Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cellular mechanisms of diastolic dysfunction

James P Morgan, MD, PhD
Section Editor
Wilson S Colucci, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Approximately one-third of patients with symptomatic congestive heart failure have a normal ejection fraction and symptoms that are entirely or in large measure a result of diastolic dysfunction. Diastolic dysfunction is caused by one or more of the following abnormalities in cardiac structure:



Infiltrative diseases

Pericardial constriction

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: May 22, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation 2002; 105:1503.
  2. Morgan JP. Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med 1991; 325:625.
  3. Periasamy M, Janssen PM. Molecular basis of diastolic dysfunction. Heart Fail Clin 2008; 4:13.
  4. Cheng H, Lederer MR, Xiao RP, et al. Excitation-contraction coupling in heart: new insights from Ca2+ sparks. Cell Calcium 1996; 20:129.
  5. Blinks JR, Endoh M. Modification of myofibrillar responsiveness to Ca++ as an inotropic mechanism. Circulation 1986; 73:III85.
  6. Katz AM. Interplay between inotropic and lusitropic effects of cyclic adenosine monophosphate on the myocardial cell. Circulation 1990; 82:I7.
  7. Applegate RJ, Walsh RA, O'Rourke RA. Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog. Circulation 1987; 76:1409.
  8. Hasenfuss G, Schillinger W, Lehnart SE, et al. Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation 1999; 99:641.
  9. Schmidt U, del Monte F, Miyamoto MI, et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation 2000; 101:790.
  10. Cross HR, Radda GK, Clarke K. The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study. Magn Reson Med 1995; 34:673.
  11. Kaumann A, Bartel S, Molenaar P, et al. Activation of beta2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure. Circulation 1999; 99:65.
  12. Katz AM. Energy requirements of contraction and relaxation: implications for inotropic stimulation of the failing heart. Basic Res Cardiol 1989; 84 Suppl 1:47.
  13. Hein S, Schaper J. Pathogenesis of dilated cardiomyopathy and heart failure: insights from cell morphology and biology. Curr Opin Cardiol 1996; 11:293.
  14. Wagoner LE, Walsh RA. The cellular pathophysiology of progression to heart failure. Curr Opin Cardiol 1996; 11:237.
  15. Davies CH, Harding SE, Poole-Wilson PA. Cellular mechanisms of contractile dysfunction in human heart failure. Eur Heart J 1996; 17:189.
  16. Perreault CL, Bing OH, Brooks WW, et al. Differential effects of cardiac hypertrophy and failure on right versus left ventricular calcium activation. Circ Res 1990; 67:707.
  17. Perreault CL, Hague NL, Ransil BJ, Morgan JP. The effects of cocaine on intracellular Ca2+ handling and myofilament Ca2+ responsiveness of ferret ventricular myocardium. Br J Pharmacol 1990; 101:679.
  18. Gwathmey JK, Morgan JP. Altered calcium handling in experimental pressure-overload hypertrophy in the ferret. Circ Res 1985; 57:836.
  19. Bentivegna LA, Ablin LW, Kihara Y, Morgan JP. Altered calcium handling in left ventricular pressure-overload hypertrophy as detected with aequorin in the isolated, perfused ferret heart. Circ Res 1991; 69:1538.
  20. Wikman-Coffelt J, Stefenelli T, Wu ST, et al. [Ca2+]i transients in the cardiomyopathic hamster heart. Circ Res 1991; 68:45.
  21. Belke DD, Dillmann WH. Altered cardiac calcium handling in diabetes. Curr Hypertens Rep 2004; 6:424.
  22. Litwin SE, Morgan JP. Captopril enhances intracellular calcium handling and beta-adrenergic responsiveness of myocardium from rats with postinfarction failure. Circ Res 1992; 71:797.
  23. Kihara Y, Grossman W, Morgan JP. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res 1989; 65:1029.
  24. Mohabir R, Lee HC, Kurz RW, Clusin WT. Effects of ischemia and hypercarbic acidosis on myocyte calcium transients, contraction, and pHi in perfused rabbit hearts. Circ Res 1991; 69:1525.
  25. Steenbergen C, Murphy E, Levy L, London RE. Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res 1987; 60:700.
  26. Gwathmey JK, Copelas L, MacKinnon R, et al. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 1987; 61:70.
  27. Gwathmey JK, Warren SE, Briggs GM, et al. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J Clin Invest 1991; 87:1023.
  28. Hasenfuss G, Reinecke H, Studer R, et al. Calcium cycling proteins and force-frequency relationship in heart failure. Basic Res Cardiol 1996; 91 Suppl 2:17.
  29. Feldman MD, Copelas L, Gwathmey JK, et al. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 1987; 75:331.
  30. Erdmann E. The effectiveness of inotropic agents in isolated cardiac preparations from the human heart. Klin Wochenschr 1988; 66:1.
