedly higher risk of in-hospital mortality than those with a stable SCAI stage. The prognostic implication of early evolution in SCAI stage in patients with CS adds to that of SCAI stage on CICU presentation.
Abstract 14207: Mobile ECG Atrial Fibrillation Prediction Enhancement Powered by Standard ECG Algorithm With Artificial Intelligence
Authors: Kihong Lee
Journal: Circulation (2023)

Introduction: Artificial intelligence (AI) using electrocardiogram (ECG) enabled to predict atrial fibrillation (AF) in patients without documented AF. It needs 12-lead ECG with tremendous data learning. Mobile 1-lead ECG is more convenient to surveil cardiac rhythm with simple measurement. However, AI-enabled arrhythmia predictability by mobile ECG is limited due to single channel utilization and longer duration for arrhythmia diagnosis. Hypothesis: We aimed to enhance mobile ECG AF prediction AI algorithm integrated with 12-lead ECG deep learning model. Methods: Based on 552,372 12-lead ECG data of 318,321 patients, a statistical AF prediction model employing a deep-learning approach was constituted. The raw data of 6,792 1-lead mobile ECGs were acquired from 6,792 patients for about 1 minute at 250Hz. A statistical AF prediction model with mobile ECG employing a deep-learning approach was constituted. Resnet structure was utilized to distinguish subtle changes of the vicinity of P-wave. Both 12-lead ECG and mobile ECG were allocated to training, validation, testing datasets in a 6:2:2 ratio. Then, we conducted transfer learning using the standard 12-lead ECG’s deep learning model to improve performance of 1-lead mobile ECG deep learning model. Results: AF was annotated in 26,541 (4.8%) with 12-lead ECG whereas 1,443 (21.2%) with 1-lead mobile ECG. The area under the curve (AUC) value for predicting AF was 0.910 with 12-lead ECG, and 0.721 with mobile ECG . The predictive performance of mobile ECG was 79.7% in accuracy, 47.5% in sensitivity and 50.3% in F1-score. The AUC value of mobile ECG after applying transfer learning based on 12-lead ECG for AF prediction was increased to 0.905 with accuracy of 89.1%, sensitivity of 71.3% and F1-score of 57.7%. Conclusions: Integration with deep learning algorithm of standard 12-lead ECG significantly improved the model performance of mobile ECG AF prediction model compared to 1-lead mobile ECG only based model. Easy application of mobile ECG with enhanced AF predictability might serve a more convenient method as a pre-emptive assistive tool to provide probabilistic prediction for PAF screening rather than 12-lead ECG.
Abstract 18414: Risk of Stroke After Atrial Fibrillation Ablation in Patients Without Pre-Ablation Left Atrial Appendage Evaluation
Authors: Kevin Lee, Iva Minga, Allyson Varley, Christopher Thorne, Jose Osorio, Matthew J Singleton, Joshua Silverstein, Mark Metzl
Journal: Circulation (2023)

Introduction: Currently, transesophageal echocardiography (TEE), intracardiac echocardiography (ICE), or CT angiography (CTA) are often though not always performed to assess the left atrial appendage (LAA) prior to ablation to reduce the risk of stroke. We seek to evaluate in a large, real-world registry if rates of stroke are similar in patients who do not have this evaluation and are on at least three weeks of anticoagulation prior to ablation. Methods: The REAL-AF registry is a multicenter prospective registry that is enrolling patients undergoing AF ablation at high-volume centers. Data from a total of 2704 patients (mean age 66 ± 11 years, 42% female) receiving index ablation for paroxysmal and persistent AF were obtained and included in the analysis. The patients who suffered strokes within 12 months of ablation were analyzed. Results: A total of 1522 (56%) patients received TEE, 1143 (42%) received ICE, 153 (6%) received both TEE and ICE, 95 (4%) received CTA, and 97 (4%) did not received any evaluation for LAA clots pre-ablation. CHA 2 DS 2 VASc was significantly higher in the not screened group compared to the screened group ((3.18 [2.84 - 3.51]) vs 2.65 [2.59 - 2.71], p &lt; 0.01). Three patients (0.1%) suffered strokes after ablation, two who had been screened by ICE, and one who had not been screened. No patients who were screened by TEE or CTA suffered strokes. All three patients with strokes were on therapeutic oral anticoagulation prior to ablation. The two patients screened with ICE had a CHA2DS2VASC of 2 and 7, while the patient without screening had a score of 6. Patients who were not screened had a statistically significant higher likelihood of having a stroke compared to those who received LAA screening with TEE, ICE, or CTA (OR = 13.2 [1.2 - 147], p = 0.04). Conclusion: While absolute rates of stroke after AF ablation are low, in our cohort occurring in only 0.1% of patients, there was a statistically significantly higher odds of developing stroke in patients who did not have their LAA screened prior to ablation.
Abstract 14241: Alcohol Exposure Among Patients With Dilated Cardiomyopathy: A Report From the DCM Precision Medicine Study
Authors: Javier Jimenez, Hanyu Ni, Jinwen Cao, Daniel Kinnamon, Elizabeth Jordan, Muni Rubens, Sandra Chaparro, Anshul Saxena, Ray E Hershberger
Journal: Circulation (2023)

