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Abstract

Objectives

Cardiac involvement in neonatal lupus erythematosis (NLE) can present as myocarditis/endocardial fibroelastosis (EFE). It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) is useful in identifying subclinical myocardial inflammation in infants exposed prenatally to anti-Ro antibodies. This study reports hs-cTnT levels in infants exposed to anti-Ro antibodies with/without cardiac NLE and reports cardiac MRI (CMR) findings in a subset of these children.

Methods

The study included 45 consecutive infants exposed prenatally to anti-Ro antibodies with (n = 7) or without (n = 38) cardiac NLE, who were seen at the SickKids NLE Clinic between 2012 and 2014. Hs-cTnT levels were measured at least once, and those infants with values of ≥30 ng/l were offered the opportunity to undergo CMR. Descriptive statistics were performed.

Results

Of 38 infants without cardiac NLE, 25 had a hs-cTnT level of ≥30 ng/l (including 1 of >113 ng/l); of these, 8 underwent CMR (all without myocarditis/EFE). All 7 infants with cardiac NLE had at least one hs-cTnT level of ≥30 ng/l, but only 2/7 had a level of >113 ng/l; 4/7 infants with cardiac NLE had CMR (all without myocarditis/EFE); 6/7 infants with cardiac NLE had their steroid treatment adjusted based on the trend in their hs-cTnT levels.

Conclusion

Only 3/45 anti-Ro antibodies–exposed infants had hs-cTnT values outside the reference range reported in healthy infants. None of 12 infants who had CMR had subclinical myocarditis/EFE. Routine measurement of hs-cTnT in every anti-Ro antibody–exposed infant is not indicated. Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac NLE.

cardiac neonatal lupus, high-sensitivity cardiac troponin T
Rheumatology key messages

  • Routine measurement of high-sensitivity cardiac troponin T (hs-cTnT) in every anti-Ro antibody–exposed infant is not indicated.

  • Subclinical myocardial inflammation was not found on cardiac MRI in infants with normal hs-cTnT values.

  • Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac neonatal lupus erythematosus.

Introduction

Neonatal lupus erythematosus (NLE) is an autoimmune disease associated with the transplacental transfer of maternal anti-Ro antibodies. Congenital heart block (CHB), myocarditis, and endocardial fibroelastosis (EFE) are manifestations of cardiac NLE [1–3]. The incidence of myocardial inflammation and fibrosis postnatally is unknown. Nonetheless, 5–30% of live-births with complete heart block develop dilated cardiomyopathy, with high odds of a need for heart failure treatment, cardiac transplantation and/or death.

Cardiac troponin T is released in response to myocardial injury and is commonly used to measure cardiac inflammation/damage [4]. The Canadian Laboratory Initiative in Pediatric RIs (CALIPER) study reported values of high-sensitivity cardiac troponin T (hs-cTnT) ranging from <3 to 113 ng/l in healthy children 0–1 year old [5]. The same study showed that hs-cTnT became undetectable in most children of ≥1 year old. No study has yet reported hs-cTnT values in infants exposed to maternal anti-Ro antibodies. It remains unclear whether this biomarker is of help in identifying infants with subclinical myocardial inflammation.

The aim of this retrospective cohort study was to determine the clinical value of measuring hs-cTnT levels in infants exposed to maternal anti-Ro antibodies with/without a diagnosis of cardiac NLE. The second aim was to correlate cardiac MRI (CMR) findings with hs-cTnT levels.

Patients and methods

Study population

Children were eligible for the study if they had at least one hs-cTnT measured within their first 6 months of life, were born to women with anti-Ro antibodies and were evaluated at least once at the SickKids Neonatal Lupus Clinic (NLE Clinic) between July 2012 and September 2014 for those with cardiac NLE and between April 2013 and September 2014 for those without cardiac NLE.

