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  • Review Article
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Potassium-channel mutations and cardiac arrhythmias—diagnosis and therapy

Nature Reviews Cardiology volume 9, pages 319–332 (2012)Cite this article

Subjects

Abstract

The coordinated generation and propagation of action potentials within cardiomyocytes creates the intrinsic electrical stimuli that are responsible for maintaining the electromechanical pump function of the human heart. The synchronous opening and closing of cardiac Na+, Ca2+, and K+ channels corresponds with the activation and inactivation of inward depolarizing (Na+ and Ca2+) and outward repolarizing (K+) currents that underlie the various phases of the cardiac action potential (resting, depolarization, plateau, and repolarization). Inherited mutations in pore-forming α subunits and accessory β subunits of cardiac K+ channels can perturb the atrial and ventricular action potential and cause various cardiac arrhythmia syndromes, including long QT syndrome, short QT syndrome, Brugada syndrome, and familial atrial fibrillation. In this Review, we summarize the current understanding of the molecular and cellular mechanisms that underlie K+-channel-mediated arrhythmia syndromes. We also describe translational advances that have led to the emerging role of genetic testing and genotype-specific therapy in the diagnosis and clinical management of individuals who harbor pathogenic mutations in genes that encode α or β subunits of cardiac K+ channels.

Key Points

  • K+ channels represent the largest and most-functionally diverse family of ion channels encoded in the human genome and have a critical role in the restitution of cardiac action potentials

  • Loss-of-function mutations in the α and β subunits that conduct IKs, IKr, and IK1 are associated with long QT syndrome (LQTS)

  • Genotype-specific approaches to the diagnosis, risk stratification, and treatment of patients with LQTS type 1 or type 2 should be utilized

  • Gain-of-function mutations in the α and β subunits that conduct Ito, IKs, IKr, IK1, and IKATP are associated with short QT syndrome, J-wave syndromes, and familial atrial fibrillation

  • The entire clinical picture should be assessed during the diagnosis of K+ channelopathies, including a 12-lead electrocardiogram, genetic tests, and a patient's clinical and family history

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Figure 1: Normal electrical activity of the heart.
Figure 2: Predicted protein topology of cardiac K+-channel α subunits.
Figure 3: Classification of cardiac K+ channelopathies stemming from mutations in α or β subunits on the basis of currents and channels.
Figure 4: Pathophysiological mechanisms of K+-channel-mediated arrhythmias at the ionic and cellular level.
Figure 5: The spectrum of QTc values and associated clinical indications for adults with a QTc value in the prolonged, borderline-prolonged, normal, borderline-short, and extremely short ranges.
Figure 6: The probabilistic nature of LQTS genetic testing.

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Acknowledgements

M. J. Ackerman is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program and the National Institutes of Health (R01-HD42569 and P01-HL094291). J. R. Giudicessi is supported by a National Heart, Lung, and Blood Institute Kirschstein NRSA Individual Predoctoral MD/PhD Fellowship (F30-HL106993).

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Authors and Affiliations

  1. Mayo Medical School, Mitchell Student Center BA-07, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    John R. Giudicessi

  2. Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Michael J. Ackerman

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Both authors contributed substantially to researching this article, discussion of its content, and writing, reviewing, and editing the manuscript before submission.

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Correspondence to Michael J. Ackerman.

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Competing interests

M. J. Ackerman is, or has previously been, a consultant for Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Transgenomic; additionally, he has applied for or holds a patent with Transgenomic. J. R. Guidicessi declares no competing interests.

Supplementary information

Supplementary Box 1

Detailed structure of K+ channels (DOC 132 kb)

Supplementary Table 1

Biophysical properties of SQTS-susceptibility mutations in genes encoding cardiac K+-channel α subunits (DOC 49 kb)

Supplementary Figure 1

Electrocardiographic hallmarks of K+-channel-mediated arrhythmias. (PDF 1005 kb)

Supplementary Figure 1 Legend

Electrocardiographic hallmarks of K+-channel-mediated arrhythmias. (DOC 30 kb)

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Giudicessi, J., Ackerman, M. Potassium-channel mutations and cardiac arrhythmias—diagnosis and therapy. Nat Rev Cardiol 9, 319–332 (2012). https://doi.org/10.1038/nrcardio.2012.3

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