tbuckley/cabot-search huggingface dataset:
Abstract 13712: Imaging Short-Chain Fatty Acid Metabolism and Transport in the Failing Heart by PET
Authors: Juan A Azcona, Anja Wacker, Chul-Hee Lee, Pradeep K Singh, Onorina Manzo, Annarita Di Lorenzo, Thomas Jeitner, John Babich, Alejandro Amor-Coarasa, James Kelly
Journal: Circulation (2023)

Introduction: Heart failure compromises the transport and oxidation of long chain fatty acids. Cardiomyocytes can compensate by using short-chain fatty acids (SCFA) which rely on other transport mechanisms. Based on this principle, we used 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), a radiolabeled SCFA analog, to assess these metabolic changes and image them by positron emission tomography (PET) in a doxorubicin-induced mouse model of cardiotoxicity. Hypothesis: We hypothesize that the increased demand for SCFA by the failing heart promotes cardiac accumulation of [ 18 F]FPA which can be imaged by PET. Methods: [ 18 F]FPA was injected intravenously into male C57BL/6J mice 10 weeks following intraperitoneal injections of 8 x 3 mg/kg doxorubicin (DOX). Dynamic PET acquisitions were performed from 60-120 min post injection of 9.25-11 MBq [ 18 F]FPA. These images were acquired in the presence or absence of 5 mg/kg AZD3965, an inhibitor of monocarboxylate transporters. Heart uptake of [ 18 F]FPA was determined by image-based quantitation and confirmed by a biodistribution study. Mechanistic [ 18 F]FPA uptake studies were also conducted in primary human cardiomyocyte (HCM) cultures. Results: Mice experiencing DOX-induced cardiotoxicity exhibited statistically significant increases in cardiac [ 18 F]FPA. AZD3965 did not significantly alter cardiac uptake but reduced uptake in all other tissues except the kidneys, the route of excretion. Additionally, [ 18 F]FPA uptake is lost in HCM for which mitochondrial acyl-CoA synthetase (ACSS) 1, but not cytosolic ACSS2, is inhibited. Conclusions: Our findings present both mechanistic and translational applications for [ 18 F]FPA. AZD3965 effectively reduced [ 18 F]FPA uptake in other tissues except for the heart and can therefore be co-administered to enhance the heart-to-background ratio. Altogether, our results indicate that [ 18 F]FPA may enter cardiac tissues by diffusion and become metabolically trapped in mitochondria.
Abstract 17121: Elevated Aortic Stiffness and Impairments in Cerebrovascular Regulation in Cancer Survivorship
Authors: Britton Scheuermann, Stephen Hammond, Vanessa-Rose Turpin, Shannon Parr, Olivia Kunkel, Kayla Smith, Carl J Ade
Journal: Circulation (2023)

Background: Approximately 46% of cancer survivors report cognitive impairments across many types of cancer, which has been associated with anti-cancer therapy and often results in reduced quality of life. Pre-clinical studies suggest that predictors of cognitive decline may involve vascular dysfunction. We aimed to characterize local (cerebrovascular reactivity and cerebral autoregulation) and global (aortic arch stiffness) vascular regulation in cancer survivorship. Methods: Cerebral autoregulation was determined using Mx, a moving 10s-windowed correlation between finger plethysmography-derived blood pressure and cerebral blood velocity of the middle cerebral artery. Higher Mx values represent pressure-passive cerebral blood flow, indicating poor cerebral autoregulation. In addition, cerebral blood velocity, blood pressure, and end-tidal CO 2 were collected during a rebreathing task. MAP was used to calculate an index of cerebrovascular conductance (CVCi). Cerebrovascular reactivity was calculated as the change in cerebral blood velocity or CVCi over the change in end-tidal CO 2 . Aortic arch stiffness, as pulse wave velocity (aaPWV), was calculated from ultrasound scans of the aortic valve and the descending aorta. Differences between groups were assessed with Mann-Whitney tests. Results: Eleven women were recruited (5 controls and 6 cancer survivors who had received treatment). Cancer types included melanoma, lymphoma, and breast cancer. Age and resting MAP were similar between groups. Mx values were higher in cancer survivors (-0.13 ± 0.14 vs. 0.14 ± 0.11, p &lt; 0.05). Cerebrovascular reactivity, both absolute (2.8 ± 1.1 vs. 1.6 ± 0.8, p = 0.05) and as CVCi (16.8 ± 2.4 vs. 2.3 ± 9.4, p &lt; 0.05), were lower in cancer survivors. aaPWV was higher in cancer survivors (2.7 ± 0.8 vs. 3.8 ± 0.6, p &lt; 0.05). Across the entire study sample, aaPWV trended towards an association only with absolute cerebrovascular reactivity (Spearman r = -0.6, p = 0.054). Conclusion: Aortic stiffness was elevated and both cerebrovascular regulatory functions were impaired in cancer survivors compared to healthy controls. Present findings highlight the importance of monitoring cerebral and global vascular function in cancer survivors at high-risk for cognitive decline.