All patients with a perinatal diagnosis of cardiac NLE, defined as first- (only if documented postnatally), second-, or third-degree CHB, myocarditis and/or EFE and seen at the NLE Clinic between July 2012 and September 2014 underwent serial measurements of hs-cTnT. We requested blood for hs-cTnT in all patients without cardiac NLE seen between April 2013 and September 2014. Hs-cTnT measurements were analysed using the Roche E170 Analyzer. Neonates with a hs-cTnT value of ≥30 ng/l were offered the opportunity to undergo a CMR to assess for myocardial inflammation. The 30 ng/l hs-cTnT threshold was selected as there was no published data at the time the study was conducted (2012–2014) on normal levels of hs-cTnT in infants (see supplementary material available at Rheumatology online). Infants with cardiac NLE underwent echocardiograms as per standard of care. Infants without cardiac NLE were initially offered the opportunity to undergo an echocardiogram. After the first 8 infants without a fetal cardiac NLE diagnosis were found to have a normal CMR and echocardiogram, it was decided to discontinue offering those examinations to the group of children without cardiac NLE. Following the publication in the CALIPER study of hs-cTnT values in healthy children 0–1 year old, we subsequently re-analyzed the data using a cut-off of 113 ng/l to describe abnormal values [5]. The study was approved by the Hospital for Sick Children Ethics Board (REB #1000047292). A waiver of consent was granted by the REB for this retrospective study.

Treatment of infants with cardiac NLE

Patients with a prenatal diagnosis of cardiac NLE were managed according to institutional guidelines (supplementary material available at Rheumatology online). Serial hs-cTnT measurements were performed, and adjustments in prednisone doses/weaning time were made based on changes in hs-cTnT.

Data collection

Eligible participants were identified in the NLE Database, which contains prospectively collected data. Information was extracted on mothers (diagnosis, maternal anti-Ro and anti-La antibody, medication intake throughout pregnancy, perinatal complications, and delivery mode). Information for infants included: sex, birth weight, neonatal complications, cardiac NLE status, infant intake of non-fluorinated steroids and IVIG, hs-cTnT values, pre/postnatal echocardiogram, postnatal ECG and CMR findings.

Echocardiogram and CMR

The echocardiographic diagnosis of carditis was based on the detection of ventricular dysfunction that improved with anti-inflammatory treatment. EFE was identified as persistent areas of abnormal echogenicity of endocardial surfaces of the cardiac chambers and/or valvar leaflets. CMR examinations were performed on a 1.5 T system (‘Avanto’, Siemens Healthineers, Erlangen, Germany). The CMR study protocol is detailed in the supplementary material available at Rheumatology online.

Statistical analysis

We used descriptive statistics for hs-cTnT in infants with and without cardiac NLE [median inter-quartile range (IQR) and range] and for the evolution of hs-cTnT over time. Characteristics of infants, mothers and first hs-cTnT values were compared using χ2, Fisher’s exact, independent t and Mann–Whitney tests as appropriate. P-values of <0.05 were regarded as statistically significant.

Results

Study population

A total of 45 infants exposed to maternal anti-Ro antibodies had hs-cTnT measured during the study period: 38 infants without and 7 infants with cardiac NLE (Table 1).

Table 1.
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Characteristics of the 45 patients

