tbuckley/cabot-search huggingface dataset:
Abstract 4119062: A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling
Authors: Hanqiang Deng, Jiasheng Zhang, Martin Schwartz
Journal: Circulation (2024)

Background: Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cell (EC) sensing of elevated fluid shear stress (FSS) from blood flow induces vessel outward remodeling to restore physiological FSS, but mechanisms are poorly understood. The Smad1/5 pathway, which is maximally activated at physiological FSS and suppressed at higher flow, opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling. Methods: In vitro flow studies used ECs in a parallel plate flow chamber. In vivo mouse studies used a carotid-jugular fistula model to induce high flow outward remodeling in the carotid artery, and femoral artery ligation to examine recovery from ischemia and arteriogenesis in the hindlimb. Results: Suppression of Smad1/5 at high FSS is mediated KLF2-dependent induction of the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes. Conclusions: Suppression of Smad1/5 through a KLF2-BMPER pathway is required for high FSS-mediated outward remodeling. Mimicking this pathway with BMP9/10 antibodies improves vascular remodeling in diabetic mice, suggesting a potential new therapeutic approach for ischemic disease.
Abstract 4120854: Case Report: Elevated HDL in Familial Hyper-Alpha-Lipoproteinemia: Atheroprotective or Atherogenic?
Authors: Zahra Manji, Jenna Mahoney, Samir Mehta, myrna sutera, Stephen Meng
Journal: Circulation (2024)

Introduction: Familial hyper-alpha-lipoproteinemia (HALP) is a heterogenous genetic lipid disorder that is found in only 8% of the population and manifests as elevated HDL levels above the 90 th percentile. HALP is due to mutations in various genes including cholesteryl ester transfer protein (CETP), hepatic lipase, or apolipoprotein C-III (APOC3). While epidemiological studies have noted an inverse relationship between high HDL and the development of coronary artery disease, recent data have shown a lack of causal atheroprotective effects. We present a case of a patient with significantly elevated HDL and peripheral vascular disease. Case Description: Patient is a 64-year-old female with past medical history of peripheral artery disease with occlusion of the left femoral artery and popliteal arteries status post angioplasty, hypertension, type 2 diabetes, alcohol use, and CKD Stage 4 who presented to the advanced lipid clinic for management of elevated lipoproteins. Patient’s laboratory data was significant for total cholesterol (TC) of 375 mg/dL, a high-density lipoprotein (HDL) of &gt;200 mg/dL, triglycerides (TG) of 66 mg/dL, and a low-density lipoprotein (LDL) of 175 mg/dL. Further testing revealed elevated apolipoprotein A-I of 231 mg/dL. Patient was subsequently initiated on a high intensity statin with improvement in her lipid panel with a TC of 247 mg/dL, HDL of 133 mg/dL, TG of 50 mg/dL, and LDL of 106 mg/dL, with plan for further uptitration of lipid therapy to target LDL &lt;70 mg/dL. Discussion: CETP exchanges cholesteryl esters from HDL for TG, making HDL smaller and more TG-rich. Studies have shown that in vitro addition of CETP and hepatic lipase, which hydrolyzes phospholipids and TG, into CETP-deficient patients led to the development of very small HDL particles that were able to remove cholesterol from lipid laden macrophages. Conversely, larger HDL molecules seen in CETP-deficient patients did not have such anti-atherogenic properties. In addition to recognizing HALP in the setting of elevated HDL, it is also important to exclude secondary causes of elevated HDL, such as primary biliary cirrhosis and high-dose niacin. Genetic testing should also be considered.
Abstract 4118360: Lipocalin10 is Critical for Macrophage Efferocytosis to Repair Myocardial Ischemia/Reperfusion Injury
Authors: Yu Zhang, Xiaohong Wang, Ruiyao Zhu, Masahide Sakabe, Debabrata Chowdhury, Zhixin Li, Jing Chen, Wei Huang, Mei Xin, Guo-Chang Fan
Journal: Circulation (2024)

