tbuckley/cabot-search huggingface dataset:
Abstract 4134249: Cardiovascular Risk Factors and Associations of Chronic Inflammatory-Related Disease in the Multi-Ethnic Study of Atherosclerosis
Authors: Evan Manning, Gautam Shroff, David Jacobs, Daniel Duprez
Journal: Circulation (2024)

Background: Inflammation plays a role in the development of cardiovascular disease (CVD). We have defined various non-cardiovascular and non-cancer conditions, both infectious and non-infectious, with a common basis of inflammation; collectively termed Chronic Inflammatory-Related Disease (ChrIRD). We have previously described that ChrIRD is common, associated with baseline inflammatory marker levels, associated with high mortality, and has a bidirectional association with CVD. The clinical implications of these data require further study. Aims: We hypothesize that many traditional risk factors for CVD are also associated with ChrIRD and that ChrIRD has additional unique risk factors. We also hypothesize that the treatment of traditional CVD risk factors is associated with a decreased likelihood of ChrIRD. Methods: We studied MESA participants free of overt CVD or significant illness at baseline. ChrIRD was determined based on review of ICD codes for hospitalizations and deaths. Incident CVD was adjudicated by review of medical records. We performed proportional hazards regression (time-dependent for CVD) to identify factors associated with a first diagnosis of ChrIRD. All variables were simultaneously entered into the model. Results: Participants (n=6155) had mean age 62±10 years and 47% male gender. ChrIRD was observed in 24% and CVD in 18%; including 8% with both conditions. Participants with a diagnosis of CVD, older age, higher heart rate, higher BMI, current or ever smoking status, higher HDL, higher baseline IL6 and GlycA levels, and NSAID use had increased likelihood of ChrIRD. Whereas those with female sex, higher total cholesterol, and statin use had a decreased likelihood of ChrIRD. Participant race/ethnicity, blood pressure, diabetes status, antihypertensive use, aspirin use, baseline CRP level, and baseline D-dimer level were not associated with ChrIRD. Regression results are summarized in Table 1. Conclusions: ChrIRD shares some risk factors with CVD, while other risk factors are opposite. Better understanding of ChrIRD could eventually lead to improved patient care.
Abstract 4137737: Demographics and Factors Influencing Mortality Among Cardiac Angiosarcoma Patients: An Analysis of the SEER Database
Authors: Rozi Khan, Aman Goyal, Agha Wali, Abdul Qahar Khan Yasinzai, Bisma Tareen, Marjan Khan, Hafeez Ullah, Asif Iqbal, Sayed Ab Reshad Ghafouri, Ahmed Mahmood, Amir Sohail, Sethi Pooja, Wael AlJaroudi, Asad Ullah
Journal: Circulation (2024)

