tbuckley/cabot-search huggingface dataset:
Abstract 18219: J-Shaped Association Between LDL-Cholesterol Level and Cardiovascular Events: A Longitudinal Follow-Up Study Over 2.4 Million Nationwide Primary Prevention Cohort
Authors: HAN-MO YANG, Chan Soon Park, Kyung-Do Han
Journal: Circulation (2023)

Introduction: Low-density lipoprotein (LDL)-cholesterol lowering treatment showed benefits in patients with high atherosclerotic cardiovascular disease (ASCVD) risk. Hypothesis: Although high LDL-cholesterol level is known to increase ASCVD risks, prognostic implications of low LDL-cholesterol level remain elusive. Methods: Using the data from a Korean Nationwide Cohort, we included 2,432,471 subjects without previous ASCVD. From 2009, subjects were followed for myocardial infarction (MI) and ischemic stroke until 2018. Subjects were stratified according to 10-year ASCVD risks (&lt;5%, 5 to &lt;7.5%, 7.5 to &lt;20%, and ≥20%) and LDL-cholesterol level (&lt;70, 70-99, 100-129, 130-159, 160-189, and ≥190 mg/dL). Results: In the overall population (median follow-up: 9.3 years), the relationship between LDL-C level and cardiovascular events showed J-shaped curve. Subjects with LDL-cholesterol &lt;70mg/dL showed increased risk of myocardial infarction compared to those with LDL-cholesterol 70 to &lt;100mg/dL after adjusting covariates in low ASCVD risk group. Similarly, subjects with LDL-cholesterol 70-99 mg/dL and 100-129 mg/dL had lower stroke risks than those with LDL-cholesterol &lt;70mg/dL in low ASCVD risk group. In contrast, LDL-cholesterol level and risks of MI and stroke showed linear association in high ASCVD risk group. Conclusions: High LDL-cholesterol level is associated with increased risk of MI or stroke, while low LDL-cholesterol level does not warrant safety from ASCVD in the primary prevention setting.
Abstract 16108: Impact of Early Intervention on Quality of Life Outcomes in Peripheral Artery Disease Patients With Chronic Total Occlusion Lesions: Results From the PORTRAIT Registry
Authors: Yasin Hussain, Carlos Mena-Hurtado, Kim G Smolderen, Gaelle Romain
Journal: Circulation (2023)

Background: Peripheral artery disease (PAD) is associated with functional impairment, decreased quality of life, and increased risk of cardiovascular events and mortality. Chronic total occlusion (CTO) lesions occur in up to 40% of PAD patients and pose a challenge for successful endovascular revascularization. We aim to evaluate the baseline characteristics, presentations, procedural outcomes, and quality of life (QOL) outcomes of CTO lesions in PAD compared to non-CTO lesions and the interaction with invasive therapy. Methods: The PORTRAIT registry is a prospective, multicenter, international study that enrolled patients with new or worsening claudication symptoms and an abnormal resting or post-exercise ankle brachial index. Patients with CTO lesions were compared to those without CTO lesions and divided into those who received early invasive treatment (revascularization within three months of enrollment) or noninvasive treatment with medical management. Quality of life outcomes were evaluated using the Peripheral Artery Questionnaire (PAQ) at baseline and during follow-up at 3, 6, and 12 months. Results: A total of 581 matched patients were identified, of which 39% had CTOs and 61% did not. Of the patients with CTOs, 31% underwent early invasive treatment and 69% were noninvasively managed. Patients with CTOs were more likely to present with higher Rutherford classification. The PAQ Summary Score was similar at baseline in patients with CTOs compared to those without CTOs. At 12-month follow-up, early invasive treatment resulted in higher PAQ summary scores in the non CTO arm (82.48 ± 22.79 vs. 67.83 ± 27.00, P&lt;0.001). In the CTO arm, while PAQ summary score was higher at 3 and 6 months in the early invasive arm, the difference was not significant at 12 months (76.18 ± 25.16 vs. 70.60 ± 24.24, P=0.14) Conclusions: Patients with CTO lesions present with higher Rutherford classification than their non-CTO counterparts and both have similar PAQ summary scores at presentation. Early invasive treatment for CTO and non-CTO lesions in PAD patients is associated with significant improvements in quality-of-life outcomes.
Abstract 15509: “Root” Endothelial Cells: A Novel Population That Regulates Lung Capillary and Artery Maintenance and Repair
Authors: Joel James, Aleksandr Dekan, Maki Niihori, Mathews Valuparampil Varghes, Olga Rafikova, Ruslan Rafikov
Journal: Circulation (2023)