Introduction: Efficient clearance of dead/dying cells by macrophages (MΦs) (termed efferocytosis) is critical for timely repairing the injured heart after ischemia/reperfusion (I/R). Prior work by us and others shows that Lipocalin 10 (Lcn10), a secreted protein of lipocalin family, can regulate MΦ polarization and is greatly downregulated in cardiac tissue of patients with heart failure. However, the potential role of Lcn10 in MΦ efferocytosis during cardiac I/R has never been investigated. Methods: Wild-type (WT) and Lcn10-knockout (KO) mice were subjected to 45 minutes of ischemia via the ligation of left anterior descending artery (LAD) followed by reperfusion. Cardiac function was measured by echocardiography. Flow cytometry was utilized to assess MΦ efferocytosis. Bone marrow-derived MΦs (BMDMs) were used to test efferocytosis in vitro and dissect mechanism. Dead cells were prepared by treating red-dye-labelled H9C2 cells with H 2 O 2 (1mM, 2h). Results: After co-culturing BMDMs with dead H9C2 cells for 2h, we observed a 25% reduction of efferocytosis in Lcn10-KO BMDMs, compared to WTs. Using Lcn10-KO mCherry mouse model (cardiomyocyte-specific overexpression of mCherry in Lcn10-KO background), we consistently found that cardiac MΦs in Lcn10-KO mice taken up fewer dead mCherry-myocytes at 4 days post-I/R surgery, leading to an increased accumulation of cardiac dead cells, higher serum levels of troponin I, greater myocardial fibrosis, and dramatically impaired cardiac function, compared to WT mCherry controls. In contrast, pre-treatment of BMDMs with recombinant Lcn10 protein (rLcn10) enhanced efferocytosis by 50%. Mechanistically, RNA-seq analysis revealed that many efferocytosis-related genes were dysregulated ( e.g., downregulation of Id 1, Id 3, Itga 8, Itga v, Cd 44, Cx3cr 1, Msr 1, and upregulation of Sirp α) in Lcn10-KO BMDMs, compared to WTs. Interestingly, most of these dysregulated genes are controlled by transcription factors Id1/3. Further studies showed that rLcn10 interacted with Cd44 and activated the expression of its downstream Id1/3, leading to enhanced MΦ efferocytosis. Importantly, rLcn10-mediated efferocytosis was greatly impaired by pre-treatment of MΦs with either anti-CD44 blocking antibody (KM201, 10µg/ml) or Id1/3 inhibitor (AGX51, 25µM). Conclusion: Our data indicate that Lcn10 is essential for MΦ efficient efferocytosis to repair I/R-induced cardiac damage though affecting the Cd44-Id1/3 signaling and its related MΦ surface receptors.
Abstract 4120229: Shift in body mass index category and associated cardiometabolic risk factors: a post hoc analysis from the SURMOUNT-4 trial
Authors: Naveed Sattar, Reshmi Srinath, Clare Lee, Hui Wang, Arian Plat
Journal: Circulation (2024)

Background: In SURMOUNT-4, participants with obesity demonstrated a mean weight reduction of 21% during the 36-week lead-in with the maximum tolerated dose (MTD) of tirzepatide (TZP). During the 52-week double-blind period, participants who switched to placebo (PBO) experienced a 14% weight regain, while those who continued TZP achieved an additional 6% weight reduction. This post hoc analysis assessed whether participants who shifted to a lower BMI category had improved cardiometabolic factors. Methods: Shift in BMI category (&lt;25 kg/m 2 , 25 to &lt;30 kg/m 2 , 30 to &lt;35 kg/m 2 , 35 to &lt;40 kg/m 2 , and ≥40 kg/m 2 ) from baseline (week 0) during the lead-in period (week 36) and at the primary endpoint (week 88) and from week 36 to week 88 was assessed in participants from SURMOUNT-4 randomized to TZP MTD (N=332) or PBO (N=329). BMI shifts were grouped into “improved” (shift to ≥1 lower category) or “not improved” (stable/attenuated [no change/shift to a higher category]). Changes from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, vitals and lipid profile were assessed. Results: From weeks 0 to 36, 296 (89%) participants improved in BMI category with TZP, and none had attenuated (Table). From weeks 36 to 88, 130 (39%) participants improved in BMI category with TZP, while the majority (99%) randomized to PBO did not. Overall, from weeks 0 to 88, 304 (92%) vs 189 (57%) participants improved in BMI category with TZP vs PBO, respectively, where the improvements observed in the PBO group originated from the 36-week lead-in period. In general, participants who improved in BMI category at week 88 were noted to have greater improvements in cardiometabolic parameters with TZP vs PBO, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, triglycerides, and cholesterol (total, non-HDL-c, LDL-c, and VLDL-c). Conclusions: In this post hoc analysis of SURMOUNT-4, the majority of TZP-treated participants shifted to lower “improved” BMI categories. Shift to an improved BMI category was accompanied by improved cardiometabolic risk factors, suggesting that TZP treatment may lower further cardiovascular outcomes. Relevant outcomes trials are ongoing.
Abstract 4121793: A Pressure-Volume Loops Approach Predicts Outcomes After Double Switch Operation For Congenitally Corrected Transposition Of The Great Arteries with Intact Ventricular Septum
Authors: Nikhil Thatte, Peter Hammer, Gerald Marx, Rebecca Beroukhim, Kimberlee Gauvreau, Ryan Callahan, Ashwin Prakash, Sitaram Emani, David Hoganson, Pedro Del Nido, Sunil Ghelani
Journal: Circulation (2024)

