Europace-2005-Smits-122-37.pdf

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REVIEW ARTICLE

Mechanisms of inherited cardiacconduction disease

Jeroen P.P. Smits*, Marieke W. Veldkamp,Arthur A.M. Wilde

Department of Clinical and Experimental Cardiology, Experimental and

Molecular Cardiology Group, Academic Medical Center, University ofAmsterdam, Room M-0-107, Meibergdreef 9, PO Box 22700,

1100 DE Amsterdam, The Netherlands

Submitted 19 March 2004, and accepted after revision 29 November 2004

KEYWORDSconduction system;sodium;ion channels;

genes;inherited

Abstract Cardiac conduction disease (CCD) is a serious disorder of the heart. Thepathophysiological mechanisms underlying CCD are diverse. In the last decade thegenes responsible for several inherited cardiac diseases associated with CCD havebeen identified. If CCD is of an inherited nature (ICCD), its underlying mechanism

can be either structural, functional or there can be overlap between these twomechanisms. If ICCD is structural in nature, it is often secondary to anatomical orhistological abnormalities of the heart. Functional ICCD is frequently found asa primary electrical disease of the heart, i.e. resulting from functionallyabnormal, or absent proteins encoded by mutated genes, often cardiac ion channelproteins involved in impulse formation.

It can thus be hypothesised that patients with inherited structural or functionalICCD suffer from fundamentally different diseases. It is worthwhile to consider thishypothesis, since it could have implications for diagnosis, treatment, prognosis and,possibly, for the patients relatives.

In this review we aim to find evidence for the idea that functional and structuralICCD are fundamentally different diseases and, if so, whether this has diagnosticand clinical consequences. 2005 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

* Corresponding author. Tel.: C31 20 566 3266; fax: C31 20 697 5458.E-mail address:[email protected](J.P.P. Smits).

1099-5129/$30 2005 Published by Elsevier Ltd on behalf of The European Society of Cardiology.doi:10.1016/j.eupc.2004.11.004

Europace (2005)7, 122e137
mailto:[email protected]:[email protected]


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Introduction

Cardiac conduction disease (CCD) is a serious, anda potentially life threatening disorder of the heart[1]. In CCD, the integrity of the conduction systemis impaired, such that impulse conduction will beslowed or even blocked and life-threatening

rhythm disturbances may ensue. The pathophysio-logical mechanisms underlying CCD are diverse,but irrespective of its cause, the ultimate treat-ment may be pacemaker implantation [1,2]. Not-withstanding that, it is worthwhile to consider thepathophysiological basis of CCD in more detail,since it may have implications for diagnosis,development of new treatment strategies, andprognosis. Also, if an inherited form of CCD issuspected, this knowledge may have consequencesfor family members of the affected individual.

Historically, CCD was viewed purely as a struc-tural disease of the heart in which macro- ormicroscopical structural abnormalities in the con-duction system underlie disruption of normalimpulse propagation. In a substantial number ofcases, however, conduction disturbances are foundto occur in the absence of anatomical abnormali-ties. In these cases, functional rather than struc-tural alterations appear to underlie conductiondisturbances (Fig. 1). Frequently functional CCD isfound to be a so-called primary electrical diseaseof the heart, a group of inherited diseases thatresult from functionally abnormal, or absent,

proteins encoded by mutated genes [3e5]. Theaffected proteins are often cardiac ion channelproteins involved in cardiac impulse formation.

It can thus be hypothesised that patients withinherited structural or functional CCD suffer fromfundamentally different diseases, although over-lap between the two pathophysiological mecha-

nisms may still exist.In this review we aim to categorise and discussreports on congenital and inherited CCD to findsupportive evidence for these ideas. The questionswe have attempted to answer while reviewingthese reports were: 1) is the reported diseasecongenital and if so, inherited or acquired? 2) whatis known about the pathophysiological mechanismof the reported disease? 3) can we relate reportedclinical parameters to a particular pathophysiolog-ical mechanism? and finally, 4) are structural andfunctional CCD indeed different diseases?

The cardiac conduction system

Structural components

Before we continue our consideration of thefundamental differences between structural andfunctional CCD, we should appraise the structuresinvolved in conduction in the heart. The cardiacconduction system enables fast and co-ordinatedcontraction of the heart. It is composed of

Figure 1 12-lead ECG of a patient with ICCD due to an SCN5A mutation. Note the widened PQ and QRS-intervals(paper speed 25 mm/sec, calibration 10 mm/mV).

