Skip to main content
SpringerLink
Log in

Alterations in Ionic Currents and Relation to Contractile Dysfunction with Severe Cardiac Hypertrophy and Failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Myocardial dysfunction with severe cardiac hypertrophy and congestive heart failure is associated with abnormalities in myocyte action potential morphology, and consequently, trans-sarcolemmal ionic currents. Determination of the primary ionic current or event which contributes to myocardial contractile dysfunction is an area of active research. This review article coalesces findings on ionic processes and systems which have direct relevance in the setting of hypertrophy and congestive heart failure. The consensus conclusion that can be drawn from human and animal studies of severe hypertrophy and/or congestive heart failure is that action potential prolongation is associated with alterations in the outward K+ currents and the inward Ca2−currents.

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

Similar content being viewed by others

References

  1. Katz AM. Heart failure. In: Katz AM. Physiology of the Heart, 2nd ed. New York: Raven Press, 1992:638–668.

    Google Scholar 

  2. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res 1994;28:933–946.

    Google Scholar 

  3. Boyden PA, Jeck CD. Ion channel function in disease. Cardiovasc Res 1995;29:312–318.

    Google Scholar 

  4. Tomaselli GF, Marban E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 1999;42: 270–283.

    Google Scholar 

  5. Katz AM. Cardiac action potential. In: Katz AM. Physiology of the Heart, 2nd ed. New York: Raven Press, 1992; 438–472.

    Google Scholar 

  6. Varro A, Papp JGy. The impact of single cell voltage clamp on the understanding of the cardiac ventricular action potential. Cardioscience 1992;3:131–144.

    Google Scholar 

  7. Bers DM. Ca influx via sarcolemmal Ca channels. 4 In: Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. Norwell, MA: Kluwer Academic Publishers, 1991;49–70.

    Google Scholar 

  8. Snyders DJ. Structure and function of cardiac potassium channels. Cardiovasc Res 1999;42:377–390.

    Google Scholar 

  9. Sorota S. Insights into the structure, distribution and function of the cardiac chloride channels. Cardiovasc Res. 1999;42:361–376.

    Google Scholar 

  10. Nuss HB, Johns DC, Kaab S, Tomaselli GF, Kass D, Lawrence JH, Marban E. Reversal of potassium channel defeciency in cells from failing hearts by adenoviral gene transfer: A prototype for gene therapy for disorders of cardiac excitability and contractility. Gene Ther 1996;3:900–912.

    Google Scholar 

  11. Bers DM, Perez-Reyes E. Ca channels in cardiac myocytes: Structure and function in Ca influx and intracellular Ca release. Cardiovasc Res 1999;42:339–360.

    Google Scholar 

  12. Matsuda H, Saigusa A, Irisawa H. Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+. Nature 1987;325:156–159.

    Google Scholar 

  13. Hartzell HC. Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Prog Biophys Mol Biol 1988;52:165–247.

    Google Scholar 

  14. Matsuda H, Lee H, Shibata F. Enhancement of rabbit sodium channels by β-adrenergic stimulation. Circ Res 1989;70:199–207.

    Google Scholar 

  15. Campbell DL, Strauss HC. Regulation of calcium channels in the heart. Adv Second Messenger Phosphoprotein Res 1995;30:25–88.

    Google Scholar 

  16. Kurachi Y, Asano Y, Takikawa R, Sugimoto T. Cardiac Ca current does not run down and is very sensitive to isoprenaline in the nystatin-method of whole cell recording. Nauyn Arch Pharmacol 1989;340:219–222.

    Google Scholar 

  17. Iijima T, Imagawa J-I, Taira N. Differential modulation by beta-adrenoceptors in inward calcium and delayed rectifier potassium current in single ventricular cells of guinea pig heart. J Pharmacol Exp Ther 1990;254:142–146.

    Google Scholar 

  18. Cleland JG, Dargie HJ. Arrhythmias, catecholamines and electrolytes. Am J Cardiol 1988;62:55A-59A.

    Google Scholar 

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

    Google Scholar 

  20. Houser SR, Freeman AR, Jaeger JM, Breisch RA, Coulson RL, Carey R, Spann JF. Resting potential changes associated with Na-K pump in failing heart muscle. Am J Physiol 1981;240:H168-H176.

