Inherited Conduction System Abnormalities -- One Group of Diseases, Many Genes

Cordula M. Wolf, M.D.; Charles I. Berul, M.D.


J Cardiovasc Electrophysiol. 2006;17(4):446-455. 

In This Article

Diseases of the CCS

CCS diseases may result from injury, may be associated with heart disease such as congenital heart malformations or cardiomyopathy, may be associated with neuromuscular disease, or rarely may be an isolated finding ( Table 1 ). Familial clustering of conduction system degeneration of unknown or idiopathic cause has led to the discovery of novel mutations resulting in progressive conduction system disease in the absence of structural heart disease ( Table 1 ).

Progressive cardiac conduction defect (PCCD), also called Lenegre or Lev disease,[11] is characterized by progressive alteration of the cardiac conduction through the His-Purkinje system with right of left bundle branch block and widening of QRS complexes, leading to complete AV block and sometimes causing syncope and sudden death. Mutations in the cardiac-specific sodium channel (SCN5A) have been associated with PCCD.[12,13,14]SCN5A encodes for the α-subunits of the voltage-gated Na+ channels (Fig. 2), which are essential for the amplitude and upstroke velocity of the cardiac action potential and important determinants for impulse propagation and conduction velocity throughout the fast conducting CCS and the working myocardium.[9]

Cellular substrates for action potential initiation and propagation. The figure illustrates the cellular components involved in action potential initiation and propagation, and highlights consequences of malfunctioning proteins due to gene mutations. Displayed are the transverse tubules of two neighboring myocytes with the distinct ion channels localized on the sarcolemma of cell 1 and the connecting gap junction connexins to the sarcolemma of cell 2. Shown are the pore regions of the ion channels (α-subunits) through which ions flow across the plasma membrane, and the cytoplasmic β-subunits. Within each subunit, the encoding gene is displayed in italics, the protein in normal font. Differences in disease status are indicated in a box next to the currents. Mutations in the sodium current INa, the pacemaker current If, and the potassium current IKir2.1 are associated with conduction system disease. Sinus node dysfunction has been described in altered calcium handling due to calsequestrin or ryanodine receptor mutations in catecholamine-induced bidirectional ventricular tachycardia (see section "Channelopathies Associated with Conduction Disease"). Transcription factors (see section "Congenital Heart Disease Associated with Conduction Disease") associated with CCS disease and nuclear membrane proteins (see section "Neuromuscular Disorders Associated with Conduction Disease") causing multisystem disorders and CCS disease are shown in the nucleus. These genes might interact with ion channels and/or gap junction proteins on a transcriptional level or through other mechanisms.

Mutation carriers usually have a long p wave and prolonged PR and QRS intervals, indicative for atrioventricular and intraventricular conduction abnormalities.[15] When electrophysiologic studies are performed, prolonged HV, but normal AH intervals, are most often noted, suggesting infra-Hisian block.[16]

The electrophysiological consequences of these SCN5A mutations are predominantly a reduction in cardiac sodium current, resulting in reduced action potential upstroke velocity and slowed impulse propagation, mainly in the fast conducting sodium-channel-dependent conduction tissue.[17] However, SCN5A mutations have also been identified in patients with isolated sick sinus syndrome[18] or with a combination of cardiac conduction disease, Brugada syndrome, and sinus bradycardia.[17] Two different mechanisms have been suggested to underlie sinus node dysfunction (SND) due to SCN5A mutations: (1) a slowed conduction between the SA node and the atria, due to an increased stimulus threshold in the atrial myocardium (the wider p waves seen in these patients are compatible with this) or (2) a disorder of the SA node itself; although predominantly calcium currents are responsible for the action potential upstroke in SA and AV nodal cell, sodium channels also play a significant role in pacemaking of the heterogeneous SA nodal tissue.[19]

