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CONGENITAL COMPLETE ATRIOVENTRICULAR BLOCK FROM FETAL LIFE TO CHILDHOOD DIAGNOSTIC AND THERAPEUTIC ASPECTS The studies presented in this thesis were performed at the Pediatric Heart Center of the Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Emma Children’s Hospital, Amsterdam Medical Center, Amsterdam, University Medical Center St. Radboud, Nijmegen, the Netherlands; Johns Hopkins Hospital, Baltimore, Maryland, Yale New Haven Hospital, New Haven, Connecticut, and the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America. The work in this thesis was supported by the Karel Frederik Foundation (Utrecht, the Netherlands), Netherlands Heart Foundation (The Hague, the Netherlands), and the Wilhelmina Children’s Hospital Fund (Utrecht, the Netherlands). Financial support by the “Stichting Kind en Afweer” (Bilthoven, the Netherlands), and the “Stichting Researchfonds Kindergeneeskunde VU medisch centrum” (Amsterdam, the Netherlands) for the publication of this thesis is gratefully acknowledged. Congenital complete atrioventricular block from fetal life to childhood: diagnostic and therapeutic aspects. - F.E.A. Udink ten Cate. Cover design: A.M. Kuenen & F.E.A. Udink ten Cate, anatomische prent van hart & vaten Printed by: HAVEKA BV, Alblasserdam Lay-out: A.M. Kuenen & F.E.A. Udink ten Cate ISBN: 90-9017594-6 Copyrights: 2003 by F.E.A. Udink ten Cate, Utrecht, The Netherlands All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or any means, electronical, mechanical, photocopying, recording or otherwise, without prior written permission of the holder of the copyright. VRIJE UNIVERSITEIT CONGENITAL COMPLETE ATRIOVENTRICULAR BLOCK FROM FETAL LIFE TO CHILDHOOD Diagnostic and therapeutic aspects ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. T. Sminia, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Geneeskunde op vrijdag 16 januari 2004 om 13.45 uur in de aula van de universiteit, De Boelelaan 1105 door Floris Emile Alexander Udink ten Cate geboren te Delft promotoren: prof.dr. J.J. Roord prof.dr. N. Sreeram Voor mijn ouders, Stien & Gerrit Marianne Jasper & Annelien “Het hart is de bron des levens, de zon van de microkosmos, zoals de zon het ook verdient het hart van de wereld genoemd te worden, want door de verdienste en het kloppen van het hart wordt het bloed in beweging gezet, vervolmaakt, geschikt gemaakt als voeding en behoed voor verderf en stolling; het hart is de persoonlijke god die door uitoefening van zijn functie het gehele lichaam voedt, verzorgt en sneller maakt, en daarmee inderdaad de fundamenten des levens legt, de bron van alle activiteit.” William Harvey, 1628 ‘On the Motion of the Heart and Blood in Animals’ TABLE of CONTENTS Chapter 1 List of abbreviations. 11 General introduction. 13 Ned Tijdschr Geneesk 2002;146:1777-81. Chapter 2 Congenital heart block in fetal life: hydrops fetalis and congestive heart failure. 37 Submitted. Chapter 3 Neonatal lupus erythematosus in three successive pregnancies. 51 Submitted. Chapter 4 Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children. 61 J Am Coll Cardiol 2001;37:1129-34. Chapter 5 Pacemaker therapy in isolated congenital complete atrioventricular block. 73 Pacing Clin Electrophyiol 2002;25:1685-91. Chapter 6 Endocardial and epicardial steroid lead pacing in the neonatal and pediatric age group. 87 Heart 2002;88:392-6. Chapter 7 General discussion & conclusions. 99 Chapter 8 Summary 105 Nederlandse samenvatting 111 Dankwoord 117 Curriculum vitae 121 List of publications 122 Chapter 9 9 10 LIST of ABBREVIATIONS AV node atrioventricular node bpm beats per minute CHB congenital heart block = second and third degree heart block. CCAVB congenital complete atrioventricular block (third-degree heart block) CHF congestive heart failure CTD connective tissue disease CTR cardio-thoracic ratio DCM dilated cardiomyopathy ELISA enzyme-linked immunosorbent assay LV left ventricle LVEDD left ventricular end-diastolic dimension LVESD left ventricular end-systolic dimension MCTD mixed connective tissue disease NLE neonatal lupus erythematosus NLS neonatal lupus syndrome PM pacemaker RA rheumatoid arthritis SA node sino-atrial node SDS-immunoblot sodium dodecyl sulfate-immunoblot SF shortening fraction SLE systemic lupus erythematosus SS Sjögren’s syndrome VHR ventricular heart rate 11 12 C H A P T E R ISOLATED CONGENITAL COMPLETE ATRIOVENTRICULAR BLOCK General Introduction Partly from: Udink ten Cate FEA, Breur JMPJ, Van Woerkom JM, Kruize AA, Stoutenbeek Ph, Meijboom EJ. Ned Tijdschr Geneesk 2002;146:1777-81 Chapter 1 GENERAL INTRODUCTION Congenital complete atrioventricular block (CCAVB) is a rare cardiac conduction disorder with an estimated incidence of 1 in 11 000 to 22 000 live births.1,2 There are two major etiologies causing this remarkble cardiac conduction defect. In approximately 25% of the patients, co-existing congenital heart disease can be identified, such as atrioventricular septal defects, left atrial isomerism, and abnormalities of the great arteries, which results in a disturbance of the electrophysiologic continuity between atria and ventricles.3,4 However, most patients have structurally normal hearts and CCAVB is caused by an abnormal development of the cardiac conducting system,5 or by antibody-mediated damage of a normal developed atrioventricular (AV) node.6 CCAVB in these cases is therefore referred to as an “isolated” condition. Isolated CCAVB was first recognized in 1901 by Morquio as a separate disease entity characterized by a slow pulse, syncope, Stokes-Adam attacks and sudden cardiac death, often occurring in families.7 An electrocardiogram of this conduction defect was reported in 1908 by Van den Heuvel,8 and CCAVB was diagnosed antepartum by Plant and Steven in 1945.9 It was not until the 1950s and the late 1960s that an association between isolated CCAVB and maternal connective tissue disease was suggested.10,11 This clinical observation was further supported by others in the 1970s.12-14 It is now generally accepted that the development of fetal CCAVB is associated with the presence of maternal autoantibodies directed to SSA/Ro – SSB/La ribonucleoprotein complex antigens.15-17 The anti-SSA/Ro and anti-SSB/La antibodies are actively transferred across the placenta, particularly between 16 and 24 weeks of gestation, and enter the fetal circulation where they induce antibody-mediated injury to the fetal cardiac conduction system and myocardium, particularly the AV node.18-20 This generalized inflammatory response cause irreversible damage to the conducting system and fibrotic replacement of parts of the conducting system. Common clinical signs and symptoms of CCAVB in the fetus and child include bradycardia, e.g. second- or third-degree (complete) heart block eventually requiring permanent pacemaker therapy, autoimmune myocarditis and subsequently ventricular dysfunction.18-20 Since Hull et al.11 in 1966 suggested an association between isolated CCAVB and maternal autoimmune disease, efforts in clinical and experimental studies have resulted in a great amount of knowledge of the pathogenesis of this rare disorder. Isolated CCAVB is a model of passively acquired cardiac autoimmune disease of the fetus and newborn.5 This chapter reviews what is currently known about the intracellular SSA/Ro–SSB/La antigen complex, the pathogenesis of CCAVB, and the advances made in diagnostic and therapeutic options from fetal life to childhood. Furthermore, the aim and outline of this thesis is firmly described. 14 General Introduction MATERNAL HEALTH, DISEASE AND RISK ESTIMATES OF CCAVB Antibodies to SSA/Ro and SSB/La antigens are frequently found in patients with connective tissue disease, including systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), subacute cutaneous lupus erythematosus, mixed connective tissue disease (MCTD), scleroderma and rheumatoid arthritis.21,22 The anti-SSA/Ro – anti-SSB/La antibodies are not only serological hallmarks of patients with systemic autoimmune disease,23 they are also known to be crucial in the pathogenesis of tissue and multi organ injury in these diseases.24-26 The highest frequencies and titres of these antibodies are reported in patients with SLE and SS. Anti-SSA/Ro antibodies are found in the sera of up to 50% of SLE patients and even a higher percentage of patients with SS.27 Anti-SSB/La antibodies are frequently found in sera associated with anti-SSA/Ro antibodies. However, anti-SSA/Ro antibodies without anti-SSB/La immunoreactivity is more commonly found in patients with SLE, while anti-SSA/Ro and anti-SSB/La antibodies is more common in SS.28 Moreover, anti-SSA/Ro antibodies are demonstrable in approximately 0.01% of the general population.29 In fact, the anti-SSA/Ro antibodies in healthy persons are identical to those found in sera of patients with either SLE or SS. Not all anti-SS-A/Ro-SSB/La antibody-positive women give birth to affected offspring. CCAVB develops in only 1 – 5% of children whose mothers have anti-SSA/Ro and/or antiSSB/La antibodies.30-33 The estimated recurrence risk of women who had a previous child with CCAVB is approximately 16 – 20%.19,34 Although 30 to 50% of mothers have SLE, SS or have undifferentiated autoimmune syndromes at the time of birth of a child with CCAVB, several studies have convincingly demonstrated that the majority of these women are asymptomatic and only have antibodies in their sera.19,35-38 However, prospective long-term follow-up studies showed that 50 – 70% of these initially asymptomatic women developed SLE or SS by a mean of 10 – 16 years after the index delivery, of which the clinical picture is generally mild.37,38 Asymptomatic women who gave birth to a child with CCAVB are therefore adviced to visit a rheumatlogist on a regularly basis. Furthermore, it has been demonstrated that anti-SSA/Ro and/or antiSSB/La antibody-positive mothers of children with CCAVB have normal structural hearts, without cardiac dysarrhythmias.39 15 Chapter 1 MOLECULAR STRUCTURE AND FUNCTION OF THE SS-A/Ro – SS-B/La ANTIGENS During the last two decades, several investigators have extensively characterized the SSA/Ro – SS-B/La antigens and their cognate autoantibodies at the molecular level.40-44 It has been shown that anti-SS-A/Ro antibodies recognize at least two antigens: a 52-kDa SS-A/Ro protein (Ro52, 475 amino acids) and a 60-kDa SS-A/Ro protein (Ro60, 525 amino acids). Anti-SS-B/La antibodies are directed against a 48-kDa SS-B/La protein (La48).40 The Ro52, Ro60 and La48 antigens reside in the cytoplasm and the nucleus of most human cells and tissues.41,42 Intracellularly, the antigens are known to be associated directly or indirectly with small cytoplasmic RNA molecules to form complex ribonucleoprotein (RNPs) particles.43,44 The SSA/Ro RNP particle consists of a Ro60 protein which is complexed with one of four short, uridine-rich RNA molecules (termed hY RNAs).45 The La48 protein is transiently associated with the Ro60 – hY RNA particle through binding the hY RNAs46 or the Ro60 directly by protein-protein interaction.47 Other transcripts which have been reported to form complexes with SS-A/Ro and SS-B/La antigens include tRNA, 7S RNA, 5S RNA, U6-RNA and a number of viral RNAs.42,48 To date, there is considerable controversy as to whether the Ro52 antigen is a component of the SS-A/Ro RNP particle.49-51 A molecular definition of all three antigens has been provided by complementary DNA (cDNA) cloning. Analysis of the Ro60 protein revealed a zinc finger and a RNA-binding consensus motif, both of which could account for its direct interaction with hY RNAs.40,52,53 It has been suggested that Ro60 may function as part of a novel quality control or discard pathway for defective 5S ribosomal RNA precursors.54 There are two isoforms of the Ro52 protein, 52-α and 52-β. The full length 52-α antigen has three distinct domains: a N-terminal region containing two distinct zinc-fingers, a central region, which has two coiled coils with heptad periodicity, one being a leucine zipper, and the C-terminal containing a “rfp-like” domain.45,55 Because the 52-α protein contains a classic zinc-finger DNA-binding domain, and its DNA-binding activity has been demonstrated,56 it is presumed that Ro52 may have a function in the transcriptional regulation of (unknown) genes.57 Recently, it was demonstrated that Ro52 plays a critical role in the enhancement of IL-2 production, an important cytokine, in T cells via the CD28-mediated signaling pathway.58 T cell stimulation is essential for the generation of an immune response and histological studies demonstrated lymphocytic infiltrates in several tissues and organs of patients with SLE or SS.59 The 52-α form is more ubiquitously expressed, whereas 52-β, an alternative mRNA transcript lacking the central leucine zipper domain, has been detected in a variety of fetal tissues, including the fetal heart.60 Gene transcription regulation may be influenced by the ratio of the two isoforms.57 16 General Introduction The La48 protein does not share antigenic determinants with either Ro52 or Ro60,61,62 and is thought to be critical for the efficient termination of RNA polymerase III transcription.63 Recent studies support an independent function of La48 in the cytoplasm where it participates in the selection of viral mRNA for the initiation of protein translation.64 The diverse cellular functions of La48 in mRNA and protein synthesis may be explained by the observation that the protein is a dsRNA unwinding enzyme.65,66 Although most of the SS-A/Ro and SS-B/La proteins can be found in the nucleus of the cell, it is presumed that these antigens bind to newly synthesized Y-RNA in the nucleus, and that the RNP-complex is subsequently transferred to the cytoplasm.42 The intracellular localization of the SS-A/Ro and SS-B/La antigens has important implications for the pathogenesis of CCAVB. This will be discussed in the next chapter. 17 Chapter 1 PATHOGENESIS Although an association between CCAVB and maternal anti-SS-A/Ro – anti-SS-B/La antibodies has been recognized for decades, the pathogenetic mechanism of CCAVB has not yet been elucidated. Evidence for an immunopathogenesis of CCAVB is based on (1) the almost invariable finding of anti-SS-A/Ro and anti-SS-B/La antibodies in mothers of children with CCAVB,13,15,19 (2) the demonstration of SS-A/Ro and SS-B/La antigens in fetal cardiac conducting system and myocardium,67,68 and (3) deposition of maternal immunoglobulins and complement in affected fetal hearts with local and generalized inflammation.16,69-71 This chapter reviews and summarizes the current knowledge of the pathogenesis of CCAVB. Cardiogenesis and transplacental passage of maternal IgG. The presence of maternal immunoglobulins in the fetal circulation is part of a normal physiologic process.5 Maternal (auto)antibodies interact with Fc receptors on the trophoblastic cell surface and are actively transported to the fetal cardiovascular system. Only Fc receptors for IgG have been described, and maternal IgM and IgA do not effectively cross the placenta. Fetal concentrations of maternal IgG are marginally detectable in the first trimester of pregnancy. These concentrations steadily increase after 17 weeks, reaching high titers of antibodies between 24 and 32 weeks of gestation.72 By approximately 8 weeks’ gestation, the fetal heart is morphologically developed and by 16 weeks the conduction system is functionally mature.73 The sinoatrial (SA) node can be recognized in the first trimester, and the three internodal conducting pathways from the SA- to the AV-node appear in the second month of pregnancy. The AV-node arises separately from the bundle of His and joins this structure at 8 weeks gestation. Therefore, the transplacental passage of maternal autoantibodies, starting at 17 weeks gestation, would not be expected to induce major structural heart defects in autoimmune-associated CCAVB. Most fetal cases of CCAVB are detected by echocardiography between 18 and 24 weeks of gestation,18 at the time when increasing titers of maternal anti-SS-A/Ro and anti-SS-B/La antibodies are present in the fetal circulation and the fetal conduction system is structurally and functionally mature. Immunohistopathology and IgG deposits. Histopathologic findings of hearts of children with CCAVB constitute an important framework for formulating hypotheses regarding the pathogenesis of CCAVB. However, few studies describing the cardiac pathology have been reported in the literature as most published reports rather emphazise clinical, physiologic, serological and maternal aspects of CCAVB. Immunofluorescent studies of fatal cases of CCAVB have demonstrated IgG deposits and several complement components in cardiac tissue, and less abundant in the kidney and skin.16,69-71 Rechlin et al.71 showed in a post-mortem study of a 34-week fetus with CCAVB that these IgG deposits, indeed, consisted of anti-SSA/Ro antibodies. The cardiac IgG deposits were not confined to the conducting system (SA- and AV-node, internodal 18 General Introduction pathways, His bundle, Purkinje fibers), but were also present as large globules in the epicardium, endocardium, and myocardium. A consistent finding of the histopathological studies is replacement of the AV-node and many other parts of the conducting system, including the SA-node, with fibrosis and calcifications.74-76 Microscopic examination revealed extensive intramural fibrosis and dystrophic calcification of many parts of the heart. In areas of fibrosis, patchy mononuclear infiltrates were seen, which supports inflammation as an important component of the etiology of CCAVB. Nonfibrotic areas showed mild to moderate disarray of cardiomyocytes and hypertrophy.76 Other abnormalities included valvular dysplasia and varying degrees of cardiomyopathy in infancy. 11,75,76 endocardial fibroelastosis, a form of dilated Deposition of maternally derived IgG and complement components, combined with the associated mononuclear infiltrates, supports the hypothesis that local or generalized inflammation occurs before the fibrotic lesions and calcifications appear. The demonstration of deposition of anti-SSA/Ro – anti-SSB/La antibodies in cardiac tissue of fetuses and neonates with CCAVB suggests that maternal antibody levels in affected compared to unaffected children may be lower due to depletion from the circulation. Consistent with this notion, lower antibody titers were measured in an affected child compared to his HLA-identical healthy twin sister.77 Furthermore, significantly lower levels of anti-SSA/Ro – anti-SSB/La antibodies were found in infants with CCAVB as compared to their mothers, while levels were similar in healthy children and their mothers.78 However, only three infants with CCAVB and two healthy infants were included in this study. More recently, measurements of 52-kDa, 60-kDa SSA/Ro antibody and 48-kDa SSB/La antibody titers in a large cohort of neonates did not reveal a selective depletion of maternal antibodies in cases with CCAVB compared to healthy controls.79 The absence of antibody depletion from the neonates circulation in this study should not be interpreted as evidence against an etiologic role for these antibodies in CCAVB.79 Data suggest that the period of maximal fetal susceptibility for antibody-mediated damage is between 18 and 24 weeks gestation. The deposition of antibodies between these weeks might not result in lower antibody titers when measured at the time of birth, or the amount of antibodies depleted may be too small to be detectable. Direct pathogenicity of SSA/Ro – SSB/La antibodies. Based on the above mentioned clinical and serological studies it was postulated that the SSA/Ro – SSB/La antibodies might be directly pathogenic on fetal cardiac (conduction) cells. This issue was illustrated by Alexander and collegues80 who demontrated that superfusion of newborn rabbit ventricular papillary muscles with IgG enriched fractions from sera containing anti-SSA/Ro – antiSSB/La antibodies significantly reduced the plateau phase of the cardiac action potential and altered the cellular calcium influx. These intruiging early observations were further supported 19 Chapter 1 by similar findings in patch-clamp experiments using isolated rabbit ventricular myocytes.81 Subsequently, the arrhythmogenic effects of anti-SSA/Ro and anti-SSB/La antibodies was demonstrated in Langendorf-perfused hearts.82,83 Additionally, these electrophysiologic studies were repeated in human fetal cardiomyocytes with similar results.83,84 The injection of human anti-SSA/Ro and anti-SSB/La antibodies in female pregnant BALB/C mice resulted in cardiac conduction abnormalities in their offspring.85 The development of a murine animal model of CCAVB and the use of electrophysiologic techniques provided new approaches to study the cellular and ionic mechanisms underlying the disease.86 All together these data provide strong evidence for a direct arrhythmogenic effect of anti-SSA/Ro and anti-SSB/La antibodies in the etiology of CCAVB. Maternal autoantibody profile. In an attempt to predict which fetus is at highest risk for the development of CCAVB, several studies have analyzed the maternal autoantibody profile and measured antibody-levels of mothers who gave birth to children with CCAVB. Analysis by either sodium dodecyl sulfate (SDS) immunoblot or ELISA revealed that 75 – 100% of sera obtained from mothers whose children had CCAVB were directed to 52-kDa SS-A/Ro antigens.34,87-92 A recent study detected maternal antibodies immunoreactive to the 52-kD SS-A/Ro antigen in sera from all mothers and their children with CCAVB, while they occurred less frequently and at lower levels in mothers with healthy children.93 The anti-52 kDa SSA/Ro antibody response of mothers with affected children was significantly dominated by antibodies directed to a specific epitope on this protein (amino acids 200 – 239) compared to the antibodies from sera of women with healthy offspring (amino acids 176 – 196). Although this distict antibody profile was also present in women who gave birth to unaffected children, the ability of antibodies to bind particular epitopes of SS-A/Ro may also be important in the pathogenesis of CCAVB. Additionally, it was found that CCAVB can develop independent of the presence of 60-kDa SS-A/Ro antibodies. Similar findings suggesting that antibodies to 60-kDa SS-A/Ro have a minor role in predicting the clinical outcome of pregnancies in SSA/Ro – SS-B/La positive women have been reported.19,91,92 Although the fine specificity of the maternal autoantibody response to SSA/Ro and SSB/La proteins does not predict the occurrence of CCAVB, women with high titers of anti-52-kDa SSA/Ro and anti-48-kDa SSB/La antibodies, in combination with a specific antibody proflie to 52-kDa SSA/Ro, may be at the highest risks of giving birth to affected children. Additional factors in the pathogenesis of CCAVB: evidence for a fetal factor? Although SS-A/Ro and SS-B/La antibodies are necessary in the pathogenesis of CCAVB, their presence is probably not in itself sufficient to induce disease. Most studies sofar do not give an appropriate explanation for the discordancy of CCAVB in monozygotic (HLA identical) twins,77,94-97 and additionally why a mother has only 1-5% risk and a recurrence risk which is much higher than the risk for an index pregnancy. This suggest that additional 20 General Introduction factors are involved in the pathogenesis of CCAVB, which confers increased individual fetal risk to specific tissue susceptibility and disease. Such environmental or fetal influences may also explain why successive pregnancies may have different outcomes, and why a mother may give birth to a healthy child after having a pregnancy complicated by CCAVB. Presently these factors or mechanisms are unknown. Translocation of SSA/Ro – SSB/La antigens to the cell surface. It is presumed that the circulating maternal antibodies bind to SSA/Ro – SSB/La antigens to form immune complexes, causing IgG deposition in fetal tissue and subsequently induce an inflammatory response. Horsfall and collegues,98 demonstrated the expression of SSA/Ro and SSB/La antigens on the cell surface of myocardial fibers of patients with CCAVB, but was unable to find cell surface expression of these antigens in healthy controls. To date, it is not known how maternal antibodies can interact with the intracellular located SSA/Ro – SSB/La antigens. Several mechanisms have been proposed to account for the translocation of intracellular antigens to the cell suface, including viral infections,99 apoptosis,100,101 17-βestradiol hormone,102 and ultraviolet light.103 All of these possibilities have been described in detail, although physiologic apoptosis in fetal cardiac tissue has received most attention. Apoptosis, or programmed cell death, is an essential physiologic component of fetal developmental morphogenesis, important for remodeling of tissues, and for maintenance of its architecture.104 Focal apoptosis is an important feature in the normal development of the embryonic outflow tract, cardiac valves, conducting system, and the coronary vasculature.105 It has been suggested that apoptosis is involved in the postnatal morphogenesis of the cardiac conducting system, as well.106 Apoptotic cells undergo a characteristic and strictly coordinated cascade of biochemical events, including cell shrinkage, staging membrane blebbing, chromatin condensation, protein fragmentation and DNA degradation.104 Both in vitro and in vivo studies have shown that nuclear antigens, including SSA/Ro and SSB/La proteins, are expressed in blebs on the surface of cells undergoing apoptosis.107-110 Induction of apoptosis in fetal human cardiomyocytes resulted in surface translocation of SSA/Ro and SSB/La antigens. Additionally, it was shown that anti-SSB/La antibodies cross the placenta and bind to apoptotic fetal myocardial cells, skin and liver in a murine in vivo model.110 This pattern of organ involvement resemble the signs and symptoms of neonatal lupus erythematosus (NLS), as will be explained in more detail in the next chapter. Normally, apoptotic cells do not evoke inflammation but are cleared by surrounding cells or are phagocytosed by macrophages. Binding of circulating maternal autoantibodies to surface antigens and subsequently complement, however, may provoke the infux of leukocytes and initiates damage to surrounding fetal cardiomyocytes.108 Furthermore, inappropriate clearance of apoptotic cells ultimately results in secondary necrosis with induction of an inflammatory response and presentation of (auto)antigens to the immunologic system.111 21 Chapter 1 At present, there is no direct evidence that maternal autoantibodies bind to SSA/Ro and SSB/La proteins in vivo, and cross-reactivity of these antibodies with target antigens other than intracellular SSA/Ro – SSB/La ribonucleoproteins has been demonstrated.112-116 Antibodies from mothers whose children had CCAVB were reported to cross-react with laminin B1 and to human cardiac myosin heavy chain.112 An unexpected observation was that affinity-purified anti-G12V autoantibodies from sera of patients with SLE recognized both the human serotoninergic 5-HT4 receptor and 52-kDa SSA/Ro protein due to a cross-reacting epitope.113,114 More recently, based on earlier electrophysiologic studies demonstrating a decreased intracellular calcium flow after perfusion of ventricular rabbit myocytes with maternal IgG, it was shown in expanded experiments that SSA/Ro – SSB/La autoantibodies inhibited L-type calcium (Ca) channels by cross-reacting with the α-subunit