tbuckley/cabot-search huggingface dataset:
Abstract 15168: The Role of Mitochondrial Fission Factor (MFF) and Increased Midzone Mitochondrial Fission in Pulmonary Arterial Hypertension: Implications for Proliferation, Mitophagy, and Apoptosis
Authors: Pierce Colpman, Kuang-Huieh Chen, Jeffrey Mewburn, Ian Goodall-Halliwell, Asish Das Gupta, Stephen L Archer
Journal: Circulation (2023)

Introduction: The obstructive vasculopathy in pulmonary arterial hypertension (PAH) results from unrestricted proliferation and impaired apoptosis of pulmonary artery smooth muscle cells (PASMC). This pseudoneoplastic phenotype is partly due to increased mitotic fission i.e. the highly coordinated processes of mitochondrial fission and nuclear division. Two types of mitochondrial fission have been reported: peripheral fission, which eliminates damaged terminal portions of mitochondria via mitophagy, and midzone fission, which is linked to mitochondrial biogenesis and cellular proliferation. While all fission involves dynamin related protein 1 (Drp1), the Drp1 binding partner differs between these processes with mitochondrial fission factor (MFF) mediating midzone fission, whilst fission protein 1 (Fis1) governs peripheral fission. Here we explore the role of MFF and Fis1 in the pathogenesis of PAH. Hypothesis: Midzone fission is increased in PAH PASMC and inhibiting midzone fission by downregulating MFF will decrease cell proliferation and induce apoptosis. Methods: MitoMeter, a mitochondrial segmentation and tracking application, was adapted for automated analysis of the location of mitochondrial fission events. Immunoblots were used to assess the expression of MFF and Fis1 in control (n=4) vs. PAH (n=5) human PASMC. Flow cytometry was used to assess cell proliferation (EdU) and rates of apoptosis (Annexin V) (n=3). Results: Midzone fission, as a % of total fission events, is increased (PAH= 48.7%±6.9, Ctrl = 28.9%± 5.1p&lt;0.05). Moreover, MFF expression is increased in PAH PASMC (p&lt;0.05). Conversely, peripheral fission is decreased (PAH=51.2%±6.9, Ctrl = 71.0±5.1). Silencing MFF inhibited midzone fission (siCtrl=54.93.1%, siMFF = 39.37.4%), while Fis1 knockdown inhibited peripheral fission in PAH PASMC (siCtrl = 45.13.1%, siFis1 = 36.91.9%), p&lt;0.05 each. Inhibiting MFF inhibited PAH PASMC proliferation (siCtrl =36.50.9%, siMFF = 23.50.5%, p&lt;0.05) and induced apoptosis in PAH PASMC (siCtrl=3.90.3% versus siMFF 7.40.2%, p&lt;0.05). Conclusion: MFF mediated midzone fission is upregulated in PAH PASMC contributing to increased proliferation, and reduced apoptosis. Inhibiting MFF may be a new therapeutic strategy in PAH.
Abstract 15963: A Novel SGK1 Inhibitor (SGK1-I), Prevents Obesity-Related Atrial Fibrillation
Authors: Aneesh Bapat, Sabindra Pradhananga, Dinesh Srinivasan, Philip Sager, Patrick T Ellinor
Journal: Circulation (2023)

