tbuckley/cabot-search huggingface dataset:
Abstract 301: An m6A Demethylase, FTO Mediates Post-transcriptional mRNA Modifications to Regulate Cardiac and Cardiomyocyte Function
Authors: Prabhu Mathiyalagan, Marta Adamiak, Joshua Mayourian, Yaxuan Liang, Yassine Sassi, Neha Agarwal, Divya Jha, Kiyotake Ishikawa, Shihong Zhang, Erik Kohlbrenner, Xiaoke Yin, Elena Chepurko, Jiqiu Chen, Maria G Trivieri, Rajvir Singh, Manuel Mayr, Kenneth Fish, Djamel Lebeche, Roger J Hajjar, Susmita Sahoo
Journal: Circulation Research (2018)

Background: Post-transcriptional modifications in the form of m6A (N6-methyladenosine) regulate mRNA fate and translation, miRNA biogenesis, lncRNA function and several cellular processes. However, m6A mechanisms in the mature post-mitotic tissues such as the mammalian heart remain unexplored. Here, we investigated the role of transcriptome-wide m6A in cardiac protein expression as well as lncRNA function. Methods: Using biochemical assays, we investigated the spatiotemporal gene expression patterns of m6A regulators in non-failing, failing (ischemic) human hearts, in mouse and pig MI models. In mouse heart, we mapped transcriptome-wide m6A by developing state-of-the-art MeRIP-seq coupled with novel bioinformatics analysis. To investigate the functional relevance of m6A to cardiac proteome, we used SILAC-LC-MS. By silencing (siRNA) m6A-reader proteins, we investigated the role of m6A in cardiomyocyte mRNA stability, decay and nuclear export. For in vivo myocardial gene delivery, we used AAV9 and adenovirus vectors. Finally, we performed immunohistology in cardiomyocytes and mouse heart tissues to study nuclei size, fibrosis and angiogenesis. Results: We discovered that the expression of m6A demethylase, FTO is decreased in ischemic myocardium and cardiomyocytes, thus in vivo FTO gene delivery resulted in attenuation of ischemia-induced increase in m6A and decrease in cardiac contractile function post-MI. FTO overexpression in mouse heart and human cardiomyocytes revealed selective demethylation (MeRIP-seq) of cardiac contractile transcripts resulting in induced contractile protein expression (SILAC-LC-MS) thus rescuing heart function post-MI. Mechanistically, we demonstrate that the cardioprotective mechanism of FTO is mediated by selective demethylation of cardiac contractile transcripts under ischemia, which prevents mRNA degradation as well as enhanced nuclear compaction. Finally, we demonstrate that FTO overexpression in mouse models of MI resulted in decreased fibrosis and enhanced angiogenesis. Conclusion: Our study provides the first description of a cardiac active m6A demethylase working at post-transcriptional level as a critical regulator of cardiac contractile function, fibrosis and angiogenesis.
Abstract 256: Precision Medicine in Cardiac Channelopathy: Integrating Genome Editing and Induced Pluripotent Stem Cells to Decipher Variant of Unknown Significance
Authors: Priyanka Garg
Journal: Circulation Research (2018)

Background: The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsade de pointes (TdP) and sudden cardiac death (SCD). Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of unknown significance (VUS), for which there is insufficient evidence of pathogenicity. Objectives: To demonstrate that genome editing of patient-specific induced pluripotent stem cells (iPSCs) can be a valuable approach to delineate the pathogenicity of VUS in cardiac channelopathy. Methods and Results: Peripheral blood mononuclear cells (PBMCs) were isolated from a carrier with a novel missense variant (T983I) in the KCNH2 (LQT2) gene and an unrelated healthy control subject. iPSCs were generated using an integration-free Sendai virus and differentiated to iPSC-derived cardiomyocytes (iPSC-CMs). Whole-cell patch clamp recordings revealed significant prolongation of the action-potential duration (APD) and reduced rapidly activating delayed rectifier K + current ( I Kr ) density in VUS iPSC-CMs compared to healthy control iPSC-CMs. ICA-105574, a potent I Kr activator, enhanced I Kr magnitude and restored normal APD in VUS iPSC-CMs. Notably, VUS iPSC-CMs exhibited greater propensity to proarrhythmia than healthy control cells in response to high-risk torsadogenic drugs (dofetilide, ibutilide, and azimilide), suggesting a compromised repolarization reserve. Finally, the selective correction of the causal variant in iPSC-CMs using CRISPR/Cas9 gene editing (isogenic control) normalized the aberrant cellular phenotype, whereas the introduction of the homozygous variant in healthy control cells recapitulated hallmark features of the LQTS disorder. Conclusions: Our results suggest that the KCNH2 T983I VUS may be classified as potentially pathogenic.