    Google Scholar 

  21. Brooksby P, Levi AJ, Jones JV. The electrophysiological characteristics of hypertrophied ventricular myocytes from the spontaneously hypertensive rat. J Hypertens 1993;11: 611–622.

    Google Scholar 

  22. Scamps F, Mayoux E, Charlemagne D, Vassort G. Calcium current in single cells isolated from normal and hypertrophied rat heart. Circ Res 1990;67:199–208.

    Google Scholar 

  23. Ryder KO, Bryant SM, Hart G. Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aorta coarctation. Cardiovasc Res 1993;27: 1278–1287.

    Google Scholar 

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

    Google Scholar 

  25. Kleiman RB, Houser SR. Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am J Physiol 1988;255:H1434-H1442.

    Google Scholar 

  26. Bouron A, Potreau D, Raymond G. The L-type calcium current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc Res 1992;26: 662–670.

    Google Scholar 

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

    Google Scholar 

  28. Tritthart H, Luedcke H, Bayer R, Stierle H, Kaufmann R. Right ventricular hypertrophy in the cat—An electrophysiological and anatomical study. J Mol Cell Cardiol 1975; 7:163–174.

    Google Scholar 

  29. Rials SJ, Xu X, Wu Y, Marinchak RA, Kowey PR. Regression of LV hypertrophy with captopril normalizes membrane currents in rabbits. Am J Physiol 1998;275:H1216-H1224.

    Google Scholar 

  30. Ryder KO, Bryant SM, Winterton SJ, Turner MA, Flores NA, Sheridan DJ, Hart G. Electrical and mechanical characteristics of isolated ventricular myocytes from guinea-pigs with left ventricular hypertrophy and congestive heart failure. J Physiol (Lond) 1993;438:181P.

    Google Scholar 

  31. Spinale FG, Clayton C, Tanaka R. Myocardial Na+, K+-ATPase in tachycardia induced cardiomyopathy. J Moll Cell Cardiol 1992;24:277–294.

    Google Scholar 

  32. Hasenfuss G, Meyer M, Schillinger W, Preuss M, Pieske B, Just H. Calcium handling proteins in the failing human heart. Basic Res Cardiol 1997;92(Suppl 1):87–93.

    Google Scholar 

  33. Bundgaard H, Kjeldsen K. Human myocardial Na-K-ATPase concentration in heart failure. Mol Cell Biochem 1996; 163–164:277–283.

    Google Scholar 

  34. Studer R, Reinecke H, Bilger J, Eschenhagen T, Bohm M, Hasenfuss G, Just H, Holtz J, Drexler H. Gene expression of the cardiac Na+-Ca2+ exchanger in end-stage human heart failure. Circ Res 1994;75:443–453.

    Google Scholar 

  35. Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 1998;37:279–289.

    Google Scholar 

  36. Spinale FG, Mukherjee R, Iannini JP, Whitebread S, Hebbar L, Clair MJ, Melton DM, Cox MH, Thomas PB, de Gasparo M. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacinginduced heart failure II. Effects on myocyte contractile processes. Circulation 1997;96:2397–2406.

    Google Scholar 

  37. Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, Holubarsch C, Posival H, Just H, Drexler H. Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in congestive heart failure due to myocardial infarction. Circ Res 1994;75:434–442.

    Google Scholar 

  38. Hatem SN, Sham JSK, Morad M. Enhanced Na+-Ca2+ exchange activity in cardiomyopathic syrian hamster. Circ Res 1994;74:253–261.

    Google Scholar 

  39. O'Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marban E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I experimental studies. Circ Res 1999;84:562–570.

    Google Scholar 

  40. Sakakibara Y, Furukawa T, Singer DH, Jia H, Backer CL, Arentzen CE, Wasserstrom JA. Sodium current in isolated human ventricular myocytes. Am J Physiol 1993;265: H1301-H1309.

