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The incidence of congenital atrioventricular (AV) block is between 1 in 15,000 and 1 in 20,000 births. It may occur in isolation or as a consequence of anomalous development of the conduction tissue in the context of a cardiac malformation. In this review, we use the term congenital AV bock to describe complete heart block when it is diagnosed in utero or at birth. The pathophysiological process is believed to be due to immune-mediated injury of the conduction system, which occurs as a result of transplacental passage of maternal anti-SSA/Ro-SSB/La antibodies. Many mothers are asymptomatic carriers, and less than one-third have a preexisting diagnosis of a rheumatological disorder. The AV block that develops months or years after birth probably occurs as a result of a different disease process that is poorly understood. The diagnosis of congenital AV block is usually confirmed by fetal echocardiography before birth and by electrocardiography after birth. The implantation of a pacemaker is recommended for symptomatic patients and for asymptomatic patients presenting with profound bradycardia, left ventricular dysfunction, a wide QRS interval, or a prolonged QT interval. It is now recognized that a subset of paced patients develop dilated cardiomyopathy and heart failure, and therefore regular follow-up is important. They are also at high risk of developing complications related to the presence of intracardiac material as a result of prolonged exposure to pacing materials. Future areas of research to minimize these risks include assessing the impact of alternative stimulation sites and the development of new cardiac stimulation techniques.
The estimated incidence of congenital atrioventricular (AV) block, a disorder that was first reported more than 100 years ago, is between 1 in 15,000 and 1 in 20,000 births.
In clinical practice, the implantation of a permanent pacemaker is recommended for symptomatic patients as well as for a subset of patients presenting with clinical characteristics known to be associated with an increased risk of syncope and sudden death.
In this review, we (1) focus on isolated congenital AV block in the absence of structural heart disease, (2) examine the key elements of an abundant, albeit sometimes antiquated literature, (3) present and discuss the pacing recommendations made in the guidelines issued by international professional societies, (4) discuss the adverse events that may affect the long-term outcome, and (5) examine whether new cardiac stimulation techniques might prevent these complications.
B. Pathophysiology of congenital AV block
Congenital AV block is a passively acquired autoimmune disease of the fetus. It is believed to be the consequence of an inflammatory response that results in tissue injury, fibrosis, and scarring of the conduction system. The transplacental entry of autoantibodies into the fetal circulation are believed to be responsible for triggering this response.
Signs of inflammation with deposition of antibodies, complement components, lymphocytic infiltrates, fibrosis, and calcifications are found in the vicinity of the conduction system.
Using the recently developed technique of line immunoassay, it has been possible to detect SSA/Ro or SSB/La antibodies in the sera of 95% of the mothers of fetuses or newborns presenting with AV block.
In contrast, autoantibodies have been detected in only a minority of mothers of children in whom AV block was diagnosed beyond the neonatal period. It has been shown that once maternal antibodies have been detected, they remain lifelong in the sera of the mothers, although the titers of the autoantibodies may change over time. This suggests a different distinct disease process.
Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.
Risk of congenital complete heart block in newborns of mothers with anti-Ro / SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women.
Between 2% and 5% of fetuses and infants whose mothers are autoantibody positive develop AV block, and in mothers who have had 1 child with congenital AV block, the risk to subsequent pregnancies is 12%–25%. In only 20%–30% of infants with congenital AV block does the mother have a previous diagnosis of a distinct autoimmune disease.
Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.
Risk of congenital complete heart block in newborns of mothers with anti-Ro / SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women.
The majority of mothers are asymptomatic despite the presence of autoantibodies. The diagnosis is usually made only after autoantibodies are detected as a result of testing after the diagnosis of congenital AV block in their newborn.
With the advent and development of fetal echocardiography, a high proportion of cases of autoimmune-mediated complete AV block are now identified in utero (in populations where routine fetal echocardiography is performed). The finding may be an incidental finding, or alternatively, investigations may have been performed because of concerns regarding fetal development.
