Cardiac Sodium-Calcium Exchange and Efficient Excitation-Contraction Coupling: Implications for Heart Disease

  • Joshua I. GoldhaberEmail author
  • Kenneth D. Philipson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


Cardiovascular disease is a leading cause of death worldwide, with ischemic heart disease alone accounting for >12% of all deaths, more than HIV/AIDS, tuberculosis, lung, and breast cancer combined. Heart disease has been the leading cause of death in the United States for the past 85 years and is a major cause of disability and health-care expenditures. The cardiac conditions most likely to result in death include heart failure and arrhythmias, both a consequence of ischemic coronary disease and myocardial infarction, though chronic hypertension and valvular diseases are also important causes of heart failure. Sodium-calcium exchange (NCX) is the dominant calcium (Ca2+) efflux mechanism in cardiac cells. Using ventricular-specific NCX knockout mice, we have found that NCX is also an essential regulator of cardiac contractility independent of sarcoplasmic reticulum Ca2+ load. During the upstroke of the action potential, sodium (Na+) ions enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum. The rise in cleft Na+, in conjunction with depolarization, causes NCX to transiently reverse. Ca2+ entry by this mechanism then “primes” the diadic cleft so that subsequent Ca2+ entry through Ca2+ channels can more efficiently trigger Ca2+ release from the sarcoplasmic reticulum. In NCX knockout mice, this mechanism is inoperative (Na+ current has no effect on the Ca2+ transient), and excitation-contraction coupling relies upon the elevated diadic cleft Ca2+ that arises from the slow extrusion of cytoplasmic Ca2+ by the ATP-dependent sarcolemmal Ca2+ pump. Thus, our data support the conclusion that NCX is an important regulator of cardiac contractility. These findings suggest that manipulation of NCX may be beneficial in the treatment of heart failure.


Sodium-calcium exchange Excitation-contraction coupling Heart ­failure Calcium channels Sodium current Contractility 


  1. W.T. Abraham, K.F. Adams, G.C. Fonarow, M.R. Costanzo, R.L. Berkowitz, T.H. LeJemtel, M.L. Cheng, J. Wynne, In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J. Am. Coll. Cardiol. 46, 57–64 (2005)PubMedCrossRefGoogle Scholar
  2. A.A. Armoundas, J. Rose, R. Aggarwal, B.D. Stuyvers, B. O’Rourke, D.A. Kass, E. Marban, S.R. Shorofsky, G.F. Tomaselli, C. William Balke, Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am. J. Physiol. Heart Circ. Physiol. 292, H1607–H1618 (2007)PubMedCrossRefGoogle Scholar
  3. D.M. Bers, W.J. Lederer, J.R. Berlin, Intracellular Ca transients in rat cardiac myocytes: role of Na-Ca exchange in excitation-contraction coupling. Am. J. Physiol. 258, C944–C954 (1990)PubMedGoogle Scholar
  4. F. Brette, C.H. Orchard, No apparent requirement for neuronal sodium channels in excitation-contraction coupling in rat ventricular myocytes. Circ. Res. 98, 667–674 (2006)PubMedCrossRefGoogle Scholar
  5. W.A. Catterall, A.L. Goldin, S.G. Waxman, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005)PubMedCrossRefGoogle Scholar
  6. Center for Disease Control and Prevention, Heart failure fact sheet (2011), Accessed 3 Dec 2011
  7. C. Chantawansri, N. Huynh, J. Yamanaka, A. Garfinkel, S.T. Lamp, M. Inoue, J.H. Bridge, J.I. Goldhaber, Effect of metabolic inhibition on couplon behavior in rabbit ventricular myocytes. Biophys. J. 94, 1656–1666 (2008)PubMedCrossRefGoogle Scholar
