Skip to main content
SpringerLink
Log in

Dysregulation of Ionic Homeostasis: Relevance for Cardiac Arrhythmias

  • Chapter
  • First Online:
Channelopathies in Heart Disease

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 6))

  • 677 Accesses

Abstract

The action potential is formed by the interaction of various sarcolemmal ionic currents. These currents are produced by the flow of ions which is driven by ionic electrochemical gradient across the sarcolemma and is mediated by ion channels. Alterations in ion channel function or trans-sarcolemmal ionic electrochemical gradients lead to alteration in ionic current and action potential which can cause arrhythmias. Extracellular and intracellular concentration of some ions can modulate the gating of ion channels. Therefore, the maintenance of the correct intra- and extracellular ionic concentrations and trans-sarcolemmal ionic gradients (ionic homeostasis) is essential for the electrical function of the heart. Alterations in ionic homeostasis can lead to profound alterations in cardiac electrophysiology and arrhythmias. In this chapter will review how dysregulation of ionic homeostasis can lead to arrhythmias with a particular emphasis on channelopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aronsen JM, Skogestad J, Lewalle A, et al. Hypokalaemia induces Ca(2+) overload and Ca(2+) waves in ventricular myocytes by reducing Na(+),K(+)-ATPase α2 activity. J Physiol. 2015;593(6):1509–21.

    Article  CAS  PubMed  Google Scholar 

  • Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198–205.

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Wang R, Chen B, et al. The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nat Med. 2014;20(2):184–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curran J, Hinton MJ, Ríos E, et al. Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase. Circ Res. 2007;100(3):391–8.

    Article  CAS  PubMed  Google Scholar 

  • Diercks DB, Shumaik GM, Harrigan RA, et al. Electrocardiographic manifestations: electrolyte abnormalities. J Emerg Med. 2004;27(2):153–60.

    Article  PubMed  Google Scholar 

  • Eisner D. Calcium in the heart: from physiology to disease. Exp Physiol. 2014;99(10):1273–82.

    Article  CAS  PubMed  Google Scholar 

  • Eisner DA, Lederer WJ. Inotropic and arrhythmogenic effects of potassium-depleted solutions on mammalian cardiac muscle. J Physiol. 1979;294:255–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Sherif N, Turitto G. Electrolyte disorders and arrhythmogenesis. Cardiol J. 2011;18(3):233–45.

    PubMed  Google Scholar 

  • Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur J Pharmacol. 2004;500(1-3):73–86.

    Article  CAS  PubMed  Google Scholar 

  • Franzini-Armstrong C, Protasi F, Ramesh V. Shape, size, and distribution of Ca(2+) release units and couplons in skeletal and cardiac muscles. Biophys J. 1999;77:1528–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fredj S, Lindegger N, Sampson KJ, et al. Altered Na+ channels promote pause-induced spontaneous diastolic activity in long QT syndrome type 3 myocytes. Circ Res. 2006;99(11):1225–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grandi E, Pasqualini FS, Pes C, et al. Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes. J Mol Cell Cardiol. 2009;46(3):332–42.

    Article  CAS  PubMed  Google Scholar 

  • Györke S, Terentyev D. Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc Res. 2008;77(2):245–55.

    Article  PubMed  CAS  Google Scholar 

  • Hancox JC, McPate MJ, El Harchi A, Zhang YH. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther. 2008;119:118–32.

    Article  CAS  PubMed  Google Scholar 

  • Hussain M, Orchard CH. Sarcoplasmic reticulum Ca2+ content, L-type Ca2+ current and the Ca2+ transient in rat myocytes during β-adrenergic stimulation. J Physiol. 1997;505:385–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindegger N, Hagen BM, Marks AR, et al. Diastolic transient inward current in long QT syndrome type 3 is caused by Ca2+ overload and inhibited by ranolazine. J Mol Cell Cardiol. 2009;47(2):326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuoka S, Hilgemann DW. Steady-state and dynamic properties of cardiac sodium-calcium exchange. Ion and voltage dependencies of the transport cycle. J Gen Physiol. 1992;100(6):963–1001.

    Article  CAS  PubMed  Google Scholar 

  • Murphy E, Eisner DA. Regulation of intracellular and mitochondrial sodium in health and disease. J Mol Cell Cardiol. 2006;41(5):782–4.