Postnatally, neonates and young children present in a wide variety of different ways. Some are asymptomatic with bradycardia and detected only during routine screening. Others may present with nonspecific symptoms, such as poor growth, abnormal tiredness, sleep disturbance, or frequent nightmares. Syncope, heart failure, or sudden death may be the first manifestation of congenital AV block in the absence of previous symptoms and signs of cardiovascular disease.
Despite recent developments in the field of electro- and magnetocardiography, fetal echocardiography remains the gold standard method for diagnosing congenital AV block.
The diagnosis is made by establishing atrioventricular dissociation by using M mode or Doppler echocardiographic techniques. Reference values have been defined, and surveillance protocols have been designed to be implemented between 16 and 24 weeks of gestation, the period during which the fetus is at the highest risk of developing complete AV block.
Complete AV block is by far the most common finding in children with AV conduction impairment. In a registry of 187 newborns with AV conduction impairment, 93% had complete AV block while 5% had first-degree and 2% had second-degree AV block.
described the electrocardiographic characteristics in a large population of patients with congenital AV block. The mean heart rate was 41 beats/min. The heart rate usually decreased as the child grew older. A broad complex escape rhythm was observed in<10% of the patients.
D.2.3. QT interval
It is recognized that Bazett’s formula may overcorrect QT interval in patients with extreme bradycardia. However, in the absence of a better alternative, it remains the most widely used method in this population.
Seven percent of the patients were identified as having a prolonged QT interval (corrected QT interval>450 ms) at the time of presentation in the study by Michaëlsson et al.
It is important to distinguish between patients with congenital heart block and prolonged QT interval and those with congenital long QT syndrome who may present with pseudo 2:1 AV block. The latter have normal AV conduction, but as a consequence of prolonged ventricular repolarization, every other P wave occurs during the ventricular refractory period and consequently does not result in ventricular depolarization.
Two mechanisms have been proposed for the development of QT prolongation in patients with congenital AV block. First, the conduction disorder and resultant bradycardia may be the initial phenomenon that subsequently leads to the development of altered repolarization. This is supported by data from animal models of chronic complete AV block.
Alternatively, patients with congenital AV block who develop QT prolongation may have a phenotypic manifestation of latent congenital long QT syndrome.
D.3. Holter monitoring
We routinely perform 24-hour electrocardiographic recordings as part of our assessment of patients with congenital heart bock. This allows mean heart rate to be assessed and episodes of RR prolongation to be documented. A certain proportion of sudden deaths occurred during sleep. A study reported an incidence of 35% of pause during the night with long R-R intervals (3000–6000 ms).
Despite the conduction disorder, many patients have a normal exercise treadmill evaluation in terms of performance. Neither exercise tolerance nor the maximum heart rate achieved with exercise can be predicted from the resting heart rate. Ectopy with exercise is frequent and occurs in 50%–70% of the patients.
Echocardiography is an important investigation in the postnatal population. It allows intracardiac structural malformations to be identified and provides an assessment of ventricular function.
Once heart block has been diagnosed, the mother should be screened for evidence of connective tissue disease. Immoassays for SSA/Ro or SSB/La antibodies should be performed.
E. Natural history of patients with congenital AV block
Spontaneous recovery from congenital AV block is very rare, though it has been reported in exceptional cases.
The high mortality observed in neonates appears to occur as a consequence of the complications of prematurity and bradycardia owing to the delayed initiation of pacing therapy. The morbidity and mortality associated with congenital AV block remains high even as the child grows and becomes an adult.
Transplacental treatment with dexamethasone to prevent myocardial inflammation as well as beta-adrenergic stimulation to increase the ventricular rate have been proposed as treatment options. They were found to significantly lower fetal mortality in a recent study.
