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Pathophysiology, clinical course, and management of congenital complete atrioventricular block

Published:February 21, 2013DOI:https://doi.org/10.1016/j.hrthm.2012.12.030

      Abstract

      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.

      Abbreviations:

      AV (atrioventricular), DCM (dilated cardiomyopathy), LV (left ventricular), RV (right ventricular)

      Keywords

      A. Introduction

      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.
      • Yater W.
      Congenital heart block: review of the literature.
      • Michaelsson M.
      • Riesenfeld T.
      • Jonzon A.
      Natural history of congenital complete atrioventricular block.
      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.
      • Vardas P.E.
      • Auricchio A.
      • Blanc J.J.
      • et al.
      European Society of Cardiology; European Heart Rhythm Association.
      • Epstein A.E.
      • DiMarco J.P.
      • Ellenbogen K.A.
      • et al.
      guideline update for implantation of cardiac pacemakers and antiarrhythmia devices.
      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.
      • McCue C.M.
      • Mantakas M.E.
      • Tingelstad J.B.
      • Ruddy S.
      Congenital heart block in newborns of mothers with connective tissue disease.
      • Taylor P.V.
      • Scott J.S.
      • Gerlis L.M.
      • Esscher E.
      • Scott O.
      Maternal antibodies against fetal cardiac antigens in congenital complete heart block.
      Signs of inflammation with deposition of antibodies, complement components, lymphocytic infiltrates, fibrosis, and calcifications are found in the vicinity of the conduction system.
      • Clancy R.M.
      • Buyon J.P.
      More to death than dying: apoptosis in the pathogenesis of SSA/Ro-SSB/La-associated congenital heart block.
      • Anderson R.H.
      • Wenick A.C.
      • Losekoot T.G.
      • Becker A.E.
      Congenitally complete heart block. Developmental aspects.
      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.
      • Costedoat-Chalumeau N.
      • Georgin-Lavialle S.
      • Amoura Z.
      • Piette J.C.
      Anti-SSA/Ro and anti-SSB/La antibody-mediated congenital heart 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.
      • Hunscher O.
      • Batista N.
      • Rivero S.
      • et al.
      Clinical and serological identification of 2 forms of complete heart block in children.
      • Brucato A.
      • Jonzon A.
      • Friedman D.
      • et al.
      Proposal for a new definition of congenital complete atrioventricular block.
      • Villain E.
      • Coastedoat-Chalumeau N.
      • Marijon E.
      • Boudjemline Y.
      • Piette J.C.
      • Bonnet D.
      Presentation and prognosis of complete atrioventricular block in childhood, according to maternal antibody status.
      Therefore, it might be appropriate to reserve the term “congenital” to the subgroup presenting with autoantibody-associated AV block.
      Anti-Ro antibodies are detected in between 1% and 2% of randomly tested pregnant women.
      • Buyon J.P.
      • Hiebert R.
      • Copel J.
      • et al.
      Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.
      • Brucato A.
      • Frassi M.
      • Franceschini F.
      • et al.
      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.
      • Buyon J.P.
      • Hiebert R.
      • Copel J.
      • et al.
      Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.
      • Brucato A.
      • Frassi M.
      • Franceschini F.
      • et al.
      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.
      • Julkunen H.
      • Eronen M.
      Long-term outcome of mothers of children with isolated heart block in Finland.

      C. Diagnosis

      C.1. Clinical presentation

      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.
      • Fouron J.C.
      • Proulx F.
      • Miro J.
      • Gosselin J.
      Doppler and M-mode ultrasonography to time fetal atrial and ventricular contractions.
      • Reed K.L.
      • Appleton C.P.
      • Anderson C.F.
      • Shenker L.
      • Sahn D.J.
      Doppler studies of vena cava flows in human fetuses: insights into normal and abnormal cardiac physiology.
      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.
      • Jaeggi E.T.
      • Hamilton R.M.
      • Silverman E.D.
      • Zamora S.A.
      • Hornberger L.K.
      Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrio-ventricular block.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.

