tbuckley/cabot-search huggingface dataset:
Abstract 4142589: GLP-1 receptor agonists slow the progression of subclinical cardiovascular risk as detected from 12-lead electrocardiograms
Authors: Lena Kaisinger, Thore Buergel, Jakob Steinfeldt
Journal: Circulation (2024)

Background: GLP-1 receptor agonists (GLP1RA) agonists have been shown to reduce cardiovascular events in patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). However, it is unclear whether early subclinical therapeutic changes can be detected from routine 12-lead electrocardiograms (ECGs). Methods: We finetuned a neural network (NN) from Pheiron’s phenotyping platform to predict subclinical risk markers from 12-lead ECGs using data from Dandelion Health, comprised of longitudinal, multimodal real-world clinical data for 106,289 patients receiving care from Sharp Healthcare in the US. Based on the finetuned NN, we predicted risk markers within an independent cohort of 48,376 patients with a history of T2D, ASCVD, or obesity and emulated a target trial to evaluate the subclinical effect of GLP1RA. The primary analysis compared percentile rank transformed ECG markers for GLP1RA and non-GLP1RA patients using inverse probability weighted (IPW) linear regression models, adjusted for key variables including demographics, comorbidities, medications, HbA1c, and BMI at baseline. Sensitivity analyses included unadjusted models, models with only covariate adjustments, and propensity score-matched models. Results: The emulated trial study cohort was, on average, 59.6 [SD 15.9] years old, predominantly female (56%), and racially diverse: 46.6% White, 25.3% Hispanic, 9.6% Asian, and 4.6% Black. Compared to the control group, the GLP1RA cohort had a higher baseline risk profile (BMI: 35.1 [SD 7.6] vs. 31.0 [SD 6.0], HbA1c: 7.1 % [SD 1.8] vs. 5.8 % [SD 0.9]) but cardiovascular risk progressed slower during the observation time: Each year of GLP1RA treatment was linked to percentile risk reductions of -1.65 (p&lt;0.001) for all-cause mortality, -1.74 (p&lt;0.001) for myocardial infarction, and -1.74 (p&lt;0.001) for stroke. These findings were directionally consistent across all sensitivity analyses. Conclusions: Our findings suggest treatment with GLP1RA slows the progression of subclinical cardiovascular risk, as detected from routine 12-lead ECGs. This illustrates the potential of ECG-based monitoring to guide therapeutic interventions and establish treatment efficacy.
Abstract 4142574: Impaired Autophagy Augments Necroptosis Signaling in the Diabetic Kidney Following Ischemia/Reperfusion.
Authors: REO TAKAHASHI, Yukika Saga, Ryusuke Hosoda, Yuki Tatekoshi, Atsushi Kuno
Journal: Circulation (2024)

Background: Diabetes mellitus (DM) elevates the risk of acute kidney injury (AKI); however, the underlying mechanisms are not fully elucidated. Necroptosis, a form of regulated cell death mediated through activation of RIPK1/RIPK3/MLKL signaling, contributes to the development of AKI. We previously reported that suppression of autophagy after renal ischemia/reperfusion (I/R) underlies the aggravation of AKI in type 2 DM. Hypothesis: Impaired autophagy amplifies necroptosis signaling in the diabetic kidney following I/R. Methods: AKI was induced by unilateral nephrectomy and 30-min renal artery occlusion/24-hour reperfusion in the contralateral kidney in OLETF, obese type 2 DM rats, and its non-diabetic control LETO. To inhibit autophagy in LETO, chloroquine (CQ, 10 mg/kg/day) was subcutaneously administered from 7 days before I/R. Rapamycin was injected to OLETF 30-min prior to ischemia to restore autophagic activity in the kidney. Renal tissues sampled before and after I/R were analyzed. Results: The serum creatinine (sCr) levels after I/R were higher in OLETF than in LETO (3.8±0.3 vs. 1.9±0.4 mg/dl, P&lt;0.05). CQ treatment elevated sCr levels in LETO while rapamycin decreased the levels in OLETF. Immunoblot analyses showed that renal protein levels of RIPK1, RIPK3, and MLKL were similar in LETO and OLETF at baseline, but RIPK1 and RIPK3 were increased after I/R in both rats. Notably, the upregulation of RIPK3 after I/R were more pronounced in OLETF than in LETO. Suppression of autophagy by CQ enhanced the increase in RIPK3 levels by I/R in LETO, while restoration of autophagy by rapamycin reduced the RIPK3 levels in OLETF. Immunostaining for RIPK3 revealed that tubular cells were sites of RIPK3 upregulation observed in OLETF and CQ-treated LETO. To determine whether changes in RIPK3 protein levels were regulated at the transcription level, we measured RIPK3 mRNA level. qPCR analysis of renal tissues demonstrated that RIPK3 mRNA levels were increased by I/R in LETO and OLETF, but the upregulation was more pronounced in OLETF than LETO. The upregulation of RIPK3 mRNA after I/R was enhanced by CQ treatment in LETO and was suppressed by rapamycin in OLETF, suggesting that the impairment in autophagy promoted transcription of RIPK3. Conclusion: Compromised autophagy augments RIPK3-mediated necroptosis signaling via the upregulation of RIPK3 transcription in the diabetic kidney following I/R.
Abstract 4142197: Abbreviated Ticagrelor-Based Dual Antiplatelet Therapy in Acute Coronary Syndrome: A Systematic Review and Meta-Analysis
Authors: Wissam Harmouch, Ravi Thakker, Umair Khalid, Wissam Khalife, Neal Kleiman, Umamahesh Rangasetty, Waleed Kayani, Hani Jneid, Bashar Al Hemyari, Ayman Elbadawi
Journal: Circulation (2024)

