Immune-Mediated Atrioventricular Block
Helena M. Gardiner
Bettina F. Cuneo
INTRODUCTION
Complete atrioventricular (AV) block was first described 119 years ago as “impaired atrioventricular syndrome.”1 The association of a slow heart rate in two daughters of a mother with “Mikulicz disease” (Sjogren syndrome) was reported in 1928.2 The description of the affected daughters from that report by Dr. RD Alyward is timeless, and the hypothesis of the underlying etiology posited by Dr. Janet Aiken 4 years later is remarkably prescient3:
… The first child, a girl…had a pulse of 40 soon after birth; she was puny baby lacking energy and was cyanosed at times. She still survives and is a healthy girl, although quiet…. The fourth was another girl and in this case a slow foetal heart rate was noted…she suffered from occasional attacks of cyanosis; at 3 months old during one of these attacks, her pulse became irregular and she died.2
The introduction of toxic bodies into the blood stream in utero would have a transient effect except…they might cause direct interference with development of the conducting system…in congenital heart-block there must have been prenatal direct interference with the conducting tract above its division….3
The association of maternal anti-Ro/SSA antibodies with fetal AV block was not reported until 1957.4 The affected infant with “congenital acute lupus erythematosus” was born with a heart rate of 45 beats per minute and died 25 min later. Postmortem cardiac examination revealed extensive endocardial fibroelastosis (EFE); no AV node or His bundle was identifiable. In 1988, Lindsey Allan and colleagues at Guy’s Hospital published the first series of 16 fetuses born to anti-Ro/SSA positive mothers with AV block.5 Twelve were liveborn, and all with fetal hydrops died.
Since these first reports of maternal anti-Ro/SSA antibody-mediated fetal and neonatal AV block, it has been recognized that inflammation and fibrosis occur not only in the AV node but also in other parts of the conduction system. Manifestations of anti-Ro-SSA-mediated conduction system disease include AV block, sinus bradycardia, junctional ectopic tachycardia, and ventricular tachycardia. These arrhythmias can be independent of AV nodal disease, herald, or co-occur with it.
This chapter will concentrate primarily on the diagnosis and presentation of AV block associated with maternal anti-Ro/SSA antibodies. Treatment of fetal AV block will be discussed in Part 4, Chapter 3, and surveillance of anti-Ro antibody positive pregnancies will be discussed in Part 5, Chapter 2.
DEFINITION OF AV BLOCK
AV block is defined as a progressive disease of the AV node (AVN) culminating in the absence of the normal electrical communication between the atrium and ventricle. In the absence of an electrocardiogram, AV conduction can be evaluated by simultaneous interrogation of flow in a vein and an artery or by mitral inflow and aortic outflow measurements, as described in Part 2, Chapter 2 (FIG. 3.5.1). 1° AV block is present when the atrial impulse is delayed, but there is still 1:1 AV conduction. 2° AV block occurs when some but not all the atrial beats are conducted to the ventricles, and 3° AV block is complete AV dissociation with no relationship between atrial and ventricular contractions (FIGS. 3.5.2, 3.5.3,3.5.4, 3.5.5).
Just under half of the reported fetal cases of AV block have structurally normal hearts and the AV block is secondary to inflammation and fibrosis of a structurally normal AVN due to maternal anti-Ro/SSA antibodies.6,7 The remainder of this chapter will be discussion of anti-Ro/SSA-mediated AV block. Other causes of fetal AV block were discussed in previous chapters. Lastly, a small proportion of pregnant women whose fetuses have 2° or 3° AV block and normally connected hearts are antibody negative. In such cases, disease may be due to a viral myocarditis, such as parvovirus,8 long QT syndrome,9 or heritable progressive cardiac conduction disorders.10
 FIGURE 3.5.1 A-C: Doppler recordings of atrial and arterial waveform pairs recorded using a single gate. They demonstrate the atrioventricular (AV) time interval may be measured from a variety of sites: the mitral valve (MV) inflow and aortic valve (AV) outflow, the aorta (Ao) and superior vena cava (SVC), and a branch pulmonary artery (PA) and a pulmonary vein (PV). |
 FIGURE 3.5.2 Cartoon showing various degrees of fetal atrioventricular (AV) block associated with anti-Ro/SSA antibody-mediated cardiac disease. Blue V, conducted ventricular beats. A, conducted atrial beats; A′, blocked atrial beats. A: Normal sinus rhythm with 1:1 conduction. B: 1° AV block. The AV interval is prolonged but each beat is conducted, C: Type 1, 2° AV block. The AV interval prolongs until a ventricular beat is dropped. D: Type 2, 2° AV block. A ventricular beat is dropped without a preceding prolonged AV interval. E: 3° AV block: no relationship between atrial and ventricular contractions. |
 FIGURE 3.5.3 1° Atrioventricular (AV) block. Spectral Doppler of mitral inflow (below baseline) and aortic outflow (above baseline) in two fetuses. A: The mitral E- and A-waves are fused (ea), and the AV interval is >200 ms. This fetus was also having rare episodes of type 2, 2° AV block (not shown). B: The AV interval is prolonged to about 180 ms, but there are still distinct mitral E- and A-waves. C: Varying AV intervals in a fetus developing 1° AV block shown by spectral Doppler. D: Signal-averaged fetal electrocardiogram showing a prolonged PR interval consistent with 1° AV block. |