However, the transplacental administration of corticosteroids to treat congenital heart block remains controversial. A recent retrospective multicenter study found no significant reduction in the occurrence of hydrops fetalis. There is the potential for harm to both mother and baby as a result of steroid use, in particular fetal neurological development may be impaired.
Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus.
Prospective randomized studies are required to evaluate these treatments before definitive guidance can be given.
Percutaneous in utero pacing has been investigated as a method for providing heart rate support. However, with use of currently available techniques it appears to be a very high risk procedure, with fetal deaths occurring within a few hours of the procedure in a high proportion of cases.
Further studies are required to improve our understanding of the natural history of congenital AV block in order to identify more accurately the fetuses at the highest risk from not being paced. Moreover, development in the techniques and technologies available to deliver in utero pacing are required before this treatment can be adopted into routine clinical practice.
F.2. Postnatal management
F.2.1. Indications for pacing
Decisions regarding the indications for, and timing of, pacing therapy must take into account the technical peculiarities associated with the pacing in young children.
F.2.1.1. Symptomatic patients
Both the North American and European guidelines recommend implantation of a pacemaker in children with congenital heart block and any of the following symptoms: syncope, congestive heart failure, or chronotropic incompetence with the limitation of physical activity. There is a consensus that patients with heart failure or syncope should be implanted without delay.
The decision-making process can be more complex in patients presenting with more subtle symptoms such as tiredness, poor growth, frequent nightmares, or naps. If clinically bradycardia is felt to be the most likely cause of the symptoms, then the recommendation is usually to advise pacing. However, the decision regarding timing of implantation warrants careful consideration, weighing up the benefits of symptom improvement against the risks associated with long-term pacing therapy.
F.2.1.2. Asymptomatic patients
As with patients who have mild symptoms, the critical decision is usually not if but rather when to initiate pacing therapy since the majority of patients require pacing at some time during their lifetime, even if they are asymptomatic when they are first diagnosed.
A number of different parameters have been assessed as markers of risk, sometimes with conflicting results.
F.2.1.2.1. Ventricular impairment
There is evidence from an observational study that cardiac pacing is beneficial in asymptomatic patients presenting with echocardiographically apparent left ventricular (LV) dilatation or dysfunction. Reductions in ventricular dimensions and improvement in ventricular function were observed after the initiation of pacing therapy.
As a result of these findings, the international guidelines recommend pacing symptomatic or asymptomatic patients with clinical or echocardiographic signs of LV dysfunction or dilatation.
F.2.1.2.2. Heart rate
Conflicting results have been found with regard to the usefulness of heart rate to predict syncope or sudden death. In their large observational study, Michaëlsson et al
found that patients with a resting heart rate<55 beats/min had significantly higher mortality than those with a higher heart rate (29% vs 4.3%). These results were, however, not replicated in 2 subsequent observational studies.
Our practice is to implant a pacemaker in asymptomatic patients when heart rate is found to be<55 beats/min in neonates or<50 beats/min in children, adolescents, and adults.
F.2.1.2.3. Pauses during spontaneous rhythm
The predictive value of pauses detected with Holter monitoring is also controversial. In an observational study, Dewey et al
However, in another study, no significant difference was observed in the incidence of syncope between patients with and without>3-second pauses during Holter monitoring.
Our practice is to implant a pacemaker in patients with>3-second pauses, without differentiating between day and night. We justify this approach on the basis that patients with congenital complete heart block are at risk of nocturnal sudden cardiac death, which is most likely due to very low nocturnal ventricular rates.
F.2.1.2.4. QRS duration
Data are available only from a relatively small numbers of patients with a broad complex escape rhythm and as yet no study has identified an increased risk of death or syncope in this group of patients.
Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus.
However, data from other populations of patients suggest that a broad complex escape rhythm occurs because of more distal block in the His-Purkinje system. Therefore, even though definitive evidence is lacking in the congenital heart block population, the international guidelines recommend implanting a pacemaker in asymptomatic patients who have a broad ventricular escape rhythm (QRS duration>120 ms).
