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Inherited cardiac arrhythmias

Nature Reviews Disease Primers volume 6, Article number: 58 (2020) Cite this article

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Abstract

The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare diseases are often the underlying cause of sudden cardiac death in young individuals and result from mutations in several genes encoding ion channels or proteins involved in their regulation. The genetic defects lead to alterations in the ionic currents that determine the morphology and duration of the cardiac action potential, and individuals with these disorders often present with syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation and history, the characteristics of the electrocardiographic recording at rest and during exercise and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic denervation and implantation of a cardioverter–defibrillator. All these arrhythmias are potentially life-threatening and have substantial negative effects on the quality of life of patients. Future research should focus on the identification of genes associated with the diseases and other risk factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.

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Fig. 1: Genes and proteins involved in the pathogenesis of inherited cardiac arrhythmias.
Fig. 2: Variability in baseline QTc.
Fig. 3: Ventricular action potential and ionic currents.
Fig. 4: Spatial dispersion of repolarization.
Fig. 5: Examples of ECG traces.
Fig. 6: Catecholaminergic polymorphic ventricular tachycardia exercise test.

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Acknowledgements

The authors thank P. De Tomasi (Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy) for an extraordinary editorial support. C.A. acknowledges support from NHLBI (HL47678, HL138103 and HL152201), the W.W. Smith Charitable Trust and the Martha and Wistar Morris Fund; C.R.B., P.J.S. and A.A.M.W. acknowledge the support of ERN GUARD-Heart; C.R.B. and A.A.M.W. acknowledge the support of the Netherlands Heart Foundation (CVON Predict2 project) and Leducq Foundation for Cardiovascular Research grant 17CVD02 “The sodium channel as a therapeutic target for prevention of lethal cardiac arrhythmias”; P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05 “Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies” and of ESCAPE-NET project (European Union’s Framework Horizon 2020 programme under grant agreement no. 733381). M.B. acknowledges support from the German Center for Cardiovascular Research (DZHK) and Hector Foundation. M.J.A. acknowledges support from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

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Authors and Affiliations

  1. Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy

    Peter J. Schwartz

  2. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Bruxelles, Belgium

    Peter J. Schwartz, Connie R. Bezzina & Arthur A. M. Wilde

  3. Department of Cardiovascular Medicine/Division of Heart Rhythm Services, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  4. Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  5. Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  6. Lankenau Institute for Medical Research and Lankenau Heart Institute, Wynnewood, PA, USA

    Charles Antzelevitch

  7. Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA

    Charles Antzelevitch

  8. Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands

    Connie R. Bezzina & Arthur A. M. Wilde

  9. 1st Department of Medicine, University Medical Center Mannheim, Mannheim, Germany

    Martin Borggrefe

  10. DZHK (German Center for Cardiovascular Research), Partner Site Mannheim, Mannheim, Germany

    Martin Borggrefe

  11. Department of Pediatrics, Division of Cardiology, Children’s Hospital Colorado, Aurora, CO, USA

    Bettina F. Cuneo

  12. Columbia University Irving Medical Centre, New York, NY, USA

    Arthur A. M. Wilde

Authors
  1. Peter J. Schwartz
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  2. Michael J. Ackerman
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  3. Charles Antzelevitch
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  4. Connie R. Bezzina
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  5. Martin Borggrefe
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  6. Bettina F. Cuneo
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  7. Arthur A. M. Wilde
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Contributions

Introduction (P.J.S.); Epidemiology (P.J.S. and C.R.B.); Mechanisms/pathophysiology (P.J.S., C.R.B., C.A., A.A.M.W., M.B. and M.J.A.); Diagnosis, screening and prevention (P.J.S., A.A.M.W., M.B. and M.J.A.); Management (P.J.S., A.A.M.W., M.B., M.J.A. and B.F.C.); Quality of life (P.J.S., A.A.M.W. and M.J.A.); Outlook (P.J.S., A.A.M.W., M.B. and M.J.A.); Overview of Primer (P.J.S.).

Corresponding author

Correspondence to Peter J. Schwartz.

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Competing interests

M.J.A. is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia and St. Jude Medical, and holds equity/royalties of AliveCor, Blue Ox Health and StemoniX. C.A. is a consultant for Novartis Institutes for BioMedical Research, Inc. and Trevena, Inc. All other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks J. Kanters, R. Kass, H. Morita, S. Nattel, S. Ohno, Y. Rudy, K. Shivkumar, M. Yano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Brugadadrugs.org: www.brugadadrugs.org

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART): http://guardheart.ern-net.eu

Glossary

U wave

A small deflection immediately following the T wave and usually in the same direction.

Polymorphic ventricular tachycardia

Rapid ventricular rhythm with a continuously varying QRS complex morphology.

Refractoriness

Also known as refractory period. The period of depolarization and repolarization of the cell membrane after excitation during which the cell cannot respond to a second electrical stimulus.

Reentry

A self-sustaining rhythm abnormality that occurs when the propagating electric impulse fails to conclude and the action potential propagates in a closed loop manner.

Torsades de Pointes

A specific form of polymorphic ventricular tachycardia characterized by a gradual change in the amplitude and twisting of the QRS complexes around the isoelectric line.

Conduction velocity

The speed at which an action potential is distributed throughout the myocardium; conduction velocity is still the primary metric for quantifying the spread of electrical activity in cardiac muscle.

Transmural dispersion of repolarization

The difference between the longest and the shortest repolarization times measured at two points across the cardiac wall.

Early afterdepolarization

Spontaneous diastolic depolarization that occurs during phase 2 and/or phase 3 of the cardiac action potential, thereby delaying repolarization.

Triggered activity

The generation of spontaneous action potentials outside the sinus node as a result of afterdepolarizations.

Focal activity

Abnormal formation of a depolarizing impulse outside the sinus node.

Wavelength

The distance travelled by the excitation wave during its refractory period.

Delayed afterdepolarizations

Spontaneous diastolic depolarizations that occur after repolarization is complete.

Bidirectional VT

A ventricular tachycardia (VT) in which the QRS axis (as seen in the frontal electrocardiogram leads) shifts 180° with each alternate beat.

J waves

Dome-like deflections of the electrocardiogram trace between the QRS complex and the ST segment.

Right ventricular outflow tract

(RVOT). An extension of the infundibulum (a conical pouch of the right ventricle) in the ventricular cavity through which the blood flows towards the pulmonary artery.

T wave alternans

Beat-to-beat variation in the polarity or amplitude of T waves; this phenomenon indicates an unevenness in the refractoriness of the myocardium and points to elevated cardiac electrical instability.

Electrical axis

The net direction of the depolarization activity, resulting from the sum of all the electrical vectors on ECG.

Bigeminy

Heart rhythm characterized by two beats close together with a pause following each pair of beats; the first beat in the pair is the sinus beat, whereas the second one is a premature contraction. Bigeminy rhythm is often associated with the sensation of the heart skipping a beat.

PVC couplets

Two premature ventricular contractions (PVCs) in consecutive heart beats.

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Schwartz, P.J., Ackerman, M.J., Antzelevitch, C. et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers 6, 58 (2020). https://doi.org/10.1038/s41572-020-0188-7

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