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Stretch modulation of cardiac contractility: importance of myocyte calcium during the slow force response

  • Sarbjot Kaur
  • Xin Shen
  • Amelia Power
  • Marie-Louise WardEmail author
Review
  • 17 Downloads

Abstract

The mechanical response of the heart to myocardial stretch has been understood since the work of muscle physiologists more than 100 years ago, whereby an increase in ventricular chamber filling during diastole increases the subsequent force of contraction. The stretch-induced increase in contraction is biphasic. There is an abrupt increase in the force that coincides with the stretch (the rapid response), which is then followed by a slower response that develops over several minutes (the slow force response, or SFR). The SFR is associated with a progressive increase in the magnitude of the Ca2+ transient, the event that initiates myocyte cross-bridge cycling and force development. However, the mechanisms underlying the stretch-dependent increase in the Ca2+ transient are still debated. This review outlines recent literature on the SFR and summarizes the different stretch-activated Ca2+ entry pathways. The SFR might result from a combination of several different cellular mechanisms initiated in response to activation of different cellular stretch sensors.

Keywords

Cardiac stretch Calcium influx Slow force response Stretch-activated channels Autocrine/paracrine response G-coupled protein receptors 

Notes

Funding information

We acknowledge funding from the University of Auckland Faculty Research and Development Fund and the Auckland Medical Research Foundation.

Compliance with ethical standards

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Human and animal rights and informed consent