    Google Scholar 

  41. Gulch RW, Baumann R, Jacob R. Analysis of myocardial action potentials in left ventricular hypertrophy of the Goldblatt rat. Basic Res Cardiol 1979;74:69–82.

    Google Scholar 

  42. Sakakibara Y, Wasserstrom JA, Furukawa T, Jia H, Arentzen CE, Hatrz RS, Singer DH. Characterization of the sodium current in single human atrial myocytes. Circ Res 1992;71:535–546.

    Google Scholar 

  43. Barrington PL, Harvey RD, Mogul DJ, Bassett AL, TenEick RE. Na current and inward rectifying K current in cardiocytes from normal and hypertrophic right ventricles of cat. Biophys J 1988;53:426.

    Google Scholar 

  44. Hemwall EL, Duthinh V, Houser SR. Comparison of slow response action potentials from normal and hypertrophied myocardium. Am J Physiol 1984;246:H675-H682.

    Google Scholar 

  45. Hicks MN, Mclntosh MA, Kane KA, Rankin AC, Cobbe SM. The electrophysiology of rabbit hearts with left ventricular hypertrophy under normal and ischaemic conditions. Cardiovasc Res 1995;30:181–186.

    Google Scholar 

  46. Cerbai E, Barbieri M, Li Q, Mugelli A. Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res 1994;28:1180–1187.

    Google Scholar 

  47. Benitah JP, Gomez AM, Bailly P, Da Ponte JP, Berson G, Delgado C, Lorente P. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol (Lond) 1993;469:111–138.

    Google Scholar 

  48. Coulombe A, Momtaz A, Richer P, Swynghedauw B, Coraboeuf E. Reduction in calcium-independent transient outward current density in DOCA salt hypertrophied rat ventricular myocytes. Pflugers Arch 1994;427:47–55.

    Google Scholar 

  49. Momtaz A, Coulombe A, Richer P, Mercadier J-J, Coraboeuf E. Action potential and plateau ionic currents in moderately and severely DOCA-salt hypertrophied rat hearts. J Mol Cell Cardiol 1996;28:2511–2522.

    Google Scholar 

  50. Tomita F, Bassett AL, Myerburg RJ, Kimura S. Diminished transient outward currents in rat hypertrophied ventricular myocytes. Circ Res 1994;75:296–303.

    Google Scholar 

  51. Potreau D, Gomez JP, Fares N. Depressed transient outward current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc Res 1995;30:440–448.

    Google Scholar 

  52. Chouabe C, Espinosa L, Megas P, Chakir A, Rougier O, Freminet A, Bonvallet R. Reduction of Ica,L and Ito1 density in hypertrophied right ventricular cells by simulated high altitude in adult rats. J Mol Cell Cardiol 1997;29:193–206.

    Google Scholar 

  53. Lee J-K, Kodama I, Honjo H, Anno T, Kamiya K, Toyama J. Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy. Am J Physiol 1997;272:H2833-H2842.

    Google Scholar 

  54. Meszaros J, Couthino JJ, Bryant SM, Ryder KO, Hart G. L-type calciumcurrent in catecholamine-induced cardiac hypertrophy in the rat. Exp Physiol 1997;82:71–83.

    Google Scholar 

  55. Li Q, Keung EC. Effects of myocardial hypertrophy on transient outward current. Am J Physiol 1980;75:73–80.

    Google Scholar 

  56. Thuringer D, Deroubaix E, Coulombe A, Coraboeuf E, Mercadier J-J. Ionic basis of the action potential prolongation in ventricular myocytes from Syrian hamsters with dilated cardiomyopathy. Cardiovasc Res 1996;31:747–757.

    Google Scholar 

  57. Wang DW, Kiyosue T, Shigematsu S, Arita M. Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol 1995;269:H1288-H1296.

    Google Scholar 

  58. Qin D, Zhang Z-H, Caref EB, Boutjdir M, Jain P, El-Sherif N. Cellular and ionic basis of arrhythmias in postinfarction remodeled ventricular myocardium. Circ Res 1996;79: 461–473.

    Google Scholar 

  59. Rozanski GJ, Xu Z, Zhang K, Patel KP. Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction. Am J Physiol 1998;274:H259-H265.

