tbuckley/cabot-search huggingface dataset:
Abstract 11012: Cognitive Dysfunction Among Patients Referred for Transcatheter Aortic Valve Implantation: Results of the Montreal Cognitive Assessment and Clinical Impact at 6 Months
Authors: Charles Monnin, Matthieu Besutti, Fiona Ecarnot, Benoit Guillon, Marion Chatot, Romain Chopard, Mohamed Chouaib Yahia, Nicolas Meneveau, Francois Schiele
Journal: Circulation (2021)

Introduction: Detection of Cognitive Dysfunction (CD) is not routinely performed among patients undergoing Transcatheter Aortic Valve Implantation (TAVI). Hypothesis: We sought to determine whether CD has an impact on the clinical course of these patients, during hospitalization at the time of TAVI and up to 6 months afterwards. Methods: The MoCA was performed before TAVI by an experienced operator in an unselected population of patients referred for TAVI. CD was defined according to the MoCA score: No CD if score ≥26, mild CD if score 18-25, moderate if 10-17 and severe if &lt;10. Multivariate Cox logistic regression analysis was used to determine the impact of CD on procedural success of TAVI, length of stay, 6 month survival, re-admission, and change in clinical status (changes in NYHA class and/or functional status). Results: MoCA was performed in 83 consecutive patients. TAVI was performed using femoral access and local anesthesia in all patients. There were no procedural deaths, and 2 deaths at 6 months. The median age was 85 years, and median Euroscore I was 11.62. The median MOCA score was 22, CD was excluded in 17(20%), mild in 50 (60%), moderate in 15 (18%) and severe in one patient. No difference was observed in rate of procedural success, 6 month mortality, re-admission, degree of dyspnea by NYHA between the different cognitive groups. Length of stay after the TAVI procedure was lower in patients without CD, compared to those with CD at any level: 3±1 days versus 4.3±1 days, p=0.045, and p=0.02 by multivariate analysis (figure). Conclusions: Among patients referred for TAVI, mild or moderate CD was observed in 80% of patients. Patients without CD had a shorter length of stay at the time of TAVI, but CD was not associated with worse prognosis or clinical status at 6 months.
Abstract 11764: Peripheral Artery Disease is an Independent Risk Factor for Heart Failure by ABI
Authors: Shubhang K Bhatt, Katie Murphy, Daniel Sykora, Marlene Girardo, Justin N Shipman, Michael Apolinario, Paul W Wennberg, David Liedl, Fadi Shamoun
Journal: Circulation (2021)

Introduction: Patients with concomitant peripheral artery disease (PAD) and heart failure (HF) are known to have increased morbidity and mortality. Though they share common risk factors, the utility of HF screening in patients with PAD remains controversial and without international consensus. We sought to clarify whether PAD is an independent risk factor for HF. Methods: We performed a retrospective analysis of adult patients without a history of heart failure who underwent ankle brachial index (ABI) measurement for any indication between 1995-2020. Patients were then stratified by ABI: PAD with low ABI (&lt;1.10), healthy (ABI= 1.10-1.39), and PAD with elevated ABI (&gt;1.39). The associations between PAD and incident diagnosis of heart failure, systolic dysfunction (HF with reduced ejection fraction, HFrEF), and diastolic dysfunction (HF with preserved ejection fraction, HFpEF) were assessed. All patient and outcomes variables were obtained using the institutional electronic health record. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, hypertension, diabetes, and active tobacco use. Results: The cohort included 36,816 patients (median follow-up 4.21 years), of whom 2,116 (5.7%) were diagnosed with HF. Among HF patients, 1,110 (3.0%) had HFrEF and 1,006 (2.7%) had HFpEF. Both low and elevated ABI groups were associated with an increased risk of HF, both HFrEF, and HFpEF. After multivariable analysis, PAD with elevated ABI was associated with higher overall HF risk (HR, 2.36 [95% CI, 2.03, 2.73]) than low ABI (HR, 1.56 [95% CI, 1.40, 1.74]) when compared to normal ABI. Similarly, PAD with elevated ABI was associated with greater risk of HFrEF (HR, 2.37 [95% CI, 1.93, 2.92]) and HFpEF (HR, 1.82 [95% CI, 1.48, 2.25]) than PAD with low ABI (HFrEF: HR 1.77 [95% CI, 1.52, 2.07], HFpEF: HR 1.31 [95% CI, 1.12, 1.52]). Conclusions: PAD, especially with elevated ABI, is an independent risk factor for heart failure even after adjusting for common HF risk factors. Our findings support HF screening in PAD patients, but longitudinal data on HF morbidity and mortality is necessary to evaluate the value of this practice.
Interstitial lung disease before and after COVID-19: a double threat?
Authors: Claudia Valenzuela, Grant Waterer, Ganesh Raghu
Journal: European Respiratory Journal (2021)