Background: Double switch operation (DSO) for congenitally corrected transposition of the great arteries with intact ventricular septum (ccTGA) has a high rate of post-DSO LV dysfunction. Hypothesis: LV pressure-volume area (PVA), a surrogate of myocardial O 2 consumption, is a superior marker of LV preparedness and is associated with adverse outcomes after DSO. Aims: 1. Derive a mathematical relationship to estimate LV PVA (ePVA) from catheterization (pressure) and imaging (volumetric) data, using directly measured PVA (mPVA) as reference 2. Assess if lower ratio of LV ePVA to RV ePVA (as an internal control) is associated with adverse outcome after DSO. Methods: Aim 1: Using conductance catheter derived invasive subpulmonary LV PV loops, mPVA was recorded as the sum of stroke work (SW) and potential energy (PE). A mathematical relationship was established with standard catheterization/imaging data to estimate ePVA. Aim 2: In a retrospective cohort, LV:RV ePVA ratio was calculated as above, and along with standard clinical metrics, assessed for relationship with a composite outcome of ≥ moderate LV dysfunction, transplant, or death post-DSO. Results: Aim 1: In 20 PV loop studies in 18 pre-DSO patients, there was a strong linear correlation between measured and estimated SW and PE (R 2 &gt; 0.9 and p&lt;0.0001 for both). ePVA yielded high agreement and low bias compared to mPVA (mean bias 0.5±11%). Aim 2: Composite outcome occurred in 6/42 DSO patients (14%). LV:RV ePVA ratio (0.57 [0.49, 0.61] vs 0.90 [0.73, 1.1], p&lt;0.001) and LV:RV pressure ratio (0.80 [0.77, 0.87] vs 1.13 [1.01, 1.23], p&lt;0.001) were lower in those with adverse outcome. There were no differences in other pre-operative parameters. On time to event analysis, lower LV:RV ePVA ratio was the strongest determinant (HR 39, 95% CI 15-100; C Index 0.94), while lower LV:RV pressure ratio was the only other predictor (HR 24, 95% CI 13-42; C Index 0.88). In 8 patients with borderline pressure ratios of 0.77-0.88, ePVA ratio was an excellent discriminator - 3 patients with ePVA ratio of ≥0.67 had good outcomes, whereas 5 patients with ePVA ratio &lt;0.67 had adverse outcomes. Conclusion: LV:RV ePVA ratio &gt;0.67 is a strong and novel predictor of LV preparedness for DSO in patients with ccTGA.
Abstract 4120741: Estrogen Regulates Abdominal Aortic Aneurysm Tregs via CD45 <sup>+</sup> Fibroblast-derived IL-33
Authors: Wangling Hu, Jingyong Li, Luna Zhai, Zhuo Chen, Ni Xia, Tingting Tang, Shaofang Nie, Zhang Min, Jiao Jiao, Bingjie Lv, Fen Yang, Yuzhi Lu, Lingfeng zha, Muyang Gu, Xia jun Hu, Shuang Wen, Dan Li, Desheng Hu, Li Zhang, Weiming Wang, jiong hu, Guo-Ping Shi, xiang cheng
Journal: Circulation (2024)

