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Jill P Buyon - One of the best experts on this subject based on the ideXlab platform.
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cell atlas of the foetal human Heart and implications for autoimmune mediated Congenital Heart Block
Cardiovascular Research, 2020Co-Authors: Hemant Suryawanshi, Jill P Buyon, Robert R Clancy, Marc K Halushka, Pavel Morozov, Thomas TuschlAbstract:Aims Investigating human Heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for normal functioning. We investigated foetal human Heart single-cell transcriptomes from mid-gestational healthy and anti-SSA/Ro associated Congenital Heart Block (CHB) samples. Methods and results Three healthy foetal human Hearts (19th to 22nd week of gestation) and one foetal Heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single-cell suspensions followed by 10× Genomics- and Illumina-based single-cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse sub-populations of endothelial cells were identified in the human Heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types of the CHB Heart compared with the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contribute to extracellular matrix deposition and subsequent fibrosis. Conclusion These data provide an information-rich resource to further our understanding of human Heart development, which, as illustrated by comparison to a Heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease.
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autoimmune mediated Congenital Heart Block
Best Practice & Research in Clinical Obstetrics & Gynaecology, 2020Co-Authors: Benjamin J Wainwright, Jill P Buyon, Amit Saxena, Rohit Bhan, Catherine Trad, Rebecca E Cohen, Peter M IzmirlyAbstract:Abstract Autoimmune-mediated Congenital Heart Block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal Heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal Heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the Block of conduction. Complete AV Block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.
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siglec 1 macrophages and the contribution of ifn to the development of autoimmune Congenital Heart Block
Journal of Immunology, 2019Co-Authors: Robert R Clancy, Marc K Halushka, Sara E Rasmussen, Tenzin Lhakhang, Miao Chang, Jill P BuyonAbstract:Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjogren syndrome, are linked with an upregulation of IFN and type I IFN–stimulated genes, including sialic acid–binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of Congenital Heart Block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro–associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal Hearts dying with CHB and three healthy gestational age-matched Hearts, and 3) autopsy tissue from three additional human CHB Hearts and one healthy Heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45 + CD11c + and CD45 + CD11c − human leukocytes flow sorted from the CHB Hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal Hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1–positive macrophages as integral to the process.
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the prevention screening and treatment of Congenital Heart Block from neonatal lupus a survey of provider practices
Rheumatology, 2018Co-Authors: Megan E B Clowse, Amanda M Eudy, Elizabeth A Kiernan, Matthew R Williams, Bonnie L Bermas, Eliza F Chakravarty, Lisa R Sammaritano, Christina D Chambers, Jill P BuyonAbstract:Objective To survey an international sample of providers to determine their current practices for the prevention, screening, and treatment of Congenital Heart Block (CHB) due to maternal Ro/SSA antibodies. Methods A survey was designed by the organizing committee of the 9th International Conference of Reproduction, Pregnancy and Rheumatic Diseases. It was sent to attendants of the conference and authors of recent publications or abstracts at ACR 2012, 2013 or 2014 on rheumatic diseases and pregnancy. Results In anti-Ro/SSA positive women, 80% of 49 respondents recommended screening by serial fetal echocardiogram (ECHO), with most starting at week 16 (59%) and stopping at week 28 (25%), although the time to stop varied widely. For women without a prior infant with neonatal lupus, respondents recommend every other week (44%) or weekly (28%) fetal ECHOs. For women with a prior infant with neonatal lupus, 80% recommend weekly fetal ECHOs. To prevent CHB, HCQ was recommended by 67% of respondents and most would start pre-pregnancy (62%). Respondents were asked about medications to treat varying degrees of CHB in a 20-week pregnant, anti-Ro and La positive SLE patient. For first degree, respondents recommended starting dexamethasone (53%) or HCQ (43%). For second degree, respondents recommended starting dexamethasone (88%). For third degree, respondents recommended starting dexamethasone (55%) or IVIg (33%), although 27% would not start treatment. Conclusion Despite the absence of official guidelines, many physicians with a focus on pregnancy and rheumatic disease have developed similar patterns in the screening, prevention and treatment of CHB.