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

References

  1. Adams JW et al (1996) Prostaglandin F2 alpha stimulates hypertrophic growth of cultured neonatal rat ventricular myocytes. J Biol Chem 271:1179–1186.  https://doi.org/10.1074/jbc.271.2.1179 CrossRefPubMedGoogle Scholar
  2. Allen DG, Kentish JC (1985) The cellular basis of the length-tension relation in cardiac muscle. J Mol Cell Cardiol 17:821–840.  https://doi.org/10.1016/s0022-2828(85)80097-3 CrossRefPubMedGoogle Scholar
  3. Allen DG, Kurihara S (1982) The effects of muscle length on intracellular calcium transients in mammalian cardiac muscle. J Physiol 327:79–94.  https://doi.org/10.1113/jphysiol.1982.sp014221 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Allen DG, Nichols CG, Smith GL (1988) The effects of changes in muscle length during diastole on the calcium transient in ferret ventricular muscle. J Physiol 406:359–370.  https://doi.org/10.1113/jphysiol.1988.sp017385 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Alvarez BV, Perez NG, Ennis IL, Camilion de Hurtado MC, Cingolani HE (1999) Mechanisms underlying the increase in force and Ca(2+) transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ Res 85:716–722.  https://doi.org/10.1161/01.res.85.8.716 CrossRefPubMedGoogle Scholar
  6. Babbitt CJ, Shai SY, Harpf AE, Pham CG, Ross RS (2002) Modulation of integrins and integrin signaling molecules in the pressure-loaded murine ventricle. Histochem Cell Biol 118:431–439.  https://doi.org/10.1007/s00418-002-0476-1 CrossRefPubMedGoogle Scholar
  7. Beech DJ, Kalli AC (2019) Force sensing by piezo channels in cardiovascular health and disease. Arterioscler Thromb Vasc Biol 39:2228–2239.  https://doi.org/10.1161/ATVBAHA.119.313348 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 21:380–387.  https://doi.org/10.1152/physiol.00019.2006 CrossRefGoogle Scholar
  9. Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49.  https://doi.org/10.1146/annurev.physiol.70.113006.100455 CrossRefPubMedGoogle Scholar
  10. Blaustein MP, Lederer WJ (1999) Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763–854.  https://doi.org/10.1152/physrev.1999.79.3.763 CrossRefPubMedGoogle Scholar
  11. Browe DM, Baumgarten CM (2003) Stretch of beta 1 integrin activates an outwardly rectifying chloride current via FAK and Src in rabbit ventricular myocytes. J Gen Physiol 122:689–702.  https://doi.org/10.1085/jgp.200308899 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Calaghan S, White E (2004a) Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart. J Physiol 559:205–214.  https://doi.org/10.1113/jphysiol.2004.069021 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Calaghan S, White E (2004b) Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart. J Physiol Lond 559:205–214CrossRefGoogle Scholar
  14. Chazov EI, Pomoinetsky VD, Geling NG, Orlova TR, Nekrasova AA, Smirnov VN (1979) Heart adaptation to acute pressure overload: an involvement of endogenous prostaglandins. Circ Res 45:205–211.  https://doi.org/10.1161/01.res.45.2.205 CrossRefPubMedGoogle Scholar
  15. Cingolani HE, Alvarez BV, Ennis IL, Camilion de Hurtado MC (1998) Stretch-induced alkalinization of feline papillary muscle: an autocrine-paracrine system. Circ Res 83:775–780.  https://doi.org/10.1161/01.res.83.8.775 CrossRefPubMedGoogle Scholar
  16. Cingolani HE, Perez NG, Pieske B, von Lewinski D, Camilion de Hurtado MC (2003) Stretch-elicited Na+/H+ exchanger activation: the autocrine/paracrine loop and its mechanical counterpart. Cardiovasc Res 57:953–960.  https://doi.org/10.1016/s0008-6363(02)00768-x CrossRefPubMedGoogle Scholar
  17. Cingolani HE, Perez NG, Cingolani OH, Ennis IL (2013) The Anrep effect: 100 years later. Am J Physiol Heart Circ Physiol 304:H175–H182.  https://doi.org/10.1152/ajpheart.00508.2012 CrossRefPubMedGoogle Scholar
  18. Coste B (2012) Piezo proteins form a new class of mechanically activated ion channels. Med Sci (Paris) 28:1056–1057.  https://doi.org/10.1051/medsci/20122812012 CrossRefGoogle Scholar
  19. Coste B et al (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:55–60.  https://doi.org/10.1126/science.1193270 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Dyachenko V, Husse B, Rueckschloss U, Isenberg G (2009) Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels. Cell Calcium 45:38–54.  https://doi.org/10.1016/j.ceca.2008.06.003 CrossRefPubMedGoogle Scholar
  21. Escobar E, Zamorano B, Gazmuri R (1983) Demonstration of prostaglandin E2 and F2 alpha in atrial tissue of patients with heart disease. Am J Cardiol 52:424–425.  https://doi.org/10.1016/0002-9149(83)90158-3 CrossRefPubMedGoogle Scholar