of this voltagegated channel.115,116 Interestingly, the AV node is largely dependent on L-type currents for a proper propagation of action potentials to the bundle of His and L-type Ca channels play a major role in excitation-contraction coupling of ventricular myocytes.86 Inhibition of the L-type Ca channels may account for the electrophysiologic abnormalities seen in children with CCAVB and might also explain the diminished left ventricular function and heart failure in some patients with CCAVB. In chronically exposed fetal hearts to maternal autoantibodies, a reduction in the density of L-type Ca channels was seen, further supporting this so called “Ca channel blockade hypothesis”.117 Additionally, the L-type Ca channel density is lower in fetal compared to mature adult cardiomyocytes, increasing the dependency on sarcolemmal calcium handling.86 It is currently not known how the inhibition of L-type calcium channels results in maternal IgG deposition, inflammation and the replacement of AV node with fatty tissue and fibrosis. This “Ca channel blockade hypothesis” does not explain all clinical, maternal and serological aspects of CCAVB although it is tempting to conclude that some signs and symptoms seen in CCAVB might be due to blockage of these Ca channels. The pathogenesis of CCAVB is complex. There are many studies supporting an immunopathogenic etiology of CCAVB, but the how and the why remains largely unknown. It is now generally accepted that CCAVB is strongly associated with maternal antibodies against intracellular 52-kDa SSA/Ro, 60-kDa SSA/Ro and 48-kDa SSB/La antigens. To date, it is not possible to predict the development of CCAVB in a fetus of an anti-SSA/Ro – antiSSB/La positive mother. However, high titers of antibodies immunoreactive with 52-kDa SSA/Ro and 48-kDa SSB/La antigens confer the highest risk for the development of CCAVB in an offspring. These maternal antibodies cross the placenta between 18 and 24 weeks gestation and enter the fetal circulation. An important (initial) component of antibodymediated injury to fetal cardiac tissue, is the deposition of maternal antibodies. Binding of complement components causes inflammation and influx of leukocytes, ultimately damaging 22 General Introduction the fetal cardiac conducting system and myocardium. Eventually scarring and fibrosis of the AV node occurs. It is not known how maternal antibodies can react with intracellular fetal antigens. Physiologic apoptosis has been shown to translocate SSA/Ro and SSB/La antigens to the cell surface of fetal cardiomyocytes, where they can interact to circulating maternal antibodies. Antibodies also cross-react with other antigens than SSA/Ro and SSB/La, including laminin B1, human cardiac myosin heavy chain, serotoninergic 5-HT4 receptor and the α-subunit of L-type calcium channels. At present, none of these findings explain, for instance, discordancy of CCAVB in monozygotic twins and the relatively low prevalence of affected offspring in antibody-positive pregnant women. Additional environmental or fetal factors are yet to be identified. Furthermore, it has become apparent that anti-SSA/Ro and anti-SSB/La antibodies can cause a variable clinical spectrum of arrhythmias and conduction abnormalities. Clear experimental and clinical evidence is emerging that the sinoatrial node may also be damaged by the maternal antibody response. Sinus bradycardia was observed in pups of female mice who were immunized with anti-SSA/Ro antibodies during pregnancy.85 Histopathological studies have illustrated the complete absence, hypoplasia or extensive fibrotic replacement of the SA node in children with CCAVB.74,118 Important clinical work was presented in a recent study by Brucato et al,32 demonstrating sinus bradycardia on electrocardiograms (ECG) of 4 infants born to antibody-positive mothers without CCAVB. The sinus bradycardia was not permanent and resolved within months after birth. The same group also found prolongation of both QT and QTc interval on ECGs performed at birth of healthy infants with maternally acquired antibodies.119 Prolongation of the QTc interval, for instance in the longQT syndrome, is a risk factor for life-threathening ventricular arrhythmias, including torsades the pointes and sudden cardiac death.120 Evenmore, there have been several published reports of first-degree heart block detected at birth.118,121 In utero, second-degree heart block is frequently encountered in fetuses before progression to irreversible CCAVB occurs. Taken together, it is postulated that perhaps many fetuses sustain a mild inflammatory insult, resulting in sinus bradycardia, QTc- and PR-interval prolongation which reverse after the disappearance of maternal anti-SSA/Ro and anti-SSB/La antibodies from the child’s circulation. These interesting new clinical observations raise many questions and it is tempting to consider ECG screening of infants born to anti-SSA/Ro – anti-SSB/La antibodypositive mothers who do not have CCAVB. It should be taken into account that postnatal progression of a second-degree heart block has been documented. 23 Chapter 1 NEONATAL LUPUS ERYTHEMATOSUS Anti-SSA/Ro and anti-SSB/La antibodies are not only associated with CCAVB, but are also related to the development of cutaneous rashes, hematological abnormalities, and liver disease in neonates.122,123 These signs and symptoms are grouped under the heading of neonatal lupus erythematosus (NLE), so called because the skin rashes of the neonate resemble those seen in patients with SLE.124 Theoretically, any combination of NLE manifestations is possible in a given neonate. Approximately 10-20% of the children have different clinical features of NLE, most commonly CCAVB together with cutaneous lesions.122,125 Chapter 3 of this thesis presents a mother with connective tissue disease and the development of several different features of NLE in three siblings of successive pregnancies. CCAVB is the most serious manifestation of NLE, because it is irreversible and eventually requires permanent pacemaker therapy. Unlike the cardiac manifestations, other organ involvement in NLE tends to be less severe and disappear with the clearence of anti-SSA/Ro – anti-SSB/La antibodies from the blood circulation of the child at approximately 6 to 8 months of life.122,123 Although most children have CCAVB, the second most common feature is cutaneous lesions. These rashes can be present at birth or may appear after exposure to sunlight. They are typically erythematous annular or polycyclic plaques, often involving the face, trunk and scalp of the neonate.122,125 Usually, no treatment is necessary and the rashes heal without scarring. Rarely, NLE dermatitis is associated with antibodies ribonucleoprotein particle U1 RNP in absence of anti-SSA/Ro – anti-SSB/La antibodies. to 126 The most common hematological abnormality is thrombocytopenia, although neutropenia, hemolytic anemia and hemochromatosis have also been reported.122,127-129 Recently, a study showed that hepatobiliary disease is a relatively common clinical finding in NLE, occurring in up to 9% of infants with NLE.130 Its clinical spectrum ranged from mild elevated aminotransferases and conjugated hyperbilirubinemia to cholestasis and severe liver failure. Some patients with central nervous system vasculopathy might also be associated with maternal anti-SSA/Ro and SSB/La antibodies.131,132 The true incidence of hematological and mild hepatic disease is not known, because blood samples are not regularly obtained from neonates without CCAVB or skin lesions. Several reports describe rheumatic diseases developing in children with NLE.133,134 The long-term outcome of children with NLE and their unaffected siblings of mothers with autoimmune disease was addressed in a recent study.135 A large prospective cohort study demonstrated that 6/49 children with NLE and none of their unaffected siblings developed a definite rheumatic or autoimmune disease (follow-up 8 – 25 years). These data suggest that children with NLE require continued follow-up, especially prior to adolescence and if the mother herself has an autoimmune disease.135 24 General Introduction DIAGNOSIS, MANAGEMENT AND LONG-TERM FOLLOW-UP OF CCAVB The first prospective study reporting the outcome and long-term follow-up of a large multicenter cohort of 418 CCAVB patients was not published until 1972.1 Although it has been suggested that isolated CCAVB is a generally benign condition, mortality rates of CCAVB in previous long-term outcome studies varied from 8% to 19%.34,136-138 Particularly, the fetal and neonatal period are associated with a high morbidity (70%) and mortality rates (30%), mostly attributable to congestive heart failure.136-140 The estimated cumulative probability of 3- and 10-year survival of children with CCAVB is 79% and 82%, respectively.136,137 Early recognition of this disease is crucial and may further improve its outcome. Fetal bradycardia and CCAVB. The presence of fetal bradycardia as a manifestation of CCAVB was first noted in 1921 and is currently the initial sign of this disorder in many cases.141 With the advent of fetal echocardiography in the 1980s, the natural history of many fetal arrhythmias have been studied and serial echocardiography has tremendously increased our insight in the outcome, management, and treatment options of these disorders.142 Fetal echocardiography is a non-invasive and safe method which allows for accurate assessment of fetal heart rate, rhythm and ventricular function.143,144 Using this method, CCAVB may now be identified in utero during the mid-second trimester of pregnancy, particularly between 16 and 30 weeks of gestation.18 Nowadays, most children are diagnosed in utero, however, still many are diagnosed at birth or in their first years of life.138 In The Netherlands, most fetal bradyarrhythmias in pregnant women, without a previous child with CCAVB or connective tissue disease, are detected on routine obstetrical auscultation at local midwife practice. When bradycardia persists, a heart rate less than 100 beats per minute (bpm), fetal echocardiographic examination is indicated and these women are referred to an experienced hospital for evaluation of the fetal arrhythmia. Because the public health is organized in this way, awareness and information of anti-SSA/Ro and antiSSB/La antibody-mediated CCAVB is not only needed for midwifes, but also for all physicians taking care of mothers and children. The diagnosis of CCAVB in utero is based upon M-mode (i.e. motion mode) echocardiographic demonstration of complete dissociation of the atrial and ventricular rates. The ventricular rate is usually around 40 - 100 bpm, while the atrial rate is normal (typically 120 to 160 bpm) and has no consistent relationship to ventricular contractions.142 Although CCAVB is not the only fetal arrhythmia presenting with bradycardia, most fetal arrhythmias are irregular and benign, and resolve prior to delivery. It is important to distinguish CCAVB from a blocked atrial ectopic rhythm, which is in general benign.142 Additionally, twodimensional ultrasound examination should be performed to look for cardiac abnormalities, 25 Chapter 1 which occur in 40 to 60 percent of fetuses with this arrhythmia.139,140 When second-degree or third-degree AV block is detected, routine serial echocardiographic monitoring is indicated for the whole pregnancy and maternal blood samples should be investigated for the presence of anti-SSA/Ro and anti-SSB/La antibodies. Some investigators, and our group, have pointed to a 1 – 4 weekly pregnancy evaluation regimen, including biophysical monitoring of fetal growth and echocardiographic assessment of heart rate and rhythm, presence of effusions, hydrops fetalis, congestive heart failure and cardiomegaly. A normal fetal heart can increase its cardiac output by changes in heart rate, ventricular size and contractility.145 In the presence of fetal CCAVB, cardiac output can only be maintained by increasing ventricular size, contractility or afterload, reflecting a changed cardiac physiology.145-147 Fetal lamb studies showed that acute changes in heart rate affected the cardiac output considerable,148 and an acute onset of CCAVB may not be tolerated by the fetus. A slow and gradual decrease in heart rate would allow the heart to adopt to the different physiologic circumstances. Severe bradycardia, or inefficient adaptation of the changed cardiac physiology to the low heart rate, is presumed to result in hydrops fetalis (accumulation of fluid in anatomic spaces) and congestive heart failure.145-147 Most fetuses tolerate CCAVB well when atrial rates are greater than 90 bpm and/or ventricular rates are greater than 55 bpm in the absence of structural heart disease.139,140 Fetal outcome depends largely on heart rate and the development of fetal hydrops. A heart rate of less than 55 bpm is associated with poor outcome and subsequent development of hydrops fetalis. Studies have shown that the mortality rates of fetuses with hydrops fetalis is 83 – 100%.139,140 Chapter 2 of this thesis describes the management, treatment and outcome of a cohort of fetuses with CCAVB. The treatment and management of the fetus with CCAVB is primarily expectant. Several attempts have been made to decrease the maternal antibody-titer and to diminish the inflammatory damage to the fetal heart.149,150 In addition, other treatment options has been applied to increase the fetal heart rate with maternal administration of beta-adrenergic agents, or with pacemaker leads placed into the fetal heart.151,152 Unfortunately, none of these therapeutic strategies have significantly changed fetal mortality and morbidity rates and there is no consensus about the efficacy of these methods. CCAVB in childhood, adolescence and adult life. The fetal outcome and prognosis of children with CCAVB in their first years of life have been firmly described in several reports.136-138 Approximately 33-67% of these children receive a permanent pacemaker device in their first year of life. The most common indication for pacing in the neonatal period is congestive heart failure. The long-term outcome of CCAVB from childhood to adult life was addresed in a follow-up study by Michaëllson and collegues,153,154 involving 102 CCAVB patients. All patients were asymptomatic during their first 15 years of life, and the mean age 26 General Introduction at follow-up was 38 years. Bradycardia related symptoms included exercise intolerance, easy fatiguability, dizziness, presyncope, syncope and Stokes-Adams attacks. Pacemakers were implanted in 53% of the patients with CCAVB after the development of symptoms. There were 10 CCAVB related deaths, of which 6 died suddenly without any preceding symptoms. The mortality rate was significantly lower in paced patients compared to unpaced patients and the authors therefore conclude that a reduction of mortality could have been achieved if pacemakers were implanted earlier in life. Additionally, it was shown that the only convincing risk factor for the occurrence of Stokes-Adams attacks and subsequently sudden death in this study was a prolonged QTc interval, observed on several occasions. Other investigators reported a prolonged QTc interval in 22 - 26% of patients with CCAVB,155,156 confirming these earlier data. The age of onset of this ECG abnormality ranged from birth to adult life. Furthermore, in one of these clinical studies, ventricular heart rates were significantly lower in children with prolongation of the QTc interval.155 Several other studies have investigated diagnostic tests which may predict sudden death due to Stokes-Adams attacks in children with CCAVB.157-160 These parameters may then be used as indications for permanent pacemaker implantation in clinical practice. However, it has been difficult to determine such straight-forward risk factors. A consensus for pacemaker therapy in a child with second-degree or third-degree AV block has been reported in the American Heart Association / American College of Cardiology guidelines.161 Recently, it was shown that some children with CCAVB developed dilated cardiomyopathy, despite of pacmaker implantation during infancy. This suggests CCAVB patients also require follow-up of there ventricular function. The true incidence of dilated cardiomyopathy in patients with CCAVB and risk factors which may predict the development of this myocardial disease have not yet been addressed. Chapter 4 describes the incidence of dilated cardiomyopathy, the outcome and risk factors in a large study group of children with CCAVB. Prophylactic pacemaker therapy. One of the most discussed issues in the management of patients with CCAVB is when to implant a pacemaker device in the asymptomatic patient. Although the view on this subject differs from medical center to medical center, most agree that a symptomatic patient with CCAVB, a child suffering from syncope or Stokes-Adams attacks, requires pacing.162 The long-term outcome of the prospective study group by Michaëlsson unsurpassably demonstrated that some adolescents who were totally asymptomatic during childhood, died a sudden cardiac death. These publications have led to the discussion if all asymptomatic children with CCAVB need prophylactic pacing to prevent future sudden cardiac death or Adam-Stokes attacks (Chapter 5).163,164 In addition, another consideration is the type of lead and device has to be implanted. There is also disagreement when to use a transvenous pacemaker device and when an epicardial system (Chapter 6). 27 Chapter 1 AIMS OF THE THESIS Given the rarity of autoimmune associated isolated CCAVB, current estimates in The Netherlands are approximately 10 – 20 new cases of CCAVB a year, a large multicenter study was initiated including the patients of six tertiary referral centers with clinical experience of the management, medical treatment, and follow-up of patients with CCAVB from the fetal period to adolesency. A total number of 149 CCAVB patients were included in this cohort, recruted from the Wilhelmina Children’s Hospital, University Medical Center, Utrecht, Emma Children’s Hospital, Amsterdam Medical Center, Amsterdam, University Medical Center St. Radboud, Nijmegen, The Netherlands and Johns Hopkins Hospital, Baltimore, Maryland, Yale New Haven Hospital, Connecticut, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America. The study was initially started in december 1999. The main purposes of this thesis is to describe the outcome, diagnostic and therapeutic management of CCAVB in fetuses, newborns and children in the new era: CHAPTER 1 summarizes the current insights and hypotheses with regard to the pathogenesis of CCAVB, and gives an overview of CCAVB from fetal life to childhood. CHAPTER 2 describes our experience with fetal heart block, its follow-up, treatment and management. Attention is focused on the development of hydrops fetalis and congestive heart failure. Neonatal lupus erythematosus is described in detail in CHAPTER 3 and reports a case which shows that different features of NLE can be present in siblings of successive pregnancies. In CHAPTER 4 we sought to assess the incidence of dilated cardiomyopathy in the CCAVB population and to identify risk factors predicting the development of dilated cardiomyopathy. 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Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of tumor necrosis factor by macrophages. J Immunol 2000;165:5345-51. 109. Tran HB, Ohlsson M, Beroukas D, Hiscock J, Bradley J, Buyon JP, Gordon TP. Subcellular redistribution of La/SSB autoantigen during physiologic apoptosis in the fetal mouse heart and conduction system: a clue to the pathogenesis of congenital heart block. Arthritis Rheum 2002;46:202-8. 110. Tran HB, Macardle PJ, Hiscock J, et al. Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus. Arthritis Rheum 2002;46:1572-9. 111. Wu X, Molinaro C, Johnson N, Casiano CA. Secondary necrosis is a source of proteolytically modified forms of specific intracellular autoantigens: implications for systemic autoimmunity. Arthritis Rheum 2001;44:264252. 112. Horsfall AC, Rose LM. Cross-reactive maternal autoantibodies and congenital heart block. J Autoimmun 1992;5:479-93. 113. Eftekhari P, Salle L, Lezoualc’h F, et al. Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 2000;30:2782-90 114. Eftekhari P, Roegel JC, Lezoualc’h F, Fischmeister R, Imbs JL, Hoebeke J. Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotonergic 5HT4 receptor. Eur J Immunol 2001;31:573-9. 115. Xiao GQ, Hu K, Boutjdir M. Direct inhibition of expressed cardiac L- and T-type calcium channels by IgG from mothers whose children have congenital heart block. Circulation 2001;103:1599-1604. 116. Qu Y, Xiao GQ, Chen L, Boutjdir M. Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca channels. J Mol Cell Cardiol 2001;33:1153-63. 117. Xiao GQ, Qu Y, Hu K, Boutjdir M. Down-regulation of L-type calcium channel in pups born to 52 kDa SSA/Ro immunized rabbits. FASEB J 2001;15:1539-45. 118. Buyon JP, Kim MY, Copel JA, Friedman D. Anti-Ro/SSA antibodies and congenital heart block: necessary but not sufficient. Arthritis Rheum 2001;44:1723-7. 119. Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43:1049-53. 120. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden death syndrome. N Engl J Med 1998;338:1709-14. 121. Rosenthal D, Druzin M, Chin C, Dubin A. A new therapeutic approach to the fetus with congenital complete heart block: preemptive, targeted therapy with dexamethasone. Obstet Gynecol 1998;92:689-91. 122. Lee LA. Neonatal lupus erythematosus. J Invest Dermatol 1993;100:9S-13S. 123. Tseng CE, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin North Am 1997;23:31-54. 124. McCuistion CH, Schoch EP. Possible discoid lupus erythematosus in a newborn infant. Report of a case with subsequent development of acute systemic lupus erythematosus in the mother. Arch Dermatol Syph 1954;70:782-5. 125. Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr 2000;137:674-80. 126. Provost TT, Watson R, Gammon WR, Radowsky M, Harley JB, Rechlin M. The neonatal lupus syndrome associated with U1RNP (nRNP) antibodies. N Eng J Med 1987;316:1135-8. 127. Watson RM, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988;124:560-3. 34 General Introduction 128. Kanagasegar S, Cimaz R, Kurien BT, Brucato A, Scofield RH. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. J Rheumatol 2002;29:187-91. 129. Schoenlebe J, Buyon JP, Zitelli BJ, Friedman D, Greco MA, Knisely AS. Neonatal hemochromatosis associated with maternal autoantibodies to Ro/SS-A and La/SS-B ribonucleoproteins. Am J Dis Child 1993;147:1072-5. 130. Lee LA, Sokol RJ, Buyon JP. Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics 2002;109:e11. 131. Cabanas F, Pellicer A, Valverde E, Morales C, Quero J. Central nervous system vasculopathy in neonatal lupus erythematosus. Pediatr Neurol 1996;15:124-6. 132. Inoue K, Fukushige J, Ohno T, Igarashi H, Hara T. Central nervous system vasculopathy associated with neonatal lupus. Pediatr Neurol 2002;26:68-70. 133. Jackson R, Gulliver M. Neonatal lupus erythematosus progressing into systemic lupus erythematosus: a 15 year follow-up. Br J Dermatol 1979;101:81-6. 134. Hübscher O, Carrillo D, Reichlin M. Congenital heart block and subsequent connective tissue disorder in adolescence. Lupus 1997;6:283-4. 135. Martin V, Lee LA, Askanase AD, Katholi M, Buyon JP. Long-term followup of children with neonatal lupus and their unaffected siblings. Arthritis Rheum 2002;46:2377-83. 136. Buyon JP, Hiebert R, Copel JA, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31:1658-66. 137. Eronen M, Siren MK, Ekblad H, Tikanoja T, Julkunen H, Paavilianen T. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86-91. 138. Jaeggi E, Hamilton RM, Silverman ED, Zamora SA, Hornberger LK. Outcome of children with fetal, neonatal or childhood diagnosis of isolated complete heart block (CHB): a single institution’s experience of 30 years. J Am Col Cardiol 2002;39:130-7. 139. Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991;91:1360-6. 140. Groves AMM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75:190-4. 141. White P, Eustis R. Congenital heart block. Am J Dis Child 1921;22:299. 142. Wood DC, Huhta JC. Fetal cardiac arrhythmias, in Rodeck CH, Whittle MJ (eds) Fetal medicine: Basic science and clinical science, first edition. Churchill Livingstone, 1999, pp 817-28. 143. Kleinman CS, Donnerstein RL, Jaffe CC, et al. Fetal echocardiography: a tool for the evaluation of in utero cardiac arrhythmias and monitoring of in utero therapy: analysis of 71 patients. Am J Cardiol 1983;51:237-43. 144. Callan NA, Maggio M, Steger S, Kan JS. Fetal echocardiography: indications for referral, prenatal diagnosis, and outcomes. Am J Perinatol 1991;8:390-4. 145. Kleinman CS, Copel JA. Fetal cardiovascular physiology and therapy. Fetal Diagn Ther 1992;7:147-57. 146. Gilbert RD. Control of fetal cardiac output during changes in blood volume. Am J Physiol 1980;238:H80-6. 147. Veille JC, Covitz W. Fetal cardiovascular hemodynamics in the presence of complete atrioventricular block. Am J Obstet Gynecol 1994;170:1258-62. 148. Rudolph AM, Heymann RL. Cardiac output in the fetal lamb: the effects of spontaneous and induced changes of heart rate on right and left ventricular output. Am J Obstet Gynecol 1976;124:183-92. 149. Buyon JP, Swersky SH, Fox HE, Bierman FZ, Winchester RJ. Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus. Arthritis Rheum 1987;30:44-9. 35 Chapter 1 150. Copel J, Buyon JP, Kleinman C. Succesful in utero therapy of fetal heart block. Am J Obstet Gynecol 1995;173:1384-90. 151. Groves AMM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995;92:3394-6. 152. Carpenter RJ Jr, Strasburger JF, Garson A Jr, Smith RT, Deter RL, Engelhardt HT Jr. Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Coll Cardiol 1986;8:1434-6. 153. Michaëlsson M, Jonzon A, Riesenfeld T. Isolated congenital complete atrioventricular block in adult life: a prospective study. Circulation 1995;92:442-9. 154. Michaëlsson M, Riesenfeld T, Jonzon A. Natural history of congenital complete atrioventricular block. Pacing Clin Electrophysiol 1997;20:2098-2101. 155. Esscher E, Michaëlsson M. Q-T interval in congenital complete heart block. Pediatr Cardiol. 1983;4:121-4. 156. Solti F, Szatmary L, Vecsey T, Rényi-Vámos Jr, Bodor E. Congenital complete heart block associated with QT prolongation. Eur Heart J 1992;13:1080-3. 157. Sholler GF, Walsh EP. Congenital complete heart block in patients without anatomic cardiac defects. Am Heart Journal 1989;118:1193-8. 158. Winkler RB, Freed MD, Nadas AS. Exercise-induced ventricular ectopy in children and young adults with complete heart block. Am Heart J 1980;99:87-92. 159. Dewey RC, Capeless MA, Levy AM. Use of ambulatory electrocardiographic monitoring to identify high-risk patients with congenital complete heart block. N Engl J Med 1987;316:835-9. 160. Levy AM, Camm AJ, Keane JF. Multiple arrhythmias detected during nocturnal monitoring in patients with congenital complete heart block. Circulation 1977;55:247-53. 161. Gregoratos G, Abrams J, Epstein AE, et al. Guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology / American Heart Association Task Force on practice guidelines. (ACC/AHA/NASPE committee to update the 1998 pacemaker guidelines). Circulation 2002;106:2145-61. 162. Friedman RA, Fenrich AL, Kertesz NJ. Congenital complete atrioventricular block: a review. Pacing Clin Electrophysiol 2001;24:168-8. 163. Odemuyiwa O, Camm AJ. Prohpylactic pacing for prevention of sudden death in congenital complete heart block? Pacing Clin Electrophysiol 1992;15:1526-30. 