Abstract 13051: Profiling CD8+ T Cell Activation in Experimental Models With LDL-R Deficiency and in Patients With Familial Hypercholesteroleamia
Authors: Giuseppe Danilo Norata, Annalisa Moregola, Fabrizia Bonacina
Journal: Circulation (2023)

Introduction and Hypothesis: Familial Hypercholesterolaemia (FH) is a rare genetic disease characterized by elevated plasma cholesterol levels, xanthomas, overt atherosclerosis and premature cardiovascular death. HoFH and severe HeFH present an elevated inflammatory burden and poorly responsive to therapeutics such as anti-PCSK9 monoclonal antibodies. Therefore, innovative approaches to diagnose the severity of the disease and control the over-activation of the immune-inflammatory response in the arterial wall of FH patients should be studied to improve the management of this genetic disease. Here we profiled the activation of CD8+ T lymphocytes from experimental models and with patients with clinical diagnosis of FH. Methods: Immunophenotypic characterization of T cells from WT and LDLR KO mice was performed in vitro and in vivo coupled to proteomics and WB analysis on isolated T cells. CD8 T cell response in FH patients, carrying mutations in the LDLR gene, was profiled. Results: LDLR mRNA expression increased after in vitro activation of CD8, but not CD4 T cells, suggesting a different regulation of cholesterol homeostasis between T cell subsets. LDLR deficiency mainly affected CD8 T cell activation as demonstrated by reduced in vitro and in vivo proliferation and cytokine production after ovalbumin vaccination of LDL-R KO T cells compared to their wild type counterpart. The addition of LDL to serum free media increased CD8 proliferation in WT but not in KO CD8 T cells. Proteomic and WB analysis showed that this phenotype is the consequence of reduced mTORC1 activation and impaired lysosomal organization. The proliferation of CD8 T cells from FH patients was less pronounced compared to sex- and age-matched controls. In addition, CD8 T cells from FH vaccinated for seasonal influenza were tested in vitro with virus-derived peptides, showing a decreased granzyme production compared to CD8 from vaccinated controls. Conclusions: LDLR plays a critical role in regulating the immunometabolic reprogramming of activated CD8 T cells by fuelling the cholesterol-lysosome-mTORC1 axis. Acknowledgments: This study is supported by a Grant from the Italian Ministry of Health: RF-2019-12370896
Abstract 16689: Stress Cardiomypoathy in the Patient on Immune Checkpoint Inhibitors; a Pharmacovigilance Study From 2013-2023 FAERS Database
Authors: Nader Alwifati, Shaden Daloub, Mohammed Faisaluddin, Mohamed Salah Mohamed, Mohamed Abosbeta, Omar Al-Ali, Uzma Iqbal
Journal: Circulation (2023)

Introduction: Immune checkpoint inhibitors (ICIs) are a form of immunotherapy widely used in the treatment of different cancers. These inhibitors function by blocking specific proteins, such as PD-1 (programmed cell death protein 1) or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), which regulate the immune response. While ICIs have demonstrated significant benefits, they can also lead to immune-related adverse drug reactions (ADRs). Although rare, cardiac immune-related ADRs are associated with high mortality rates. Hypothesis: The aim of this study to investigate the potential association between stress cardiomyopathy and the use of immune checkpoint inhibitors. Methods: We conducted an analysis using individual case safety reports obtained from the FDA Adverse Event Reporting System (FAERS) Database. These reports encompassed the period from the marketing authorization of each specific ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) up until March 2023. The synthesized data was further examined based on outcome severity, age, and gender. Results: Among 9,772 individual cardiac adverse events associated with immune checkpoint inhibitors, 121 cases (1.2%) of stress cardiomyopathy were reported from 2013 to 2023. The highest occurrence of stress cardiomyopathy adverse events (57.8%) was observed in the age group of 65-85 , compared to 26.4% in the age group of 14-64. Females were more frequently affected, accounting for 55.3% of the cases, while males constituted 41.3%. The three most commonly reported ICIs associated with stress cardiomyopathy were pembrolizumab (39.6%), nivolumab (33.8%), and ipilimumab (16.5%). Among the 121 cases, 19% resulted in mortality, while 26.5% had life-threatening outcomes. Additionally, 79.3% of cases required hospitalization, 5.7% experienced disability, and 57.8% had outcomes that were not characterized. Conclusions: Immune checkpoint inhibitor-induced cardiac ADRs, specifically stress cardiomyopathy, were found to be serious and associated with unfavorable outcomes. Physicians should remain vigilant regarding cardiac symptoms in patients receiving immune checkpoint inhibitors, as early detection can improve overall outcomes.
Abstract 17538: The Weekend Effect on In-Hospital Outcomes of Elderly Patients With Acute Ischemic Stroke and Concurrent COVID-19 Infection: A Nationwide Multicenter Study
Authors: Adil S Mohammed, Suvidha Manne, Hafeezuddin Ahmed, Harshavardhan Polamarasetty, Muneeb Siddiqui, Azeem Arastu, Sravya Gayatri Vanukuru, Bhagya Lakshmi Devarala, Narendranath Reddy Ganampet, Sanmayi Jayaprakash, Sandeep Singh, Rupak Desai
Journal: Circulation (2023)

Background: Acute ischemic stroke (AIS) and COVID-19 are individually associated with poor outcomes. The impact of the pandemic on the US healthcare system, including staff shortages and disparities, may have delayed timely interventions and adherence to guidelines. We investigated the Weekend Effect on outcomes in elderly patients with AIS and COVID-19 to better understand its relationship during the challenging pandemic period. Methods: Using ICD-10-CM codes, we analyzed AIS and COVID-19 hospitalizations among the elderly (&gt;65 years) from the 2020 National Inpatient Sample. Weekday and weekend admissions were compared for baseline characteristics, comorbidities, and outcomes. The multivariable analysis was adjusted for confounding variables. A two-tailed p&lt;0.05 was considered significant. Results: Of 14,070 total AIS and concurrent COVID-19 admissions among the elderly, 10,425 were on weekdays, and 3645 were on weekends. While both cohorts exhibited comparable age distributions, the weekend admissions had a higher percentage of females (47.1% vs. 45.2%) and whites (59.5% vs. 58.1%). They had a higher prevalence of hypertension (82.2% vs. 78.6%), hyperlipidemia (52.9% vs. 50.1%), chronic pulmonary disease (19.1% vs. 17%), obesity (15% vs. 13.6%), depression (10.2% vs. 8.2%). Additionally, all-cause mortality (33.5% vs. 32.5%) and cardiogenic shock (1.9% vs. 1.7%) were slightly higher among weekend admissions. Upon adjusting for confounding factors, the overall mortality rate among weekend admissions showed no significant association, aOR-1.15 [95%CI:0.42-0.96; p-0.169]. Conclusion: Although there is a higher prevalence of comorbidities and overall mortality among weekend admissions, no significant association between the Weekend Effect and poor in-hospital outcomes in elderly COVID-19 patients with AIS was noted. However, ensuring adequate staffing and resource availability during weekends may enhance the quality of care provided.