      D. Investigations

      D.1. Fetal echocardiography

      Despite recent developments in the field of electro- and magnetocardiography, fetal echocardiography remains the gold standard method for diagnosing congenital AV block.
      • Fouron J.C.
      • Proulx F.
      • Miro J.
      • Gosselin J.
      Doppler and M-mode ultrasonography to time fetal atrial and ventricular contractions.
      • Reed K.L.
      • Appleton C.P.
      • Anderson C.F.
      • Shenker L.
      • Sahn D.J.
      Doppler studies of vena cava flows in human fetuses: insights into normal and abnormal cardiac physiology.
      • Andelfinger G.
      • Fouron J.C.
      • Sonesson S.E.
      • Proulx F.
      Reference values for time intervals between atrial and ventricular contractions of the fetal heart measured by two Doppler techniques.
      • Van Bergen A.H.
      • Cuneo B.F.
      • Davis N.
      Prospective echocardiographic evaluation of atrioventricular conduction in fetuses with maternal Sjogren’s antibodies.
      • Chia E.L.
      • Ho T.F.
      • Rauff M.
      • Yip W.C.
      Cardiac time intervals of normal fetuses using noninvasive fetal electrocardiography.
      • Gardiner H.M.
      • Belmar C.
      • Pasquini L.
      • et al.
      Fetal ECG: a novel predictor of atrioventricular block in anti-Ro positive pregnancies.
      • Wakai R.T.
      • Leuthold A.C.
      • Cripe L.
      • Martin C.B.
      Assessment of fetal rhythm in complete congenital heart block by magnetocardiography.
      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.
      • Andelfinger G.
      • Fouron J.C.
      • Sonesson S.E.
      • Proulx F.
      Reference values for time intervals between atrial and ventricular contractions of the fetal heart measured by two Doppler techniques.

      D.2. Electrocardiogram

      D.2.1. 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.
      • Askanase A.D.
      • Friedman D.M.
      • Copel J.
      • et al.
      Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies.

      D.2.2. Bradycardia and QRS duration

      Michaëlsson et al
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      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.
      • Benatar A.
      • Ramet J.
      • Decraene T.
      • Vandenplas Y.
      QT interval in normal infants during sleep with concurrent evaluation of QT correction formulae.
      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.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      We recommend serial measurements are made, as the incidence may be as high as 22% if multiple measurements are made.
      • Esscher E.
      • Michaëlsson M.Q.-T.
      interval in congenital complete heart block.
      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.
      • Volders P.G.
      • Sipido K.R.
      • Vos M.A.
      • Kulcsár A.
      • Verduyn S.C.
      • Wellens H.J.
      Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes.
      • Volders P.G.
      • Sipido K.R.
      • Vos M.A.
      • et al.
      Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes.
      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).
      • Levy A.M.
      • Camm A.J.
      • Keane J.F.
      Multiple arrhythmias detected during nocturnal monitoring in patients with congenital complete heart block.

      D.4. Exercise testing

      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.
      • Winkler R.B.
      • Freed M.D.
      • Nadas A.S.
      Exercise-induced ventricular ectopy in children and young adults with complete heart block.
      • Ikkos D.
      • Hanson J.S.
      Response to exercise in congenital complete atrioventricular block.
      • Reybrouck T.
      • Vanden Eynde B.
      • Dumoulin M.
      • Van der Hauwaert L.G.
      Cardiorespiratory response to exercise in congenital complete atrioventricular block.

      D.5. Echocardiography

      Echocardiography is an important investigation in the postnatal population. It allows intracardiac structural malformations to be identified and provides an assessment of ventricular function.
      • Beaufort-Krol G.
      • Schasfoort-Van Leeuwen M.J.
      • Stienstra Y.
      • Bink-Boelkens M.
      Longitudinal echocardiographic follow-up in children with congenital complete atrioventricular block.

      D.6. Other investigations

      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.
      • De Raet J.
      • Rega F.
      • Meyns B.
      Late recovery of atrioventricular conduction after pacemaker implantation for complete heart block in congenital heart disease: fact or fluke?.
      The estimated overall mortality of nonpaced patients with isolated complete congenital AV block is 8%–16% in infants and 4%–8% in children and adults.
      • Jaeggi E.T.
      • Hamilton R.M.
      • Silverman E.D.
      • Zamora S.A.
      • Hornberger L.K.
      Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrio-ventricular block.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      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.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.

