tbuckley/cabot-search huggingface dataset:
Abstract 4125887: Aladyn Individual: Dynamic Individual Comorbidity Modeling for Genomic Discovery and Clinical Prediction
Authors: Sarah Urbut, Yi Ding, Kodi Taraszka, Ming Wai Yeung, Aniruddh Patel, Whitney Hornsby, Rui Duan, Alexander Gusev, Giovanni Parmigiani, Pradeep Natarajan
Journal: Circulation (2024)

Intro: Considering comorbidity patterns for both discovery and prediction of individual disease trajectories is essential for personalized medicine. Existing methods often lack genetic integration and interpretability. We develop an approach suited for dynamic environments that combines genetics with individual and population level-trajectories for enhanced discovery and prediction. Method: Our method employs a dynamic Bayesian hierarchical latent allocation framework to learn and predict disease trajectories. Leveraging longitudinal electronic health care data from 485,698 UK Biobank participants and 287,012 All of Us Research Program participants, we aim to learn individual and population level disease trajectories for 352 distinct conditions. Genetic risks inform the model in two fundamental ways: First, we introduce a genetic warping parameter that recognizes the tendency of an individual to experience events earlier or later within these profiles while retaining the relative order of progression (1a). Second, we introduce a gaussian process to combine individual and population level trends in comorbidity profile prevalence over time (1b), whose mean is augmented by genetic predilection. Finally, we allow for profile weights to update with each new diagnoses, merging prediction and classification. Results: Our results indicate stark disparities in disease progression; individuals at high genetic risk for myocardial infarction experience events nearly a decade earlier than those at low risk (median age of onset 53.7 [53.1-53.9] vs 62.6 years [61.4-63.1]) (1b). Our model dynamically updates and predicts correct diagnoses 79.5% more frequently than existing topic-modeling approaches (1c,d). The dynamic approach adjusts disease profiles by at least 11.7% annually for 50% of individuals, with 65% experiencing over a 10% change in comorbidity profiles. Simulation results confirm the model's superior accuracy [51.4-41%], precision [50.9 vs 39.9%], and recall [48.4 vs 39.2%] compared to fixed-weight approaches. Summary: We offer a novel approach for integrating genetic risk with dynamic modeling of complex disease profiles for joint biologic discovery and personalized clinical prediction over the lifetime.
Abstract 4125893: Deciphering the Mechanism of Action of Drug Combinations by Boolean Modeling of Transcriptomes: a Case Study of Atorvastatin/Simvastatin and Ezetimibe
Authors: Ruisheng Wang, Matteo Pedrelli, Osman Ahmed, Paolo Garagnani, Paolo Parini, Joseph Loscalzo
Journal: Circulation (2024)

Introduction: Drug combinations offer increased therapeutic efficacy and reduced toxicity and plays a vital role in treating chronic complex diseases. Understanding a drug combination's mechanism of action (MoA) can provide important insights into its therapeutic efficacy. The MoA of many FDA-approved drugs, however, often remains unclear. Methods: In this study, we investigated the combination of a statin [atorvastatin (ATO) or simvastatin (SIM) plus ezetimibe (EZE)] and utilized drug-treated RNA-seq transcriptome data from SOAT2-only-HepG2 cells (treated with ATO 5 umol/L, EZE, 25 umol/L, their combination or vehicle) and from liver biopsies of patients with uncomplicated cholesterol gallstone disease in the Stockholm Study (a single-blind, randomized trial with SIM 80 mg daily, EZE 10 mg daily, their combination, or placebo) to decipher the underlying molecular mechanisms of the drug combination. We proposed a Boolean logical modeling framework to simulate the MoA of a drug combination. Specifically, fourteen two-variable Boolean models were used to describe the combinatory relationships of ATO/SIM and EZE. Thereafter, a pattern matching approach was applied to associate drug-induced differentially expressed genes with the idealized differential expression templates derived from Boolean models. Results: We found 1,560 and 594 genes differentially expressed in at least one treatment condition in SOAT2-only-HepG2 cells and liver biopsies, respectively. Our analysis revealed both expected and novel combinatorial modes of ATO/SIM and EZE. For example, ATO independently activates downstream genes (i.e. B 4 (ATO,EZE)=ATO), and ATO and EZE synergistically inhibits downstream genes (i.e. B 15 (ATO,EZE)=NOT (ATO AND EZE)) , as the two most prevalent MoAs in SOAT2-only-HepG2 cells (Figure 1). Similarly, the combination of SIM and EZE synergistically inhibiting downstream genes was also the most prevalent MoA in the liver biopsies. We mapped the downstream genes of each combinatorial mode to the human interactome and obtained underlying subnetworks, which are important for understanding the therapeutic effects of the drug combination. Functional enrichment and disease-association analyses of the downstream suggest the additional therapeutic indications of the drugs. Conclusion: Drug-induced transcriptomes are informative in deciphering the MoA of drug combinations using Boolean logical modeling. This framework can be easily extended to the combinations of three drugs.
Abstract 4125106: Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis; A Meta-Analysis.
Authors: rand sabanci, Moiz Saeed, Adolfo Martinez Salazar, Andrew Kim, Zan Siddiqi, Mohammad Saad Salam, Karuna Rayamajhi, Abela George
Journal: Circulation (2024)