Introduction: Alcohol-related cardiomyopathy is characterized by cardiac dysfunction and dilatation due to prolonged and excessive alcohol (ETOH) consumption. This study aims to determine the prevalence, use patterns and genetic associations of ETOH exposure in patient with dilated cardiomyopathy (DCM) and their first-degree relatives (FDR). Hypothesis: 1. There is increased prevalence of EOTH use among patients who develop DCM. 2. Non-genetic co-morbidities are more common in patients who use ETOH and developed DCM. 3. Probands and FDR who use ETOH and develop DCM are more likely to have genetic variants. Methods: We analyzed clinical and genetic data on individuals aged 18 and older enrolled in the US DCM Precision Medicine Study. Partial and full DCM phenotypic expression were included in the analysis. The AUDIT-C score was used to evaluate the intensity of ETOH use. ETOH use and presence of DCM-related rare genetic variants were examined in FDRs using GEE type logistic mixed models adjusted for intra-family correlation and site heterogeneity. Results: A total of 2,595 subjects (1,188 probands and 1,407 FDRs) were included. Prior and current ETOH users were 270 (23%) and 546 (46%) for probands, and 30 (10%) and 168 (54%) for FDRs with DCM/partial DCM. Avg. years of drinking were 25.2 for probands and 24.0 for FDRs with DCM/partial DCM; the percent with AUDIT-C positive scores were 31.5 for probands and 32.7 for FDRs with DCM/partial DCM. In probands, moderate or high/severe ETOH use was more likely to be in men, white, Hispanic and those with &lt;/=12 yrs. of education (p&amp;lt;0.001). Patients drinking heavily were more likely to have hypertension, diabetes, hypercholesterolemia, and history of arrhythmia/conduction disease. Among FDRs, DCM/partial DCM was associated with the presence of DCM-related variants but not with moderate-severe drinking years in quartile after controlling for demographics and comorbidities. ETOH use did not modify the genetic effect on DCM/partial DCM. Conclusions: There is a high prevalence of prior or current ETOH use among probands and FDRs with DCM/partial DCM with an average ETOH use between 24-25 yrs. ETOH use was not found to associate with DCM or to modify the association between the presence of genetic variants and development of DCM.
Abstract 15451: Regulations of Nrf2 by Nf-κB in Ischemic Heart Failure
Authors: Evelyn Navar, Phung Thai, Daphne Diloretto, Padmini Sirish, Xiao-Dong Zhang, Nipavan Chiamvimonvat, Anne A Knowlton
Journal: Circulation (2023)

Introduction: Oxidative stress is an important pathophysiological factor in the development and progression of ischemic heart failure (IHF). Nuclear factor E2-related factor 2 (Nrf2) is a major regulator of the protective antioxidant response and has been found to decrease by 50% in IHF. However, the mechanism of Nrf2 downregulation remains incompletely understood. NF-kB is a critical transcription factor that influences many cellular processes and is activated in IHF with increased reactive oxygen species (ROS). We hypothesize that activation of NF-kB may underlie the decreased Nrf2 activity in IHF. Methods and Results: To induce IHF, we performed left anterior descending coronary artery (LAD) ligation surgery in Sprague Dawley rats and FVB/NJ mice. We found a significant reduction in cardiac function after LAD surgery in ischemia/reperfusion (I/R) mice relative to sham-operated mice using echocardiography. Tissue sample analyses reveal a crucial role of NF-kB activation in the regulation of Nrf2 in IHF. Additionally, after 2 weeks of I/R, we found that rats treated with Nrf2 overexpressed lentivirus demonstrated greater pressure development than rats with vehicle treatment. Using rat cardiac myoblast cells (H9C2) and western blot analysis, we tested the expression of cytosolic and nuclear Nrf2 and p65 (a component of NF-kB) following time- and dose-dependent treatments of H2O2. We found that p65 activation inhibited Nrf2 activity, while inhibitions of p65 nuclear translocation prevented the decrease in Nrf2 nuclear activities. We then generated a knockout of p65 in H9C2 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using CRISPR-Cas9 technology to test NF-κB regulation on the Nrf2 activities, which further strengthened our previous findings. Conclusions: Taken together, our data support the critical role of NF-kB activation in the regulation of Nrf2 in IHF, providing new insights into possible molecular targets for the treatment of IHF through the regulation of the protective antioxidant response.
Abstract 255: Independent Association of Interleukin 6 With Neuronal Injury Depend on Cardiac Arrest Severity in the Patients With Post Resuscitation Care
Authors: Dong Young Lee, Jung Soo Park, Yeonho You, Changshin Kang, Jinhong Min, Yong Nam In, So Young Jeon
Journal: Circulation (2023)