Introduction: Obesity is an important risk factor for atrial fibrillation. We have previously demonstrated the protective effect of genetic SGK1 inhibition in a mouse model of obesity-related atrial fibrillation (AF). SGK1-I is a novel and potent SGK1 inhibitor that has been shown to reduce late sodium current and has currently entered clinical trials as a potential treatment of long QT syndrome. Hypothesis: We sought to assess the efficacy of pharmacologic SGK1 inhibition in a mouse model of obesity-related AF. Methods: Wild type C57/Bl6 mice were fed a high fat diet containing 60% cholesterol (by calories) compounded with (HFD-SGK1i) or without (HFD) SGK1-I for 10 weeks. After feeding, the mice were assayed with invasive electrophysiology studies (EPS), optical mapping, and biochemical assays. Results: There were no significant differences in rate of weight gain, final body weight, fasting glucose, glucose tolerance, or tail-cuff blood pressure between the two groups of mice throughout the study. During EPS, there were no differences in nodal (sinus and atrio-ventricular) function or tissue (atrial/ventricular) refractory periods. However, HFD-SGK1i mice were significantly protected from obesity-related inducible AF during EPS, with a lower rate of AF inducibility (5.7% versus 1.5%, p&lt;0.0001) and a lower total AF burden (35±54 versus 5.5±10.7 s, p=0.04). Optical mapping revealed abbreviated right (RA), but not left (LA), atrial action potential duration (APD) and attenuated inter-atrial APD differences in HFD-SGK1i mice as compared to HFD mice. In this context, Western blotting data demonstrated greater RA (versus LA) SGK1 activity/expression resulting from HFD, suggesting that SGK1 signaling may contribute to inter-atrial heterogeneity caused by HFD. Finally, protein expression of NLRP3 inflammasome components, Caspase-1 and ASC, as well as TGF-β expression were decreased in the SGK1-1 group; consistent with anti-inflammatory and anti-fibrotic signaling resulting from SGK1-I treatment. Conclusion: SGK1-I protects mice from obesity-related AF. These data further highlight SGK1 and its inhibition as a compelling target in cardiac arrhythmogenesis.
Abstract 15734: Local Admixture Mapping of Metabolites in African Americans
Authors: Daniel E Cruz, Laura M Raffield, Shuliang Deng, James Wilson, Robert E Gerszten
Journal: Circulation (2023)

Introduction: There is increasing evidence that metabolite levels in African Americans (AA) are influenced by population differentiated genetic variation. We investigated how local genetic ancestry may be associated with levels of circulating plasma metabolites using metabolomic profiling in the Jackson Heart Study, an AA cohort, in an attempt to identify additional genetic determinants of metabolite levels. Hypothesis: Certain metabolites will be associated with local African genetic ancestry. Methods: We performed admixture mapping using local ancestry estimates (probabilities of whether an individual has 0, 1 or 2 alleles of African ancestry at each site in the genome from RFMix, based on similarity to 1000G reference panel) from TOPMed sequencing data for autosomal SNPs. Associations were then tested for 302 targeted metabolites measured using LC-MS. Each local ancestry regression model was adjusted for age, sex, and estimated global ancestry. We used a previously established significance threshold for local African ancestry analysis, p&lt;2.1X10 -5 . We further adjusted findings for previously reported GWAS variants in conditional analysis. Results: There were 38 local admixture mapping signals for 32 metabolites. Fourteen metabolite signals survived conditional analysis and represent signals distinct from those identified in single variant GWAS. Metabolites of note include the branched chain amino acids, whose association with cardiometabolic disease has been shown to differ based on self-identified race. Conclusions: We present local admixture mapping results providing further evidence that population differentiated genetic variants influence circulating levels of plasma metabolites. For a large proportion of our findings, admixture associations were not attenuated by conditioning on previously reported SNPs from GWAS studies. These analyses suggest that admixture mapping may identify association signals that are missed by GWAS, and may help to elucidate population differences affecting key biologic pathways.
Abstract 14407: Right Ventricular Myocardial Stiffening is Associated With Pulmonary Arterial Stiffening in Pulmonary Hypertension
Authors: Sunder Neelakantan, EDWARD P MANNING, Peng Zhang, Gaurav Choudhary, Reza Avazmohammadi
Journal: Circulation (2023)