Background: Internationally, drug-coated balloons have emerged as a new treatment approach in In-Stent Restenosis (ISR) offering localized drug delivery to inhibit neointimal growth without the need for additional stent layers. However, their use has not been assessed or approved in the United States. Paclitaxel-coated balloons (PCBs) are gaining traction as alternatives for in-stent restenosis patients. Yet, their safety and effectiveness compared to uncoated balloons remain uncertain. This meta-analysis seeks to systematically assess PCBs' safety and efficacy for ISR treatment by comparing them to uncoated balloons. Research Question: Are paclitaxel-coated balloons (PCBs) superior to uncoated balloons (UCBs) in terms of safety and efficacy for the treatment of coronary in-stent restenosis (ISR)? Aims: Systematically assess the safety and efficacy of paclitaxel-coated balloons (PCBs) compared to uncoated balloons (UCBs) for the treatment of coronary in-stent restenosis (ISR). Methods: A comprehensive literature review was conducted utilizing multiple databases up to May 2024, focusing on randomized controlled trials comparing PCB vs UCB in patients with coronary in-stent restenosis. Six randomized controlled trials with a total of 1,347 patients who completed 1-year follow-up were included. Dichotomous data were calculated as odds ratios (ORs) and 95% confidence intervals (95% CI). P&lt;0.05 was considered to indicate a statistically significant difference. The primary outcomes included Target Lesion Revascularization (TLR), Myocardial Infarction (MI), Stent Thrombosis (ST) and Total Mortality (TM). Results: Compared with patients who underwent UCB angioplasty, those in the PCB group exhibited a clear superiority in TLR [odds ratio (OR), 0.21; 95% CI [ 0.11,0.41]; P&lt;0.00001], and MI [odds ratio (OR), 0.55; 95% CI [0.33,0.91]; P&lt;0.02]. ST was numerically lower in the PCB arm without statistical significance (OR, 0.21; 95% CI [0.03,1.48]; P=0.11). TM was also numerically lower with PCB without reaching statistical significance (OR, 0.60; 95% CI [0.32,1.11]; P=0.10). Conclusion: This meta analysis supports that PCBs are associated with superior outcomes when compared with UCBs in the management of ISR. Paclitaxel-coated balloons are an effective treatment option for patients with coronary in-stent restenosis as demonstrated by superior outcomes in target lesion revascularization and recurrent myocardial infarction.
Abstract 4125334: Disparities In Clinical And Demographic Outcomes Of Non-Acute Myocardial Infarction-Associated Cardiogenic Shock In African American Vs. Non-African American Patients: An Analysis From The National Inpatient Sample Database
Authors: Nismat Javed, Preeti Jadhav, Sridhar Chilimuri, Jonathan Bella
Journal: Circulation (2024)

