Skip to main content

Advertisement

SpringerLink
Log in

Current understanding of the pathophysiological mechanisms responsible for inappropriate sinus tachycardia: role of the If “funny” current

  • Published:
Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

Background

Together with the afferent branches of the autonomic nervous system, the sinoatrial node (SAN) forms a functional unit whose function is to fire rhythmic action potentials at a rate optimal for coping with the metabolic needs of the body. Dysfunctional behavior of this complex unit may thus result in SAN rhythm disorders. Among these disorders, there is the inappropriate sinus tachycardia (IST) which occurs when an unjustified fast SAN rate is present.

Methods

We here present a critical review of the role of pacemaker f/HCN channels in cardiac rhythm generation and modulation and their involvement in IST.

Results

Recent evidence demonstrates that a familial form of IST is associated with a gain-of-function mutation in the HCN4 pacemaker channel (R524Q) which confers an increased sensitivity to the second messenger cAMP, a key mediator in sympathetic modulation.

Conclusions

This finding is consistent with the general view that hypersympathetic tone is one of the causes of IST and introduces the novel concept of defective funny channel-dependent tachyarrhythmias.

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

  1. Dobrzynski, H., Anderson, R. H., Atkinson, A., Borbas, Z., D’Souza, A., Fraser, J. F., et al. (2013). Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues. Pharmacology and Therapeutics, 139(2), 260–288.

    Article  CAS  PubMed  Google Scholar 

  2. Chandler, N. J., Greener, I. D., Tellez, J. O., Inada, S., Musa, H., Molenaar, P., et al. (2009). Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation, 119(12), 1562–1575.

    Article  PubMed  Google Scholar 

  3. DiFrancesco, D., Ferroni, A., Mazzanti, M., & Tromba, C. (1986). Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. The Journal of Physiology, 377, 61–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Remme, C. A., Verkerk, A. O., Hoogaars, W. M., Aanhaanen, W. T., Scicluna, B. P., Annink, C., et al. (2009). The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium. Basic Research in Cardiology, 104(5), 511–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kodama, I., Nikmaram, M. R., Boyett, M. R., Suzuki, R., Honjo, H., & Owen, J. M. (1997). Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. The American Journal of Physiology, 272(6 Pt 2), H2793–H2806.

    CAS  PubMed  Google Scholar 

  6. Milanesi, R., Bucchi, A., & Baruscotti, M. (2015). The genetic basis for inherited forms of sinoatrial dysfunction and atrioventricular node dysfunction. Journal of Interventional Cardiac Electrophysiology, 43(2), 121–134.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Honjo, H., Boyett, M. R., Kodama, I., & Toyama, J. (1996). Correlation between electrical activity and the size of rabbit sino-atrial node cells. The Journal of Physiology, 496(Pt 3), 795–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Boyett, M. R., Dobrzynski, H., Lancaster, M. K., Jones, S. A., Honjo, H., & Kodama, I. (2003). Sophisticated architecture is required for the sinoatrial node to perform its normal pacemaker function. Journal of Cardiovascular Electrophysiology, 14(1), 104–106.

    Article  PubMed  Google Scholar 

  9. Boyett, M. R., Honjo, H., & Kodama, I. (2000). The sinoatrial node, a heterogeneous pacemaker structure. Cardiovascular Research, 47(4), 658–687.

    Article  CAS  PubMed  Google Scholar 

  10. Issa, Z. I., Miller M. J., Zipes, D. P. (2012). Electrophysiological mechanisms of cardiac arrhythmias. In: E. Saunders (Ed.), Clinical arrhythmology and electrophysiology. A companion to Braunwald’s heart disease (2nd ed., pp. 36-61).

  11. Abramochkin, D. V., Kuzmin, V. S., Sukhova, G. S., & Rosenshtraukh, L. V. (2009). Modulation of rabbit sinoatrial node activation sequence by acetylcholine and isoproterenol investigated with optical mapping technique. Acta Physiologica (Oxford), 196(4), 385–394.

    Article  CAS  Google Scholar 

  12. Gianni, C., Di Biase, L., Mohanty, S., Gokoglan, Y., Gunes, M. F., Horton, R., et al. (2015). Catheter ablation of inappropriate sinus tachycardia. Journal of Interventional Cardiac Electrophysiology.

  13. Keith, A. (1942). The Sino-auricular node: a historical note. British Heart Journal, 4(3), 77–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. DiFrancesco, D. (1993). Pacemaker mechanisms in cardiac tissue. Annual Review of Physiology, 55, 455–472.