      F. Management

      F.1. Prenatal management

      Left untreated, congenital, antibody-mediated AV block is associated with a fetal and neonatal mortality ranging between 14% and 34%.
      • Groves A.M.
      • Allan L.D.
      • Rosenthal E.
      Outcome of isolated congenital complete heart block diagnosed in utero.
      • Jaeggi E.T.
      • Fouron J.C.
      • Silverman E.D.
      • Ryan G.
      • Smallhorn J.
      • Hornberger L.K.
      Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease.
      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.
      • Jaeggi E.T.
      • Fouron J.C.
      • Silverman E.D.
      • Ryan G.
      • Smallhorn J.
      • Hornberger L.K.
      Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease.
      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.
      • Saleeb S.
      • Copel J.
      • Friedman D.
      • Buyon J.P.
      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.
      • Pisoni C.N.
      • Brucato A.
      • Ruffatti A.
      • et al.
      Failure of intravenous immunoglobulin to prevent congenital heart block: findings of a multicenter, prospective, observational study.
      • Modi N.
      • Lewis H.
      • Al-Naqeeb N.
      • Ajayi-Obe M.
      • Dore C.J.
      • Rutherford M.
      The effects of repeated antenatal glucocorticoid therapy on the developing brain.
      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.
      • Walkinshaw S.A.
      • Welch C.R.
      • McCormack J.
      • Walsh K.
      In utero pacing for fetal congenital heart block.
      • Assad R.S.
      • Zielinsky P.
      • Kalil R.
      • et al.
      New lead for in utero pacing for fetal congenital heart block.
      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.
      • Beaufort-Krol G.
      • Schasfoort-Van Leeuwen M.J.
      • Stienstra Y.
      • Bink-Boelkens M.
      Longitudinal echocardiographic follow-up in children with congenital complete atrioventricular block.
      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
      • Michaëlsson M.
      • Engle M.A.
      Congenital complete heart block: an international study of the natural history.
      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.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      • Sholler G.F.
      • Walsh E.P.
      Congenital complete heart block in patients without anatomic cardiac defects.
      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
      • Dewey R.C.
      • Capeless M.A.
      • Levy A.M.
      Use of ambulatory electrocardiographic monitoring to identify high-risk patients with congenital complete heart block.
      found that patients who had a heart rate<50 beats/min or pauses>3 seconds on Holter monitoring had an increased incidence of syncope and sudden death.
      • Dewey R.C.
      • Capeless M.A.
      • Levy A.M.
      Use of ambulatory electrocardiographic monitoring to identify high-risk patients with congenital complete heart block.
      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.
      • Sholler G.F.
      • Walsh E.P.
      Congenital complete heart block in patients without anatomic cardiac defects.
      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.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      • Andelfinger G.
      • Fouron J.C.
      • Sonesson S.E.
      • Proulx F.
      Reference values for time intervals between atrial and ventricular contractions of the fetal heart measured by two Doppler techniques.
      • Van Bergen A.H.
      • Cuneo B.F.
      • Davis N.
      Prospective echocardiographic evaluation of atrioventricular conduction in fetuses with maternal Sjogren’s antibodies.
      • Chia E.L.
      • Ho T.F.
      • Rauff M.
      • Yip W.C.