Background: Limited knowledge exists regarding non-acute myocardial infarction-associated cardiogenic shock (nACS-CS) and its associated outcomes within the African American population. Aim: This investigation aimed to examine the clinical outcomes of nACS-CS in the African American population compared to the non-African-American population in the United States. Methods: The National Inpatient Sample (NIS) database was employed to identify hospitalizations with nACS-CS from 2018 to 2020. Patients were categorized as either African Americans or non-African Americans. Statistical analyses, including Chi-square and t-tests, were conducted using STATA version 18. Results: Out of 8,607 nACS-CS hospitalizations, 1,325 (15.4%) involved African Americans between 2018 and 2020 (Figure 1a). African American patients with nACS-CS tended to be younger (60.9±16.6 vs. 65.8±16.7 years; p &lt; 0.05). Moreover, the length of stay for this cohort was notably longer (16.2±0.75 vs. 14.8±0.32 days; p &lt; 0.05). The demographic age group affected by cardiogenic shock exhibited a decreasing trend as time progressed up to 2020 (p-trend&lt;0.05; Figure 1b). The mean hospital charges were also higher for the African American cohort (p&lt;0.05). In-hospital mortality also showed a progressive increase among African Americans over time (p&lt;0.05). Conclusion: Among African American patients with nACS-CS, there is an escalating burden on healthcare, evidenced by a progressively younger demographic being affected over time, coupled with worsening rates of in-hospital mortality. Furthermore, there is a higher mean cost of hospitalization and a prolonged length of stay compared to their non-African American counterparts.
Abstract 4125719: Efficacy of Prodromal Symptom Assessment in Prognostic Stratification of Acute Myocarditis
Authors: Yoshiki Kawai, Takahiro Jimba, Shun Kohsaka, Yasuhiro Maejima, Takashi Hiruma, Yumiko Hosoya, Taishi Yonetsu, Takeshi Yamamoto, Morimasa Takayama
Journal: Circulation (2024)

Introduction: The outcomes of acute myocarditis are heterogeneous and can lead to clinically significant consequences. However, the patient characteristics associated with adverse outcomes at presentation are not fully understood. Objection: To investigate the association between the presence or absence of prodromal symptoms and in-hospital mortality in patients admitted with acute myocarditis. Methods: We analyzed multicenter data registry (Tokyo CCU Network Database, comprising 76 institutions in the Tokyo metropolitan area). The study included 261 cases with acute myocarditis from January 2017 to December 2020, among which 260 required hospitalization from the emergency department. Patients were grouped based on the presence or absence of prodromal symptoms prior to hospitalization. Prodromal symptoms include the following: (a) chest pain; (b) dyspnea; (c) fever; (d) ful-like symptoms; and (e) others.The primary outcome was in-hospital death. Results: Among the 261 patients with acute myocarditis, 187 patients (71.6%) exhibited prodromal symptoms, and 74 patients (28.3%) did not. The primary outcome occurred in 19 patients (25.6%) without prodromal symptoms and in 20 patients (10.6%) with prodromal symptoms (hazard ratio, 2.87; 95% CI, 1.34 to 6.13; P=0.004, Figure 1A). A multivariable-adjusted Cox regression analysis confirmed that the absence of prodromal symptoms was an independent predictor of poor prognosis, even after adjusting for age, sex and the history of diabetes and hypertension. Notably, this trend was pronounced among patients with Killip classes 2-4, revealing higher in-hospital mortality rate in the patients without prodromal symptoms compared to those with prodromal symptoms (48.6% vs 11.7%; P &lt; 0.001, Figure 1B). Conclusions: This study demonstrates that the absence of prodromal symptoms in patients with acute myocarditis is an independent predictor of poor prognosis, especially for patients presented with Killip classes 2-4.
Abstract 4126333: <i>TRPC6 A404V</i> is a gain-of-function variant associated with doxorubicin-induced cardiotoxicity in patients
Authors: Ying Wu, Xiaojing Sun, Ruxing Wang, Nadine Norton, Hon-Chi Lee, Tong Lu
Journal: Circulation (2024)