No cardiac NLE (N = 38)Cardiac NLE (N = 7)P values
Maternal characteristics
  Maternal diagnosis0.03
  Asymptomatic6 (16)4 (58)
  SLE24 (63)1 (14)
  SS4 (10)1 (14)
  SLE/SS1 (3)0 (0)
  UCTD2 (5)0 (0)
  APS0 (0)1 (14)
  Dysautonomia1 (3)0 (0)
  Positive anti-La antibody12 (32)4 (57)0.24
  Maternal intake of fluorinated steroids0 (0)7 (100)<0.01
  Maternal intake of IVIG1 (3)4 (58)<0.01
  Maternal intake of non-fluorinated steroids7 (18)0 (0)0.57
  Maternal intake of antimalarials14 (37)1 (14)0.40
  Prenatal complicationsa8 (21)3 (43)0.34
  Vaginal delivery24 (63)1 (14)0.03
Infant characteristics
  Sex F:M19:19 (50:50)5:2 (71:29)0.42
  Gestational age, weeks38.0 (37.0–39.0)35.5 (34.5–38.0)0.03
  Birth weight, kg3.0 (2.6–3.5)2.3 (1.8–2.5)0.02
  Neonatal complicationsb9 (24)2 (29)0.99
  Infant received non-fluorinated steroids0 (0)7 (100)<0.01
  Infant received IVIG0 (0)5 (71)<0.01
  Age at first hs-cTnT measurement, days55 (43–78)5 (2–26)<0.01
  First hs-cTnT measurement, ng/l37 (24–61)67 (49–310)c0.03
No cardiac NLE (N = 38)Cardiac NLE (N = 7)P values
Maternal characteristics
  Maternal diagnosis0.03
  Asymptomatic6 (16)4 (58)
  SLE24 (63)1 (14)
  SS4 (10)1 (14)
  SLE/SS1 (3)0 (0)
  UCTD2 (5)0 (0)
  APS0 (0)1 (14)
  Dysautonomia1 (3)0 (0)
  Positive anti-La antibody12 (32)4 (57)0.24
  Maternal intake of fluorinated steroids0 (0)7 (100)<0.01
  Maternal intake of IVIG1 (3)4 (58)<0.01
  Maternal intake of non-fluorinated steroids7 (18)0 (0)0.57
  Maternal intake of antimalarials14 (37)1 (14)0.40
  Prenatal complicationsa8 (21)3 (43)0.34
  Vaginal delivery24 (63)1 (14)0.03
Infant characteristics
  Sex F:M19:19 (50:50)5:2 (71:29)0.42
  Gestational age, weeks38.0 (37.0–39.0)35.5 (34.5–38.0)0.03
  Birth weight, kg3.0 (2.6–3.5)2.3 (1.8–2.5)0.02
  Neonatal complicationsb9 (24)2 (29)0.99
  Infant received non-fluorinated steroids0 (0)7 (100)<0.01
  Infant received IVIG0 (0)5 (71)<0.01
  Age at first hs-cTnT measurement, days55 (43–78)5 (2–26)<0.01
  First hs-cTnT measurement, ng/l37 (24–61)67 (49–310)c0.03

Data shown as median (IQR) or N (%), unless otherwise specified.

a

Prenatal complications in mothers of infants without cardiac NLE: premature rupture of membranes (N = 1), deep venous thrombosis (N = 1), pemphigoïd gestationis (N = 1), hypertension (N = 2), oligohydramnios (N = 1), maternal fever during labour (N = 1) and fetal growth delay (N = 1); prenatal complications in mothers of infants with cardiac NLE: paronychia and upper respiratory tract infection (N = 1), oligohydramnios (N = 1) and gestational diabetes (N = 1).

b

Neonatal complications in infants without cardiac NLE: NLE-related thrombocytopenia (N = 1), hyperbilirubinemia requiring phototherapy (N = 2), umbilical cord knot (N = 1), nuchal cord, vacuum-assisted delivery and CPAP requirement for 24 h (N = 1), hypoglycaemia (N = 1), transient heart-rate irregularity (N = 1), gastrointestinal infection (N = 1) and group B Streptococcal sepsis and hyperbilirubinemia requiring phototherapy (N = 1); neonatal complications in infants with cardiac NLE: intubation and haemodynamic instability requiring vasopressors (N = 2).

c

Median (IQR) of first hs-cTnT measurement, ng/l in cardiac NLE infants (N = 5) without a pacemaker inserted: 65 (37–78); P = 0.20 vs infants without cardiac NLE. CPAP: continuous positive airway pressure; F: female; hs-cTnT: high-sensitivity cardiac troponin T; IQR: interquartile range; M: male; NLE: neonatal lupus erythematosus.