Introduction: Pulmonary capillary endothelial cells (ECs) are vital for various lung functions, such as maintaining the capillary network, promoting angiogenesis and facilitating gas and nutrient exchange. Recent advancements in single-cell transcriptomics have uncovered novel populations of general capillary ECs (gCaps) in the lungs. Understanding specialized EC types provides valuable insights into pulmonary vascular diseases. We aimed to challenge current understanding of the regenerative capabilities of lung resident ECs. Methods: Highly enriched ECs isolated from rat and mouse lungs underwent single-cell transcriptomics to explore EC population diversity. Results: UMAP annotation of ECs identified five novel general capillary cell populations (gCaps A-E). Lineage confirmation was achieved by Apelin receptor expression. Two distinct zonations (AV-zonation) were observed between pulmonary artery and vein ECs, with specific gCaps phenotypes (A: Clic4+, B: Flot1+, D: Scn7a+, E: Lingo2+), indicating a gradual phenotypic transition from arterial to vein ECs. Within the AV-zonation, a small population of gCapB (Flot1+) cells, resided at the interface of small artery ECs and gCap A and D, exhibiting characteristics of Root cells. RNA velocity analysis suggested Root cells as the origin of capillary and arterial cell lineages. PAGA analysis revealed high transcriptional similarity between gCapB and gCaps A, D, E and arterial cells, suggesting gCapB's role in capillary and arteriole formation and repair. Root cells exhibited upregulation of transcription factors Fos and Jun, promoting EC proliferation and angiogenesis, along with the Foxo and associated cell cycle regulation pathways. Root cells also displayed high G2M and S scores, indicating mitotic activity, supporting their role as the origin of capillary and arterial ECs. Elevated expression of CDKn1a and 1c, crucial for stem cell maintenance and differentiation further implied the repair potential of Root cells. Conclusions: Root Cells (gCapB) play a crucial role in regulating capillary and arteriole formation and repair by serving as a source of capillary and arterial ECs. These findings enhance our understanding of pulmonary vascular maintenance and repair mechanisms.
Abstract 15873: Association of Heart Failure With Lipoprotein (a) Level: A Systematic Review and Meta-Analysis of Observational and Mendelian Randomization Studies
Authors: Sandeep Singh, Rupak Desai, Dyutima Singh, Brian Brereton, Sara-Joan Pinto-Sietsma
Journal: Circulation (2023)

Background and Aims: The rising incidence of heart failure (HF) in the Western world, despite advancing clinical care, necessitates further exploration of preventive tools and strategies. Lipoprotein(a) [Lp(a)], a recognized cardiovascular risk factor, has been implicated in heart failure. However, existing evidence is inconclusive, which is the impetus for this meta-analysis. Methods: We systematically searched PubMed/Medline, EMBASE, and Scopus for studies on the association of Lp(a) with heart failure occurrence until February 2023. Pooled hazard ratios (HR) and odds ratios (OR) were estimated using random effects models, and heterogeneity was assessed using I2 statistics. Leave-one-out sensitivity analyses were performed by sequentially removing one study at a time. Results: After screening, 11 study populations were included, consisting of 7 mendelian randomization (MR) and 2 adjusted observational studies. MR analysis showed a significant association between increasing Lp(a) levels and heart failure risk (OR 1.064, 95% CI: 1.043-1.086, I2= 97.59%, p&lt;0.001) (Fig 1a). However, in the observational studies, Lp(a) ≥30mg/dL was not associated with increased heart failure risk after adjusting for confounders (OR 0.97, 95% CI: 0.64-1.47, I2=62.01%, p=0.894) (Fig 1b). Leave-one-out sensitivity analysis confirmed the robustness of the MR findings (Fig 1b). Conclusions: Our meta-analysis of mendelian randomization data demonstrates an association between increasing Lp(a) levels and increased risk of heart failure. The underlying mechanisms, whether direct effects on heart muscle contraction or increased risk of ischemic cardiac disease, require further elucidation.
Abstract 16402: Pitx2c-Conditional Knockout Mice May Become a Useful Model to Elucidate the Pathogenesis of Post-Capillary Pulmonary Hypertension
Authors: Daiki Seya, Takahiro Inoue, Sunsuke Baba, Toru Akaike, Susumu Minamisawa
Journal: Circulation (2023)

