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      Genetics of channelopathies associated with sudden cardiac death

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          Abstract

          Recent technological advances in cardiology have resulted in new guidelines for the diagnosis, treatment and prevention of diseases. Despite these improvements, sudden death remains one of the main challenges to clinicians because the majority of diseases associated with sudden cardiac death are characterized by incomplete penetrance and variable expressivity. Hence, patients may be unaware of their illness, and physical activity can be the trigger for syncope as first symptom of the disease. Most common causes of sudden cardiac death are congenital alterations and structural heart diseases, although a significant number remain unexplained after comprehensive autopsy. In these unresolved cases, channelopathies are considered the first potential cause of death. Since all these diseases are of genetic origin, family members could be at risk, despite being asymptomatic. Genetics has also benefited from technological advances, and genetic testing has been incorporated into the sudden death field, identifying the cause in clinically affected patients, asymptomatic family members and post-mortem cases without conclusive diagnosis. This review focuses on recent advances in the genetics of channelopathies associated with sudden cardiac death.

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          Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.

          W. J. Lederer, Florence Kyndt, Hervé Le Hir … (2003)
          Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.
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            Sudden death associated with short-QT syndrome linked to mutations in HERG.

            Ramon Brugada, Guido Pollevick, M Menéndez … (2004)
            Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
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              Risk stratification for sudden cardiac death: current status and challenges for the future†

              Hein J.J. Wellens, Peter J. Schwartz, FRED W. LINDEMANS … (2014)
              Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Glob Cardiol Sci Pract
                Journal ID (iso-abbrev): Glob Cardiol Sci Pract
                Journal ID (pmc): GCSP
                Journal ID (publisher-id): GCSP
                Title: Global Cardiology Science & Practice
                Publisher: Bloomsbury Qatar Foundation Journals (Qatar )
                ISSN (Electronic): 2305-7823
                Publication date Collection: 2015
                Publication date (Electronic): 13 October 2015
                Volume: 2015
                Issue: 3
                Electronic Location Identifier: 39
                Affiliations
                [1] 1Cardiovascular Genetics Center, University of Girona – IDIBGI, Spain
                [2] 2Department of Medical Sciences, School of Medicine, University of Girona, Spain
                [3] 3Unit of Arrhythmias, Hospital Sant Joan de Deu, University of Barcelona, Spain
                [4] 4Unit of Arrhythmias, Hospital Clinic de Barcelona, University of Barcelona, Spain
                Author notes
                Article
                Publisher ID: gcsp.2015.39
                DOI: 10.5339/gcsp.2015.39
                PMC ID: 4625210
                PubMed ID: 26566530
                SO-VID: 0e86be17-d79a-4032-913f-28c9b9f7deb6
                Copyright © © 2015 Campuzano, Sarquella-Brugada, Brugada, Brugada, licensee Bloomsbury Qatar Foundation Journals.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 March 2015
                Date accepted : 30 June 2015
                Categories
                Subject: Review Article

                Keywords: sudden cardiac death,arrhythmias,channelopathies,genetics
                Data availability:
                Keywords: sudden cardiac death, arrhythmias, channelopathies, genetics

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