  8. H. Cheng, W.J. Lederer, M.B. Cannell, Calcium sparks - elementary events underlying excitation-contraction coupling in heart muscle. Science 262, 740–744 (1993)PubMedCrossRefGoogle Scholar
  9. J.A. Copello, S. Barg, H. Onoue, S. Fleischer, Heterogeneity of Ca2+ gating of skeletal muscle and cardiac ryanodine receptors. Biophys. J. 73, 141–156 (1997)PubMedCrossRefGoogle Scholar
  10. U. Elkayam, G. Tasissa, C. Binanay, L. Stevenson, M. Gheorghiade, J. Warnica, J. Young, B. Rayburn, J. Rogers, T. Demarco, Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am. Heart J. 153, 98–104 (2007)PubMedCrossRefGoogle Scholar
  11. A. Fabiato, Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am. J. Physiol. 245, C1–C14 (1983)PubMedGoogle Scholar
  12. G.M. Felker, R.L. Benza, A.B. Chandler, J.D. Leimberger, M.S. Cuffe, R.M. Califf, M. Gheorghiade, C.M. O’Connor, Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J. Am. Coll. Cardiol. 41, 997–1003 (2003)PubMedCrossRefGoogle Scholar
  13. M. Flesch, R.H. Schwinger, F. Schiffer, K. Frank, M. Südkamp, F. Kuhn-Regnier, G. Arnold, M. Böhm, Evidence for functional relevance of an enhanced expression of the Na+-Ca2+ exchanger in failing human myocardium. Circulation 94, 992–1002 (1996)PubMedCrossRefGoogle Scholar
  14. G.C. Fonarow, C.W. Yancy, A.F. Hernandez, E.D. Peterson, J.A. Spertus, P.A. Heidenreich, Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am. Heart J. 161, 1024–1030 (2011). e1023PubMedCrossRefGoogle Scholar
  15. C. Franzini-Armstrong, F. Protasi, V. Ramesh, Shape, size, and distribution of Ca2+ release units and couplons in skeletal and cardiac muscles. Biophys. J. 77, 1528–1539 (1999)PubMedCrossRefGoogle Scholar
  16. C. Gershome, E. Lin, H. Kashihara, L. Hove-Madsen, G.F. Tibbits, Colocalization of voltage-gated Na+ channels with the Na+/Ca2+ exchanger in rabbit cardiomyocytes during development. Am. J. Physiol. Heart Circ. Physiol. 300, H300–H311 (2011)PubMedCrossRefGoogle Scholar
  17. A.L. Goldin, Resurgence of sodium channel research. Annu. Rev. Physiol. 63, 871–894 (2001)PubMedCrossRefGoogle Scholar
  18. A.M. Gomez, S. Guatimosim, K.W. Dilly, G. Vassort, W.J. Lederer, Heart failure after myocardial infarction - Altered excitation-contraction coupling. Circulation 104, 688–693 (2001)PubMedCrossRefGoogle Scholar
  19. R.J. Hajjar, J.K. Gwathmey, Direct evidence of changes in myofilament responsiveness to Ca2+ during hypoxia and reoxygenation in myocardium. Am. J. Physiol. 259, H784–H795 (1990)PubMedGoogle Scholar
  20. G. Hasenfuss, B. Pieske, Calcium cycling in congestive heart failure. J. Mol. Cell. Cardiol. 34, 951–969 (2002)PubMedCrossRefGoogle Scholar
  21. R.A. Haworth, A.B. Goknur, Control of the Na-Ca exchanger in isolated heart cells. II. Beta-dependent activation in normal cells by intracellular calcium. Circ. Res. 69, 1514–1524 (1991)PubMedCrossRefGoogle Scholar
  22. S.A. Henderson, J.I. Goldhaber, J.M. So, T. Han, C. Motter, A. Ngo, C. Chantawansri, M.R. Ritter, M. Friedlander, D.A. Nicoll, J.S. Frank, M.C. Jordan, K.P. Roos, R.S. Ross, K.D. Philipson, Functional adult myocardium in the absence of Na+-Ca2+ exchange: cardiac-specific knockout of NCX1. Circ. Res. 95, 604–611 (2004)PubMedCrossRefGoogle Scholar
  23. I.A. Hobai, B. O’Rourke, Enhanced Ca2+-activated Na+-Ca2+ exchange activity in canine pacing-induced heart failure. Circ. Res. 87, 690–698 (2000)PubMedCrossRefGoogle Scholar
  24. K. Imahashi, C. Pott, J.I. Goldhaber, C. Steenbergen, K.D. Philipson, E. Murphy, Cardiac-specific ablation of the Na+/Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ. Res. 97, 916–921 (2005)PubMedCrossRefGoogle Scholar