Table 1.
Open in new tab

Characteristics of the 45 patients

No cardiac NLE (N = 38)Cardiac NLE (N = 7)P values
Maternal characteristics
  Maternal diagnosis0.03
  Asymptomatic6 (16)4 (58)
  SLE24 (63)1 (14)
  SS4 (10)1 (14)
  SLE/SS1 (3)0 (0)
  UCTD2 (5)0 (0)
  APS0 (0)1 (14)
  Dysautonomia1 (3)0 (0)
  Positive anti-La antibody12 (32)4 (57)0.24
  Maternal intake of fluorinated steroids0 (0)7 (100)<0.01
  Maternal intake of IVIG1 (3)4 (58)<0.01
  Maternal intake of non-fluorinated steroids7 (18)0 (0)0.57
  Maternal intake of antimalarials14 (37)1 (14)0.40
  Prenatal complicationsa8 (21)3 (43)0.34
  Vaginal delivery24 (63)1 (14)0.03
Infant characteristics
  Sex F:M19:19 (50:50)5:2 (71:29)0.42
  Gestational age, weeks38.0 (37.0–39.0)35.5 (34.5–38.0)0.03
  Birth weight, kg3.0 (2.6–3.5)2.3 (1.8–2.5)0.02
  Neonatal complicationsb9 (24)2 (29)0.99
  Infant received non-fluorinated steroids0 (0)7 (100)<0.01
  Infant received IVIG0 (0)5 (71)<0.01
  Age at first hs-cTnT measurement, days55 (43–78)5 (2–26)<0.01
  First hs-cTnT measurement, ng/l37 (24–61)67 (49–310)c0.03
No cardiac NLE (N = 38)Cardiac NLE (N = 7)P values
Maternal characteristics
  Maternal diagnosis0.03
  Asymptomatic6 (16)4 (58)
  SLE24 (63)1 (14)
  SS4 (10)1 (14)
  SLE/SS1 (3)0 (0)
  UCTD2 (5)0 (0)
  APS0 (0)1 (14)
  Dysautonomia1 (3)0 (0)
  Positive anti-La antibody12 (32)4 (57)0.24
  Maternal intake of fluorinated steroids0 (0)7 (100)<0.01
  Maternal intake of IVIG1 (3)4 (58)<0.01
  Maternal intake of non-fluorinated steroids7 (18)0 (0)0.57
  Maternal intake of antimalarials14 (37)1 (14)0.40
  Prenatal complicationsa8 (21)3 (43)0.34
  Vaginal delivery24 (63)1 (14)0.03
Infant characteristics
  Sex F:M19:19 (50:50)5:2 (71:29)0.42
  Gestational age, weeks38.0 (37.0–39.0)35.5 (34.5–38.0)0.03
  Birth weight, kg3.0 (2.6–3.5)2.3 (1.8–2.5)0.02
  Neonatal complicationsb9 (24)2 (29)0.99
  Infant received non-fluorinated steroids0 (0)7 (100)<0.01
  Infant received IVIG0 (0)5 (71)<0.01
  Age at first hs-cTnT measurement, days55 (43–78)5 (2–26)<0.01
  First hs-cTnT measurement, ng/l37 (24–61)67 (49–310)c0.03

Data shown as median (IQR) or N (%), unless otherwise specified.

a

Prenatal complications in mothers of infants without cardiac NLE: premature rupture of membranes (N = 1), deep venous thrombosis (N = 1), pemphigoïd gestationis (N = 1), hypertension (N = 2), oligohydramnios (N = 1), maternal fever during labour (N = 1) and fetal growth delay (N = 1); prenatal complications in mothers of infants with cardiac NLE: paronychia and upper respiratory tract infection (N = 1), oligohydramnios (N = 1) and gestational diabetes (N = 1).

b

Neonatal complications in infants without cardiac NLE: NLE-related thrombocytopenia (N = 1), hyperbilirubinemia requiring phototherapy (N = 2), umbilical cord knot (N = 1), nuchal cord, vacuum-assisted delivery and CPAP requirement for 24 h (N = 1), hypoglycaemia (N = 1), transient heart-rate irregularity (N = 1), gastrointestinal infection (N = 1) and group B Streptococcal sepsis and hyperbilirubinemia requiring phototherapy (N = 1); neonatal complications in infants with cardiac NLE: intubation and haemodynamic instability requiring vasopressors (N = 2).

c

Median (IQR) of first hs-cTnT measurement, ng/l in cardiac NLE infants (N = 5) without a pacemaker inserted: 65 (37–78); P = 0.20 vs infants without cardiac NLE. CPAP: continuous positive airway pressure; F: female; hs-cTnT: high-sensitivity cardiac troponin T; IQR: interquartile range; M: male; NLE: neonatal lupus erythematosus.