Introduction: Pulmonary hypertension (PH) increases vascular resistance in the lung leading to remodeling of the proximal pulmonary artery (PA). PH also leads to the right ventricular (RV) remodeling following increased RV afterload. Studies of tissue remodeling in PH have focused on either the RV or PA, leaving the understanding of the RV-PA remodeling relationship elusive. We hypothesize that PA proximal tissue stiffening is associated with RV free wall (RVFW) stiffening. Methods: The mild model of PH was developed by placing SD rats (n=6) in a hypoxia chamber (10% O2) for 3 weeks, followed by one week of normoxia. The severe model of PH was developed by injecting one dose of SU5416 (20 mg/kg sc) into CDF rats (n=6) followed by the hypoxia protocol. Control rats (n=6 each for SD and CDF) were kept in normoxia at all times. Each group was half male and half female. RVFW and main PA tissues were harvested and characterized through mechanical tests. Tissue stiffness was calculated as the slope of the ensemble stress-strain curve (sum of circumferential and longitudinal stress) at a large strain (&gt;30%) for the RVFW and PA specimens. Results: RVSP increased, and PAT decreased in both models. These changes were significant only in the severe model (Figs. 1A, B). Similarly, RVFW and PA stiffnesses increased significantly only in the severe model (Figs. 1C, D). A significant positive correlation between RVFW and PA stiffness was observed (R2 = 0.59, p=0.0001, Fig. 1E). Conclusions. Our results demonstrate, for the first time, a significant correlation between RVFW and PA stiffening in PH. Proximal PA stiffening changes the pulsatile component of the RV afterload, contributing to the RVFW stiffening, which is known to be a key precursor of RV failure. Our results suggest that the proximal PA stiffening may worsen RV stiffening independent of increases in PA distal resistance. Further studies are needed to determine the role of resistive vs. pulsatile RV afterload in the outcome of RV remodeling.
Abstract 14493: Association of Circulating Ketone Bodies With Cognitive Performance and Dementia in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Parag A Chevli, Christopher L Schaich, Elad Shemesh, Alexis Wood, Margery Connelly, Luqman Arafath Thazhathuveetil Kunahamed, Anurag Mehta, Vardhmaan Jain, Suzanne Craft, Timothy M Hughes, Michael D Shapiro
Journal: Circulation (2023)

Introduction: There is growing interest in the association between circulating ketone bodies (KB) and cognitive function, especially in the context of aging and neurodegenerative diseases. Aim: To examine the prospective association of KB with cognitive performance and clinical dementia among participants without baseline cardiovascular disease (CVD). Methods: KB were measured in 6786 MESA participants by nuclear magnetic resonance spectroscopy at Exam 1 (2000-02). Plasma levels of the 3 ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone) were summed as total KB. Cognitive performance was assessed in 4392 participants at Exam 5 (2010-12) by the Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) tests and re-administered to a subset (n=1838) at Exam 6 (2016-18). We examined the association of total KB with Exam 5 cognitive test performance and with the change in scores from Exam 5 to Exam 6 using multivariable linear regression. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with incident dementia. Incident dementia was identified by ICD codes at hospitalization or death (2000-2018) Results: A total of 6786 participants were included in the analysis (mean age 62 (10) years at Exam 1, 53% women, 61% non-White). There were 585 incident dementia events over a median follow-up of 16.7 yrs. In a fully adjusted model, a doubling of total KB was associated with a greater risk of incident dementia [HR (95% CI): 1.21 (1.05-1.39)]. Total KB were associated with worse Exam 5 DS performance [β (95% CI): -0.28 (-0.44,-0.12)]. However, we did not find an association between total KB and a decline in cognitive performance ( Figure ). Conclusion: In a multi-ethnic population free of baseline CVD, elevated KB levels were associated with incident dementia and worse performance on a test of working memory.
Abstract 14764: Underuse of Preventive Care Among Female Sudden Death Victims
Authors: Schuyler Bain, Susan Keen, Gabriella Day, Kaitlin Shartle, Elizabeth Senter, Camille Bourgeois, Michael Daniels, Ross J Simpson
Journal: Circulation (2023)