164. Friedman RA. Congenital AV block: Pace me now or pace me later? Circulation 1995;92:283-5. 36 C H A P T E R Congenital Heart Block in Fetal Life: HYDROPS FETALIS AND CONGESTIVE HEART FAILURE Udink ten Cate FEA, Breur JMPJ, van Woerkom JM, Kruize AA, Stoutenbeek P, Meijboom EJ, Sreeram N. Submitted. ABSTRACT Objectives. We sought to assess the cardiovascular hemodynamics in fetuses with congenital heart block (CHB), the prevalence of hydrops fetalis, and heart failure by means of serial echocardiographic examination. Methods. Fifteen fetuses with CHB of 13 women were identified and monitered for a median of 14 weeks (range 1-21). Results. CHB was detected at a median age of 24 weeks gestation (range 18 to 37). Second degree atrioventricular (AV) block (2nd) was initially detected in 6/15 (40%) fetuses and progressed to congenital complete AV block (CCAVB) in 83% during pregnancy. CHB was significantly earlier detected in women known with connective tissue disease (CTD; n=6) compared to asymptomatic women (mean 22.3 ± 3.4 vs 26.8 ± 4.8 weeks; p < 0.05). Maternal SSA/Ro-SSB/La antibodies were detected in 12/13 (92%) women. The median initial fetal ventricular heart rate was 62 bpm (range 44 to 90), which decreased significantly in 7/15 (47%) (p < 0.05) and did not change in 8/15 fetuses. Fetal pericardiopleural effusions and ascites were common findings. Hydrops and heart failure developed in 7 fetuses (47%), and improved in 2 after treatment with dexamethason 4 mg/day. Cardiomegaly and cardiac hypertrophy developed in 10 fetuses during gestation. One fetus died in utero of dilated cardiomyopathy. The cumulative probability of 1-year survival was 87%. The neonatal morbidity was high (53%) and pacemakers were implanted in 11 children (73%). Conclusions. Serial echocardiographic evaluation is a feasible method for assessment, monitoring and therapeutic management of fetal CHB. The fetus with CHB is able to maintain a sufficient cardiac output. Fetal hydrops and heart failure are common and result in considerable perinatal morbidity and mortality. 38 Congenital heart block in fetal life CONGENITAL HEART BLOCK IN FETAL LIFE INTRODUCTION CHB is a rare passively acquired autoimmune disease affecting the developing cardiac conduction system in children born to mothers with SSA/Ro and/or SSB/La antibodies in their sera.1,2 These women are frequently diagnosed having autoimmune diseases including systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS), but they may be asymptomatic.3,4 Maternal SSA/Ro and SSB/La autoantibodies are thought to cross the placenta between 18 and 24 weeks gestation and mediate inflammatory injury to the fetal conduction system and the myocardium.5-8 CCAVB develops in 1 – 5% of children whose mothers have anti-SSA/Ro and/or anti-SSB/La antibodies and the estimated recurrence risk of women who had a previous child with CCAVB is approximately 16 – 20%.2,9 CHB, usually detected in utero by fetal echocardiography, is associated with high morbidity and mortality.10-12 More than 60% of the children surviving the fetal and neonatal period eventually require permanent pacing.10 The first prenatally detectable abnormality in these fetuses is not ventricular dysfunction, due to a generalized myocarditis, but bradycardia.13 Earlier studies showed that fetal outcome is largely dependent on the ventricular escape rate and the development of hydrops fetalis.14,15 Several attempts have been made to decrease the maternal antibody-titer and to diminish the inflammatory damage to the fetal heart.16,17 Unfortunately, none of these strategies has significantly changed fetal mortality and morbidity rates. A better understanding of perinatal hemodynamics would enhance our insight in pathogenesis and clinical course of fetal CHB, which might result in better therapeutic options. However, reports on serial echocardiograms in mothers at high risk for a pregnancy complicated by CHB is limited and assessment of cardiovascular hemodynamics in fetal CHB has only been based on few cases.18,19 This study describes our experience with CHB diagnosed in utero, its clinical course and therapeutic management. In behalf of a better understanding of cardiovascular hemodynamic factors in fetal outcome of CHB, including the development of hydrops fetalis and heart failure, serial echocardiographic reports of 15 pregnancies were reviewed and analyzed. 39 Chapter 2 METHODS Study patients. From 1985 to 2001, 15 fetuses with congenital AV block were identified between 18 and 37 weeks gestation, and serially monitored by echocardiography at the Children’s Heart Center of the Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands. Medical records of the children were reviewed for birth weight, Apgar scores, incidences of additional neonatal lupus features (lupus like rashes, hematologic abnormalities, liver disease) and morbidity. Data on obstetric history, referral indication, medications taken during pregnancy, gestational age at birth, mode of delivery, the presence of maternal SSA/Ro-SSB/La antibodies, and possible maternal connective tissue disease (CTD) were obtained. A diagnosis of primary SS was based on the preliminary criteria for the classification of SS,20 and women were classified as having SLE according to the revised criteria of the American College of Rheumatology.21 Secondary SS was defined as primary Sjögren’s syndrome with one other autoimmune disease. Echocardiographic parameters and serial monitoring. We reviewed all serial fetal echocardiographic records to assess age of diagnosis (defined as the first prenatal record of second or third degree AV block), atrial and ventricular heart rate, cardiomegaly, and cardiac contractility. Subsequently, development or resolution of pericardial effusion, pleural effusion, ascites or hydrops fetalis and congestive heart failure, presence of valve insufficiency, and cardiac hypertrophy were evaluated. Cardiomegaly was defined as a left or right ventricular diameter in the > 90th percentile, as previously described.22 Hydrops fetalis was defined as the presence of at least two of the following items: pericardial effusion, pleural effusion, ascites and skin edema. Mothers were reviewed once in 2-4 weeks, and weekly if signs of fetal hydrops or cardiac compromise were observed. Postnatal studies. Postnatal echocardiographic studies and/or electrocardiograms (ECG) confirmed second or third degree block in all patients. ECG showed normal small QRS complexes in all neonates. Chest radiographs were reviewed for cardiac enlargement, pulmonary edema and pleural effusion. Heart size was expressed as CT-ratio and a CT-ratio > 0.60 indicated cardiomegaly. Data were collected on age and indication of pacemaker implantation. Statistical analysis. Data are presented as mean ± SD or median (range). Student’s t-test or Mann-Whitney U test for paired samples were performed when applicable. A P-value of < 0.05 was considered statistically significant. 40 Congenital heart block in fetal life TABLE 1 Clinical and Demographic Characteristics of Fetuses with Congenital Heart Block Patient Maternal antianti- Steroids GA Birth Apgar Mode of disease SSA/Ro SSB/La (wks) (wks) Weight score delivery Outcome PM 1 (M) - - - - 37 3065 g 9, 10 CS alive + 2 (F) - + - - 30 1565 g 7, 8 CS alive + 3 (F) SLE + + - 24 370 g - - IUD - 4 (M) SLE + + - 29 900 g 7, 7 CS alive + 5 (F) - + + - 41 3360 g 8, 9 vag alive + 6 (M) - + + 31 40 3700 g 8, 9 CS alive + 7 (F) RA/sec SS + + 21 39 2880 g 9, 10 vag alive + 8 (M) - + + - 37 3370 g 8, 9 CS alive - 9 (M) SLE + + - 40 5000 g 9, 10 CS alive + 10 (M) - + - - 38 3040 g 7, 9 CS alive + 11 (M) SLE/sec SS + + 20 37 2500 g 8, 9 CS alive - 12 (M) + + - 41 3750 g 3, 8 vag alive + 13 (F) SLE/ sec SS + + - 40 3230 g 7, 9 CS alive - 14 (M) SLE/ sec SS + + - 37 2880 g 8, 9 CS alive + 15 (M) + + - 39 3635 g 9, 10 vag alive + SS - CS = cesarean section; F= female; GA = gestational age; IUD = intrauterine death; PM = pacemaker; RA= rheumatoid arthritis; SLE = systemic lupus erythematosus; (sec) SS = (secondary) Sjögren's syndrome; vag= vaginal delivery; wks = weeks. 41 Chapter 2 RESULTS Study patients. The clinical characteristics of 15 fetuses with second or complete AV block are outlined in Table 1. Referral to our clinic was indicated due to detection of fetal bradycardia in 7 pregnancies. Four women were referred because of known CTD and two women had CTD and had previously given birth to a child with CCAVB. Maternal CTD was present in 6/13 (46%) mothers (SLE: n=2; SLE and secondary SS: n=2; rheumatoid arthritis (RA) and secondary SS: n=1; SS: n=1). ANA were present in all mothers, SSA/Ro and SSB/La antibodies were positive in 12/13 (92%) women on immunoblot (SSA/Ro: n=2; SSA/Ro and SSB/La: n=10). The mother of patients 3 and 4 had a worsening clinical course of her SLE during pregnancy. She developed a severe serositis (pleuritis and pericarditis) necessitating admission to our hospital. Initial echocardiographic study of AV block. Initial echocardiographic characteristics are presented in Table 2. Standard echocardiography confirmed a normal cardiac anatomy in all patients. Median age of detection of CHB was 24 weeks gestation (range 18 to 37), and in 14/15 fetuses CHB was detected before 30 weeks. CHB was significantly earlier detected in the group of women with CTD compared to the asymptomatic women (mean 22.3 ± 3.4 vs 26.8 ± 4.8; p < 0.05). The median atrial rate was 143 beats per minute (bpm) (range 114 to 172) and median ventricular rate was 62 bpm (range 44 to 90) (Figure 1). Second degree AV block was initially detected in 6/15 (40%) fetuses (4/6 of women with known CTD) and CCAVB in 9/15. Two mothers with high anti-SSA/Ro-SSB/La titers, and CTD had previously given birth to a child with CCAVB. Serial fetal echocardiographic monitoring starting at 12 weeks was employed because of the relatively high recurrence risk. Fetal heart rates of 134-160 bpm were initially measured. Dysrhythmia or an alternating sinus rhythm and second degree AV block occurred in their fetuses (patients 11, and 14) at respectively 16 and 18 weeks gestation, before the onset of second degree AV block. A progression to second degree block developed within 2-3 weeks. Patient 3 presented with CCAVB and fetal hydrops, cardiomegaly and hypertrophy of the interventricular septum. One other fetus had pericardial effusion at presentation. Cardiomegaly was observed in 4/15 (27%) (2nd: n=1; CCAVB: n=3) and hypertrophy in 2 others. No valvular insufficiency was initially present. Serial echocardiographic findings throughout pregnancy. In total 113 prenatal echocardiographic reports were reviewed: median 5 per patient (range 2-23) with a median follow-up of 14 weeks (range 1-21). In 47% of the patients, ventricular heart rate decreased significantly with advancing gestation (p < 0.05) and fell below 55 bpm in 6/7 fetuses (Figure 1). During pregnancy, in these 7 fetuses, nonimmune hydrops and congestive heart failure developed, resolving in 3, 42 Age 3rd 3rd 3rd 3rd 37 25 22 18 24 22 19 26 26 21 20 29 28 24 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 162 140 148 50 9 13 12 64 70 14 90 19 17 64 90 16 11 21 18 17 16 54 62 60 72 57 48 3 6 - resolved - - - + - - resolved resolved - - initial + + hydrops Fetal resolved + - - - + - resolved - + - - - - - - - + - - - - - + - - - - + + resolved + + - Ascites resolved - + - + effusion Pleural - - - + + + effusion Pericardial Sub- - - - - - - - - + - - - - - - edema cutaneous + - initial - - - + - - - + + + + + + + - + + initial + - TV / MV - - - - - - TV - - - - - - - VI + initial Hypertrophy - initial initial initial CM 2nd = second degree atrioventricular block; 3rd = third degree / complete atrioventricular block; + = developed with advancing gestation; age of diagnosis = age of congenital heart block detection; AR = atrial rate; bpm = beats per minute; CM = cardiomegaly; initial = present at first echocardiographic evaluation; MV= mitral valve regurgitation; resolved = effusion improved or fully resolvedduring follow-up; TV= tricuspid valve insufficiency; VI = valve insufficiency. 3rd 2nd 2nd 160 145 2nd 2nd 136 114 138 140 140 172 155 60 74 150 2 (wks) (bpm) 44 Follow-up VR 133 (bpm) AR 3rd 2nd 3rd 3rd 3rd 2nd block (wks) Initial (no.) Patient diagnosis TABLE 2 Serial Echocardiographic Evaluation of Congenital Heart Block Congenital heart block in fetal life 43 Chapter 2 in one spontaneously and in two after initiation of dexamethason treatment (4 mg/day). In the majority of the fetuses (8/15), the same ventricular heart rate was maintained. In 5/6 fetuses, second-degree block progressed to CCAVB within 2-3 weeks and persisted in one throughout pregnancy, still being present at 8 months after birth. CCAVB did not reverse spontaneously in any of the patients. The occurrence of fetal effusions is shown in Table 2. Pericardial effusion (53%) was seen in 2 fetuses at presentation, developed in 7 late in pregnancy, subsequently resolving in 3, but reappeared in one. Pleural effusion and ascites developed in 3 (20%) and 4 (27%) fetuses respectively, and ascites resolved in 2 patients. In one patient, subcutaneous edema developed and persisted throughout pregnancy. Cardiomegaly was initially seen in 4 fetuses and developed in 6 later in pregnancy (67%). The cardiomegaly remained after birth in 8 infants and was demonstrated through chest radiographs and/or postnatal echocardiographic evaluation. No pulmonary edema or pleural effusion was seen on chest radiographs. Cardiac hypertrophy was initially present in one and developed in 9 more fetuses (67%). Mitral and tricuspid valve insufficiency developed in 2 fetuses, one resolving during pregnancy and one postnatally after implantation of a Ventricular Heart Rate (beats per minute) pacemaker device. 100 90 80 70 60 50 40 30 16 20 24 28 32 36 40 G e s ta tio n a l A g e (w ee k s ) Figure 1 Initial ventricular heart rate at presentation of congenital heart block and with advancing gestation. = initial second degree heart block; ● = initial complete heart block. Corticosteroid therapy for the fetal AV block. Three women received dexamethasone 4 mg/day for fetal AV block (Table 1). Therapy was continued until the end of pregnancy in 2 women; in 1 therapy was discontinued after fetal hydrops had resolved. However, hydrops reappeared in this pregnancy with advancing gestation. Dexamethasone was initiated in one fetus with second degree block, but unfortunately, the second degree block progressed to CCAVB. This child had postnatally periods of hypoglyceamia probably due to adrenal insuffiency secondary to dexamethasone treatment. 44 Congenital heart block in fetal life Fetal outcome and pacemaker implantation. Patient 3 developed a dilated cardiomyopathy in early second trimester and died of congestive heart failure within 2 weeks after CCAVB and hydrops fetalis had been detected. Patients 6 and 10 developed respectively 9 months and 4 years after birth dilated cardiomyopathy and died.23 The cumulative probability of 1-year survival was 87%. The morbidity was high (53%). Five neonates had congestive heart failure at birth; IRDS developed in 1; adrenal insufficiency in 1 neonate and 1 child developed a neonatal lupus associated rash. Pacemakers were implanted in 11 children (73%) at a median age of 2 days postnatally (range 2 days – 2.1 years). Indications included: heart failure (n=4); low heart rate (n=4); and low heart rate with ventricular extrasystoles (n=3). DISCUSSION The association of CHB and maternal SSA/Ro and SSB/La antibodies is well described and has been known for decades.1,10,11 Maternal immunoglobulins are transported to the fetal circulation as part of a normal physiologic transfer process which protects the neonate against microorganisms in the first months of life. The SS-A/Ro-SSB/La autoantibodies enter the fetal circulation between 18 and 24 weeks gestation,5 and may induce permanent damage to the atrioventricular (AV) node and transient injury to the myocardium. In this report, second- or third degree block could be detected between 18 and 30 weeks gestation in 93% of the fetuses. Fetal AV block was significantly earlier detected (20-24 weeks) in women with CTD and/or a previous child with CCAVB, compared to the asymptomatic women who were referred to our clinic for assessment of fetal bradycardia. This suggests that the gestational period of increased fetal cardiac susceptibility for CHB is between 20-24 weeks.5,10-15 Interestingly, we observed dysrhythmia and an alternating fetal heart rhythm of sinus rhythm with periods of second degree heart block in two of these high risk pregnancies, before second degree AV block was established. Additionally, second degree block was the initial observed conduction abnormality in 40% of the fetuses which progressed to CCAVB in 5 fetuses within 1-4 weeks. In summary, one might speculate that the antibody-mediated damage to the AV node is most presumably initiated even before fetal bradycardia is clinically detectable on echocardiography. Furthermore, the pathogenesis of CHB might be an ongoing inflammatory process subsequently resulting in fibrosis of the AV node and its surrounding cardiac tissue, which theoretically might be prevented or reversed by introducing fluorinated corticosteroids in early pregnancy.10,24,25 Several investigators have reported such a reversibility of second degree AV block after initiation of fluorinated corticosteroid therapy (dexamethasone or bethamethasone), whilst 45 Chapter 2 CCAVB appeared to be irreversible once established.17,24,25 However, the safety and longterm effects of repeated courses of corticosteroid therapy during fetal life may be questioned. Retarded brain growth has been observed in fetal sheep after administration of single and repeated courses of corticosteroids in addition to an increasing number of reported adverse effects of fetal steroid therapy.26-28 Although several case reports have described successful intrauterine treatments, there has been no large prospective randomized trial defining the efficacy and safety of fluorinated steroids in the (prophylactic) treatment of fetal heart block. Therefore, treatment with fluorinated steroids should be considered only in those fetuses when dysrhythmias, incomplete block or development of hydrops fetalis is observed. Prophylactic corticosteroid treatment is not advisable. Fetal outcome depends largely on heart rate: a low heart rate (< 55 bpm) is associated with poor outcome and subsequent hydrops fetalis.14,18,19 Our findings are comparable with the previously reported series.15 In our study, the majority of the fetuses (53%) maintained the same ventricular rate, but when the ventricular heart rate decreased significantly with advancing gestation, fetal hydrops and congestive heart failure developed. This might suggest a relation between heart rate and deterioration of cardiac function, which could not be confirmed however, due to the small study group and the retrospective character of this study. Serial echocardiographic monitoring of fetal CHB revealed a high incidence of pleuropericardial effusions, ascites and hydrops. Although the effussions showed a tendency towards resolving, some effusions reappeared with advancing gestation. This suggests that the development, resolution and reapperance of effusions might represent a general finding in the natural history of fetal CHB.17 Fetal hydrops improved significantly in one fetus after dexamethasone treatment, allowing successful elective cesarean section, and hydrops fetalis resolved completely in another fetus. Cardiomegaly, secondary to ventricular dilation, is a common feature in children with CCAVB, both pre- and postnatally.23,29,30 Cardiomegaly developed in 67% of our cases during pregnancy and was present at birth in 53%. A new finding in this study is the occurrence of cardiac hypertrophy in fetal CCAVB. Hypertrophy of the left and right ventricles or interventricular septum developed in 67% of the fetuses, usually in addition to cardiomegaly. Cardiac hypertrophy might therefore present another compensatory mechanism to the increased load in CHB. It is presently not known, whether the associated hypertrophy is fully beneficial initially, or during follow-up. In conclusion, during the last two decades, a growing awareness and knowledge of autoimmune associated CCAVB in rheumatology, obstetric and pediatric practices, combined with the technical evolution of ultrasound, has increasingly resulted in a shift from postnatal to in utero detection of CHB. In our review of 15 fetal cases of CHB, serial echocardiographic 46 Congenital heart block in fetal life monitoring was a feasible and non-invasive method for assessment, monitoring and therapeutic management of fetal CHB. Moreover, with the use of fetal echocardiography, an elective cesarean section could be performed when hydrops fetalis and subsequent congestive heart failure developed or in those pregnancies at high risk for adverse fetal outcome. The fetus with CCAVB is able to maintain a sufficient cardiac output in the presence of sustained bradycardia by increasing its ventricular size and subsequent development of cardiac hypertrophy. Although a relation between heart rate and deterioration of cardiac function is postulated, this could not be proved due to small patient numbers. Pericardiopleural effusions are frequently encountered, resolving and reappearing even without therapy. It is not known if the development of hydrops and heart failure is secondary to low cardiac output or if the generalized tissue inflammation contributes to the effusions. In fetuses monitored early on, progression of AV block occurred during a time-window between 20 and 24 weeks of gestation. This suggests that any therapy directed towards prevention of progressive conduction disturbance should be instituted during or before this time-frame. Prospective studies in high risk pregnancies are needed to study cardiovascular hemodynamics and the development of fetal hydrops and congestive heart failure. 47 Chapter 2 REFERENCES 1. McCue CM, Mantakas ME, Tingelstad JB, Ruddy S. Congenital heart block in newborns of mothers with connective tissue disease. Circulation 1977;56:82-90. 2. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Int Med 1994;120:544-51. 3. Chameides L, Truex RC, Vetter V, Rashkind WJ, Galioto FM, Noonan JA. Association of maternal systemic lupus erythematosus with congenital complete heart block. N Eng J Med 1977;297:1204-7. 4. Scott JS, Maddison PJ, Taylor PV, Esscher E, Scott O, Skinner RP. Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. N Engl J Med 1983;309:209-12. 5. Buyon JP, Waltuck J, Kleinman C, Copel J. In utero identification and therapy of congenital heart block. Lupus 1995;4:116-21. 6. Litsey SE, Noonan JA, O’Connor WN, Cottrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block: demonstration of immunoglobulin in cardiac tissue. N Engl J Med 1985;312:98-100. 7. Taylor PV, Scott JS, Gerlis LM, Path FRC, Esscher E, Scott O. Maternal antibodies against fetal cardiac antigens in congenital complete heart block. N Engl Med J 1986;315:667-72. 8. Buyon JP, Swersky SH, Fox HE, Bierman FZ, Winchester RJ. Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus. Arthritis Rheum 1987;30:44-9. 9. Brucato A, Frassi M, Franceschini F, et al. Risk of congenital heart block in newborns of mothers with antiRo/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 2001;44:1832-5. 10. Buyon JP, Hiebert R, Copel JA, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31:1658-66. 11. Jaeggi E, Hamilton RM, Silverman ED, Zamora SA, Hornberger LK. Outcome of children with fetal, neonatal or childhood diagnosis of isolated complete heart block (CHB): a single institution’s experience of 30 years. J Am Col Cardiol 2002;39:130-7. 12. Eronen M, Siren MK, Ekblad H, Tikanoja T, Julkunen H, Paavilianen T. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86-91. 13. Buyon JP. Autoimmune-associated congenital heart block: Bringing bedside challenges to the bench. In Kammer GM, Tsokos GC, ed. Lupus: Molecular and cellular pathogenesis. NJ, Humana Press, 1999:492513. 14. Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991;91:1360-6. 15. Groves AMM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75:190-4. 16. Julkunen H, Kaaja R, Wallgren E, Teramo K. Isolated congenital heart block: fetal outcome and familial incidence of heart block. Obstet Gynecol 1993;82:11-6. 17. Saleeb S, Copel J, Friedman D, Buyon JP. Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block. Arthritis Rheum 1999;42:2335-45. 18. Vielle JC, Covitz W. Fetal cardiovascular hemodynamics in the presence of complete atrioventricular block. Am J Obstet Gynecol 1994;170:1258-62. 19. Eronen M, Heikkilä P, Teramo K. Congenital complete heart block in the fetus: hemodynamic features, antenatal treatment, and outcome in six cases. Pediatr Cardiol 2001;22:385-92. 20. Vitali C, Bombardieri S, Moutsopoulos H, et al. Preliminary criteria for the classification of Sjögren’s syndrome: results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993;36:340-7. 48 Congenital heart block in fetal life 21. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. 22. Allan LD, Joseph MD, Boyd EGCA, Campbell S, Tynan MJ. M mode echocardiography in the developing human fetus. Br Heart J 1982;47:573-84. 23. Udink ten Cate FEA, Breur JMPJ, Cohen MI, et al. Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children. J Am Coll Cardiol 2001;37:1129-34. 24. Theander EBA, Gudmundsson S, Salomonsson S, Wahren-Herlenius M, Manthorpe R. Primary Sjögen’s syndrome: treatment of fetal incomplete atrioventricular block with dexamethasone. J Rheumatol 2001;28:373-6. 25. Rosenthal D, Druzin M, Chin C, Dubin A. A new therapeutic approach to the fetus with congenital complete heart block: preemptive, targeted therapy with dexamethasone. Obstet Gynecol 1998;92:689-91. 26. Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213-8. 27. Gramsbergen A, Mulder EJH. The influence of betamethasone and dexamethasone on motor development in young rats. Pediatr Res 1998;144:105-10. 28. Bakker JM, Kavelaars A, Kamphuis PJGH, et al. Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune disease in adult rats. J Immunol 2000;165:5932-7. 29. Paladini D, Chita SK, Allan LD. Prenatal measurement of cardiothoracic ratio in evaluation of heart disease. Arch Dis Child 1990;65:20-3. 30. Sholler GF, Walsh EP. Congenital complete heart block in patients without anatomic cardiac defects. Am Heart Journal 1989;118:1193-8. 49 Chapter 2 50 C H A P T E R Neonatal Lupus Erythematosus in Three Successive Pregnancies Udink ten Cate FEA, Van Woerkom JM, Kruize AA, Sreeram N, Roord JJ, Derksen RHWM . Submitted Chapter 3 ABSTRACT Neonatal lupus erythematosus (NLE) is a passively acquired autoimmune-mediated disorder associated with the transplacental passage of maternal anti-SSA/Ro and antiSSB/La autoantibodies. The major clinical manifestations are isolated congenital heart block and transient cutaneous lesions. Other symptoms include hematologic and hepatic abnormalities. We report a 29-year old woman with systemic lupus erythematosus (SLE) and secondary Sjögren’s syndrome (SS) who gave birth in three successive pregnancies to three children with cardiac, cutaneous and hematologic manifestations of neonatal lupus erythematosus (NLE). She was anti-SSA/Ro and anti-SSB/La antibody positive and had recurrent flares of disease activity during pregnancy. It is unusual to see different manifestations of NLE in one child, and it is rare to find different features of NLE in siblings of three successive pregnancies. Irrespective of the NLE manifestations in a previous affected child, asymptomatic and symptomatic women with known anti-SSA/Ro and/or anti-SSB/La antibodies should be closely monitored during successive pregnancies for fetal bradycardia. 