Background and Aims: Cardiac angiosarcoma is a rare and highly aggressive cancer originating from the endothelial cells lining the heart. It accounts for approximately 30% of all primary cardiac tumors. Given its aggressive nature and poor prognosis, it is critical to enhance our understanding of its epidemiology and the factors influencing mortality. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to gather data spanning from 2000 to 2021 using the International Classification of Diseases for Oncology (ICD-O-3), anatomical codes (C38.0-Heart), and histological code 9120. Results: We identified 194 patients with cardiac angiosarcoma, of which 102 were males and 92 were females. The majority of patients were aged 50 years or younger (59%). Non-Hispanic whites constituted the largest group (56%), followed by non-Hispanic blacks (18%), and Hispanics (16%). Mortality data showed that 91% of the diagnosed patients died (n=176), with a mean survival period of 15 months after diagnosis. The overall survival rate at 1 year was 0.461 (95% CI: 0.39-0.53), at 3 years was 0.09 (95% CI: 0.05-0.14) and at 5 years was 0.052 (95% CI: 0.03-0.10). Advanced age (51-70 years) compared to the 0-50 year age group (HR: 0.57; 95% CI: 0.003-1.14; p=0.049), distant stage (HR: 0.91; 95% CI: 0.01-1.83; p=0.047), patients who did not receive therapeutic radiation therapy compared to those who did (HR: 2.69; 95% CI: 0.10-5.28; p=0.042), and patients who did not undergo surgical resection for angiosarcoma compared to those who did (HR=1.232; 95% CI: 0.69-1,77; p&lt;0.001) were factors associated with increased mortality. Female gender (p=0.248, as compared to males), different races of non-Hispanic White (p=0.849), non-Hispanic Black (p=0.34), non-Hispanic Asian or Pacific Islander (p=0.24), as compared to Hispanics, tumor sizes of 6-10 cms (p=0.957), or more than 10 cm (p=0.273), as compared to &lt; 5 cm, grade of tumor (III; p=0.682, and grade IV; p=0.281, as compared to grade I), median household income of more than 65000 USD (p=0.069) as compared to less than that, and no chemotherapy (p=0.851) compared to those that received chemotherapy, were not associated with a significant increase in mortality. Conclusions: Cardiac angiosarcoma is associated with a high mortality rate. Factors contributing to increased mortality include advanced age, distant stage of disease at diagnosis, not receiving radiation therapy, and not undergoing surgical resection.
Abstract 4134364: Predicted Low-Density Lipoprotein Cholesterol and Cardiovascular Outcomes Lowering With Inclisiran in Patients With or Without stroke: Insights from SIRIUS in silico trial.
Authors: Pierre Amarenco, Denis Angoulvant, Alexandre Bastien, Emmanuelle Bechet, Franck Boccara, Jean-Pierre Boissel, Bertrand Cariou, Eulalie Courcelles, Alizee diatchenko, Anne Filipovics, Riad Kahoul, Solene Granjeon-Noriot, Guillaume Mahe, Emmanuel Peyronnet, Lolita Portal, Solene Porte, Yishu Wang, Philippe Steg
Journal: Circulation (2024)

Introduction: Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Research question: This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS). Methods: The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses. Results: Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively). Conclusion: SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).
Abstract 4134912: Geographic, Gender,&amp;Racial Trends in Mortality Due to Coronary Artery Disease in Diabetes among Adults Aged 25 and Older in the United States, 1999-2020: A CDC WONDER Database Analysis
Authors: Muhammad Abdullah Naveed, Ahila Ali, Sivaram Neppala, Muhammad Omer Rehan, Bazil Azeem, Rabia Iqbal, Himaja Dutt Chigurupati, Yasar Sattar, Timir Paul
Journal: Circulation (2024)

Background: Coronary artery disease (CAD) is a significant contributor to mortality among adults with diabetes mellitus (DM) in the United States. This study examines the patterns of CAD-related mortality in individuals aged 25 and above with DM, with a particular focus on geographic, gender, and racial/ethnic discrepancies from 1999 to 2020. Methods: The study analyzed death certificate information from the CDC WONDER database from 1999 to 2020. Age-adjusted mortality rates (AAMRs), annual percent change (APC), and average annual percentage change (AAPC) were computed per 100,000 individuals, categorized by year, gender, race/ethnicity, and geographic areas. Results: Between 1999 and 2020, CAD in individuals with DM resulted in 1,462,279 deaths among adults aged 25 and above in the United States. The majority of these deaths occurred in medical facilities (44.2%) and at home (29.3%). The overall age-AAMR for CAD in DM-related deaths decreased from 36.3 in 1999 to 31.7 in 2020, with an AAPC of -0.96 (95% CI: -1.29 to -0.77 p &lt; 0.000001). Men had higher AAMRs (41.6) compared to women (22.6), with a more significant decrease in women (AAPC: -2.10, p &lt; 0.000001) than in men (AAPC: -0.34, p = 0.001200). Racial/ethnic disparities showed the highest AAMRs in American Indians/Alaska Natives (43.6), followed by Blacks (37.8), Hispanics (33.8), Whites (29.7), and Asians/Pacific Islanders (22.5). The most significant decrease was in Hispanics (AAPC: -1.64, p &lt; 0.000001). Geographically, AAMRs ranged from 13.7 in Nevada to 51.3 in West Virginia, with the highest mortality observed in the Midwest (AAMR: 34.5). Nonmetropolitan areas exhibited higher AAMRs (35.2) than metropolitan areas (29.7), with a more pronounced decrease in urban areas (AAPC: -1.22, p &lt; 0.000001) compared to nonmetropolitan areas (AAPC: -0.03, p = 0.854629). Conclusion: The decrease in AAMRs for CAD among individuals with DM from 1999 to 2020 indicates improvements in healthcare management. However, the ongoing disparities based on race, gender, and geography call for targeted public health interventions to guarantee fair access to cardiovascular care. Additional endeavors are necessary to comprehend and alleviate the root causes of these inequalities.
Abstract 4137396: Evolution of Tricuspid Regurgitation and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction: Insights from the PURSUIT-HFpEF Registry
Authors: Masato Okada, Nobuaki Tanaka, Katsuomi Iwakura, Masahiro Seo, Takaharu Hayashi, Masamichi Yano, Takahisa Yamada, Yasumura Yoshio, Shungo Hikoso, Daisaku Nakatani, Yohei Sotomi, Yasushi Sakata
Journal: Circulation (2024)