<b>Pre-existing ILD and pulmonary fibrosis increases the risk to manifest severe COVID-19. Residual interstitial lung changes and sequelae have been observed in COVID-19 survivors. A closer and standardised long-term follow-up of these patients is needed.</b>https://bit.ly/3jWBPCG
Abstract 10102: Duration of Disease and the Quality of Life of the Patients with Atrial Fibrillation
Authors: Ryo Nakamaru, Nobuhiro Ikemura, John Spertus, Takehiro Kimura, Yoshinori Katsumata, Taishi Fujisawa, Hiroshi Miyama, Keiichi Fukuda, Seiji Takatsuki, Shun Kohsaka
Journal: Circulation (2021)

Introduction: Several recent studies have reported that early rhythm control for atrial fibrillation (AF) was associated with a lower risk of adverse cardiovascular outcomes than usual care. However, the effects of early intervention for AF on patients’ reported quality of life (QOL) in real-world patients, outside of selected clinical trials, have not been investigated. Methods: We analyzed 2,892 patients from a prospective, multicenter registry of consecutive AF patients (KiCS-AF) enrolled between 2012 to 2018 in Japan. Patients were divided into quartiles according to their AF duration (time interval between AF diagnosis and referral to the cardiology service; Q1 median 0 days [IQR:0-0], Q2 14 [7-22], Q3 119 [55-329], Q4 1968 [1122-3590]). The quartiles of AF duration were then compared with patients’ QOL improvement, as assessed by changes in the Atrial Fibrillation Effect on Quality-of-Life-overall summary score (AFEQ-OS [0 to 100]; higher score reflecting better QOL) over 1 year after the treatment initiation with analysis of covariance adjusted for differences in baseline characteristics. Results: Patients with the shortest duration of AF (Q1) were more likely to be older, female, and to have a higher incidence of heart failure compared with other groups. At 1 year, patients had improved AFEQT-OS scores, regardless of AF duration (adjusted difference [standard error], Q1, 8.2 [0.6], Q2 8.7 [0.6], Q3 8.7 [0.5], Q4 8.0 [0.5], p=0.67). The adjusted differences were similar in patients that underwent rhythm- (Q1 12.3 [0.7], Q2 12.2 [0.7], Q3 10.9 [0.7], Q4 12.2 [0.7], p=0.41) or rate-control strategy (Q1 3.3 [0.7], Q2 4.4 [0.8], Q3 4.5 [0.7], Q4 3.7 [0.8], p=0.64: Figure). Conclusions: The duration of AF was not associated with QOL improvement, regardless of treatment strategy. For symptomatic patients, the duration of AF should not be a deterrent to treatment.
Abstract 9610: High Levels of Myeloperoxidase Are Similar Across ASCVD Risk Groups and Are Associated with Markers of Liver Fibrosis and Kidney Function in a Workforce Population
Authors: Olga A Iakoubova, Judy Louie, Dov Shiffman, Michael Mcphaul, Marc S Penn
Journal: Circulation (2021)