    Google Scholar 

  60. Lue WM, Boyden PA. Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current. Circulation 1992;85:1175–1188.

    Google Scholar 

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

    Google Scholar 

  62. Nabauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 1996;93:168–177.

    Google Scholar 

  63. Wettwer E, Amos GJ, Posival H, Ravens U. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res 1994;75:473–482.

    Google Scholar 

  64. Delbridge LMD, Satoh H, Yuan W, Bassani JWM, Qi M, Ginsburg KS, Samarel AM, Bers DM. Cardiac myocyte volume, Ca2+ fluxes, and sarcoplasmic reticulum loading in pressure-overload hypertrophy. Am J Physiol 1997;272: H2425-H2435.

    Google Scholar 

  65. Bryant SM, Shipsey SJ, Hart G. Regional differences in electrical and mechanical properties of myocytes from guinea-pig hearts with mild left ventricular hypertrophy. Cardiovasc Res 1997;35:315–323.

    Google Scholar 

  66. Ryder KO, Bryant SM, Hart G. Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc Res 1993;27: 1278–1287.

    Google Scholar 

  67. Nuss HB, Houser SR. Voltage dependence of contraction and calcium current in severely hypertrophied feline ventricular myocytes. J Mol Cell Cardiol 1991;23:717–726.

    Google Scholar 

  68. Nuss HB, Houser SR. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res 1993;73:777–782.

    Google Scholar 

  69. Ming Z, Nordin C, Siri F, Aronson RS. Reduced calcium current density in single myocytes isolated from hypertrophied failing guinea pig hearts. J Mol Cell Cardiol 1994;26:1133–1143.

    Google Scholar 

  70. Xiao Y-F, McArdle JJ. Elevated density and altered pharmacologic properties of myocardial calcium current of the spontaneously hypertensive rat. J Hypertens 1994;12:783–790.

    Google Scholar 

  71. Keung EC. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium. Circ Res 1989;64:753–763.

    Google Scholar 

  72. Sen L, O'Neill M, Marsh JD, Smith TW. Inotropic and calcium kinetic effects of calcium channel agonist and antagonist in isolated cardiacmyocytes fromcardiomyopathic hamsters. Circ Res 1990;67:599–608.

    Google Scholar 

  73. Rossner HL. Calcium current in congestive heart failure of hamster cardiomyopathy. Am J Physiol 1991;260: H1179-H1186.

    Google Scholar 

  74. Kruger C, Erdmann E, Nabauer M, Beuckelmann DJ. Intracellular calcium handling in isolated ventricular myocytes from cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure. Cell Calcium 1994;16:500–508.

    Google Scholar 

  75. Zhang X-Q, Moore RL, Tillotson DL, Cheung JY. Calcium currents in postinfarction rat cardiac myocytes. Am J Physiol 1995;269:C1464-C1473.

    Google Scholar 

  76. Santos PE, Barcellos LC, Mill JG, Masuda MO. Ventricular action potential and L-type calcium channel in infarct-induced hypertrophy in rats. J Cardiovasc Electrophysiol 1995;6:1004–1014.

    Google Scholar 

  77. Mukherjee R, Hewett KW, Walker JD, Basler CG, Spinale FG. Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure. Cardiovasc Res 1998;37:432–444.

    Google Scholar 

  78. Yao A, Su Z, Nonaka A, Zubair I, Spitzer KW, Bridge JHB, Muelheims G, Ross J Jr, Barry WH. Abnormal myocyte Ca2+ homoeostasis in rabbits with pacing-induced heart failure. Am J Physiol 1998;274:H1441-H1448.

    Google Scholar 

  79. Beuckelmann DJ. Contributions of Ca2+-influx via the Ltype Ca2+-current and Ca2+-release from the sarcoplasmic reticulum to [Ca2+]i-transients in human myocytes. Basic Res Cardiol 1997;92(Suppl 1):105–110.

    Google Scholar 

  80. Beuckelmann DJ, Erdmann E. Ca2+-currents and intracellular [Ca2+]i-transients in single ventricular myocytes isolated from terminally failing human hearts. Basic Res Cardiol 1992;87(Suppl 1):235–243.