Addressing the Adequacy of Current MPN Pain Management Strategies: An International Survey of 502 Patients By the MPN Quality of Life Study Group
Authors: Holly L. Geyer, Robyn M. Scherber, Gina Mazza, Blake T. Langlais, Ruben A. Mesa, Leslie Padrnos, Amylou C. Dueck, Jeanne Palmer
Journal: Blood (2018)
PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
Authors: Laszlo Kovacs, Yapeng Cao, Weihong Han, Louise Meadows, Anita Kovacs-Kasa, Dmitry Kondrikov, Alexander D. Verin, Scott A. Barman, Zheng Dong, Yuqing Huo, Yunchao Su
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.
Reply
Authors: Jaclyn LoPiccolo, Michael I. Brener, Kiyoko Oshima, Evan J. Lipson, James P. Hamilton
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Lipson consults and received grants from Bristol‐Myers Squibb and Merck. He consults for Array BioPharma, EMD Serono, Macrogenics, Millennium, and Novartis. We agree with Dr. Hadzic that nodular regenerative hyperplasia (NRH) may be an underdiagnosed disease, perhaps owing to its variable clinical course and the limited availability of subspecialty pathologists trained in recognizing its histological appearance. Furthermore, many patients who develop noncirrhotic portal hypertension in the context of receiving immunomodulatory therapies as part of treatment for advanced malignancies may not undergo liver biopsy given their overall goals of care. Of particular interest is the potential role of immune dysregulation in the development of NRH. As Dr. Hadzic points out, the presence of infiltrating CD8+ T cells producing interferon (IFN)‐γ in liver biopsies of patients with NRH suggests a T cell–mediated process. Expression of programmed death ligand 1 (PD‐L1) and programmed death ligand 2 (PD‐L2), the major ligands for PD‐1, is induced by IFN‐γ, which appears to play a role in tumor immune evasion.1 Blockade of the immunoregulatory pathway comprised of PD‐1 and its ligands may break immune tolerance, thereby activating T cells against tumor and sinusoidal endothelial cells. Thus, we agree that so‐called “idiosyncratic” cases of NRH that arise in association with certain drugs are likely to have substrate‐specific genetic underpinnings. Large‐scale genomic studies may be helpful in elucidating which patients might be particularly susceptible to developing NRH when they receive immunomodulating medications.
BODY MASS INDEX, FITNESS, AND MORTALITY IN PATIENTS WITH DIABETES: EVALUATING THE FAT BUT FIT PARADOX IN THE FIT PROJECT COHORT
Authors: Seamus P. Whelton, Paul McAuley, Olusola Orimoloye, Clinton Brawner, Jonathan Ehrman, Steven Keteyian, Mouaz Al-Mallah, Michael Blaha
Journal: Journal of the American College of Cardiology (2019)
IMPACT OF NEUROLOGICAL PERFORMANCE ON DEFIBRILLATOR IMPLANTATION RATES AND LONG-TERM MORTALITY IN SUDDEN CARDIAC ARREST SURVIVORS
Authors: Amr Barakat, Alvin Thalappillil, Dingxin Qin, Laith Alkukhun, Norman Wang, Evan Adelstein, Sandeep Jain, N.A. Estes, Samir Saba
Journal: Journal of the American College of Cardiology (2019)
Oral bacteria colonize and compete with gut microbiota in gnotobiotic mice
Authors: Bolei Li, Yang Ge, Lei Cheng, Benhua Zeng, Jinzhao Yu, Xian Peng, Jianhua Zhao, Wenxia Li, Biao Ren, Mingyun Li, Hong Wei, Xuedong Zhou
Journal: International Journal of Oral Science (2019)

