Primary Arrhythmogenic Cardiomyopathies. Channelopathies

Inherited arrhythmogenic diseases
Channelopathies: clinical relevance


In the past two decades, a growing number of inherited arrhythmogenic diseases have been described, clinically characterized by the presence of tachyarrhythmias and sudden cardiac death (SCD) in patients, usually young, with a morphologically intact heart.


Table 1. Inherited arrhythmogenic diseases

  • Long QT syndrome (LQTS)
  • Short QT syndrome (SQTS)
  • Brugada syndrome (BrS)
  • Early repolaization syndrome (ERS)
  • Sick sinus Syndrome (SSS)
  • Congenital atrial standstill
  • Sudden infant death syndrome (SIDS)
  • Progressive cardiac conduction disease (DCCD)
  • Catecolaminergic polymorphic ventricular tachycarda (CPVT)
  • Familial atrial fibrillation (AF).
  • Idiopathic ventricular tachycardia (VT)
  • Dilated cardiomyopathy 1E (CMD1E)
  • Multifocal ectopic Purkinje-related premature contractions (MEPPC)
  • Overlaping syndromes

Congenital diseases are associated to mutations in the genes encoding the alpha and other subunits of the cardiac ion channels or those encoding any of the proteins that form the channelosome of the different cardiac ion channels. These mutations change, sometimes only in subtle ways, the functioning of ion channels altering the electrical properties of cardiac myocytes. Therefore, we talk about CHANNELOPATHIES to describe diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. The channelopathies are PRIMARY ARRHYTHMOGENIC CARDIOMYOPATHIES genetically determined, i.e., they are pure electrical diseases that are not secondary to an underlying structural heart disease (dilated/hypertrophic cardiomyopathies), although some channelopathies can produce not only electrical, but also structural alterations (eg, the BrS).

Mutations can increase or decrease the ion current generated by the affected channel, i.e. they can produce a gain- or a loss-of-function, respectively. The loss of function often leads to a recessive disease. Mutations causing an increase in channel function are inherited in a dominant fashion. This is the case of Na+ channel mutations that are associated with the inhibition of the inactivation process, alterations in the voltage dependence of inactivation or delay in coupling the activation and inactivation processes.

In many channelopathies, the functional channel is not a single protein product of a gene, but rather a multimer of the same gene product. In tetrameric K+ channels the mutated gene is transcribed into a protein 4 times and those identical 4 proteins bind together to create a single channel in the membrane that coassemble with beta subunits and other proteins. Some mutations cause one or more of those proteins to fail to coassemble correctly, so that at the end there are fewer channels in the membrane, but all the channels located into the membrane are functional. This is a haploinsufficiency mutation, and it confers a ≤50% reduction in channel function. However, when a protein successfully assembles in the membrane is not functional, the presence of the abnormal protein alters or shuts down the entire multimeric channel. This is a dominant negative mutation, causing a >50% reduction in channel function. Thus, dominant negative mutations typically conferring a more severe impact.

Channelopathies: clinical relevance

The functional analysis of these channelopathies have become an important tool to:

  1. Obtain a better understanding of the molecular substrate involved in the pathophysiology of primary arrhythmogenic diseases and gain insight into the mechanisms involved in the SCD.
  2. Determine the functional role of of the different proteins of the channelosome of Na+, Ca2+ and K+ channels under pathophysiological conditions (how the mutation alters channel function) and analyze the relationship between topology and function of the different subunits that form the structure of the ion channel.
  3. Identify the molecular determinants of the biophysical properties of the channels (ion selectivity, voltage- and time-dependency of activation, inactivation, deactivation and reactivation).
  4. Stratify the risk of the patient based on the location and functional consequences of the mutation. It has been found that mutations localized in the transmembrane segments or in the pore of the α-subunit of the Kv11.1 channel exert a dominant negative effect and are associated more cardiac events (syncope and SCD) than those located in the C-terminal.
  5. Correlate genotype and phenotype.
  6. Design of genetic diagnostic tests more sensitive and specific and therapeutic strategies based on the consequences (gain or loss of function) of the mutation responsible for the disease. Thus, Na+ channel blockers (mexiletine, flecainide) can correct the QT prolongation in patients with gain-of-function mutations in the SCN5A gene (LQTS3), the normalization of the serum potassium in patients with mutations in the KCNH2 gene (hypokalemia inhibits IKrsub>) and potassium channel agonists (nicorandil) in patients with LQTS2, while quinidine (that block Ito) can normalize the ST segment in patients with BrS. Strategies are also being designed to retrieve traffic mutated those channels that are not inserted in the cell membrane.

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