  31. Näbauer M, Böhm M, Brown L, et al. Positive inotropic effects in isolated ventricular myocardium from non-failing and terminally failing human hearts. Eur J Clin Invest 1988; 18:600.
  32. Fifer MA, Bourdillon PD, Lorell BH. Altered left ventricular diastolic properties during pacing-induced angina in patients with aortic stenosis. Circulation 1986; 74:675.
  33. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures. Circulation 1983; 67:521.
  34. Bronzwaer JG, de Bruyne B, Ascoop CA, Paulus WJ. Comparative effects of pacing-induced and balloon coronary occlusion ischemia on left ventricular diastolic function in man. Circulation 1991; 84:211.
  35. Apstein CS, Grossman W. Opposite initial effects of supply and demand ischemia on left ventricular diastolic compliance: the ischemia-diastolic paradox. J Mol Cell Cardiol 1987; 19:119.
  36. Eberli FR, Weinberg EO, Grice WN, et al. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res 1991; 68:466.
  37. Mochizuki T, Eberli FR, Apstein CS, Lorell BH. Exacerbation of ischemic dysfunction by angiotensin II in red cell-perfused rabbit hearts. Effects on coronary flow, contractility, and high-energy phosphate metabolism. J Clin Invest 1992; 89:490.
  38. Wexler LF, Weinberg EO, Ingwall JS, Apstein CS. Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts. Circ Res 1986; 59:515.
  39. Katz AM, Tada M. The "stone heart": a challenge to the biochemist. Am J Cardiol 1972; 29:578.
  40. Hearse DJ, Garlick PB, Humphrey SM. Ischemic contracture of the myocardium: mechanisms and prevention. Am J Cardiol 1977; 39:986.
  41. Ventura-Clapier R, Veksler V. Myocardial ischemic contracture. Metabolites affect rigor tension development and stiffness. Circ Res 1994; 74:920.
  42. Yamashita H, Sata M, Sugiura S, et al. ADP inhibits the sliding velocity of fluorescent actin filaments on cardiac and skeletal myosins. Circ Res 1994; 74:1027.
  43. Tian R, Christe ME, Spindler M, et al. Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart. J Clin Invest 1997; 99:745.
  44. Varma N, Eberli FR, Apstein CS. Increased diastolic chamber stiffness during demand ischemia: response to quick length change differentiates rigor-activated from calcium-activated tension. Circulation 2000; 101:2185.
  45. Eberli FR, Strömer H, Ferrell MA, et al. Lack of direct role for calcium in ischemic diastolic dysfunction in isolated hearts. Circulation 2000; 102:2643.
  46. Varma N, Eberli FR, Apstein CS. Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate. J Am Coll Cardiol 2001; 37:2144.
  47. Varma N, Morgan JP, Apstein CS. Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate. Am J Physiol Heart Circ Physiol 2003; 284:H758.
  48. Lefkowitz RJ, Hausdorff WP, Caron MG. Role of phosphorylation in desensitization of the beta-adrenoceptor. Trends Pharmacol Sci 1990; 11:190.
  49. Collins S, Bolanowski MA, Caron MG, Lefkowitz RJ. Genetic regulation of beta-adrenergic receptors. Annu Rev Physiol 1989; 51:203.
  50. Brodde OE. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 1991; 43:203.
  51. Bristow MR, Hershberger RE, Port JD, et al. Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 1990; 82:I12.
  52. Bristow MR, Ginsburg R, Umans V, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 1986; 59:297.
  53. Altschuld RA, Starling RC, Hamlin RL, et al. Response of failing canine and human heart cells to beta 2-adrenergic stimulation. Circulation 1995; 92:1612.
  54. Bristow MR, Anderson FL, Port JD, et al. Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation 1991; 84:1024.
  55. Gauthier C, Tavernier G, Charpentier F, et al. Functional beta3-adrenoceptor in the human heart. J Clin Invest 1996; 98:556.
  56. Rasmussen RP, Minobe W, Bristow MR. Calcium antagonist binding sites in failing and nonfailing human ventricular myocardium. Biochem Pharmacol 1990; 39:691.
  57. Kaczorowski GJ, Slaughter RS, King VF, Garcia ML. Inhibitors of sodium-calcium exchange: identification and development of probes of transport activity. Biochim Biophys Acta 1989; 988:287.
  58. Schouten VJ, ter Keurs HE, Quaegebeur JM. Influence of electrogenic Na/Ca exchange on the action potential in human heart muscle. Cardiovasc Res 1990; 24:758.
  59. Wankerl M, Schwartz K. Calcium transport proteins in the nonfailing and failing heart: gene expression and function. J Mol Med (Berl) 1995; 73:487.