Background: Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) channel contribute to heart failure (HF) and focal segmental glomerulosclerosis in humans. Our GWAS results indicated that the TRPC6 A404V variant, having a minor allele frequency of 12% in the population, is associated with doxorubicin-induced cardiotoxicity. However, the underlying ionic mechanisms of this variant have not been fully examined. Methods: Combining patch clamp recording, site-directed mutagenesis, and in-silico analysis, we evaluated the TRPC6 A404V variant function. Results: Whole-cell TRPC6 currents were elicited in HEK293 cells using a voltage ramp protocol from -100 mV to +100 mV with a holding potential of -60 mV, 48 hours after transfection with TRPC6 WT or A404V cDNAs. The inward-current densities at -100 mV and the outward-current densities at +100 mV for TRPC6 WT and A404V variant were similar at baseline. However, after exposure to 50 μM 1-oleoyl acetyl-sn-glycerol (OAG, a TRPC6 activator), these current densities were significantly increased by 2.6-fold and 4.5-fold respectively in the WT (n=20 cells), and by 8.4-fold and 8.9-fold respectively in the A404V variant (n=12 cells, p&lt;0.05 vs. WT). The OAG effects were abolished by superfusion with 1 μM BI-749327 (a specific TRPC6 inhibitor). Moreover, a 24-hour treatment with 0.5 μM doxorubicin (DOX) further amplified the effects of OAG, increasing the total inward- and outward-current densities by 7.2-fold and 9.5-fold respectively in TRPC6 WT (n=11 cells), and by 13.9-fold and 14.7-fold respectively in the A404V variant (n=13 cells, p&lt;0.05 vs. WT). In comparison, the OAG effects on TRPC6 WT and A404V channels were not potentiated by treatment with 0.5 μM doxorubicinol (DOXol, a metabolite of DOX) for 24 h (n=10-12 cells, p=N.S.). Molecular docking studies showed that OAG had a lower binding energy (-5.60 kcal/mol) and a smaller apparent equilibrium constant (Kd) of 0.079 mM with the A404V variant, compared to those of -4.49 kcal/mol and 0.511 mM respectively with TTRPC6 WT. Conclusion: TRPC6 A404V is a gain-of-function variant with a higher binding affinity to OAG. Treatment with DOX but not DOXol greatly enhances TRPC6 WT and A404V channel activation by OAG. Thus, cancer patients carrying the TRPC6 A404V variant may be more vulnerable to develop HF upon treatment with anthracycline.
Abstract 4126895: Bridging the Gap in San Joaquin Valley LGBTQ+ Cardiovascular Disease and Mental Health Disparities
Authors: Maha Siddiqui
Journal: Circulation (2024)

Introduction: LGBTQ+ adults experience discrimination and violence that lead to stressors in daily life. Homophobia affects the mental health of the growing San Joaquin Valley (SJV) LGBTQ+ community leading to psychological distress and mental health concerns which can further lead to High Blood Pressure (HBP) and cardiovascular disease (CVD). SJV has a growing rate of LGBTQ+ migrants from the Bay Area who may be at risk for psychological distress and CVD. With a diverse community of low income and minority groups, the lack of physicians do not represent the workforce of SJV. Objectives: Trainees conducted Kessler psychological distress tests, HBP and CVD screenings across college campuses and community events to reduce the risk of CVD and spread awareness about mental health, CVD and its implications in the LGBTQ+ population due to environmental racism in the most underserved region for health care, SJV. Methods: I trained and provided mentorship to medically ambitious diverse low-income high school to instill a passion in them to come back after their medical education to practice medicine and promote LGBTQ+ health equity in SJV. Students conducted weekly Kessler psychological distress tests, HBP screenings and serve as a health technology coach. Each student monitored 2 hypertensive and psychological distressed patients. Kessler psychological distress tests and CVD screenings were conducted at college campuses to spread awareness about LGBTQ+ mental health and heart health and track psychological distress and HBP in the LGBTQ+ community. Findings: -About 88% (98 of 112) experienced some form of discrimination from a health care professional -About 57% (64 of 112) of SJV LGBTQ+ population are at risk for CVD -About 14% (16 of 112) of SJV LGBTQ+ population are Stage 1 hypertensive -About 76% (83 of 112) of SJV LGBTQ+ population are at risk for hypertension and are psychologically distressed Direct Outcomes: -Youth learned the value of empathy and service to disadvantaged LGBTQ+ communities through the program and volunteering -LGBTQ+ empowerment and students are determined to pursue medicine and address community concerns -Awareness, education among LGBTQ+ community for better heart and mental health -Better understanding in how to manage and seek referral for mental health and health systems concerns -Students learned about SJV health disparities and applied precision medicine to their own health inequity projects in SJV -Improved LGBTQ+ patient provider trust
Abstract 4126731: Cumulative Cardiovascular Health in Young Adulthood and Systemic Target Organ Damage: The Coronary Artery Risk Development In Young Adults (CARDIA) Study
Authors: James Guo, Hongyan Ning, Kiang Liu, John Wilkins, Ankeet Bhatt, Donald Lloyd-Jones
Journal: Circulation (2024)