Mechanisms of inherited cardiac conduction disease 123


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specialized cardiac structures that are responsi-ble for impulse formation and propagation. Thecardiac impulse is generated by the sinus node inthe right atrium, and is conducted to the leftatrium via the Bachmann bundle. From the atria,electrical activity is transmitted to the ventricu-lar myocardium through the atrioventricular

node, the bundle of His, the right and left bundlebranches, and the Purkinje fibre network succes-sively, to ensure synchronized contraction of theheart.

Macro- or microscopical structural abnormal-ities in CCD may occur at any level in theconduction system and disrupt normal impulsepropagation. These structural abnormalities mayrange from partial or total absence of structures,to gradual replacement of the normal tissues byfatty and/or fibrous tissue and calcification.

Functional components

The cardiac impulse, or action potential, is gener-ated in the sinoatrial node through the combinedaction of several different types of ion conductingproteins [3e6]. Briefly, the main players in theupstroke and repolarization of the SA node actionpotential are the depolarizing L- and T-typecalcium currents and the repolarizing delayedrectifier potassium currents respectively [6]. Therepolarization of the action potential is followedby the diastolic depolarization, a slow spontaneous

depolarization towards the threshold for generat-ing another action potential. For fast propagationof the action potential through the atria, His-Purkinje system and the ventricles, the voltagegated sodium channel and gap junctions are ofmajor importance[3e5]. The speed of depolariza-tion of the cells in these tissues, which is repre-sented by the upstroke velocity of the actionpotential, is dependent on the magnitude of thesodium current and thus on sodium channel func-tion and availability[4]. The depolarizing currentis transmitted from cell to cell through intercellu-lar channels, the gap junction channels [7,8].These channels are constructed of two hemi-channels, each composed of 6 protein subunits,the connexins[9].

Developments in molecular biology and geneticshave increased our understanding of the molecularmechanisms of inherited cardiac conduction ab-normalities and arrhythmia syndromes in general.We now know that these familial primary electricaldiseases of the heart, that occur in the absence ofstructural heart disease or systemic disease, resultfrom mutations in cardiac ion channel genes and

associated or modifying proteins, such as cytoskel-etal proteins[3,10].

Methods

The Medline/OVID literature database wassearched for original reports using the searchterms: cardiac, conduction, congenital, genetics,heart, inherited, Lenegre, Lev, SCN5Aand sodiumchannel. In addition, relevant references in thisset of papers which were not identified by theMedline/Ovid literature database, were also re-trieved. To complete our database we checked forfollow up reports on the original publications. Wehave limited our search to original reports oncardiac phenotypes.

Reviewing and comparing data from originalreports (Tables 1e3) that span more than 50 yearsof scientific progress, comes with some problems.

Firstly, the earlier reports are mainly case reportsof small groups of patients, or individual patients.For the study of the inherited nature of diseasesand genetic screening, large patient-groups areneeded. Such screening could not be performed inearlier times, since the techniques for geneticanalysis have become available only very recently.Only in the more recent studies, the presence ofmutations in the SCN5A, PRKAG2, NKX2-5 andLMNA genes was investigated. These genes wererecently found to be linked to cardiomyopathies(isolated), conduction disease and (isolated) ar-

rhythmias (Tables 1e

3). Secondly, in most reportsthe presence of discrete structural, histologicalabnormalities of the heart and the specializedconduction system cannot always be excludedbecause of the limited diagnostic possibilities inthose days or because they were not sought for.Also, some individuals reported to have CCD mayhave been suffering from other cardiac diseasesassociated with fainting spells and arrhythmiasthat have only recently been recognized, such asthe Brugada syndrome.