52 Neonatal lupus erythematosus NEONATAL LUPUS ERYTHEMATOSUS INTRODUCTION Congenital complete atrioventricular block (CCAVB) is an uncommon immune-mediated disease that is associated with transplacental transfer of maternal-autoantibodies against antigens of the SSA/Ro and SSB/La ribonucleoprotein complex. Like other IgG molecules, anti-SSA/Ro and anti-SSB/La antibodies are actively transferred across the placenta between 16 – 24 weeks of gestation and may damage the developing heart, resulting in clinical detectable fetal bradycardia.3-5 CCAVB constitutes the most serious and permanent manifestation of neonatal lupus erythematosus (NLE).1,2 Other manifestations in the newborn that are associated with maternal anti-SS-A/Ro and SS-B/La antibodies include cutaneous lesions, hematologic and liver abnormalities.6-8 Although most mothers of children with NLE are asymptomatic, some have symptoms and signs of systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) or undifferentiated autoimmune disease.2 A recent study of 144 mothers showed that the distribution of disease was 17% SLE, 24% SS, 7% SLE/SS, 20% undifferentiated autoimmune syndrome, and 33% were asymptomatic at the time of birth of a child with CCAVB.9 Cardiac or cutaneous manifestations are present in approximately 70% of children with NLE. Only a small percentage of these affected children express more than one manifestation of NLE.9 Approximately 10% of newborns have both lupus dermatitis and CCAVB. The most serious manifestation of NLE, CCAVB, develops in only 1 – 5% of children whose mothers have anti-SSA/Ro and/or anti-SSB/La antibodies. The estimated recurrence risk of women who had a previous child with CCAVB is approximately 16 – 20%. Therefore, it is rare to find different and multiple manifestations of NLE in siblings. We report a woman with SLE and secondary SS in whom three successive pregnancies resulted in offspring with multiple manifestations of NLE. 53 Chapter 3 CASE REPORTS A Caucasian woman, born in 1972 developed recurrent erythematous facial rashes after sunexposure when she was eighteen years old. In 1991, this was accompanied by erythematous lesions at the finger tips and toes, malaise, polyarthralgia and intermittent subfebrile temperature. Abnormal laboratory tests included anaemia caused by heterozygous β-thalassaemia minor, hypergammaglobulinaemia, antinuclear antibodies (ANA 1:4000) and anti-SS-A/Ro and anti-SS-B/La antibodies (immunoblot showed SS-A/Ro 52 kD and 60 kD, and SS-B/La 45 kD). Anti-dsDNA and anti-U1RNP antibodies were absent. Treatment with hydroxychloroquin was started in November 1991 when there was persistent arthralgia, retrosternal pain and increased diffuse loss of hair. Hydroxychloroquin treatment was stopped four months later when she was pregnant. During pregnancy, skin rashes (CDLE type in the face and chilblain type on hands and feet) were treated locally. Fetal echocardiography at 28 weeks’ gestation was abnormal with initially intermittent episodes of bradycardia and arrhythmia, that persisted later on with fetal heart rates between 60-70 beats per minute. Because the mother experienced a decrease in fetal activity, together with the finding of oligohydramnion and persistent fetal bradycardia, cesarean section was performed at 39 6/7 weeks gestation. A daughter of 3230 grams was born with Apgar scores of 9 and 10 at 1 and 5 minutes respectively and a heart rate of 60 bpm. Echocardiography confirmed a normal structural heart and a second-degree Wenckebach block was noted on electrocardiography (EKG). There were no signs of cutaneous neonatal lupus disease. She is doing well and is symptom free at age 11 years, without pacemaker implantation. In October 1993 the mother had intermittent parotid swelling in absence of sicca complaints and normal production of tears (Schirmer test). A sublabial salivary biopsy showed periductal foci with mononuclear cells characteristic for Sjögren’s syndrome. In 1995 she was pregnant again. At a gestational age of 8 weeks she had an extensive papular rash that was compatible with subacute cutaneous lupus shortly after receiving penicillin for an urinary tract infection. Low-dose prednisone was given. Three months later a vasculitic type skin rash was noted with polyarthralgia and high-grade fever. The daily dose of prednisone was increased to 1 mg/kg. Serial fetal echocardiographic studies did not reveal any cardiac conducting abnormalities during pregnancy. After spontaneous rupture of the membranes, an elective cesarean section was performed at 36 1/7 weeks gestation. A healthy male infant was born, weighing 3310 g. An EKG showed no evidence of heart block. Seven days after birth, an erythematous annular rash was noted on the head, trunk and extremities. Laboratory tests showed an absolute neutrophil count of 600 – 800 / mm3 during the first months of life. Platelet count was 133,000 / mm3 at 2 days postnatally, further decreased to 113,000 / mm3 and returned to normal at 3 months of age. The skin rashes disappeared at 6 months of age. Infectious and bone marrow diseases, which may cause continued mild 54 Neonatal lupus erythematosus neutropenia were excluded. It was concluded that the neutropenia was secondary to the maternal autoantibodies. The child received antibiotics in an prophylactic dosage and the neutropenia resolved at 6 months of age. The maternal course of disease over the years was characterized by a variety of skin rashes (photosensitive rashes, malar rashes, chilblain lupus and subacute cutaneous lupus SCLE type lesions). In 1999 she became pregnant again and fetal serial echocardiographic monitoring was initiated. At 26 weeks of gestation, persistent fetal bradycardia was found on a routine echocardiographic study, which were performed every 3 – 4 weeks of pregnancy. Pericardial and pleural effusion developed during the third trimester of pregnancy and the fetal heart rate decreased to rates under 50 beats per minute. Cesarean section was performed at 36 1/7 weeks, because of fetal distress and the cardiac decompensation. A boy was born weighing 2880 g and received a single chamber ventricular (VVIR) pacemaker at the second day of life. Then, an annular erythematous lupus rash was noted on the trunk and face. Laboratory testing performed at the second day of life showed normal white blood count and platelet count of 146,000 / mm3, which normalized at 2 months of age. No petechial or purpuric eruption was seen. The neonate was positive for anti-SSA/Ro and antiSS-B/La antibodies and the rash resolved at 7 months of life concommitant with the dissapearance of the maternal autoantibodies from the child’s circulation. No maternal antibodies could be measured in his blood. DISCUSSION Neonatal lupus erythematosus was first observed in 1954 in offspring of mothers with SLE.10 A lupus dermatitis was seen in an infant which resembles the clinical picture of skin lesions seen in patients with SLE. Since an association between maternal SSA/Ro – SSB/La antibodies and the development of CCAVB in their children was recognized,2,3 evidence has emerged suggesting that these autoantibodies may also be involved in the pathogenesis of several other lesions, including cutaneous, hematologic and hepatic abnormalities.7,8,11 Presently, these signs and symptoms are grouped under the heading of the neonatal lupus syndrome. The most serious manifestation of NLE is second- or third-degree atrioventricular block, occurring in 50 – 60% of newborns with NLE. Clinical and experimental evidence suggest that these maternal autoantibodies enter the fetal circulation between 18 and 24 weeks gestation, as part of the physiological transplacental passage of maternal IgG, and induce antibody-mediated damage to an otherwise structurally normal fetal heart.1-5 The characteristic histopathological findings in the hearts of children with CCAVB is fibrosis and calcification of the AV node. Furthermore, immunohistopathological studies demonstrated maternal IgG deposition, complement components and diffuse mononuclear cell 55 Chapter 3 infiltrates,5,12,13 supporting autoimmune-mediated inflammation as an important component in the etiology of CCAVB. Not all women with SSA/Ro and SSB/La antibodies give birth to children with NLE. The risk is 1-5% for an index pregnancy and recurrence occurs in 16% of successive pregnancies.2,14 Moreover, discordancy in monozygotic twins for CCAVB has been reported, suggesting that additional fetal or environmental factors are necessary in the pathogenesis of NLE.15 Two of the three siblings in this report developed heart block in utero. One child presented with second-degree heart block, and the other presented with CCAVB requiring pacing in the first days of life. Approximately 60% of the children surviving the fetal period eventually require pacemaker implantation and the cumulative probability of 3-year survival has been estimated to be 79%.14 It has been shown in clinical studies that seconddegree heart block can progress to irreversible CCAVB in utero or postnatally,16 suggesting that CCAVB results from an ongoing inflammatory response. This observation combined with the proposed antibody-mediated inflammation in these children, and the high mortality and morbidity rates reported in fetal heart block,17 has stimulated the search for useful intrauterine therapeutic regimens to prevent or reverse the cardiac inflammatory response.18,19 Furthermore, attempts have been made to increase the fetal heart rate using sympathicomimetics and fetal pacemaker therapy.20,21 However, none of these therapies have significantly changed the outcome of fetal heart block. Although the classic cardiac manifestation of NLE is CCAVB, recent studies report a wide range of conduction abnormalities associated with maternal anti-SSA/Ro - anti-SSB/La antibodies, including sinus bradycardia, first-degree heart block and QT interval prolongation.16,22,23 An EKG taken at birth of child B did not reveal any conducting abnormalities. Other cardiac disorders include endocardial fibroelastosis and dilated cardiomyopathy.24 Unlike the irreversible cardiac manifestations, other organ involvement in NLS tends to be less severe and disappear with the clearence of maternal antibodies from the infant’s blood at 6 – 8 months of life. The second most common manifestation of NLE is lupus dermatitis, which was present in child B and C, at the seventh day of life and at birth respectively. This is in accordance to other reported cases in which two thirds of the skin lesions were present at birth or appeared within the first weeks of life, sometimes after exposure to sunlight.6,9,11 Experimental studies have shown that ultraviolet light induces translocation of intracellular SSA/Ro antigens to the cell membrane of keratinocytes where they can interact with circulating maternal anti-SSA/Ro – anti-SSB/La antibodies.25 Histologic examination of NLE dermatitis biopsies showed resembling features with subacute lupus erythematosus.6 In addition, immunofluorescent studies demonstrated granular deposition of IgG, IgM and C3 at the dermo-epidermal junction in these specimens.26 Although protection against sun exposure is advisable in children of antibody-positive mothers, ultraviolet light is not invariable required for most NLE rashes to occur. The cutaneous lesions are typically 56 Neonatal lupus erythematosus erythematous annular, as in our children, or polycyclic plaques, often involving the face, neck, trunk and scalp of the neonate. Usually, no treatment is necessary and the rashes heal without scarring. The annular erythematous rash on the trunk, face and extremities of both children disappeared at 8 months of age without residual pigmentation or teleangiectasia. Although most mothers of infants with lupus dermatitis have antibodies against SSA/Ro and SSB/La antigens, less commonly antibodies only directed to U1-RNP can be found.27 The woman in this case report developed skin rashes during pregnancy. Neiman and collegues,28 showed that active maternal cutaneous disease during pregnancy did not correlate with dermatological manifestations of NLE in their children. The most common hematological abnormality in NLE is thrombocytopenia, although neutropenia, hemolytic anemia and hemochromatosis have also been reported.6,8,9 In one report, 10% of the infants with NLE had thrombocytopenia, generally associated with other features of the disease.29 Petechial or purpuric lesions was the initial feature seen in these infants. Although the platelet count was only mildly decreased in child B and C, it was probably part of NLE in these children. The platelet count increased with decreasing maternal antibody levels. In addition, a neutropenia requiring antibiotic prophylactic therapy was demonstrated in child B, which resolved after the clearence of maternal antibodies. Kanagasegar and collegues,8 demonstrated the direct interaction of anti-60 kDa SSA/Ro antibodies with neutrophils, suggesting that these antibodies may be directly involved in the pathogenesis of neutropenia. Furthermore, because most newborns without cardiac or cutaneous manifestations of NLE do not undergo complete blood count, they suggested that the incidence of (isolated) NLE neutropenia may be much higher than previously recognized. Recently, a study showed that hepatobiliary disease is a relatively common clinical finding in NLE.7 Its clinical spectrum ranges from mild elevated aminotransferases and conjugated hyperbilirubinemia to cholestasis and severe liver failure. No signs or symptoms of liver disease was present in our children. Theoretically, any combination of NLE manifestations is possible in a given neonate, however, most children have CHB or skin lesions alone. Approximately 10% of cases have both cardiac conduction disease and cutaneous lesions.6,9 In addition, given the risk of 1-2% for an antibody-positive mothers to give birth to an affected child and the recurrence risk of 16%,2,16 it is even more intruiging to see cardiac, cutaneous and hematologic manifestations of NLE in siblings of three successive pregnancies and multiple manifestations in child B and C. Moreover, laboratory testing was not performed in child A, therefore we do not know if neutropenia, thrombocytopenia or liver disease was present. There are two other reports describing NLE in four siblings and in triplets of mothers with connective tissue disease.30,31 All successive siblings developed cutaneous lesions, three after phototherapy for neonatal hyperbilirubinaemia, and one infant had both lupus-dermatitis and second-degree heart 57 Chapter 3 block. Hematological abnormalities and skin rashes were present in triplets and one infant also had increased transaminases. It has been postulated that transplacental passage of anti-platelet antibodies could have been responsible, at least partially, for the decrease in platelet count and thrombocytopenia,30 although hematological manifestations may more closely parallel maternal disease.9 Most mothers who give birth to an affected child are initially asymptomatic and approximately 30 – 50% of these women subsequently develop autoimmune disease.2,6,32 Two recent studies suggest that mothers who have children with cutaneous lesions alone were more likely to have rheumatic disease than mothers who gave birth to children with CHB.28,33 Moreover, a significantly greater number of mothers of children with cutaneous NLE developed rheumatic disease compared to mothers of children with CHB. These clinical findings may reflect differences in maternal autoantibody response, which could account for the development of lupus dermatitis in some infants and CCAVB in other children. In addition, it has previously been shown that high levels of anti-52-kD SSA/Ro and anti-48SSB/La antibodies confine the highest risk for the development of CCAVB in offspring. Only few studies have analyzed the antibody response in mothers of children with CCAVB and mothers of children with cutaneous manifestations of NLE. Silverman and collegues34 showed that anti-48 kD SSB/La antibody titer was significantly elevated in sera of mothers of children with dermatological NLE compared to sera of mothers of children with CHB, which suggests differences in the fine specificity of autoantibodies in mothers of children with different manifestations of NLE. However, large studies analyzing maternal antibody profiles during successive pregnancies with crossover of NLE manifestations in their offspring have not yet been performed. Taken together, it is tempting to suggest that a specific antibody response in our mother could account for the disease expression in all three siblings. On the other hand a mother can give birth to three affected children, although the estimated risk is 15% for the index pregnancy and 16% for each successive pregnancy. There are still many issues to be addressed with regard to the pathogenesis of NLE. In conclusion, we report a woman with SLE and secondary SS who gave birth to three siblings with several manifestations of NLE. Although crossover of NLE manifestations have been reported in siblings, the occurrence of cardiac, lupus dermatitis and hematologic abnormalities in offspring of three successive pregnancies is rare. Irrespective of the NLE manifestations in a previous affected child, asymptomatic and symptomatic women should be monitored during successive pregnancies for fetal bradycardia. 58 Neonatal lupus erythematosus REFERENCES 1. McCue CM, Mantakas ME, Tingelstad JB, Ruddy S. Congenital heart block in newborns of mothers with connective tissue disease. Circulation 1977;56:82-90. 2. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Int Med 1994;120:544-51. 3. Scott JS, Maddison PJ, Taylor PV, Esscher E, Scott O, Skinner RP. Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. N Engl J Med 1983;309:209-12. 4. Buyon JP, Waltuck J, Kleinman C, Copel J. In utero identification and therapy of congenital heart block. Lupus 1995;4:116-21. 5. Litsey SE, Noonan JA, O’Connor WN, Cottrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block: demonstration of immunoglobulin in cardiac tissue. N Engl J Med 1985;312:98-100. 6. Lee LA. Neonatal lupus erythematosus. J Invest Dermatol 1993;100:9S-13S. 7. Lee LA, Sokol RJ, Buyon JP. Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics 2002;109:e11. 8. Kanagasegar S, Cimaz R, Kurien BT, Brucato A, Scofield RH. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. J Rheumatol 2002;29:187-91. 9. Tseng CE, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin North Am 1997;23:31-54. 10. McCuistion CH, Schoch EP. Possible discoid lupus erythematosus in a newborn infant: report of a case with subsequent development of acute systemic lupus erythematosus in the mother. Arch Dermatol 1954;70:7825. 11. Lee LA, Norris DA, Weston WL. Neonatal lupus and the pathogenesis of cutaneous lupus. Pediatr Dermatol 1986;3:491-7. 12. Ho YS, Esscher E, Anderson RH, Michaelsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol 1986;58:291-294. 13. Meckler KA, Kapur RP. Congenital heart block and associated cardiac pathology in neonatal lupus syndrome. Pediatr Dev Pathol 1998;1:136-42. 14. Buyon JP, Hiebert R, Copel JA, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31:1658-66. 15. Cooley HM, Keech CL, Melny BJ, Menahem S, Morahan G, Kay TWH. Monozygotic twins discordant for congenital complete heart block. Arthritis Rheum 1997;40:381-4. 16. Askanase AD, Friedman DM, Copel J, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies. Lupus 2002;11:145-51. 17. Groves AMM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75:190-4. 18. Copel J, Buyon JP, Kleinman C. Succesful in utero therapy of fetal heart block. Am J Obstet Gynecol 1995;173:1384-90. 19. Leij van der JN, Visser GHA, Bink-Boelkens MTHE, Meilof JF, Kallenberg CGM. Successful outcome of pregnancy after treatment of maternal anti-Ro (SSA) antibodies with immunosuppressive therapy and plasmapheresis. Prenatal diagnosis 1994;14:1003-7. 20. Groves AMM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995;92:3394-6. 21. Carpenter RJ Jr, Strasburger JF, Garson A Jr, Smith RT, Deter RL, Engelhardt HT Jr. Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Coll Cardiol 1986;8:1434-6. 59 Chapter 3 22. Brucato A, Frassi M, Franceschini F, et al. Risk of congenital heart block in newborns of mothers with antiRo/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 2001;44:1832-5. 23. Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43:1049-53. 24. 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. 25. Lee LA, Weston WL, Krueger GG,et al. An animal model of antibody binding in cutaneous lupus. Arthritis Rheum 1986;29:782-8. 26. Lee LA, Gaither KK, Coulter SN, Norris DA, Harley JB. Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice. J Clin Invest 1989;83:1556-62. 27. Solomon BA, Laude TA, Shalita AR. Neonatal lupus erythematosus: discordant disease expression of U1RNP-positive antibodies in fraternal twins – is this a subset of neonatal lupus or a new distinct syndrome? J Am Acad Dermatol 1995;32:858-62. 28. Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr 2000;137:674-80. 29. Watson RM, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988;124:560-3. 30. Gawkrodger DJ, Beveridge GW. Neonatal lupus erythematosus in four successive siblings born to a mother with discoid lupus erythematosus. Br J Dermatol 1984;111:683-7. 31. Yazici Y, Onel K, Sammaritano L. Neonatal lupus erythematosus in triplets. J Rheumatol 2000;27:807-9. 32. Julkunen H, Eronen M. Long-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum 2001;44:647-52. 33. Lawrence S, Luy L, Laxer R, Krafchik B, Silverman E. The health of children with cutaneous neonatal lupus erythematosus differs from that of mothers of children with congenital heart block. Am J Med 2000;108:705-9. 34. Silverman ED, Buyon JP, Laxer RM, et al. Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus. Clin Exp Immunol 1995;100:499-505. 60 C H A P T E R Dilated Cardiomyopathy in Isolated Congenital Complete Atrioventricular Block: EARLY AND LONG-TERM RISK IN CHILDREN Udink ten Cate FEA, Breur JMPJ, Cohen MI, Boramanand N, Kapusta L, Crosson JE, Brenner JI, Lubbers LJ, Friedman AH, Vetter VL, Meijboom EJ. J Am Coll Cardiol 2001;37:1129-34. Chapter 4 ABSTRACT Objectives. We sought to identify the risk factors predicting the development of dilated cardiomyopathy (DCM) in patients with isolated congenital atrioventricular block (CCAVB). Background. Recently evidence has emerged that a subset of patients with CCAVB develop DCM. Methods. This was a retrospective study of 149 CCAVB patients who had heart size and left ventricular function assessed by echocardiography and chest radiographs over a followup period of 10 ± 7 years. Results. Nine patients developed DCM at the age of 6.5 ± 5.0 years. No definite cause could be identified. In these 9, CCAVB was diagnosed in eight at 23 ± 2.3 weeks gestation and in one at birth. Maternal anti-SSA/Ro and anti-SSB/La antibodies were confirmed in seven of the nine patients. Pacemakers were implanted in eight patients in the first month and in one patient at five years of age. The initial left ventricular end-diastolic dimension (LVEDD) was in the 96th ± 2.6 percentile and the cardiothoracic (CT) ratio was 64 ± 3.8% in the nine patients who developed DCM, and differed significantly in patients with CCAVB (p<0.005) who did not develop DCM. The LVEDD and CT ratio did not decrease in the patients with CCAVB and DCM, but decreased significantly in the patients CCAVB without DCM (p<0.001) once pacing was initiated. Two patients with DCM died within 2 months of diagnosis; one patient is neurologically compromised; two patients received a heart transplant; and four patients are listed for heart transplantation. Conclusions. Isolated CCAVB is associated with a long-term risk for the development of DCM. Risk factors may be anti-SSA/Ro and anti-SSB/La antibodies, increased heart size at initial evaluation, and the absence of pacemaker-associated improvement. 