  22. Eu JP, Sun J, Xu L, Stamler JS, Meissner G (2000) The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499–509.  https://doi.org/10.1016/s0092-8674(00)00054-4 CrossRefPubMedGoogle Scholar
  23. Fabiato A, Fabiato F (1975) Dependence of the contractile activation of skinned cardiac cells on the sarcomere length. Nature 256:54–56.  https://doi.org/10.1038/256054a0 CrossRefPubMedGoogle Scholar
  24. Fillion D, Devost D, Sleno R, Inoue A, Hebert TE (2019) Asymmetric recruitment of beta-Arrestin1/2 by the angiotensin II type I and prostaglandin F2alpha receptor dimer front. Endocrinol (Lausanne) 10:162.  https://doi.org/10.3389/fendo.2019.00162 CrossRefGoogle Scholar
  25. Frank O (1895) Zur Dynamik des Herzmuskels : Habilitationsschrift zur Erlangung der Venia Legendi der Medizinischen Fakultät der Ludwig-Mazimilians-Universität zu München. Druck von R, OldenbourgGoogle Scholar
  26. Freichel M et al (2017) TRP channels in the heart. In: Emir TLR (ed) nd. Neurobiology of TRP Channels. Frontiers in Neuroscience, Boca Raton, pp 149–185.  https://doi.org/10.4324/9781315152837-9 CrossRefGoogle Scholar
  27. Fukuda N, Granzier HL (2005) Titin/connectin-based modulation of the Frank-Starling mechanism of the heart. J Muscle Res Cell Motil 26:319–323.  https://doi.org/10.1007/s10974-005-9038-1 CrossRefPubMedGoogle Scholar
  28. Gordon AM, Huxley AF, Julian FJ (1966) The variation in isometric tension with sarcomere length in vertebrate muscle fibres. J Physiol 184:170–192.  https://doi.org/10.1113/jphysiol.1966.sp007909 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Goupil E et al (2015) Angiotensin II type I and prostaglandin F2alpha receptors cooperatively modulate signaling in vascular smooth muscle cells. J Biol Chem 290:3137–3148.  https://doi.org/10.1074/jbc.M114.631119 CrossRefPubMedGoogle Scholar
  30. Guharay F, Sachs F (1984) Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle. J Physiol 352:685–701.  https://doi.org/10.1113/jphysiol.1984.sp015317 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37:279–289.  https://doi.org/10.1016/s0008-6363(97)00277-0 CrossRefPubMedGoogle Scholar
  32. Hibberd MG, Jewell BR (1982) Calcium- and length-dependent force production in rat ventricular muscle. J Physiol 329:527–540.  https://doi.org/10.1113/jphysiol.1982.sp014317 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Hof T, Chaigne S, Recalde A, Salle L, Brette F, Guinamard R (2019) Transient receptor potential channels in cardiac health and disease. Nat Rev Cardiol 16:344–360.  https://doi.org/10.1038/s41569-018-0145-2 CrossRefPubMedGoogle Scholar
  34. Hongo K, White E, Le Guennec JY, Orchard CH (1996) Changes in [Ca2+]i, [Na+]i and Ca2+ current in isolated rat ventricular myocytes following an increase in cell length. J Physiol 491(Pt 3):609–619.  https://doi.org/10.1113/jphysiol.1996.sp021243 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Inoue R, Jian Z, Kawarabayashi Y (2009) Mechanosensitive TRP channels in cardiovascular pathophysiology. Pharmacol Ther 123:371–385.  https://doi.org/10.1016/j.pharmthera.2009.05.009 CrossRefPubMedGoogle Scholar
  36. Iribe G, Jin H, Kaihara K, Naruse K (2010) Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes. Exp Physiol 95:699–711.  https://doi.org/10.1113/expphysiol.2009.051896 CrossRefPubMedGoogle Scholar
  37. Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I, Kamkin A (2003) Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Prog Biophys Mol Biol 82:43–56.  https://doi.org/10.1016/s0079-6107(03)00004-x CrossRefPubMedGoogle Scholar
  38. Kamkin A, Kiseleva I, Isenberg G (2000) Stretch-activated currents in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 48:409–420.  https://doi.org/10.1016/s0008-6363(00)00208-x CrossRefPubMedGoogle Scholar
  39. Kentish JC, Wrzosek A (1998) Changes in force and cytosolic Ca2+ concentration after length changes in isolated rat ventricular trabeculae. J Physiol 506(Pt 2):431–444.  https://doi.org/10.1111/j.1469-7793.1998.431bw.x CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kockskamper J et al (2008a) Angiotensin II and myosin light-chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium. Cardiovasc Res 79:642–651.  https://doi.org/10.1093/cvr/cvn126 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kockskamper J et al (2008b) The slow force response to stretch in atrial and ventricular myocardium from human heart: functional relevance and subcellular mechanisms. Prog Biophys Mol Biol 97:250–267.  https://doi.org/10.1016/j.pbiomolbio.2008.02.026 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lai J et al (1996) Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo am. J Physiol 271:H2197–H2208.  https://doi.org/10.1152/ajpheart.1996.271.6.H2197 CrossRefGoogle Scholar