In contrast to loss-of-function SCN5A mutations described in CCS disorders and the Brugada syndrome, a gain-of-function of the sodium channel is seen in the long QT syndrome (LQT) type 3, leading to a maintained depolarizing current present during the plateau phase and thus prolonging the action potential.[20] Interestingly, overlapping phenotypes of Brugada syndrome,[13] LQT syndrome, and inherited conduction system defects have been reported[21] in some families. Additional mutations in genes other than SCN5A, allele penetrance, and/or developmental factors may influence the relationship between conduction disease and Na+-channel function. An example for how modifier genes can contribute to phenotype diversity is the description of a family in which atrial standstill, a rare arrhythmia, has been associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene.[22] Homozygosity can furthermore influence disease phenotype. Recessive SCN5A mutations were mostly associated with CCS disorders,[15,18] but the number of patient reports is too small to make definitive conclusions regarding gene dose effects. However, it is evident that homozygous mutations in the SCN5A gene can cause a highly lethal combination of LQT syndrome and two-to-one atrioventricular block in infants.[15,23]

Another channelopathy that has been associated with conduction system disorders is the LQT7, or Andersen-Tawil syndrome, cause by mutations in the KCNJ2 encoding an inward rectifier potassium channel, Kir2.1 (Fig. 2). This syndrome is characterized by potassium-sensitive periodic paralysis, ventricular arrhythmias, and dysmorphic features.[24] Besides QT interval prolongation, Andersen-Tawil patients may present with conduction abnormalities, such as AV block, bundle branch block, or unspecific intraventricular conduction delay.[25]

SND commonly occurs in adults with acquired heart disease, during antiarrhythmic therapy, or after surgically corrected congenital heart disease. However, SND also appears in the absence of identifiable cardiac abnormalities. Recently, mutations in the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) gene, one of the four genes encoding for the pacemaker current If ( Table 1 , Figs. 1 and 2), have been identified in patients with idiopathic sinus node disease[26] or with SND in combination with prolonged QT intervals and ventricular tachycardia.[27] Functional in vitro studies have shown that these mutations cause altered biophysical properties of the If current, thereby slowing the diastolic depolarization in sinus nodal cells.[26,27] Mice deficient for HCN4 die in utero. Their hearts display slowed cardiac contraction and lack "primitive" pacemaker cells, providing evidence that HCN4 is essential for proper functioning of the developing CCS.[28]

SND has also been reported as one of the clinical features in patients suffering from autosomal-recessive catecholaminergic polymorphic ventricular tachycardia (CPVT),[29] but the mechanism is still unclear. Arrhythmias in CPVT are typically triggered by catecholamine surges as occurs with exercise and emotion.[30] Autosomal-recessive CPVT is caused by mutations in the calsequestrin gene CASQ2,[31] the autosomal-dominant form by mutations located in the ryanodine receptor 2 gene (RyR2).[32,33]RyR2 mutations are found in approximately 50% of the CPVT patients, while the prevalence of CASQ2 mutations is not known. Calsequestrin and ryanodine receptors are involved in intracellular calcium homeostasis and excitation—contraction coupling[31] (Fig. 2). Catecholamines, increased sodium current, and other known precipitating factors induce intracellular calcium overload and this can trigger both early and delayed after depolarizations. SND in this disease entity might be caused by altered intracellular calcium handling or calcium ion currents, influencing automaticity of SA nodal pacemaker cells.

Many human congenital heart diseases are accompanied by functional abnormalities of the conduction system, either directly related to developmental abnormalities[10,34] or as a consequence of the unique myocardial substrate created by large septal patches, extensive suture lines, long-standing cyanosis, and abnormal pressure/volume status. There may be remodelling of ion channels, gap junctions, and/or receptor density and distribution, as a result of congenital or surgical substrates. Chronic pressure or volume overload may also stimulate molecular biological responses to altered physiological conditions.

Transcription factors are early embryonic genes that initiate the program for gene expression. Therefore, transcription factor mutations may perturb the entry of a cell into a specific cardiac lineage, such as the conduction system,[3] thereby disturbing development or causing degeneration (see Fig. 2). A core transcriptional network that involves homeodomain, zinc, and T-box factors appear to guide cardiac specification and differentiation.