History

Historical description of cardiacconduction disease

Without actual electrical recordings we are leftguessing at the mechanisms of what are the firstdescriptions of fainting spells. It was not untilthe beginning of the 20th century that the de-velopment of the electrocardiogram by WillemEinthoven (1860e1927) made electrical recordings

124 J.P.P. Smits et al.


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of impulse conduction through the heart possible.Giovanni Battista Morgagni (1682e1771)[11], how-ever, was probably the first to link recurringfainting episodes in a man to a simultaneouslyobserved slow pulse rate. In the 19th century firstRobert Adams (1827)[12]and later William Stokes(1854) [13] made similar observations. The first

known report of an Adams-Stokes attack combinedwith ECG recordings came from van den Heuvel[14] who described a case of congenital heartblock. Lenegre and Lev combined clinical obser-vations, ECG recordings and detailed post mortemstudies of the heart, whereby they proved theirdirect relationship in the 1960s [15e18] Thenames Lenegre and Lev have thenceforth becomesynonymous with (progressive) cardiac conductiondisease. Electrocardiographically, both Lenegreand Lev disease are characterized by chronicconduction delay through the His-Purkinje system,resulting in partial or complete AV-block and right

or left bundle branch block [15e18]. In bothdiseases a sclerodegenerative process causesfibrosis of the His-Purkinje fibres. The severityand extent of the fibrosis in these diseases,however, is different[15e18]. In Lenegre disease,a diffuse fibrotic degeneration is limited to theconduction fibres, while in Lev disease the scle-rodegenerative abnormalities affect both the spe-cialized conduction system and the fibrousskeleton of the heart. An inherited componentmay be involved in both diseases. However, par-ticularly Lev disease may be a variation of the

normal ageing process[19].

Congenital or inherited abnormalities incardiac conduction

The recognition that CCD can as well be inheritedas acquired, dates from the beginning of lastcentury. In 1901 Morquio described, what wasprobably congenital complete atrioventricularblock in a family [20]. The disease was presentedwith syncopal periods and slow pulse rates. Con-genital heart block had, at that time, already beenreported in newborns from mothers suffering fromconnective tissue diseases. Other, early recog-nized causes for congenital CCD are infectiousdiseases such as diphtheria, rheumatic fever andcongenital syphilis[21e23]. Due to the absence ofelectrocardiographic, or histological analysis, ex-act diagnosis is difficult in these early cases ofcongenital CCD.

The discovery of gene mutations that arecausally involved in inherited CCD is relativelyrecent. Nowadays for example, mutations havebeen found in genes encoding (transcription)

factors that regulate cardiac morphogenesis. Suchmutations cause inherited CCD due to, or incombination with, cardiac malformations[24e31].

Similarly, mutations have been found in in-herited non-structural CCD, often encoding cardi-ac ion channel proteins [32e44]. Some genesinvolved in non structural inherited CCD, however,

remain to be identified. A good example are tworeports from 1977 on two types of progressivecongenital or familial heart block (PFHB), type Iand II, among families in South Africa [45,46]. In1995, PFHB type I was linked to a gene located onchromosome 19q13.2eq13.3 [47,48]. This discov-ery proved the inherited nature of the disease butthe pathophysiological mechanism, the affectedprotein and the genetic defect have not yet beenidentified.

Structural CCD

In the case of structural CCD, anatomical abnor-malities underlie the impairment of normal im-pulse propagation. This concerns macro- ormicroscopical structural abnormalities that mayoccur at any level in the conduction system. Thestructural abnormalities, as mentioned, may rangefrom partial or total absence of structures togradual replacement by fatty and/or fibrous in-filtration and calcification. In many reports, theterm structural heart disease is reserved for overtanatomical abnormalities of the heart and doesoften not include the specialized conduction sys-tem, which is often not studied (Tables 1e3).Therefore, hearts that are considered to be struc-turally normal may still have histological abnor-malities, such as focal myocarditis or segmentalcardiomyopathy. Structural CCD may be eithercongenital or inherited (Fig. 2).

Structural CCD of congenital nature

The causes of congenital structural CCD are many,they can be part of a syndrome and be associatedwith abnormalities in other organ systems. Forexample, anatomical heart defects may occur inchromosomal disorders like Downs, Edwards,Pateaus or Turners syndromes [22,23]. Althoughcongenital anatomical heart defects frequentlyoccur in these and other chromosomal disorders,still in the majority of cases no chromosomalabnormalities can be found[22,23]. Other causesof structural heart disease may be intra-uterineexposure to infectious or toxic agents (e.g.nicotine, drugs) [22,23]. As mentioned before,



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Table 1 Patients with inherited cardiac conduction disease related to anatomical abnormalities of the heart and/or the

Refere nce Nu mber of

cases/

investigated

Sex Age of

onset

(yr)

ECG

characteristics

Abnormal

anatomy

heart

Abnormal

anatomy

conduction

system

Histology

myocardium

Histology

conduction

system

Inh

Wendkos

1947[84]

6/3 ? B Complete AV

block WPW

Y Y e e AD

Griffith

1965[85]

8/5 ? C 1,2nd/complete

AV block/SCD

e NA HCF NA AD

Lev 1967[83] 2 cases ?/\ IU/C Complete AV block ASD Y/Y ICF ICF ?