Background: Tricuspid regurgitation (TR) is prevalent in patients with heart failure with preserved ejection fraction (HFpEF). However, due to its high vulnerability to hemodynamic loads, the long-term observation may heighten its prognostic values. Purpose: To investigate the evolution of TR and its impact on clinical outcomes in patients with HFpEF. Methods: An analysis was performed from a prospective multicenter observational registry for HFpEF (PURSUIT-HFpEF Registry) conducted in the Osaka region of Japan. A total of 1238 patients hospitalized for acute heart failure (HF) (diagnosed by using Framingham criteria) met the inclusion criteria: an LVEF ≥50% and brain natriuretic peptide level ≥100 pg/ml. After excluding patients who died within 1 year, we included 761 patients (age 82 ± 9 years; men, 45%; atrial fibrillation, 37%) whose echocardiographic data at discharge and 1 year were available. Results: At discharge, 165 patients (21.7%) had moderate to severe TR, which increased to 185 patients (24.3%) at 1 year. Patients were categorized into 4 groups based on the TR evolution: no or mild TR that remained unchanged (n = 522 [69%]), no or mild TR that worsened to moderate to severe (n = 74 [9.7%]), moderate to severe TR that improved to no or mild (n = 54 [7.1%]), and moderate to severe TR that remained unchanged (n = 111 [15%]). During a subsequent follow-up of 33 months, patients with persistent moderate to severe TR had significantly higher mortality rates than the other groups (25.7% vs. 27.0% vs. 27.8% vs. 44.1%, log-rank p &lt; 0.001). Even after adjusting for age, sex, body mass index, left atrial diameter, and left ventricular filling pressure, persistent moderate to severe TR was independently associated with subsequent mortality (hazard ratio, 2.06, 95% confidence interval 1.42-2.99, p &lt; 0.001) Conclusions: During a one-year follow-up, changes in the TR severity were not rare in patients with HFpEF. Persistent moderate to severe TR alone was associated with subsequent mortality, highlighting the need to address persistent TR to improve the prognosis.
Abstract 4134298: Dipeptidyl Peptidase 4 Promotes Pressure Overload-Induced Heart Failure through enhancing Antigen Presentation
Authors: Kun Yu, Minyu Liao, Du Tang, Wang Ling, Wenqiang Zhu, Xiaohui Liu, Jixin Zhong, Xiaoquan Rao
Journal: Circulation (2024)

Background: Antigen presentation to CD4+ T cells plays a critical role in heart failure (HF). Dipeptidyl peptidase 4 (DPP4) has been shown to promote the activation of T lymphocytes. This study aims to investigate the role of DPP4 in antigen presentation in pressure overload-induced HF. Methods: To examine the role of DPP4 in antigen presentation during HF, we tested the recruitment and function of dendritic cells (DCs) in transverse aortic constriction (TAC)-induced HF mice. To further investigate, we generated DPP4 knockout mice and induced bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs were then adoptively transferred into OT-II mice, whose DCs require specific exogenous ovalbumin loading to activate CD4+ T cells. RNA-Seq analysis was performed to elucidate the mechanisms by which DPP4 affects the function of DCs. Results: We observed an increased quantity of DCs in the hearts and mediastinal lymph nodes of TAC mice, accompanied by elevated expression of DPP4. These DCs exhibited enhanced antigen-presenting abilities, resulting in increased activation of CD4+ T cells. DPP4 knockout suppressed DC maturation and attenuated their antigen-presenting capabilities. We found that OT-II mice subjected to TAC showed preserved cardiac function compared to wild-type (WT) mice. However, OT-II mice that received adoptive transfer of DPP4+/+ BMDCs exhibited worse cardiac function compared to those receiving DPP4-/- BMDCs, indicating that DPP4 in DCs contributes to HF progression. RNA-Seq analysis indicated that DPP4 in DCs influenced the T cell receptor signaling pathway and T cell differentiation. Mechanistically, DPP4 was found to inhibit the E3 ubiquitin ligase MARCH1 from binding to MHCII, thereby stabilizing MHCII through preventing its ubiquitin-dependent degradation in DCs. Conclusion: This study elucidates the significance of DPP4 in enhancing antigen presentation during heart failure. We propose that DPP4 represents a potential therapeutic target for heart failure.
Abstract 4134148: Reduced BMPR2 in Monocytes De-represses HERV-K and Sustains Inflammation in Pulmonary Arterial Hypertension
Authors: Mir Adil, Aiqin Cao, Mauro Lago-Docampo, Chongyang Zhang, Marlene Rabinovitch
Journal: Circulation (2024)