Introduction: Few randomized clinical trials (RCTs) have evaluated the safety and efficacy of abbreviated Ticagrelor-based dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS); however, these RCTs were underpowered to detect differences in hard clinical outcomes. Research Question: What effect does abbreviated Ticagrelor-based DAPT have on risk of ischemic and bleeding events in ACS? Methods: A systematic search of MEDLINE, Cochrane, and Scopus databases was performed through 05/2024, for trials that compared abbreviated (≤ 3-months) versus standard 12-months Ticagrelor-based DAPT in ACS. The primary endpoint was all-cause mortality. Endpoints were measured at 12-months after DAPT initiation. Data were pooled using random-effects model. Heterogeneity was assessed via Chi-squared and Higgin’s I 2 test. RevMan 5.0 (Cochrane Collaboration, Oxford, United Kingdom) was utilized to perform statistical analysis. Results: Five trials were included in this analysis with 21,407 patients assessed. ULTIMATE-DAPT, T-PASS, and GLOBAL LEADERS-ACS assessed 1-month DAPT duration while TICO and TWILIGHT-ACS assessed 3-months DAPT duration. The average age was 62.7 years and 22.7% were women. Hypertension (61.7%), dyslipidemia (49.9%), diabetes (27.8%), and chronic kidney disease (12.7%) were the most common comorbidities. ACS presentations included NSTEMI (40.1%), unstable angina (35.2%), and STEMI (31.5%). Abbreviated Ticagrelor-based DAPT was associated with lower risk of all-cause mortality (RR 0.78; 95% CI 0.62-0.98, I 2 =0%) compared with standard duration DAPT. There was no differences between groups in cardiovascular death (RR 0.65; 95% CI 0.41-1.03, I 2 =0%), myocardial infarction (RR 1.04; 95% CI 0.85-1.27, I 2 =0%), stent thrombosis (RR 0.97; 95% CI 0.64-1.45, I 2 =0%), or ischemic stroke (RR 0.90; 95% CI 0.62-1.30, I 2 =0%). Abbreviated DAPT duration was associated with lower risk of major bleeding (RR 0.50; 95% CI 0.38-0.66, I 2 =46%). Conclusion: Our analysis includes the totality of randomized data evaluating the merits of abbreviated Ticagrelor-based DAPT after ACS. The salient study finding was the observed reduced risk of all-cause mortality with abbreviated DAPT approach, which was driven by reduced bleeding risk.
Abstract 4142236: Safety and Efficacy of Early Aspirin Versus Aspirin Plus Low Molecular Weight Heparin in Patients with Ischemic Stroke and Immobility: A Multi-National Database Study
Authors: Suhas Nareddy, Kyle Chang, Bryce Hambach, Christiana Prucnal, Elvin Hernandez, Lisa Sovory
Journal: Circulation (2024)