Lev 1971[18] 1 case e C CHB/VT/VF/

complete AV block

Hypertrophy

postductal

coarctation

Y FECC FECC ?

Lev 1971[18] 1 case e B Complete AV block ASD Y FECC FECC ?

Waxman

1975[86]

28/6 _>\ A

(O40y)

pr. AV block

abnormal QRS

AF/VT/SCD

C SA node: F

AV node:F

His bundle:F

e NA AD

Anderson

1977[87]

1 case \ B CCHB C Abnormal

connection A

and AV node/

no RBB

NA NA Ca

Anderson

1977[87]

1 case _ IU Bradyc ardia IU/

CCHB/smallQRS/frequent PVCs

ASD/F Abnormal

connection Aand AV node/

no RBB

NA NA C

Anderson

1977[87]

1 case \ IU Bradyc ardia IU/

CCHB/small QRS

Hypoplastic

central

fibrous body

Discontinuity

AV junction

and Ventricle

NA NA C

Stephan1985[88]

19/5 _>\ A RBBBCLAD/CHB/progressive

None None F central fibrousbody and part of

ventricular septum

FibrosisHis bundle,

LPF, LAF, RBB

AD

Bezzina

2003[37]

5/2 _Z\ B Broad complex

tachycardia/atrial

and ventricular

conduction

delay/SCD

VHCD Y FECCCNCI F CH

Miller

1972[89]

1 case \ IU/B Complete AV

block RBBBC

LAHB RBBBC

LPHB

Y Y FE FCC ?

Schott

1998[25]

4 families

(nZ29, 15,

11 and 9)

_/\ ? Prog ressive AV block/

16% AV block no

structural heart

defects/SD

Cardiac

septation

defects

NA NA NA AD

Benson

1999[29]

4 families

(nZ11, 15,

13 and 7)C2 groups*1

_/\ ? 1e3rd degree AV

block, AV block

principal finding

in 23% of cases

Cardiac septation

defects

NA NA NA AD

Hosoda

1999[31]

1 family

(nZ8)

? AA AV block/AF with

slow AV conduction

ASD NA NA NA AD

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infectious diseases like diphtheria, syphilis andrheumatic fever had a significant role in congenitalCCD in the past. Although nowadays relatively lessfrequent, viral and bacterial infectious diseasesstill have a role in congenital CCD[21e23]. Finally,another important cause of congenital structuralCCD, is intra-uterine exposure to maternal auto-

antibodies. Because the structural abnormalities inthese cases may be very subtle or even absent, theunderlying mechanism will be considered sepa-rately below.

Autoimmune mechanismsAutoimmune diseases can affect the whole cardio-vascular system including the cardiac conductionsystem[49e59]. CCD in autoimmune disease maybe secondary to myocarditis because of inflamma-tion and infiltration, as in Systemic Lupus Eryth-ematosus (SLE), scleroderma and polymyositis[49e55]. Vasculitis and obliterative endarteritisare examples of autoimmune diseases that in-directly affect the myocardium by causing ischae-mia[53e55]. Cardiac conduction may be affected

to a variable degree in the various autoimmunediseases. In HLA-B27 associated diseases for in-stance, such as the seronegative spondylarthropa-thies, CCD is of frequent occurrence althoughstructural abnormalities may be absent (see later)[56e59]. In this latter group the conduction ab-normalities usually consist of A-V block, sinus node

disease and bradycardia. These abnormalities canbe permanent or intermittent. The latter arguesfor a reversible, functional, inflammatory processrather than fibrosis (see later)[54e59].