  25. J.S. Ingwall, R.G. Weiss, Is the failing heart energy starved?: on using chemical energy to support cardiac function. Circ. Res. 95, 135–145 (2004)PubMedCrossRefGoogle Scholar
  26. M. Inoue, J.H. Bridge, Ca2+ sparks in rabbit ventricular myocytes evoked by action potentials: involvement of clusters of L-type Ca2+ channels. Circ. Res. 92, 532–538 (2003)PubMedCrossRefGoogle Scholar
  27. S.A. John, B. Ribalet, J.N. Weiss, K.D. Philipson, M. Ottolia, Ca2+-dependent structural rearrangements within Na+-Ca2+ exchanger dimers. Proc. Natl. Acad. Sci. U. S. A. 108, 1699–1704 (2011)PubMedCrossRefGoogle Scholar
  28. W.J. Koch, R.J. Lefkowitz, H.A. Rockman, Functional consequences of altering myocardial adrenergic receptor signaling. Annu. Rev. Physiol. 62, 237–260 (2000)PubMedCrossRefGoogle Scholar
  29. O. Kohmoto, A.J. Levi, J.H.B. Bridge, Relation between reverse sodium-calcium exchange and sarcoplasmic reticulum calcium release in guinea pig ventricular cells. Circ. Res. 74, 550–554 (1994)CrossRefGoogle Scholar
  30. R. Larbig, N. Torres, J.H. Bridge, J.I. Goldhaber, K.D. Philipson, Activation of reverse Na+-Ca2+ exchange by the Na+ current augments the cardiac Ca2+ transient: evidence from NCX knockout mice. J. Physiol. 588, 3267–3276 (2010)PubMedCrossRefGoogle Scholar
  31. N. Leblanc, J.R. Hume, Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science 248, 372–376 (1990)PubMedCrossRefGoogle Scholar
  32. G.T. Lines, J.B. Sande, W.E. Louch, H.K. Mørk, P. Grøttum, O.M. Sejersted, Contribution of the Na+/Ca2+ Exchanger to Rapid Ca2+ Release in Cardiomyocytes. Biophys. J. 91, 779–792 (2006)PubMedCrossRefGoogle Scholar
  33. P. Lipp, E. Niggli, Sodium current-induced calcium ­signals in isolated guinea-pig ventricular myocytes. J. Physiol. 474, 439–446 (1994)PubMedGoogle Scholar
  34. S.E. Litwin, D. Zhang, J.H. Bridge, Dyssynchronous Ca2+ sparks in myocytes from infarcted hearts. Circ. Res. 87, 1040–1047 (2000)PubMedCrossRefGoogle Scholar
  35. B. London, J.W. Krueger, Contraction in voltage-clamped, internally perfused single heart cells. J. Gen. Physiol. 88, 475–505 (1986)PubMedCrossRefGoogle Scholar
  36. J.R. Lopez-Lopez, P.S. Shacklock, C.W. Balke, W.G. Wier, Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science 268, 1042–1045 (1995)PubMedCrossRefGoogle Scholar
  37. S.K. Maier, R.E. Westenbroek, K.A. Schenkman, E.O. Feigl, T. Scheuer, W.A. Catterall, An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc. Natl. Acad. Sci. U. S. A. 99, 4073–4078 (2002)PubMedCrossRefGoogle Scholar
  38. A.R. Marks, Cardiac intracellular calcium release channels: role in heart failure. Circ. Res. 87, 8–11 (2000)PubMedCrossRefGoogle Scholar
  39. G. Meissner, Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu. Rev. Physiol. 56, 485–508 (1994)PubMedCrossRefGoogle Scholar
  40. Z.A. Nagy, L. Virag, A. Toth, P. Biliczki, K. Acsai, T. Banyasz, P. Nanasi, J.G. Papp, A. Varro, Selective inhibition of sodium-calcium exchanger by SEA-0400 decreases early and delayed after depolarization in canine heart. Br. J. Pharmacol. 143, 827–831 (2004)PubMedCrossRefGoogle Scholar
  41. P. Neco, B. Rose, N. Huynh, R. Zhang, J.H. Bridge, K.D. Philipson, J.I. Goldhaber, Sodium-calcium exchange is essential for effective triggering of calcium release in mouse heart. Biophys. J. 99, 755–764 (2010)PubMedCrossRefGoogle Scholar
  42. H.B. Nuss, S.R. Houser, Sodium-calcium exchange-mediated contractions in feline ventricular myocytes. Am. J. Physiol. 263, H1161–H1169 (1992)PubMedGoogle Scholar
  43. E. Polakova, A. Zahradnikova Jr., J. Pavelkova, I. Zahradnik, A. Zahradnikova, Local calcium release activation by DHPR calcium channel openings in rat cardiac myocytes. J. Physiol. (London) 586, 3839–3854 (2008)CrossRefGoogle Scholar