Background: Early aspirin is standard of care after acute ischemic stroke (AIS). There is increased incidence of venous thromboembolism (VTE) in patients with AIS and reduced mobility, but thromboprophylaxis with low molecular weight heparin (LMWH) must be weighed against the risk of bleeding. We compared safety and efficacy of early aspirin with or without LMWH in AIS and reduced mobility. Methods: Patients with AIS and Modified Rankin Scale of 4-5 were identified in the TriNetX Research Database. Patients were categorized as either aspirin alone or aspirin plus LMWH within 72 hours of AIS. We excluded patients receiving any other anticoagulant, thrombolytic agents, or with history of long-term anticoagulation or atrial fibrillation. Bivariable analysis was performed with chi-square and independent t -tests. Cohorts were then 1:1 propensity score-matched by 26 relevant covariables including demographics, comorbidities, and medications. Outcomes were all-cause mortality, VTE, intracranial hemorrhage, and extracranial hemorrhage at 30 and 90 days. Results: We included 2,572 patients in each cohort. Mean age and SD was 71±13, and 48% were male. There was no significant difference in all-cause mortality in patients treated with aspirin alone versus aspirin plus LMWH at 30 days (RR=1.1, 95% CI: 0.91-1.3) or 90 days (RR=1.2, 95% CI: 0.98-1.3). Similarly, the risks of VTE and intracranial or extracranial hemorrhage were not significantly different at either timepoint. Conclusions: In patients with AIS and reduced mobility, the early addition of LMWH to aspirin may have similar risks of bleeding, all-cause mortality, and VTE.
Abstract 4142500: Intrauterine Tobacco Smoke Exposure Affects Cardiac Geometry and Function in Infants
Authors: Kenji Harada, Yukiko Harada, Miho Hatakeyama-Sasaki, Yuichi Nakamoto, Manatomo Toyono
Journal: Circulation (2024)

Background: Environmental tobacco smoke (ETS) exposure is associated with increased risk of cardiovascular events, however, there is little information on when cardiovascular functional changes begin to occur. The purpose of this study is to assess blood pressure and cardiac function in infants exposed to ETS . Methods: A total of 224 infants aged 4 months, 78 infants who have been exposed to tobacco smoking since intrauterine life and 146 controls without ETS exposure, underwent echocardiographic study. Left atrial anteroposterior diameter, left ventricular end-diastolic volume, ejection fraction, mass, and mass-to-volume ratio were measured. Transmitral peak flow velocities during early and late diastole and mitral annular myocardial velocities during early and late diastole were measured. Left atrial systolic force was calculated. Isovolumic relaxation time and tissue Doppler-derived myocardial performance index were assessed. Effective arterial elastance was estimated by end-systolic pressure/stroke volume index. End-systolic elastance was calculated by a modified single-beat method. Results: Body mass index was similar between the 2 groups (p &gt;0.05). Systolic and diastolic blood pressures were significantly higher in ETS-exposed infants with than in controls (112 ± 10 vs. 109 ± 9 and 63 ± 8 vs 60 ± 8 mmHg, respectively, p &lt;0.05). Compared with controls, left atrial size, left ventricular mass, and mitral annular myocardial velocities during late diastole were significantly higher (1.6 ± 0.16 vs. 1.4 ± 0.20 cm, 13.7 ± 3.1 vs. 12.6 ± 2.9 g, and 8.4 ± 2.2 vs. 7.6 ± 2.0 cm/sec, respectively, p &lt; 0.05) in infants exposed to ETS. Ejection fraction, isovolumic relaxation time, myocardial performance index, end-systolic elastance, and effective arterial elastance did not differ between the 2 groups. Conclusions: The present study indicates that tobacco smoke exposure can adversely affect blood pressure, cardiac geometry, and function even in early infancy. Passive smoking may contribute to the increased prevalence of cardiovascular diseases in later life.
Abstract 4142562: Mesenchymal Stromal Cell Delivery through Cardiopulmonary Bypass in Pediatric Cardiac Surgery – MeDCaP Phase I Trial
Authors: Soichiro Henmi, Kumi Kobayashi, David Zurakowski, Steven Staffa, Kenneth Fulton, Anushree Datar, Jay Tanna, Chase McCann, Mark Nuszkowski, Nina Deutsch, Sarah Schlatterer, Mary Donofrio, Fahmida Hoq, Patrick Hanley, Gil Wernovsky, YVES D'UDEKEM, Shriprasad Deshpande, Catherine Bollard, Nobuyuki Ishibashi
Journal: Circulation (2024)