Structural CCD of inherited nature

Septation defectsMutations have been identified in familial forms ofcardiac malformations. These mutations havebeen found in genes encoding proteins that regu-late septation of the heart, resulting in atrialseptal defects (ASD) or ventricular septal defects(VSD) [24e31]. Mutations in TBX5, a T-box tran-scription factor, have been identified in patientssuffering from Holt-Oram syndrome [24]. This

CONGENITAL BUTNOT INHERITED

maternal Anti Ro/SSA

antibodies

exposure to toxic agents

structural normal heart CONDUCTION DISEASE structural abnormal heart

CONGENITAL ACQUIRED

ischaemic

traumatic

autoimmune

infectious

neoplasmata

ageing (Lev disease)

CONGENITAL BUT

NOT INHERITED

maternal Anti Ro/SSA

antibodies

exposure to toxic agents

exposure to infectious

agents

chromosomal abnormalities

Lenegre/ Lev disease

INHERITED

NKX2-5 mutations

(transcription factors)

PRKAG2mutations (protein

kinase subunit)

LMNAgene mutations

(Lamin A/C)

some muscular dystrophies

(SCN5Asodium channel

mutations)

CONGENITALACQUIRED

drugs

electrolyte abnormalities

INHERITED

SCN5Asodium channel

mutations

gap junction gene

mutations

fatty acid oxidation

disorders

PRKAG2mutations

(protein kinase subunit)

LMNAgene mutations

(Lamin A/C)

Figure 2 Flow diagram for conduction disease.



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autosomal inherited syndrome is characterized bycardiac septation defects and extra-cardiac abnor-malities. Sometimes, mutation carriers have CCDand atrial fibrillation in the absence of septationdefects.

Mutations in NKX2.5, encoding a homeoboxtranscription factor, have been found in cases of

familial ASD without extracardiac abnormalities(Table 1)[25e31]. Although the initial descriptionwas in individuals with autosomal inherited ASDand progressive AV block, it now seems that theclinical spectrum may be more diverse, includingalso VSD and tetralogy of Fallot. Finally, a numberof familial cases of cardiac septation defectswith progressive AV block have been diagnosed inwhich the involved proteins and genes still awaitidentification.

The cytoskeletonMutations in genes encoding cytoskeletal proteins

and nuclear membrane proteins have been foundto be causally involved in inherited cardiomyopa-thies and muscular dystrophies (Table 1)[60e68].An intact cytoskeleton is required for propermyocyte structure and is additionally involved incell signalling processes.

Cardiac arrhythmias and conduction diseaseare common in patients suffering from musculardystrophies and dilated cardiomyopathies (DCM)[60e62]. Mutations in the LMNA gene, encodinglaminin, have been described to be causally in-volved in autosomal dominant Emery-Dreifuss

muscular dystrophy, as well as in families withDCM and severe cardiac conduction defects with-out skeletal muscle involvement [60]. In theselatter families, however, some individuals hadsevere conduction abnormalities in the absenceof DCM or other clinically identified structuralheart disease [60,63,65e68]. In these patientsCCD probably precedes the development of DCM.

Protein kinase disordersRecently a mutation (R302Q) in the PRKAG2 gene,which encodes for a regulatory subunit (g-2)of adenosine monophosphate-activated proteinkinase (AMPK), has been described (Table 1)[69].This mutation was found in patients with theWolff-Parkinson-White (WPW) syndrome, a diseasecharacterized by ventricular preexcitation, atrialfibrillation and conduction defects. In 76% of thecarriers of the R302Q mutation, in addition topreexitation, conduction disease was found, suchas SA- and AV-block. Hypertrophy was found in 26percent of the mutation carriers. Mutations in thePRKAG2 gene thus cause structural heart disease,such as accessory conduction pathways between

the atrial and ventricular myocardium, and cardiachypertrophy[69].

Functional CCD

Functional CCD we defined as CCD without any

structural, anatomical or histological abnormali-ties of the myocardium and its conduction system.In these circumstances the detrimental effects oncardiac conduction are usually due to alteredfunction of cardiac ion channels or associatedproteins, similar to the primary electrical diseasesof the heart among which is inherited CCD. Like instructural CCD, we can distinguish acquired, con-genital and inherited forms. Isolated CCD mayprecede other disease symptoms and in some casesfunctional CCD may be the first symptom ofa disease that eventually will result in structuraldamage to the heart[63e68].