    Article  CAS  PubMed  Google Scholar 

  15. Baruscotti, M., Barbuti, A., & Bucchi, A. (2010). The cardiac pacemaker current. Journal of Molecular and Cellular Cardiology, 48(1), 55–64.

    Article  CAS  PubMed  Google Scholar 

  16. Barbuti, A., Baruscotti, M., & DiFrancesco, D. (2007). The pacemaker current: from basics to the clinics. Journal of Cardiovascular Electrophysiology, 18(3), 342–347.

    Article  PubMed  Google Scholar 

  17. DiFrancesco, D., & Noble, D. (2012). The funny current has a major pacemaking role in the sinus node. Heart Rhythm, 9(2), 299–301.

    Article  PubMed  Google Scholar 

  18. Yaniv, Y., Lakatta, E. G., & Maltsev, V. A. (2015). From two competing oscillators to one coupled-clock pacemaker cell system. Frontiers in Physiology, 6, 28. eCollection 2015.

    PubMed  PubMed Central  Google Scholar 

  19. Lakatta, E. G., & DiFrancesco, D. (2009). What keeps us ticking: a funny current, a calcium clock, or both? Journal of Molecular and Cellular Cardiology, 47(2), 157–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yaniv, Y., Stern, M. D., Lakatta, E. G., & Maltsev, V. A. (2013). Mechanisms of beat-to-beat regulation of cardiac pacemaker cell function by Ca2+ cycling dynamics. Biophysical Journal, 105(7), 1551–1561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Codvelle, M. M., & Boucher, H. (1939). Permanent sinus tachycardia without high frequency functional disorders. Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris, 54, 849–1852.

    Google Scholar 

  22. Sheldon, R. S., Grubb, B. P., 2nd, Olshansky, B., Shen, W. K., Calkins, H., Brignole, M., et al. (2015). 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm, 12(6), e41–e63.

    Article  PubMed  Google Scholar 

  23. Still, A. M., Raatikainen, P., Ylitalo, A., Kauma, H., Ikaheimo, M., Antero Kesaniemi, Y., et al. (2005). Prevalence, characteristics and natural course of inappropriate sinus tachycardia. Europace, 7(2), 104–112.

    Article  PubMed  Google Scholar 

  24. Lopera, G., Castellanos, A., Moleiro, F., Huikuri, H. V., & Myerburg, R. J. (2003). Chronic inappropriate sinus tachycardia in elderly females. Annals of Noninvasive Electrocardiology, 8(2), 139–143.

    Article  PubMed  Google Scholar 

  25. Pellegrini, C. N., & Scheinman, M. M. (2015). Epidemiology and definition of inappropriate sinus tachycardia. Journal of Interventional Cardiac Electrophysiology.

  26. Moreira, J. M., Curimbaba, J., Filho, H. C., & Pimenta, J. (2006). Persistent inappropriate sinus tachycardia after radiofrequency ablation of left lateral accessory pathway. Journal of Cardiovascaluar Electrophysiology, 17(6), 678–681.

    Article  Google Scholar 

  27. Skeberis, V., Simonis, F., Tsakonas, K., Celiker, A., Andries, E., & Brugada, P. (1994). Inappropriate sinus tachycardia following radiofrequency ablation of AV nodal tachycardia: incidence and clinical significance. Pacing and Clinical Electrophysiology, 17(5 Pt 1), 924–927.

    Article  CAS  PubMed  Google Scholar 

  28. Pappone, C., Stabile, G., Oreto, G., De Simone, A., Rillo, M., Mazzone, P., et al. (1997). Inappropriate sinus tachycardia after radiofrequency ablation of para-Hisian accessory pathways. Journal of Cardiovascular Electrophysiology, 8(12), 1357–1365.

    Article  CAS  PubMed  Google Scholar 

  29. Kocovic, D. Z., Harada, T., Shea, J. B., Soroff, D., & Friedman, P. L. (1993). Alterations of heart rate and of heart rate variability after radiofrequency catheter ablation of supraventricular tachycardia. Delineation of parasympathetic pathways in the human heart. Circulation, 88(4 Pt 1), 1671–1681.

    Article  CAS  PubMed  Google Scholar 

  30. Winum, P. F., Cayla, G., Rubini, M., Beck, L., & Messner-Pellenc, P. (2009). A case of cardiomyopathy induced by inappropriate sinus tachycardia and cured by ivabradine. Pacing and Clinical Electrophysiology, 32(7), 942–944.