Background&amp;Rationale: Human endogenous retroviral (HERV) elements are embedded in 8% of our genome. They remain quiescent but can be transiently activated by viral infection to induce an interferon (IFN) response. In pulmonary arterial hypertension (PAH), HERV-K expression is elevated in myeloid cells, and thus can promote inflammation observed in pulmonary arteries (PAs) with progressive obstructive remodeling. PAH is linked to a mutation or a decrease in BMPR2 expression which our laboratory has recently shown in monocytes (MONO). HERVs are silenced by SUMOylated (S) TRIM28 (KAP1, a methylase) and SPEN (a histone deacetylase) factors that are also sequestered by the lnc RNA XIST which is increased in females to inactivate the extra X-chromosome. When TRIM28 is phosphorylated (P) by DNA-PK, it loses methylase activity and can act as a transcription factor. Hypothesis: Reduced BMPR2 in MONO results in DNA-PK mediated P-TRIM28 causing demethylation of XIST targets (X-related genes) and HERV-K thus increasing their expression. Competitive SPEN binding to the increased XIST also de-represses HERV-K . Approach: We used THP-1 MONOs with BMPR2 shRNA and induced pluripotent stem cell (i) MONOs derived from BMPR2 mutant PAH patients and assessed HERV-K , XIST , IFNs and related our findings to DNA-PK–P-TRIM28 and sequestration of SPEN. Results: XIST and HERV-K mRNA were significantly elevated in THP-1 MONOs with shBMPR2 vs. shControl and in PAH-iMONO vs. control iMONO based on gender. Reduced BMPR2 also increased IFN genes. These findings were consistent with nuclear DNA-PK and P-TRIM28 shown to bind in affinity purification mass spectrometry analysis. Bisulfite conversion assay demonstrated decreased methylation of HERV-K in BMPR2 -deficient MONOs attributed to a reduction in the methylase S-TRIM28. RNA-IP in THP-1 MONOs with shBMPR2 vs. shControl indicated increased binding of XIST with TRIM28 and SPEN, suggesting a competitive reduction in binding to HERV-K. Conclusions: Loss of BMPR2 increases XIST and HERV-K in MONO related to DNA-PK induced P-TRIM28 and reduced methylase S-TRIM28. Increased HERV-K may also be a function of the increase in XIST sequestering its deacetylase SPEN. These molecular features underlie a chronic HERV-K -IFN inflammatory response in PAH. They may explain the female predisposition to PAH, because the increase in XIST in females heightens the propensity to activate HERV-K -IFN signaling and chronic inflammation in PAs infiltrated by MONO.
Abstract 4132291: Assessing the Efficacy of Preventive Percutaneous Coronary Intervention vs Optimal Medical Therapy for the Treatment of Vulnerable Plaque: A Meta-analysis
Authors: Nicholas Mootz, Chaitanya Rojulpote, Divya Verma, Kishore Harjai, Chien-Jung Lin
Journal: Circulation (2024)