The oral microbiota is associated with oral diseases and digestive systemic diseases. Nevertheless, the causal relationship between them has not been completely elucidated, and colonisation of the gut by oral bacteria is not clear due to the limitations of existing research models. The aim of this study was to develop a human oral microbiota-associated (HOMA) mouse model and to investigate the ecological invasion into the gut. By transplanting human saliva into germ-free (GF) mice, a HOMA mouse model was first constructed. 16S rRNA gene sequencing was used to reveal the biogeography of oral bacteria along the cephalocaudal axis of the digestive tract. In the HOMA mice, 84.78% of the detected genus-level taxa were specific to the donor. Principal component analysis (PCA) revealed that the donor oral microbiota clustered with those of the HOMA mice and were distinct from those of specific pathogen-free (SPF) mice. In HOMA mice, OTU counts decreased from the stomach and small intestine to the distal gut. The distal gut was dominated by Streptococcus, Veillonella, Haemophilus, Fusobacterium, Trichococcus and Actinomyces. HOMA mice and human microbiota-associated (HMA) mice along with the GF mice were then cohoused. Microbial communities of cohoused mice clustered together and were significantly separated from those of HOMA mice and HMA mice. The Source Tracker analysis and network analysis revealed more significant ecological invasion from oral bacteria in the small intestines, compared to the distal gut, of cohoused mice. In conclusion, a HOMA mouse model was successfully established. By overcoming the physical and microbial barrier, oral bacteria colonised the gut and profiled the gut microbiota, especially in the small intestine. Swabbing the mouths of germ-free mice with human saliva can provide an effective mouse model for studying the roles of human oral bacteria in mouth and gut diseases. The human oral microbiota-associated (HOMA) mice were developed by Lei Cheng of Sichuan University and colleagues in China and bred alone for 35 days. A significant proportion (85%) of the types of bacteria present in the human donors' saliva successfully established themselves in the germ-free mice and colonised various parts of their guts. When the HOMA mice were co-bred with other types of mouse models, digestive tract bacteria transferred to them, preventing oral bacteria from significantly colonising the gut. The researchers conclude that a HOMA model was successfully established and could help overcome current limitations in investigations related to human oral bacteria and disease.
Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration
Authors: Emily G. O’Koren, Chen Yu, Mikael Klingeborn, Alicia Y.W. Wong, Cameron L. Prigge, Rose Mathew, Joan Kalnitsky, Rasha A. Msallam, Aymeric Silvin, Jeremy N. Kay, Catherine Bowes Rickman, Vadim Y. Arshavsky, Florent Ginhoux, Miriam Merad, Daniel R. Saban
Journal: Immunity (2019)
WORK-RELATED MUSCULOSKELETAL PAIN AMONG CARDIAC SONOGRAPHERS COMPARED TO A LARGE CONTROL GROUP OF PEER EMPLOYEES: A MULTISITE CROSS-SECTIONAL STUDY
Authors: Sergio Barros-Gomes, Nicholas Orme, Lara F. Nhola, Karen Helfinstine, Sorin V. Pislaru, Garvan C. Kane, Mandeep Singh, Patricia A. Pellikka
Journal: Journal of the American College of Cardiology (2019)
UTILITY OF CARDIAC MAGNETIC RESONANCE FOR PREDICTING SUITABILITY OF NATIVE RIGHT VENTRICULAR OUTFLOW TRACT DIMENSIONS IN PATIENTS UNDERGOING ATTEMPTED TRANS-CATHETER PULMONARY VALVE REPLACEMENT
Authors: Keyur Mehta, Tacy Downing, Nao Sasaki, Joshua Gruber, Juan Carlos Muniz
Journal: Journal of the American College of Cardiology (2019)
OUTCOMES AFTER HEART TRANSPLANTATION FOR LIGHT-CHAIN COMPARED TO TRANSTHYRETIN AMYLOIDOSIS
Authors: Leonard Chiu, Maryjane Farr, Kelly Axsom, Paolo Colombo, Jeffeny De Los Santos, A. Reshad Garan, Jeff Goldsmith, Jennifer Haythe, Stephen Helmke, Evelyn Horn, Farhana Latif, Sun Hi Lee, Edward Lin, Yoshifumi Naka, Susan Restaino, Hiroo Takayama, Koji Takeda, Sergio Teruya, Melana Yuzefpolskaya, Mathew Maurer
Journal: Journal of the American College of Cardiology (2019)
BLOOD PRESSURE TIME IN THERAPEUTIC RANGE, BUT NOT VISIT-TO-VISIT VARIABILITY, PREDICTS CARDIOVASCULAR EVENTS AMONG TREATED HYPERTENSIVE PATIENTS: DATA FROM A 6-YEAR FOLLOW-UP STUDY
Authors: Konstantinos P. Tsioufis, Alexandros Kasiakogias, Panagiotis Iliakis, Dimitris Konstantinidis, Ioannis Leontsinis, Christos Fragoulis, Kyriakos Dimitriadis, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2019)