    Article  PubMed  Google Scholar 

  31. Romeo, E., Grimaldi, N., Sarubbi, B., D’Alto, M., Santarpia, G., Scognamiglio, G., et al. (2011). A pediatric case of cardiomyopathy induced by inappropriate sinus tachycardia: efficacy of ivabradine. Pediatric Cardiology, 32(6), 842–845.

    Article  PubMed  Google Scholar 

  32. Brady, P. A., Low, P. A., & Shen, W. K. (2005). Inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome, and overlapping syndromes. Pacing and Clinical Electrophysiology, 28(10), 1112–1121.

    Article  PubMed  Google Scholar 

  33. Grubb, B. P., Kanjwal, M. Y., & Kosinski, D. J. (2001). Review: the postural orthostatic tachycardia syndrome: current concepts in pathophysiology diagnosis and management. Journal of Interventional Cardiac Electrophysiology, 5(1), 9–16.

    Article  CAS  PubMed  Google Scholar 

  34. Nwazue, V. C., Paranjape, S. Y., Black, B. K., Biaggioni, I., Diedrich, A., Dupont, W. D., et al. (2014). Postural tachycardia syndrome and inappropriate sinus tachycardia: role of autonomic modulation and sinus node automaticity. Journal of the American Heart Association, 3(2), e000700.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shen, W. K., Low, P. A., Jahangir, A., Munger, T. M., Friedman, P. A., Osborn, M. J., et al. (2001). Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome? Pacing and Clinical Electrophysiology, 24(2), 217–230.

    Article  CAS  PubMed  Google Scholar 

  36. Marrouche, N. F., Beheiry, S., Tomassoni, G., Cole, C., Bash, D., Dresing, T., et al. (2002). Three-dimensional nonfluoroscopic mapping and ablation of inappropriate sinus tachycardia. Procedural strategies and long-term outcome. Journal of the American College of Cardiology, 39(6), 1046–1054.

    Article  PubMed  Google Scholar 

  37. Martino, A., Lupo, P. P., Foresti, S., De Ambroggi, G., de Ruvo, E., Sciarra, L., Cappato, R., & Calò, L. (2015). Treatment of inappropriate sinus tachycardia with ivabradine. Journal of Interventional Cardiac Electrophysiology.

  38. Olshansky, B., & Sullivan, R. M. (2013). Inappropriate sinus tachycardia. Journal of the American College of Cardiology, 61(8), 793–801.

    Article  PubMed  Google Scholar 

  39. Salazar Adum, J. P., & Arora, R. (2015). Treatment of inappropriate sinus tachycardia. American Journal of Therapeutics.

  40. Nattel, S. (2006). Inappropriate sinus tachycardia and beta-receptor autoantibodies: a mechanistic breakthrough? Heart Rhythm, 3(10), 1187–1188.

    Article  PubMed  Google Scholar 

  41. Leon, H., Guzman, J. C., Kuusela, T., Dillenburg, R., Kamath, M., & Morillo, C. A. (2005). Impaired baroreflex gain in patients with inappropriate sinus tachycardia. Journal of Cardiovascular Electrophysiology, 16(1), 64–68.

    Article  PubMed  Google Scholar 

  42. Still, A. M., Huikuri, H. V., Airaksinen, K. E., Koistinen, M. J., Kettunen, R., Hartikainen, J., et al. (2002). Impaired negative chronotropic response to adenosine in patients with inappropriate sinus tachycardia. Journal of Cardiovascular Electrophysiology, 13(6), 557–562.

    Article  PubMed  Google Scholar 

  43. Morillo, C. A., Klein, G. J., Thakur, R. K., Li, H., Zardini, M., & Yee, R. (1994). Mechanism of ‘inappropriate’ sinus tachycardia. Role of sympathovagal balance. Circulation, 90(2), 873–877.

    Article  CAS  PubMed  Google Scholar 

  44. Chiale, P. A., Garro, H. A., Schmidberg, J., Sanchez, R. A., Acunzo, R. S., Lago, M., et al. (2006). Inappropriate sinus tachycardia may be related to an immunologic disorder involving cardiac beta andrenergic receptors. Heart Rhythm, 3(10), 1182–1186.

    Article  PubMed  Google Scholar 

  45. Brown, H. F., DiFrancesco, D., & Noble, S. J. (1979). How does adrenaline accelerate the heart? Nature, 280(5719), 235–236.