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cardiac fibroblast transcriptome analyses support a role for interferogenic profibrotic and inflammatory genes in anti ssa ro associated Congenital Heart Block
American Journal of Physiology-heart and Circulatory Physiology, 2017Co-Authors: Robert R Clancy, Androo J Markham, Tanisha Jackson, Sara E Rasmussen, Miroslav Blumenberg, Jill P BuyonAbstract:Congenital Heart Block is a rare disease of the fetal Heart caused by anti-Ro autoantibodies in the mother that result in death and lifelong Heart pacing of survivors. This study provides in vivo a...
Robert R Clancy - One of the best experts on this subject based on the ideXlab platform.
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hydroxychloroquine to prevent recurrent Congenital Heart Block in fetuses of anti ssa ro positive mothers
Journal of the American College of Cardiology, 2020Co-Authors: Peter M Izmirly, Deborah M Friedman, Robert R Clancy, Rebecca E Cohen, Joshua A Copel, Nathalie Costedoatchalumeau, Mimi Y Kim, Colin K L Phoon, Bettina F Cuneo, Kimberly RobinsAbstract:Abstract Background Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro–mediated Congenital Heart Block (CHB). Objectives Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. Methods This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon’s optimal approach. Anti-SSA/Ro–positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. Results By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). Conclusions These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573 )
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cell atlas of the foetal human Heart and implications for autoimmune mediated Congenital Heart Block
Cardiovascular Research, 2020Co-Authors: Hemant Suryawanshi, Jill P Buyon, Robert R Clancy, Marc K Halushka, Pavel Morozov, Thomas TuschlAbstract:Aims Investigating human Heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for normal functioning. We investigated foetal human Heart single-cell transcriptomes from mid-gestational healthy and anti-SSA/Ro associated Congenital Heart Block (CHB) samples. Methods and results Three healthy foetal human Hearts (19th to 22nd week of gestation) and one foetal Heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single-cell suspensions followed by 10× Genomics- and Illumina-based single-cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse sub-populations of endothelial cells were identified in the human Heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types of the CHB Heart compared with the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contribute to extracellular matrix deposition and subsequent fibrosis. Conclusion These data provide an information-rich resource to further our understanding of human Heart development, which, as illustrated by comparison to a Heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease.
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siglec 1 macrophages and the contribution of ifn to the development of autoimmune Congenital Heart Block
Journal of Immunology, 2019Co-Authors: Robert R Clancy, Marc K Halushka, Sara E Rasmussen, Tenzin Lhakhang, Miao Chang, Jill P BuyonAbstract:Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjogren syndrome, are linked with an upregulation of IFN and type I IFN–stimulated genes, including sialic acid–binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of Congenital Heart Block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro–associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal Hearts dying with CHB and three healthy gestational age-matched Hearts, and 3) autopsy tissue from three additional human CHB Hearts and one healthy Heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45 + CD11c + and CD45 + CD11c − human leukocytes flow sorted from the CHB Hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal Hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1–positive macrophages as integral to the process.
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ii 11 siglec 1 macrophages and the contribution of ifn to the development of autoimmune Congenital Heart Block
Lupus science & medicine, 2018Co-Authors: Robert R ClancyAbstract:Background Given that diseases associated with anti-Ro such as SLE and Sjogren’s syndrome associate with an upregulation of type I interferons, recent attention has focused on a potential role for IFN in the pathogenesis of Congenital Heart Block (CHB). Based on the consistent demonstration of macrophages and multinucleated giant cells in areas of injury, it is relevant that Sialic Acid Binding Ig Like Lectin 1 (SIGLEC1), a receptor on monocytes/macrophages is upregulated by IFN. Functionally, Siglec-1 expressing macrophages might play an important role as effector cells in fibrosis. Accordingly, this study leveraged both autopsy tissue and freshly isolated macrophages from a fetal Heart dying with CHB to address whether IFN-α contributes to the pathogenesis of CHB by regulating activated macrophages in affected cardiac tissue. Methods Three approaches were taken to evaluate Siglec-1 expression. Transcriptomic analysis was performed on macrophages freshly isolated from a fetal Heart dying with CHB at 19 weeks and a Heart from an otherwise healthy electively terminated fetus using (DAPI negative cells with isolation by flow using antibodies to CD45). Immunohistochemistry was performed on another fetal Heart dying with CHB. In vitro experiments utilized cultured healthy human macrophages transfected with anti-SSA/Ro- associated ssRNA as a proxy for the in vivo conditions. Results Transcriptomes of the two Hearts for each isolated leukocyte fraction were compared. By following 213 IFN inducible genes, there was enrichment of targeted transcripts in CHB vs control (p=0.0001) and SIGLEC1, which was 200-fold more abundant in CHB vs control and ranked among the top three differentially expressed candidates. In another fetal Heart dying with CHB, Siglec1 staining as detected by antibody HPA053457 was prominent in areas of injury. By morphology, the two cell types expressing Siglec 1 were macrophages and dendritic cells. In vitro experiments were performed in accordance with previous laboratory work, in which a model of anti-SSA/Ro-associated injury exploits macrophages stimulated with the ssRNA component (hY3) of the SSA/Ro immune complex. IFN inducible genes (15 transcripts) were among the 30 most highly upregulated genes in hY3 stimulated conditions and SIGLEC1 was two-fold more abundant in CHB vs control. Given the enrichment of type I IFN-responsive genes in the macrophage transcriptome, a WISH cell line was selected to evaluate supernatants from macrophages transfected with hY3. IFIT1 MX1, and EIF2AK2 transcripts were significantly increased in the WISH cells treated with hY3 macrophage supernatants, but not macrophage supernatants alone (n=7, p=0.02). Conclusion These data now provide a link between IFN and the inflammatory and possibly fibrosing component of CHB and position Siglec-1 positive macrophages as integral to the process.