Introduction: Pulmonary hypertension (PH) is an intractable disease that causes cardiopulmonary dysfunction due to elevated pulmonary arterial pressure. The pathogenesis of PH varies greatly depending on whether the primary lesion is upstream or downstream of the pulmonary capillaries, and the latter, post-capillary PH (pc-PH) caused by pulmonary vein stenosis/obstruction or left heart disease, currently has not an appropriate animal models to study its pathophysiology and pharmacological effects. Hypothesis: We hypothesized that a tissue-specific deletion of a gene involved in the formation of pulmonary veins could create a pathological mouse model of pc-PH. Methods: Focusing on the homeobox transcription factor Pitx2c, which has been reported to be indispensable for the formation of pulmonary veins, we generated Pitx2c-conditional knockout (cKO) mice specific for pulmonary vein and atrial myocardium by crossing Pitx2c-floxed mouse lines with Cre mouse lines for sarcolipin, a sarcoplasmic reticulum membrane protein. Then, we examined the cardiac morphology and hemodynamics of the Pitx2c-cKO mice. Results: Tissue weights of 8-week-old Pitx2c-cKO mice showed that the relative weights of both atria (especially the right atrium), right ventricle and lungs were significantly increased in Pitx2c-cKO mice, while the relative weight of the left ventricle was decreased. Furthermore, echocardiography performed on 3-month-old Pitx2c-cKO mice revealed that the right ventricle was markedly enlarged in Pitx2c-cKO mice, with enlarged pulmonary artery annulus diameter and increased velocity time integral (VTI) of blood flow through the right ventricular outflow tract. Pitx2c-cKO mice also had significantly decreased left ventricular end-diastolic diameter (LVDd), end-systolic diameter (LVDs), and mass (LVM). On the other hand, there was no difference in left ventricular fractional shortening (%FS) or tricuspid annular plane systolic excursion (TAPSE), indicating no cardiac dysfunction in Pitx2c-cKO mice. Cardiac catheterization also revealed elevated right ventricular pressure in some Pitx2c-cKO mice. Conclusion: These primary findings suggest that the Pitx2c-cKO mice may be a model for understanding the pathogenesis of pc-PH.
Abstract 213: High-Throughput Analysis of Mitochondrial Morphology in Neurons Post-Mitochondrial Transplantation
Authors: Eriko Nakamura, Cyrus Kuschner, Tomoaki Aoki, Yusuke Endo, Lance B Becker, Kei Hayashida
Journal: Circulation (2023)

Background: Mitochondrial transplantation (MTx) improves neurological and survival outcomes in rats after cardiac arrest. However, the impact of transferred mitochondria on native mitochondrial features in neurons remains poorly assessed. Evaluating mitochondrial morphology provides insights into post-MTx mitochondrial dynamics in recipient neurons, aiding the understanding of cellular processes and targeted therapy development. Aim: To investigate whether increased uptake of donor mitochondria influences the morphology of native mitochondrial networks in neurons. Methods: We conducted in vitro MTx using the HT-22 neuron cell line. Native mitochondria in neurons were pre-labeled with MitoTracker Green. Extracellular mitochondria were isolated from healthy adult rat muscle tissue, labeled with MitoTracker Deep Red, and co-cultured with neurons. Confocal microscopy captured 2D fluorescence images. MitoHacker, a computational program, facilitated high-throughput analysis of 27 mitochondrial morphometric markers. Results: We analyzed 62 images of cells ( Figure ). MitoHacker successfully identified features of native and transferred donor mitochondria. Linear regression analysis revealed that total donor mitochondrial area had positive correlations with native mitochondrial counts, total area, minor axis length of mitochondrion, mitochondrial averaged density, and mitochondrial branch length, and a negative correlation with distance between mitochondrial location and nucleus (all P&lt;0.05). These findings suggest that increased amounts of transferred mitochondria can positively influence native mitochondrial biogenesis, proliferation, accumulation, and activated mitochondrial dynamics and networking in recipient neurons. Conclusion: Using the deep learning-based mitochondrial morphology analysis, our study provides evidence that MTx significantly impacts mitochondrial morphology and dynamics in recipient cells.
Abstract 170: Late CCL23 Response is Associated With Poor Outcomes After Cardiac Arrest
Authors: Sergey V Ryzhov, Joanne T deKay, Elena Chepurko, Vadim Chepurko, Lacey Knudsen, Christine Lord, Meghan Searight, Sergey Tsibulnikov, Michael P Robich, Douglas B Sawyer, David Gagnon, Teresa May, Richard Riker, David B. Seder
Journal: Circulation (2023)

