Skip to main content
SpringerLink
Log in

Differential expression of potassium channels and abnormal conduction in experimental tachycardia-induced heart failure

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Heart failure causes electrophysiological changes in the heart. Downregulation of repolarizing K+-currents leads to a prolongation of the cardiac action potential. Nevertheless, little is known about the differential expression of atrial and ventricular K+-channels in the failing heart. Ten rabbits underwent progressive rapid right ventricular pacing for 30 days. Digitized ECGs and echocardiograms were obtained. Left ventricular and left atrial tissue was harvested and mRNA levels of BNP, Kv4.3, rERG, Kv1.5, and KvLQT1 were measured by real time PCR. Experimental heart failure was characterized by left ventricular dilatation (13 ± 1 mm vs. 9 ± 1, p < .001), depressed fractional shortening (25 ± 5% vs. 40 ± 4, p < .001), and left atrial remodeling with increased diameter (16 mm ± 2 vs. 12 ± 1, p = .002) and weight (1.3 g ± 0.2 vs. 0.5 ± 0.1, p = .01). A prolongation of P-wave (44 ± 5 ms vs. 40 ± 4, p = .001) and PQ-interval (73 ± 10 ms vs. 66 ± 9, p = .009) occurred. In heart failure, BNP mRNA levels showed a significant upregulation in the left ventricle and atrium (1.83 AU ±1.31 vs. 0.67 ± 0.65, p < .05 and 7.16 AU ±1.76 vs. 0.77 ± 0.48, p < .05). Left ventricular Kv1.5 mRNA was reduced by 50% (p < .001) and KvLQT1 was reduced by 70% (p < .001). rERG and Kv4.3 mRNA were unchanged (n = ns). In contrast, left atrial Kv4.3 and KvLQT1 were reduced by 70% (p < .001), whereas rERG and Kv1.5 were unchanged (p = ns). Significant correlations were present between BNP and K+-channel expressions. Heart failure is characterized by significant changes in the gene expression of repolarizing K+-currents with a differential atrial and ventricular pattern. These molecular changes occur together with changes in cardiac function, geometry, conduction, and BNP expression and provide a functional basis for electrical vulnerability in heart failure.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Akar FG, Wu RC, Juang GJ, Tian Y, Burysek M, DiSilvestre D, Xiong W, Armoundas AA, Tomaselli GF (2005) Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure. Am J Physiol Heart Circ Physiol 288:2887–2896

    Article  Google Scholar 

  • Beuckelmann DJ, Nabauer M, Erdmann E (1993) Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73:379–385

    PubMed  CAS  Google Scholar 

  • Brundel BJ, Van Gelder I, Henning RH, Tieleman RG, Tuinenburg AE, Wietses M, Grandjean JG, Van Gilst WH, Crijns HJ (2001) Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 103:684–690

    PubMed  CAS  Google Scholar 

  • Cha TJ, Ehrlich JR, Zhang L, Nattel S (2004a) Atrial ionic remodeling induced by atrial tachycardia in the presence of congestive heart failure. Circulation 110:1520–1526

    Article  PubMed  Google Scholar 

  • Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, Nattel S (2004b) Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure. Circulation 109:412–418

    Article  PubMed  Google Scholar 

  • Choy AM, Kupershmidt S, Lang CC, Pierson RN, Roden DM (1996) Regional expression of HERG and KvLQT1 in heart failure. Circulation 94(suppl I):I–164, Abstract

    Google Scholar 

  • Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M (1991) A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303–310

    Article  PubMed  CAS  Google Scholar 

  • Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich JR, Nattel S, Hohnloser SH (2002) Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets. J Cardiovasc Electrophysiol 13:399–405

    Article  PubMed  Google Scholar 

  • Kaab S, Nuss HB, Chiamvimonvat N, O’Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF (1996) Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 78:262–273

    PubMed  CAS  Google Scholar 

  • Kaab S, Dixon J, Duc J, Ashen D, Nabauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98:1383–1393

    PubMed  CAS  Google Scholar 

  • Le Grand BL, Hatem S, Deroubaix E, Couetil JP, Coraboeuf E (1994) Depressed transient outward and calcium currents in dilated human atria. Cardiovasc Res 28:548–556

    Article  PubMed  Google Scholar 

  • Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95

    PubMed  CAS  Google Scholar 

  • Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S (2000) Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 101:2631–2638

    PubMed  CAS  Google Scholar 

  • Li GR, Lau CP, Ducharme A, Tardif JC, Nattel S (2002) Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283:1031–1041

    Google Scholar 

  • Luchner A, Stevens TL, Borgeson DD, Redfield M, Wei CM, Porter JG, Burnett JC Jr (1998) Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure. Am J Physiol 274:1684–1689