Background: Sudden death accounts for approximately 10% of deaths among working age adults. The rate of sudden death among females is one third lower than males, although the burden of chronic medical conditions are similar in victims of both sexes. The reasons for this difference are unclear and may be important in addressing preventive screening underutilization, as preventive screenings have been shown to reduce morbidity and mortality. Research Questions: Does utilization of preventive services differ among sudden death victims and living controls? Do these differences vary by sex? Aims: We aim to describe receipt of preventive screenings and influenza vaccination in sudden death victims and to compare these rates to those of a living control population. Methods: Clinical records from 267 out-of-hospital sudden death victims aged 18-64 in Wake County, North Carolina from 2013-2015 and 1112 demographically matched living controls from the same county and time were compared. Victims were identified by screening Emergency Medical Service records and adjudicated to exclude expected deaths from chronic disease, trauma, suicide, and overdose. Records were systematically reviewed for evidence of influenza vaccination and receipt of colon, cervical, and breast cancer screenings within the past five years, according to USPSTF criteria. Percentage of individuals who received each preventive screening were compared using means difference tests. Binomial regression was performed to investigate the effect of insurance status on preventive care receipt Results: Rates of colonoscopy and influenza vaccination were similar between cases and controls among both sexes. Female victims had low utilization of preventive services and were less likely to have received Pap smears (24.1% vs 50.9%; p&lt;0.001) and mammography (44.0% vs 65.2%; p&lt;0.001) compared to controls. While these differences can be partially explained by insurance status, with both private and public insurance being protective, screening differences remained significant. Conclusion: Significant differences in preventive screenings are present among female sudden death victims and may represent an important behavioral pattern to identify and intervene upon in these vulnerable patients.
Abstract 18437: Efficacy and Safety of Dapagliflozin in Patients With Heart Failure and Previous Myocardial Infarction
Authors: Alexander Peikert, Muthiah Vaduganathan, Brian L Claggett, Ian J Kulac, Alberto Foà, Akshay S Desai, Pardeep S Jhund, Carolyn S Lam, Mikhail N Kosiborod, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Adrian F Hernandez, Sanjiv J Shah, David L DeMets, Lars Kober, Piotr Ponikowski, Marc S Sabatine, Magnus Petersson, Anna Maria Langkilde, John J McMurray, Scott D Solomon
Journal: Circulation (2023)

Introduction: Patients with HF and history of myocardial infarction (MI) may represent a distinct subpopulation with unique pathways of disease progression and elevated risk of clinical events. Whether SGLT2 inhibitors may modify disease trajectory in such individuals is uncertain. Methods: The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with LVEF ≤40% and &gt;40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular (CV) death or worsening HF. Results: Of the total of 11,007 patients, 3,731 (34%) had a prior MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (HR 1.12 [95% CI 1.02-1.24]; Left Panel ). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83 [95% CI 0.72-0.96]) and without prior MI (HR 0.76 [95% CI 0.68-0.85]; P i nteraction =0.36), with consistent benefits on key secondary outcomes as well ( Right Panel ). Serious adverse events did not occur more frequently with dapagliflozin, irrespective of prior MI. Conclusions: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the spectrum of ejection fraction. Dapagliflozin consistently and safely reduces the risk of adverse cardiovascular outcomes, regardless of previous MI. Ongoing trials are actively examining SGLT2 inhibitors when introduced early after acute MI.
Abstract 15706: Common- and Rare-Variant Genetic Architecture of Heart Failure Across the Allele Frequency Spectrum
Authors: David S Lee, John Depaolo, Krishna Aragam, Kiran Biddinger, Mitchell Conery, Ozan Dikilitas, Atlas Khan, Megan Puckelwartz, Nosheen Reza, Benjamin A Satterfield, Zoltan Arany, Thomas P Cappola, Sharlene Day, Jacob Joseph, Elizabeth M McNally, Anjali T Owens, Benjamin F Voight, Michael Levin, Scott M Damrauer
Journal: Circulation (2023)