F.2.1.2.5. Complex ventricular ectopy
Importance of ventricular ectopy as a predictor for sudden cardiac death has not been determined.
The international guidelines recommend implantation of a pacemaker in patients with congenital AV block and a prolonged QT interval. The implantation of a defibrillator is limited to patients with repeated episodes of syncope or documented torsades de pointes despite optimal medical therapy. This is supported by the findings from observational studies that report favorable outcomes after the implantation of a pacemaker.
In this specific population, the pacing strategy is highly center specific and may vary widely between North American and European centers. Children presenting with complete AV block and a normal ventricular function may initially be paced in the VVIR mode, pending an upgrade to the VDD/DDD mode in adolescence; alternatively, they may receive a dual-chamber pacemaker as initial therapy.
Epicardial systems are usually chosen for the youngest children, while endocardial pacing is postponed until the child weighs>10 kg or is≥2 years of age. An intracardiac approach is, therefore, usually chosen when allowed by the anatomical substrate. In some medical centers, transvenous implants are offered to the youngest patients, a strategy enabled by the development of thinner leads.
In contrast, other centers defer endocardial implantation until at least 5–8 years of age.
A number of factors are taken into consideration when deciding between an epicardial and an endocardial approach to pacing and include the following:
1.
Preference of the family and local expertise; some families prefer to opt for the least invasive approach.
2.
Historically, concerns regarding high initial and long-term capture thresholds of epicardial leads have sometimes steered implanters away from epicardial leads. However, these concerns are now less relevant since the advent of epicardial leads with steroid-eluting tips that appear to be equivalent to endocardial leads in terms of performance, prolonging the battery life and limiting the need for repeat operations.
Concerns regarding the risk of vascular or valvular injury caused by endocardial leads as well as the increasing likelihood of mismatch between leads and their recipients associated with somatic growth.
4.
The potentially fatal complications associated with the extraction of transvenous leads, which remains a relatively high-risk dangerous procedure, particularly in children.
The functional and hemodynamic potential advantages offered by an epicardial LV placement in small children compared with right ventricular (RV) apical pacing.
Pending direct comparison in prospective randomized studies, an initial epicardial approach seems preferable in early childhood, with a view to preserve the venous network for expected lifelong pacing.
H. Outcome of paced patients
After the implantation of a pacemaker, it was often assumed that children presenting with congenital AV block would go on to enjoy an average quality of life. However, various studies have demonstrated that some patients are prone to developing severe systolic dysfunction despite the early institution of cardiac pacing.
In published studies of congenital complete AV block diagnosed in utero or at birth, the prevalence of dilated cardiomyopathy (DCM) ranges between 5% and ∼30%.
The detrimental effects of maternal antibodies directed against fetal cardiac tissue provided evidence in favor of the immunopathologic role played by the SSA/Ro and SSB/La antibodies in congenital AV block. The deposition of immunoglobulin G throughout the myocardium observed in postmortem immunofluorescent studies also suggests a strong relationship between SSA/Ro and SSB/La antibodies and the development of DCM.
Most patients with congenital AV block implanted with a pacemaker will be ventriculary paced 100% of the time. In view of the myocardial dystrophic changes and adverse remodeling caused by ventricular desynchronization, RV pacing has been proposed as a potentially important cause of DCM in this patient group.
In some patients, normalization of systolic function has been observed after the discontinuation of RV pacing or after upgrade to CRT; this would not be expected to occur if ongoing myocarditis or other autoimmune factors were the only cause of DCM.
Dilated cardiomyopathy associated with dual-chamber pacing in infants: improvement through either left ventricular cardiac resynchronization or programming the pacemaker off allowing intrinsic normal conduction.
However, doubts persist with respect to the relationship between RV pacing and the development of DCM. Indeed, a study has linked the presence of antibodies to the development of DCM with RV pacing.