62 Dilated Cardiomyopathy DILATED CARDIOMYOPATHY INTRODUCTION The prognosis for children with congenital complete atrioventricular block (CCAVB) has been considered relatively benign, with a normal life-expectancy, although the majority of patients eventually require pacemaker implantation.1 However, evidence has recently emerged that a subset of these patients develop dilated cardiomyopathy (DCM) despite early pacemaker implantation.2 Most reported patients were diagnosed in utero to have CCAVB associated with maternal auto-antibodies directed to SSA/Ro and SSB/La 3 ribonucleoproteins. The SSA/Ro and SSB/La antibody-induced injury to the fetal conducting system of the heart can cause isolated CCAVB. This manifestation is well described,4 but associated DCM is less well-studied.2 The purposes of this retrospective study were to investigate the prognostic signs in isolated CCAVB and to identify risk factors that may predict the development of DCM in a subgroup of these patients. We studied all children diagnosed with isolated CCAVB in the participating medical centers since 1972, focusing on patients who received a pacemaker and patients who subsequently developed DCM in the follow-up period. METHODS Study group. The study group comprised all children with CCAVB in the absence of associated structural heart disease, diagnosed since 1972 at the Pediatric Heart Center of the Wilhelmina Children’s Hospital/University Medical Center, Utrecht; University Medical Center St. Radboud, Nijmegen; Amsterdam Medical Center, Amsterdam, the Netherlands; the Johns Hopkins Hospital, Baltimore; Yale New Haven Hospital, New Haven; and Children’s Hospital of Philadelphia, Philadelphia. Echocardiograms during pregnancy and/or additional ECG recordings during infancy confirmed complete and permanent atrioventricular (AV) block. A total of 149 patients with isolated CCAVB were studied after echocardiographic confirmation of normal cardiac anatomy. Pacemakers were implanted in 111 patients during follow-up. To evaluate the effect of pacing in patients with CCAVB, the 38 patients with CCAVB who did not undergo pacing were excluded from the analysis. However, none of these 38 patients developed a dilated cardiomyopathy over 7.0 ± 6.0 years. Study patients were assigned to two groups according to whether they subsequently developed DCM (CCAVB/DCM group) or not (CCAVB group). The CCAVB/DCM group included nine patients who developed DCM after the diagnosis of isolated CCAVB was made. No patient was diagnosed with DCM at the time the CCAVB was first diagnosed. The 63 Chapter 4 CCAVB group consisted of the remaining 102 patients with isolated CCAVB and a pacemaker, but without signs or symptoms of cardiomyopathy. Clinical data and definitions. Available demographic data of the study cohort including, gender, age at diagnosis of AV block, heart rate at initial cardiac evaluation, and the presence or absence of maternal auto-antibodies to 48-kD SSB/La, 52-kD SSA/Ro and 60kD SSA/Ro ribonucleoproteins were retrospectively reviewed. Information regarding the presence of fetal hydrops, mode of delivery, birth weight, gestational age at birth, heart rate and condition at birth was also assessed. Heart rate and age at pacemaker implantation were documented. Abstracted data included pacemaker mode, pacemaker complications, and pacemaker re-implantations. All available echocardiograms performed in utero and during the neonatal period, infancy, childhood and adolescence were reviewed. Left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were measured, and p-values (percentile of heart size corrected for weight) were estimated for every LVEDD,5 before and after the cardiomyopathy was diagnosed. Shortening fraction (SF) was calculated as (LVEDD – LVESD) / LVEDD x 100%.6 Chest radiographs were reviewed for cardiac enlargement, pulmonary venous congestion, pulmonary edema, atelectasis and/or pleural effusions. Heart size was expressed as cardiothoracic (CT) ratio and graded for each individual patient. A CT ratio > 0.60 indicated cardiomegaly in infants ≤ 1 month of age. In children > 1 month, a CT ratio > 0.50 indicated cardiomegaly, and was categorized as mild (CT ratio 0.50 to 0.60), moderate (CT ratio of 0.60 to 0.65) or severe (CT ratio 0.65).7 Dilated cardiomyopathy was defined as LVEDD > 97th percentile with SF < 25%.8 Other identifiable causes of ventricular dysfunction (i.e., myocarditis) were not encountered. Analysis of data. Comparisons between the CCAVB/DCM group and the CCAVB group were performed by using the unpaired two-sample t test or Mann-Whitney analysis for the continuous data, and chi-square analysis or Fisher’s exact test for binary variables. Data are presented as the mean value ± SD. The follow-up data on heart size and function (LVEDD, SF and CT ratio) were analyzed with linear regression. A p value <0.05 was considered statistically significant. RESULTS Clinical characteristics of study cohort. There were significant demographic differences between the patients with isolated CCAVB (n = 102) and those with CCAVB who subsequently developed DCM (n = 9) (Table 1). The age at diagnosis of CCAVB differed significantly between the groups (CCAVB: 24 ± 45 months; CCAVB/DCM: 23 ± 1 weeks gestational age, p < 0.001). The average heart rate measured at birth was significantly lower in the patients with CCAVB and DCM. The mean length of follow-up was similar between the 64 Dilated Cardiomyopathy two groups (CCAVB: 10.1 ± 6.0 years; CCAVB/DCM: 10.0 ± 6.1 years, p > 0.10). The antiSSA/Ro and anti-SSB/La antibodies were identified in 40 (77%) of 52 patients with CCAVB who did not develop DCM. Laboratory studies were not performed in the remaining 50 patients with CCAVB. TABLE 1 Study Characteristics of 111 CCAVB Patients Cardiomyopathy Control P Value Patients Patients (Group A; n= 9) (Group B; n= 102) (m/f) 7/2 45/57 NS (months) –3 ± 1 24 ± 44 < 0.001 prenatal 8 (89%) 27 (26%) < 0.001 at birth 1 (11%) 25 (25%) 0 50 (49%) Sex Age of diagnosis postnatal HR at birth (beats/min) 43 ± 6 62 ± 14 < 0.001 Follow-up (months) 123 ± 73 121 ± 74 NS 1 (11%) 3 (3%) - 8 53 normal 3 (37%) 22 (42%) - SC 5 (63%) 31 (58%) - (n) 8 53 (weeks) 37 ± 3 37 ± 3 NS 2 (22%) 1 (1%) NS Hydrops Mode of delivery Gestational age Mortality (n) Data presented are mean values ± SD or number (%) of patients. HR = heart rate; NS = no significant difference; SC= sectio cesarean. Dilated cardiomyopathy was diagnosed in nine patients (8%) at 6.5 ± 5.0 years (median: 5.7 years [range 0.4 to 16]) (Fig. 1, Table 2). Five of the nine patients with DCM were delivered by cesarean section. Hydrops was observed in one patient. Maternal laboratory studies confirmed anti-SSA/Ro and anti-SSB/La antibodies in seven (78%) of these nine patients. In one patient, no antibodies were identified, and in the one remaining patient, no tests were performed. No other features of the neonatal lupus syndrome were noted. Signs and symptoms at the time of diagnosis of DCM included congestive heart failure (n = 8), increasing fatigue with exertion (n = 5), chest pain (n = 2), dyspnea (n = 4), and/or poor feeding (n = 2). Physical examination findings revealed hepatomegaly (n = 3), hyperactive precordium (n = 3), crepitations (n = 2) and/or poor perfusion of lower extremities (n = 2). No patient with DCM had a history suggestive of familial cardiomyopathy. Outcomes. All patients with DCM had serial echocardiograms and chest radiographs for 25 months of follow-up (range 2 – 144) after the initial diagnosis. Cardiac catheterization was 65 Chapter 4 performed in four of these nine patients at the time of diagnosis. The mean cardiac index was 2.5 liters/min per m2 (range 2.3 to 2.7). The pulmonary artery systolic pressure was 27 mm Hg (range 21 to 32), and the LV end-diastolic pressure was 15 mm Hg (range 12 to 18). Six of these nine patients did well initially on medical treatment, but the SF diminished with duration of follow-up (Fig. 2). The LVEDD measurements were ≥ 97th percentile during follow-up of the patients with DCM. Two patients died within two months of the diagnosis, secondary to multiorgan system failure. Two other patients received a heart transplant three months and 7.5 years after the initial diagnosis. Four patients with DCM are currently awaiting heart transplantation. One patient was resuscitated shortly after the diagnosis and is neurologically compromised. 100 % Without Cardiomyopathy 95 1 % 90 9 % 85 80 75 70 || 65 0 2 4 6 8 10 12 14 16 18 F o l lo w - u p (y e a rs ) F ig u r e 1 . K a p la n - M e ie r c u r v e p r e s e n t in g fr e e d o m fr o m d e v e lo p in g a c a r d io m y o p a t h y in y e a r s a f t e r t h e in it ia l d ia g n o s is o f C C A V B . Pathology and etiology. Endomyocardial biopsies were obtained in four patients with DCM (44%) and revealed no signs of myocarditis, infection or carnitine deficiency. There was no evidence of coronary artery abnormalities detected by echocardiograms in these nine patients. Skeletal muscle biopsies obtained from one patient with DCM, who was antiSSA/Ro and anti-SSB/La antibody-positive revealed a deficiency of the adenine nucleotide translocator (ANT) (Sengers’syndrome).9 This patient died at 10 months of age. Pacemaker therapy. The median age at pacemaker implantation of the patients with CCAVB and DCM was significantly younger (7 days [range 1 day to 5 years]) than that of the 102 patients with CCAVB (4 years [range 1 day to 19 years]) (p < 0.05). The median heart rate at pacemaker implantation in the CCAVB/DCM group was 50 beats/min (range 42 to 124), and in the CCAVB group, 55 beats/min (range 37 to 104) (p > 0.10). 66 Dilated Cardiomyopathy The indication for pacemaker implantation in the DCM group included: 1) heart rate < 50 beats/min (n = 5, 56%); 2) progressive bradycardia noted on ambulatory monitors (n = 1, 11%); and 3) congestive heart failure (n = 3, 33%). Isolated premature ventricular contractions were observed in six patients (67%). However, no patient in the CCAVB/DCM group had higher grade ectopy, including couplets or salvos of ventricular tachycardia. An endocardial device was implanted in two patients, and an epicardial system in seven patients. Indication for pacing in the 102 patients with CCAVB included: 1) heart rate < 50 beats/min (n = 48, 47%); 2) progressive bradycardia (n = 10, 10%); 3) syncope (n = 11, 11%); 4) pauses > 3.5 seconds seen on ambulatory monitoring (n = 12, 11%); 5) exercise intolerance (n = 10, 10%); and 6) heart failure (n = 11, 11%). Isolated premature ventricular contractions were seen in 22 patients (21%), and ventricular couplets in six (6%). Ventricular tacycardia was not observed. Endocardial devices were initially implanted in 46 patients with CCAVB, and epicardial leads in 56 patients. TABLE 2 Study Characteristics of Dilated Cardiomyopathy Patients Age Patient Gender Diagnosis HR Initial Initial Initial Indication PM at Birth CTR LVEDD SF Implantation (M/F) DCM (bpm) (%) (%ile) (%) 1 M 15y9m 45 63 97 35 progressive bradycardia A 2 M 5m 50 70 97 32 HR < 50 bpm A 3 F 14y5m 30 71 - - HR < 50 bpm A 4 M 9m 42 61 97 45 CHF D 5 M 4y2m 46 61 97 31 CHF D 6 M 2y5m 45 63 - - HR < 50 bpm A 7 M 8y - 62 97 33 CHF A 8 M 9y9m - 65 90 29 HR < 50 bpm A 9 F 5y8m 45 59 97 40 CHF A A = alive; bpm = beats per minute; CHF = congestive heart failure; CTR = cardiothoracic ratio; D = died; DCM = dilated cardiomyopathy; HR = heart rate; LVEDD = left ventricular end-diastolic dimension; PM = pacemaker; SF = shorthening fraction There was no significant difference in the type of pacing employed between the two study cohorts. Dual-chamber pacemakers were implanted in two patients with CCAVB and DCM (22%) and 39 patients with CCAVB (38%). Single-ventricular chamber pacing was employed in the remaining seven patients with CCAVB and DCM (78%) and in 63 patients with CCAVB (62%). Re-implantations were indicated in six patients with CCAVB and DCM (67%) and in 80 patients with CCAVB (78%, p > 0.10) due to generator depletion or lead failure. Echocardiographic measurements. Initial echocardiograms at the time of CCAVB diagnosis were obtained in 94 patients (85%) (CCAVB/DCM: n = 7; CCAVB: n = 87) (Table 67 Chapter 4 3). The initial LVEDD (CCAVB/DCM: 96th percentile ± 2.6; CCAVB: 76th percentile ± 24.0; p < 0.005), without a significant difference in LV function (CCAVB/DCM: 36.0 ± 5.2%; CCAVB: 39 ± 7.9%; p > 0.10). 30 25 SF (%) 20 15 10 5 0 0 n = 9 1 n = 9 2 3 4 n = 9 n = 7 n = 7 5 n = 7 6 7 8 n = 4 n = 4 n = 4 9 n = 4 10 11 12 n = 4 n = 4 n = 4 F o l lo w - u p (m o n th s ) F ig u r e 2 . S h o r t e n in g f r a c t io n ( S F % ) o f 9 p a t ie n t s in t h e fir s t 1 2 m o n t h s a f t e r p r e s e n t a t io n o f d ila t e d c a r d io m y o p a t h y , li n e = a v e r a g e a n d r a n g e a t g iv e n t im e s . Mild mitral regurgitation was seen in four patients with DCM and persisted on serial echocardiograms during follow-up. Initial LVEDD values > 97th percentile were measured in 22 patients with CCAVB (21%) and showed a decrease in LVEDD < 97th percentile within 4.0 ± 3.5 years after pacemaker implantation. The initial SF in these patients was 38 ± 7.1%. Over 6.5 ± 5.0 years, the nine patients with CCAVB who eventually developed a DCM continued to have a LVEDD > 97th percentile ± 1.8%, as well as a decrease in SF from 35.8 ± 5.1% to 11 ± 5.0%. This was significantly different from the CCAVB cohort (n = 102), which showed a significant decrease in LVEDD to 65th percentile ± 20% (p < 0.001), without a change in LV function (36 ± 3.6%, p < 0.01), 7.0 ± 6.0 years after pacing. A decrease in heart size was initiated within two months (range 1 month to 1 year) after pacemaker implantation. Radiographic features. Initial chest radiographs were available for all nine patients who eventually developed DCM (Table 3). There was no radiographic evidence of pulmonary venous congestion, edema or atelectasis. All nine patients had cardiomegaly, graded as mild (n = 4), moderate (n = 2), or severe (n = 3). An initial CT ratio of 64.0 ± 3.8% was measured in the CCAVB/DCM group and remained relatively constant over 6.5 ± 5.0 years at 63.0 ± 6.8%. Mild vascular congestion and perihilar edema were observed in two patients on the initial chest radiographs and at mid-term follow-up. 68 Dilated Cardiomyopathy The CT ratio in the CCAVB group decreased significantly with initiation of pacing from 57.0 ± 7.2% to 49.0 ± 6.3% (p < 0.01) over a 7.5 ± 4.6 years of follow-up. This decrease in CT ratio was not seen in the CCAVB/DCM group during a similar follow-up period. TABLE 3 Initial Heart Size and Function in Cardiomyopathy Patients and Controls Cardiomyopathy Control P Patients Patients Value (n= 9) (n= 102) n 7 87 (%ile) 95.8 ± 2.6 75.9 ± 24.3 < 0.005 (%) 35.8 ± 5.1 40.1 ± 6.2 < 0.5 n 9 76 (%) 64.0 ± 3.8 57.1 ± 7.2 < 0.005 0 20 (26%) - mild 4 (44%) 40 (53%) - moderate 2 (22%) 11 (14%) - severe 3 (34%) 5 (7%) - Echocardiographs LVEDD SF Chest Radiographs CT ratio normal Data presented are mean values ± SD or number (%) of patients. CTR = cardiothoracic ratio; LVEDD = left ventricular end-diastolic dimension; SF = shortening fraction. DISCUSSION Dilated cardiomyopathy. DCM is a heterogeneous group of myocardial diseases characterized by dilation and impaired systolic function of the heart.5,10 Although specific causes can be identified such as myocarditis, familial cardiomyopathies, endocardial fibroelastosis and metabolic disorders, most cases are idiopathic.11-13 Similarly no additional etiology event could be identified in the 9 isolated CCAVB patients who eventually developed DCM. Anti-SSA/Ro and anti-SSB/La autoantibodies. Anti-SSA/Ro – anti-SSB/La antibodies have been suggested to be a major determinant in the CCAVB patients who eventually developed a DCM.1,2 Evidence for a potential immuno-pathological role of anti-SSA/Ro and anti-SSB/La antibodies in CCAVB has been described in several studies.3,4 Immunofluorescent studies have shown IgG deposition throughout the myocardium on postmortem examination.14,15 Taylor and colleagues demonstrated maternal antibodies directed against fetal cardiac tissue.16 Although these studies suggest a strong relationship between maternal antibodies and SSA/Ro and SSB/La ribonucleoproteins and the following DCM,1,2,17 the actual mechanism of the disease process has not yet been documented. SSA/Ro and SSB/La antibody-mediated AV block was confirmed in seven of the nine patients who 69 Chapter 4 developed a DCM. However, 40 of 52 tested CCAVB patients, who did not develop a DCM, were also SSA/Ro and SSB/La positive. Thus antibody positivity is not predictive of those CCAVB patients who developed a DCM. ANT deficiency. Although myocardial biopsies did not provide any specific information concerning the DCM, skeletal muscle biopsies in one patient revealed a deficiency of the adenine nucleotide translocator, which is associated with Sengers' syndrome.10 Sengers’ syndrome consists of a triad of congenital cataracts, mitochondrial myopathy, and hypertrophic cardiomyopathy, and is not known to cause DCM.18 This observation may be described as a new clinical finding, and warrants further investigation. Pacemaker implantation. A previous study indicates that at least 10% of SSA/Ro and SSB/La antibody associated CCAVB patients do not respond favorably to pacemaker implantation secondary to more diffuse cardiac involvement.2 This study observed a similar incidence (8%, 9/111) of patients whereby pacemaker implantation did not decrease the left ventricular end-diastolic dimension. Although cardiomegaly is a common feature in the CCAVB population, severe dilation of the LV is rare.8 Some reports postulate that the increased heart size may be related to LV remodeling and reorganization of myofibers secondary to an increase in stroke volume and maintenance of a normal cardiac output in the face of chronic bradycardia.19,20 Severe LV dilation may be associated with a less effective adaptation to this complex physiology. This study reported that CCAVB patients with marked LV dilation at presentation who lack a reduction of heart size with pacemaker implantation are at risk for developing a DCM. Pacemaker induced DCM can be offered as possible etiologic factor in these patients. This however seems unlikely in regard to the vast majority of the paced patients responding favorably on pacemaker support. In fact 22 patients who did not develop a DCM and whose initial LVEDD exceeded the 97th percentile had a reduction in the LVEDD with pacing. Etiology. In the absence of a clear etiology for the pathogenesis of DCM in the CCAVB population we presume that DCM is associated with isolated CCAVB and may be a separate pre-existing condition in some patients. This hypothesis is based on such common denominators as the presence of anti-SSA/Ro and anti-SSB/La antibodies, lower heart rate at birth, prenatal diagnosis of the CCAVB, initial cardiac enlargement and diminished LV shortening despite early pacemaker implantation. The availability of cardiac transplantation as a therapeutic option has increased the importance of early and accurate diagnosis. Two patients were successfully transplanted and are still alive without any recurrence of a dilated cardiomyopathy. Serial echocardiograms evaluating for left ventricular dimensions is therefore advisable and may allow for early medical management (i.e. upgrade to a DDD pacemaker system) and listing for potential orthotypic heart transplantation. 70 Dilated Cardiomyopathy Conclusions. Children with isolated CCAVB are at risk for developing a DCM. Risk factors might include an early increased CT ratio and LV dilation with little or no improvement in ventricular size with pacing, a prenatal diagnosis of CCAVB, and a low heart rate at birth. The development of this cardiomyopathy seems to be independent of the age of pacemaker implantation. The relatively common occurrence of positive maternal auto-antibodies in the CCAVB group (79%) and CCAVB/DCM (87%) makes this an unlikely explanation for the development of a DCM. DCM can be considered as an association of the isolated CCAVB in some patients. These are major issues, which should be discussed at the time of diagnosis. 71 Chapter 4 REFERENCES 1. Michaelsson M, Riesenfeld T, Jonzon A. Natural history of congenital complete atrioventricular block. Pacing Clin Electrophysiol 1997;20:2098-101. 2. Taylor-Albert E, Reichlin M, Toews WH, Overholt ED, Lee LA. Delayed dilated cardiomyopathy as a manifestation of neonatal lupus: case reports, autoantibody analysis, and management. Pediatr 1997;99:7335. 3. Buyon JP, Hiebert R, Copel JA, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31:1658-66. 4. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: Outcome in mothers and children. Ann Intern Med 1994;120:544-51. 5. First T, Skovranek J. Normal values of M-mode echocardiographic parameters in children. Cesk Pediatr 1984;39:699-708. 6. Snider AR, Serwer GA, Ritter SB. Methods for obtaining quantitative information from the echocardiographic examination. In: DeYoung, editor. Echocardiography in pediatric heart disease. St. Louis, Missouri: MosbyYear Book, Inc. 1997:133-234. 7. Sholler GF, Walsh EP. Congenital complete heart block in patients without anatomic cardiac defects. Am Heart J 1989;118:1193-8. 8. Towbin JA. Pediatric myocardial disease. Pediatr Cardiol 1999;46:289-312. 9. Robbins RC, Bernstein D, Berry GJ, VanMeurs KP, Frankel LR, Reitz BA. Cardiac transplantation for hypertrofic cardiomyopathy associated with sengers’syndrome. Ann Thorac Surg 1995;60:1425-7. 10. Matitiau A, Perez-Atayde A, et al. Infantile dilated cardiomyopathy: Relation of outcome to left ventricle mechanisms, hemodynamics and histology at the time of presentation. Circulation 1994;90:1310-8. 11. Akagi T, Benson LN, Lightfoot NE, Chin K, Wilson G, Freedom RM. Natural history of dilated cardiomyopathy in children. Am Heart J 1991;121:1502-6. 12. Gunteroth WG. Congestive cardiomyopathy in children. J Am Coll Cardiol 1990;15:194-5. 13. Chen S-C, Nouri S, Balfour I, Jureidini S, Appleton S. Clinical profile of congestive cardiomyopathy in children. J Am Coll Cardiol 1990;15:189-93. 14. Litsey SE, Noonan JA, O’Connor WN, Cotrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block. N Engl J Med 1985;312:98-100. 15. Lee LA, Coulter S, Erner S, et al. Cardiac immunoglobulin deposition in congenital heart block associated with maternal anti-Ro autoantibodies. Am J Med 1987;83:793-6. 16. Taylor PV, Scott JS, Gerlis, et al. Maternal antibodies against fetal cardiac antigens in congenital complete heart block. N Engl J Med 1986;315:667-72. 17. Leatherbury L, Chandra RS, Shapiro SR, Perry LW. Value of endomyocardial biopsy in infants, children and adolescents with dilated or hypertrophic cardiomyopathy and myocarditis. J Am Coll Cardiol 1988;12:154754. 18. Smeitink JAM, Sengers RCA, Trijbels JMF, et al. Fatal neonatal cardiomyopathy associated with cataract and mitochondrial myopathy. Eur J Pediatr 1989;148:656-9. 19. Kertesz NJ, Friedman RA, Colan SD, et al. Left ventricular mechanisms and geometry in patients with congenital complete atrioventricular block. Circulation 1997;96:3430-5. 20. Manno BV, Hakki A-H, Eshaghpour E, Iskandrian AS. Left ventricular function at rest and during exercise in congenital complete heart block: a radionuclide angiographic evaluation. Am J Cardiol 1983;52:92-4. 72 C H A P T E R Pacemaker Therapy in Isolated Congenital Complete Atrioventricular Block Breur JMPJ, Udink ten Cate FEA, Kapusta L, Cohen MI, Crosson JE, Boramanand N, Lubbers LJ, Friedman AH, Brenner JI, Vetter VL, Sreeram N, Meijboom EJ. Pacing Clin Electrophysiol 2002;25:1685-91. Chapter 5 ABSTRACT Objectives. The aim of this study was to evaluate the effect of pacemaker (PM) therapy in patients with isolated congenital complete atrioventricular block (CCAVB). Patients with CCAVB eventually qualify for PM implantation, however timing remains controversial. Methods. Retrospective evaluation of left ventricular end-diastolic diameter (LVEDD), shortening fraction (SF) and cardiothoracic ratio (CTR) in 149 CCAVB patients, before, at and after PM implantation. Results. LVEDD shows an average increase of 0.48 %ile/month in non PM patients, and an average decrease of 0.88 %ile/month in PM patients. SF shows an average increase of 0.10 %/month in non-PM, and an average decrease of 0.32 %/month in PM. CTR shows an average increase of 0.02 %/month in non-PM, and an average decrease of 0.19 %/month in PM patients. The difference between non-PM and PM groups is significant (p=0.05) for all variables. Symptomatic patients show no significant change in LVEDD after PM therapy (from 66.5 %ile before to 68.5 %ile after PM). Asymptomatic patients do show a significant (p<0.001) decrease in LVEDD after PM therapy (from 78.4 %ile before to 73.3 %ile after PM). CTR does not differ significantly between symptomatic and asymptomatic patients before PM therapy (58 % and 57 % respectively). CTR does differ significantly (p<0.001) between symptomatic and asymptomatic patients after PM therapy (52 % and 48 % respectively). Conclusions. Heart size and SF are increased in most patients with isolated CCAVB. PM implantation is associated with decrease in heart size and normalization of SF in most patients. Indications for PM therapy in children may require reevaluation in asymptomatic patients with increased cardiac size and decreased cardiac function. 74 Pacemaker therapy PACEMAKER THERAPY INTRODUCTION Congenital complete atrioventricular block (CCAVB) is an uncommon cardiac conduction defect occurring in 1 of every 15,000 to 20,000 live births.1 Associated structural heart disease is present in approximately 30% of these patients.2 Isolated CCAVB detected at or before birth is strongly associated with maternal auto-antibodies directed to SS-A/Ro and SS-B/La ribonucleoproteins, which are also known to cause the neonatal lupus syndrome (NLS).3-6 Atrioventricular (AV) block diagnosed later in life is not known to be associated with anti-SS-A/Ro antibodies.7 Several investigators published the presence of cardiomegaly in asymptomatic and symptomatic CCAVB patients.8-12 The timing of pacemaker (PM) implantation, however, strongly depends on the presence of symptoms and the indications are still not well defined.13 Eventually, almost all patients become symptomatic and will require PM intervention. The purpose of this retrospective multicenter study is to determine whether pacemaker treatment is associated with a decrease in cardiac dimensions and/or improvement in heart function and to review indications and optimal timing of current pacing practice. METHODS Patient Population. Medical records of patients diagnosed with congenital complete atrioventricular block between 1972 and 2000 of the Wilhelmina Children’s Hospital/UMC Utrecht, Academic Medical Center, Amsterdam, University Medical Center St. Radboud, Nijmegen, the Netherlands, the Johns Hopkins Hospital, Baltimore, MD, Yale New Haven Hospital, New Haven, CT, and the Children’s Hospital of Philadelphia, Philadelphia, PA, USA, were examined retrospectively. Complete heart block was defined as complete when absence of conduction between atrium and ventricle was observed by echocardiography in the fetus or by electrocardiography (ECG) in the patient. Patients with inflammatory disease or a metabolic disorder other than SLE or maternal lupus that might have caused the AV block were excluded. Included were 149 patients with isolated CCAVB with confirmation of normal cardiac anatomy. Repeated ECG recordings during infancy and childhood confirmed a complete and permanent AV block. Demographic data included sex, age of prenatal or postnatal diagnosis of AV block, follow-up time, degree of initial AV block and presence of maternal auto-antibodies to SSA/Ro and SSB/La ribonucleoproteins. All patient charts were reviewed for birth weight, gestational age at birth, mode of delivery, heart rate at birth, presence of fetal hydrops, condition at birth, and mortality. 75 Chapter 5 TABLE 1 Study Characteristics of 149 CCAVB Patients Nonpaced Paced All Patients Patients Patients P (n = 149) (n = 38) (n = 111) Value (m/f) 73/76 21/17 52/59 NS (months) 23 ± 46 20 ± 50 24 ± 45 NS prenatal 45 (30%) 10 (26%) 35 (32%) NS at birth 35 (24%) 9 (24%) 26 (23%) NS postnatal 69 (46%) 19 (50%) 50 (45%) NS (months) 122 ± 79 124 ± 94 121 ± 74 NS (g) 2930 ± 644 3072 ± 524 2856 ± 686 NS (wks) 38 ± 3 39 ± 2 37 ± 3 < 0.035 Mode of delivery 81 (54%) 21 (55%) 60 (54%) NS natural 35 (23%) 10 (26%) 25 (23%) NS SC 46 (31%) 11 (29%) 35 (32%) NS 65 ± 22 75 ± 22 60 ± 20 < 0.035 Hydrops 3 (2%) 1 (3%) 2 (2%) NS BBB 11 (7%) 5 (13%) 6 (5%) NS VES 30 (20%) 11 (29%) 19 (17%) NS Sex Age diagnosis Follow-up Birth weight Gestational age HR at birth (beats/min) ECG atrial rate ventricular rate (Z-score) 0.595 0.509 NS (Z-score) –0.930 –0.911 NS Holter minimal rate (Z-score) –0.860 –0.940 NS 0 3 (3%) NS Mortality 3 (2%) Data presented are mean values ± SD or number (%) of patients. BBB = bundle branch block; CCAVB = congenital complete atrioventricular block; CS = cesarean section; ECG = electrocardiogram; HR = heart rate; NS = no significant difference; VES = ventricular extrasystoles. Study patients were assigned to two groups, patients with (PM group) and without PM implantation (non-PM group). Indications, mode of pacing, and age at PM implantation were documented, complications, and re-implantations noted. The group of PM patients was further divided into two subgroups based on presence or absence of symptoms at the time of implantation. Two second subgroups were created by dividing the PM patients by mode, ventricular pacing (VVI) or dual chamber pacing (DDD). Patients who developed a dilated cardiomyopathy (DCM) were excluded from all subgroups. Clinical Data. All available electrocardiograms (ECGs) and 24-h ambulatory ECGs (Holter) were evaluated to assess atrial and ventricular rates, longest RR interval, degree of initial AV block, and the occurrence of premature ventricular contractions. The presence of complete or incomplete bundle branch block (BBB) and ventricular extra systoles (VES) were also noted. 