  43. Li J et al (2014) Piezo1 integration of vascular architecture with physiological force. Nature 515:279–282.  https://doi.org/10.1038/nature13701 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Liu C, Montell C (2015) Forcing open TRP channels: mechanical gating as a unifying activation mechanism. Biochem Biophys Res Commun 460:22–25.  https://doi.org/10.1016/j.bbrc.2015.02.067 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Luers C, Fialka F, Elgner A, Zhu D, Kockskamper J, von Lewinski D, Pieske B (2005) Stretch-dependent modulation of [Na+]i, [Ca2+]i, and pHi in rabbit myocardium--a mechanism for the slow force response. Cardiovasc Res 68:454–463.  https://doi.org/10.1016/j.cardiores.2005.07.001 CrossRefPubMedGoogle Scholar
  46. Murthy SE, Dubin AE, Patapoutian A (2017) Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat Rev Mol Cell Biol 18:771–783.  https://doi.org/10.1038/nrm.2017.92 CrossRefPubMedGoogle Scholar
  47. Nichols CG, Hanck DA, Jewell BR (1988) The Anrep effect: an intrinsic myocardial mechanism. Can J Physiol Pharmacol 66:924–929.  https://doi.org/10.1139/y88-150 CrossRefPubMedGoogle Scholar
  48. Niederer SA, Smith NP (2007) A mathematical model of the slow force response to stretch in rat ventricular myocytes. Biophys J 92:4030–4044CrossRefGoogle Scholar
  49. Ohtsu H, Suzuki H, Nakashima H, Dhobale S, Frank GD, Motley ED, Eguchi S (2006) Angiotensin II signal transduction through small GTP-binding proteins: mechanism and significance in vascular smooth muscle cells. Hypertension 48:534–540.  https://doi.org/10.1161/01.HYP.0000237975.90870.eb CrossRefPubMedGoogle Scholar
  50. Parmley WW, Chuck L (1973) Length-dependent changes in myocardial contractile state. Am J Phys 224:1195–1199.  https://doi.org/10.1152/ajplegacy.1973.224.5.1195 CrossRefGoogle Scholar
  51. Patterson SW, Starling EH (1914) On the mechanical factors which determine the output of the ventricles. J Physiol 48:357–379.  https://doi.org/10.1113/jphysiol.1914.sp001669 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Perez NG, de Hurtado MC, Cingolani HE (2001) Reverse mode of the Na+-Ca2+ exchange after myocardial stretch: underlying mechanism of the slow force response. Circ Res 88:376–382.  https://doi.org/10.1161/01.res.88.4.376 CrossRefPubMedGoogle Scholar
  53. Petroff MG, Kim SH, Pepe S, Dessy C, Marban E, Balligand JL, Sollott SJ (2001) Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 3:867–873.  https://doi.org/10.1038/ncb1001-867 CrossRefPubMedGoogle Scholar
  54. Ridone P, Vassalli M, Martinac B (2019) Piezo1 mechanosensitive channels: what are they and why are they important. Biophys Rev 11:795–805.  https://doi.org/10.1007/s12551-019-00584-5 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sadoshima J, Izumo S (1993) Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J 12:1681–1692CrossRefGoogle Scholar
  56. Shai SY et al (2002) Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circ Res 90:458–464.  https://doi.org/10.1161/hh0402.105790 CrossRefPubMedGoogle Scholar
  57. Shen X, Cannell MB, Ward ML (2013) Effect of SR load and pH regulatory mechanisms on stretch-dependent Ca(2+) entry during the slow force response. J Mol Cell Cardiol 63:37–46.  https://doi.org/10.1016/j.yjmcc.2013.07.008 CrossRefPubMedGoogle Scholar
  58. Shen X, Kaur S, Power A, Williams LZ, Ward ML (2016) Positive inotropic effect of prostaglandin F2alpha in rat ventricular Trabeculae. J Cardiovasc Pharmacol 68:81–88.  https://doi.org/10.1097/FJC.0000000000000392 CrossRefPubMedGoogle Scholar
  59. Sleno R et al (2017) Conformational biosensors reveal allosteric interactions between heterodimeric AT1 angiotensin and prostaglandin F2alpha receptors. J Biol Chem 292:12139–12152.  https://doi.org/10.1074/jbc.M117.793877 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Suchyna TM et al (2000) Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol 115:583–598.  https://doi.org/10.1085/jgp.115.5.583 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Suchyna TM, Tape SE, Koeppe RE 2nd, Andersen OS, Sachs F, Gottlieb PA (2004) Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature 430:235–240.  https://doi.org/10.1038/nature02743 CrossRefPubMedGoogle Scholar