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cardiac fibroblast transcriptome analyses support a role for interferogenic profibrotic and inflammatory genes in anti ssa ro associated Congenital Heart Block
American Journal of Physiology-heart and Circulatory Physiology, 2017Co-Authors: Robert R Clancy, Androo J Markham, Tanisha Jackson, Sara E Rasmussen, Miroslav Blumenberg, Jill P BuyonAbstract:Congenital Heart Block is a rare disease of the fetal Heart caused by anti-Ro autoantibodies in the mother that result in death and lifelong Heart pacing of survivors. This study provides in vivo a...
Marie Wahrenherlenius - One of the best experts on this subject based on the ideXlab platform.
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effects of maternal medication on long term outcome in Congenital Heart Block remain to be established response to comorbidity and long term outcome in patients with Congenital Heart Block and their siblings exposed to ro ssa autoantibodies in utero
Annals of the Rheumatic Diseases, 2020Co-Authors: Johannes Mofors, Svenerik Sonesson, Marie WahrenherleniusAbstract:We thank Satis and colleagues for opening the discussion on a potential influence of maternal immunomodulatory treatment on the long-term outcome of Congenital Heart Block (CHB)1 and welcome their questions to help clarify some aspects of our study.2 Whether immunomodulatory treatment administered to the mother—as part of her own rheumatic disease treatment or intended to ameliorate the fetal cardiac inflammation in CHB—influences any outcome in CHB is a current matter of debate. Satis and colleagues cite several studies supporting a role …
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benefits of fetal echocardiographic surveillance in pregnancies at risk of Congenital Heart Block single center study of 212 anti ro52 positive pregnancies
Ultrasound in Obstetrics & Gynecology, 2019Co-Authors: Svenerik Sonesson, A Ambrosi, Marie WahrenherleniusAbstract:Objectives Assuming that autoimmune Congenital Heart Block (CHB) is a progressive disease amenable to therapeutic modulation, we introduced a surveillance program for at-risk pregnancies with the dual aim of investigating if fetal atrioventricular Block (AVB) could be detected and treated before becoming complete and irreversible, and to establish the incidence of AVB I, II and III in a large prospective cohort. Methods This was a prospective study of 212 anti-Ro52 antibody-exposed pregnancies at risk of fetal AVB that were followed weekly between 18 and 24 weeks' gestation at our tertiary fetal cardiology center from 2000 to 2015. A 12-lead electrocardiogram (ECG) was recorded within 1 week after birth. Fetal Doppler atrioventricular (AV) intervals were converted to Z-scores using reference standard values derived from normal pregnancies. Each fetus was represented by the average value of the two recordings, obtained at two consecutive visits, which resulted in the longest AV interval. AV interval values were classified into normal AV conduction (Z-score ≤ 2.0) and three levels of delayed AV conduction: Z-score > 2.0 and ≤ 3.0, Z-score > 3.0 and ≤ 4.0, and Z-score > 4.0. Results AVB II or III developed in 6/204 (2.9%) pregnancies without a CHB history and 1/8 (12.5%) of those with a CHB history. AV intervals > 2 and ≤ 3, > 3 and ≤ 4, and > 4 were detected in 16.0%, 7.5% and 2.8% of cases, respectively, and were related to the PR interval on 185 available ECGs. Three of the five cases with AVB III and one of two cases with 2:1 AVB II developed within 1 week of AV interval Z-score of 1.0, 1.9, 2.8 and 1.9, respectively. Transplacental treatment with betamethasone was associated with restoration of 1:1 AV conduction in the two fetuses with AVB II, with a better long-term result (normal ECG vs AVB I or II) observed in the case in which treatment was started within 1 week after AVB developed. Betamethasone treatment did not reverse AVB III, although a temporary effect on AV conduction was observed in 1/5 cases. Notably, the three cases in which treatment was started within 1 week after AVB III development responded with a higher ventricular rate than the other two cases and did not require pacemaker implantation until a later age (2-5 years vs 1.5-2 months). Conclusion Fetal AV interval is a poor predictor of CHB progression, but CHB surveillance still allows detection of fetuses with AVB II or III shortly after its development, allowing for timely treatment initiation and potentially better outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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comorbidity and long term outcome in patients with Congenital Heart Block and their siblings exposed to ro ssa autoantibodies in utero
