tbuckley/cabot-search huggingface dataset:
Abstract 17022: Transcriptomic Analysis of Calciphylaxis Tissue Reveals Novel Genes Related to Vascular Calcification and Overlap With Coronary Artery Disease
Authors: Sujin Lee, Kangsan Roh, Kuldeep Singh, Wanlin Jiang, Katrina Ostrom, Claire Birchenough, Lova Kajuluri, Adam L Johnson, Scott Krinsky, Houda Bouchouari, Christian L Lino Cardenas, Matthew Eagleton, Rosalynn M Nazarian, Clint L Miller, Sagar Nigwekar, Rajeev Malhotra
Journal: Circulation (2023)

Introduction: Calciphylaxis is a rare, understudied disease of accelerated vascular calcification affecting the skin and soft tissue leading to painful wounds, amputations, and reduced survival. The underlying mechanisms of calciphylaxis remain incompletely understood. Objective: In this study, we aimed to identify altered signaling pathways and novel differentially expressed genes (DEGs) associated with calciphylaxis and to characterize the protein expression of top DEGs in the vasculature. Methods: 6 case and 3 control tissues were obtained from our institution’s calciphylaxis biorepository (NCT03032835). RNA sequencing analysis and pathway analysis were performed using the KEGG database. Immunofluorescent (IF) staining with co-localization analysis was performed on independent case-control samples for the top 9 upregulated DEGs. In vitro functional assessment was performed using human vascular smooth muscle cells (VSMC). Results: 783 DEGs (FDR-adjusted p-value ≤0.05) were identified, 543 of which were upregulated (Fig 1A). 27 altered pathways enriched for calcification, thrombosis, and inflammation were identified. The top 9 upregulated DEGs (adjusted p-values ≤1.2 x10-7) were KYNU, IFI16, KCNJ15, RAB31, FNDC1, HIF1α, DEPP1, NFIL3, and TSP1. On IF, 7 of the top 9 upregulated DEGs exhibited higher protein expression compared to matched controls, some of which are highlighted in Figure 1B. These 7 genes were all upregulated in RNA sequencing analysis of human coronary arteries with atherosclerotic lesions compared to coronaries without lesions. Functional assessment of the top 3 genes in this coronary artery disease analysis (FNDC1, KYNU &amp; KCNJ15) revealed potent effects on calcification, proliferation, and migration of VSMCs. Conclusions: Novel genes identified in this transcriptomic study of calciphylaxis uncovered similarities with coronary artery disease and have identified previously unknown regulators of VSMC calcification.
Abstract 18780: Prognostic Value of Cardiovascular Magnetic Resonance Feature Tracking Strain in Patients With Suspected Cardiac Sarcoidosis
Authors: Yugene Guo, Sanya Chhikara, Parag Bawaskar, Pal Athwal, Jeremy Markowitz, Lisa Von Wald, Henri Roukoz, Chetan Shenoy
Journal: Circulation (2023)

Background: Cardiac sarcoidosis (CS) is associated with a high risk of ventricular arrhythmia (VA) and heart failure (HF). Cardiovascular magnetic resonance imaging (CMR) is often used for the diagnosis and prognostication of suspected CS. Small studies have shown promise for ventricular strain as a marker of adverse outcomes in suspected CS. Aim: We aimed to investigate the prognostic value of CMR global longitudinal strain (GLS) in patients with suspected CS. Methods: Using a retrospective cohort design, we studied consecutive patients with histologically proven sarcoidosis who underwent CMR for the evaluation of suspected CS from 2004 to 2021. Feature-tracking GLS was assessed for the left and right ventricles (LV and RV). Kaplan-Meier and Cox proportional hazards regression analyses were used to determine the association between GLS, and VA and HF composite endpoints. Results: Among 557 patients (mean age 54 years, 47% women), the median LVGLS was -14.8% and the median RVGLS was -16.2%. Over a median follow-up of 5.8 years, 39 patients reached the VA endpoint, and 63 reached the HF endpoint. On Kaplan-Meier