Introduction: Chemokines mediate the entrance and migration of leukocytes to inflamed tissue areas, contributing to the intensity of local inflammation. We found a high level of circulating chemokines, CCL2, CCL4, and CCL23, in patients resuscitated after cardiac arrest (CA). Hypothesis: The level of circulating chemokines is associated with systemic immune cell response, neurologic injury, and outcome after cardiac arrest. Goal: To characterize temporal chemokine and immune cell responses to cardiac arrest. Methods: A total of 42 patients after CA and 22 control subjects who underwent coronary artery bypass grafting (CABG) were enrolled. ELISA was used to determine chemokines in plasma at 6 hr, 24 hr, 48 hr, and 72 hr after CA and in CABG patients pre-operatively. Flow cytometry was used to determine subpopulations of immune cells. We measured changes in chemokines over time and the association of chemokine levels with outcome, markers of inflammation, and brain injury. A mouse model of CA was employed to assess the activation of human neutrophils locally in brain tissue. Results: Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a late elevation in CCL23 at 48 hours after resuscitation. A higher level of CCL23 was associated with a worse cerebral performance category score (r s =0.3, p=0.042) and higher mortality (r s =0.3, p=0.039). Positive correlations were found between CCL23 and an increased number of neutrophils, cellular mediators of inflammation, and levels of neuron-specific enolase. To study the potential role of neutrophil activation locally in injured brain tissue, we injected human post-CA neutrophils into the bloodstream of successfully resuscitated mice and measured the CCL23 in human neutrophils in mouse blood and brain 24 hours after resuscitation. An increased level of CCL23 production was found in mouse brain neutrophils compared to those in the peripheral circulation. Conclusion: It is well known that an early intense inflammatory response is associated with poor outcomes after CA. Our new data indicate that late activation of neutrophils in brain tissue may represent an additional mechanism contributing to ongoing brain tissue injury via the production of CCL23 after cardiac arrest.
Abstract 14970: Left Ventricular Assist Device Outcomes 5 Years From Heart Transplant Allocation Score Change
Authors: Jacob Agronin, Meredith Brown, Val Rakita, Yoshiya Toyoda, Mohammed Kashem
Journal: Circulation (2023)

Background: The United Network for Organ Sharing (UNOS) adopted new criteria for the heart allocation score on 10/18/2018 to reflect changing trends of candidates’ mortality while awaiting transplant. We examined the impact of these policy changes on rates of left ventricular assist device (LVAD) implantation and outcomes posttransplant from a relatively newer UNOS database. Methods: The UNOS registry was used to identify first-time adult heart recipients with LVAD at listing or transplant who underwent transplantation between 1/1/2016 and 3/10/2020. Survival data was collected through 3/30/2023. Those listed prior to 10/18/2018 but transplanted after were excluded. Patients were divided into before or after change groups. Demographics and clinical parameters were compared. Survival was analyzed with Kaplan-Meier curves and log-rank tests. A p&lt;0.05 was considered significant. Results: We identified 4599 heart recipients with LVAD in the before (n=3767) and after (n=832) score change eras. The after group had a lower rate of LVAD implantation while listed compared to the before group (19.4% vs 34.5%, p&lt;0.0001), younger average age (53.1 ± 12.2 vs 54.1 ± 11.9, p=0.0350) and more likely to be female (24.9% vs 19.6%, p=0.0007); in both groups, most recipients (62%) were white. There was significantly farther distance from the donor hospital to transplant center in the after group (259.5 ± 246.8 NM vs 143.2 ± 182.1 NM, p&lt;0.0001) and decreased waitlist days (83.5 ± 103.5 vs 369.0 ± 458.5, p&lt;0.0001). Recipients in the after group were more likely to receive a CDC increased-risk donor organ (37.5% vs 30.2%, p=0.0002). Survival at 5-years was significantly reduced in the after group (60.5% vs 78.9%, p&lt;0.0001). Conclusions: The allocation score change in 2018 yielded considerable changes in MCSD implantation strategy and survival. The rate of LVAD implantation decreased with profoundly worse 5-year survival, showing further divergence from prior short term posttransplant data.
Abstract 12759: Thymidine Phosphorylase Enhances SARS-CoV-2 Spike Protein and Platelet Factor 4 Complex Formation: A Potential Novel Mechanism That May Account for COVID-19-Associated Thrombosis
Authors: Renat Roytenberg, Hong Yue, Autumn DeHart, Krista Denning, Wei Li
Journal: Circulation (2023)