Abstract 13049: Electrophysiological Mechanism of Potassium Channel KCNQ1 p.V162M Mutation Induced Atrial Tachycardia and Epilepsy
Authors: zhiqing chen, jinyan Xie, yang Liu, Kui Hong
Journal: Circulation (2023)

Objective: Arrhythmia and epilepsy are the causes of syncope and sudden death. Both of them are associated with abnormal function of potassium ion channels. Delayed rectified potassium current (IKs) is generated by combining the α subunit of potassium ion channel encoded by KCNQ1 gene with the β subunit encoded by KCNE1 gene. It plays an important role in electrical excitation and K+ circulation of nerve cells. In this study, a patient with atrial arrhythmia and epilepsy with a history of syncope was identified by genetic testing as having a mutation in the KCNQ1 p.V162M gene. The purpose of this study was to investigate the effect of KCNQ1 p.V162M mutation on the structure and function of potassium ion channels. Methods: The mutant plasmid KCNQ1-p.V162M was constructed for cell transfection. The expression of protein and mRNA were analyzed by western blotting and real-time quantitative PCR. The IKs of the two groups were detected by whole-cell patch clamp technique. Results: Whole exon gene sequencing revealed that the patient carried the KCNQ1 p.V162M mutation. The results of molecular biology experiment showed that mRNA, KCNQ1 total protein and membrane protein expressions in mutant group were significantly lower than those in wild group. Whole-cell patch clamp results showed that the peak current density and tail current of IKs in the mutant group were significantly decreased compared with those in the wild group, indicating that the mutation of KCNQ1 p.V162M could lead to decreased function of potassium ion channels. Conclusions: KCNQ1 p.V162M mutation can lead to decreased expression of KCNQ1 protein and decreased function of potassium ion channel, which may be the potential mechanism of atrial tachycardia and epilepsy induced by this mutation.
Abstract 17640: Myocardial Infarction Quality of Care and Outcomes in Asian American Subgroups
Authors: Aishwarya Vijay, Mark D Huffman, Namratha Kandula, Donald M Lloyd-Jones, powell O jose, Eugene Yang, Abhinav Goyal, Sadiya S Khan, Nilay S Shah
Journal: Circulation (2023)

Introduction: Cardiovascular mortality differs across Asian American subgroups, but myocardial infarction (MI) hospitalization outcomes or quality of care have not been reported in these populations. Hypothesis: MI quality and outcomes differ among Asian Americans, with worse outcomes compared with non-Hispanic White (NHW) adults. Methods: Participants from 711 hospitals in the AHA Get with the Guidelines Coronary Artery Disease registry were age ≥18 years with ST-elevation MI (STEMI), identified as Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese, or NHW. Odds of in-hospital mortality, door-to-balloon time &lt;90 minutes, and door-to-electrocardiogram (ECG) time &lt;10 minutes were evaluated in each Asian American subgroup vs. NHW with sex-stratified multivariable logistic regression models, adjusted for age, CVD history, smoking, body mass index, LDL cholesterol, diabetes, hypertension, and health insurance. Results: Among Asian American (3,591 female; 10,660 male) and NHW (108,071 female; 224,899 male) patients with STEMI, adjusted odds of in-hospital mortality vs. NHW were higher in Korean (odds ratio [OR] 1.139, 95% confidence interval [CI] 1.021-1.271) and Vietnamese (OR 1.158, 95% CI 1.053-1.273) female patients (Figure). Likelihood of achieving door-to-balloon time &lt;90 minutes among STEMI patients was lower in Chinese (OR 0.846, 95% CI 0.734-0.975) and Filipina (OR 0.699, 95% CI 0.616-0.793) female patients, and Chinese (OR 0.932, 95% CI 0.877-0.990), Filipino (OR 0.922, 95% CI 0.853-0.998), and Vietnamese (OR 0.890, 95% CI 0.812-0.976) male patients. Similar patterns were seen in achieving door-to-ECG time &lt;10 minutes. Conclusions: STEMI outcomes and quality of care may vary among Asian American subgroups. Quality improvement programs must identify and address the factors that result in suboptimal MI outcomes and care among Asian American patients.