Infants without cardiac NLE

Characteristics of the 38 infants without cardiac NLE are summarized in Table 1. hs-cTnT measurements were obtained at a median (IQR) age of 55 (43–78) days of life and displayed values of from 7 to 132 ng/l. One infant had an abnormally high hs-cTnT value of >113 ng/l (132 ng/l at 42 days of life) [4]. Parents of 8/25 infants (32%) with hs-cTnT of ≥30 ng/l agreed to CMR being performed at a median (IQR) age of 72 (57–80) days old. Values of hs-cTnT in these 8 infants were: 30, 36, 38, 53, 97, 105, 106 and 132 ng/l, measured between 8 and 49 days prior to the CMR. All 8 infants had no evidence of myocarditis/EFE on CMR (Supplementary Table S1, available at Rheumatology online). Echocardiogram was performed in 4/8 infants, with normal findings in all.

Infants with cardiac NLE

Characteristics of the seven cardiac NLE cases are summarized in Table 2. Initial values of hs-cTnT measured at a median of 5 (IQR 2–26) days ranged from 25 to 536 ng/l. Two infants (subjects 3 and 7) had hs-cTnT of >113 ng/l [5] at initial measurement, but both recently had a pacemaker (PM) inserted (1 and 4 days prior to the first hs-cTnT measurement). At the time of hs-cTnT elevation, these two infants had unexplained elevated PM-sensing thresholds suggestive of myocardial inflammation. All seven cardiac NLE children had at least one hs-cTnT value of ≥30 ng/l. Four of the seven cases had fetal echocardiographic findings compatible with myocarditis/EFE that, despite treatment, persisted in two on postnatal echocardiography. Postnatal CMR obtained in 4/7 at a median age of 37 days old displayed no signs of myocarditis/EFE, including one patient who had myocarditis/EFE on postnatal echocardiogram (patient 6).

Table 2.
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Detailed investigations in seven infants with cardiac neonatal lupus erythematosus

Prenatal investigations
Postnatal investigations
Postnatal CMR
hs-cTnT
PM
CHBEFE/myocarditisCHBAge at echo, daysMyocarditis/EFE on echoAge at CMR, daysMyocarditis/EFE on CMRFirst hs-cTnT, ng/l (age in days)Highest hs-cTnT, ng/l (age in days)hs-cTnT closest to CMR, ng/l (age in days)Age at PM, days
1NonePresentNone1PresentNot doneNot done25 (5)38 (77)Not doneN/A
2First to thirdPresentNone3Absent97Absent49 (12)78 (32)50 (66)N/A
3ThirdAbsentThird1AbsentNot doneNot done536 (2)792 (4)Not done1
4ThirdPresentThird1Absent3Absent67 (2)67 (2)67 (2)7
5FirstAbsentFirst6Absent38Absent88 (26)88 (26)78 (38)N/A
6NonePresentNone2Present36Absent65 (28)65 (28)7 (36)N/A
7ThirdAbsentThird1AbsentNot doneNot done310 (5)310 (5)Not done1
Prenatal investigations
Postnatal investigations
Postnatal CMR
hs-cTnT
PM
CHBEFE/myocarditisCHBAge at echo, daysMyocarditis/EFE on echoAge at CMR, daysMyocarditis/EFE on CMRFirst hs-cTnT, ng/l (age in days)Highest hs-cTnT, ng/l (age in days)hs-cTnT closest to CMR, ng/l (age in days)Age at PM, days
1NonePresentNone1PresentNot doneNot done25 (5)38 (77)Not doneN/A
2First to thirdPresentNone3Absent97Absent49 (12)78 (32)50 (66)N/A
3ThirdAbsentThird1AbsentNot doneNot done536 (2)792 (4)Not done1
4ThirdPresentThird1Absent3Absent67 (2)67 (2)67 (2)7
5FirstAbsentFirst6Absent38Absent88 (26)88 (26)78 (38)N/A
6NonePresentNone2Present36Absent65 (28)65 (28)7 (36)N/A
7ThirdAbsentThird1AbsentNot doneNot done310 (5)310 (5)Not done1

CHB: congenital heart block; CMR: cardiac magnetic resonance; echo: echocardiogram; EFE: endocardial fibroelastosis; hs-cTnT: high-sensitivity cardiac troponin T; N/A: not applicable; PM: pacemaker.