SACUBITRIL/VALSARTAN REDUCES READMISSIONS AND IMPROVES EJECTION FRACTION IN PATIENTS WITH CHRONIC SYSTOLIC HEART FAILURE IN THE CINCINNATI MERCY HEALTH SYSTEM
Authors: Lynne Wagoner, Victoria Walton, Rebecca Blanton, Rosann Giesting, Karen Helferich, Kelly Valen
Journal: Journal of the American College of Cardiology (2019)
HIGH FIVE-YEAR SURVIVAL IN HEART FAILURE PATIENTS YOUNGER THAN 70 YEARS WITHOUT SEVERE COMORBIDITIES
Authors: Christian Madelaire, Finn Gustafsson, Lynne Stevenson, Søren L. Kristensen, Lars Kober, Julie Andersen, Maria D'Souza, Christian Torp-Pedersen, Gunnar Gislason, Morten Schou
Journal: Journal of the American College of Cardiology (2019)
INTENSITY OF LIPID LOWERING THERAPY AMONG PATIENTS WITH POLYVASCULAR DISEASE: INSIGHTS FROM THE GOULD REGISTRY
Authors: Ben Peterson, Deepak L. Bhatt, Mikhail Kosiborod, Christie Ballantyne, James de Lemos, Robert Rosenson, Kiran Philip, Katherine Mues, Shushama Alam, Yuyin Liu, Christopher Cannon
Journal: Journal of the American College of Cardiology (2019)
EVALUATE AND COMPARE INCIDENCE OF CARDIOMYOPATHY ASSOCIATED WITH TRASTUZUMAB, PERTUZUMAB, LAPATINIB, NERATINIB, AND TDM-1 USED IN TREATMENT OF HER-2 POSITIVE BREAST CANCER
Authors: Hetavi Mahida, Ishan Patel, Haisam Abid, Dawn Calderon, Bharatsinh Gharia
Journal: Journal of the American College of Cardiology (2019)
Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis
Authors: Rongkun Li, Yahui Wang, Xiaoxin Zhang, Mingxuan Feng, Jun Ma, Jun Li, Xiaomei Yang, Fang Fang, Qiang Xia, Zhigang Zhang, Mingyi Shang, Shuheng Jiang
Journal: Molecular Cancer (2019)

Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting. LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis. Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC.
ARE WE REALLY THAT DIFFERENT? ASSESSING INTER-RATER AGREEMENT OF EXPERIENCED PHYSICIANS ON THE APPROPRIATENESS OF TESTING IN PATIENTS WHO PRESENT TO THE EMERGENCY DEPARTMENT WITH CHEST PAIN
Authors: Mehrdad Ghahramani, Brandon Peterson, Mohammed Ruzieh, Matthew Nudy, Brian M. McGillen, Marcin Kuzma, Richard M. Pescatore, Ross Rodgers, Andrew Foy
Journal: Journal of the American College of Cardiology (2019)
Impact of Early Immune Reconstitution after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide
Authors: Nieves Dorado, Ana Pérez-Corral, Mi Kwon, Laura Solán, Rebeca Bailén, Cristina Pascual, David Serrano, Javier Anguita, Pascual Balsalobre, Carolina Martínez-Laperche, Jose Luis Díez-Martín
Journal: Blood (2018)
TRENDS IN TRANSCATHETER AND OPERATIVE CLOSURE OF PATENT DUCTUS ARTERIOSUS IN UNITED STATES NEONATAL INTENSIVE CARE UNITS
Authors: Connor Grady, Andrew Glatz, Marisa E. Millenson, Lihai Song, Yoav Dori, Matthew Gillespie, Jonathan Rome, Michael L. O'Byrne
Journal: Journal of the American College of Cardiology (2019)
Abstract 285: Glycogen Receptor Antagonism Ameliorates Progression of Heart Failure
Authors: Chen GAO, Shuxun (Vincent) Ren, Junyi Yu, Dung Thai, John Lu, Zheqing Cai, Cunyu Zeng, Hai Yan, Yibin Wang
Journal: Circulation Research (2018)

Glucagon is an important hormone for glycemic control with counter-balancing function vs. insulin, and treatment of glucagon receptor antibody is shown to be efficacious for type I and type II diabetes. It was reported recently that systemic treatment of glucagon aggravated myocardial injury and pathological remodeling in heart in a glucagon receptor dependent manner, while cardiomyocyte specific inactivation of glucagon receptor protected heart from ischemic injury and remodeling, implicating the therapeutic potential of targeting glucagon receptor for heart failure. In this report, we investigated the functional outcome of glucagon receptor antagonist treatment in mice following myocardial infarction (MI) and pressure-overload using a humanized monoclonal