Background/Purpose Women with Sjogren’s Syndrome (SS) and anti-Ro antibodies face the risk of a pregnancy complicated by fetal congenital heart block (CHB).  Identification of maternal and fetal biomarkers which associate with development and morbidity of CHB should provide clues to pathogenesis with translational implications for management.   Several candidates were chosen based on potential roles in cardiac disease, inflammation and fibrosis: 1) C-reactive Protein (CRP), elevated in fetal sepsis and hypoxia 2) NT-proBNP, elevated in neonates with congenital heart disease  3) Matrix Metalloproteinase-2 (MMP2), a proinflammatory/profibrotic factor associated with heart failure in adults 4) Urokinase plasminogen activator, its receptor and plasminogen (UPA, UPAR, PGN), proteins in a cascade induced by anti-Ro binding to apoptotic cardiocytes, resulting in TGFb activation 5) Vitamin D, negative regulator in TGFb signaling and fibrosis.  

Methods Sera from anti-Ro positive mothers and cord blood from their CHB and unaffected children in the Research Registry for Neonatal Lupus were analyzed.  Cord CRP and NT-proBNP were assessed on Luminex and MMP2, UPA, UPAR and PGN by ELISA.  Maternal vitamin D 25-OH was analyzed by LC-MS.  Logistic regression was applied to identify predictors of CHB, fetal echo endocardial fibroelastosis (EFE) and hydrops, need for and age at pacemaker (PM) placement, and requirement of B-Blocker, digoxin, and/or ACE-I on long term follow up.  Confounders were added stepwise, including maternal steroid, HCQ and IVIg use, race, maternal SS/lupus, child’s gender, gestational week (GW) of delivery, and GW of greatest disease vulnerability during winter.  Skewed data were log transformed for normalization. 

Results Log transformed levels of cord CRP positively associated with CHB and hydrops in 50 affected and 62 unaffected cases (adjusted OR 1.65, p=0.02, OR 3.7, p=0.02).  Log cord NT-proBNP positively associated with CHB and hydrops in 57 affected and 65 unaffected (OR 2.24, p<0.001, OR 2.46, p=0.02).  Log cord MMP2 positively associated with CHB in 36 affected and 28 unaffected (OR 20.23, p=0.01).   Cord UPA (OR 45.42, p<0.001), UPAR (OR 12.99, p=0.03) and log PGN (OR 38.28, p=<0.001) were positively associated with CHB in 27 affected and 22 unaffected.   UPA and log PGN (OR 1.22, p=0.02, OR 1.27, p=0.03) were positively associated with cardiac meds (mean age at follow-up 7.34 ± 4.93 y) in 18 affected cases.  Other cord biomarkers did not associate with PM, timing of PM or cardiac meds.  Although maternal vitamin D at GW 20 of CHB and healthy pregnancies were equivalent (34.3 ± 11.8 in 50 CHB and 34.1 ± 14.5 ng/mL in 81 unaffected), levels were negatively associated with fetal EFE (OR 0.89, p=0.03), and positively associated with later age at PM (p=0.01) in CHB cases.  

Conclusion Elevated inflammatory markers in neonates with CHB and extranodal disease support close follow up to identify worsening heart function.  The association of NT-proBNP supports consideration of this maker as a diagnostic during amniocentesis.  Elevations of MMP2, UPA, UPAR and PGN in CHB children suggest therapies aimed at decreasing fibrosis.  Optimizing maternal vitamin D levels could become routine in the management of all anti-Ro positive pregnancies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-biomarkers-of-inflammation-and-fibrosis-in-advancing-diagnosis-prognosis-and-treatment-of-anti-ro-associated-congenital-heart-block/