Acquired forms of functional CCD

Acquired functional CCD may be induced by sev-eral drugs, especially antiarrhythmic and anaes-thetic drugs, and their effects are reversible.Additionally, there are several naturally occurringtoxins, which may affect conduction. The workingmechanism of these toxins on conduction is oftenthrough a direct effect on ion channel function.Disturbances of ion concentrations in intra- orextracellular fluids may additionally be a causeof CCD.

Functional CCD of congenital nature

Autoimmune mechanismsNext to the inflammatory mechanism giving rise tostructural forms of CCD in autoimmune diseases,there may also be a functional component inneonates born from mothers suffering from SLEor other connective tissue diseases [56e59].Namely, in a number of cases, the congenital heartblock may be transient and regress when thematernal IgG antibodies are washed out [56e59].Usually these individuals have 1st degree A-V blockcombined with sinus bradycardia. Maternal SSA/Roand/or SSB/La (IgG) antibodies that cross thetransplacental membrane and enter the foetalcirculation underlie this CCD[56e59]. In order toelucidate the mechanism, Boutjdir et al. retro-gradely perfused a human foetal heart on a Langen-dorff perfusion system with purified IgG antibodiesfrom a mother who gave birth to a child with CCDand who was diagnosed as having SLE. In this



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system they were able to induce a partially re-versible complete A-V block [57]. Similar resultsare obtained in different animal experimentalmodels[56]. It is postulated that the block is dueto modification of the L-type calcium channels infoetal A-V node myocytes by maternal IgG anti-bodies[59]. Although the number of cases where

functional CCD in these children is involved islimited, it is worthwhile considering its role be-cause it may present a pharmacologically treat-able form of CCD.

Functional CCD of inherited nature

Protein kinase disordersRecently a missense mutation (R531G) and anotherconstitutively active mutation (T172D) in thePRKAG2gene have been described in patients withWPW syndrome [70]. In contrast to the R302Qmutation in the PRKAG2 gene (see above) [69],carriers of these two mutations did not havecardiac hypertrophy but did have sinoatrial oratrioventricular block [70]. Because these muta-tions occur in the gene encoding the g2 regulatorysubunit of AMP-activated protein kinase, they mayhave an effect on cardiac conduction by affectingthe phosphorylation state of several cardiac ionchannels [71], as has been shown for the T172Dmutation. This mutation affected the inactivationproperties of the human cardiac sodium channel ina cell expression model. In addition, AMPK hasbeen shown to be a modifier of other human ion

channels besides the cardiac sodium channel[71].

Fatty acid oxidation disordersFatty acid oxidation disorders are inborn errors ofmetabolism that affect normal transport andmetabolism of fatty acids due to enzymatic de-fects[72]. The heart is one of the organs that maybe affected and cardiomyopathy with conductionand rhythm abnormalities may be one of thepresenting symptoms[73,74]. Fatty acid oxidationdisorders can also present as conduction diseaseand atrial arrhythmias, without structural heartdisease. Usually these patients have defects inenzymes that regulate mitochondrial transport oflong-chain fatty acids (carnitine palmitoyl trans-ferase type II, carnitine-acylcarnitine translocase)[72e74].

The pathophysiology of conduction disease andother clinical features in fatty acid oxidationdisorders, results from accumulation of fatty acidmetabolites downstream from the enzyme defect[73]. The long chain fatty acid metabolites accu-mulating in these enzyme defects may be toxic tomyocytes, but additionally they may affect ion

channel proteins. They have been shown to reducethe inward rectifying KC and depolarizing NaC

current, to activate Ca2C channels, and to impairgap-junction hemi-channel interaction [73]. Withthe exception of the effects on Ca2C channels,these alterations negatively affect conduction inthe heart. Since multiple types of ion currents are

simultaneously affected, they may deliver a sub-strate for cardiac arrhythmias. These disorders arerare, and probably underestimated, but presenta potentially treatable cause of childhood arrhyth-mias and conduction disease.