analyses, patients with either LVGLS or RVGLS worse than the median had a higher estimated cumulative incidence of both endpoints compared with patients with GLS better than the median (log-rank P&lt;0.001 for all comparisons). On multivariable regression analyses, LVGLS was not associated with the VA endpoint [hazard ratio (HR) 0.93 per 1% worsening; 95% confidence interval (CI) 0.83-1.05; P=0.25], but RVGLS was independently associated (HR 1.13 per 1% worsening; 95% CI 1.02-1.25; P=0.015) in a model that included the extent of late gadolinium enhancement (LGE) and the presence of the high-risk CMR phenotype. Neither LVGLS (HR 1.08, 95% CI 0.98-1.12; P=0.11) nor RVGLS (HR 1.04, 95% CI 0.96-1.13; P=0.31) were independently associated with the HF endpoint in a model that included age, pulmonary hypertension, and the high-risk CMR phenotype. Conclusions: In patients with suspected CS, RVGLS was independently associated with long-term VA but not HF outcomes, while LVGLS was not independently associated with either. Research is warranted into the role of CMR RVGLS to aid clinical decision-making regarding implantable cardioverter-defibrillators.
Abstract 18737: Coronary Artery Calcium for Allocation of Aspirin in Light of the 2022 USPSTF Guideline Recommendations: Results From the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Dhiran Verghese, Ellen Boakye, Michael J Blaha, Sanjay Manubolu, Jairo Aldana, April Kinninger, Zeina A Dardari, Robert Cubeddu, Mazen Albaghdadi, Michael D Miedema, Joseph Yeboah, Sion Roy, Miguel Cainzos, Matthew J Budoff
Journal: Circulation (2023)

Introduction: The 2022 USPSTF guidelines issued a grade C recommendation for aspirin in patients aged 40-59 and recommended against its use in patients ≥ 60 years. We sought to assess if coronary artery calcium (CAC) would allow for personalized allocation of aspirin. Methods: Using MESA, aspirin naïve participants without high-risk bleeding features were identified. Participants were grouped by age into &lt;60, ≥ 60 and stratified by CAC and ASCVD risk. The number needed to treat (NNT 5 ) and number needed to harm (NNH 5 ) was assessed by applying a 11% relative risk reduction in CVD and a 44% relative risk increase in major bleeding (2022 USPSTF meta-analysis) to the observed CVD and bleeding events from MESA Results: Of 6,814 participants, 4,506 met inclusion criteria. 2,235 were &lt;60 years and 2,268 were ≥ 60 years. Figure-1 displays the interplay between baseline estimated ASCVD risk and CAC burden. In participants &lt;60 years of age, both CAC and ASCVD risk &gt;10% identified subgroups in whom the NNT was lower than the NNH: CAC 1-99 (NNT 5 -313, NNH 5 -517); CAC ≥100 (NNT 5 -152, NNH 5 -367); ASCVD risk &gt;10% (NNT 5 -155, NNH 5 -554) Fig-1. In those ≥ 60 years CAC ≥100 identified subgroups with a lower NNT 5 -128 than NNH 5 -168, while ASCVD risk stratification did not. 6% of adults &lt;60 years with &lt;10% ASCVD risk and 30.3% of adults ≥ 60 years who had CAC ≥100, and who demonstrated benefit from the use of Aspirin, would not qualify for the use of aspirin using only ASCVD risk as per the 2022 USPSTF guideline recommendations. Conclusions: CAC identifies subgroups of patients &lt;60 as well as those ≥ 60 years who would derive a net benefit from aspirin in primary prevention. A significant proportion of patients will be missed if only ASCVD risk scores are used for allocation of aspirin. CAC should be used to risk stratify individuals to personalize the allocation of aspirin
Abstract 17016: Mitral Valve Prolapse Induces Localized Left Ventricular Fibrosis in a Novel Large Animal Model
Authors: Antonia van Kampen, Jordan Morningstar, Yasufumi Nagata, Guillaume GOUDOT, David Izquierdo-Garcia, Peter Caravan, Luis Guerrero, Koushiar Yaghoubian, Rebecca Woodcock, Michael A Borger, Serguei Melnitchouk, Russell A Norris, Robert A Levine
Journal: Circulation (2023)