Introduction: Scattered studies suggest that SARS-CoV-2 spike protein (SP) promotes platelet activation, though the exact mechanism is unknown. Thymidine phosphorylase (TYMP), which facilitates platelet activation and thrombosis, is significantly increased in the plasma and lungs of COVID-19 patients, suggesting that TYMP may play a role in the COVID-19 milieu. Hypothesis: We hypothesize that TYMP enhances SP/platelet factor 4 (PF4) complex formation and inhibition of TYMP attenuates SP-induced thrombosis and/or inflammation. Methods: BEAS-2B cells were treated with SP- or its receptor binding domain (RBD)-containing COS-7 cell lysate, or control cell lysate (p3.1) and TYMP and STAT3 expression were determined by western blot. The effect of SP on thrombosis was examined in K18-hACE2 and K18-hACE2/ Tymp -/- mice using the ferric chloride-induced carotid artery injury thrombosis model. SP-, TYMP-, or PF4-encoding plasmids were co-transfected into COS-7 and their protein interactions were assessed using co-IP, Blue Native-PAGE, and immunocytochemistry. Results: SP increased expression of TYMP and pY705-STAT3 in BEAS-2B. siRNA-mediated knockdown of TYMP reduced STAT3 activation. SP significantly enhanced thrombosis in the K18-hACE2 mice, which was inhibited by simultaneously treating mice with tipiracil, a selective TYMP inhibitor ( Figure ). K18-hACE2/ Tymp -/- mice were resistant to SP-enhanced thrombosis. For the first time, we found that SP, PF4, and TYMP form a complex whose formation is dose-dependently enhanced by TYMP. Conclusions: Our studies suggest that SARS-CoV-2 SP enhances TYMP expression and is prothrombotic and proinflammatory. TYMP inhibition, either via genetic knockout or by its chemical inhibitor, attenuates SP-enhanced thrombosis. TYMP promotes the formation of a PF4/SP complex, which provides a novel insight into COVID-19-associated thrombosis. TYMP could be a novel therapeutic target for COVID-19-associated sequelae.
Abstract 16393: Incident Cardiometabolic Risk Factors in Breast Cancer Patients Stratified by Race and Ethnicity
Authors: Andrea E Diaz, Marilyn L Kwan, Cecile A Laurent, Janise M Roh, Carlos Iribarren, Jamal S Rana, Lawrence H Kushi, Kerryn Reding, Eileen Rillamas-Sun, Charles P Quesenberry, Heather Greenlee, Richard K Cheng
Journal: Circulation (2023)

Background: The development of incident cardiometabolic risk factors in racial and ethnic minority groups of women with breast cancer (BC) has not been well-characterized. Hypothesis: We expect a higher risk of incident cardiometabolic risk factors [hypertension (HTN), diabetes (DM), dyslipidemia] in racial and ethnic minority women with BC without a history of these conditions compared with non-Hispanic White (NHW) women with BC. Methods: The Pathways Heart Study is a prospective cohort study of women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California. Cumulative incidence rates of incident HTN, DM, and dyslipidemia determined from the electronic health record (using two separate ICD 9/10 codes in the 2 years prior to BC diagnosis, lab values, and medication dispensings) were calculated using a competing risk framework for overall death. Sub-distribution hazard ratios for incident HTN, DM, and dyslipidemia were estimated using Fine and Gray proportional hazards regression, adjusted for a priori identified covariables, and stratified by race and ethnicity. Results: A total of 14,942 women with BC had mean age 61.2 years and were 65% NHW, 7.5% Black, 14.4% Asian, 11.9% Hispanic, 0.4% Pacific Islander, and 0.8% American Indian/Alaska Native. Compared to NHW women, Black, Hispanic, Asian, and Pacific Islander women had higher risk of incident DM (Table 1). Black and Asian women had higher risk of incident HTN compared with NHW women. Asian women had higher risk of incident dyslipidemia compared with NHW women. Conclusions: Racially and/or ethnically diverse women with BC experienced higher risk of incident DM, HTN, and dyslipidemia compared with NHW women with BC. Asian women consistently had a higher risk of each cardiometabolic risk factor. It is critical to better characterize health disparities in the field of cardio-oncology to inform future cardiovascular disease prevention and treatment strategies.