Table 2.
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Detailed investigations in seven infants with cardiac neonatal lupus erythematosus

Prenatal investigations
Postnatal investigations
Postnatal CMR
hs-cTnT
PM
CHBEFE/myocarditisCHBAge at echo, daysMyocarditis/EFE on echoAge at CMR, daysMyocarditis/EFE on CMRFirst hs-cTnT, ng/l (age in days)Highest hs-cTnT, ng/l (age in days)hs-cTnT closest to CMR, ng/l (age in days)Age at PM, days
1NonePresentNone1PresentNot doneNot done25 (5)38 (77)Not doneN/A
2First to thirdPresentNone3Absent97Absent49 (12)78 (32)50 (66)N/A
3ThirdAbsentThird1AbsentNot doneNot done536 (2)792 (4)Not done1
4ThirdPresentThird1Absent3Absent67 (2)67 (2)67 (2)7
5FirstAbsentFirst6Absent38Absent88 (26)88 (26)78 (38)N/A
6NonePresentNone2Present36Absent65 (28)65 (28)7 (36)N/A
7ThirdAbsentThird1AbsentNot doneNot done310 (5)310 (5)Not done1
Prenatal investigations
Postnatal investigations
Postnatal CMR
hs-cTnT
PM
CHBEFE/myocarditisCHBAge at echo, daysMyocarditis/EFE on echoAge at CMR, daysMyocarditis/EFE on CMRFirst hs-cTnT, ng/l (age in days)Highest hs-cTnT, ng/l (age in days)hs-cTnT closest to CMR, ng/l (age in days)Age at PM, days
1NonePresentNone1PresentNot doneNot done25 (5)38 (77)Not doneN/A
2First to thirdPresentNone3Absent97Absent49 (12)78 (32)50 (66)N/A
3ThirdAbsentThird1AbsentNot doneNot done536 (2)792 (4)Not done1
4ThirdPresentThird1Absent3Absent67 (2)67 (2)67 (2)7
5FirstAbsentFirst6Absent38Absent88 (26)88 (26)78 (38)N/A
6NonePresentNone2Present36Absent65 (28)65 (28)7 (36)N/A
7ThirdAbsentThird1AbsentNot doneNot done310 (5)310 (5)Not done1

CHB: congenital heart block; CMR: cardiac magnetic resonance; echo: echocardiogram; EFE: endocardial fibroelastosis; hs-cTnT: high-sensitivity cardiac troponin T; N/A: not applicable; PM: pacemaker.

Serial measurements of hs-cTnT assisted steroid weaning in infants with cardiac NLE

The seven infants with cardiac NLE had a median (IQR) of 5 (4–18) measurements of hs-cTnT during the post-natal period. The median (IQR) value of the highest hs-cTnT was 67 (49–310) ng/l, measured at a median (IQR) age of 5 (2–26) days. The median (IQR) value of the last hs-cTnT was 19 (11–36) ng/l measured at a median (IQR) age of 133 (103–355) days. Apart from subject 5, all infants had at least one temporary increase in hs-cTnT. Among those 6 infants, hs-cTnT increment was captured on 16 measurements, with a median (IQR) increment of 10 (5–27) ng/l at a median (IQR) age of 58 (33–112) days of life. In 6/7 infants, the prednisone weaning scheme was modified due to either an increase in hs-cTnT or a slower-than-expected decrease in hs-cTnT (5 infants) or both (1 infant). Supplementary Fig. S1, available at Rheumatology online, illustrates an example of how serial measurements of hs-cTnT were used to direct prednisone therapy.

Discussion

Cardiac involvement is the NLE complication with the highest mortality/morbidity [6, 7]. Echocardiogram can underappreciate myocarditis/EFE and the true extent of the disease [3]. A biomarker that can identify infants with myocarditis below the threshold of detection by echocardiogram is desirable. hs-cTnT could be a potential candidate biomarker of cardiac involvement in NLE [8]. In this retrospective study of 45 infants exposed to anti-Ro antibodies who had hs-cTnT measured at least once within their first 6 months of life, only 3 infants (2 with cardiac NLE and 1 without cardiac NLE) had hs-cTnT values higher than what has been described in a group of healthy children ≤1 year old [5]. All 3 infants had an excellent long-term cardiac outcome (see supplementary material available at Rheumatology online).