    Article  CAS  PubMed  Google Scholar 

  46. DiFrancesco, D. (1981). A new interpretation of the pace-maker current in calf Purkinje fibres. Journal of Physiology, 314, 359–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. DiFrancesco, D. (1981). A study of the ionic nature of the pace-maker current in calf Purkinje fibres. Journal of Physiology, 314, 377–393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. DiFrancesco, D. (2010). The role of the funny current in pacemaker activity. Circulation Research, 106(3), 434–446.

    Article  CAS  PubMed  Google Scholar 

  49. Baruscotti, M., Bucchi, A., & Difrancesco, D. (2005). Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacology and Therapeutics, 107(1), 59–79.

    Article  CAS  PubMed  Google Scholar 

  50. DiFrancesco, D., & Tortora, P. (1991). Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 351(6322), 145–147.

    Article  CAS  PubMed  Google Scholar 

  51. DiFrancesco, D., & Tromba, C. (1988). Inhibition of the hyperpolarization-activated current (if) induced by acetylcholine in rabbit sino-atrial node myocytes. Journal of Physiology, 405, 477–491.

    Article  PubMed  PubMed Central  Google Scholar 

  52. DiFrancesco, D., & Tromba, C. (1988). Muscarinic control of the hyperpolarization-activated current (if) in rabbit sino-atrial node myocytes. Journal of Physiology, 405, 493–510.

    Article  PubMed  PubMed Central  Google Scholar 

  53. DiFrancesco, D., Ducouret, P., & Robinson, R. B. (1989). Muscarinic modulation of cardiac rate at low acetylcholine concentrations. Science, 243(4891), 669–671.

    Article  CAS  PubMed  Google Scholar 

  54. DiFrancesco, D., & Mangoni, M. (1994). Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node. Journal of Physiology, 474(3), 473–482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chang, F., Cohen, I. S., DiFrancesco, D., Rosen, M. R., & Tromba, C. (1991). Effects of protein kinase inhibitors on canine Purkinje fibre pacemaker depolarization and the pacemaker current i(f). Journal of Physiology, 440, 367–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Accili, E. A., Redaelli, G., & DiFrancesco, D. (1997). Differential control of the hyperpolarization-activated current (i(f)) by cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes. Journal of Physiology, 500(Pt 3), 643–651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Qu, J., Kryukova, Y., Potapova, I. A., Doronin, S. V., Larsen, M., Krishnamurthy, G., et al. (2004). MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. The Journal of Biological Chemistry, 279(42), 43497–43502.

    Article  CAS  PubMed  Google Scholar 

  58. Barbuti, A., Gravante, B., Riolfo, M., Milanesi, R., Terragni, B., & DiFrancesco, D. (2004). Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circulation Research, 94(10), 1325–1331.

    Article  CAS  PubMed  Google Scholar 

  59. Pian, P., Bucchi, A., Robinson, R. B., & Siegelbaum, S. A. (2006). Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. The Journal of General Physiology, 128(5), 593–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pian, P., Bucchi, A., Decostanzo, A., Robinson, R. B., & Siegelbaum, S. A. (2007). Modulation of cyclic nucleotide-regulated HCN channels by PIP(2) and receptors coupled to phospholipase C. Pflugers Archiv, 455(1), 125–145.

    Article  CAS  PubMed  Google Scholar 

  61. Li, C. H., Zhang, Q., Teng, B., Mustafa, S. J., Huang, J. Y., & Yu, H. G. (2008). Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531. America Journal of Physiology Cell Physiology, 294(1), C355–C362.

    Article  CAS  Google Scholar 

  62. Wu, J. Y., & Cohen, I. S. (1997). Tyrosine kinase inhibition reduces i(f) in rabbit sinoatrial node myocytes. Pflugers Archiv, 434(5), 509–514.

    Article  CAS  PubMed  Google Scholar 

  63. Santoro, B., Grant, S. G., Bartsch, D., & Kandel, E. R. (1997). Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proceedings of the National Academy of Sciences of the United States of America, 94(26), 14815–14820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gauss, R., Seifert, R., & Kaupp, U. B. (1998). Molecular identification of a hyperpolarization-activated channel in sea urchin sperm. Nature, 393(6685), 583–587.

    Article  CAS  PubMed  Google Scholar 

  65. Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F., & Biel, M. (1998). A family of hyperpolarization-activated mammalian cation channels. Nature, 393(6685), 587–591.

    Article  CAS  PubMed  Google Scholar 

  66. Shi, W., Wymore, R., Yu, H., Wu, J., Wymore, R. T., Pan, Z., et al. (1999). Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circulation Research, 85(1), e1–e6.