      Cardiac time intervals of normal fetuses using noninvasive fetal electrocardiography.
      • Gardiner H.M.
      • Belmar C.
      • Pasquini L.
      • et al.
      Fetal ECG: a novel predictor of atrioventricular block in anti-Ro positive pregnancies.
      • Wakai R.T.
      • Leuthold A.C.
      • Cripe L.
      • Martin C.B.
      Assessment of fetal rhythm in complete congenital heart block by magnetocardiography.
      • Askanase A.D.
      • Friedman D.M.
      • Copel J.
      • et al.
      Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies.
      • Benatar A.
      • Ramet J.
      • Decraene T.
      • Vandenplas Y.
      QT interval in normal infants during sleep with concurrent evaluation of QT correction formulae.
      • Esscher E.
      • Michaëlsson M.Q.-T.
      interval in congenital complete heart block.
      • Volders P.G.
      • Sipido K.R.
      • Vos M.A.
      • Kulcsár A.
      • Verduyn S.C.
      • Wellens H.J.
      Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes.
      • Volders P.G.
      • Sipido K.R.
      • Vos M.A.
      • et al.
      Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes.
      • Levy A.M.
      • Camm A.J.
      • Keane J.F.
      Multiple arrhythmias detected during nocturnal monitoring in patients with congenital complete heart block.
      • Winkler R.B.
      • Freed M.D.
      • Nadas A.S.
      Exercise-induced ventricular ectopy in children and young adults with complete heart block.
      • Ikkos D.
      • Hanson J.S.
      Response to exercise in congenital complete atrioventricular block.
      • Reybrouck T.
      • Vanden Eynde B.
      • Dumoulin M.
      • Van der Hauwaert L.G.
      Cardiorespiratory response to exercise in congenital complete atrioventricular block.
      • Beaufort-Krol G.
      • Schasfoort-Van Leeuwen M.J.
      • Stienstra Y.
      • Bink-Boelkens M.
      Longitudinal echocardiographic follow-up in children with congenital complete atrioventricular block.
      • De Raet J.
      • Rega F.
      • Meyns B.
      Late recovery of atrioventricular conduction after pacemaker implantation for complete heart block in congenital heart disease: fact or fluke?.
      • Groves A.M.
      • Allan L.D.
      • Rosenthal E.
      Outcome of isolated congenital complete heart block diagnosed in utero.
      • Jaeggi E.T.
      • Fouron J.C.
      • Silverman E.D.
      • Ryan G.
      • Smallhorn J.
      • Hornberger L.K.
      Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease.
      • Saleeb S.
      • Copel J.
      • Friedman D.
      • Buyon J.P.
      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.
      • Pisoni C.N.
      • Brucato A.
      • Ruffatti A.
      • et al.
      Failure of intravenous immunoglobulin to prevent congenital heart block: findings of a multicenter, prospective, observational study.
      • Modi N.
      • Lewis H.
      • Al-Naqeeb N.
      • Ajayi-Obe M.
      • Dore C.J.
      • Rutherford M.
      The effects of repeated antenatal glucocorticoid therapy on the developing brain.
      • Walkinshaw S.A.
      • Welch C.R.
      • McCormack J.
      • Walsh K.
      In utero pacing for fetal congenital heart block.
      • Assad R.S.
      • Zielinsky P.
      • Kalil R.
      • et al.
      New lead for in utero pacing for fetal congenital heart block.
      • Michaëlsson M.
      • Engle M.A.
      Congenital complete heart block: an international study of the natural history.
      • Sholler G.F.
      • Walsh E.P.
      Congenital complete heart block in patients without anatomic cardiac defects.
      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.
      • Sholler G.F.
      • Walsh E.P.
      Congenital complete heart block in patients without anatomic cardiac defects.