Finally, a high mean paced heart rate is also a hypothetical cause of DCM, particularly after the implantation of dual-chamber pacemakers, though DCM has been observed in patients with normal average heart rates.
Restoration of cardiac function by setting the ventricular pacing at a lower range in an infant with congenital complete atrioventricular block and dilated cardiomyopathy.
The testing of these various hypotheses has been limited by small sample sizes. Furthermore, the relative importance of these putative mechanisms is complex and indeed they may interact with each other.
J. Complications due to intracardiac leads
The reported average 5-year survival rate of endocardial leads in children ranges between 76% and 89%, while reoperations for failure or complications due to epicardial leads have been observed in 15%–20% of the patients.
While long-term data are lacking, lead failure rates over several decades are likely to be close to 100%. Venograms obtained after the implantation of permanent transvenous leads have revealed the presence of nearly occluded or high-grade stenoses of the great cardiac veins in nearly 25% of children and young adults, as well as a high prevalence of occlusions occurring after>20 years of cardiac pacing.
Heart rate, rhythm, and ventricular function should be followed closely by using serial echocardiograms at regular intervals since ventricular dysfunction may appear at a young age or after decades of cardiac pacing.
There is an increasing focus on developing methods that do not use intracardiac leads.
L. Robot-assisted thoracoscopic implantation of LV epicardial leads
Robot-assisted pacemaker implantation allows the benefits of epicardial pacing to be obtained with minimally invasive surgery. It requires a short hospitalization and, like transvenous implantation, is cosmetically sparing (Figure 1). It has recently been developed in a few highly specialized medical centers and is promising because it overcomes some of the limitations of conventional cardiac pacing.
de Cannière D. Robotic-enhanced biventricular resynchronization: an alternative to endovenous cardiac resynchronization therapy in chronic heart failure.
It eliminates the risk of endovascular lead endocarditis and venous thromboses. It also allows the pacing stimulus to be delivered to the LV lead and thus may overcome the risks associated with chronic RV pacing. Long-term data and controlled trials will be required to demonstrate the advantages of LV pacing over RV pacing.
Figure 1A: The chest roentgenogram of a 17-year-old man who has been implanted with a “traditional” transvenous dual-chamber pacemaker system (1 right atrial lead and 1 right ventricular lead). B: The chest roentgenogram of a 17-year-old woman who received an epicardial system using a robot-assisted thoracoscopic approach (1 left atrial lead and 1 left ventricular lead) (C–E). Both patients healed rapidly and were discharged from the hospital within 72 hours.
The main limitation with robot-assisted pacemaker implantation is that currently it is available only in a few specialized centers.
M. The next anticipated breakthrough: Leadless pacing
Since the majority of complications are due to the presence of leads within the vascular system and ventricular cavity, the development of a leadless pacing system with capsules containing a battery implanted directly inside the heart chamber seems to represent the most promising future of cardiac pacing.
The prototypes tested in animals have been implanted in the RV cavity via the femoral vein. The small size of the device should allow its rapid endothelialization, limiting the risk of dislodgement or endocarditis. Its implementation in humans is expected within 1–3 years. Further technological developments should later enable the implantation of these devices within the LV cavity, which should allow more physiological pacing. Biological pacing is also under active investigation, but the road to the first clinical applicability may be much longer.
Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.
Risk of congenital complete heart block in newborns of mothers with anti-Ro / SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women.
Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus.
Dilated cardiomyopathy associated with dual-chamber pacing in infants: improvement through either left ventricular cardiac resynchronization or programming the pacemaker off allowing intrinsic normal conduction.
Restoration of cardiac function by setting the ventricular pacing at a lower range in an infant with congenital complete atrioventricular block and dilated cardiomyopathy.
de Cannière D. Robotic-enhanced biventricular resynchronization: an alternative to endovenous cardiac resynchronization therapy in chronic heart failure.
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