76 Pacemaker therapy Left ventricular (LV) function was evaluated by two-dimensional Doppler and M-mode echocardiography. Left ventricular end-diastolic dimension (LVEDD) and left ventricular endsystolic dimension (LVESD) were measured. LVEDD increases with weight, therefor a Pvalue corrected for weight was calculated for every LVEDD.15 Shortening fraction (SF) was calculated as (LVEDD- LVESD)/ LVEDD. This calculation was only performed in patients with a normal QRS complex seen on ECG. A cardiothoracic ratio (CTR) > 0.50 indicated cardiomegaly (in children > 1 month). Statistical analysis. The clinical parameters displayed in table 1 were analyzed comparing NPM and PM groups, using the T-test for continuous data and a chi-square test for noncontinuous data. The first available ECG and/or Holter of the PM and non-PM group were compared by calculating Z-scores for age specific minimal, maximal and average heart rates.16 A two-sample T-test for independent groups was used to compare the average Zscores of the PM and non-PM groups. Patients with PM (%) 100 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 Age (years) FIGURE 1. The cumulative incidence of pacemaker implantation through time. Linear regression was used to evaluate a change in LVEDD, SF and CTR over time. When possible, two linear regression functions per variable were calculated for patients with more than one measurement of LVEDD, SF or CTR. One function was calculated with the measurements of the variables prior to PM implantation, representing the natural history of CCAVB. A second function was calculated after pacemaker implantation, representing the change in the variables due to PM therapy. The slopes of these functions could be positive, negative, or zero. The fraction analyses17 were calculated comparing the decrease in cardiac size or contractility in PM and non-PM groups to see if one of the groups contained a significant higher percentage (fraction) of patients showing a decrease in LVEDD, SF and/or 77 Chapter 5 CTR. Second, individual linear regression functions calculated for the change in LVEDD, SF and CTR were averaged, providing one function per variable. The averaged functions of the non-PM group represent the change in LVEDD, SF and CTR prior to pacemaker implantation or the natural history of CCAVB. Averaged functions of the PM group represent the change in LVEDD, SF and CTR after PM implant. The difference between the change in LVEDD, SF and CTR in PM and non-PM groups can be attributed to the effect of PM therapy and is represented by the difference between the slopes of the averaged functions. A two sample ttest for independent groups was used to compare this difference. To compare the symptomatic and asymptomatic group at the time of PM implantation, all the measurements of LVEDD, SF and CTR closest to or at PM implant were compared to the most current measurements of these variables using a two sample t-test for independent groups. The individual linear regression functions for LVEDD, SF and CTR after PM implantation were subdivided according to PM mode (VVI or DDD), averaged and analyzed with a two sample t-test for independent groups. A p-value ≤ 0.05 was considered significant. Bradycardia (52) Unknown Indication (10) Pauses (12) Syncope (9) Heart Failure (10) Exercise Intolerance (8) Progressive Bradycardia (6) Cardiac Arrest (1) Failure to Thrive (3) 0 20 40 60 FIGURE 2. Indications of pacemaker therapy. RESULTS Patient population. The data from 149 CCAVB patients with isolated CCAVB was reviewed. Demographic data and a comparison of patients in the PM and non-PM groups are detailed in Table 1. Except for gestational age at birth and heart rate at birth, the PM and non-PM groups do not show any significant initial demographic differences. Although no explanation can be provided for an earlier delivery in these patients, heart rate might be considered as an expression of severity of AV block and the overall lower rate which will cause a more serious increase in heart size. Av block was first diagnosed in utero in 45(30%) 78 Pacemaker therapy TABLE 2 Pacemaker Data from 111 CCAVB Patients Transvenous Epicardial n (%) n (%) 47 (42%) 64 (58%) 97.9 ± 58.3 31.0 ± 42.1 Switch† 1 18 19 No. of reimplantations 84 101 185 45.8 ± 35.7 49.4 ± 44.2 First implant Age at first implant* Intervention-free Total P n 111 <0.001 <0.001 60.3 ± 60.7 47.7 ± 40.6 period* Data is presented in months as mean ± SD. †Switch from transvenous to epicardial or switch from epicardial to transvenous device respectively. Age of pacemaker implantation is significantly lower in the epicardial group (P < 0.001), the intervention-free period is significantly longer in this group (P < 0.001). cases, at delivery in 35 (23%), and during the first year of life in 17 (11%) patients. Diagnosis was made after age 1 year in 52 (35%) of patients. Although, the majority had third-degree block, in 20% (10 fetuses/neonates and 20 children) second-degree block progressed to complete block during follow-up. The median age of diagnosis was 0 months (ranging from 20 weeks of gestation to 17 years). The median follow up period was 9 years and 4 months (1 month – 39 years). Neonatal lupus syndrome. In 48 (32%) patients, isolated CCAVB was associated with the presence of maternal SSA/Ro and SSB/La autoantibodies, of whom 39 developed NLS. CCAVB was diagnosed prenatally in 67% of these cases, at birth in 21% and early in life in 12% of these patients. Pacemaker implantation. PM insertion was performed in 111 patients (74%) (Figure 1) during a follow-up period of 122 ± 79 months (Table 2). Indications for pacing13 are noted in Figure 2. Dual chamber pacing (DDD) was initiated in 33 (30%) patients, single chamber (ventricular) pacing (VVI,VDD,VDI) in 78 (70%). Postpericardiotomy syndrome occurred in 5 patients. Measures of left ventricular function and cardiac size. An echocardiograhic LVEDD was available in 124 (83%) and a SF in 114 (77%) of the 149 patients. In addition, 113 (76%) patients had had chest X-ray examinations. Because there were no significant differences in clinical characteristics of the PM and the non-PM groups, data concerning heart size and function from both groups (prior to PM implantation) was combined to accomplish an analysis of the natural history of CCAVB. 79 Chapter 5 PM, non-PM. Multiple LVEDD measurements before PM implantation were available in 35 patients. Multiple LVEDD measurements after PM implantation were available in 41 patients. There was a significantly greater percentage of patients in the PM group (79%) who had a decrease in LVEDD when compared to the non-PM group (53%) (p=0.009). Figure 3 demonstrates the increase in LVEDD in the non- PM group and decrease in the PM group. Multiple SF measurements before PM implantation were available in 34 patients and after PM implantation in 30 patients. In the non-PM group, 52% versus 72% in the PM group had decreasing SFs (p=0.055). The two averaged functions are shown in Figure 4. Multiple CTR measurements before PM implantation were available in 44 patients, after PM implantation in 57 patients. In the non-PM group 63% showed a decrease in CTR versus 96% in the PM group, a significant difference (p<0.0001). The averaged individual linear regression functions are shown in Figure 5. TABLE 3 Heart Size and Function of 32 Symptomatic and 70 Asymptomatic CCAVB Patients without DCM Before PM* After PM† Symptomatic Asymptomatic Symptomatic Asymptomatic Patients Patients Patients Patients n = 32 n n = 70 n n = 32 n n = 70 n LVEDD (%ile) 66.5 ± 31.0 22 78.4 ± 21.0 44 68.5 ± 19.0 17 73.3 ± 19.0 33 SF (%) 39.9 ± 5.6 21 42.2 ± 5.3 34 36.9 ± 6.3 15 35.6 ± 6.6 27 CTR (%) 58.0 ± 6.7 21 57.0 ± 5.9 46 51.7 ± 6.7 22 48.4 ± 5.7 39 Data presented are mean values ± SD or number (%) of patients. *before PM = measurement at or before pacemaker implantation; †after PM = most recent measurement. See text for comparative statistics. CTR = cardiothoracic ratio; DCM = dilated cardiomyopathy; LVEDD = left ventricular end-diastolic diameter; SF = shorthening fraction. Symptomatic, asymptomatic. At PM implantation, 32 (31%) patients had symptoms that could be attributed to heart block, 70 (69%) patients were symptom-free. Where Figure 2 shows a favorable response of LVEDD to PM therapy in the CCAVB population, Table 3 shows that only asymptomatic patients contribute to this effect. Only asymptomatic patients show a significant decrease in LVEDD after PM therapy (p < 0.001) SF and CTR decrease after PM therapy in the symptomatic and asymptomatic patients, however, the effect of PM therapy is significantly more pronounced in the asymptomatic group (Table 3). The symptomatic and asymptomatic groups show a significant decrease in SF after PM therapy (p < 0.001 in both), however, SFs at PM implantation and after PM implantation also differ. The decrease of SF in the asymptomatic group (42% to 36%) is, therefore, significantly greater when compared to the symptomatic group (40% to 37%). The 80 Pacemaker therapy difference in CTR between the symptomatic (58%) and asymptomatic (57%) groups is not significant at PM implantation. After PM implantation, however, CTR has decreased to 48% in the asymptomatic group compared to 52% in the symptomatic group which is a significant difference (p<0.001). VVI, DDD. There was a decrease in the LVEDD and CTR after PM implantation, but there was no difference when patients with VVI pacing were compared to patients with DDD pacing. Cardiomyopathy. Nine (6%) of 149 patients developed dilated cardiomyopathy (DCM), all despite PM therapy. Seven (78%) of these nine were SS-A/SS-B positive, 1 (11%) was negative and 1 (11%) patient was not antibody tested. Eight of nine DCM patients were symptomatic at the time of PM implantation. LVEDD (%ile) 100 80 60 40 non-PM 20 PM 0 0 10 20 30 40 50 60 Age (months) FIGURE 3. Left ventricular end-diastolic dimension development differs between the pacemaker (PM) and nonPM groups. Non-PM: Y = 68 + 0.48X, PM : Y = 81 – 0.88X. Zero represents birth in the non-PM group and moment of PM implantation in the PM group. A significant difference between the slopes of the paced and nonpaced groups (P < 0.05) exists. The Y-axis percentiles represent P values of LVEDD within a normal population. DISCUSSION Anti-SSA/Ro autoantibodies are associated with an early diagnosis of the AV block. The authors observed that patients with CCAVB may develop DCM even in the absence of SSA/Ro and SS-B/L antibodies. Therefore, this population should be followed for DCM even after PM implantation. The type of lead placement shows a significant difference in the intervention-free interval between transvenous and epicardial. A recommendation for epicardial lead placement 81 Chapter 5 seems warranted, however, specifically since PM technology and experience are improving, this may change over time once the long-term outcome of vein patency in patients with transvenous pacing leads placed as infants will be determined. SHORTENING FRACTION (SF %) 50 40 30 20 non-PM 10 PM 0 0 10 20 30 40 50 60 Age (months) FIGURE 4. Shortening fraction development differs between the pacemaker (PM) and non-PM groups. Non-PM: Y = 36 + 0.10X, PM: Y = 35 – 0.32X. Zero represents birth in the non-PM group and moment of PM implantation in the PM group. Slopes differ significantly between the paced and nonpaced groups (P < 0.05). CARDIOTHORACIC RATIO (CTR %) 70 60 50 40 non-PM 30 PM 20 0 10 20 30 40 50 60 Age (months) FIGURE 5. Cardiothoracic ratio development differs between the pacemaker (PM) and non-PM groups. NonPM: Y = 57 + 0.02X, PM: Y = 58 – 0.19X. Zero represents birth in the non-PM group and moment of PM implantation in the PM group. Slopes differ significantly between the paced and nonpaced groups (P < 0.05). 82 Pacemaker therapy No difference in outcome was recorded between VVI and DDD PM mode. In young babies this can be used as an argument for the implantation of a single transvenous ventricular lead and VVI pacing. While, in reverse, the follow-up period in the DDD group is too short to prove a positive result of the physiologic pacing mode. The results of this study demonstrate that most unpaced patients with CCAVB have cardiomegaly on chest radiographs and LV enlargement on echocardiography. Although several studies have reported radiographic evidence of cardiomegaly in these patients,10-13 none has documented the natural progression of cardiac enlargement and LV dysfunction during long-term follow-up in paced and nonpaced children. A recent study by Kertesz et. al.11 concludes that a moderately enlarged LV with normal geometry, normal wall stress and enhanced systolic function during the first two decades of life is a common observation in this group of patients. The finding that LV enlargement in most patients continues to progress to or over the 90%ile in the absence of cardiac pacing, suggesting that a progression of LV enlargement may portend eventual congestive heart failure. Other investigators have postulated that the cardiomegaly in patients with CCAVB may be related to LV remodeling and reorganization of myofibers to increase stroke volume and maintain a normal cardiac output in the face of low heart rate. This study demonstrates that the increase in LV size and depressed myocardial function can be reversed by pacemaker therapy. This may result in a decreased stress on the LV over time, suggesting that asymptomatic patients may also benefit hemodynamically from pacing. Most patients receiving pacemaker devices show a decrease in heart size on echocardiographic evaluation and chest x-ray after pacemaker implantation. A hyperdynamic LV (SF > 35%) is common in unpaced patients, which tends to decrease to normal ranges after pacing. Specifically, patients who have an initial normal LVEDD, and a rapid progression of the LV dilation seem to benefit of early PM implantation. This suggests that cardiomegaly is an additional risk factor, indicating the possible need for pacemaker implantation in asymptomatic patients. The decrease in cardiomegaly occurs relatively quickly (months), but a return to normal heart size is a slow process in most patients . One report suggests that cardiomegaly seen on x-ray film and atrial enlargement on electrocardiogram are independent predictors of symptoms and poor outcome in non-paced patients.17 This study demonstrates that symptomatic patients are likely to have severe LV dilation and cardiomegaly and are less likely to have resolution of these abnormalities after PM implantation. Signs and symptoms due to complete heart block might be the first stage in a process of irrecoverable heart damage, possibly followed by the development of a dilated cardiomyopathy. The fact that 8 out of 40 (20%) symptomatic patients develop a dilated cardiomyopathy contrasted with 1 out of 71 (1%) asymptomatic patients further strengthens this hypothesis. The development of DCM despite pacemaker implantation has been 83 Chapter 5 observed by others previously.18,19 Although the precise background of this DCM is unknown, it seems to be related to immune-mediated damage.20 PM therapy has become a relatively safe and common intervention in childhood, albeit not without both short and long-term risk. These developments in conjunction with our findings suggest that indications for pacemaker therapy in children with CCAVB may require reassessment. Regular ECG, echocardiographic and radiographic monitoring is necessary for adequate follow-up of asymptomatic CCAVB patients. If cardiac size increases or left ventricular function decreases too rapidly or stabilizes at the same abnormal level, intervention is advisable. Study limitations. This study is limited because of the retrospective aspect which makes comparisons at fixed time intervals complicated. In addition, a number of patients are included in which the diagnosis of CCAVB is assumed although they were only diagnosed after 1 year of age. Conclusions. Cardiomegaly is a common observation in CCAVB and decreases to normal heart size in almost all paced patients, except for a small group with DCM. In asymptomatic patients, LVEDD, SF, and CTR respond better to PM therapy than patients who are symptomatic at the time of PM implant. Since most patients with CCAVB eventually become symptomatic and require pacing, the timing of PM implantation might be reconsidered. With the recent improvement in PM technology, asymptomatic patients with progressive increase or persisting high values of LVEDD and/or CTR should be included to prevent future congestive heart failure. 84 Pacemaker therapy REFERENCES 1. Kleinman CS, Donnerstein RL. Fetal echocardiography: A tool for evaluation of in utero cardiac arrhythmias and monitoring of in utero therapy: analysis of 71 patients. Am J Cardiol. 1983;51:237-43. 2. Ross BA. Atrioventricular block. In Garson A Jr, Bricker JT, McNamara DG, eds. The Science and Practice of Pediatric Cardiology. Philadelphia, Pa: Lea & Febiger; 1990:1803. 3. Litsey SE, Noonan JA, O’Connor, et al. Maternal connective tissue disease and congenital heart block. N Engl J Med. 1985;312:98-100. 4. Buyon JP, Hiebert R, Copel JA, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31:1658-66. 5. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: Outcome in mothers and children. Ann Intern Med.1994;120:544-51. 6. Buyon JP, Ben-Chetrit E, Karp S, et al. Acquired congenital heart block. Pattern of maternal antibody response to biochemically defined antigens of the SSA/Ro-SSB/La system in neonatal lupus. J Clin Invest. 1989;84:627-34. 7. Frohn-Mulder IM, Meilof JF, Szatmari A, et al. Clinical significance of maternal anti-Ro/SS-A antibodies in children with isolated heart block. J Am Coll Cardiol 1994;23:1677-81. 8. Michaelsson M, Jonzon A, Riesenfeld T. Isolated congenital complete atrioventricular block in adult life: a prospective study. Circulation 1995;91:442-9. 9. Esscher EB. Congenital complete heart block in adoloscence and adult life: a follow-up study. Eur Heart J. 1981;2:281-8. 10. Nakamura FF, Nadas AS. Complete heart block in infants and children. N Engl J Med. 1964;270:1261-8. 11. Kertesz NJ, Friedman RA, Colan SD, et al. Left ventricular mechanics and geometry in patients with congenital complete atrioventricular block. Circulation 1997;96:3430-5. 12. Jaffe RB, Sherman SA, Condon VR, et al. Congenital complete heart block. Radiographic findings in 13 patients without associated defects. Radiology 1976;121:435-9. 13. Gregoratos G, Cheitlin MD, Conill A, et al. ACC/AHA Guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the ACC/AHA task force on practice guidelines (committee on pacemaker implantation). J Am Coll Cardiol 1998;31:1175-1206. 14. First T, Skovranek J. Normal Values of M-mode echocardiographic parameters in children. Cesk Pediatr 1984;39:699-708. 15. Berstein D. History and Physical Examination. In: Behrman RE, Kliegman RH, Jenson HB. Nelson Textbook of Pediatrics 16th edition, W.B. Saunders Company, 2000;1347:table 429-4. 16. Pestman WR. Mathematical Statistics. Berlin, Germany, Walter de Gruyter Verlag, 1998; section II.7. 17. Sholler GF, Walsh EP. Congenital complete heart block in patients without anatomic cardiac defects. Am Heart Journal 1989;118:1193-8. 18. Eronen M, Siren MK, Ekblad H, et al. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86-91. 19. Udink ten Cate FEA, Breur JMPJ, Cohen MI et al. Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children. J Am Coll Cardiol 2001;37:1129-34. 20. Taylor-Albert E, Reichlin M, Toews WH, et al. Delayed dilated cardiomyopathy as a manifestation of neonatal lupus: case reports, autoantibody analysis, and management. Pediatrics 1997;99:733-5. 85 Chapter 5 86 Endocardial & epicardial leads C H A P T E R Endocardial and Epicardial Steroid Lead Pacing in the Neonatal and Pediatric Age Group Udink ten Cate FEA, Breur JMPJ, Boramanand N, Crosson JE, Friedman AH, Brenner JI, Meijboom EJ, Sreeram N. Heart 2002;88:392-6. Chapter 6 ABSTRACT Objectives. To compare the performance of steroid eluting epicardial and endocardial leads in infants and children requiring permanent pacing. Methods. Evaluation of pacing and sensing characteristics, impedances and longevity of 159 steroid eluting leads implanted in 95 children. Group A consisted of 24 children weighing less than 15 kg with 15 endocardial leads (5 atrial; 10 ventricular) and 19 epicardial leads (5 atrial; 14 ventricular). Group B consisted of 71 children weighing more than 15 kg with 106 endocardial leads (56 atrial; 58 ventricular) and 19 epicardial leads (9 atrial; 10 ventricular). Results. Group A: Stimulation thresholds were lower for ventricular endocardial leads at implant (atrial: 0.92 ± 0.57 v 1.13 ± 0.09, not significant (NS); ventricular: 0.84 ± 0.54 v 1.59 ± 0.64, p < 0.014) and at two year follow up (atrial: 0.57 ± 0.11 v 0.85 ± 0.35 (NS); ventricular: 0.64 ± 0.24 v 1.65 ± 0.69, p < 0.003). Impedance and sensing thresholds did not differ significantly at implant and follow up. Group B: Stimulation thresholds were lower for ventricular endocardial leads at implant (atrial: 0.73 ± 0.53 v 0.90 ± 0.40, NS; ventricular: 0.72 ± 0.48 v 1.48 ± 0.58, p < 0.001) and at follow up (atrial: 0.74 ± 0.35 v 0.91 ± 0.53, NS; ventricular: 0.88 ± 0.46 v 1.55 ± 0.96, p < 0.009). Impedance did not differ. Sensing thresholds were also better for ventricular endocardial leads at follow-up (ventricular: 9.1 ± 5.2 v 14.2 ± 6.4, p < 0.02). Complications requiring intervention occured in both groups (n= 7 for endocardial vs n= 18 for epicardial leads). Conclusions. Endocardial and epicardial steroid eluting leads have comparable performance in the pediatric population. 88 Endocardial & epicardial leads ENDOCARDIAL & EPICARDIAL LEADS INTRODUCTION The introduction of steroid eluting pacing leads in the pediatric population has resulted in a notable improvement of lead performance and pacemaker longevity.1-5 Several studies have shown encouraging advantages using epicardial and endocardial steroid eluting leads instead of conventional non-steroid leads.6-14 The addition of steroid-elution limits the inflammatory response at the electrode-tissue interface, resulting in better acute and chronic stimulation thresholds and improved battery longevity.15 There has been no systematic comparison of steroid eluting endocardial and epicardial leads in the pediatric age-group. We report the results of a retrospective multicenter review comparing the performance and longevity of steroid eluting epicardial and endocardial leads in the pediatric population requiring permanent pacemaker therapy between August 1990 and February 2000. METHODS Study patients. The study group compromised all neonatal and pediatric patients who presented to one of the three tertiary referral centres between August 1990 and February 2000 for implantation of a permanent pacing device with steroid eluting leads. In all, 95 patients underwent implantation of 121 endocardial and 38 epicardial steroid eluting leads (endocardial: 59 active fixation and 62 passive fixation; 101 bipolar and 20 unipolar; epicardial: 7 bipolar and 31 unipolar). We reviewed patient and pacing data of all 95 children retrospectively and compared the performance and survival rate of endocardial and epicardial steroid eluting leads. Patients were assigned into two groups: group A (neonates and small children) comprised 24 children weighing < 15 kg and group B consisted of 71 children weighing > 15 kg. Patient characteristics and indications for pacing are shown in Table 1. Group A showed no difference in patient demographics and characteristics. Age and weight at pacemaker implantation were significantly different between patients in group B who received endocardial or epicardial steroid eluting leads. The choice for epicardial or endocardial pacing systems in this study was based on institutional preference and experience of the cardiologist. The evaluated pacing measurements included stimulation voltage thresholds with a pulse width of 0.5 ms, sensing thresholds (P and R wave amplitudes), and impedances. At least one follow up measurement was available for all children. Patients were also reviewed for complications requiring reoperations or additional diagnostic testing during follow up. Lead failure was defined as unacceptably high thresholds making lead revision necessary. 89 Chapter 6 Pulse generators and Steroid-eluting leads. Mode of pacing, implanted generators and steroid eluting leads in group A and B are shown in Table 2 and 3 respectively. Group A consisted of 15 endocardial (5 atrial; 10 ventricular leads) and 19 epicardial steroid-leads (5 atrial; 14 ventricular leads). Group B consisted of 106 endocardial steroid (49 atrial; 57 ventricular leads), 8 endocardial non-steroid leads (7 atrial; 1 ventricular leads) and 19 epicardial steroid-leads (9 atrial; 10 ventricular leads). TABLE 1 Study Characteristics of 95 Pacemaker Patients Group A Group B Endocardial Epicardial Leads Leads n 10 14 M/F 5/5 7/7 (years) 1.4 ± 1.1 (kg) Follow-up (years) Indication n Endocardial Epicardial Leads Leads 61 10 NS 31/30 5/5 NS 1.5 ± 1.1 NS 15.0 ± 5.1 9.7 ± 7.5 < 0.05 10.3 ± 4.5 8.5 ± 3.8 NS 41.8 ± 18.5 27.0 ± 15.7 < 0.02 2.0 ± 1.0 2.4 ± 2.2 NS 2.1 ± 1.9 2.8 ± 1.3 NS post-operative block 4 (40%) 4 (29%) NS 25 (41%) 8 (80%) NS CCAVB* 5 (50%) 7 (50%) NS 24 (39%) 1 (10%) NS 0 3 (21%) < 0.012 0 0 0 0 9 (15%) 1 (10%) NS 1 (10%) 0 1 (2%) 1 (10%) NS 0 0 2 (3%) 0 NS Number of Patients Sex Age at Implantation Weight at Implant 2nd degree block SN dysfunction long QTsyndrome cardiac arrest P NS P Data presented are mean values ± SD or number (%) of patients. * CCAVB= congenital complete atrioventricular block; NS = significant difference; SN = sinus node. Group A = children weighing < 15 kg; Group B: children weighing > 15 kg. Statstical analysis. Study characteristics of group A and group B were compared using Student’s t-test for continues data and Chi-square analysis or Fisher’s exact test for binary variables. Data were presented as mean ± 1 SD. Follow-up data of lead performance were analyzed using paired t-test. P values of less than 0.05 was considered statistically significant for all tests. 