      F.2.1.2.6. Prolonged QT interval

      There is good evidence that QT prolongation is a risk factor for syncope or sudden death in patients with congenital heart block.
      • Michaëlsson M.
      • Jonzon A.
      • Riesenfeld T.
      Isolated congenital complete atrioventricular block in adult life: a prospective study.
      • Esscher E.
      • Michaëlsson M.Q.-T.
      interval in congenital complete heart block.
      • Solti F.
      • Szatmáry L.
      • Vecsey T.
      • Rényi-Vámos Jr, F.
      • Bodor E.
      Congenital complete heart block associated with QT prolongation.
      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.
      • Solti F.
      • Szatmáry L.
      • Vecsey T.
      • Rényi-Vámos Jr, F.
      • Bodor E.
      Congenital complete heart block associated with QT prolongation.

      G. Pacing strategies

      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.
      • Berul C.I.
      • Cecchin F.
      American Heart Association American College of Cardiology. Indications and techniques of pediatric cardiac pacing.
      • Cohen M.I.
      • Bush D.M.
      • Vetter V.L.
      • et al.
      Permanent epicardial pacing in pediatric patients: seventeen years of experience and 1200 outpatient visits.
      • Villain E.
      • Martelli H.
      • Bonnet D.
      • Iserin L.
      • Butera G.
      • Kachaner J.
      Characteristics and results of epicardial pacing in neonates and infants.
      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.
      • Robledo-Nolasco R.
      • Ortiz-Avalos M.
      • Rodriguez-Diez G.
      • et al.
      Transvenous pacing in children weighing less than 10 kilograms.
      • Kammeraad J.A.
      • Rosenthal E.
      • Bostock J.
      • Rogers J.
      • Sreeram N.
      Endocardial pacemaker implantation in infants weighing<or =10 kilograms.
      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.
        • Karpawich P.P.
        Technical aspects of pacing in adult and pediatric congenital heart disease.
        • Fortescue E.B.
        • Berul C.I.
        • Cecchin F.
        • Walsh E.P.
        • Triedman J.K.
        • Alexander M.E.
        Comparison of modern steroid-eluting epicardial and thin transvenous pacemaker leads in pediatric and congenital heart disease patients.
      • 3.
        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.
        • Cecchin F.
        • Atallah J.
        • Walsh E.P.
        • Triedman J.K.
        • Alexander M.E.
        • Berul C.I.
        Lead extraction in pediatric and congenital heart disease patients.
      • 5.
        The functional and hemodynamic potential advantages offered by an epicardial LV placement in small children compared with right ventricular (RV) apical pacing.
        • van Geldorp I.E.
        • Vanagt W.Y.
        • Prinzen F.W.
        • Delhaas T.
        Chronic ventricular pacing in children: toward prevention of pacing-induced heart disease.
        • Udink ten Cate F.E.
        • Breur J.M.
        • Cohen M.I.
        • et al.
        Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children.
        • Thambo J.B.
        • Bordachar P.
        • Garrigue S.
        • et al.
        Detrimental ventricular remodelling in patients with congenital complete heart block and chronic right ventricular apical pacing.
        • Karpawich P.P.
        • Rabah R.
        • Haas J.E.
        Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block.
      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.
      • Udink ten Cate F.E.
      • Breur J.M.
      • Cohen M.I.
      • et al.
      Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children.
      • Thambo J.B.
      • Bordachar P.
      • Garrigue S.
      • et al.
      Detrimental ventricular remodelling in patients with congenital complete heart block and chronic right ventricular apical pacing.
      • Karpawich P.P.
      • Rabah R.
      • Haas J.E.
      Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block.
      • Moak J.P.
      • Barron K.S.
      • Hougen T.J.
      • et al.
      Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela.
      • Klug D.
      • Vaksmann G.
      • Jarwe M.
      • et al.
      Pacemaker lead infection in young patients.
      • Rozmus G.
      • Daubert J.P.
      • Huang D.T.
      • Rosero S.
      • Hall B.
      • Francis C.
      Venous thrombosis and stenosis after implantation of pacemakers and defibrillators.
      • Bar-Cohen Y.
      • Berul C.I.
      • Alexander M.E.
      • et al.
      Age, size, and lead factors alone do not predict venous obstruction in children and young adults with transvenous lead systems.
      • Cohen M.I.
      • Bush D.M.
      • Gaynor J.W.
      • Vetter V.L.
      • Tanel R.E.
      • Rhodes L.A.
      Pediatric pacemaker infections: twenty years of experience.