Background: High blood levels of free myeloperoxidase (MPO) identify patients at risk for cardiovascular disease. We investigated levels of MPO according to 10-year ASCVD risk and the association between high MPO and markers of liver fibrosis and kidney disease. Methods: The study included participants in employer-sponsored annual health assessment (August 2020 to March 2021, n=33,984, 63% women, median age 47, IQR 36 to 56). Age and sex adjusted logistic models assessed the association between high MPO and non-alcoholic fatty liver disease (NAFLD) fibrosis score, liver Fibrosis-4 (FIB4) score, and estimated glomerular filtration rate (eGFR), stratified by 10-year ASCVD risk groups. Results: High MPO (&gt;540 pmol/L) was found in 3% (n =925), 4% (n=184), and 5% (n =63) of the low (&lt;7.5%), intermediate (7.5% to 20%), and high (&gt;20% or prevalent disease) ASCVD risk groups, respectively. High MPO (&gt;540 vs. ≤540 pmol/L) was associated with high NAFLD fibrosis score (&gt;0.676 vs. &lt;-1.455): OR = 4.7, 95%CI 3.5 to 6.2, high FIB4 score (&gt;3.25 vs. ≤3.25): OR =3.4, 95%CI 1.8 to 6.4 and low eGFR (&lt;60 vs. ≥60 mL/min/1.73m 2 ): OR =1.8, 95%CI 1.4 to 2.4. The associations varied according to ASCVD risk (Figure). In the high ASCVD risk group, MPO was not associated with either NAFLD fibrosis score, FIB4 score, or eGFR (P ≥0.2 for all) and the risk differed according to ASCVD risk group (&gt;20% vs. ≤20%) for NAFLD fibrosis score (P int =0.03) and eGFR (P int =0.01). Conclusion: The fraction of those with high MPO did not appreciably differ across ASCVD risk groups and most participants with high MPO levels in this workforce population were in the low ASCVD risk group. This observation is consistent with the hypothesis that subjects in the high ASCVD risk group are more likely to be receiving preventive therapies, whereas guidelines dictate that those in moderate and low risk groups may not. Investigating the association of MPO levels in ASCVD risk groups according to preventive therapy intensity is warranted.
Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice
Authors: Yipeng Sui, Zhaojie Meng, Jianzhong Chen, Jingwei Liu, Rebecca Hernandez, Miko B. Gonzales, Taesik Gwag, Andrew J. Morris, Changcheng Zhou
Journal: Environmental Health Perspectives (2021)

Background: Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo. Objective: We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors. Methods: Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD. Results: DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings. Discussion: Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs. https://doi.org/10.1289/EHP9262
Abstract 10203: Effect of Hydroxychloroquine on Endothelial Function in Older Adults with Moderate-Severe Sleep Apnea: A Randomized Clinical Trial
Authors: Leticia Maria Tedesco Silva, Gustavo Waclawovsky, Liliana Boll, Beatriz Juliana Caye Rossi, Bruna Eibel, Sandro Cadaval Gonçalves, Maria Irigoyen, Denis Martinez
Journal: Circulation (2021)

Introduction: Obstructive sleep apnea (OSA) is considered a low-grade chronic inflammatory disease. OSA impairs endothelial function and increases cardiovascular mortality. Hydroxychloroquine (HCQ), an anti-inflammatory drug, seems to reduce cardiovascular mortality. In animal and in vitro models, HCQ improved endothelial function. Its effects on endothelial function of patients with OSA is unknown. Hypothesis: Hydroxychloroquine can improve endothelial function in patients with OSA. Methods: Adults older than 65 years with an apnea-hypopnea index (AHI) greater than 15 events/hour were allocated to receive either 400mg of HCQ or placebo daily for eight-weeks. The randomization was computer-generated and pharmacy-controlled. Participants and outcome evaluators were blinded to the group allocation. Home sleep apnea test and measurements of flow-mediated dilation of brachial artery (FMD) and peripheral artery tonometry (PAT) were performed at baseline and follow-up in a research facility. The primary outcomes were the change in FMD (Δ%FMD) and change in PAT reactive-hyperemia index (ΔRHI). Change in AHI (ΔAHI) was a secondary outcome. Generalized estimating equations were used to verify time*group interaction. Results: Fourteen patients were assigned to the HCQ group and fifteen patients to the placebo group between April 2019 and May 2020 with no losses to follow-up. The recruitment was interrupted due to COVID-19 pandemic. Mean Δ%FMD was 0.35 (95% CI –4.26 to 4.97) in placebo group and 0.48 (95% CI –4.08 to 5.04) in HCQ group. Mean ΔRHI was 0.02 (95% CI -0.11 to 0.07) in placebo group and 0.05 (95% CI -0.24 to 0.13) in HCQ group. Mean ΔAHI was 7 (95% CI -1 to 15) in placebo group and -4 (95% CI -11 to 2) in HCQ group. P values for time*group interaction were 0.97, 0.74 and 0.04, respectively. No important adverse events have occurred. Conclusions: In this trial, HCQ did not improve endothelial function measured by FMD and PAT in older adults with OSA. A slight but significant reduction in AHI was observed in HCQ group, suggesting that some specific inflammatory mechanisms participate in OSA causation that could become a future therapeutic approach.
A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
Authors: Victor Pallarès, Ugutz Unzueta, Aïda Falgàs, Anna Aviñó, Yáiza Núñez, Annabel García-León, Laura Sánchez-García, Naroa Serna, Alberto Gallardo, Lorena Alba-Castellón, Patricia Álamo, Jorge Sierra, Lídia Cedó, Ramon Eritja, Antonio Villaverde, Esther Vázquez, Isolda Casanova, Ramon Mangues
Journal: Biomaterials (2021)

Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4+ AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4+ AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4+ leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.
Abstract 10162: NT-proBNP is Associated with Stroke, Heart Failure Hospitalizations, and Death in Patients with Atrial Fibrillation Without Oral Anticoagulation Regardless of Heart Rhythm
Authors: Maria Tomasdottir, Ziad Hijazi, Johan Lindback, Alexander Benz, Stuart J Connolly, John W Eikelboom, Agneta G Siegbahn, Lars C Wallentin, Jonas Oldgren
Journal: Circulation (2021)

Background: NT-proBNP is elevated in patients with a diagnosis of atrial fibrillation (AF) and associated with risk of stroke and other outcomes. The associations have mainly been studied in patients on oral anticoagulation and not considering if samples were obtained during AF or sinus rhythm. We investigated the association of NT-proBNP with heart rhythm and cardiovascular (CV) events in patients with AF without oral anticoagulation. Methods: Plasma samples were obtained at baseline in 3184 patients with diagnosis of AF (2142 in AF rhythm at blood sampling) receiving aspirin in two multicenter randomized clinical trials with median follow-up 1.2 years (AVERROES) and 3.8 years (ACTIVE A), respectively. NT-proBNP was analyzed using Elecsys electrochemiluminescence immunoassay. Association of NT-proBNP with clinical variables was assessed with multivariable linear regression models. Association with outcomes were estimated with Cox-regression models adjusting for clinical variables. Results: Median age was 71 years, 57.8% were men, and median NT-proBNP 713 ng/L (25 th -75 th percentiles, 282-1388 ng/L). Variables contributing to NT-proBNP level were, in reducing order: AF rhythm (ratio of geometric means 2.9), age, creatinine, and prior heart failure. Levels of NT-proBNP were significantly associated with ischemic stroke (HR 3 rd vs 1 st quartile 2.1, 95%CI 1.5-3.0), heart failure hospitalizations (HR 2.2, 95%CI 1.6-2.9), and CV death (HR 2.4, 95% CI 1.8-3.3), all p&lt;0.001, without significant interaction with AF rhythm. Figure depicts NT-proBNP distribution by rhythm and association with ischemic stroke. Conclusion: In patients with a diagnosis AF, plasma levels of NT-proBNP are three times higher during AF rhythm compared with sinus rhythm. Higher levels of NT-proBNP are independently associated with ischemic stroke, heart failure hospitalizations, and CV death in AF patients without oral anticoagulation treatment, irrespective of heart rhythm.
High Prevalence of CHF and Diabetes in AML Long-Term Survivors - a Patient Forever?
Authors: Anna Sophia Moret, Eva Telzerow, Maja Rothenberg-Thurley, Maria Cristina Sauerland, Elke Burgard, Friederike H. A. Mumm, Jan Braess, Bernhard J. Wörmann, Utz Krug, Wolfgang E. Berdel, Wolfgang Hiddemann, Karsten Spiekermann, Pia Heußner, Klaus Kraywinkel, Dennis Görlich, Klaus H. Metzeler
Journal: Blood (2021)
Abstract 10391: Elevated Plasma Branched-Chain Amino Acids Level Promotes Atherosclerosis Progression by Facilitating Macrophage Polarization Toward M1 Phenotype That Results in the Increase of Inflammation
Authors: Shuai Zhao, Kun Lian, Chengxiang Li
Journal: Circulation (2021)