Members of the NK-2 class of homeodomain transcription factors are expressed in both vertebrate and invertebrate hearts, and play key roles in determination and differentiation (for review see[35,36]). Nkx2.5 is a vertebrate homeobox gene with a sequence homology to the Drosophila tinman, which is required for the dorsal mesoderm specification. Failure of early tinman function results in the lack of heart formation (hence the gene name "tinman" adapted from the Wizard of Oz). Nkx2.5 has been shown to be critically involved in development of the CCS. In addition to DNA binding, the Nkx2.5 homeodomain plays critical roles in transcriptional regulation by nuclear translocation of Nkx2.5 proteins and protein–protein interaction with other transcription factors.[37] Loss-of-function mutations in the homeobox transcription factor NKX2.5[38,39] cause a loss of DNA-binding activity of this gene.[40] These null mutations are associated with progressive atrioventricular node dysfunction and other diffuse conduction system abnormalities. In addition, mutations in human Nkx2.5 cause a variety of nonsyndromic congenital heart disease, including l-transposition of the great arteries, heterotaxy with left atrial isomerism, tetralogy of Fallot, Ebstein anomaly, and atrial and ventricular septal defects, associated with varying degrees of atrioventricular block.[38,39,40,41] The absence of heart block in other frequently seen major structural heart defects suggests the specificity of Nkx2.5 in the etiology of atrioventricular node disease.[41] Progressive electrophysiological abnormalities in individuals with normal heart structure or after correction of atrial septal defects and a high incidence of sudden death in affected individuals indicate that normal amounts of NKX2.5 are required for physiologic atrioventricular node function throughout life.[38] Studies in Nkx2.5-deficient mice have shown that Nkx2.5 insufficiency perturbs the conduction system during development resulting in hypoplasia of the atrioventricular node, His bundle, and Purkinje system, and that it manifests as a postnatal conduction defect.[41,42,43,44] Nkx2.5 regulates downstream the expression of other genes, such as e-Hand, Cx40, Cx43, and ANF, and can bind to GATA4, a zinc finger domain protein, which is also highly expressed in both the atria and the CCS.[45,46] Downregulation of Cx40 in Nkx2.5 mutation can be considered as a potential cause of the conduction defect because first the Cx40 promoter contains Nkx2.5 binding sites[47] and second the homozygous Cx40 knockout mice display heart block.[48] However, Nkx2.5 haploinsufficient mice revealed the same cellular expression level of Cx40 in the conduction system cell, suggesting that there are fewer cells in Nkx2.5± conduction system, but each cell has a normal amount of connexin isoforms.[42]

Members of the T-box gene family (Tbx) of transcription factors are other important early regulators of cardiac development and have been implicated in human genetic syndromes with congenital cardiac malformations. T-box proteins—named after its founding member, the T protein, now known as Brachyury ("short tail" in Greek)—are characterized by the presence of a highly conserved 180-amino acid, sequence-specific, DNA-binding domain. T-box proteins function as transcription factors, and interact with transcriptional coactivators and corepressors, nucleosome assembly proteins, and chromatin-modifying proteins. The presence of both activating and repression domains in the same T-box protein suggests that these transcription factors display distinct functions in different developmental or molecular contexts (for review see[49,50]).

Mutations in the T-box transcription factor Tbx5 cause Holt-Oram syndrome,[51] manifest by congenital heart disease—most commonly secundum type atrial septal defects, associated with progressive atrioventricular block, and upper limb deformities typically involving the radius and/or thumb.[51] Less commonly, Holt-Oram patients have structurally normal hearts and only clinically manifest with AV block and subtle hand malformations. Studies in Tbx5 haploinsufficient mice have recently shown that the T-box transcription factor Tbx5 plays a critical role in development and maturation of the CCS and that electrophysiologic defects in Holt-Oram syndrome reflect a developmental abnormality of the conduction system.[47,52] The presence of atrial septal defects (ASDs) did not correlate with the severity of morphologic defects in the central conduction system of Tbx5 haploinsufficient mice suggesting that Tbx5 has a direct role in conduction system development independent of its role in structural heart development.[52] Because ANF, Cx40, Irx4, Mlc2v, GATA4, Nkx2.5, and Hey2 transcript levels are altered in Tbx5-deficient mice,[47] it is thought that Tbx5 directly or indirectly regulates expression of one or several of these genes (Fig. 2).