Background: Mitral valve prolapse (MVP) has recently been associated with localized left ventricular (LV) fibrosis linked to malignant arrhythmia and sudden cardiac death. However, fibrosis mechanisms remain unknown, with no large animal model to distinguish mechanical and genetic influences. Goals: We tested the hypothesis that surgically induced MVP leads to localized myocardial fibrosis in LV regions mechanically linked to the mitral valve, aiming to establish a reproducible large animal model of MVP as a platform for mechanistic studies. Methods: In 6 adolescent sheep, MVP was created surgically by replacing primary chordae tendineae to P2 with longer artificial chords. Intraoperative echocardiography and LV pressure-volume loops were obtained. After 7 months recovery, cardiac MRI with gadolinium and T1-mapping were done before end-of-study surgery with repeat echo and pressure-volume loops. Three sham surgery sheep were similarly studied. Myocardial samples from valve-linked papillary muscle and inferobasal LV and control septal regions were analyzed by histology. Bulk RNA was sequenced on samples from 3 MVP and 3 sham sheep. Results: All 6 MVP sheep showed pronounced localized LV fibrosis in valve-linked regions but not control regions on MRI, with replacement fibrosis by Masson’s trichrome stain. Sham sheep had no fibrosis, with similar LV function and contractility at end-of-study. RNA sequencing revealed gene expression differences between the two LV regions in MVP sheep and the valve-linked regions of MVP vs sham sheep. Conclusions: In a novel surgically created large animal model of MVP, localized fibrosis is induced in formerly healthy LV myocardium. This suggests a mechanical mechanism is sufficient to create the localized LV fibrosis associated with arrhythmia in MVP patients. This model provides a platform to study fibrosis mechanisms and investigate therapeutic approaches to avoid catastrophic events in MVP patients.
Abstract 195: Dose-Dependent Induction of Nitric Oxide Production in Human Induced Pluripotent Stem Cell-Derived Endothelial Cells by Poloxamer 188
Authors: Gaoxian Chen, Ian Y Chen, Zhu Li, Matthias L Riess, Detlef Obal
Journal: Circulation (2023)

Background: Poloxamer 188 (P188), a triblock copolymer, protects against ischemia/reperfusion injury. The precise mechanisms remain incompletely understood. Human induced pluripotent stem cells (hiPSCs) constitute a unique model system, allowing the parallel generation of different cell types from individual patients to study drug-specific effects in human tissue. Here, we aimed to investigate the potential of P188 to induce nitric oxide (NO) production in hiPSC-derived endothelial cells (ECs) and its effect on cell viability during hypoxia-reoxygenation. Methods: hiPSC-ECs were cultured in phenol red-free endothelial Cell Growth Medium-2 and subjected to hypoxia (1% oxygen) at 37°C for 36 hours. At the end of hypoxia, the cell culture medium was supplemented with NO-sensitive fluorescent dye DAF-FM diacetate (1:5000 dilution, final concentration 1 uM, 30 min). Hypoxic medium was removed, and P188 at different concentrations (0.1 nM to 100 nM) was added for 8 hours. DAF fluorescence and cell viability were assessed at the end of reoxygenation. One-Way ANOVA &amp; Dunn's post hoc test was utilized for statistical analysis (* P &lt; 0.05 vs. untreated control group). Results: P188 dose-dependently increased hiPSC-ECs viability (control group: 53±2%, 0.01 nM P188: 59±2%, 100 nM P188: 64±5%). Interestingly, DAF fluorescence increased dose-dependently as well (control group: 182±9%, 0.1 nM P188: 199±11%, 100 nM P188: 264±4%, data expressed as percent of normoxic cells, n=3 / treatment). Conclusion: This suggests that P188 protects hiPSC-ECs with increased NO production, shedding new light on the underlying mechanisms of its cardioprotective effects.