Introduction/Background: Neurodevelopmental impairment is a challenge for many children with complex congenital heart disease who undergo surgical intervention with cardiopulmonary bypass during the early postnatal period. Research Questions/Hypothesis: We hypothesized that bone marrow-derived mesenchymal stromal cell (BM-MSC) delivery through cardiopulmonary bypass (CPB) will improve neurodevelopmental outcome and post-operative course. Goals/Aims: The primary goal of this single-center, dose-escalation phase 1 trial was to assess the safety/feasibility and determine the maximum tolerated dose (MTD) of BM-MSC treatment. Methods/Approach: Inclusion criteria of the phase 1 trial were neonates/infants (ages ≤ 6 months) who underwent scheduled two-ventricle repair without arch reconstruction. Dose escalation was guided by a modified continual reassessment method at four dose levels (1-40x10^6 cells/kg). Dose limiting toxicity was assessed for 45 days after BM-MSC delivery. Secondary endpoints before discharge were compared with a historical cohort (n=222) by inverse probability of treatment weighting (IPTW) using the propensity score to balance the groups. Results/Data: Seventeen patients were enrolled from July 2020 to June 2023 (ventricular septal defect, n=9; tetralogy of Fallot, n=7; transposition of the great arteries, n=1; male, n=10). There were 3 serious adverse events all of which were related to cardiac surgery and not the BM-MSC product (junctional ectopic tachycardia, n=2; diaphragm paresis, n=1). Among 50 total events, there were no adverse events related to BM-MSCs. The BM-MSC dose was successfully escalated to the planned MTD (40x10^6 cells/kg), demonstrating safety and feasibility of this therapeutic delivery strategy. Consistent with results indicating little interference on CPB functions, electron microscopy studies showed no BM-MSC adherence on the CPB filter mesh at the MTD. Multivariable analyses with IPTW identified a reduction of CO2 and lactate levels in MeDCaP cases. We observed differences in white blood cell, monocyte, and platelet numbers between the two groups, suggesting possible interaction between endogenous blood cells and applied BM-MSCs. Conclusions: We confirmed the safety and feasibility of BM-MSC treatment during CPB at the proposed MTD level. Successful design and completion of a future phase 2 trial is needed to determine efficacy.
Abstract 4142502: Stepwise Screening with AI-Enhanced Electrocardiogram and Point-of-Care Ultrasound Improves Cost Savings of Structural Heart Disease Detection Compared to AI-Enhanced Electrocardiogram Alone
Authors: Reid Schlesinger, Francisco Alexandrino, Jared Bird, Garvan Kane, Abhishek Deshmukh, Patricia Pellikka, Jae Oh, Peter Noseworthy, Francisco Lopez-Jimenez, Paul Friedman, Sorin Pislaru, Gal Tsaban
Journal: Circulation (2024)

Background: AI-ECG is a cost-effective tool for left ventricular dysfunction (LVD) screening. However, its cost-effectiveness for other forms of structural heart disease (SHD) is unknown. While AI-ECG is inexpensive, a drawback is low positive predictive value (PPV), which leads to high costs from unnecessary follow-up tests. Therefore, strategies to improve the yield of AI-ECG-based screening are needed. Aim: To evaluate the cost savings of a stepwise approach to SHD screening with AI-ECG followed by POCUS compared to AI-ECG alone. Methods: 286 adult outpatients undergoing AI-ECG were selected at random. Participants received same-day POCUS and had a recent TTE (our gold standard for SHD). We evaluated four SHDs: aortic stenosis (AS), cardiac amyloidosis (CA), HCM, and LVD. The costs of AI-ECG ($75) and TTE ($1,305) were obtained from Healthcare Bluebook. The cost of POCUS ($100) was estimated independently. Cost savings were analyzed for simultaneous screening for all forms of SHD and screening for individual SHDs. Results: AI-ECG identified potential SHD in 125 patients, but only 39 were true positives by TTE (31% PPV). In AI-ECG positive patients, POCUS demonstrated findings of SHD in 52/125. Compared to TTE, this stepwise approach yielded 32 true positives and 20 false positives (62% PPV). The cost per patient diagnosed with SHD was $4,733 with AI-ECG alone but decreased to $3,182 with stepwise screening (33% cost savings). Screening for individual SHDs resulted in cost reduction from $18,724 to $6,315 (66% savings) for AS, $21,023 to $12,230 (42% savings) for CA, $9,883 to $6,175 (38% savings) for HCM, and $4,019 to $3,582 (11% savings) for LVD. Conclusions: Stepwise screening for SHD with AI-ECG followed by POCUS significantly reduces costs compared to AI-ECG alone. We also suggest a model for parallel screening for multiple SHDs, which is likely more cost-effective than screening for individual SHDs.
Abstract 4142226: Quantifying the influence of baseline body weight on sex differences in semaglutide-associated weight loss
Authors: Matthew Levy, Natalie Telis, Lisa McEwen, Kelly Schiabor Barrett, Alexandre Bolze, Simon White, Douglas Stoller, Christopher Chapman, C. Anwar Chahal, Daniel Judge, Douglas Olson, Joseph Grzymski, Nicole Washington, Elizabeth Cirulli
Journal: Circulation (2024)