    Article  CAS  PubMed  Google Scholar 

  • Pezhouman A, Singh N, Song Z. Molecular basis of hypokalemia-induced ventricular fibrillation. Circulation. 2015;132(16):1528–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Postema PG, Vlaar AP, DeVries JH, Tan HL. Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis. Europace. 2011;13(10):1509–10.

    Article  PubMed  Google Scholar 

  • Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  • Radwański PB, Brunello L, Veeraraghavan R, et al. Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release. Cardiovasc Res. 2015;106(1):143–52.

    Article  PubMed  CAS  Google Scholar 

  • Radwański PB, Ho HT, Veeraraghavan R, et al. Neuronal Na+ channels are integral components of pro-arrhythmic Na+/Ca2+ signaling nanodomain that promotes cardiac arrhythmias during β-adrenergic stimulation. JACC Basic Transl Sci. 2016;1(4):251–66.

    Article  PubMed  PubMed Central  Google Scholar 

  • Remme CA. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J Physiol. 2013;591(17):4099–116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81(2):299–307.

    Article  CAS  PubMed  Google Scholar 

  • Shattock MJ. Phospholemman: its role in normal cardiac physiology and potential as a druggable target in disease. Curr Opin Pharmacol. 2009;9(2):160–6.

    Article  CAS  PubMed  Google Scholar 

  • Sikkel MB, Collins TP, Rowlands C, et al. Flecainide reduces Ca(2+) spark and wave frequency via inhibition of the sarcolemmal sodium current. Cardiovasc Res. 2013;98(2):286–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith PL, Baukrowitz T, Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature. 1996;379:833–6.

    Article  CAS  PubMed  Google Scholar 

  • Terentyev D, Rees CM, Li W, et al. Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome. Circ Res. 2014;115(11):919–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trafford AW, Díaz ME, Negretti N, Eisner DA. Enhanced Ca2+ current and decreased Ca2+ efflux restore sarcoplasmic reticulum Ca2+ content after depletion. Circ Res. 1997;81(4):477–84.

    Article  CAS  PubMed  Google Scholar 

  • Trafford AW, Díaz ME, Sibbring GC. Eisner DA Modulation of CICR has no maintained effect on systolic Ca2+: simultaneous measurements of sarcoplasmic reticulum and sarcolemmal Ca2+ fluxes in rat ventricular myocytes. J Physiol. 2000;522(Pt 2):259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart. 2013;99(7):497–504.

    Article  PubMed  CAS  Google Scholar 

  • van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57(22):2244–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Venetucci LA, Trafford AW, Eisner DA. Increasing ryanodine receptor open probability alone does not produce arrhythmogenic calcium waves: threshold sarcoplasmic reticulum calcium content is required. Circ Res. 2007;100(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  • Venetucci LA, Trafford AW, O’Neill SC, Eisner DA. The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res. 2008;77(2):285–92.

    Article  CAS  PubMed  Google Scholar 

  • Venetucci L, Denegri M, Napolitano C, Priori SG. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012;9(10):561–75.

    Article  CAS  PubMed  Google Scholar 

  • Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15(4):380–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Zhou Q, Smith CD, et al. Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure. Biochem J. 2015;470(2):233–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Q, Xiao J, Jiang D, et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med. 2011;17(8):1003–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Sciences, University of Manchester, Manchester, UK

    Claire Hopton & Miriam Lettieri

  2. Division of Cardiovascular Sciences, University of Manchester, Manchester Heart Centre, Manchester Foundation Trust, Manchester, UK

    Luigi Venetucci

Authors
  1. Claire Hopton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luigi Venetucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miriam Lettieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luigi Venetucci .

Editor information

Editors and Affiliations

  1. Department of Cardiology and HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Heidelberg, Germany

    Dierk Thomas

  2. Dept. of Clinical & Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Carol Ann Remme

Ethics declarations

Funding

Claire Hopton is funded by a BHF Clinical Research Training Fellowship. Miriam Lettieri is funded by a BHF Studentship.

Conflict of Interest

Claire Hopton declares that she has no conflict of interest. Luigi Venetucci declares that he has no conflict of interest. Miriam Lettieri declares that she has no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hopton, C., Venetucci, L., Lettieri, M. (2018). Dysregulation of Ionic Homeostasis: Relevance for Cardiac Arrhythmias. In: Thomas, D., Remme, C. (eds) Channelopathies in Heart Disease . Cardiac and Vascular Biology, vol 6. Springer, Cham. https://doi.org/10.1007/978-3-319-77812-9_6

Download citation

Publish with us

Policies and ethics

Search

Navigation