The cytoskeletonSometimes the first and most prominent symptomof inherited cardiomyopathy or muscular dys-trophy is isolated CCD, without or before thedevelopment of detectable structural cardiac ab-normalities[60,63e67]. It may be speculated thatin these cases, mutations in cytoskeletal proteins

directly or indirectly, alter ion channel function.Some recent studies that show the association ofion channel and cytoskeletal proteins, support thisview. That is, the intracellular located protein g-syntrophin, associates and interacts with the poreforming a-subunit of the cardiac sodium channel,thereby regulating its membrane expression andgating behaviour [75]. As mentioned previously,this ion channel is vital for normal cardiac con-duction. Syntrophin additionally associates withthe cell-membrane associated proteins dystrophinand ankyrin, the latter are known to interact with

the modulatory b-subunits of rat brain voltagegated sodium channels [75e78]. b-Subunits aresmall transmembrane proteins that have extracel-lular regions which interact with extracellularmatrix proteins [77]. Disruption of cytoskeletalorganization may therefore be involved in abnor-malities of cardiac conduction, as much arisingfrom structural as from functional malfunction[79e99]. Inversely, these interactions may addi-tionally explain why in some cases of sodiumchannel mutations, exaggerated fibrosis is found,probably resulting from abnormal function orexpression of sodium channels [36,37]. The roleof the cytoskeleton in electrical diseases of theheart was additionally convincingly proven by theidentification of a loss-of-function mutation inankyrin in the long QT syndrome type 4[10].

Mutations in the SCN5A geneThe first and as yet only gene that has been foundto play a role in functional familial CCD is SCN5A,encoding the a-subunit of the cardiac sodiumchannel (hH1) [32e44]. In 1999, in one familywith progressive CCD and in another with



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non-progressive CCD, a causal relationship wasfound with two different mutations in the SCN5Agene [32]. Both these mutations resulted in non-functional human cardiac sodium channels. Car-riers of these mutations are thus expected to haveonly 50% of the normally available sodium chan-nels, namely those encoded by their normal allele.

Consequently, a considerable reduction in depola-rizing sodium current is to be anticipated, whichwill give rise to a slowing of conduction. Othermutations in theSCN5Agene involved in CCD alterthe function of sodium channels. These mutationsusually reduce the cardiac sodium current byreduction of their membrane expression, probablythrough actions of the quality control system in theendoplasmatic reticulum of the cell, or by chang-ing the gating properties of the channel[3].

Presently 11 SCN5A mutations have been pub-lished that are causally related to inherited car-diac conduction disease[32e44]. Combinations of

SCN5A mutations and degenerative abnormalitieshave, however, also been reported and it is likelythat such combinations will also be present inageing SCN5A mutation carriers as well [36].

Polymorphisms in the connexin geneConnexins are the building blocks of gap junctionchannels that functionally and electrically connectcardiac myocytes [7,9]. They are responsible forcoupling and current conduction between neigh-bour myocytes[7,9]. Presently only one polymor-phism in the atrial connexin40 gene has been

identified in familial atrial standstill and CCD.These patients additionally carried an SCN5Amutation (D1275N) that reduced Na-current[38].

Relationship betweenpathophysiological mechanismunderlying CCD and clinical phenotype

Comparison of the clinical symptoms that accom-pany structural or functional CCD respectively,reveal some (small) differences that relate to theage of clinical manifestation, the extent of the

disease, and the incidence of arrhythmias.

Age of clinical manifestation

Symptoms of structural congenital CCD due toanatomical defects of the heart and the conduc-tion system, such as those found in chromosomaldisorders and septation defects due to mutationsin transcription factor genes, may already bepresent in utero or at birth. However, in the greatmajority of the reports where these defects were

found to be causally related to mutations inPRKAG2, NKX2-5 or LMNA, the disease is recog-nized at an adult age (Table 1) [27,30,31,60,63e70]. Presenting symptoms may therefore be due tothe structural cardiac abnormalities (e.g. shunt-ing) or due to conduction abnormalities. Symptomsof congenital CCD caused by sclerodegenerative

abnormalities, e.g. due to the autoimmune mech-anism, are often already present at an early age[49e51,57e59].

Functional congenital CCD, on the other hand,may be incompatible with life or becomes evidentearly in life (Table 2) [32,33,35,37,38,42,43,44].However, in one report on CCD associated witha reduction in INa due to a mutation in SCN5A,symptoms of CCD appeared only later in life[36].On the basis of this report we may speculate thata reduction in available functional sodium chan-nels, and the consequent reduction in INa, canprobably be tolerated to some extent. The effects

of a reduction in INa may therefore sometimes notbecome evident until a later age, when conductionin the heart becomes impaired because of thenaturally occurring ageing process. Interestingly,the normal ageing process usually involves sclero-sis, although evidence is emerging that sclerosis isenhanced in carriers of loss-of-function SCN5Amutations[36,37].