Background: Males tend to lose less weight than females with semaglutide, a GLP-1 receptor agonist, for unknown reasons. One hypothesis is that lower average body weight in females may result in greater drug exposure, leading to more weight loss. Objective: Leveraging a multi-state network of clinico-genomic cohorts, we aimed to quantify the extent to which sex differences in baseline body weight could explain semaglutide-associated weight loss differences between males and females. Methods: We utilized electronic health record data and clinical-grade sequencing from multiple U.S. cohorts (n&gt;100k). Among individuals starting semaglutide with BMI ≥27 kg/m 2 (consistent with guidelines), we analyzed weight measurements over a 12-month use period. A BMI polygenic score (PGS) using 27k variants (PGS001228) was calculated. Percent weight change was modeled using mixed effects models with quadratic and cubic terms for time and interaction terms with baseline weight, sex, and confounders (semaglutide dose, age, ancestry, BMI PGS, comorbidities, medications). We also conducted a mediation analysis to test whether baseline weight mediated the relationship between sex and weight loss. Results: Among 959 females and 352 males, 7,381 weight measurements occurred over a median of 8.9 months (IQR: 6.2-10.8). Median baseline weight was 102 kg (IQR: 90-119) for females and 114 kg (IQR: 100-133) for males. Median weight loss at 6- and 12-months was 5.2% (IQR: 1.9-9.1) and 6.5% (IQR: 2.0-11.8) for females and 3.3% (IQR: 1.0-6.5) and 4.5% (IQR: 1.3-7.7) for males. After adjustment, male sex was associated with a lower rate of weight loss (β=+0.95% [per 6 months], p=0.003). Other factors associated with lower weight loss were BMI PGS (β=+1.28% [top vs bottom quintile], p=0.002), type 2 diabetes (β=+0.88%, p=0.006), hypertension (β=+0.72%, p=0.025), obstructive sleep apnea (β=+0.65%, p=0.032), and insulin use (β=+0.76%, p=0.035). In the mediation analysis, the proportion of the sex-weight loss association that could be explained by baseline weight was 8.4% (95% CI: 2.9-20.6) and 16.0% (95% CI: 10.7-26.2) at 6- and 12-months. Conclusions: Baseline body weight explained only a small fraction of the observed sex difference in semaglutide-associated weight loss, suggesting that other factors (e.g., hormonal) may play a more significant role. Findings also highlight the impact of traditional metabolic risk factors and BMI-associated genetic variants on weight loss with semaglutide.
Abstract 4142424: The impact of the stress hyperglycemia ratio on adverse prognosis in patients with chronic thromboembolic pulmonary hypertension
Authors: Yijia Wang, Li Xin, Zhihua Huang, Anqi Duan, sicheng zhang, Luyang Gao, Sicong Li, Zhihui Zhao, qing zhao, Qin Luo, Zhihong Liu
Journal: Circulation (2024)

Background: Risk assessment for chronic thromboembolic pulmonary hypertension (CTEPH) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress. Meanwhile, stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. However, the relationship between SHR and adverse prognosis is uncertain. This study aimed to investigate the prognostic value of SHR in CTEPH patients. Methods: A total of 451 CTEPH patients with available baseline SHR measurement were enrolled between February 2014 to July 2023 at Fuwai hospital. The predictive values of SHR for adverse events were assessed. Results: During a median follow-up of 21 months, 89 (19.7%) CTEPH patients experienced adverse clinical outcomes. Kaplan-Meier curve analysis revealed that the cumulative adverse event rates were significant higher in the SHR≥0.747 with CTEPH patients, compared with patients in the SHR&lt;0.747. The multivariable analysis revealed that high level of SHR, whether as a continuous variable or categorical variable, were independent risk factor for adverse events after adjusting various confounding factors. Restricted cubic spline also revealed a correlation between SHR and the risk of adverse events after adjusted clinical risk factors ( p value for non-linearity=0.871). Furthermore, when incorporating SHR into the baseline risk model, a significant improvement in the predictive ability for adverse prognosis was noted in CTEPH patients, as evidenced by the C-statistic rising from 0.690 to 0.711 ( p value=0.037). Significant enhancements in continuous net reclassification improvement, and integrated discrimination improvement were also observed as a result of incorporating the SHR into the baseline risk model ( p value &lt;0.05). Conclusions: The high level of SHR was independently associated with long-term adverse prognosis risk in CTEPH patients. The integration of SHR into the baseline risk model may have improved the accuracy in predicting the risk of adverse prognosis. Our findings support the utility of SHR as a reliable indicator for clinical outcome risk stratification of CTEPH patients in the real world. Further research is needed to explore whether interventions targeting SHR can improve the clinical outcomes for patients with CTEPH.