  44. C. Pott, K.D. Philipson, J.I. Goldhaber, Excitation-contraction coupling in Na+-Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux. Circ. Res. 97, 1288–1295 (2005)PubMedCrossRefGoogle Scholar
  45. C. Pott, M. Yip, J.I. Goldhaber, K.D. Philipson, Regulation of cardiac L-type Ca2+ current in Na+-Ca2+ exchanger knockout mice: functional coupling of the Ca2+ channel and the Na+-Ca2+ exchanger. Biophys. J. 92, 1431–1437 (2007a)PubMedCrossRefGoogle Scholar
  46. C. Pott, X. Ren, D.X. Tran, M.J. Yang, S. Henderson, M.C. Jordan, K.P. Roos, A. Garfinkel, K.D. Philipson, J.I. Goldhaber, Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice. Am. J. Physiol. Cell Physiol. 292, C968–C973 (2007b)PubMedCrossRefGoogle Scholar
  47. V.L. Roger, A.S. Go, D.M. Lloyd-Jones, R.J. Adams, J.D. Berry, T.M. Brown, M.R. Carnethon, S. Dai, G. de Simone, E.S. Ford, C.S. Fox, H.J. Fullerton, C. Gillespie, K.J. Greenlund, S.M. Hailpern, J.A. Heit, P.M. Ho, V.J. Howard, B.M. Kissela, S.J. Kittner, D.T. Lackland, J.H. Lichtman, L.D. Lisabeth, D.M. Makuc, G.M. Marcus, A. Marelli, D.B. Matchar, M.M. McDermott, J.B. Meigs, C.S. Moy, D. Mozaffarian, M.E. Mussolino, G. Nichol, N.P. Paynter, W.D. Rosamond, P.D. Sorlie, R.S. Stafford, T.N. Turan, M.B. Turner, N.D. Wong, J. Wylie-Rosett, Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation 124, e18–e209 (2011)CrossRefGoogle Scholar
  48. U. Schmidt, R.J. Hajjar, P.A. Helm, C.S. Kim, A.A. Doye, J.K. Gwathmey, Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J. Mol. Cell. Cardiol. 30, 1929–1937 (1998)PubMedCrossRefGoogle Scholar
  49. J.S. Sham, L. Cleemann, M. Morad, Gating of the cardiac Ca2+ release channel: the role of Na+ current and Na+-Ca2+ exchange. Science 255, 850–853 (1992)PubMedCrossRefGoogle Scholar
  50. K.R. Sipido, E. Carmeliet, A. Pappano, Na+ current and Ca2+ release from the sarcoplasmic reticulum during action potentials in guinea-pig ventricular myocytes. J. Physiol. (London) 489, 1–17 (1995)Google Scholar
  51. K.R. Sipido, M. Maes, F. Van de Werf, Low efficiency of Ca2+ entry through the Na+-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+-Ca2+ exchange. Circ. Res. 81, 1034–1044 (1997)PubMedCrossRefGoogle Scholar
  52. M.D. Stern, Theory of excitation-contraction coupling in cardiac muscle. Biophys. J. 63, 497–517 (1992)PubMedCrossRefGoogle Scholar
  53. M.D. Stern, G. Pizarro, E. Rios, Local control model of excitation-contraction coupling in skeletal muscle. J. Gen. Physiol. 110, 415–440 (1997)PubMedCrossRefGoogle Scholar
  54. R. Studer, H. Reinecke, J. Bilger, T. Eschenhagen, M. Bohm, G. Hasenfuss, H. Just, J. Holtz, H. Drexler, Gene expression of the cardiac Na+-Ca2+ exchanger in end-stage human heart failure. Circ. Res. 75, 443–453 (1994)PubMedCrossRefGoogle Scholar
  55. N.S. Torres, R. Larbig, A.N. Rock, J.I. Goldhaber, J.H. Bridge, Na+ currents are required for efficient excitation-contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na+ channel to triggering Ca2+ release from the sarcoplasmic reticulum. J. Physiol. 588, 4249–4260 (2010)PubMedCrossRefGoogle Scholar
  56. J.A. Wasserstrom, A.M. Vites, The role of Na+-Ca2+ exchange in activation of excitation-contraction coupling in rat ventricular myocytes. J. Physiol. 493, 529–542 (1996)PubMedGoogle Scholar
  57. World Health Organization, The top 10 causes of death (2011), Accessed 3 Dec 2011

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Cedars-Sinai Heart InstituteLos AngelesUSA

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