      I. Development of dilated cardiomyopathy

      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%.
      • Udink ten Cate F.E.
      • Breur J.M.
      • Cohen M.I.
      • et al.
      Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children.
      • Thambo J.B.
      • Bordachar P.
      • Garrigue S.
      • et al.
      Detrimental ventricular remodelling in patients with congenital complete heart block and chronic right ventricular apical pacing.
      • Karpawich P.P.
      • Rabah R.
      • Haas J.E.
      Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block.
      • Moak J.P.
      • Barron K.S.
      • Hougen T.J.
      • et al.
      Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela.
      Late-onset DCM in patients with complete heart block may be a sequela of in utero autoimmune myocarditis or due to its postnatal reactivation.
      • Taylor P.V.
      • Scott J.S.
      • Gerlis L.M.
      • Esscher E.
      • Scott O.
      Maternal antibodies against fetal cardiac antigens in congenital complete heart block.
      • Clancy R.M.
      • Buyon J.P.
      More to death than dying: apoptosis in the pathogenesis of SSA/Ro-SSB/La-associated congenital heart block.
      • Anderson R.H.
      • Wenick A.C.
      • Losekoot T.G.
      • Becker A.E.
      Congenitally complete heart block. Developmental aspects.
      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.
      • Udink ten Cate F.E.
      • Breur J.M.
      • Cohen M.I.
      • et al.
      Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children.
      • Thambo J.B.
      • Bordachar P.
      • Garrigue S.
      • et al.
      Detrimental ventricular remodelling in patients with congenital complete heart block and chronic right ventricular apical pacing.
      • Karpawich P.P.
      • Rabah R.
      • Haas J.E.
      Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block.
      • Moak J.P.
      • Barron K.S.
      • Hougen T.J.
      • et al.
      Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela.
      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.
      • Moak J.P.
      • Hasbani K.
      • Ramwell C.
      • et al.
      Dilated cardiomyopathy following right ventricular pacing for AV block in young patients: resolution after upgrading to biventricular pacing systems.
      • Janousek J.
      • Tomek V.
      • Chaloupecky V.
      • Gebauer R.A.
      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.
      • Sagar S.
      • Shen W.K.
      • Asirvatham S.J.
      • et al.
      Effect of long-term right ventricular pacing in young adults with structurally normal heart.
      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.
      • Chen C.A.
      • Chang C.I.
      • Wang J.K.
      • et al.
      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.
      • Berul C.I.
      • Cecchin F.
      American Heart Association American College of Cardiology. Indications and techniques of pediatric cardiac pacing.
      • Cohen M.I.
      • Bush D.M.
      • Vetter V.L.
      • et al.
      Permanent epicardial pacing in pediatric patients: seventeen years of experience and 1200 outpatient visits.
      • Villain E.
      • Martelli H.
      • Bonnet D.
      • Iserin L.
      • Butera G.
      • Kachaner J.
      Characteristics and results of epicardial pacing in neonates and infants.
      • Robledo-Nolasco R.
      • Ortiz-Avalos M.
      • Rodriguez-Diez G.
      • et al.
      Transvenous pacing in children weighing less than 10 kilograms.
      • Kammeraad J.A.
      • Rosenthal E.
      • Bostock J.
      • Rogers J.
      • Sreeram N.
      Endocardial pacemaker implantation in infants weighing<or =10 kilograms.
      • Karpawich P.P.
      Technical aspects of pacing in adult and pediatric congenital heart disease.
      • Fortescue E.B.
      • Berul C.I.
      • Cecchin F.
      • Walsh E.P.
      • Triedman J.K.
      • Alexander M.E.
      Comparison of modern steroid-eluting epicardial and thin transvenous pacemaker leads in pediatric and congenital heart disease patients.
      • Cecchin F.
      • Atallah J.
      • Walsh E.P.
      • Triedman J.K.
      • Alexander M.E.
      • Berul C.I.
      Lead extraction in pediatric and congenital heart disease 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.
      • Bar-Cohen Y.
      • Berul C.I.
      • Alexander M.E.
      • et al.
      Age, size, and lead factors alone do not predict venous obstruction in children and young adults with transvenous lead systems.
      While infectious complications have been described, the precise risk of endocarditis over a lifetime of pacing is not known.
      • Klug D.
      • Vaksmann G.
      • Jarwe M.
      • et al.
      Pacemaker lead infection in young patients.
      • Cohen M.I.
      • Bush D.M.
      • Gaynor J.W.
      • Vetter V.L.
      • Tanel R.E.
      • Rhodes L.A.
      Pediatric pacemaker infections: twenty years of experience.

      K. Alternate treatment options

      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.
      • Balmer C.
      • Fasnacht M.
      • Rahn M.
      • Molinari L.
      • Bauersfeld U.
      Europace: long-term follow up of children with congenital complete atrioventricular block and the impact of pacemaker therapy.
      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.
      • Jansens J.L.
      • Jottrand M.
      • Preumont N.
      • Stoupel E.
      de Cannière D. Robotic-enhanced biventricular resynchronization: an alternative to endovenous cardiac resynchronization therapy in chronic heart failure.
      • DeRose J.J.
      • Ashton R.C.
      • Belsley S.
      • et al.
      Robotically assisted left ventricular epicardial lead implantation for biventricular pacing.
      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 thumbnail gr1
      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.
      • Beck H.
      • Boden W.E.
      • Patibandla S.
      • et al.
      50th anniversary of the first successful permanent pacemaker implantation in the United States: historical review and future directions.
      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.
      • Rosen M.R.
      • Robinson R.B.
      • Brink P.R.
      • Cohen I.S.
      The road to biological pacing.

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