Abstract 15146: Superior Outcomes of Dual-Arterial Compared With Single-Arterial CABG Are Maintained in Low-Volume Centers in the Veterans Health Administration
Authors: Ajami Gikandi, Tran Dinh, Zhibao Mi, Ellen Dematt, JACQUELYN quin, Miguel Haime, SCOTT KINLAY, Allison L Tsao, Kousick Biswas, Marco A Zenati
Journal: Circulation (2023)

Introduction: A 2023 report of the STS Adult Cardiac Surgery Database (ACSD) demonstrated worse clinical outcomes with dual arterial CABG (DAG) compared to single arterial CABG (SAG) at low DAG volume centers (&lt;30 DAG/year). It is unclear how generalizable these results are to low DAG volume centers in the Veterans Health Administration (VHA). Objective: We investigated outcomes of DAG with bilateral internal thoracic artery (BITA) or radial artery (RA) plus vein grafts (VG) compared to SAG using a left internal thoracic artery (LITA) graft plus VG in the VHA. Methods: This study analyzed data from 25,969 patients undergoing isolated CABG between 2005 and 2015 at 44 VHA hospitals (all performing&lt;30 DAG/year). The primary outcome was 5-year mortality, and the secondary outcome was a composite of major adverse cardiac and cerebrovascular events (MACCE; all deaths, myocardial infarction, stroke, or repeat revascularization). Results: 1,261 patients (4.9%) received DAG (66.8% LITA plus RA/VG and 33.2% BITA/VG) and 24,708 patients (95.1%) had SAG. Median age and grafts per patient for DAG and SAG were 62 and 63 years and 3.0 and 3.0 grafts, respectively. At 5 years, mortality rates for DAG (10.6% [134 events]) were significantly lower vs. SAG (16.2% [4,011 events]). Similarly, MACCE were lower for DAG (22.0% [278 events]) vs. SAG (28.6% [7,078 events]). Kaplan-Meier analysis for all deaths showed a hazard ratio (HR) of 0.64 (95% CI: 0.54 to 0.76) favoring DAG (Figure). A covariate-adjusted Cox model for DAG vs SAG revealed adjusted HR of 0.70 (95% CI: 0.58 to 0.85) for all-cause mortality and 0.80 (95% CI: 0.70 to 0.91) for MACCE. Conclusions: In contrast to a recent STS-ACSD analysis, DAG in the VHA was associated with significantly improved 5-year survival and rates of MACCE compared to SAG. Additional studies are needed to understand the observed lack of negative DAG low-volume/outcome relationship in the VHA.