Background: Sexual dimorphisms manifest during the progression of abdominal aortic aneurysm (AAA). Regulatory T cells (Tregs) are a subset of T cells characterized by their immunosuppressive and tissue-repairing functions, therefore playing a protective role in AAA. Aims: We aim to elucidate the mechanism underlying sexual dimorphism in Tregs presented in AAA aortas, which is significant for unraveling the pathogenesis of AAA and developing gender-specific therapeutic approaches. Methods and Results: AAA mice were induced by receiving porcine pancreatic elastase. By flow cytometry, we observed that ovariectomy (OVX) increased the ratio of Tregs in female mice, while estrogen led to a decrease in aortic Tregs. Additionally, compared to littermate controls, estrogen receptor α (ERα) KO mice exhibited an increase in Treg ratio. Similar results were observed for the ST2 + Treg ratio. IL-33, as an alarming molecule, can promote the maintenance of ST2 + Tregs in tissues. Western blot revealed lower IL-33 expression levels in female mice than in male mice. By analyzing the IL-33 expression profiles of various cells in AAA tissue, we found that IL-33 mainly originates from fibroblasts. We found two subpopulations of fibroblasts, CD45 + and CD45 - fibroblasts. Immunofluorescence on the aortas verified the presence of cells co-expressing CD45 and PDGFRα in AAA fragments. Furthermore, IL-33 expression only showed gender differences in CD45 + fibroblasts. Adoptive transfer of CD45.1 + mouse bone marrow macrophages into CD45.2 + mice revealed that aortic CD45.1 + cells could regain the PDGFRα phenotype, with a lower proportion of female PDGFRα + cells in CD45.2 - CD45.1 + cells than in male mice. Lyz2(cre/+); Rosa26(tdtomato/+) mice showed the presence of lyz2-tdtomato + cells expressing PDGFRα in the aortic adventitia after AAA induction. This suggests that CD45 + fibroblasts are partially derived from bone marrow macrophages, which can migrate to aneurysms and acquire a PDGFRα phenotype. Conclusions: Female sex hormones negatively regulate CD45 + fibroblast formation and IL-33 secretion between female and male mice during AAA. This resulted in reduced Treg function in female mice compared to male mice.
Abstract 4119613: Evaluation of Gender, Racial and Ethnic Differences in Time to PCI in the Pre and Post Covid-19 Era
Authors: Jack Jnani, Maikel Kamel, Spencer Weintraub, Riya George, Brandon Impastato, Aditya Sood, Andrew Tsai, Ji-Cheng Hsieh, Austin Cheng, Jack Alboucai, Kishen Bulsara, Shreya Srivastava, Miguel Alvarez Villela, Matthew Griffin, Matthew Pierce
Journal: Circulation (2024)

Introduction: Percutaneous Coronary Intervention (PCI) is recommended for reperfusion of patients presenting with ST-segment myocardial infarction (STEMI) within 90 minutes. In this study, we sought to identify differences in PCI timing based on gender, race and ethnicity in the pre- and post-COVID era. Methods: We collected retrospective data on 760 patients admitted with STEMI at our quaternary academic medical center from 2018-2022. We defined our binary outcome as time to PCI less than 90 minutes, and adjusted for transfers from outside hospitals. We utilized univariate logistic regression analysis to analyze the association of demographic, clinical, and cardiac catheterization details on our outcome. We then utilized multivariate logistic regression analysis to determine the association of our covariates of interests with time to PCI. The logistic regression model was adjusted for collinearity which were deemed not significant. Results: Among our study population, COVID did not significantly impact whether or not a patient had a diagnostic cardiac catheterization on univariate analysis (OR 2.68, 95% CI 0.61-18.40, p=0.23). However, the post-COVID era was significantly associated with a delayed time to PCI on multivariate analysis [OR 1.62, 95% CI 1.04-2.55, p=0.035) [Figure 1]. In addition, females were 1.8x more likely to have a delayed PCI than males on multivariate regression [OR 1.80, 95% CI 1.10-2.95, p= 0.019) [Figure 1]. Interestingly, on multivariate analysis, females were more likely to have delayed reperfusion in the pre-COVID era (OR 2.92, 1.29-6.77,p= 0.01) but not the post-COVID era (OR 1.54, 0.78-3.06,p=0.2134). Patients in the post-COVID era had increased risk of having their culprit coronary not revascularized on multivariate analysis (OR 2.85, 1.2-8.03, p= 0.03). Conclusions: At our center, COVID did not significantly impact cardiac catheterization rates. However, COVID was significantly associated with delayed reperfusion timing and not revascularizing culprit vessels. Females were much more likely to have a delayed PCI than males in the pre-COVID era which was not seen following COVID-19.
Abstract 4121234: Macrophage activation in aorticorenal ganglion as a potential trigger to induce renal sympathetic overactivation-related ventricular arrhythmias after acute myocardial infarction
Authors: Wenxi Lian, Wenfeng Hu, Dongze Zhang
Journal: Circulation (2024)