Introduction: Rupture and thrombosis of lipid-rich atherosclerotic plaques (vulnerable plaques) contributes to majority of acute coronary syndrome (ACS). Current guidelines recommend optimal medical therapy (OMT) for stabilization of vulnerable plaques. Recent evidence of preventive percutaneous intervention (PCI) as a targeted treatment shows improvement in outcomes in these patients. Hypothesis/Goals/Aims: We aim to evaluate the efficacy of preventive percutaneous coronary intervention (PCI) compared to optimal medical therapy (OMT) for treatment of non-vulnerable plaque within five years of follow up from available selected randomized controlled trials (RCTs). Methods: PubMed, Cochrane, OVID, and NIH Clinical Trials were searched for RCTs evaluating preventive PCI compared to standard of care medical therapy. All trials reported primary common endpoints as death from cardiac cause and myocardial infarction (MI). Secondary outcomes included all-cause mortality, any revascularization, hospitalization for unstable and progressive angina, and composite death (any cause, MI, or any revascularization). Sub analyses for secondary outcomes were included if measured by RCT. A fixed effect model with Mantel-Haenszel statistical method was used to calculate risk ratios, Z scores, and a 95% confidence interval. Results: Ten RCTs (n=15955 patients) were included. Preventive PCI of vulnerable plaques revealed a significant benefit in lowering incidence of MI (RR: 0.86 [0.77, 0.86], p=0.01) and death from cardiac cause (RR: 0.73 [0.62, 0.86], p=0.004). Similarly, patients undergoing preventive PCI had a lower incidence of hospitalization for unstable or progressive angina (RR: 0.75 [0.62, 0.91], p&lt;0.0001) and composite death (RR: 0.55 [0.46, 0.67], p&lt;0.001). No difference was noted in all-cause mortality. Incidence of revascularization had a significant benefit with OMT therapy compared to preventive PCI (RR: 1.84 [1.75, 1.94], p&lt;0.0001). Conclusion: Preventive PCI in vulnerable plaque demonstrates cardiovascular benefit as a result from lower incidence of MI, death from cardiac cause, composite death and fewer hospitalization for unstable or progressive angina.
Abstract 4135082: Small dense low-density lipoprotein cholesterol and risk of peripheral artery disease
Authors: Mie Balling, Borge Nordestgaard, Anne Langsted, Anette Varbo, PIA KAMSTRUP, Shoaib Afzal
Journal: Circulation (2024)

Background: High levels of small dense low-density lipoprotein (sdLDL) is a hallmark of dyslipidemia; however, studies on sdLDL cholesterol levels and risk of peripheral artery disease are sparse and results inconclusive. Hypothesis: We tested the hypothesis that higher levels of sdLDL cholesterol are associated with increased risk of peripheral artery disease in a primary prevention setting. Methods: We studied 31,036 individuals free of lipid-lowering therapy, ischemic stroke, and myocardial infarction at study entry in 2013-2017. All had fresh sample measurements of sdLDL cholesterol. During a median follow-up on 6.2 years, 155 were diagnosed with peripheral artery disease. The association was confirmed using ankle-brachial index (ABI) ≤ 0.9 as endpoint. Lastly, as comparison across different vascular beds risk estimates for myocardial infarction and ischemic stroke were calculated. Results: Higher levels of sdLDL cholesterol were associated with higher risk of peripheral artery disease and an ABI ≤ 0.9 illustrated by cubic splines multivariable adjusted for sex, systolic blood pressure, education, body mass index (BMI), diabetes, large buoyant LDL cholesterol, and age. Per 1 mmol/L (37 mg/dL) higher sdLDL cholesterol hazard ratio for peripheral artery disease was 2.01 (95% CI: 1.41-2.85) and odds ratio for an ABI ≤ 0.9 was 1.51 (95% CI: 1.07-2.14) in multivariable adjusted models. The cumulative incidence of peripheral artery disease was respectively 1.5%, 2.5%, and 3.5% for individuals having a sdLDL cholesterol in the 1 st -50 th , 51 st -90 th , and the 91 st -100 th percentiles at age 80. For the 91 st -100 th versus the 1 st -50 th percentile a hazard ratio on 2.51 (95% CI: 1.50-4.20) for peripheral artery disease, 2.18 (95% CI: 1.58-3.01) for myocardial infarction, and 1.85 (95% CI: 1.37-2.49) for ischemic stroke was found. Furthermore, the association of higher sdLDL cholesterol with increased risk of peripheral artery disease was robust in sensitivity analyses. Conclusion: Higher levels of sdLDL cholesterol were robustly associated with increased risk of peripheral artery disease in a primary prevention setting.