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Abstract Number: L13

Fetal Cardiac Targets Identify the Autoantibodies Associated with Congenital Heart Block

Stephanie Benjamin1, Lisa Vi2, Diptendu Chatterjee1, Edgar Jaeggi1, Marie Wahren-Herlenius3, Amelia Ruffatti4, Linda Hiraki5, Michelle Lohbihler2, Lusia Sepiashvili1, Carl Laskin6, Meena Fatah1, Daniela Dominguez5, Lawrence Ng5, Anthony Gramolini2, Vincent Christoffels7, Stephanie Protze2 and Robert Hamilton8, 1Hospital for Sick Children, Toronto, ON, Canada, 2University of Toronto, Toronto, ON, Canada, 3Karolinska Institutet, Stockholm, Stockholms Lan, Sweden, 4Universitå di Padova, Padova, Italy, 5The Hospital for Sick Children, Toronto, ON, Canada, 6Mt. Sinai Hospital/University of Toronto, Toronto, ON, Canada, 7Amsterdam UMC, Amsterdam, Zuid-Holland, Netherlands, 8Hospital for Sick Children, Markham, ON, Canada

Meeting: ACR Convergence 2022

Date of first publication: October 18, 2022

Keywords: Autoantibody(ies), Biomarkers, Late-Breaking 2022, pregnancy, Sjögren's syndrome, Systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 14, 2022

Session Title: (L07–L17) Late-Breaking Abstract Poster

Session Type: Poster Session D

Session Time: 1:00PM-3:00PM

Background/Purpose: Autoimmune congenital heart block (CHB+) affects the fetus of mothers with anti-Ro antibodies. Anti-Ro (Ro+) antibodies (Abs) are usually present in maternal sera when the fetus or newborn develops CHB, but only 2% of Ro+ pregnancies result in CHB, making it difficult to select pregnancies for screening or therapy.

We hypothesized that maternal Abs can be characterized based on fetal heart conduction system protein targets and may better predict CHB+ pregnancies.

Methods: We screened maternal serum Abs using protein targets isolated from 20-wk. normal fetal myocardium, and separately using proteins from stem cell-derived ventricular-like cardiomyocytes (VLCMs). Tissues/cells were solubilized, and used as a source of proteins to create 2-dimensional (2D) gels for Ab discovery.

Results: Sera from 3 Ro+ CHB+ pregnancies drawn at term (Figure 1: D, E, F) identified up to 30 Ab targets to fetal myocardium, compared to 3 Ro+ pregnancies without CHB (CHB-, Figure 1: A, B, C), where only Abs to Ro and La were present. Sera drawn sequentially later throughout seven affected pregnancies (Figure 1: 1 to 7) identified fewer VLCM protein targets of Abs in early pregnancy (16 to 18 weeks), compared to later in pregnancy (19.7+ weeks). Serum from three Ro+ CHB- pregnancies (Figure 1: 8 to 10), as well as from three normal non-pregnant females (Figure 1: 11 to 13) did not demonstrate any Abs to VLCM proteins.

Mass spectrometry guided selection of 13 protein candidates, for which Abs were confirmed in CHB against seven commercial proteins (Figure 2: A1, A2 and B, p=0.0018 by serum, p=0.0045 by patient, Fisher Exact Test), of which 4 predicted CHB before its occurrence (Figure 2: A1, A2), including anti-ATP1A1. Validation studies to date in 10 additional Ro+ sera with heart block outcomes (compared to Ro+ pregnancies with normal outcomes) demonstrate that Abs to ATP1A1 are identified as early as 7 wks. gestation and are always present in CHB pregnancies (among an expanding set of antibodies through pregnancy) and are absent in Ro+ pregnancies with normal outcomes. (Figure 3) In contrast, sera from three Ro+ pregnancies without CHB (Figure 2: C), as well as from three normal non-pregnant females (Figure 2:D) did not demonstrate any Abs. The difference between discovery cohort pregnancies that later developed CHB and either control group was statistically significant (p=0.0286, Fisher Exact Test). Abs to ATP1A1 were identified in 10/10 CHB pregnancies versus 0/10 normal pregnancies in the validation cohort. (p < 0.01)

Conclusion: We discovered Abs against fetal protein targets that were predictive for CHB and confirmed these in an independent validation cohort. Further studies in early pregnancy and preconception should be performed to determine how early prediction is possible.

Better targeting of at-risk pregnancies for CHB might avoid many fetal cardiac assessments in these mothers, and guide preventive therapy.

Supporting image 1

Figure 1: Top Panel: Maternal serum antibodies at term detected by 2D gel of fetal myocardial proteins. A, B and C are 3 different CHB- pregnancies and D, E and F are 3 different CHB+ pregnancies. Bottom panel: Maternal serum antibodies throughout CHB pregnancies (1 to 7) detected by 2D gel of stem cell-derived ventricular-like cardiomyocyte proteins, compared to CHB- pregnancy sera (8 to 10) and normal young women (11 to 13).

Supporting image 2

Figure 2: Western blot confirmation of maternal serum autoantibodies from all Ro+ CHB+ pregnancies (A1, A2, B) compared to Ro+ CHB- pregnancies (C) and normal young women (D). Prior to the development of CHB, four autoantibodies are consistently identified (A1, A2).

Supporting image 3

Figure 3: Validation cohorts: Ro+ CHB+ sera (top 10 blots) demonstrate sequentially fewer autoantibodies as sera are sampled earlier in pregnancies, with only antibodies to ATPA1 present at 7 wks. gestation. anti-ATPA1 antibodies are always present in CHB+ sera, and absent in Ro+ CHB- sera (bottom 10 blots)


Disclosures: S. Benjamin, None; L. Vi, None; D. Chatterjee, None; E. Jaeggi, None; M. Wahren-Herlenius, Merck KGaA, Janssen Pharmaceutical NV; A. Ruffatti, None; L. Hiraki, Janssen; M. Lohbihler, None; L. Sepiashvili, None; C. Laskin, None; M. Fatah, None; D. Dominguez, None; L. Ng, None; A. Gramolini, None; V. Christoffels, None; S. Protze, None; R. Hamilton, None.

To cite this abstract in AMA style:

Benjamin S, Vi L, Chatterjee D, Jaeggi E, Wahren-Herlenius M, Ruffatti A, Hiraki L, Lohbihler M, Sepiashvili L, Laskin C, Fatah M, Dominguez D, Ng L, Gramolini A, Christoffels V, Protze S, Hamilton R. Fetal Cardiac Targets Identify the Autoantibodies Associated with Congenital Heart Block [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/fetal-cardiac-targets-identify-the-autoantibodies-associated-with-congenital-heart-block/. Accessed February 5, 2023.
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