Annals of the Rheumatic Diseases, 2019Co-Authors: Johannes Mofors, Stina Salomonsson, Svenerik Sonesson, Aurelie Ambrosi, Hakan Eliasson, Amanda Skog, Michael Fored, Anders Ekbom, Gunnar Bergman, Marie WahrenherleniusAbstract:Objective Congenital Heart Block (CHB) may develop in fetuses of Ro/SSA autoantibody-positive women. Given the rarity of CHB, information on comorbidity and complications later in life is difficult to systematically collect for large groups of patients. We therefore used nation-wide healthcare registers to investigate comorbidity and outcomes in patients with CHB and their siblings. Methods Data from patients with CHB (n= 119) and their siblings (n= 128), all born to anti-Ro/SSA-positive mothers, and from matched healthy controls (n= 1,190) and their siblings (n= 1,071), were retrieved from the Swedish National Patient Register. Analyses were performed by Cox proportional hazard modelling. Results Individuals with CHB had a significantly increased risk of cardiovascular comorbidity, with cardiomyopathy and/or Heart failure observed in 20 (16.8%) patients versus 3 (0.3%) controls, yielding a HR of 70.0 (95% CI 20.8 to 235.4), and with a HR for cerebral infarction of 39.9 (95% CI 4.5 to 357.3). Patients with CHB also had a higher risk of infections. Pacemaker treatment was associated with a decreased risk of cerebral infarction but increased risks of cardiomyopathy/Heart failure and infection. The risk of systemic connective tissue disorder was also increased in patients with CHB (HR 11.8, 95% CI 4.0 to 11.8), and both patients with CHB and their siblings had an increased risk to develop any of 15 common autoimmune conditions (HR 5.7, 95% CI 2.83 to 11.69 and 3.6, 95% CI 1.7 to 8.0, respectively). Conclusions The data indicate an increased risk of several cardiovascular, infectious and autoimmune diseases in patients with CHB, with the latter risk shared by their siblings.
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outcome in 212 anti ro ssa positive pregnancies and population based incidence of Congenital Heart Block
Acta Obstetricia et Gynecologica Scandinavica, 2016Co-Authors: Amanda Skog, Marie Wahrenherlenius, Linda Lagnefeldt, Peter Conner, Svenerik SonessonAbstract:Introduction We investigated the effects of maternal autoimmune disease and fetal Congenital Heart Block (CHB) on pregnancy outcomes in anti-Ro/SSA-positive women and assessed the population-based incidence of isolated CHB. Material and methods One hundred and ninety nine anti-Ro/SSA-positive pregnancies were prospectively followed at our center (2000–2013). Seven fetuses developed atrioventricular Block (AVB) II–III. In this period, another 13 anti-Ro/SSA-positive pregnancies were referred for fetal bradycardia, subsequently diagnosed with AVB II–III. Cesarean section rates, gestational age, body measurements at birth, and the incidence of CHB in these 212 pregnancies were analyzed in relation to fetal atrioventricular conduction and maternal diagnosis and compared with data from the Medical Birth Registry on 352 104 pregnancies in the Stockholm County. Results The prevalence of maternal systemic lupus erythematosus (SLE) and primary Sjogren's syndrome and the outcomes at birth were similar in normal conduction and AVB I cases. Only 1/20 AVB II–III cases (0/7 in the surveillance group) had a mother diagnosed with SLE, compared with 73/192 in cases with normal conduction or AVB I. Excluding cases with AVB II–III, SLE mothers more frequently delivered by cesarean section (31% vs. 20%, p < 0.05) and had a higher incidence of preterm birth (13% vs. 5.8%, p < 0.05) than the county population. Both SLE and primary Sjogren's syndrome mothers had a fourfold greater rate of growth-retarded babies (10.11% vs. 2.2%, p < 0.001). The incidence of autoantibody-related AVB II–III in Stockholm County was 1/23 300. Conclusion This study of CHB provides new information on the incidence of CHB and outcome of pregnancy in anti-Ro/SSA-positive women, which has clinical relevance when counseling rheumatic patients considering pregnancy.