 FIGURE 3.5.3 Cont’d |
 FIGURE 3.5.4 2° Atrioventricular (AV) block. A: Simultaneous M-mode through the atrium (a) and the ventricle (V) showing a regular atrial rhythm. Occasionally the ventricle does not contract. Although this is 2° AV block, one cannot tell if it is type 1 or type 2. B: M-mode and fetal magnetocardiography (fMCG) of a fetus with intermittent type 2, 2° AV block. a, atrial contractions that are conducted; a′, atrial contractions that are blocked. Note that occasionally two atrial beats in a row are conducted. The maternal rhythm tracing is shown in the bottom tracing and the fetal tracing is shown on the top tracing of the fMCG. C: Spectral Doppler showing mitral inflow (above baseline) and aortic outflow (below baseline) of a fetus in type 1, 2° AV block. The a to Ao interval prolongs between the first and second beats, and the third atrial beat (*) is not conducted. D: Spectral Doppler of superior vena cava (SVC) and aorta (Ao). Reverse flow in the SVC corresponds to atrial contractions. E: Spectral Doppler of mitral inflow with fused ea waves and aortic outflow. Note the a-Ao interval (the a-v interval) is equal for each conducted ventricular beat. (B, Modified from Cuneo BF, Strasburger JF, Wakai RT, Ovadia M. Conduction System Disease in Fetuses Evaluated for Irregular Cardiac Rhythm. Fetal Diagn Ther. 2006;21:307-313.) |
 FIGURE 3.5.4 Cont’d |
 FIGURE 3.5.5 Complete atrioventricular (AV) block. A: Spectral Doppler of superior vena cava (above baseline) and aortic flow (below baseline). Atrial contractions (a) (below baseline) bear no relation to ventricular contractions (V). The atrial rate is 152 bpm and the ventricular rate is 66 bpm. B: Mitral inflow and aortic Doppler showing fused ea waves. Close appraisal of the AV interval shows it is not consistent, thus there is 3° AV block. |
PREVALENCE OF ANTI-RO/SSA ANTIBODIES
Anti-Ro/SSA antibodies are detected in 1% to 2% of all women,11 many of whom have no symptoms of connective tissue disease. Maternal anti-Ro/SSA antibodies cross the placenta from about 12 gestational weeks, and set up an inflammatory process, usually in the fetal AVN and myocardium that may result in fibrosis. Most fetuses with AV block are detected between 18 and 25 gestational weeks.12,13 Women with thyroid disease have a higher risk of fetal AV block,14 as do babies born in the spring or to nonwhite women.15,16 Prenatal AV block is reported in only 2% to 3% of the population of
pregnant women who have anti-Ro/SSA antibodies, but this risk increases to 15% to 20% for subsequent pregnancies, and recurrence of 3° AV block is more common in female fetuses.17
pregnant women who have anti-Ro/SSA antibodies, but this risk increases to 15% to 20% for subsequent pregnancies, and recurrence of 3° AV block is more common in female fetuses.17
SPECTRUM OF ANTI-RO/SSA-MEDIATED CARDIAC DISEASE
The spectrum of fetal cardiac disease associated with maternal anti-Ro/SSA antibodies includes a more generalized inflammatory process in the fetus and neonate, including a classical skin rash (FIG. 3.5.6). The cardiac component is often referred to as cardiac neonatal lupus erythematosus (cardiac-NLE),15,18 even though the infant does not have lupus erythematosus. Both the sinoatrial node and AVN may be involved, the former resulting in sinus bradycardia19,20 (FIG. 3.5.7), atrial flutter,20 or atrial standstill.21 More commonly, maternal anti-Ro/SSA antibodies cause an early second trimester generalized myocarditis in the fetus characterized by AV valve regurgitation and, more rarely, rupture of the chordae.22 Myocardial fibrosis, suggesting EFE may be seen on echocardiography, with or without signs of AV block (FIG. 3.5.8).23,24
The signature finding of anti-Ro/SSA antibody-mediated cardiac disease is AV block. In the most usual form of 3° AV block, there is inflammation predominantly of the AVN; thus, the atrial rate usually lies within the normal range and is regular, while the ventricular rate arises independently and is slow at less than or equal to 70 beats per minute. Clinically, gestational age at onset may be helpful in differentiating the likely cause of fetal bradycardia: anti-Ro/SSA antibody-mediated 3° AV block is usually established at 18 to 25 weeks of gestation. In contrast, blocked atrial bigeminy often presents later and resolves spontaneously either near term or after birth (see Part 1, Chapter 3). Long QT syndrome tends to present with 2°, not 3° AV block later in the third trimester (see Part 3, Chapter 7). However, age at presentation and age at arrhythmia onset are not the same. The gestational age at last documented normal heart rate is an important piece of information in the evaluation of the fetus with AV block, regardless of the etiology.
The development of 3° AV block is believed to be progressive, from 1° to 2° to 3°. Consequently, screening efforts have focused on ultrasound evaluation of anti-Ro/SSA antibody-positive pregnancies to detect a prolonged AV interval (1° AV block) or signs of myocardial inflammation.25 The hypothesis was that treatment of 1° AV block would forestall progression to more advanced AV block. Surveillance of the anti-Ro/SSA positive pregnancy will be discussed in detail in Part 5, Chapter 2.
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