Abstract 18622: The Role of MicroRNA-98 in the Context of Myocardial Ischemia-Reperfusion Injury During Late Pregnancy
Authors: Laila Aryan, Lejla Medzikovic, Min Li, Gregoire Ruffenach, Shadie Rahman, Leana Esdin, Ehsan Bastanhagh, Wasila Sun, Yalda A Afshar, Mansoureh Eghbali
Journal: Circulation (2023)

BACKGROUND: We have shown that the late-pregnant (LP) rodent exhibits a higher susceptibility to myocardial ischemia-reperfusion injury (IRI) compared to non-pregnant (NP). The molecular mechanisms remain unclear. The dysregulation of multiple microRNAs (miRs) in IRI suggests their potential as promising targets for therapeutic interventions. Methods: Female Sprague-Dawley rats in both NP and LP states underwent occlusion of the left anterior descending coronary artery (LAD) for a duration of 45 minutes, followed by reperfusion for 3 hours or 24 hours. Expression of miR was assessed via fluorescent in situ hybridization. MicroRNA-microarray profiling was conducted on hearts of NP and LP rats subjected to IRI. Female H9c2 rat cardiomyoblast cells were transfected with miR mimics and inhibitors, and subjected to hypoxia/reoxygenation. Blood samples were obtained from NP, LP, and ischemic heart disease (IHD) patients. MiR98 inhibitor was administered at the initiation of reperfusion. Results: MicroRNA-microarray analysis revealed upregulation of microRNA-98-5p (miR-98) in LV of LP at baseline, and a further upregulation after IRI. The expression of Stat3 and Pgc-1α were decreased in LV of LP rats compared to NP rats upon IRI. Fluorescent in situ hybridization revealed expression of miR-98 in cardiomyocytes in NP rats, which was increased in LP rats. Overexpression of miR-98 in vitro in female H9c2 cells decreased Stat3 and Pgc-1α levels, and promoted apoptosis, oxidative stress, and inflammatory markers. MiR-98 inhibitor in LP rats at the onset of reperfusion reduced infarct size, apoptosis, oxidative stress, and inflammatory markers and was associated with upregulation of Stat3 and Pgc-1α. In humans, plasma miR-98 levels were significantly higher in healthy LP compared to healthy NP individuals and even higher in LP patients with IHD patients. CONCLUSIONS: We show the detrimental effects of miR-98 by promoting cardiomyocyte oxidative stress, inflammation, and apoptosis via its targets Stat3 and Pgc-1α in the context of late pregnancy. MiR-98 could be a novel cardio-protective strategy or biomarker in late pregnancy.
Abstract 16897: The Association of Lipoprotein(a) With Major Adverse Cardiovascular Events Among Individuals With and Without Baseline Atherosclerotic Cardiovascular Disease: The Mass General Brigham Lp(a) Registry
Authors: Adam N Berman, David Biery, Stephanie Besser, Avinainder Singh, Brittany N Weber, Daniel M Huck, Sanjay Divakaran, Jon Hainer, Arthur Shiyovich, Gurleen Kaur, Michael J Blaha, Christopher P Cannon, Jorge Plutzky, James L Januzzi, John N Booth, J. A Lopez, Shia Kent, Khurram Nasir, Marcelo Di Carli, Deepak L Bhatt, Ron Blankstein
Journal: Circulation (2023)

Introduction: Lipoprotein(a) [Lp(a)] is associated with increased atherosclerotic cardiovascular disease (ASCVD) events. However, whether the optimal Lp(a) threshold for risk-assessment should differ based on baseline ASCVD status is unknown. Hypothesis: To assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without a history of ASCVD. Methods: Retrospective cohort of patients with Lp(a) measured at two academic medical centers in Boston, MA from 2000-2019. To assess the association of Lp(a) with incident MACE (cardiovascular mortality, myocardial infarction, or ischemic stroke), the following Lp(a) percentile groups were generated: 1 st -50 th (0 - 41 nmol/L; reference), 51 st -70 th (42 - 111 nmol/L), 71 st -90 th (112 - 215 nmol/L), 91 st -100 th (&gt;216 nmol/L). Individuals with severe renal dysfunction or a malignant neoplasm were excluded. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. Results: After applying eligibility criteria, 16,419 patients (median age 60, 41% female) were analyzed with a median follow up of 11.9 years. Patients with ASCVD were older and had higher rates of cardiovascular risk factors. Among the 10,181 (62%) patients with a history of ASCVD, individuals in the 71 st -90 th and 91 st -100 th percentile groups had similarly increased hazards of MACE (adjusted HR = 1.33, p&lt;0.001 and adjusted HR = 1.34, p&lt;0.001 respectively). Among the 6,238 individuals without baseline ASCVD, only individuals in the 91 st -100 th Lp(a) percentile group had a significantly increase hazard of MACE (adjusted HR 2.05, p&lt;0.001), Figure . Conclusions: In a large, contemporary US cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the Lp(a) threshold for risk assessment may be lower in secondary prevention when compared with primary prevention.
Abstract 18584: Predictive Accuracy Of The Pooled Cohort Equations For Estimating Atherosclerotic Cardiovascular Disease Risk Among Women Exposed To Potentially Cardiotoxic Breast Cancer Therapies
Authors: Vanessa P Patterson, Heather Anderson, Laura Saba, Lavanya Kondapalli
Journal: Circulation (2023)

Introduction: Risk estimation is a critical component in clinical decision making for preventive cardiovascular care. Suboptimal identification and management of cardiovascular disease (CVD) risk, may contribute to excess CVD morbidity and mortality among breast cancer (BC) patients and survivors. This study aimed to assess the performance of the Pooled Cohort Equations (PCEs) in predicting atherosclerotic cardiovascular disease (ASCVD) events among a real-world population of adult women treated for BC. Methods: Using electronic medical record data collected between Jan. 1, 2011 and Jan. 31, 2023, this external validation study retrospectively identified a cohort of BC women, age 40-79, without history of ASCVD in the one year prior to initiation of a potentially cardiotoxic BC therapy. For all cohort members with cholesterol and blood pressure measurements recorded within one year prior to the index cancer therapy exposure (n=1,239), a 5-year ASCVD risk estimate was calculated. Predictive accuracy of the risk estimate was assessed using a Poisson model-based framework for calibration, including evaluation of calibration-in-the-large, the calibration slope, and calibration plots. To account for potential biases related to informative censoring, calibration was assessed among an inverse probability of censoring weighted (IPCW) pseudopopulation with stabilized and unstabilized weights, and a complete case cohort (n=306). Results: Among the IPCW pseudopopulation, calibration-in-the-large, expressed as a standardized incidence ratio, was 1.85 (95% CI: 1.73, 1.98), indicating that, on average, women in this subpopulation experience a significantly higher number of ASCVD events than expected from baseline PCE risk estimates. The calibration slope, estimated at 0.55 (95% CI: 0.45, 0.66), and evaluation of calibration plots, further indicate particularly poor performance of the PCEs at low and high levels of estimated risk. Findings were consistent across the assessed populations. Conclusions: When calculated prior to initiation of a potentially cardiotoxic BC therapy, the PCEs significantly underestimate 5-year ASCVD risk for BC women, indicating this commonly used ASCVD risk estimate is poorly calibrated for this subpopulation.