Background: Heart failure (HF) is a complex trait influenced by environmental and genetic factors. Genome-wide association studies (GWAS) have found common genetic variants associated with HF risk, but the extent that common and rare variants explain risk and implicate similar genes and pathways in HF remains less understood. Methods: For common variants, we meta-analyze existing GWAS of all-cause HF with data from the Million Veteran Program, including 207,346 individuals with HF and 2,151,210 without in diverse populations. We examine rare coding variants in the Penn Medicine BioBank (PMBB) using gene-collapsing association studies and burden heritability regression. We test for an interaction between a polygenic risk score (PRS) based on our GWAS meta-analysis and truncating variants in TTN (TTNtv). Results: GWAS meta-analysis identified 176 risk loci (146 previously unreported), implicating known risk factors for HF and genes involved in cardiac development. New signals at GIPR/ GLP1R highlight potential contributions of dysregulated glucose homeostasis and metabolism in HF. Gene collapsing studies identified associations between HF and rare loss-of-function variants in TTN (OR 2.94, 95% CI 2.43-3.56) and MYBPC3 (OR 7.71, 95% CI 3.97-14.97) at exome-wide significance. HF heritability mediated through common variants (4.5%) was significantly higher than for rare variants (1.8%), but rare variant heritability was further enriched in cardiomyopathy genes compared to common variants (27-fold vs. 3.4-fold). We found a significant interaction between a new multi-ancestry HF-associated PRS (AUC 0.72, 95% CI 0.72-0.73) and TTNtv carrier status (interaction OR 1.32, 95% CI 1.06-1.64). Conclusions: Common and rare variants contribute to HF heritability. Common variant HF heritability is highly polygenic, while rare variant burden heritability appears more concentrated in core cardiomyopathy genes. HF risk conferred by TTNtv carrier status is further increased by an individual’s polygenic contribution. Our results support the continued inclusion of cardiomyopathy genes in rare-variant genetic testing panels for HF but suggest a meaningful polygenic component to HF exists that is not currently captured by clinical genetic testing.
Abstract 15030: Dapagliflozin Reduces Myocardial and Renal NF-kB Expression in Preclinical Models Exposed to Doxorubicin Through Myd-88 and NLRP3 Pathways: An Hystological Study
Authors: Nicola Maurea, Maria L Canale, Irma Bisceglia, Martina Iovine, Andrea Paccone, Alessia Merola, Domenico Gabrielli, Giuseppe Palma, Antonio Luciano, Francesca Bruzzese, Federica Zito Matino, Renato Franco, Vincenzo Quagliariello
Journal: Circulation (2023)

Background: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and HFrEF, conditions that commonly coexist and are interrelated pathophysiologically. Hypothesis: We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p&lt;0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p&lt;0.005). Hystology evaluation indicate reduction NF-kB expression in myocardial and renal tissue in DOXO-DAPA vs DOXO. Radial strain (RS) is 38.8% in DAPA-DOXO vs 14.1% in DOXO groups (P &lt; 0.05); longitudinal strain (LS) is - 23.4 % in DAPA-DOXO vs - 10.5% in DOXO groups (P &lt; 0.001) Conclusion: The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Abstract 13089: Plasma Proteomics and Risk of Incident Ischemic Stroke: Meta-Analysis of the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS)
Authors: Wendy Wang, Rizwan Kalani, Michael J Zhang, Jim S Pankow, Kamakshi Lakshminarayan, Alvaro Alonso, Pamela L Lutsey, W T Longstreth, Christie M Ballantyne, Kuni Matsushita, Adrienne Tin, Michelle C Johansen, Rebecca F Gottesman, Josef Coresh, Wei Pan, Keenan Walker, Susan R Heckbert, Lin Y Chen
Journal: Circulation (2023)

Background: Proteomic profiling can screen large numbers of proteins to discover novel biomarkers related to ischemic stroke. However, prior studies have used a targeted approach or assessed a limited number of proteins (&lt;1300). Using data from the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), we examined the prospective association between 4954 plasma protein targets and incident ischemic stroke. Methods: Participants free of prevalent stroke at the time of proteomic profiling were included. Proteomics data were obtained from the 1990-92 exam in ARIC and the 1992-93 exam in CHS. Plasma proteins were quantified using the aptamer-based SOMAScan platform. Ischemic stroke events were ascertained and adjudicated through 2019 in ARIC and June 30, 2015 in CHS. Cox proportional hazards models adjusting for demographics, ischemic stroke risk factors, and estimated glomerular filtration rate were used. ARIC and CHS results were combined using fixed-effects meta-analysis. A Bonferroni-corrected p&lt;1.01e-5 was considered significant. Results: Median follow-up time in ARIC and CHS were 25 and 12 years, respectively. Among 10,856 ARIC participants (mean age 57 years, 56% female, 23% Black), 890 had an incident ischemic stroke. Among 3,283 CHS participants (mean age 74 years, 62% female, 18% Black), 507 had an incident ischemic stroke. In the meta-analysis, 44 proteins were significantly associated with incident ischemic stroke, of which 32 have not been previously reported ( Figure ). Of the 32, amyloid-like protein and kit ligand were the most strongly associated with ischemic stroke; each SD increment in log 2 (amyloid-like protein) and log 2 (kit ligand) were associated with 20% and 19% lower risk of ischemic stroke. Conclusion: In a meta-analysis of two community-based cohorts, we identified 32 novel protein associations with incident ischemic stroke. Further research is needed to determine causal associations.