Every infant born with cardiac NLE during the study period had hs-cTnT measured serially, and only two had hs-cTnT values above normal for age. These two infants had complete CHB without myocarditis/EFE on pre- and postnatal echocardiogram. Unfortunately, neither of the infants had a CMR; therefore, we could not assess whether the elevated hs-cTnT values reflected underlying myocarditis that was not appreciated by echocardiogram. Both had PM insertion prior to the first hs-cTnT measurement, and it is possible that the procedure contributed to the elevated levels [9].

Thirty-seven of 38 infants without obvious cardiac NLE manifestations had hs-cTnT within the normal range [5]; CMR performed in a subset of these subjects, including the one with hs-cTnT value above normal for age, did not show evidence of subclinical myocarditis/EFE. Therefore, routinely measuring hs-cTnT after birth in infants exposed to anti-Ro antibodies without evidence of cardiac NLE during pre- and postnatal screening is not indicated.

First values of hs-cTNT were higher in infants with cardiac NLE, as compared with children without cardiac NLE. Although this could reflect underlying myocardial injury/inflammation, it could also be explained by the fact that measurements were taken earlier in time and/or, for some, due to PM insertion. A study performed on 83 anti-Ro antibody–exposed infants found that cord blood levels of troponin I were not significantly different between those with vs those without cardiac NLE [10]. As pointed out by authors, the troponin I assay might not have been sensitive enough to detect a small difference that the high-sensitive assay might have found.

Four infants with cardiac NLE had a CMR done (all without myocarditis/EFE), although 3/4 had a fetal echocardiogram that showed myocarditis/EFE, which persisted postnatally in one. The only patient with an early CMR (day 3) also had a normal echocardiogram postnatally. The fact that the 3 patients with myocarditis/EFE on fetal and/or postnatal echocardiogram all had normal CMR may seem surprising. However, by the time the CMR had been performed, all 3 were on steroid therapy. On the other hand, echocardiography comprises a degree of subjectivity; therefore, the discrepancy may have been due to false-positive prenatal or false-negative postnatal echocardiograms. CMR has been recognized as more sensitive than echocardiogram in detecting myocardial inflammation/fibrosis in multiple entities in the cardiology literature [11–14]. Another possibility is that what was interpreted as myocarditis on pre/postnatal fetal echocardiograms represent only end-stage disease: fibrosis without myocarditis and therefore no association with troponin levels is expected.

This study shows for the first time the evolution of hs-cTnT during the first few months of life in a small group of infants with cardiac NLE. The trend in all 7 children was for improvement over time, but 6/7 infants had a transient increase in hs-cTnT values. These fluctuations may be explained by intralaboratory or physiologic variation of hs-cTnT and/or PM insertion. Subtle myocardial inflammation could explain elevation or a slower-than-expected decrease in hs-cTnT, although we were not able to demonstrate this in our study by CMR/echocardiogram. Serially following hs-cTnT in infants with cardiac NLE was informative, as an unexplained rise in values or values remaining persistently above normal for age may be an early clue for an ongoing cardiac injury.

Limitations of the study include a small sample size; therefore, it may not be representative of the total anti-Ro antibody–exposed population. In addition, only a subset of children exposed to anti-Ro antibody (12/45) underwent CMR. In infants with cardiac NLE, all CMRs were performed after the initiation of glucocorticoid/IVIG. This could have limited our ability to detect myocardial inflammation. Similarly, all cardiac NLE infants received immunomodulatory treatments in utero/postnatally. This could explain why most had hs-cTNT levels within normal for age, as there was no ongoing myocardial inflammation due to adequate anti-inflammatory treatment. As discussed previously, the elevated hs-cTnT level in both infants with cardiac NLE may have been due to PM insertion performed prior to the first hs-cTnT measurement in these two infants. In addition, infants with cardiac NLE had hs-cTnT measurements done earlier in time than those without cardiac NLE, which may explain higher absolute values in the former group. Lastly, infants with cardiac NLE had repeated measurements of hs-cTnT, which might have increased the probability of finding abnormal results in that group.

In this study of 45 infants exposed to maternal anti-Ro antibodies, almost all children had hs-cTnT values within normal reference for age. Routine measurements of hs-cTnT in infants without cardiac NLE on pre/postnatal screening is not indicated. Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac NLE.