90 Endocardial & epicardial leads RESULTS Stimulation threshold. Group A: Atrial stimulation thresholds at implant and at two year follow up were lower for endocardial steroid leads, but no statistical analysis could be undertaken owing to the small numbers. Ventricular stimulation thresholds were lower for endocardial leads than for epicardial leads both at implant (p < 0.014) and at two year follow up (p < 0.003) (Table 4). During follow up there was a decrease in stimulation threshold for endocardial steroid leads. Group B: Stimulation thresholds were similar for atrial leads at implant and at two year follow up in the two groups. Ventricular stimulation thresholds were lower for endocardial leads than for epicardial leads both at implant (p < 0.001) and at two year follow up (p < 0.009). TABLE 2 Pulse Generators and Pacing Mode Group A Endocardial Epicardial Group B Endocardial Epicardial (n= 10) (n= 14) (n= 61) (n= 10) Gem II (Medtronic) - - 1 - Kappa (Medtronic) - 1 24 2 Legend (Medtronic) - 3 1 3 10 10 15 5 Affinity (Pacesetter) - - 7 - Synchrony (Pacesetter) - - 6 - Trilogy (Pacesetter) - - 2 - Paragon (Pacesetter) - - 3 - Delta (CPI) - - 2 - DDD 5 (50%) 5 (36%) 53 (86%) 9 (90%) VVI 5 (50%) 9 (64%) 3 (5%) 1 (10%) AAI - - 3 (5%) - VDD - - 1 (2%) - Cardioverter - - 1 (2%) - Generator (Company) Thera (Medtronic) Pacing Mode Medtronic, Inc., Minneapolis, MN; Pacesetter, Inc., Sylmar, CA; Cardiac Pacemakers Inc., St. Paul, MN 91 Chapter 6 Lead impedance. Group A: Atrial lead impedance at implant and at the two year follow up was higher for endocardial steroid leads. Ventricular lead impedance was similar at implant and at the two year follow up for both endocardial and epicardial leads (Table 4). During follow up, impedance did not change for endocardial leads but decreased for epicardial leads. Group B: Impedance for atrial leads and ventricular leads at implant and at two year follow up did not differ significantly between endocardial and epicardial leads. Sensing thresholds. Group A: P wave amplitudes at implant were lower for endocardial leads than for epicardial leads. At the two year follow up P wave amplitudes were similar for both endocardial and epicardial leads (Table 4). R wave amplitudes were not significantly different at implant and the two year follow up. Group B: P wave amplitudes at implant and two year follow up did not differ significantly. R wave amplitudes of endocardial leads were lower at implant, and remained lower at two year follow up (p < 0.02). There were no significant intraindividual differences for pacing thresholds, sensing thresholds and impedances at each follow up visit. Complications & further procedures. Group A: No early complications requiring medical intervention occurred in children weighing less than 15 kg who received endocardial pacing systems. Six patients with epicardial pacemakers had procedure related or other complications: postpericardiotomy syndrome (n= 2, requiring hospitalization), pneumothorax (n= 1), abdominal hernia at pacemaker location (n= 1, the hernia was surgically corrected), displacement of atrial lead (n= 1), ventricular lead failure (n= 1). Late complications occurred in one endocardially paced patient who developed pacemaker syndrome 1.5 years after implantation of a VVIR pacemaker. Her pacemaker system was upgraded to a dual chamber device through the same subclavian vein. Pacemaker replacement was required in five patients who received epicardial leads because of battery depletion, 2.1 ± 1.0 years after implantation. Medical re-interventions occurred more often in patients receiving epicardial leads during two year follow up. Group B: Early complications in endocardially paced patients occurred in two patients who required repositioning of their atrial leads. Postpericardiotomy syndrome complicated the early postoperative period in two epicardially paced patients, and wound infection in one patient. Late interventions were required in four patients with endocardial leads and in five patients with epicardial leads. Two endocardially paced patients required repositioning of their atrial leads 2.1 and 2.4 years after implant. Pacemaker replacement because of battery depletion was necessary in two patients, 3.0 and 4.0 years after implant. Three patients with epicardial leads required lead replacement (two atrial; one ventricular) owing to unacceptably high thresholds, at 1.0, 1.5 and 1.8 year after implant, respectively. Pacemaker replacement was required in two patients, 1.5 and 2.8 years after implantation. There was no significant difference in lead survival comparing endocardial and epicardial leads in group B. 92 Endocardial & epicardial leads TABLE 3 Characteristics of Endocardial and Epicardial steroid-eluting leads ENDOCARDIAL Group A Atrial Ventricular (n= 5) (n= 10) Group B Atrial Ventricular (n= 49) (n= 57) Medtronic 4023 - 1 - 2 4024 - - 1 - 4033 - 2 - 11 4067 1 2 1 11 4068 3 4 19 9 4533 1 - 2 - 4568 - - 5 - 5024 - - - 5 5038 - - - 1 5068 - - 1 3 5076 - 1 - - 5524 - - 4 3 5534 - - 2 - 5523 - - 1 - 6945 - - - 1 Tendril DX 1388 T - - 8 5 CPI 4168 - - 1 1 4268 - - 1 1 4269 - - 3 5 EPICARDIAL Group A Atrial Ventricular (n= 5) (n= 14) Medtronic 2823 4965 4968 10366 1 2 2 1 8 2 3 Group B Atrial Ventricular (n= 9) (n= 10) 3 6 3 1 1 5 Medtronic, Inc., Minneapolis, MN; Pacesetter, Inc., Sylmar, CA; Cardiac Pacemakers, Inc., St. Paul, MN 93 Chapter 6 Active fixation versus passive fixation. In all, 59 endocardial active fixation leads (30 atrial; 29 ventricular leads) and 62 endocardial passive fixation leads (31 atrial; 31 ventricular leads) were implanted in 71 patients. Atrial and ventricular stimulation thresholds were not significantly different at implant (atrial: 0.73 ± 0.32 V v 0.74 ± 0.38 V, p > 0.10; ventricular: 0.71 ± 0.28 V v 0.57 ± 0.36 V, p > 0.10) or at the two year follow up (atrial: 0.55 ± 0.15 V v 1.10 ± 0.70 V, p > 0.10; ventricular: 0.69 ± 0.34 V v 0.92 ± 0.65 V, p > 0.10). Atrial and ventricular lead impedance did not differ significantly between active and passive fixation leads at implant (atrial: 553.7 ± 119.9 Ω v 580.1 ± 168.9 Ω, p > 0.10; ventricular: 629.3 ± 157.4 Ω v 633.8 ± 171.6 Ω, p > 0.10) or at the two year follow up (atrial: 628.9 ± 96.2 Ω v 675.6 ± 203.8 Ω, p > 0.10; ventricular: 576.2 ± 81.6 Ω v 664.2 ± 246.6 Ω, p > 0.10). P wave and R wave amplitudes did not differ significantly at implant (atrial: 3.13 ± 1.49 mV v 3.49 ± 1.34 mV, p > 0.10; ventricular: 8.66 ± 3.19 mV v 9.59 ± 4.11 mV, p > 0.10) or at the two years after implantation (2.88 ± 1.19 mV v 3.20 ± 1.71 mV, p > 0.10; ventricular: ventricular 9.21 ± 2.52 mV v 8.03 ± 2.83 mV, p > 0.10). DISCUSSION Background. Most children requiring permanent pacemaker therapy receive their pacemaker by the epicardial approach.4,5 The reasons for preferring the epicardial approach are patient size and anatomic considerations in patients with abnormal venous connections or complex congenital heart defects. Implantation of endocardial leads in young patients also has to take account of somatic growth,10-14 which will require further advancement of the lead. The major concern with endocardial leads is the risk of venous thrombosis.7 There are no large studies addressing this issue in young patients with endocardial pacing systems, but lead size relative to the size of the vein appears to be an important factor in determining this risk. On the other hand, the technique of epicardial permanent pacing is more invasive, often involving sternotomy. It is often complicated by post-pericardiotomy syndrome.9 Standard (non-steroid eluting) epicardial leads have been associated with a high incidence of rapidly increasing pacing and sensing thresholds following implantation, requiring early lead and generator replacement. In a recent publication, steroid eluting epicardial leads compared favourably with standard (non-steroid eluting) endocardial leads.7 There has, however, been no study to date comparing endocardial and epicardial steroid eluting leads in children. 94 Chapter 6 TABLE 4 Pacing, Sensing Characteristics and Impedances at Implant and Follow-up Group A Endocardial Epicardial Leads Leads ACUTE Atrial Leads Stimulation threshold Impedance Sensing threshold CHRONIC Atrial Leads Stimulation threshold Impedance Sensing threshold n 5 (V) 0.92 ± 0.57 (Ohms) 639 ± 148 (mV) 2.9 ± 1.1 n 4 (V) 0.57 ± 0.11 (Ohms) 626 ± 136 (mV) 3.0 ± 1.8 P 3 1.13 ± 0.09 552 ± 129 4.5 ± 1.6 - 2 0.85 ± 0.35 609 ± 152 3.9 ± 1.5 - Group B Endocardial Epicardial Leads Leads 51 9 0.73 ± 0.33 563 ± 163 3.4 ± 1.6 0.90 ± 0.40 615 ± 142 3.0 ± 1.6 19 9 0.74 ± 0.35 612 ± 189 3.1 ± 1.5 0.91 ± 0.53 591 ± 116 3.9 ± 2.0 55 11 P NS NS NS NS NS NS ACUTE Ventricular Leads n 9 13 Stimulation threshold (V) 0.84 ± 0.54 1.59 ± 0.64 < 0.014 0.72 ± 0.48 1.48 ± 0.58 < 0.001 (Ohms) (mV) 697 ± 162 9.7 ± 4.9 610 ± 180 12.8 ± 7.2 NS NS 656 ± 183 9.1 ± 6.2 683 ± 197 12.6 ± 7.4 NS NS n 7 8 24 10 0.88 ± 0.46 633 ± 183 9.1 ± 5.2 1.55 ± 0.96 625 ± 178 14.2 ± 6.4 Impedance Sensing threshold CHRONIC Ventricular Leads Stimulation threshold Impedance Sensing threshold (V) 0.64 ± 0.24 (Ohms) 716 ± 282 (mV) 9.6 ± 1.9 1.65 ± 0.69 548 ± 225 9.6 ± 3.3 < 0.003 NS NS < 0.009 NS < 0.02 Data presented are mean values ± SD or number (%) of patients. - = No statistical analysis could be performed due to a small number of measurements. Group A = children weighing < 15 kg; Group B weighing > 15 kg. NS = no significant difference. The present study. This study shows improved pacing thresholds for ventricular endocardial steroid eluting leads versus epicardial steroid eluting leads during short term follow up. At atrial level, no significant differences were observed. More epicardial leads and generators needed to be replaced for early lead or generator failure. In addition, there were fewer procedure related complications associated with implantation of an endocardial pacemaker system. Most implanted endocardial systems in neonates and small children are single chamber ventricular pacemaker. Interestingly, during the study period the majority of epicardial pacemaker systems implanted at our institutions were also single chamber systems. This 95 Chapter 6 was true both for patients requiring pacemaker implantation for congenital atrioventricular (AV) block and those with acquired AV block following open heart surgical procedures for congenital heart defects. Two patients in our series who required pacing for congenital AV block developed dilated cardiomyopathy at follow up. This occurred exclusively in patients with dual chamber epicardial pacemaker systems. This study demonstrates the efficacy of transvenous pacing, even in young infants. However, more needs to be learned about the potential for vascular complications in young patients receiving transvenous leads. None of the patients has required abandonment of a non-functional lead in the vascular system at short term follow up. This is evidently important, considering the lifelong requirement for pacemaker treatment and therefore the need for unobstructed vascular access. Newer techniques for recanalization of occluded vessels using a laser sheath16,17 are at present only applicable to larger children, and are not without complications. Study limitations. There was a significant difference in the age distribution and weight at implant between patients receiving endocardial or epicardial leads in group B, the endocardially paced patients being older. This reflects institutional bias in choice of method for permanent pacing, with the majority of centers choosing an epicardial pacemaker system in relatively younger patients. Various pulse generators were used in the three centers and epicardial leads were predominantly unipolar, whereas 83% of endocardial leads were bipolar. This may also contribute to the differences in lead survival and pacing characteristics. Conclusions. This study shows comparable lead performances for endocardial and epicardial steroid eluting leads. Despite the apparently higher incidence of complications associated with epicardial pacing, epicardial permanent pacing in smaller children with preservation of the veins for later use appears to be a rational approach to pacing treatment in the pediatric population. 96 Endocardial & epicardial leads REFERENCES 1. Santini M, De Seta F, The Italian multicenter study group on low output stimulation. Do steroid-eluting electrodes really have better performance than other state-of-the-art designs? Pacing Clin Electrophysiol 1993;16:722-728. 2. Stojanov P, Djorjevic M, Velimirovic D, Belkic K. Assessment of long-term stability of chronic ventricular pacing thresholds in steroid-eluting electrodes. Pacing Clin Electrophysiol 1992;16:1417-1420. 3. Kruse IB. Long-term performance of endocardial leads with steroid eluting electrodes. Pacing Clin Electrophysiol 1986;9:1217-1219. 4. Goldman-Cutler N, Karpawich PP, Cavitt D, Hakimi M, Walters HL. Steroid-eluting epicardial pacing electrodes: six year experience of pacing thresholds in a growing pediatric population. Pacing Clin Electrophysiol 1997;20:2943-2948. 5. Johns JA, Fish FA, Burger JD, Hammon JW. Steroid-eluting epicardial pacing leads in pediatric patients: encouraging early results. J Am Coll Cardiol 1992;20:395-401. 6. Wiegand UKH, Potratz J, Bonnemeier H, et al. Long-term superiority of steroid elution in atrial active fixation platinum leads. Pacing Clin Electrophysiol 2000;23:1003-1009. 7. Beaufort-Krol GCM, Mulder H, Nagelkerke D, Waterbolk TW, Bink-Boelens MTh. Comparison of longevity, pacing, and sensing characteristics of steroid-eluting epicardial versus conventional endocardial pacing leads in children. J Thorac Cardiovasc Surg 1999;117:523-528. 8. Radovsky AS, Van Vleet JF, Stokes KB, Tacker Jr WA. Paired comparisons of steroid-eluting and nonsteroid endocardial pacemakers in dogs: Electrical performance and morphologic alterations. Pacing Clin Electrophysiol 1988;11:1085-1094. 9. Gillette PC, Shannon C, Blair H, Garson A, Porter CJ, McNamara DG. Transvenous pacing in pediatric patients. Am Heart J 1983;105:843-7. 10. Ward DE, Jones S, Shinebourne EA. Long-term transvenous pacing in children weighing ten kilograms or less. Int J Cardiol 1987;15:112-5. 11. Till JA, Jones S, Rowland E, Shinebourne EA, Ward DE. Endocardial pacing in infants and children 15 kg or less in weight: medium-term follow-up. Pacing Clin Electrophysiol 1990;13:1385-92. 12. Molina J, Dunnigan AC, Crosson JE. Implantation of transvenous pacemakers in infants and small children. Ann Thorac Surg 1995;59:689-94. 13. Epstein ML, Knauf DG, Alexander JA. Long-term follow-up of transvenous cardiac pacing in children. Am J Cardiol 1986;57:889-90. 14. Gillette PC, Zeigler V, Bradham GB, Kinsella P: Pediatric transvenous pacing: a concern for venous thrombosis? Pacing Clin Electrophysiol 1988;11:1935-39. 15. Mond HG, Stokes KB. The electrode-tissue interface: the revolutionary role of steroid elution. Pacing Clin Electrophysiol 1992; 15:95-107. 16. Bracke FA, Van Gelder LM, Sreeram N, Meijer A. Exchange of pacing or defibrillator leads following laser sheath extraction of non-functional leads in patients with ipsilateral obstructed venous access. Heart 2000;83:e12. 17. Madigan NP, Curtis JJ, Sanfelippo JF. Difficulty of extraction of chronically implanted tined ventricular endocardial leads. J Am Coll Cardiol 1984;3:724-731. 97 Chapter 6 98 C H A P T E R General Discussion & Conclusions Chapter 7 GENERAL DISCUSSION & CONCLUSIONS Since the first description of congenital heart block in 1901 by Morquio, much has been learned about the nature of this intruiging disorder. It was not untill the ‘80s when an association between maternal anti-SSA/Ro – anti-SSB/La antibodies and the development of CCAVB in their offspring was suggested. These early observations has been of fundamental importance in the understanding of this passively acquired cardiac-autoimmune disease. Later studies were pointed towards a molecular definition of the 52-kD, 60-kD SSA/Ro and 48-kD SSBLa antigens and antibodies. Clinical and epidemiologic data showed that antiSSA/Ro and anti-SSB/La antibodies alone were not sufficient to cause disease and it is now generally accepted that additional maternal, fetal or environmental factors are required in the pathogenesis of CCAVB. Several hypothesis have been postulated to explain the development of CCAVB at the molecular level. Physiologic apoptosis and cross-reactivity of anti-SSA/Ro – anti-SSB/La antibodies with other target antigens have been proposed as possible disease mechanisms. However, the exact pathogenetic mechanism which causes the irreversible damage to the heart in susceptible fetuses has yet to be elucidated. This thesis describes the diagnostic and therapeutic features of CCAVB from fetal life to childhood. In addition, the development of dilated cardiomyopathy in a subset of children with CCAVB is described and the recent discussion on (prophylactic) pacemaker therapy in asymptomatic children is reviewed. With the advent of fetal echocardiography most cases of CCAVB are detected in utero before 30 weeks gestation. Serial echocardiographic monitoring of these fetuses has tremendously increased our understanding of the pathogenesis, natural history, management and possible therapeutic options of CCAVB diagnosed in utero. It is known that high titers of maternal anti-SSA/Ro – anti-SSB/La antibodies are transferred across the placenta between 18 and 24 weeks gestation. These antibodies induce an antibody-mediated inflammatory response to a structural normal fetal heart. The inflammation subsequently causes damage and destruction of parts of the cardiac conducting system, particularly the AV node, and myocardium. Clinically this may result in bradycardia, myocarditis and congestive heart failure. The immunopathogenic etiology of CCAVB and the high morbidity and mortality rates in the fetal period has encouraged the search for effective intra-uterine treatments. Different therapeutic regimens have been administered to the mother, which may inhibit inflammation and may decrease maternal antibody-load in the fetal heart, before and after the onset of CCAVB. Others have attempted to increase the fetal heart rate, in order to reverse hydrops 100 General discussion & conclusions fetalis and to prevent further deterioration of the fetal cardiac function. The experience of treatment of fetal congenital heart block is largely based on single case reports. Current therapies have not yet significantly decreased morbidity and mortality rates in fetal life. To date, many questions remain unanswered with regard to the optimal therapeutic options in the fetal period. A large randomized prospective trial has to be initiated to adjust the effectiveness and safety of several proposed therapeutic regimens. It is also possible that most treatments are initiated when the antibody-mediated damage has already been done. Clinical studies have demonstrated that CCAVB probably progresses through stages, which subsequently results in irreversible CCAVB (chapter 2).1-3 Moreover, fetal echocardiography is limited in its ability to detect second-degree heart block, and first-degree heart block may not be detectable at all.4 Taken together, treatment has to be initiated before or in an early stage of the induction of antibody-mediated damage to the heart. Future research should be focused on detecting arrhythmias at an early stage. Fetal magnetocardiography might detect arrhythmias before the pathological cascades are activated which result in irreversible damage. Although this might be an option in women with a previous child with CCAVB or in women with connective tissue diseases and anti-SSA/Ro – anti-SSB/La antibodies, most women first come to medical attention after they have given birth to a child with CCAVB. The prognosis of children with CCAVB after the fetal and neonatal period is in general favorable. Most children receive a pacemaker in their first year of life. Dilated cardiomyopathy (DCM) is of concern in a subgroup of patients with CCAVB. Despite of early institution of a pacemaker, 8% of the children in our cohort developed DCM at a mean followup period of 6.5 ± 5 years. Currently, it is not known why some children develop DCM and other children with CCAVB do not even need pacing. The prognosis among patients with CCAVB and DCM is in general poor (Chapter 4), as the disease is usually well advanced by the time it is diagnosed. Therefore, it is important to identify those patients who are at highest risk for deterioration of their cardiac function and to elucidate the pathogenesis of this myocardial disease in children with CCAVB. Identification of patients with CCAVB and DCM at an earlier stage of the disease, would possibly improve their prognosis by early pharmacological intervention or elective heart transplantation. Both the multicenter design of the study and the size of the study population provided sufficient data to obtain clinical risk factors for those children at risk for the development of DCM. The most important risk factor for the development of DCM was a large left ventricle before pacemaker implantation whithout a pacemaker-associated decrease in cardiac size to a normal or subnormal size. Cardiomegaly is a common finding in children with CCAVB.5 It is also a common and 101 Chapter 7 sometimes reversible feature in the fetal period (see Chapter 2). A normal heart can increase its cardiac output by changes in heart rate, ventricular size and contractility, concordant with the Frank-Starling relationship. The fetus or child with CCAVB has to increase the stroke volume to maintain a sufficient cardiac output. Subsequently, this results in ventricular dilatation, which is clinical apparent on chest radiographs and echocardiographs. It is reasonable to assume that longstanding bradycardia and ventricular dilatation results in structural remodeling and hypertrophy. Furthermore, recent experimental and clinical evidence is emerging to support the notion that perhaps many fetuses sustain mild inflammation without the subsequent initiation of a pathological cascade leading to irreversible CCAVB.6 In addition, fetuses with CCAVB might also sustain a variable degree of inflammation and damage to the cardiac conducting system and myocardium, suggesting that a subset of children with CCAVB are more susceptible for the development of DCM than other children. Therefore, the development of DCM in children with CCAVB is a pre-existing condition which progresses to clinical heart failure in some patients, despite early pacemaker implantation. FUTURE DIRECTIONS Although it is a relatively uncommon complication, a subset of children with CCAVB develop overt DCM during follow-up, despite early institution of a pacemaker. The pathogenesis of myocardial disease in these children with CCAVB has not yet been recognized. Nevertheless, there are no clinical signs and symptoms which may predict those children at highest risk for the develop of DCM. The prognosis among patients with CCAVB and DCM is poor, as the disease is usually well advanced by the time it is diagnosed. Therefore, identification of patients at an earlier stage of the disease and initiation of early pharmacological intervention may hopefully have a positive impact on prognosis. However, heart size alone and absence of pacemaker-associated improvement are not sensitive measurements for the detection of DCM in an early stage. A noninvasive marker of early cardiac decompensation would therefore be helpful in monitoring disease progression in patients with CCAVB. Recent reports have shown that plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are known to be sensitive clinical markers of left ventricular (LV) dysfunction in the general population.7,8 The natriuretic peptides are a family of closely related gene products which are synthesized in the ventricular myocardium and atria. Although most studies have been performed in adult cardiology, there may be clinical applications in children with congential heart disease and arrhythmias as well. High levels of ANP have been reported in children with pressure and / or volume overload secondary to congenital heart disease, especially when congestive heart failure is present.9,10 Measuring 102 General discussion & conclusions these natriuretic peptides may be useful in the assessment of children with CCAVB and may predict future DCM. In addition, if there is a correlation between asymptomatic LV dysfunction and natriuretic peptide titers in children with CCAVB, levels of these peptides might also be useful in deciding which asymptomatic patient with CCAVB need pacing. Future prospective studies on the natural history of heart size, using echocardiography in combination with ANP and BNP levels, should be performed in children with CCAVB. 103 Chapter 7 REFERENCES 1. Buyon JP, Kim MY, Copel JA, Friedman DM. Anti-Ro/SSA antibodies and congenital heart block: necessary but not sufficient. Arthritis Rheum 2001;44:1723-7. 2. Gordon PA, Khamashta MA, Hughes GRV, Rosenthal E. A normal ECG at birth does not exclude significant congenital cardiac conduction disease associated with maternal anti-Ro antibodies. Rheumatology 2001;40:939-40. 3. Askanase AD, Friedman DM, Copel J, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies. Lupus 2002;11:145-51. 4. Glickstein JS, Buyon JP, Friedman DM. Pulsed doppler echocardiographic assessment of the fetal PR interval. Am J Cardiol 2000;86:236-39. 5. Sholler GF, Walsh EP. Congenital complete heart block in patients without anatomic cardiac defects. Am Heart J 1989;118:1193-8. 6. Rosenthal E. Spectrum of conduction abnormalities associated with maternal anti-Ro antibodies. Lupus 2002;11:135-6. 7. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321-8. 8. Maisel A. B-type natriuretic peptide levels: diagnostic and prognostic in congestive heart failure. What’s next? Circulation 2002;105:2328-31. 9. Tulevski II, Groenink M, van der Wall EE, et al. Increased brain and atrial natriuretic peptides in patients with chronic right ventricular pressure overload: correlation between plasma neurohormones and right ventricular dysfunction. Heart 2001;86:27-30. 10. Bidlingmaier JW, Döhlemann C, Kuhnle U, Strom T, Lang RE. Comparison of plasma atrial natriuretic peptide levels in healthy children from birth to adolescence and in children with cardiac diseases. Pediatr Res 1986;20:1328-31. 