    Google Scholar 

  81. Mewes T, Ravens U. L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. J Mol Cell Cardiol 1994;26:1307–1320.

    Google Scholar 

  82. Ouadid H, Albat B, Nargeot J. Calcium currents in diseased human cardiac cells. J Cardiovasc Pharmacol 1995;25: 282–291.

    Google Scholar 

  83. Takahashi T, Allen PD, Lacro RV, Marks AR, Dennis AR, Schoen FJ, Grossman W, Marsh JD, Izumo S. Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure. J Clin Invest 1992;90:927–935.

    Google Scholar 

  84. Mukherjee R, Spinale FG. L-type calcium channel abundance and function with cardiac hypertrophy and failure: A review. J Mol Cell Cardiol 1998;30:1899–1916.

    Google Scholar 

  85. Yue DT. Quenching the spark in the heart. Science 1997;276: 755–756.

    Google Scholar 

  86. Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 1997;276: 800–806.

    Google Scholar 

  87. Furukawa T, Bassett AL, Furukawa N, Kimura S, Myerburg RJ. The ionic mechanism of reperfusion-induced early afterdepolarizations feline left ventricular hypertrophy. J Clin Invest 1993;91:1521–1531.

    Google Scholar 

  88. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. β-1 and β-2 Adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contractions and selective β1-receptor down regulation in heart failure. Circ Res 1986;59:297–309.

    Google Scholar 

  89. Richard S, Leclercq F, Lemaire S, Piot C, Nargeot J. Ca2+ currents in compensated hypertrophy and heart failure. Cardiovasc Res 1998;37:300–311.

    Google Scholar 

  90. Balke CW, Shorofsky SR. Alterations in calcium handling in cardiac hypertrophy and heart failure. Cardiovasc Res 1998;37:290–299.

    Google Scholar 

  91. Swynghedauw B, Besse S, Assayag P, Carre F, Chevalier B, Charlemagne D, Delcayre C, Hardouin S, Heymes C, Moalic JM. Molecular and cellular biology of the senescent hypertrophied and failing heart. Am J Cardiol 1995;76:2D-7D.

    Google Scholar 

  92. Haverkamp W, Hindricks G, Fechtrup C, Borggrefe M, Breithardt G. Sodium channel blockers in the treatment of ventricular arrhythmias: different effects in the normal, ischaemic or failing heart? Eur Heart J 1997;12(Suppl F):10–17.

    Google Scholar 

  93. ten Eick RE, Whalley DW, Rasmussen HH. Connections: Heart disease, cellular electrophysiology, and ion channels. FASEB J 1992;6:2568–2580.

    Google Scholar 

  94. Hiraoka M, Sawanobori T, Kawano S, Hirano Y, Furukawa T. Functions of cardiac ion channels under normal and pathological conditions. Jpn Heart J 1996;37:693–707.

    Google Scholar 

  95. Lawrence JH, Johns DC, Chiamvimonvat N, Nuss HB, Marban E. Prospects for genetic manipulation of cardiac excitability. Adv Exp Med Biol 1995;382:41–48.

    Google Scholar 

  96. Wang Q, Chen Q, Li H, Towbin JA. Molecular genetics of long QT syndrome from genes to patients. Curr Opin Cardiol 1997;12:310–320.

    Google Scholar 

  97. Saffitz JE, Schuessler RB, Yamada KA. Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res 1999;42:309–317.

    Google Scholar 

  98. Severs NJ. Pathophysiology of gap junctions in heart disease. J Cardiovasc Electrophysiol 1994;5:462–475.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC

    Rupak Mukherjee & Francis G. Spinale

Authors
  1. Rupak Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis G. Spinale
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mukherjee, R., Spinale, F.G. Alterations in Ionic Currents and Relation to Contractile Dysfunction with Severe Cardiac Hypertrophy and Failure. Heart Fail Rev 4, 319–327 (1999). https://doi.org/10.1023/A:1009899502335

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009899502335

Search

Navigation