Supplementary material

Supplementary material is available at Rheumatology online.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

References

1

Brito-Zeron
P
,
Izmirly
PM
,
Ramos-Casals
M
,
Buyon
JP
,
Khamashta
MA.
The clinical spectrum of autoimmune congenital heart block
.
Nat Rev Rheumatol
2015
;
11
:
301
–
12
.

Google Scholar

Crossref
Search ADS
PubMed

 
2

Nield
L
,
Silverman
ED
,
Smallhorn
JF
 et al.
Endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block
.
J Am Coll Cardiol
2002
;
40
:
796
–
802
.

Google Scholar

Crossref
Search ADS
PubMed

 
3

Llanos
C
,
Friedman
DM
,
Saxena
A
 et al.
Anatomical and pathological findings in hearts from fetuses and infants with cardiac manifestations of neonatal lupus
.
Rheumatology
2012
;
51
:
1086
–
92
.

Google Scholar

Crossref
Search ADS
PubMed

 
4

Thygesen
K
,
Mair
J
,
Giannitsis
E
 et al.
How to use high-sensitivity cardiac troponins in acute cardiac care
.
Eur Heart J
2012
;
33
:
2252
–
7
.

Google Scholar

Crossref
Search ADS
PubMed

 
5

Bohn
MK
,
Higgins
V
,
Kavsak
P
,
Hoffman
B
,
Adeli
K.
High-sensitivity generation 5 cardiac troponin T sex- and age-specific 99th percentiles in the CALIPER cohort of healthy children and adolescents
.
Clin Chem
2019
;
65
:
589
–
91
.

Google Scholar

Crossref
Search ADS
PubMed

 
6

Izmirly
PM
,
Saxena
A
,
Kim
MY
 et al.
Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro–associated cardiac neonatal lupus
.
Circulation
2011
;
124
:
1927
–
35
.

Google Scholar

Crossref
Search ADS
PubMed

 
7

Morel
N
,
Levesque
K
,
Maltret
A
 et al. ;
Lupus néonatal group
.
Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus
.
Int J Cardiol
2017
;
248
:
263
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
8

Sramko
M
,
Kubanek
M
,
Tintera
J
 et al.
Utility of combination of cardiac magnetic resonance imaging and high-sensitivity cardiac troponin T assay in diagnosis of inflammatory cardiomyopathy
.
Am J Cardiol
2013
;
111
:
258
–
64
.

Google Scholar

Crossref
Search ADS
PubMed

 
9

Blazek
P
,
Ferri-Certic
J
,
Vrazic
H
 et al.
Pacemaker implantation associated myocardial micro-damage: a randomised comparison between active and passive fixation leads
.
Sci Rep
2018
;
8
:
4870
.

Google Scholar

Crossref
Search ADS
PubMed

 
10

Saxena
A
,
Izmirly
PM
,
Han
SW
 et al.
Serum biomarkers of inflammation, fibrosis, and cardiac function in facilitating diagnosis, prognosis, and treatment of anti-SSA/Ro–associated cardiac neonatal lupus
.
J Am Coll Cardiol
2015
;
66
:
930
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
11

Friedrich
MG
,
Sechtem
U
,
Schulz-Menger
J
 et al. ;
International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis
.
Cardiovascular magnetic resonance in myocarditis: a JACC white paper
.
J Am Coll Cardiol
2009
;
53
:
1475
–
87
.

Google Scholar

Crossref
Search ADS
PubMed

 
12

Pennell
DJ.
Cardiovascular magnetic resonance
.
Circulation
2010
;
121
:
692
–
705
.

Google Scholar

Crossref
Search ADS
PubMed

 
13

Tworetzky
W
,
del Nido
PJ
,
Powell
AJ
 et al.
Usefulness of magnetic resonance imaging of left ventricular endocardial fibroelastosis in infants after fetal intervention for aortic valve stenosis
.
Am J Cardiol
2005
;
96
:
1568
–
70
.

Google Scholar

Crossref
Search ADS
PubMed

 
14

Podlesnikar
T
,
Delgado
V
,
Bax
JJ.
Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease
.
Int J Cardiovasc Imaging
2018
;
34
:
97
–
112
.

Google Scholar

Crossref
Search ADS
PubMed

 
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