    Article  CAS  PubMed  Google Scholar 

  67. Brioschi, C., Micheloni, S., Tellez, J. O., Pisoni, G., Longhi, R., Moroni, P., et al. (2009). Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node. Journal of Molecular and Cellular Cardiology, 47(2), 221–227.

    Article  CAS  PubMed  Google Scholar 

  68. Li, N., Csepe, T. A., Hansen, B. J., Dobrzynski, H., Higgins, R. S., Kilic, A., et al. (2015). Molecular mapping of sinoatrial node HCN channel expression in the human heart. Circulation. Arrhythmia and Electrophysiology, 8(5), 1219–1227.

    Article  CAS  PubMed  Google Scholar 

  69. Viscomi, C., Altomare, C., Bucchi, A., Camatini, E., Baruscotti, M., Moroni, A., et al. (2001). C terminus-mediated control of voltage and cAMP gating of hyperpolarization-activated cyclic nucleotide-gated channels. The Journal of Biological Chemistry, 276(32), 29930–29934.

    Article  CAS  PubMed  Google Scholar 

  70. Suenari, K., Cheng, C. C., Chen, Y. C., Lin, Y. K., Nakano, Y., Kihara, Y., et al. (2012). Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis. Journal of Cardiovascular Electrophysiology, 23(2), 200–206.

    Article  PubMed  Google Scholar 

  71. Chen, Y. J., Chen, S. A., Chang, M. S., & Lin, C. I. (2000). Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation. Cardiovascular Research, 48(2), 265–273.

    Article  CAS  PubMed  Google Scholar 

  72. Perez-Lugones, A., McMahon, J. T., Ratliff, N. B., Saliba, W. I., Schweikert, R. A., Marrouche, N. F., et al. (2003). Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation. Journal of Cardiovascular Electrophysiology, 14(8), 803–809.

    Article  PubMed  Google Scholar 

  73. Greenwood, I. A., & Prestwich, S. A. (2002). Characteristics of hyperpolarization-activated cation currents in portal vein smooth muscle cells. American Journal of Physiology - Cell Physiology, 282(4), C744–C753.

    Article  CAS  PubMed  Google Scholar 

  74. Ashcroft, F. (1999). Ion channels and disease. Published: October 1999. Academic Press. ISBN: 978-0-12-065310-2.

  75. Baruscotti, M., Bucchi, A., Viscomi, C., Mandelli, G., Consalez, G., Gnecchi-Rusconi, T., et al. (2011). Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proceedings of the National Academy of Sciences of the United States of America, 108(4), 1705–1710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mangoni, M. E., & Nargeot, J. (2008). Genesis and regulation of the heart automaticity. Physiological Review, 88(3), 919–982.

    Article  CAS  Google Scholar 

  77. Verkerk, A. O., & Wilders, R. (2015). Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. International Journal of Molecular Sciences, 16(2), 3071–3094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. DiFrancesco, D. (2015). HCN4, Sinus bradycardia and atrial fibrillation. Arrhythmia & Electrophysiology Review, 4(4(1)).

  79. Baruscotti, M., Bucchi, A., Milanesi, R., Paina, M., Barbuti, A., Gnecchi-Ruscone, T., et al. (2015). A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia. European Heart Journal.

  80. DiFrancesco, D. (2013). Funny channel gene mutations associated with arrhythmias. Journal of Physiology, 591(Pt 17), 4117–4124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biosciences, Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, via Celoria 26, 20133, Milano, Italy

    Mirko Baruscotti, Annalisa Bucchi & Dario DiFrancesco

  2. Cardiovascular Department, “Ospedali Riuniti di Trieste”, University Hospital, Trieste, Italy

    Elisabetta Bianco

Authors
  1. Mirko Baruscotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabetta Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annalisa Bucchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dario DiFrancesco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mirko Baruscotti or Dario DiFrancesco.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Funding

This work was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca [PRIN 2010BWY8E9] and from the UE [LSHM-CT-2006-018676 NORMACOR] to DD, and from Fondazione Cariplo to MB [CLARIFY, 2014–0822] and to DD [ACROSS, 2014–0728].

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baruscotti, M., Bianco, E., Bucchi, A. et al. Current understanding of the pathophysiological mechanisms responsible for inappropriate sinus tachycardia: role of the If “funny” current. J Interv Card Electrophysiol 46, 19–28 (2016). https://doi.org/10.1007/s10840-015-0097-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10840-015-0097-y

Keywords

Search

Navigation