  60. Caroni P, Carafoli E. An ATP-dependent Ca2+-pumping system in dog heart sarcolemma. Nature 1980; 283:765.
  61. Sutko JL, Ito K, Kenyon JL. Ryanodine: a modifier of sarcoplasmic reticulum calcium release in striated muscle. Fed Proc 1985; 44:2984.
  62. Dillmann WH. Regulation of expression of cardiac sarcoplasmic reticulum proteins under pathophysiological conditions. Mol Cell Biochem 1996; 157:125.
  63. de la Bastie D, Levitsky D, Rappaport L, et al. Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res 1990; 66:554.
  64. Gwathmey JK, Slawsky MT, Hajjar RJ, et al. Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest 1990; 85:1599.
  65. ter Keurs HE. Heart failure and Starling's Law of the heart. Can J Cardiol 1996; 12:1047.
  66. Rüegg JC, Morano I. Calcium-sensitivity modulation of cardiac myofibrillar proteins. J Cardiovasc Pharmacol 1989; 14 Suppl 3:S20.
  67. Morano I, Arndt H, Gärtner C, Rüegg JC. Skinned fibers of human atrium and ventricle: myosin isoenzymes and contractility. Circ Res 1988; 62:632.
  68. Hajjar RJ, Gwathmey JK, Briggs GM, Morgan JP. Differential effect of DPI 201-106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest 1988; 82:1578.
  69. Wankerl M, Böhm M, Morano I, et al. Calcium sensitivity and myosin light chain pattern of atrial and ventricular skinned cardiac fibers from patients with various kinds of cardiac disease. J Mol Cell Cardiol 1990; 22:1425.
  70. D'Agnolo A, Luciani GB, Mazzucco A, et al. Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 1992; 85:518.
  71. Lowe JE, Jennings RB, Reimer KA. Cardiac rigor mortis in dogs. J Mol Cell Cardiol 1979; 11:1017.
  72. Lamb HJ, Beyerbacht HP, van der Laarse A, et al. Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999; 99:2261.
  73. Apstein CS, Deckelbaum L, Hagopian L, Hood WB Jr. Acute cardiac ischemia and reperfusion: contractility, relaxation, and glycolysis. Am J Physiol 1978; 235:H637.
  74. Apstein CS, Gravino FN, Haudenschild CC. Determinants of a protective effect of glucose and insulin on the ischemic myocardium. Effects on contractile function, diastolic compliance, metabolism, and ultrastructure during ischemia and reperfusion. Circ Res 1983; 52:515.
  75. Schaefer S, Prussel E, Carr LJ. Requirement of glycolytic substrate for metabolic recovery during moderate low flow ischemia. J Mol Cell Cardiol 1995; 27:2167.
  76. Vanoverschelde JL, Janier MF, Bakke JE, et al. Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion. Am J Physiol 1994; 267:H1785.
  77. Kagaya Y, Weinberg EO, Ito N, et al. Glycolytic inhibition: effects on diastolic relaxation and intracellular calcium handling in hypertrophied rat ventricular myocytes. J Clin Invest 1995; 95:2766.
  78. Tian R, Nascimben L, Ingwall JS, Lorell BH. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 1997; 96:1313.
  79. Cunningham MJ, Apstein CS, Weinberg EO, et al. Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia. Circ Res 1990; 66:406.
  80. Weiss J, Hiltbrand B. Functional compartmentation of glycolytic versus oxidative metabolism in isolated rabbit heart. J Clin Invest 1985; 75:436.
  81. Cunningham MJ, Apstein CS, Weinberg EO, Lorell BH. Deleterious effect of ouabain on myocardial function during hypoxia. Am J Physiol 1989; 256:H681.
  82. Lorell BH, Isoyama S, Grice WN, et al. Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts. Circ Res 1988; 63:457.
  83. Weinberg EO, Apstein CS, Vogel WM. Impaired myocardial relaxation is improved by combined beta-adrenergic stimulation and calcium channel blockade. J Mol Cell Cardiol 1991; 23:S68.
  84. Raman VK, Lee YA, Lindpaintner K. The cardiac renin-angiotensin-aldosterone system and hypertensive cardiac hypertrophy. Am J Cardiol 1995; 76:18D.
  85. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993; 153:937.
  86. Schunkert H, Dzau VJ, Tang SS, et al. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990; 86:1913.
  87. Eberli FR, Apstein CS, Ngoy S, Lorell BH. Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modification by specific inhibition of cardiac angiotensin converting enzyme. Circ Res 1992; 70:931.
  88. Helmes M, Trombitás K, Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ Res 1996; 79:619.
  89. Helmes M, Lim CC, Liao R, et al. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol 2003; 121:97.
  90. Cheng CP, Noda T, Nozawa T, Little WC. Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow. Circ Res 1993; 72:795.
  91. Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 2002; 30:201.