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Electrical Diseases of the Heart pp 583–603Cite as

Progressive Cardiac Conduction Disease

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Abstract

Cardiac conduction disease (CCD) is a common medical problem, with about 3 million people worldwide with pacemakers and 600,000 implanted each year. Despite its prevalence, very little is known about the molecular pathogenesis of CCD in the general population. Therefore, investigators have turned to cases of syndromic and isolated familial conduction system disease to gain insights.

Isolated familial CCD can result from a diverse set of genetic mutations rather than a single unifying cause or pathway. Mutations in ion channels SCN5A, SCN1B and TRMP4 encoding respectively the pore forming cardiac sodium channel Nav1.5, the Nav1.5 auxiliary regulatory subunit and a monovalent-permeable, nonselective cation channel have been identified in several families. The disease-causing mechanisms are loss of function in abnormal SCN5A and SCN1b channel whereas abnormal TRPM4 channel impairs endocytosis and leads to elevated TRPM4 channel density at the cell surface corresponding to a gain-of-function mechanism. Abnormal cell-to-cell communication due to a missense mutation in GJA5 encoding Connexin 40 also causes CCD in rare cases.

Besides isolated CCD, many diseases such as dilated or restrictive, cardiomyopathies associate cardiac conduction defects. Mutations in Nkx2.5, a cardiac specific transcription factor, Lamin A/C, a gene encoding a nuclear membrane protein and PRKAG2, a gene encoding a protein kinase subunit also lead to CCD.

In addition to Mendelian diseases caused by rare variants with strong effects, common variants can also impact electrocardiographic traits in the general population. Multiple associations identified loci to pathways with established role in ventricular conduction, transcription factors and calcium-handling proteins.

Altogether, CCD appears to be a phenotypical and genetically heterogeneous condition. The number of ways that the conduction system may fail speaks to the underlying complexity of this highly specialized tissue that is only now beginning to be unraveled by genetic investigations.

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Authors and Affiliations

  1. l’institut du thorax, Unité Inserm UMR 1087/CNRS UMR 6291, 8 Quai Moncousu, BP 70721, Nantes, 44007, France

    Jean-Jacques Schott PhD

  2. l’institut du thorax, Inserm UMR1087, Nantes, France

    Flavien Charpentier PhD

  3. l’institut du thorax, CHU de Nantes, Nantes, France

    Hervé Le Marec MD, PhD

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  1. Jean-Jacques Schott PhD
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  2. Flavien Charpentier PhD
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  3. Hervé Le Marec MD, PhD
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Correspondence to Jean-Jacques Schott PhD .

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  1. , Department of Internal Medicine, UMDNJ-RWJ Medical School, Robert Wood Johnson Pl. 1, New Brunswick, 08903-0019, New Jersey, USA

    Ihor Gussak

  2. , Gordon K. Moe Scholar, Masonic Medical Research Laboratory, Bleecker Street, Utica, 13501-1787, New York, USA

    Charles Antzelevitch

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Schott, JJ., Charpentier, F., Le Marec, H. (2013). Progressive Cardiac Conduction Disease. In: Gussak, I., Antzelevitch, C. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-4471-4881-4_34

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