Anatomical and pathological findings in hearts from fetuses and infants with cardiac manifestations of neonatal lupus

Llanos, Carolina; Friedman, Deborah; Saxena, Amit; Izmirly, Peter; Tseng, Chung E.; Dische, Renata; Abellar, Rosanna; Halushka, Marc K.; Clancy, Robert M.; Buyon, Jill P.

doi:10.1093/rheumatology/ker515

Cited by 106 publications

(92 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amniotic fluid NT-proBNP has been correlated with echocardiography in twin-twin transfusion syndrome and has been proposed as a marker for fetal cardiac health (14,35). Because fetal echocardiograms may underestimate pathologic findings in cardiac NL (36), a sensitive method to predict clinical manifestations in utero, such as amniotic fluid NT-proBNP, could provide utility in guiding and monitoring treatment of cardiac NL.…”

Section: Discussionmentioning

confidence: 99%

Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro–Associated Cardiac Neonatal Lupus

Saxena

Izmirly

Han

et al. 2015

Journal of the American College of Cardiology

Self Cite

View full text Add to dashboard Cite

BACKGROUND Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, and cardiac dysfunction: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D. OBJECTIVES Identification of maternal and fetal biomarkers associated with development and morbidity of cardiac NL should provide clues to pathogenesis with translational implications for management. METHODS Cord and maternal blood samples (139 each) collected during pregnancies at risk for cardiac NL were available for study. Levels of cord and maternal CRP, cord NT-proBNP, and cord troponin I were evaluated using multiplex assays. Cord and maternal vitamin D were assessed by liquid chromatography-mass spectrometry. MMP-2, uPA, uPAR, and plasminogen were evaluated using ELISA. RESULTS Cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in cardiac NL-affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of cardiac NL development, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality in cardiac NL. Maternal CRP and cord troponin I levels did not differ between the groups. Cord and maternal vitamin D levels were not significantly associated with cardiac NL, but average maternal vitamin D level during pregnancy was positively associated with longer time to postnatal pacemaker placement. CONCLUSIONS These data support the association of fetal reactive inflammatory and fibrotic components with development and morbidity of cardiac NL. Following CRP and NT-proBNP levels after birth can potentially monitor severity and progression of cardiac NL. MMP-2 and the uPA/uPAR/plasminogen cascade provide therapeutic targets to decrease fibrosis. Although decreased vitamin D did not confer increased risk, given the positive influence on postnatal outcomes, maternal levels should be optimized.

show abstract

Section: Discussionmentioning

confidence: 99%

Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro–Associated Cardiac Neonatal Lupus

Saxena

Izmirly

Han

et al. 2015

Journal of the American College of Cardiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The signature manifestation of cardiac-NL is congenital heart block (CHB) whose histologic correlate is fibrosis of the atrioventricular node surrounded by infiltrating macrophages and giant cells [2,3]. The mechanism by which maternal antibodies initiate and eventuate in cardiac scarring has been challenging to define, in part because the target cardiac antigens are normally sequestered intracellularly.…”

Section: Introductionmentioning

confidence: 99%

Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block

Clancy

Markham

Reed

et al. 2016

Journal of Autoimmunity

Self Cite

View full text Add to dashboard Cite

Based on the consistent demonstration of fibrosis of the atrioventricular node surrounded by macrophages and multinucleated giant cells in anti-Ro antibody exposed fetuses dying with heart block, this study focuses on macrophage signaling stimulated by ssRNA associated with the Ro60 protein and the impact of antagonizing innate cell drivers such as TLR7/8. Transcriptome and epigenetic modifications which affect transcription factors, NF-κB and STAT1, were selected to evaluate the phenotype of macrophages in which TLR7/8 was ligated following treatment with either anti-Ro60/Ro60/hY3 RNA immune complexes or transfection with hY3. Based on microarray, TNF and IL6 were among the most highly upregulated genes in both stimulated conditions, each of which was significantly inhibited by preincubation with hydroxychloroquine (HCQ). In contrast, following stimulation of macrophages with either TNF-α or IFN-α, which do not signal through TLR, the resultant gene expression was refractory to HCQ. Ligation of TLR7/8 resulted in increased histone methylation as measured by increased H3K4me2, a requirement for binding of NF-κB at certain promoters, specifically the kB1 region in the TNF promoter (ChIP-qPCR), which was significantly decreased by HCQ. In summary, these results support that the HCQ-sensitive phenotype of hY3 stimulated macrophages reflects the bifurcation of TLR downstream signals involving NF-κB and STAT 1 pathways and for the former dimethylation of H3K4. Accordingly, HCQ may act more as a preventive measure in downregulating the initial production of IFN-α or TNF-α and not affect the resultant autocoid stimulation reflected in TNF-α and IFN-α responsive genes. The beneficial scope of antimalarials in the prevention of organ damage, inclusive of heart block in an anti-Ro offspring or more broadly SLE, may include in part, a mechanism targeting TLR-dependent epigenetic modification.

show abstract

“…One of these fetuses had aortic insuffi ciency and stenosis together with severe pulmonary valve stenosis and mild hypoplasia of the mitral and tricuspid valve leafl ets. Pre-mortem echocardiograms did not consistently predict the pathological fi ndings on autopsy [ 50 ].…”

Section: Cardiac Manifestationsmentioning

confidence: 83%

“…Autoantibody-mediated heart block in NL is typically associated with a structurally normal heart; however, structural abnormalities such as fl ail mitral valve secondary to chordal disruption from EFE have been reported [ 49 ]. In an evaluation of 18 autopsies of cardiac-NL cases from the RRNL, fi brosis of the AV node and distal conduction system was the most characteristic histopathological fi nding [ 50 ]. However, fi brosis of the SA node and bundle of His, EFE, and valvular damage were also part of the spectrum of anti-SSA/Ro injury.…”

Section: Cardiac Manifestationsmentioning

confidence: 99%

Neonatal Lupus

Mendez

Saxena

Buyon

et al. 2014

Contraception and Pregnancy in Patients With Rheumatic Disease

Self Cite

View full text Add to dashboard Cite

Anatomical and pathological findings in hearts from fetuses and infants with cardiac manifestations of neonatal lupus

Cited by 106 publications

References 29 publications

Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro–Associated Cardiac Neonatal Lupus

Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro–Associated Cardiac Neonatal Lupus

Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block

Neonatal Lupus

Contact Info

Product

Resources

About