    Google Scholar 

  • Luchner A, Borgeson DD, Grantham JA, Friedrich E, Riegger GA, Burnett JC Jr, Redfield MM (2000) Relationship between left ventricular wall stress and ANP gene expression during the evolution of rapid ventricular pacing-induced heart failure in the dog. Eur J Heart Fail 2:379–386

    Article  PubMed  CAS  Google Scholar 

  • Luchner A, Muders F, Dietl O, Friedrich E, Blumberg F, Protter AA, Riegger GA, Elsner D (2001) Differential expression of cardiac ANP and BNP in a rabbit model of progressive left ventricular dysfunction. Cardiovasc Res 51:601–607

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee R, Hewett KW, Spinale FG (1995) Myocyte electrophysiological properties following the development of supraventricular tachycardia-induced cardiomyopathy. J Mol Cell Cardiol 27:1333–1348

    Article  PubMed  CAS  Google Scholar 

  • Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226

    Article  PubMed  CAS  Google Scholar 

  • Nattel S, Yue L, Wang Z (1999) Cardiac ultrarapid delayed rectifiers: a novel potassium current family o f functional similarity and molecular diversity. Cell Physiol Biochem 9:217–226

    Article  PubMed  CAS  Google Scholar 

  • Pereon Y, Demolombe S, Baro I, Drouin E, Charpentier F, Escande D (2000) Differential expression of KvLQT1 isoforms across the human ventricular wall. Am J Physiol Heart Circ Physiol 278:1908–1915

    Google Scholar 

  • Perrella MA, Schwab TR, O’Murchu B, Redfield MM, Wei CM, Edwards BS, Burnett JC Jr (1992) Cardiac atrial natriuretic factor during evolution of congestive heart failure. Am J Physiol 262:1248–1255

    Google Scholar 

  • Rose J, Armoundas AA, Tian Y, DiSilvestre D, Burysek M, Halperin V, O’Rourke B, Kass DA, Marban E, Tomaselli GF (2005) Molecular correlates of altered expression of potassium currents in failing rabbit myocardium. Am J Physiol Heart Circ Physiol 288:2077–2087

    Article  Google Scholar 

  • Rozanski GJ, Xu Z, Whitney RT, Murakami H, Zucker IH (1997) Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing. J Mol Cell Cardiol 29:721–732

    Article  PubMed  CAS  Google Scholar 

  • Schneider HJ, Husser O, Rihm M, Fredersdorf S, Birner C, Dhein S, Muders F, Jeron A, Goegelein H, Riegger GA, Luchner A (2009) Safety of the novel atrial-selective K(+)-channel blocker AVE0118 in experimental heart failure. Naunyn Schmiedebergs Arch Pharmacol 379:225–232

    Article  PubMed  CAS  Google Scholar 

  • Shimizu W, Antzelevitch C (1998) Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 98:2314–2322

    PubMed  CAS  Google Scholar 

  • The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293–302

    Article  Google Scholar 

  • Tomaselli GF, Zipes DP (2004) What causes sudden death in heart failure? Circ Res 95:754–763

    Article  PubMed  CAS  Google Scholar 

  • Tsuji Y, Opthof T, Kamiya K, Yasui K, Liu W, Lu Z, Kodama I (2000) Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle. Cardiovasc Res 48:300–309

    Article  PubMed  CAS  Google Scholar 

  • Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM (1997) Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res 80:772–781

    PubMed  Google Scholar 

  • Wang Z, Fermini B, Nattel S (1993) Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents. Circ Res 73:1061–1076

    PubMed  CAS  Google Scholar 

  • Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S (1997) Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 81:512–525

    PubMed  CAS  Google Scholar 

  • Zicha S, Xiao L, Stafford S, Cha TJ, Han W, Varro A, Nattel S (2004) Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts. J Physiol 561:735–748

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

All authors declare that they do not have any conflicts of interest.

Author information

Authors and Affiliations

  1. Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Franz-Josef-Strauss-Allee 11, D-93055, Regensburg, Germany

    Christoph Birner, Oliver Husser, Andreas Jeron, Munhie Rihm, Sabine Fredersdorf, Markus Resch, Peter Schmid, Dierk Endemann, Günter Riegger & Andreas Luchner

Authors
  1. Christoph Birner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Husser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Jeron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Munhie Rihm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabine Fredersdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Resch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dierk Endemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Günter Riegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andreas Luchner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph Birner.

Additional information

Christoph Birner and Oliver Husser contributed equally in this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Birner, C., Husser, O., Jeron, A. et al. Differential expression of potassium channels and abnormal conduction in experimental tachycardia-induced heart failure. Naunyn-Schmiedeberg's Arch Pharmacol 385, 473–480 (2012). https://doi.org/10.1007/s00210-011-0723-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-011-0723-x

Keywords

Search

Navigation