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molecular mechanisms of Congenital Heart Block
Experimental Cell Research, 2014Co-Authors: Aurelie Ambrosi, Svenerik Sonesson, Marie WahrenherleniusAbstract:Abstract Autoantibody-associated Congenital Heart Block (CHB) is a passively acquired autoimmune condition associated with maternal anti-Ro/SSA antibodies and primarily affecting electric signal conduction at the atrioventricular node in the fetal Heart. CHB occurs in 1–2% of anti-Ro/SSA antibody-positive pregancies and has a recurrence rate of 12–20% in a subsequent pregnancy. Despite the long-recognized association between maternal anti-Ro/SSA autoantibodies and CHB, the molecular mechanisms underlying CHB pathogenesis are not fully understood, but several targets for the maternal autoantibodies in the fetal Heart have been suggested. Recent studies also indicate that fetal susceptibility genes determine whether an autoantibody-exposed fetus will develop CHB or not, and begin to identify such genes. In this article, we review the different lines of investigation undertaken to elucidate the molecular pathways involved in CHB development and reflect on the hypotheses put forward to explain CHB pathogenesis as well as on the questions left unanswered and that should guide future studies.
Deborah M Friedman - One of the best experts on this subject based on the ideXlab platform.
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hydroxychloroquine to prevent recurrent Congenital Heart Block in fetuses of anti ssa ro positive mothers
Journal of the American College of Cardiology, 2020Co-Authors: Peter M Izmirly, Deborah M Friedman, Robert R Clancy, Rebecca E Cohen, Joshua A Copel, Nathalie Costedoatchalumeau, Mimi Y Kim, Colin K L Phoon, Bettina F Cuneo, Kimberly RobinsAbstract:Abstract Background Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro–mediated Congenital Heart Block (CHB). Objectives Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. Methods This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon’s optimal approach. Anti-SSA/Ro–positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. Results By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). Conclusions These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573 )
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prevention and treatment in utero of autoimmune associated Congenital Heart Block
Cardiology in Review, 2014Co-Authors: Amit Saxena, Jill P Buyon, Peter M Izmirly, Barbara Mendez, Deborah M FriedmanAbstract:Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease, including Congenital Heart Block and cardiomyopathy, called cardiac neonatal lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third-degree Heart Block in NL, although several treatments have shown some effectiveness in incomplete Heart Block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. β-agonists have been used to increase fetal Heart rates in utero. The endurance of β-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.
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cardiac manifestations of neonatal lupus a review of autoantibody associated Congenital Heart Block and its impact in an adult population
Cardiology in Review, 2011Co-Authors: Christine Capone, Jill P Buyon, Deborah M Friedman, William H FrishmanAbstract:Within the last decade the prevalence of adult patients living with Congenital Heart disease equals that seen in children. This expanding population poses a challenge to clinical cardiologists who will be caring for patients with the clinical manifestations of this condition. Neonatal lupus is a model of passively acquired autoimmunity and is responsible for the majority of clinical cases of Congenital Heart Block (CHB). This review will focus on the presentation, pathophysiology, and the long-term follow-up of CHB associated with neonatal lupus, and discuss important diagnostic tests, familial implications, and pacemaker issues associated with the care of an adult with CHB.
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association of the idiotype antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune associated Congenital Heart Block
Arthritis & Rheumatism, 2011Co-Authors: John G Routsias, Jill P Buyon, Deborah M Friedman, Robert R Clancy, Carolina Llanos, Nikolaos C Kyriakidis, Haralampos M Moutsopoulos, Athanasios G TzioufasAbstract:Objective Congenital Heart Block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ~18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype: antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.