Abstract 18571: Fetal Sirolimus Therapy for Giant Cardiac Rhabdomyoma
Authors: Razleen Brar, Amanda Kalan, Rukmini R Komarlu
Journal: Circulation (2023)

Background: Cardiac rhabdomyomas in tuberous sclerosis regress spontaneously, large masses can cause hemodynamic compromise. Fetal sirolimus therapy cause regression. We report a case of successful fetal therapy in mother with fetally diagnosed tuberous sclerosis (TS). Case: A 22 year old female with uncomplicated pregnancy and negative cardiac history presented for fetal echocardiogram at 21 weeks due to cardiac masses. Fetal echocardiogram: levocardia, normal segmental cardiac anatomy, d-looped ventricles, normally related great arteries. Multiple masses seen in both ventricles, largest in LV free wall from base to apex and another involving mitral papillary muscle, no initial obstruction, patent ductal and aortic arches. Amniocentesis confirmed diagnosis of TS. Fetus was followed with serial monitoring of cardiac outputs and size of masses. At 30 weeks, LV mass had doubled from 1.7 to 4 cm with LV diastolic dysfunction and reduced cavity size, large pericardial effusion, left ventricular outflow tract obstruction (LVOTO). IVC was mildly dilated with liver enlargement. Fetal MRI confirmed diagnosis of rhabdomyoma with small subependymal nodules. Given LVOTO and large effusion, mother was started on sirolimus therapy with loading dose of 5 mg and subsequent dose adjustments for target trough sirolimus of 10 to 15 ng/ml. Serial mother monitored with labs, weekly ultrasounds and echocardiograms. Mass decreased in size with resolution of effusion and LVOTO. At 37 weeks, due to oligohydramnios, baby was delivered without hemodynamic compromise. Postnatally no LVOTO and normal systolic function with mass measuring ~ 2.0 cm. Baby has been followed off sirolimus therapy. Role of Imaging: Serial echocardiograms enabled optimal decision making to treat mother with sirolimus therapy. Conclusions: Maternal sirolimus therapy can help regress cardiac rhabdomyomas with hemodynamic implications with serial close outpatient monitoring.
Abstract 169: Effect of Fingolimod-Induced Leucocyte Sequestration on Inflammatory Response and Neurological Damages in a Porcine Model of Cardiac Arrest
Authors: Yara Abi Zeid Daou, Antoine Bois, Naoto Watanabe, Estelle Faucher, Fanny Lidouren, Mathieu Surenaud, Sophie Hue, Matthias Kohlhauer, Bijan Ghaleh, Renaud Tissier
Journal: Circulation (2023)

Introduction: Early alterations in immune function are observed after cardiac arrest, with sepsis-like syndrome and cerebral infiltration by leucocytes. Hypothesis: The pharmacological sequestration of leucocytes within lymphoid tissues with the sphingosine 1-phosphate analog fingolimod could mitigate the inflammatory response and provide neuroprotection after cardiac arrest. Methods: Anesthetized pigs underwent 14 min of ventricular fibrillation followed by resuscitation. Animals randomly received fingolimod (1 mg/kg i.v.) or saline two hours prior to cardiac arrest (n=6 in each group). Blood samples were collected for blood cells count and dosages of cytokines (Luminex) and neurofilament light chain (NFL, Quantmetrix). Neurological dysfunction was assessed 24 hours after cardiac arrest. Results: In the Fingolimod group, total blood leucocytes and lymphocytes counts were reduced as compared to Controls, both prior to and after cardiac arrest (Figure 1A). Conversely, blood levels of Interleukin [IL]-R1a, IL-6, IL-8, IL-18 were not different among groups (e.g., Figure 1B for IL-1Ra). As illustrated in Figures 1C and 1D, NFL blood levels and neurological dysfunction score were also not different in both groups after cardiac arrest. Conclusion: Despite reducing blood total leucocytes and lymphocytes count, fingolimod did mitigate neither the circulating levels of pro- or anti-inflammatory cytokines nor the neurological damage following cardiac arrest. Leucocytes sequestration in lymphocyte tissue might not be sufficient to provide neuroprotection after cardiac arrest. Figure 1: Blood lymphocytes (A), Interleukin-1Ra blood level (B), Neurofilament light chain blood level (NFL; C) and Neurological Dysfunction score at Day 1 after cardiac arrest