Abstract 16295: Glucose Homeostasis and Frequency of Pre-Heart Failure in Hispanics/Latinos: Insights From the Echocardiographic Study of Latinos (ECHO SOL)
Authors: Priscilla Duran Luciano, Patricia chavez, Katrina Swett, Jianwen Cai, Sonia Ponce, Gregory A Talavera, Mayank M Kansal, Martha L Daviglus, Neil Schneiderman, Daniela Sotres-Alvarez, Matthew A Allison, Robert Ostfeld, Leonor Corsino, Carlos J Rodriguez
Journal: Circulation (2023)

BACKGROUND: Diabetes Mellitus (DM) is an independent risk factor for heart failure (HF), yet research on the association of glucose homeostasis with pre-HF is limited. We assessed glucose homeostasis longitudinally in relation to prevalent and incident pre-HF in the Echocardiographic Study of Latinos, Echo-SOL. Methods: Serial echocardiograms from 1595 adults (mean age 56.4 years), 61% female, from Echo SOL were analyzed on average 4.3 years apart. Prevalent pre-HF was defined as the presence of one of the following parameters: LVEF &lt;50%, global longitudinal strain &gt; -15%, diastolic dysfunction ≥ grade 1, left ventricular mass index &gt;115 in men/&gt;95 in women, relative wall thickness &gt;0.42. Glucose homeostasis was assessed at baseline (2008-2011) by fasting plasma glucose (FGP), oral glucose tolerance test (OGTT), and hemoglobin A1C (A1C) and categorized as normal glucose tolerance [NGT]: FPG&lt;100 mg/dL, OGTT &lt;140 mg/dL, and A1C &lt;5.7%; prediabetes [PDM]: FPG 100-125 mg/dL, OGTT 140-199 mg/dL, or A1C 5.7-6.4%. Among those with prevalent DM, controlled DM [CDM] was defined as A1C &lt;7%, and uncontrolled DM [UDM] as A1C &gt;7%. Incident pre-HF was assessed at visit 2 (2014-2017) among those free of pre-HF at visit 1. Complex survey design is accounted for in all analyses. Results: Over time there was increased frequency of UDM with decreased frequency of NGT (Figure) . Prevalent pre-HF (72.5% overall) gradually increased as glucose homeostasis worsened: 50.5% NGT, 69.2% PDM, 78.3% CDM, 86% UDM, p value &lt;0.05. Incident pre-HF (56.2% overall) occurred more frequently among baseline dysregulated glucose categories: 65.5% PDM, 71.3% UDM, p value &lt;0.05. CONCLUSION: Pre-HF rates, in both the non-DM and DM groups, increase with worsening and uncontrolled glucose homeostasis. Early detection of antecedent PDM stages and uncontrolled diabetes may offer opportunities to prevent clinical HF.
Abstract 15927: Polyunsaturated Fatty Acid Levels and Their Relationship With Peak Exercise Measures in HFpEF
Authors: Cheshta Prasad, Joseph Campain, Joan Helmering, Clarence Hale, Michelle Chen, Murielle Veniant-Ellison, Rajeev Malhotra, Gregory Lewis
Journal: Circulation (2023)

Background: Polyunsaturated fatty acids (PUFAs) regulate the inflammatory cascade and have been implicated in potential pathologic and therapeutic roles in heart failure with preserved LVEF (HFpEF). The purpose of this study was to explore the relationship between plasma levels of omega-3 (ω-3) fatty acids and invasive hemodynamic profiles characteristic of early HFpEF. Methods: In a single-center referral cohort undergoing evaluation for exertional dyspnea and suspected HFpEF, we assayed ω-3 concentrations in plasma by liquid chromatography. We derived an ω-3 score by summing Z-scores of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Linear regression was used to relate plasma ω -3 levels to simultaneously collected physiologic data from cardiopulmonary exercise testing (CPET) with invasive catheterization. Results: 588 patients (52% female, age 62 ± 12 years, BMI 30 ± 6 kg/m 2 , peak oxygen uptake (VO 2 ) 15.5 ± 5.1 mL/min/kg [76 ± 20% predicted], NTproBNP 118 [33 - 405] pg/mL) were studied. Median ω -3 concentrations were 72 [46 - 107] pg/mL for EPA and 315 [225 - 457] pg/mL for DHA. Female sex and increased age were associated with higher levels of ω-3 fatty acids ( Table , p=0.03). After adjustment for age, sex, and BMI, a higher ω-3 score was associated with greater exercise capacity measured by peak VO 2 (p&lt;0.001) and peak workload (p&lt;0.001) along with an increase in peak exercise peripheral O 2 extraction (CavO 2 ; p &lt; 0.001). Notably, increased ω-3 score was associated with lower supine pulmonary capillary wedge pressure (PCWP; p=0.03), PCWP to cardiac output (CO) slope during exercise (p = 0.009), and NTproBNP (p &lt; 0.001). Conclusion: These data demonstrate that circulating ω-3 fatty acid levels are associated with exercise capacity and both central cardiac and peripheral function in HFpEF. Further studies are needed to unravel the relationship between modulation of plasma PUFAs and rest and exercise hemodynamic profiles of HFpEF.