Primary Arrhythmogenic Cardiomyopathies. Channelopathies  

PCCD, also called Lenegre-Lev disease (Lenegre, 1964; Lev et al., 1970), is one of the most common cardiac conduction disturbances and represents a serious and potentially life-threatening disorder, being one of the majo causes of pacemaker implantation in developes countries (Mond and Proclamer, 2011). Electrocardiographically is characterized by a progressive slowing of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death (Smits et al., 2005). The degree of impaired cardiac conduction may progress with advancing age. In the ECG there is a marked prolongation of the P wave and the PR interval and a widening of the QRS complex without ST segment elevation or QT prolongation. Patients with sinusal pauses or bradycardia present dizziness and syncope. Stokes-Adams syndrome, seizures or SCD appear in the presence of complete heart block. In some patients, PCCD is characterized by age-related disease, degenerative fibrosis of the His-Purkinje system, resulting in bundle branch blocks and eventually complete AV block (Probst et al., 2003). PCCD represents the major cause of pacemaker implantation in the world and is considered a primary degenerative disease or an exaggerated aging process with sclerosis affecting only the conduction tissue. 

Progressive familial heart block type I (PFHBI, PFHB1) is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. The ECG presents evidence of bundle branch disease, i.e., right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes. In contrast, in the type II (PFHBII, PFHB2), the onset of complete heart block is associated with narrow QRS complexes. The propagation of the cardiac impulses originating from the sinus node to the atria and vetricles, both voltage-gated sodium channel and gap junctions play a key role; the former determine cellular excitability and the latter serves as the depolarizing current transmitted from cell to cell.

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1. Genetic basis

The genetic basis of the PCCD mostly remains elusive, albeit in 20–30% of probands, disease-causing mutations were reported in several genes. The cardiomyocytes from SCN5A+/- mice show a 50% reduction in INa and their hearts present several conduction disturbances including AV block, intraventricular conduction delay, prolonged ventricular refractoriness and TV. These findings allow us to relate the loss of function of Na+ channels with very disparate clinical phenotypes (Papadatos et al., 2002). In patients without cardiac structural diseases, reduced sodium current due to mutations in SCN5A gene which slows intra-atrial and intra-ventricular conduction is the most important mechanism in congenital cardiac conduction disease (Schott et al., 1999; Wang et al., 2002; Viswanathan et al., 2003). The mutaciones decrease INa amplitude by reducing the Nav1.5 trafficking to the sarcolemma (trafficking deffects) or as a consequence of altered gating disturbances (Probst et al., 2003; Schott et al., 1999; Tan et al., 2001; Amin et al., 2010). This latter mechanism incluyes:
1) A depolarizing shift of the Na+ channel activation curve, resulting from a reduction in the rate of channel activation or decreased channel sensitivity to the voltage required for activation which reduces the AP upstroke velocity, a primary determinant of conduction velocity;
2) A shift of the inactivation curve to more negative potentials;
3) An increase in the rapid inactivation or slower recovery from inactivation. A missense mutation (G514C) causes unequal depolarizing shifts in the voltage-dependence of activation and inactivation such that a smaller number of channels are activated at typical threshold voltages (Tang et al., 2001). Other mutations causing isolated conduction disturbances (G298S and D1595N) reduce channel availability by enhancing the tendency of channels to undergo slow inactivation in combination with a complex mix of gain- and loss-of-function defects (Wang et al., 2002).

Watanabe et al (2008) identified mutations in SCN1B sequences encoding the β1 and β1B transcript variants in patients with conduction disease and/or BrS. β1 and β1B variants modulate the function of the major cardiac sodium channel α subunit Nav1.5 and the identified SCN1B mutations blunt or inhibit this effect. Both normal and mutant β1-subunits are expressed to a higher degree in the Purkinje fibers than in the ventricles, so that INa reduction in Purkinje fiber myocytes may underlie prolongation of PR and QRS intervals, and right or left bundle branch block in PCCD.

Some SCN5A mutations produce PCCD associated with a BrS (Kyndt et al., 2001; Smits et al., 2005) or LQT3 (Probst et al., 2003). Carriers of these mutations have only 50% of the normally available Na+ channels which results in a slowing of conduction velocity manifest as impaired atrioventricular conduction (heart block), slowed intramyocardial conduction velocity, or atrial inexcitability (atrial standstill) (Tang et al., 2001; Wang et al., 2002; Groenewegen et al., 2003; Benson et al., 2003). Mutations in SCN5A geneare also associated with heterogeneous familial disorders of cardiac conduction manifest as impaired atrioventricular conduction (heart block), slowed intramyocardial conduction velocity (usually located in the His-Purkinje system), or atrial inexcitability (atrial standstill) (Schott et al., 1999; Wang et al., 2002; Groenewegen et al., 2003; Benson et al., 2003). The degree of impaired cardiac conduction may progress with advancing age and is generally not associated with prolongation of the QT interval or ECG changes consistent with BrS. Inheritance of heart block is most cases autosomal dominant. However, atrial standstill has been reported to occur either as a recessive disorder of SCN5A (congenital sick sinus syndrome) (Benson et al., 2003) or by digenic inheritance of a heterozygous SCN5A mutation with a promoter variant in the connexin-40 gene (Groenewegen et al., 2003). SCN5A mutations have also been discovered in families segregating impaired cardiac conduction, supraventricular arrhythmia, and dilated cardiomyopathy (McNair et al., 2004; Olson 2005). Therefore, structural and functional PCCDs may share the same pathophysiological background.