glucagon receptor antagonist antibody REMD2.59. Mice treated with REMD2.59 after myocardial infarction showed significantly reduced scar sizes, blunted cardiac hypertrophy and fibrotic remodeling, and attenuated contractile dysfunction at four weeks after myocardial infarction comparing to mice treated with vehicle as controls. In contrast, treatment of glucagon aggravated these pathological manifestations triggered by myocardial infarction. Furthermore, treatment with REMD2.59 at the onset of pressure-overload significantly suppressed the development of cardiac hypertrophy and chamber dilation with marked preservation of cardiac systolic and diastolic function. More remarkably, initiation of REMD2.59 treatment two weeks after pressure-overload significantly blunted the progression of cardiac pathology with remarkable recovery of hypertrophic gene induction. These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to block both onset and progression of heart failure.
CARDIOPROTECTIVE AND ANTI INFLAMMATORY EFFECTS OF A SELECTIVE INHIBITOR OF THE SODIUM GLUCOSE COTRANSPORTER 2 (EMPAGLIFOZIN) IN DOXORUBICIN INDUCED CARDIOTOXICITY
Authors: Nicola Maurea, Vincenzo Quagliariello, Carmela Coppola, Giovanna Piscopo, Rosario Vincenzo Iaffaioli, Gerardo Botti
Journal: Journal of the American College of Cardiology (2019)
VERY LONG-TERM CLINICAL OUTCOMES FOLLOWING IMPLANTATION OF BIODEGRADABLE POLYMER VERSUS DURABLE POLYMER DRUG-ELUTING STENT: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Satoshi Suzuki, Yohei Sotomi, Pannipa Suwannsom, Tomoaki Kobayashi, Atsushi Hirayama, Yoshiharu Higuchi
Journal: Journal of the American College of Cardiology (2019)
Affinity Maturation of the Anti–Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis
Authors: Sarah Kongpachith, Nithya Lingampalli, Chia‐Hsin Ju, Lisa K. Blum, Daniel R. Lu, Serra E. Elliott, Rong Mao, William H. Robinson
Journal: Arthritis & Rheumatology (2019)

Objective Anti–citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). While epitope spreading of the serum ACPA response is believed to contribute to RA pathogenesis, little is understood regarding how this phenomenon occurs. This study was undertaken to analyze the antibody repertoires of individuals with RA to gain insight into the mechanisms leading to epitope spreading of the serum ACPA response in RA. Methods Plasmablasts from the blood of 6 RA patients were stained with citrullinated peptide tetramers to identify ACPA‐producing B cells by flow cytometry. Plasmablasts were single‐cell sorted and sequenced to obtain antibody repertoires. Sixty‐nine antibodies were recombinantly expressed, and their anticitrulline reactivities were characterized using a cyclic citrullinated peptide enzyme‐linked immuosorbent assay and synovial antigen arrays. Thirty‐six mutated antibodies designed either to represent ancestral antibodies or to test paratope residues critical for binding, as determined from molecular modeling studies, were also tested for anticitrulline reactivities. Results Clonally related monoclonal ACPAs and their shared ancestral antibodies each exhibited differential reactivity against citrullinated antigens. Molecular modeling identified residues within the complementarity‐determining region loops and framework regions predicted to be important for citrullinated antigen binding. Affinity maturation resulted in mutations of these key residues, which conferred binding to different citrullinated epitopes and/or increased polyreactivity to citrullinated epitopes. Conclusion These results demonstrate that the different somatic hypermutations accumulated by clonally related B cells during affinity maturation alter the antibody paratope to mediate epitope spreading and polyreactivity of the ACPA response in RA, suggesting that these may be key properties that likely contribute to the pathogenicity of ACPAs.