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Pathophysiology of diastolic heart failure

Michael R Zile, MD
William H Gaasch, MD
Section Editor
Wilson S Colucci, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Heart failure (HF) can be defined as the inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal filling pressures. There are two major mechanisms by which this can occur.

Systolic dysfunction, in which there is impaired cardiac contractile function.

Diastolic dysfunction, in which there is abnormal cardiac relaxation, stiffness or filling

The pathophysiology of diastolic HF will be reviewed here. The clinical manifestations, diagnosis, treatment, and prognosis of diastolic HF, and the management of systolic HF are discussed separately. (See "Clinical manifestations and diagnosis of heart failure with preserved ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the therapy of heart failure with reduced ejection fraction".)


It is important to define and distinguish several terms when classifying patients with heart failure (HF).


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Literature review current through: Sep 2016. | This topic last updated: Sep 15, 2014.
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  1. Quiñones MA, Zile MR, Massie BM, et al. Chronic heart failure: a report from the Dartmouth Diastole Discourses. Congest Heart Fail 2006; 12:162.
  2. Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation 2006; 113:296.
  3. Drazner MH. The progression of hypertensive heart disease. Circulation 2011; 123:327.
  4. Zile MR, Gaasch WH, Carroll JD, et al. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001; 104:779.
  5. Zile MR. Heart failure with preserved ejection fraction: is this diastolic heart failure? J Am Coll Cardiol 2003; 41:1519.
  6. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med 2004; 351:1097.
  7. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004; 350:1953.
  8. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005; 111:2306.
  9. Little WC, Zile MR. HFpEF: cardiovascular abnormalities not just comorbidities. Circ Heart Fail 2012; 5:669.
  10. Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the framingham heart study of the national heart, lung, and blood institute. Circulation 2009; 119:3070.
  11. Paulus WJ, van Ballegoij JJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth! J Am Coll Cardiol 2010; 55:526.
  12. Gaasch WH, Delorey DE, Kueffer FJ, Zile MR. Distribution of left ventricular ejection fraction in patients with ischemic and hypertensive heart disease and chronic heart failure. Am J Cardiol 2009; 104:1413.
  13. Desai RV, Ahmed MI, Mujib M, et al. Natural history of concentric left ventricular geometry in community-dwelling older adults without heart failure during seven years of follow-up. Am J Cardiol 2011; 107:321.
  14. Rame JE, Ramilo M, Spencer N, et al. Development of a depressed left ventricular ejection fraction in patients with left ventricular hypertrophy and a normal ejection fraction. Am J Cardiol 2004; 93:234.
  15. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355:260.
  16. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003; 289:194.
  17. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002; 288:2144.
  18. Brucks S, Little WC, Chao T, et al. Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005; 95:603.
  19. Gaasch WH, Delorey DE, St John Sutton MG, Zile MR. Patterns of structural and functional remodeling of the left ventricle in chronic heart failure. Am J Cardiol 2008; 102:459.
  20. Zile MR, Gaasch WH, Anand IS, et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial. Circulation 2010; 121:1393.
  21. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362:777.
  22. Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114:397.
  23. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27:2338.
  24. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359:2456.
  25. van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009; 53:2150.
  26. Zile MR, Baicu CF, Bonnema DD. Diastolic heart failure: definitions and terminology. Prog Cardiovasc Dis 2005; 47:307.
  27. Cheng CP, Igarashi Y, Little WC. Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992; 70:9.
  28. 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.
  29. Little WC, Cheng CP. Modulation of diastolic dysfunction in the intact heart. In: Diastolic Relaxation of the Heart, 2nd ed, Lorell BH, Grossman W (Eds), Kluwer Academic Publishers, Boston 1994. p.167.
  30. Little WC. Diastolic dysfunction beyond distensibility: adverse effects of ventricular dilatation. Circulation 2005; 112:2888.
  31. Katz AM. Physiology of the Heart, Raven Press, New York 1992. p.178.
  32. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Dynamics of left ventricular filling at rest and during exercise. Circulation 1983; 68:59.
  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. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002; 105:1387.
  35. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006; 47:500.
  36. Lester SJ, Tajik AJ, Nishimura RA, et al. Unlocking the mysteries of diastolic function: deciphering the Rosetta Stone 10 years later. J Am Coll Cardiol 2008; 51:679.
  37. Nagueh SF, Mikati I, Kopelen HA, et al. Doppler estimation of left ventricular filling pressure in sinus tachycardia. A new application of tissue doppler imaging. Circulation 1998; 98:1644.