Gain-of-function mutations of the TRPM4 gene transmitted with an autosomal dominant inheritance and incomplete penetrance have been associated with the progressive familial heart block type I (PFHBI) (Kruse et al., 2008; Liu et al., 2010, 2013). TRPM4 channels carrying PFHBI and ICCD display a dominant gain-of-function phenotype that is not associated with alterations in biophysical properties, but with an increase in TRPM4 current density (Kruse et al., 2008). The underlying mechanisms leading to conduction block caused by TRPM4 dysfunction are not yet understood. It has been suggested that gain-of-function mutations may depolarize the membrane potential ate the level of the His-Purkinje conduction system, reduce the availability of the cardiac Na+ channels and slow both the excitability and impulse propagation of the cardiac impulses (Abriel et al., 2012; Kruse and Pongs, 2014; Daumy et al., 2016). The mutation (E7K) in the N-terminus of TRPM4 attenuates deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface (Kruse and Pongs, 2014). However, sumoylation of theTRPM4 protein could not be reproduced by another group (Syam et al., 2016). Other variations in the TRPM4 gene are linked to AV conduction block, right bundle branch block (RBBB), bradycardia, and to the BrS (Stallmeyer et al., 2012; Lui et al., 2013; Daumy et al., 2016). Indeed, TRPM4 mutations may account for a significant portion of inherited forms of RBBB (25%) and AV block (10%) (Stallmeyer et al., 2012). Another cohort study in 248 patients with BrS revealed 11 additional mutations in 20 in patients not carrying mutations in the known susceptibility genes for the BrS (Liu et al., 2013). These mutants revealed decreased, increased and unchanged channel activity. Daumy et al (2016) identified 2 extra mutationsby applying targeted next-generation sequencing in 95 unrelated patients with PCCD. In all of these studies, the phenotype of patients with TRPM4 mutations was very variable and the penetrance incomplete, suggesting additional factors modulating the disease.

Heterozygous mutations in NKX2.5, a homeobox transcription factor, leads to atrioventricular (AV) conduction block without associated congenital heart defects (Benson et al., 1999; Scott et al., 1998). The LMNA gene encodes the ubiquitous inner-nuclear membrane protein lamin A/C, responsible for maintaining the structural integrity and stability of the nuclear envelope and in gene replication and chromatin organization. Mutations in LMNA gene have been described in patients with dilated cardiomyopathy (DCM) with conduction system disease and/or AV block, resulting in a higher risk of SCD  (Arbustini et al., 2002; Becane et al., 2000; Fatkin et al., 1999). Male carriers have a worse prognosis due to the high prevalence of malignant ventricular arrhythmias and end-stage heart failure (Arimura et al., 2013).

Gollob et al (2001) identified a novel mutation (Arg531Gly) in the  the gamma-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease.

The KCNK17 gene, encoding the pH-sensitive cardiac two-pore domain potassium channel (K2P) TASK-4 (or TALK-2) , which is strongly expressed in human Purkinje cells, has been identified as a novel contributor to progressive and severe cardiac conduction disorder combined with idiopathic ventricular fibrillation. A gain-of-function mutation in the KCNK17 gene (G88R), located in the extracellular loop between the first transmembrane segment and the first pore domain, leads to a strong increase in TASK-4 conductance (Friedrich et al., 2014). The mutation is likely to promote repolarization of the cardiac action potential, which in turn might favor reentry arrhythmias due to a shortened effective refectory period. In addition, as TASK-4 is preferentially expressed in Purkinje fibers, the gain-of-function mutation might hyperpolarize the membranes of cells in the conduction system and thus slow conductivity.

In a patient with PFHBI a germline GJA5 (Cx40) mutation (Q58L) associated with progressive familial conduction block and sudden cardiac death  resulted in marked reduction of junctional conductance and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions (Makita et al., 2012). The protein expressed (Cx40-Q58L) failed to form functional gap junctions in an exogenous expression system and decreased the probability of gap junction formation in cells co-expressing the WT protein.


Table. Genetic loci and genes associated with progressive cardiac conduction disease





Functional effect



α subunit of Nav1.5









NK homeobox5




γ2 subunit of PKA




laminin A/C




α subunit





Connexin 40


(+): gain-of-function. (-): loss-of-function

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2. Treatment

The ultimate treatment is pacemaker implantation.

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3. References

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