Background: Ischemia-related ventricular arrhythmia is the leading cause of death in patients after acute myocardial infarction (AMI). Although the therapeutic potential of renal denervation (RDN) for ventricular arrhythmias has been reported, RDN-induced adverse complications partially limit its use in the clinic. Since neuroinflammation has recently emerged as a key factor for sympathetic overactivation in the central and peripheral nervous systems, this study aims to test if macrophage activation in renal sympathetic postganglionic (RSP) neurons located in the aorticorenal ganglion (ARG) contributes to renal sympathetic overactivation-related ventricular arrhythmogenesis post-AMI. Methods and Results: AMI was induced by surgical ligation of the left anterior descending artery in rats. Data from immunofluorescence staining showed that the expression of Iba1, TNF-α, and IL-1β was increased in ARGs at 3 days post-AMI rats compared with sham rats, suggesting that macrophage activation and neuroinflammation occurred in the ARG at an early stage after AMI. Direct recording of renal sympathetic nerve activity (RSNA) found that the RSNA was much higher in the 3 days post-AMI rats than in sham rats. To validate the contribution of macrophage activation to AMI-elevated RSNA, we depleted macrophages in ARGs by local microinjection of clodronate liposomes (CL) into ARGs. Immunofluorescence staining data showed that microinjection of CL into ARGs attenuated the AMI-induced macrophage activation (Iba1) and neuroinflammation (TNF-α and IL-1β) in ARGs. Flow cytometry data also confirmed that macrophage depletion in ARGs reduced the AMI-elevated macrophage infiltration in ARGs, which was accompanied by a significant decrease in RSNA in CL-treated AMI rats. To test the ventricular arrhythmogenesis post-AMI, we measured ventricular tachycardia/fibrillation (VT/VF) from 24-hour telemetry ECG recording in conscious rats. Our data showed that macrophage depletion in ARGs alleviated AMI-induced ventricular arrhythmogenesis, as evidenced by a significant reduction in the occurrence of VT/VF in CL-treated AMI rats. Conclusion: These data suggest that macrophage activation and neuroinflammation in the ARG might be critical factors responsible for the renal sympathetic overactivation-related ventricular arrhythmia post-AMI. Inhibiting macrophage activation and neuroinflammation in the ARG could be an effective strategy to achieve the antiarrhythmic effect of RDN after AMI.
Abstract 4120496: Cannabis Use Among Heart Failure Hospitalizations and Cardiovascular Outcomes. A Five-Year Retrospective Study
Authors: Endurance Evbayekha, Deana Mikhalkova, Chioma Enyi, Adeolu Oladunjoye, Onyedika Ilonze
Journal: Circulation (2024)

Introduction: The use of cannabis is on the rise. A few retrospective studies have demonstrated an association between cannabis use and ischemic heart disease and stroke. However, its implications in the already established heart failure (HF) population has not been well studied. We aimed to address this gap. Methods: We employed the National Inpatient Sample database (2016-2020) and used ICD-10 codes to identify all patients ≥18 years old with a history of HF. Then, we divided them into two groups: those with and without a history of cannabis use. A greedy nearest-neighbor 1:1 propensity score matching (PSM) followed by multivariable logistic regression analysis was used to account for baseline differences (including cigarette smoking) and to predict the outcomes. The outcomes were ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), uncontrolled hypertension (HTN), arrhythmias, acute kidney injury (AKI), and stroke. Results: Of the 4,283,620 HF hospitalizations, 1.6% (67,795) used cannabis, and 72% (48,825) were male. Compared to the non-cannabis group, the group with cannabis use was younger, with a mean age of 53 vs 68 years, p&lt;0.0001. After PSM, 56,233 with a history of cannabis use were matched to 56,233 hospitalizations without cannabis use history. The population with cannabis use had a higher association with uncontrolled HTN 1.5 (1.4-1.6), NSTEMI 1.3 (1.23-1.36), STEMI 1.15 (1.05-1.25), stroke 1.14 (1.05-1.23), and AKI 1.05 (1.02-1.1), (p&lt;0.0001, for each). Arrhythmias 0.96 (0.94-1.01, p=0.1) did not differ between both groups. Conclusion: Among the hospitalized HF population, those with a history of cannabis use had a higher association with uncontrolled HTN, STEMI, NSTEMI, AKI, and stroke. They were also younger than their non-cannabis use counterparts. More research is needed to determine the significance of these findings.