Extent of the disease

In structural CCD, the conduction abnormalities

are often localized in a specific part of thespecialized conduction system. Obviously, in CCDassociated with chromosomal disorders or muta-tions in transcription factor genes, conductionproblems are limited to the part of the specializedconduction system involved in the septation de-fect. Symptoms of congenital CCD caused bysclerodegenerative abnormalities, e.g. due to theautoimmune mechanism, are mostly restricted tothe AV-nodal region [49e51,57e59]. The onlyexception, forms the group of DCM due to LMNAmutations, in which the atria, the bundle of His,the bundle branches and the working myocardiumare affected[60e62].

If we consider the group of purely functionalCCD, without structural abnormalities, this groupis mainly represented by cases of CCD due toSCN5A mutations. Cardiac conduction seems tobe more generally impaired in reports where anSCN5Amutation is involved. This is to be expectedin view of the fact that the cardiac sodium channelis present and functional throughout all regions ofthe heart. A mouse model with a loss-of-functionSCN5A mutation, nicely supports this view [82].



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Mice homozygous for the mutation display in vivoimpaired atrioventricular conduction and prepara-tions of the isolated hearts show impaired atrio-ventricular, delayed intramyocardial conductionand increased ventricular refractoriness. Besidesthese abnormalities, ventricular tachycardia dueto reentry occurred in the isolated hearts[82].

Cardiac arrhythmias

Because of the limited information and the lownumber of patients in many of the clinical reports,a statement about the incidence of arrhythmias inrelation to structural or functional CCD, is pre-carious. The occurrence of tachyarrhythmias andsudden cardiac death (SCD), may be expected tobe more frequent in patients with CCD that carryloss-of-function SCN5A mutations, comparablewith patients with SCN5A-associated idiopathicVF and Brugada syndrome[3]. Evaluation ofTables1e3shows that this difference is not as clear asexpected. In the 26 reports on structural CCD(Table 1) SCD is reported 8 times and in 6 cases(dilated) cardiomyopathy is involved. Atrial ar-rhythmias are reported 10, and ventricular ar-rhythmias 3 times (Table 1). In the 11 reports onCCD in the presence of an SCN5Amutation (Table 2)SCD is reported twice and ventricular arrhythmias3 times. Among the 16 reports of congenital CDD ofunknown cause (Table 3), SCD is reported 6 times,of which 5 times due to complete heart block. Inthis group atrial or ventricular arrhythmia (broad

complex tachycardia of unknown origin) is re-ported once. Thus, from these numbers cardiacarrhythmias do not seem to be more frequentamong patients with functional CCD due toSCN5Amutations.

Conclusions

In congenital CCD there are two pathophysiologicalpathways, a structural and a functional. Eachpathway can be further divided in inherited,congenital or acquired pathophysiological mecha-nisms (Fig. 2). Structural and functional CCD aretwo mechanistically different diseases which mayhowever have some overlap. Reduced sodiumcurrent due to mutations in the SCN5A gene,encoding the cardiac sodium channel, is the mostimportant mechanism in congenital CCD withoutstructural abnormalities and may already be symp-tomatic at an early age. Additionally, this mecha-nism may be involved in congenital CCD associatedwith abnormalities of the cytoskeleton of the heart[60,68].

More detailed knowledge of the function of thecardiac sodium channel, by studying inheritedelectrical disorders like congenital CCD, may en-able us to develop a pharmacological treatmentfor this form of congenital CCD. Additionally it mayenable us to develop drugs to treat other cardiacdiseases that are caused by loss-of-functionSCN5A

mutations. Until then, the treatment for SCN5Arelated CCD is pacemaker implantation, as in otherforms of CCD. Due to the fact that the wholemyocardium may be affected in SCN5A relatedCCD, pacemaker treatment may, however, be lesssuccessful in these circumstances[33].

Hence, for both treatment and scientific pur-poses, an accurate, genetic diagnosis in inheritedCCD is important.

Acknowledgements

This work was supported by grants from theNetherlands Organisation for Scientific Research,NWO grant no. 902-16-193 (J.P.P.S., M.W.V. andA.A.M.W.) and the Netherlands Heart Foundation,NHS grant 2000.059 (A.A.M.W.).

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