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evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for Congenital Heart Block results of a multicenter prospective open label clinical trial
Arthritis & Rheumatism, 2010Co-Authors: Deborah M Friedman, Peter M Izmirly, Joshua A Copel, Carolina Llanos, Brigit Brock, John Byron, Karen Cummiskey, Mary Anne Dooley, Jill Foley, Cornelia GravesAbstract:Objective The recurrence rate of anti-SSA/Ro associated Congenital Heart Block (CHB) is 17%. Reversal of 3rd degree Block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, IVIG was evaluated as a preventative therapy for CHB.
Peter M Izmirly - One of the best experts on this subject based on the ideXlab platform.
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hydroxychloroquine to prevent recurrent Congenital Heart Block in fetuses of anti ssa ro positive mothers
Journal of the American College of Cardiology, 2020Co-Authors: Peter M Izmirly, Deborah M Friedman, Robert R Clancy, Rebecca E Cohen, Joshua A Copel, Nathalie Costedoatchalumeau, Mimi Y Kim, Colin K L Phoon, Bettina F Cuneo, Kimberly RobinsAbstract:Abstract Background Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro–mediated Congenital Heart Block (CHB). Objectives Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. Methods This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon’s optimal approach. Anti-SSA/Ro–positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. Results By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). Conclusions These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573 )
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autoimmune mediated Congenital Heart Block
Best Practice & Research in Clinical Obstetrics & Gynaecology, 2020Co-Authors: Benjamin J Wainwright, Jill P Buyon, Amit Saxena, Rohit Bhan, Catherine Trad, Rebecca E Cohen, Peter M IzmirlyAbstract:Abstract Autoimmune-mediated Congenital Heart Block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal Heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal Heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the Block of conduction. Complete AV Block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.
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autoimmune Congenital Heart Block complex and unusual situations
Lupus, 2016Co-Authors: Pilar Britozeron, Jill P Buyon, Peter M Izmirly, Manuel Ramoscasals, Munther A KhamashtaAbstract:Autoimmune Congenital Heart Block (ACHB) is an immune-mediated cardiac disease included among the manifestations collectively referred to as neonatal lupus. The placental transference of maternal Ro/La autoantibodies may damage the conduction tissues during fetal development leading to Blocking of signal conduction at the atrioventricular (AV) node in an otherwise structurally normal Heart. Irreversible complete AV Block is the main cardiac manifestation of ACHB, but some babies may develop endocardial fibroelastosis, valvular insufficiency, and/or frank cardiomyopathies with significantly reduced cardiac function requiring transplant. The severity of ACHB is illustrated by a global mortality rate of 20% and pacemaker rates of at least 64%, often within the first year of life. This review analyses the main complex and/or unusual clinical situations associated with ACHB, including unusual maternal immunological profiles, infrequent maternal autoimmune diseases, cardiac damage unrelated to AV Block, fetal invasive management, late complications after birth, risk of Congenital Heart Block (CHB) in ovodonation and in vitro fertilization techniques, the role of maternal features other than autoimmunity, the influence of the birth order or the risk of CHB in twins and triplets.
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the clinical spectrum of autoimmune Congenital Heart Block
Nature Reviews Rheumatology, 2015Co-Authors: Pilar Britozeron, Jill P Buyon, Peter M Izmirly, Manuel Ramoscasals, Munther A KhamashtaAbstract:Autoimmune Congenital Heart Block is more likely to occur in the babies of women with rheumatic diseases, particularly women seropositive for anti-Ro or anti-La autoantibodies. Here, the authors provide advice for the management of these women and their babies in juxtaposition to a systematic assessment of the epidemiology and classification of the disease.
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prevention and treatment in utero of autoimmune associated Congenital Heart Block
Cardiology in Review, 2014Co-Authors: Amit Saxena, Jill P Buyon, Peter M Izmirly, Barbara Mendez, Deborah M FriedmanAbstract:Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease, including Congenital Heart Block and cardiomyopathy, called cardiac neonatal lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third-degree Heart Block in NL, although several treatments have shown some effectiveness in incomplete Heart Block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. β-agonists have been used to increase fetal Heart rates in utero. The endurance of β-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.