Another transcription factor that has been associated with conduction system defects is HF-1b, a SP1-related transcription factor preferentially expressed in the CCS and ventricular myocytes.[53] Mice deficient for HF-1b are prone to sudden death and show atrioventricular AV block.[53] A downregulation and misdistribution of Cx40 in Purkinje fibers has been shown in these mice,[53] suggesting that HF-1b-dependent downstream pathways may play a role in trafficking of the Cx40 protein to gap junctional sites[53] (Fig. 2).

Intercellular conduction and propagation of the cardiac action potential is dependent on electrical connections between myocytes, termed gap junctions.[54] Gap junctions are clusters of intercellular channels formed by transmembrane proteins of the connexin (Cx) family[55] (Fig. 2). Variations in connexin expression might contribute to the differences in intercellular resistance and conduction velocity that occur in different cardiac tissues. Conduction velocities are highest in the Purkinje network and slowest in the nodal tissue in order to achieve the coordinated ventricular contraction.[56]

A downregulation of the gap junction protein Cx40 has been hypothesized to be a unifying genetic mechanism responsible for the atrioventricular conduction defect in Nkx2.5,[45] Tbx5,[47] and HF-1b transcription factor mutations.

Cx43 is the major gap junction protein in the mammalian myocardium[55,57] and is expressed to a much lesser extent in the AV node, His bundle, and bundle branches.[10] Gap junctions in the sinus and AV nodes and proximal His bundle mostly contain both Cx40 and Cx45.[58,59,60] Murine models of connexin deficiencies have allowed insight into the molecular determinants of intercellular electrical communication. Modulation of specific connexin isoforms may lead to chamber-specific conduction defects.[61]

As gap junctions are a critical determinant of intercellular conduction, disturbances of gap junctional content and location may account for abnormalities of impulse propagation and also contribute to arrhythmias[62,63,64] (see Fig. 2).

Several different types of muscular dystrophies, such as Emery-Dreifuss,[65,66] limb girdle muscular dystrophy type 1B,[67,68] and myotonic dystrophy[69,70] are associated with cardiac conduction defects. Patients typically present with sinus bradycardia, first or higher degree AV block, and bundle branch block, with vulnerability for sudden cardiac death.[71] Engineered mouse models of these muscular diseases recapitulate the clinical conduction system phenotypes, allowing further molecular biological investigations.

It has been recently shown that mutations in the gene encoding for the inner nuclear membrane protein lamin A/C (LMNA) cause a dilated cardiomyopathy associated with conduction system defects[72,73,74,75] and a muscular dystrophy with conduction system defects (Emery-Dreifuss muscular dystrophy[65,66]). In addition, LMNA is implicated in a variety of other diseases, such as the Hutchinson-Gilford syndrome,[76] mandibuloacral dysplasia,[77] Charcot-Marie-Tooth Disorder type 2,[78] atypical Werner's syndrome,[79] and the Dunnigan type familial partial lipodystrophy,[80] most of which are also associated with CCS defects.[79,81]

In patients with mutations in the LMNA gene and CCS defects, the AV node and specialized conduction system are progressively replaced by fibrofatty tissue and patients die suddenly at a young age.[66,72,82]

The molecular mechanisms by which mutations in the LMNA gene cause cardiac disease are poorly understood. Lamins are members of the intermediate filament family and they form part of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane[83,84,85] (Fig. 2). Lamins are involved in multiple interactions with themselves,[86] with proteins of the nucleus of the nuclear envelope (e.g., emerin[84,87]), and with chromatin.[88] Lamin A/C is necessary for the structural integrity of the nucleus[89] and therefore it is thought that myocardial cells that are exposed to mechanical stress[90,91] suffer cell damage.[84,89] It is furthermore known that lamin A/C interacts in the transcriptional process of other genes by binding to chromosomal structures.[77]

A similar mechanism could be responsible for CCS disease observed in myotonic dystrophy, the most common type of muscular dystrophy in adult patients.