Introduction: Cardiovascular health (CVH) in young adulthood (YA) is strongly associated with subclinical and clinical outcomes in later life. Longitudinal patterns of CVH exposure through YA (e.g., cumulative CVH exposure) may be particularly important. However, no studies have assessed cumulative CVH in YA and its association with target organ damage (TOD). Methods: CVH was defined using Life’s Essential 8 (LE8) score. CARDIA participants (ppts) with CVH assessed at ≥3 exams over 20 years of follow-up in YA (year [Y]0 to Y20 exams; mean ages 25 to 45 years) were included. Cumulative LE8 scores (cumLE8; higher = better CVH over time) were calculated as the sum of LE8 scores through YA carried forward between exams measured as point*years. Eight markers of TOD (listed in Results) were measured at subsequent exams (Y20 or Y25) including cardiac, renal, pulmonary, and neurologic markers. Associations of cumLE8 with markers of TOD were assessed using partial effects regression models adjusted for race, sex, and maximal education. Results: There were 3,485 ppts (43.4% men, 46.2% Black) with mean cumLE8 score of 1,448.6 (SD 211.4) point*years. Higher cumLE8 in YA was linearly associated with lower measures of cardiac (left ventricular mass index, carotid intima media thickness, prevalence of coronary artery calcium), renal (estimated glomerular filtration rate [eGFR] in men), and neurologic damage (proportion of white matter hyperintensity on brain MRI) ( Figure ). Higher cumLE8 was also linearly associated with better lung function (forced expiratory volume in 1 second, forced vital capacity). Urine albumin-creatinine ratio (in men and women) and eGFR (in women) were non-linearly associated with cumLE8. Conclusions: Our findings underscore the importance of high cumLE8 in YA and its association with reduced onset of TOD later in life. Primordial prevention strategies are needed to achieve and maintain high CVH through the critical period of YA.
Abstract 4126262: The impact of angiotensin receptor neprilysin inhibitors on the elderly population with heart failure and reduced ejection fraction: data from the real world
Authors: jorge Balaguer German, MARCELINO CORTES GARCIA, Carlos Rodriguez Lopez, Jose Maria Romero Otero, Jose Antonio Esteban Chapel, Luis Nieto Roca, Mikel Taibo Urquia, Ana Maria Pello Lazaro, Jose Tunon
Journal: Circulation (2024)

Heart failure (HF) remains a disease of increasing prevalence and morbidity. Validation of new lines of therapy in the elderly are required due to the progressive ageing of the world's population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyse the effect of Angiotensin Receptor–Neprilysin Inhibitors (ARNI) in this subgroup of patients. We conducted a single-centre, real-world observational study. We consecutively enrolled all patients aged ≥75 years diagnosed with HFrEF (defined as an ejection fraction &lt;40%) and theorical indication for treatment with ARNI from November 2019 to January 2021. The main outcomes analysed were all cause mortality and admission due to HF. In order to avoid potential confounding factors, we performed a propensity-score (PS) matched analysis. Patients matching was performed in a 1:1 ratio with the nearest neighbour method. A total of 364 patients were recruited (total population). The mean age was 84.1 years of which 67% were male. 81% were hypertensive and 33.5% diabetic. The main cause of ventricular dysfunction was ischemic with 50.2%. At inclusion 55.8% were in NYHA functional class II and the mean LVEF was 29.8%. After PS matching, we selected 184 patients (study population), 92 with ARNI. As compared with non ARNI group, the ARNI patients showed higher use of mineralocorticoid receptor antagonists (MRA) (59.8% vs 43.5%, p&lt; 0.05) and SGLT2 inhibitors (40.2% vs 6%, p&lt;0.05). Other treatments were otherwise similar in both groups. There were not significant differences in relation with age, etiology or comorbidities between ARNI group and non-ARNI group. During a median follow-up of 39 months, total mortality was 31.5% (58 patients). After a Cox logistic regression analysis, ARNI therapy was shown to be an independent protective variable with respect to total mortality [HR 0.6 (0.4-1), p 0.05]. The figure shows the Kaplan-Meier survival curves for total mortality in patients with and without ARNI treatment. In summary, treatment of HFrEF remains a significant challenge in managing HF patients, especially in the elderly. According to our data, treatment with ARNI in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show us that ARNI therapy could improve prognosis in the elderly with HFrEF in a real-world study.