Aim: A recent trial did not demonstrate a significant relationship between interleukin 6 (IL-6) and neuronal injury, such as neuron-specific enolase (NSE). However, it is a well-understood concept throughout medicine that treatment effects depend on injury or disease severity. We hypothesize that IL-6 is independently associated with NSE according to cardiac arrest severity. Thus, this study aimed to investigate the relationship of IL-6 with NSE during post-resuscitation care according to cardiac arrest severity. Methods: This retrospective study included patients who underwent post-resuscitation care. IL-6 and NSE were measured at 0, 24, 48, and 72 h immediately after applying the temperature control device. We divided the cohort into three groups of low, moderate, and severe severity based on the “Revised Post-Cardiac Arrest Syndrome for Therapeutic Hypothermia” scoring system. Stepwise linear regression was performed to analyze the correlation of the entire IL-6 measured at all times with the inflammatory, myocardial injury, and neuronal injury markers to account for other covariables. Results: Of the 111 enrolled patients, 22, 59, and 28 were in low, moderate, and severe severity groups, respectively. Median IL-6 and NSE were significantly different between groups (IL-6, 145.2 pg/mL vs. 949.7 pg/mL vs. 1100.7 pg/mL, p = 0.001; NSE, 24.4 ng/mL vs. 48.7 ng/mL vs. 63.2 ng/mL, p = 0.001). Stepwise linear regression analysis revealed that the IL-6 did not significantly correlate with other markers in low severity groups (F = 2.38, p = 0.13); however, in the severe severity group, IL-6 was independently correlated with NSE in severe severity groups (β = 8.16, p = 0.001). Conclusion: IL-6 level was associated with cardiac arrest severity. IL-6 was independently correlated with NSE in the severe severity group but not in low to moderate severity groups. Therefore, the correlation between IL-6 and neuronal injury markers may be dependent on the cardiac arrest severity.
Abstract 18443: Early Inflammation in βII-Spectrin Deficient Hearts Promote Cardiac Remodeling and Heart Failure
Authors: Shane S Scott, Anna Matzko, Ashley Greenlee, Ethan Schwendeman, Sakima A Smith
Journal: Circulation (2023)

Background: Dysregulation of cardiac cytoskeletal proteins such as βII-spectrin has been recognized to promote accelerated heart failure (HF) and arrhythmias in human and mouse models. However, the mechanism by which βII-spectrin dysregulation underlies HF is poorly understood. Hypothesis: We hypothesized that cardiomyocyte loss of βII-spectrin leads to recruitment of inflammatory macrophages that augment cardiac remodeling by promoting arrhythmogenesis and increased susceptibility to HF. Methods: Cardiomyocyte-specific βII-spectrin knockout (βII-cKO) and control mice (βII-flox) were generated and harvested for RNA-sequencing (RNA-seq), qRT-PCR (to validate candidate inflammatory genes), immunohistochemistry, immunoblotting, and flow cytometry. siRNA was also used to knockdown βII-spectrin in cultured cells to validate that direct loss of βII-spectrin contributes to immune cell recruitment. Transaortic constriction (TAC) was used to induce pressure overload. Results: RNA-seq demonstrated an early significant increase of inflammatory macrophages and T cell markers following βII-spectrin loss. Consistent with RNA-seq and qRT-PCR results, immunohistochemistry demonstrated an increase in CD45 positive cells in juvenile βII-cKO mouse hearts compared to control. siRNA targeted depletion of βII-spectrin in cultured cardiomyocyte led to increased expression and secretion of TGFβ-1 protein, which can promote infiltrating of immune cells. Notably, accelerated HF at two weeks was observed in βII-cKO mice compared to controls after TAC. Conclusions: These data suggest that βII-spectrin loss may mediate inflammation via the TGFβ-1 pathway, which in part contributes to βII-spectrin-mediated accelerated HF. Furthermore, these are the first data implicating βII-spectrin in the TGFβ1-immune signaling pathway in cardiomyocytes.