  62. Tan PM, Buchholz KS, Omens JH, McCulloch AD, Saucerman JJ (2017) Predictive model identifies key network regulators of cardiomyocyte mechano-signaling. PLoS Comput Biol 13:e1005854.  https://doi.org/10.1371/journal.pcbi.1005854 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Tavi P, Han C, Weckstrom M (1998) Mechanisms of stretch-induced changes in [Ca2+]i in rat atrial myocytes: role of increased troponin C affinity and stretch-activated ion channels. Circ Res 83:1165–1177.  https://doi.org/10.1161/01.res.83.11.1165 CrossRefPubMedGoogle Scholar
  64. Todaka K, Ogino K, Gu A, Burkhoff D (1998) Effect of ventricular stretch on contractile strength, calcium transient, and cAMP in intact canine hearts am. J Physiol 274:H990–H1000.  https://doi.org/10.1152/ajpheart.1998.274.3.H990 CrossRefGoogle Scholar
  65. Vandenburgh HH, Solerssi R, Shansky J, Adams JW, Henderson SA (1996) Mechanical stimulation of organogenic cardiomyocyte growth in vitro. Am J Phys 270:C1284–C1292.  https://doi.org/10.1152/ajpcell.1996.270.5.C1284 CrossRefGoogle Scholar
  66. Vargas LA, Diaz RG, Swenson ER, Perez NG, Alvarez BV (2013) Inhibition of carbonic anhydrase prevents the Na(+)/H(+) exchanger 1-dependent slow force response to rat myocardial stretch am. J Physiol Heart Circ Physiol 305:H228–H237.  https://doi.org/10.1152/ajpheart.00055.2013 CrossRefGoogle Scholar
  67. von Anrep G (1912) On the part played by the suprarenals in the normal vascular reactions of the body. J Physiol 45:307–317.  https://doi.org/10.1113/jphysiol.1912.sp001553 CrossRefGoogle Scholar
  68. von Lewinski D, Stumme B, Maier LS, Luers C, Bers DM, Pieske B (2003) Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent. Cardiovasc Res 57:1052–1061.  https://doi.org/10.1016/s0008-6363(02)00830-1 CrossRefGoogle Scholar
  69. von Lewinski D, Stumme B, Fialka F, Luers C, Pieske B (2004) Functional relevance of the stretch-dependent slow force response in failing human myocardium. Circ Res 94:1392–1398.  https://doi.org/10.1161/01.RES.0000129181.48395.ff CrossRefGoogle Scholar
  70. Ward ML, Pope AJ, Loiselle DS, Cannell MB (2003) Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat hearts. J Physiol 546:537–550CrossRefGoogle Scholar
  71. Ward ML, Williams IA, Chu Y, Cooper PJ, Ju YK, Allen DG (2008) Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy. Prog Biophys Mol Biol 97:232–249.  https://doi.org/10.1016/j.pbiomolbio.2008.02.009 CrossRefPubMedGoogle Scholar
  72. Ward ML, Shen X, Greenwood DR (2014) Use of liquid chromatography-mass spectrometry (LC-MS) to detect substances of nanomolar concentration in the coronary effluent of isolated perfused hearts. Prog Biophys Mol Biol 115:270–278.  https://doi.org/10.1016/j.pbiomolbio.2014.07.005 CrossRefPubMedGoogle Scholar
  73. Watanabe T et al (1994) Prostaglandin F2 alpha enhances tyrosine phosphorylation and DNA synthesis through phospholipase C-coupled receptor via Ca(2+)-dependent intracellular pathway in NIH-3T3 cells. J Biol Chem 269:17619–17625PubMedGoogle Scholar
  74. White E (2006) Mechanosensitive channels: therapeutic targets in the myocardium? Curr Pharm Des 12:3645–3663.  https://doi.org/10.2174/138161206778522083 CrossRefPubMedGoogle Scholar
  75. Wu J, Lewis AH, Grandl J (2017) Touch, Tension, and transduction - the function and regulation of piezo ion channels. Trends Biochem Sci 42:57–71.  https://doi.org/10.1016/j.tibs.2016.09.004 CrossRefPubMedGoogle Scholar
  76. Yew SF, Reeves KA, Woodward B (1998) Effects of prostaglandin F2 alpha on intracellular pH, intracellular calcium, cell shortening and L-type calcium currents in rat myocytes. Cardiovasc Res 40:538–545.  https://doi.org/10.1016/s0008-6363(98)00195-3 CrossRefPubMedGoogle Scholar
  77. Youm JB et al (2006) A mathematical model of pacemaker activity recorded from mouse small intestine. Philos Trans A Math Phys Eng Sci 364:1135–1154.  https://doi.org/10.1098/rsta.2006.1759 CrossRefPubMedGoogle Scholar
  78. Zeng T, Bett GC, Sachs F (2000) Stretch-activated whole cell currents in adult rat cardiac myocytes. Am J Physiol Heart Circ Physiol 278:H548–H557.  https://doi.org/10.1152/ajpheart.2000.278.2.H548 CrossRefPubMedGoogle Scholar

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© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Institute for Experimental Medical ResearchOslo University Hospital and University of OsloOsloNorway
  3. 3.K.G.Jebsen Center for Cardiac ResearchOsloNorway
  4. 4.Department of PhysiologyUniversity of OtagoDunedinNew Zealand

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