Myotonic dystrophy is an autosomal dominant inherited disorder in which the muscles contract but have decreasing ability to relax, causing muscle weakness. Other symptoms in this multisystem disorder include cataracts and progressive deterioration in CCS function. Higher degree AV block and bundle branch block are the most common conduction system defects. Some patients die suddenly from rhythm disturbances. Histopathological findings are remarkable for fibrofatty infiltration of the SA and AV node.

Myotonic dystrophy is caused by expanded CUG repeats in an untranslated region of the myotonic dystrophy protein kinase gene. There are several theories how CUG expansions in an untranslated region of the DMPK gene cause this heterogeneous disease phenotype involving muscle, CCS, and the eyes. The most likely molecular mechanism is that these CUG expansions alter the expression of other genes (Fig. 2). Two mechanisms have been proposed: firstly, it is known that CUG binding proteins under normal circumstances are involved in regulation and splicing of other gene products, e.g., cardiac troponin T.[92,93] Therefore, expanded CUG repeats could lead to a misregulation of CUG binding proteins and therefore affect expression or splicing of other genes, e.g., genes involved in a proper functioning conduction system.[94] Secondly, it has been also shown that mutant RNA binds and sequesters transcription factors. Diverse genes are consequently reduced in expression.[88] Mouse models of DMPK deficiency show variable degrees of AV block.[69,95]

In summary, CCS disease in multisystem disorders is still poorly understood. However, the molecular mechanism by which mutations in one gene cause different phenotypes is believed to be a transcriptional misregulation of downstream genes.

Wolff-Parkinson-White (WPW) syndrome is caused by accessory atrioventricular connections bypassing the AV node and His bundle and affects 1–3 persons per 1,000 population.[96] The accessory pathway may conduct faster than the AV node and cause ventricular preexcitation that manifests on the ECG as a short PR interval and a slurred upstroke of the QRS complex ("delta wave"). Most patients with WPW syndrome have otherwise structurally normal hearts and the majority are not evidently inherited.[97]

The molecular mechanisms by which accessory bypass are formed are still unclear. In normal murine CCS development, a bundle of specialized conduction tissue fibers coursing from the LA toward the LV along its free wall have been observed.[98] The persistence of this tract directly connecting atrial and ventricular myocardium and bypassing the more slowly conducting AV node may contribute to ventricular preexcitation.[98] On the cellular levels, accessory pathways seem to display intact intercalated disks with normal gap junctions composed of connexin43 and distributed as in ventricular myocardium.[99] Some pathways are found to show abnormal myocytes characterized by aberrant myofibrillar organization and abnormal mitochondria.

In a small portion of WPW patients, accessory pathways occur in association with congenital heart defects. Approximately 6–30% of patients with Ebstein anomaly have WPW syndrome. Other congenital defects that are associated with WPW include corrected transposition of the great vessels and coronary sinus diverticulae.[96]

In a small percentage of cases, WPW syndrome is familial and associated with hypertrophic cardiomyopathy.[100] Mutations in the PRKAG2 gene and other glycogen storage diseases such as Pompe[101] and Danon disease[102] may also display abnormal electrical atrioventricular connections. Patients with mutations on the PRKAG2 gene have a variable combination of glycogen storage cardiomyopathy, progressive conduction system disease including sinus bradycardia and atrioventricular block, ventricular preexcitation, arrhythmias, and sudden death.[103]PRKAG2 encodes for the adenosine monophasphate (AMP) activated protein kinase (AMPK), which regulates intracellular energy. AMPK is activated in states of increased ATP demands, such as stress or exercise.[104] The activation of the AMPK results in an increased glucose uptake, increased glycolysis, increased fatty acid, and decreased protein synthesis. AMPK may also be involved in other gene transcriptions.[105] Ventricular preexcitation is presumably caused by annulus fibrosis disruption and glycogen deposition, distinct from the muscular-appearing bypass tracts observed in typical WPW syndrome.[106,107]