Introduction: Few studies have reported that whether elevated plasma branched-chain amino acids (BCAA) level is causally related to atherosclerosis (AS) and the mechanism involved. Methods: First, the plasma BCAA level of 258 atherosclerotic cardiovascular disease (ASCVD) patients and 188 normal people was measured. Second, plaque volume, stability and inflammation of AS mice were evaluated. Third, we assayed BCAA level, catabolism-promoting genes and inflammation in the circulating monocytes of ASCVD patients and abdominal macrophages of AS mice. Fourth, inflammation and macrophage polarization were evaluated in BCAA catabolic deficient RAW 264.7 cells. Finally, mitochondrial hydrogen peroxide (mtH 2 O 2 ), nuclear H 2 O 2 and High mobility group box 1 (HMGB1) levels in RAW 264.7 cells were measured and RAW 264.7 cells-overexpressing catalase targeted to mitochondria (MCAT), nucleus (NCAT) and HMGB1KD RAW 264.7 cells were built to detect their effect on macrophage polarization. Results: First, we found that plasma BCAA level was an independent risk factor of ASCVD. Second, we also found plasma BCAA level was elevated in AS mice, which led to the increase of plaque volume and instability, as well as inflammation. The growth of plaque instability was characterized by increased macrophage amounts and decreased smooth muscle cells (SMCs) and collagen contents. Conversely, when plasma BCAA level was lowered, the above phenomena could be reversed. Third, elevated plasma BCAA level resulting from BCAA catabolic defect occurred in the monocytes of ASCVD patients and the abdominal macrophages of AS mice, which increased inflammatory response by promoting the polarization of macrophages toward M1 phenotype. Fourth, elevated BCAA level-mediated macrophage polarization toward M1 phenotype was regulated by increasing mtH 2 O 2 level to induce secretion of HMGB1 by increasing nuclear H 2 O 2 level. Finally, the improvement of BCAA catabolism of macrophages alleviated AS progression in mice. Conclusions: Our data demonstrates that elevated plasma BCAA level is an independent risk factor of ASCVD and promotes AS progression, indicating that plasma BCAA level might be a therapeutic target for ASCVD.
Abstract P322: Ror2: A Novel Regulator Of Cardiomyocyte Structure And Target Of Right Ventricular Failure
Authors: Jonathan J Edwards, Keita Uchida, Swapnil V Shewale, Nora Yucel, Emily A Scarborough, Yifan Yang, Li Li, Benjamin Prosser, Zoltan Arany
Journal: Circulation Research (2021)

Introduction: We recently identified the fetal noncanonical WNT receptor ROR2 as being re-expressed in human right ventricular failure (RVF), but the myocardial role of ROR2 remains poorly described. Hypothesis: We assessed if ROR2 expression influences cardiomyocyte structure or contributes to RVF pathogenesis. Methods: ROR2 gain- and loss-of-function (ROR2 GOF and ROR2 LOF ) NRVMs were generated using adenoviral-delivered ROR2 cDNA or shRNA and cultured on nanopatterned substrates. NRVM structure was assessed by confocal microscopy (minimum n=3 replicates, &gt;30 cells/condition). NRVM gene expression was characterized by RNAseq. The impact of ROR2 on RV structure and function was assessed using AAV9-mediated cardiac ROR2 delivery, in 4-week old C57BL/6 mice (vs GFP), and echocardiography and hemodynamics (n= 8, 50% male). Results: ROR2 GOF disrupts non-sarcomeric and sarcomeric NRVM structure, exhibiting smaller (500 vs. 711 μm 2 , p = 7.4x10 -23 ) and rounder (aspect ratio 2.1 vs. 3.1, p=1.9x10 -16 ) shape and fragmented sarcomeres (Figure). Whereas, ROR2 LOF NRVMs demonstrate a striking peripheralization of α-actinin and β-catenin. Gene-set enrichment analyses of ROR2 GOF NRVMs reveal upregulation of cytokinesis, mitosis, microtubule regulation, and insulin like growth factor receptor signaling. By 4 weeks after induction of ROR2 GOF in vivo , mice exhibit biventricular dilation and systolic dysfunction (TAPSE 0.85 vs 1.2 mm, p = 2.1x10 -5 ; right ventricular outflow dimension 2.0 vs 1.7 mm, p = 0.001, LV EDV 33.5 vs 28.6 μL, p = 0.05; LV ejection fraction 63% vs 69%, p = 0.015). RV diastolic function is reduced in ROR2 GOF (E:e’ 21.8 vs 18.6, p = 0.004 and RV EDP 2.9 vs 1.0 mmHg, p = 0.06). Conclusions: ROR2 GOF causes biventricular dilation, systolic and diastolic dysfunction in vivo . In vitro, ROR2 GOF NRVMs exhibit an immaturity phenotype with maintenance of proliferation gene program. In contrast, ROR2 LOF NRVMs form a tight monolayer with enhanced cell-cell borders.