  38. Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006; 113:2089.
  39. Borbély A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation 2005; 111:774.
  40. van Heerebeek L, Borbély A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006; 113:1966.
  41. Persson H, Lonn E, Edner M, et al. Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence:results from the CHARM Echocardiographic Substudy-CHARMES. J Am Coll Cardiol 2007; 49:687.
  42. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 2007; 115:1982.
  43. Melenovsky V, Borlaug BA, Rosen B, et al. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 2007; 49:198.
  44. Martos R, Baugh J, Ledwidge M, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 2007; 115:888.
  45. Little WC, Zile MR, Klein A, et al. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006; 98:383.
  46. Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999; 33:1567.
  47. Little WC, Wesley-Farrington DJ, Hoyle J, et al. Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004; 43:288.
  48. Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17.
  49. Vinch CS, Aurigemma GP, Hill JC, et al. Usefulness of clinical variables, echocardiography, and levels of brain natriuretic peptide and norepinephrine to distinguish systolic and diastolic causes of acute heart failure. Am J Cardiol 2003; 91:1140.
  50. Zile MR, Bourge RC, Bennett TD, et al. Application of implantable hemodynamic monitoring in the management of patients with diastolic heart failure: a subgroup analysis of the COMPASS-HF trial. J Card Fail 2008; 14:816.
  51. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008; 118:1433.
  52. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251.
  53. Yancy CW, Lopatin M, Stevenson LW, et al. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006; 47:76.
  54. Brucks S, Little WC, Chao T, et al. Relation of anemia to diastolic heart failure and the effect on outcome. Am J Cardiol 2004; 93:1055.
  55. Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 2005; 112:357.
  56. O'Meara E, Clayton T, McEntegart MB, et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation 2006; 113:986.
  57. Zile MR. Treating diastolic heart failure with statins: "phat" chance for pleiotropic benefits. Circulation 2005; 112:300.
  58. Katz AM, Zile MR. New molecular mechanism in diastolic heart failure. Circulation 2006; 113:1922.
  59. Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation 2002; 105:1195.
  60. Yip G, Wang M, Zhang Y, et al. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002; 87:121.
  61. Petrie MC, Caruana L, Berry C, McMurray JJ. "Diastolic heart failure" or heart failure caused by subtle left ventricular systolic dysfunction? Heart 2002; 87:29.
  62. Nikitin NP, Witte KK, Clark AL, Cleland JG. Color tissue Doppler-derived long-axis left ventricular function in heart failure with preserved global systolic function. Am J Cardiol 2002; 90:1174.
  63. Wang J, Kurrelmeyer KM, Torre-Amione G, Nagueh SF. Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol 2007; 49:88.
  64. Yu CM, Zhang Q, Yip GW, et al. Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition. J Am Coll Cardiol 2007; 49:97.
  65. 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.
  66. Cave AC, Ingwall JS, Friedrich J, et al. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation 2000; 101:2090.
  67. Saupe KW, Eberli FR, Ingwall JS, Apstein CS. Metabolic support as an adjunct to inotropic support in the hypoperfused heart. J Mol Cell Cardiol 2001; 33:261.
  68. 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.
  69. Steine K, Stugaard M, Smiseth OA. Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation 1999; 99:2048.
  70. 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.
  71. 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.
  72. 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.
  73. Pepine CJ, Wiener L. Relationship of anginal symptoms to lung mechanics during myocardial ischemia. Circulation 1972; 46:863.
  74. McKenney PA, Apstein CS, Mendes LA, et al. Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery. J Am Coll Cardiol 1994; 24:1189.
  75. McKenney PA, Apstein CS, Mendes LA, et al. Immediate effect of aortic valve replacement for aortic stenosis on left ventricular diastolic chamber stiffness. Am J Cardiol 1999; 84:914.
  76. Bolli R. Myocardial 'stunning' in man. Circulation 1992; 86:1671.
  77. 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.
  78. Isoyama S. Interplay of hypertrophy and myocardial ischemia. In: Diastolic Relaxation of the Heart, Lorell BH, Grossman W (Eds), Kluwer Academic Publishers, Boston 1992. p.203.
  79. Tomanek RJ, Wessel TJ, Harrison DG. Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs. Am J Physiol 1991; 261:H1011.
  80. Eberli FR, Ritter M, Schwitter J, et al. Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement. Eur Heart J 1991; 12:127.
  81. Marcus ML, Koyanagi S, Harrison DG, et al. Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am J Med 1983; 75:62.
  82. Ishihara K, Zile MR, Nagatsu M, et al. Coronary blood flow after the regression of pressure-overload left ventricular hypertrophy. Circ Res 1992; 71:1472.
  83. MacCarthy PA, Shah AM. Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy. Circulation 2000; 101:1854.
  84. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62:263.
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