104 C H A P T E R Summary Samenvatting Chapter 8 SUMMARY INTRODUCTION Congenital complete atrioventricular block (CCAVB) is a rare cardiac conduction disorder with an estimated incidence of 1 in 11 000 to 22 000 live births. In approximately 25% of the patients, co-existing congenital heart disease can be identified, which causes discontinuity of the conducting pathway between atria and ventricles. However, most patients have structurally normal hearts and CCAVB in these cases is associated with maternal antibodies immunoreactive with 52-kDa SSA/Ro, 60-kDa SSA/Ro and 48-kDa SSB/La ribonucleoproteins. Maternal connective tissue disease (CTD), i.e. systemic lupus erythematosus (SLE), Sjögen’s syndrome (SS) or mixed connective tissue disease (MCTD), is present in 30 – 50% of mothers who give birth to a child with CCAVB. However, most women do not have signs and symptoms of autoimmune disease at the time of birth of a child with CCAVB, but they are at risk of developing CTD at follow-up. The pathogenesis of CCAVB is thought to result from the transplacental passage of maternal anti-SSA/Ro and anti-SSB/La antibodies to the fetal circulation between 16 – 24 weeks gestation. The antibody-mediated inflammatory response may damage the fetal cardiac conducting system and myocardium, ultimately resulting in scarring and fibrosis of the AV node, resulting in irreversible CCAVB. Clinical and laboratory studies suggest that anti-SSA/Ro and anti-SSB/La antibodies are necessary but not sufficient to cause CCAVB. Maternal anti-SSA/Ro and anti-SSB/La antibodies can be detected in up to 95% of women who give birth to a child with CCAVB. It has been demonstrated that anti-SSA/Ro antibodies perturb ion influx in fetal cardiomyocytes, providing evidence for a direct arrhythmogenic effect of these antibodies. However, if anti-SSA/Ro antibodies are present in the sera of pregnant women, the risk of CCAVB has been reported to be only 1 – 5%. By contrast, the estimated recurrence risk is approximately 16 – 20%. Moreover, there is no explanation for the discordancy of CCAVB in monozygotic, i.e. HLA identical, twins. Taken together, there is strong evidence to suggest that additional, not yet identified, factors are necessary in the pathogenesis of CCAVB. Proposed mechanisms of pathogenesis include apoptosis and cross-reactivity of maternal antibodies with L-type calcium channels and other antigens. A molecular basis for the pathogenetic cascade of events, subsequently resulting in fibrosis of the AV-node, has yet to be defined. At present, CCAVB is usually detected in utero by fetal echocardiography during the second trimester of pregnancy. The presenting manifestation of fetal CCAVB is bradycardia in many cases, although myocarditis/endocarditis, hydrops fetalis and congestive heart 106 Summary failure are frequent associated features. Fetal outcome depends largely on heart rate and development of fetal hydrops. A heart rate of less than 55 beats per minute (bpm) and/or hydrops fetalis is associated with poor outcome. The diagnosis of fetal autoimmune-CCAVB is based on the echocardiographic demonstration of complete dissociation of atrial and ventricular rates. Treatment of fetal congenital heart block (CHB) has focused on established CCAVB and prophylactic treatment in high-risk pregnancies and pregnancies of women with known anti-SSA/Ro antibodies. Several attempts have been made to decrease the maternal antibody-titer and to diminish the inflammatory damage to the fetal heart. Other treatment options has been applied to increase the fetal heart rate with maternal administration of betaadrenergic agents, or with pacemaker leads placed into the fetal heart. Unfortunately, none of these strategies has significantly changed fetal outcome, and fetal CHB is associated with high morbidity and mortality. More than 60% of children with CCAVB eventually require permanent pacemaker (PM) therapy. One of the most discussed issues in the management of patients with CCAVB is when to implant a pacemaker device in the asymptomatic patient. Another important consideration in the management of CCAVB in infancy and childhood is to the type of lead and device to be implanted. There is disagreement with regard to the feasability and safety of transvenous leads in children weighing less than 15 kg. Most children receive their PM by the epicardial approach. The reasons for preferring the epicardial approach are patient size and anatomic considerations in patients with complex congenital heart defects. Implantation of endocardial leads in young patients also has to take account of somatic growth, which will require further advancement of the lead. The major concern of the transvenous approach is the risk of venous thrombosis. A new observation is that a subset of CCAVB patients develop dilated cardiomyopathy (DCM) during follow-up, despite of PM therapy. RESULTS Chapter 1 reviews what is currently known about the intracellular SSA/Ro–SSB/La antigen complex, describes the pathogenesis of CCAVB, and the advances made in diagnostic and therapeutic options from fetal life to childhood. The aims and outline of this thesis are presented. In Chapter 2 our experience with fetal CHB, its follow-up, treatment and management is described. Fifteen fetuses with CHB of 13 women were identified and monitered for a median of 14 weeks (range 1 to 21). In all, 113 prenatal echocardiographic reports were reviewed. CHB was detected at a median age of 24 weeks gestation (range 18 to 37). Maternal SSA/Ro-SSB/La antibodies were detected in 12/13 (92%) women and autoimmune disease was present in 6/13 (46%) mothers. Maternal dexamethasone treatment was initiated in 107 Chapter 8 three cases. In one fetus to reverse second-degree AV block, and in two fetuses for treatment of congestive heart failure (CHF). CHF improved after initiation of dexamethasone administration. However, dexamethasone did not prevent progression of second-degree AV block to CCAVB. Moreover, dexamethasone induced mild adrenal insuffiency in this child, presenting with hypoglycaemia in the newborn period. The majority of the fetuses (53%) maintained the same ventriculra heart rate (VHR) during pregnancy. In some, VHR decreased significantly with advancing gestation, and fetal hydrops and CHF subsequently developed, particularly when VHR dropped below 55 bpm. This suggests a relation between heart rate and deterioration of cardiac function. Cardiomegaly and cardiac hypertrophy developed in 10 fetuses, and represent adaptation of the changed cardiac physiology to the low heart rate. Furthermore, pericardiopleural effusion and ascites are common findings on serial echocardiographic evaluation, resolving and reappearing spontaneously or after treatment in some fetuses. The cumulative probability of 1year survival was 87%. One fetus died in utero of DCM. The neonatal morbidity was high (53%) and PMs were implanted in 11 children (73%). In Chapter 3 we report a 29-year old woman with SLE and secondary SS who gave birth to three children with neonatal lupus erythematosus (NLE) in three successive pregnancies. Two children presented with fetal CHB. The second child had CCAVB, requiring PM therapy, and presented with hematological abnormalities and lupus dermatitis after birth. Her last pregnancy resulted in a neonate with skin rash and trombocytopenia. All non-cardiac manifestation of NLE resolved spontaneously during infancy. Although CCAVB constitutes the most serious and permanent manifestation of NLE, many children born to mothers with anti-SSA/Ro and anti-SSB/La antibodies may develop hematological, cutaneous or liver abnormalities. Of all affected children, only a small number express more than one manifestation of NLE. Therefore, this case represents a very unusual cohort of successive siblings with a broad spectrum of cardiac and non-cardiac manifestations of NLE. In Chapter 4 we sought to assess the incidence of dilated cardiomyopathy and to identify risk factors which may predict the development of DCM in children with CCAVB. The study group comprised 149 children with CCAVB and PMs were implanted in 111 patients. Nine paced children (8%) developed DCM at a mean age of 6.5 ± 5.0 years. None of the unpaced group developed DCM during follow-up. When we compared all chest radiographs and echocardiographs, there were some significant differences in heart size of children with CCAVB who developed DCM and those who did not develop DCM. The most important risk factors for the development of DCM was a large left ventricle before pacing, without a pacemaker-associated decrease in cardiac size to a normal or subnormal size. Patients with 108 Summary CCAVB may require monitoring of their ventricular size and function during follow-up. We believe that those children who develop DCM despite of pacing, sustained severe antibodymediated cardiac damage in the fetal period. The development of DCM in children with CCAVB is a pre-existing condition which progresses to clinical heart failure in some patients. In Chapter 5, the natural history of cardiac enlargement and left ventricular (LV) function is assessed using chest radiographs and serial echocardiographic studies in 102 paced and 38 non-paced children with CCAVB during long-term follow-up. Cardiomegaly and hyperdynamic ventricular function are common findings in paced and unpaced children with CCAVB. The results of this study demonstrate that pacing is associated with a decrease in cardiac size and normalization of shorthening fraction (SF). LV enlargement in most unpaced patients continue to progress to or over the 90%ile corrected for bodyweight, and may represent an unfavorable hemodynamical state. Interestingly, left ventricular end-diastolic dimension (LVEDD), SF, and cardiothoracic ratio (CTR) measurements in asymptomatic patients, responded better to PM therapy than patients who suffered from bradycardia related symptoms at the time of PM implant. Symptomatic patients are likely to have severe LV dilation and cardiomegaly and are less likely to have resolution of these abnormalities after PM implantation. Furthermore, 8/40 symptomatic paced children developed DCM, suggesting that heart size may be a relative indication for pacing. The type of lead placement shows a significant difference in the intervention-free interval between transvenous and epicardial. A recommendation for epicardial lead placement seems warranted. However, since PM technology and experience are improving, this view may change over time once the long-term outcome of vein patency in patients with transvenous pacing leads placed as infants will be determined. No difference in cardiac size was recorded between single-chamber (ventricular, VVI) and dual-chamber (atrioventricular, DDD) pacing mode. Chapter 6 compares the pacing and sensing characteristics, impedances and longevity of 159 steroid eluting epicardial and endocardial leads in infants and children requiring permanent pacing. In all, 95 patients underwent implantation of 121 endocardial and 38 epicardial steroid eluting leads. Furthermore, group A (neonates and small children) comprised 24 children weighing < 15 kg and group B consisted of 71 children weighing > 15 kg. This study shows comparable lead performances for endocardial and epicardial steroid eluting leads in both age-groups. Despite the apparently higher incidence of complications associated with epicardial pacing, epicardial permanent pacing in smaller children with preservation of the veins for later use appears to be a rational approach to pacing treatment in the pediatric population. 109 Chapter 8 DISCUSSION & CONCLUSIONS Chapter 7 discusses the results of this thesis and directions for future research are proposed. 110 Samenvatting SAMENVATTING INLEIDING Het congenitale complete atrioventriculaire blok (CCAVB) is een zeldzame hartgeleidingsstoornis met een incidentie van 1 op 11.000 – 22.000 levendgeborenen. In 25% van de patiënten met deze hartritmestoornis wordt een aangeboren hartafwijking gevonden, die de discontinuiteit tussen atria en ventrikels veroorzaakt. De meeste patiënten hebben een normaal aangelegd hart en wordt het CCAVB geïnduceerd door maternale autoantistoffen gericht tegen 52-kD en 60-kD SS-A/Ro en 48-kD SS-B/La ribonucleoproteinen. Ongeveer 30 – 50% van de moeders die een kind met CCAVB krijgen hebben zelf een autoimmuunziekte, zoals systemische lupus erythematosus (SLE), Sjögren’s syndroom (SS) of mixed connective tissue disease (MCTD). De meeste moeders hebben zelf geen klachten die kunnen passen bij een auto-immuunziekte. Van deze groep asymptomatische vrouwen ontwikkelt een aanzienlijk deel alsnog een auto-immuunziekte. Een belangrijke eerste stap in de pathogenese van CCAVB is het transplacentale transport van maternale anti-SSA/Ro en anti-SSB/La antistoffen naar de foetale circulatie gedurende het tweede trimester van de zwangerschap. Deze maternale autoantistoffen veroorzaken inflammatoire schade aan het foetale geleidingssysteem en myocardium, wat uiteindelijk resulteert in fibrosering van de AV-knoop. Klinische en experimentele studies tonen aan dat de maternale anti-SSA/Ro en antiSSB/La antistoffen noodzakelijk zijn in de pathogenese van CCAVB, maar dat de aanwezigheid van deze antistoffen in de bloedsomloop van het kind alleen niet voldoende is. Anti-SSA/Ro en anti-SSB/La antistoffen komen bij meer dan 95% van de moeders van een kind met CCAVB voor. Daarnaast is bekend dat anti-SSA/Ro antistoffen de influx van ionen in cardiomyocyten kunnen verstoren. Ondanks deze aanwijzingen voor de betrokkenheid van anti-SSA/Ro en anti-SSB/La antistoffen in de pathogenese van CCAVB blijkt dat vrouwen met deze antistoffen een kans van 1 – 5% hebben op het krijgen van een kind met CCAVB. Zelfs bij een eerdere CCAVB zwangerschap is de herhalingskans 16 – 20%. Ook een monozygote tweelingzwangerschap betekent niet automatisch dat beide kinderen CCAVB ontwikkelen. Dit impliceert dat nog onbekende, additionele factoren verantwoordelijk zijn voor het ontstaan van CCAVB. Zowel apoptose als kruis-reactiviteit van anti-SSA/Ro en antiSSB/La antistoffen met L-type calcium kanalen of andere antigenen spelen waarschijnlijk een belangrijke rol in de pathogenese. Met foetale echocardiografie wordt het CCAVB vaak rond een zwangerschapsduur van 1824 weken gedetecteerd. CCAVB presenteert zich meestal als een persisterende foetale bradycardie. Vaak zijn ook tekenen van myocarditis/endocarditis, hydrops foetalis of hartfalen aanwezig. De prognose van de foetus met CCAVB is vooral afhankelijk van het 111 Chapter 8 ventriculaire ’escape’ ritme en het optreden van hydrops foetalis. Een lage hartfrequentie (<55 slagen/min) en/of het onstaan van hydrops foetalis zijn beide geassocieerd met een slechte prognose. Het echocardiogram bij CCAVB toont een dissociatie tussen het atriale en ventriculaire hartritme: geen enkele atriale actie potentiaal wordt voortgeleid naar de ventrikels. Diverse medicamenteuze therapieën zijn toegepast om CCAVB in utero te behandelen. Sommige van deze therapeutische interventies zijn erop gericht de maternale antistoffen-titer te verlagen of de inflammatoire reactie in het foetale hart te verminderen. Behandeling van de foetale bradycardie met sympathicomimetica of “in-utero-pacing” is ook beschreven. Geen van deze therapieën hebben tot nog toe geleid tot een betere prognose. In deze tijd is het foetale CCAVB nog altijd geassocieerd met een hoge morbiditeit en mortaliteit. Meer dan 60% van de kinderen met CCAVB krijgen voor hun twintigste levensjaar een pacemaker (PM). Wanneer bradycardie gerelateerde symptomen ontstaan bestaat er een duidelijke medische indicatie voor een PM. Het tijdstip van PM implantatie in de asymptomatische patiënt is controversieel. Daarnaast is de keuze van het type pacemaker draad en van het PM systeem zelf essentieel. Er bestaat op dit moment geen overeenstemming over de veiligheid en toepasbaarheid van endocardiale pacemakers in kinderen met een gewicht van < 15 kg. De meeste kinderen krijgen een epicardiale pacemaker. Redenen hiervoor zijn het lichaamsoppervlak van de patiënt en anatomische afwegingen in patiënten met complexe aangeboren hartafwijkingen. Bij het plaatsen van een endocardiale pacemaker dient rekening gehouden te worden met de groei van het kind en is het risico op veneuze trombose een belangrijke en vaak doorslaggevend argument vóór de keuze van een epicardiale pacemaker. Recent is gebleken dat kinderen met CCAVB een verhoogd risico hebben op het ontwikkelen van een gedilateerde cardiomyopathie (DCM), ondanks de plaatsing van een pacemaker. RESULTATEN Hoofdstuk 1 geeft een overzicht van de meest recente inzichten in de pathogenese van het CCAVB. Daarnaast worden de prognsose en de behandelingsmogelijkheden van het kind met CCAVB in de foetale, neonatale en kinderleeftijd beschreven. Ten slotte worden de achtergronden en doelstellingen van de studies die gepresenteerd zijn in dit proefschrift besproken. In hoofdstuk 2 worden de prognose, de zwangerschapsbegeleiding en de therapeutische mogelijkheden van het foetale congenitale hart blok (CHB) besproken. In 15 zwangerschappen van 13 moeders werd CHB bij de foetus gediagnosticeerd. Deze zwangerschappen werden gemiddeld 14 weken (1 – 21) gevolgd. In totaal werden 113 112 Samenvatting prenatale echocardiografische rapporten beoordeeld. Het foetale hart blok is gemiddeld bij een zwangerschapsduur van 24 weken (18 – 37) ontdekt. Maternale anti-SSA/Ro en antiSSB/La antistoffen zijn bij 12/13 (92%) van de moeders aangetoond. In drie zwangerschappen is een behandeling met dexamethason gestart. De indicaties in twee gevallen waren hartfalen bij de foetus en behandeling van een tweede-graads hart blok in de derde. Klinisch verbeterde het hartfalen door de dexamethason. Progressie van het tweedegraads hart blok naar CCAVB werd niet voorkomen en de dexamethason induceerde een milde bijnierinsufficiëntie bij het kind, welke zich presenteerde met hypoglycaemieën in de neonatale periode. De meeste foetussen (53%) hadden gedurende de zwangerschap een gelijkblijvend hartfrequentie. Hydrops foetalis en hartfalen ontstonden voornamelijk bij foetussen met een hartfrequentie lager dan 55 slagen/minuut. Dit impliceert dat er een relatie bestaat tussen de hartfrequentie en een verslechterende hartfunctie. Cardiomegalie en hypertrofie zijn fysiologische aanpassingen van het hart aan de lagere hartfrequenties en ontwikkelde zich bij 10 foetussen. Pericardvocht, pleuravocht en ascites werden frequent waargenomen gedurende de controle echo’s. Deze vochtcollecties konden spontaan verdwijnen, maar ook weer onstaan. De 1-jaarsoverlevingskans van dit cohort was 87%. Eén foetus ontwikkelde een gedilateerde cardiomyopathie en overleed. De morbiditeit in de neonatale periode was hoog (53%) en 11 kinderen kregen een PM (73%). In Hoofdstuk 3 wordt een moeder met SLE en SS beschreven bij wie al haar drie kinderen zich gedurende de foetale of neonatale periode presenteerden met symptomen van het neonatale lupus syndroom (NLS). Twee kinderen presenteerden zich in utero met CHB. Het tweede kind had naast CCAVB, waarvoor een pacemaker werd geplaatst, ook hematologische- en huid-afwijkingen. Het derde kind had zowel huidafwijkingen als een trombocytopenie. Naast het CCAVB bestaan er associaties tussen maternale anti-SSA/Ro en anti-SSB/La antistoffen en neonatale afwijkingen aan huid, bloedbeeld en lever. In tegenstelling tot het CCAVB, dat irreversibel is, zijn de niet-cardiale symptomen van het NLS reversibel met het verdwijnen van de maternale antistoffen uit de circulatie van de neonaat. Alle niet-cardiale afwijkingen van het NLS verdwenen spontaan gedurende de zuigelingenperiode. Van alle kinderen die zich met NLS presenteren, heeft maar een klein percentage meerdere symptomen van NLS. Dit hoofdstuk beschrijft een zeldzame casus van een moeder met drie kinderen die zich presenteerden met een breed spectrum aan NLS gerelateerde klachten en symptomen. Hoofdstuk 4 beschrijft de incidentie van DCM in een populatie van 149 kinderen met CCAVB en worden risicofactoren voor het ontwikkelen van een DCM beschreven. Van de 113 Chapter 8 149 kinderen met CCAVB uit dit studiecohort hadden 111 kinderen een PM. Negen (8%) patiëntjes uit de PM-groep kregen een DCM op een leeftijd van gemiddeld 6,5 ± 5,0 jaar. Geen van de 38 kinderen uit de CCAVB-groep zonder pacemaker ontwikkelde een DCM. Er waren significante verschillen in de hartgrootte van kinderen met CCAVB die DCM kregen vergeleken met de groep kinderen die geen DCM ontwikkelden. De belangrijkste risicofactoren voor het krijgen van een DCM was een vergroot linker ventrikel voor het plaatsen van een pacemaker en het uitblijven van normalisatie van de LV nadat een PM was geimplanteerd. Regelmatige controle van de ventriculaire functie is wenselijk bij kinderen met CCAVB. De kinderen die ondanks het plaatsen van een pacemaker een DCM ontwikkelen, hebben in de foetale periode waarschijnlijk meer inflammatoire schade aan het hart geleden. DCM is een pre-existente conditie die bij sommige kinderen met CCAVB hartfalen zal veroorzaken. In Hoofdstuk 5 wordt het beloop van de hartgrootte en de ventrikelfunctie in de tijd beschreven in een groep van 102 CCAVB kinderen met een PM en 38 CCAVB kinderen zonder PM. Cardiomegalie en een hyperdynamisch linker hart worden frequent gezien in zowel CCAVB kinderen met als zonder PM. Na het plaatsen van een PM wordt er een afname van de hartgrootte geobserveerd en een normalisering van de shorthening fraction (SF). De hartgrootte in de meeste patiënten zonder PM bleef toenemen tot waarden boven de 90-ste percentiel gecorrigeerd voor lichaamsoppervlak. Daarnaast verbeterden de LVEDD, SF en CTR waardes aanzienlijk in de groep asymptomatische patiënten met CCAVB die een pacemaker kregen, vergeleken met de groep CCAVB kinderen die bradycardie-gerelateerde klachten hadden op het moment van pacemakerimplantatie. Symptomatische kinderen met CCAVB hadden ten tijde van het plaatsen van een PM een significant groter hart zonder een afname na PM plaatsing. Daarnaast, ontwikkelden 8 van de 40 symptomatische patiënten een DCM. Geconcludeerd kan worden dat hartgrootte een relatieve indicatie is voor het plaatsen van een PM. Er bestond een significant verschil in de interventie-vrije periode tussen endocardiale en epicardiale pacemakers. Tevens was er geen verschil in de afname van de hartgrootte in de groep kinderen die een VVI (waarbij alleen de rechter ventrikel gepaced wordt) of een DDD (zowel atrium als ventrikel gestimuleerd) pacemaker had. Hoofdstuk 6 vergelijkt de duurzaamheid, impedanties en pacemakerkarakteristieken van 159 corticosteroïd bevattende endocardiale (=transveneuze) en epicardiale pacemaker draden in een groep van 95 zuigelingen en kinderen. Er werden in totaal 121 endocardialeen 38 epicardiale-pacemakersystemen geplaatst. Groep A bestond uit 24 neonaten en kinderen met een gewicht van minder dan 15 kg. Groep B bestond uit 71 kinderen met een 114 Samenvatting gewicht van meer dan 15 kg. De resultaten van deze studie laten vergelijkbare uitkomsten zien van zowel epicardiale- als endocardiale-pacemakersystemen. Ondanks de hogere incidentie van complicaties in de groep kinderen met epicardiale PMs, lijkt een epicardiale PM een goede eerste keuze te zijn bij die kinderen met een relatief kleine diameter van het veneuze systeem. DISCUSSIE & CONCLUSIES In Hoofdstuk 7 wordt een slotbeschouwing gehouden en worden suggesties gegeven voor toekomstig onderzoek. 115 Chapter 8 116 C H A P T E R Dankwoord Curriculum Vitae List of Publications Dankwoord DANKWOORD Promoveren doe je niet alleen en zonder een woord van dank is dit proefschrift dan ook niet af. Graag wil ik alle mensen bedanken die mij tijdens de totstandkoming van dit proefschrift hebben geholpen en aangemoedigd. De volgende personen wil ik extra bedanken: Prof.dr. J.J. Roord. Beste John, het afgelopen jaar heb ik keer op keer, met veel plezier, de voortgang van “het boekje” met je mogen bespreken in de vroege uurtjes voor de overdracht. Voor de file uit is zo wel een heel treffend motto geworden… Je bent niet alleen een groots opleider maar je hebt mij ook de steun en begeleiding gegeven die nodig was om het proefschrift te voltooien. Prof.dr. N. Sreeram. Beste Sreeram, mijn interesse en enthousiasme voor de kindercardiologie is door jou zonder meer tot bloei gekomen. Niet alleen door jouw kunde en kennis, maar ook door je uitzonderlijke expertise op het gebied van wetenschap heb ik met veel plezier kennis mogen maken met de wondere wereld van het wetenschappelijk onderzoek. De vele uurtjes en vele kopjes koffie in de katheterisatie kamer hebben daar zeker een bijgedrage aan geleverd! Het was altijd feest als ik bij je langskwam. Ik ben trots dat jij mijn promotor bent! Dr. E.J. Meijboom. Beste Erik Jan, het wetenschappelijk onderzoek in dit proefschrift zou zonder jou nooit hebben kunnen plaatsvinden. Wat allemaal begon als een wetenschappelijke stage in het “oude” WKZ, kon mede door jou steun, motivatie en begeleiding uitgroeien tot een stage in diverse vooraanstaande ziekenhuizen in de Verenigde Staten. Heel veel dank daarvoor. Dr. A.A. Kruize en drs. J.M. van Woerkom. Beste Aike en Jan Maarten, iedere promovendus heeft rotsvaste ondersteuning nodig. Jullie zijn in mijn geval “de rotsen in de branding” geweest. In ben jullie zeer erkentelijk voor het optimisme en alle betrokkenheid. Jane, Paul, and Mike, many thanks for the very pleasant stay at your home. I will never forget your kindness and warmth; it made the trip to the States unforgettable. Nicole Boramanand, Joel Brenner, Mitchell Cohen, Alan Friedman, Victoria Vetter, you are gratefully acknowledged for your enthusiasm and many helpful comments. Thanks! 118 Dankwoord Hans Breur wil ik bedanken voor zijn inzet en betrokkenheid bij het verrichten van het onderzoek. De leescommissie, bestaande uit: dr. R.H.W.M. Derksen, prof.dr. B.A.C. Dijkmans, prof.dr. W.P.F. Fetter, prof.dr. H.P. van Geijn, prof.dr. J.J. Ottenkamp en dr. M.A. Sobotka, mijn dank dat u allen plaats heeft willen nemen in de leescommissie. Alle co-auteurs wil ik bedanken voor hun bijdragen aan de diverse publicaties. Dr. C. Jansen. Beste Cees, hier een woord van dank voor alle mooie verhalen tijdens mijn co-schap en je enthousiaste kijk op het promoveren! Graag wil ik A.J. Kok, M. Pekelharing-Berghuis, G.J. van der Vlist en W.J. de Waal, kinderartsen uit het Diakonessenhuis te Utrecht, bedanken voor hun ongekende enthousiasme voor het onderzoek gedurende mijn co-schap kindergeneeskunde. Met veel plezier denk ik terug aan dit prachtige co-schap! Eelco en Sing, betere paranimfen kan ik me niet wensen. Jullie vriendschap is super-steun geweest. Bij het schrijven van dit dankwoord realiseer ik me maar al te goed dat ik jullie, en al mijn andere vrienden en vriendinnen, toch enige periodes heb verwaarloosd, ondanks mijn voornemen dat te voorkomen. Een ander voornemen is om dat minimaal driedubbel in te halen! Sing, nu is het jouw beurt om een boekje te schrijven! Mijn ouders wil ik bedanken voor hun ongekende steun, enthousiasme, betrokkenheid en alles waar ze in het leven voor staan. Zij hebben mij geleerd kansen in het leven te creëren en deze optimaal te gebruiken. Jullie kijk op het leven en de wereld heeft veel voor mij betekend. Ik ben erg trots op mijn lieve ouders! Lieve Marianne, je bent het beste wat me in mijn leven is overkomen. Mede daarom ben ik erg blij dat “het boekje” eindelijk af is en we hand in hand de wereld weer kunnen gaan verkennen! Laten we beginnen met de Himalaya! Bedankt voor al je steun, geduld en opbeurende woorden in moeilijke tijden. De lay-out van het proefschrift ziet er fantastisch uit! 119 Chapter 9 120 Dankwoord CURRICULUM VITAE De auteur van dit proefschrift werd op 14 oktober 1974 geboren te Delft. De middelbare school heeft hij in eerste instantie genoten aan het Christelijk Lyceum te Veenendaal en na de verhuizing afgerond aan het Wagenings Lyceum te Wageningen. In 1994 behaalde hij het VWO diploma en startte hij met de studie Farmacie aan de Universiteit van Utrecht. Na de loting van 1996 kon eindelijk begonnen worden met de studie Geneeskunde in Utrecht. Het doctoraal examen Geneeskunde behaalde hij in oktober 1999 en zijn artsexamen in augustus 2002. De wetenschappelijke stage heeft hij uitgevoerd aan het Kinderhartcentrum van het Wilhelmina Kinderziekenhuis te Utrecht onder begeleiding van dr. E.J. Meijboom. Begin 2000 kreeg hij de studentenreisbeurs van de Nederlandse Hartstichting ten behoeve van het Dr. E. Dekker programma 2000. Zijn onderzoek werd van december 1999 – mei 2000 voortgezet aan het Johns Hopkins Hospital, Baltimore, Maryland (J.E. Crosson, J.I. Brenner), Yale New Haven Hospital, New Haven, Connecticut (A.H. Friedman) en the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania (MI Cohen, VL Vetter), de Verenigde Staten. De auteur is gedurende zijn studententijd actief geweest in verschillende commissies. Van 1997 –1998 was hij local elective coordinator van de Utrecht Medical Exchange Foundation (UMEF) en van 1998 – 1999 penningmeester van de International Federation of Medical Students’ Associations – Utrecht (IFMSA-Utrecht). Ook heeft hij zich ingezet voor de Summerschool Emergency Medicine in 1998 en Vascular Medicine in 1999 aan de Universiteit van Utrecht. In oktober 2002 kon hij beginnen met de opleiding Kindergeneeskunde aan het Vrije Universiteit medisch centrum (VUmc) te Amsterdam (opleider: prof.dr. J.J. Roord). Per 1 oktober 2003 is hij begonnen met het perifere deel van de opleiding in het St. Elisabeth Ziekenhuis te Tilburg (opleider: dr. P.J. van Dijken). 121 Chapter 9 LIST of PUBLICATIONS 1. Udink ten Cate FEA, Breur JMPJ, Cohen MI, Boramanand N, Kapusta L, Crosson JE, Brenner JI, Lubbers LJ, Friedman AH, Vetter VL, Meijboom EJ. Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children. J Am Coll Cardiol 2001; 37:1129-34. 2. Udink ten Cate FEA, Breur JMPJ, Van Woerkom JM, Kruize AA, Stoutenbeek Ph, Meijboom EJ. Het congenitale complete atrioventriculaire blok bij kinderen: pathogenese en kliniek. Ned Tijdschr Geneeskd 2002;146:1777-81. 3. Udink ten Cate FEA, Breur JMPJ, Boramanand N, Crosson JE, Friedman AH, Brenner JI, Meijboom EJ, Sreeram N. Endocardial and epicardial steroid lead pacing in the neonatal and paediatric age group. Heart 2002;88:392-6. 4. Udink ten Cate FEA. Acute hoogteziekte: een verklaring voor het onstaan van longoedeem. Ned Tijdschr Geneeskd-S 2002;5:8. 5. Breur JMPJ, Udink ten Cate FEA, Kapusta L, Cohen MI, Crosson JE, Boramanand N, Lubbers LJ, Friedman AH, Brenner JI, Vetter VL, Sreeram N, Meijboom EJ. Pacemaker therapy in isolated congenital complete atrioventricular block. Pacing Clin Electrophysiol 2002;25:1681-91. 6. Vorstman JAS, de Ranitz A, Udink ten Cate FEA, Beemer FA, Kahn RS. Een uvula bifida bij een patiënte met schizofrenie als teken van het 22q11 deletie syndroom. Ned Tijdschr Geneeskd 2002;146:2033-6. 7. Udink ten Cate FEA, Van Woerkom JM, Kruize AA, Sreeram N, Roord JJ, Derksen RHWM. Neonatal lupus erythematosus in three successive pregnancies. Submitted. 8. Udink ten Cate FEA, Breur JMPJ, Van Woerkom JM, Kruize AA, Stoutenbeek Ph, Meijboom EJ, Sreeram N. Congenital heart block in fetal life: hydrops fetalis and congestive heart failure. Submitted. 122