Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diastolic heart failure: mechanisms and controversies

Abstract

Epidemiological and experimental studies have documented both the rising burden of diastolic heart failure (DHF) and several mechanisms that distinguish this disease from systolic heart failure (SHF). Controversies continue to surround the term 'DHF' as well as its existence as a pathophysiological entity distinct from SHF. Approximately half of all patients who present with heart failure have near-normal systolic function and predominately abnormal diastolic function. Recent reports counter the commonly held belief that survival of patients with DHF is better than that of patients with SHF. The challenges associated with managing the DHF phenotype arise from the heterogeneous etiologies of the condition that include aging, diabetes mellitus, hypertension and ischemia. Lack of diastolic distensibility in DHF has been attributed primarily to hypertrophy and fibrosis. Extracellular matrix and cytoskeletal components including matrix metalloproteinases, titin isoforms, and the quality and quantity of collagen are implicated in DHF development. Impaired active relaxation of the contractile apparatus also contributes to DHF. Novel therapeutic targets that address the pathophysiology of this disease are being actively explored, although as yet there are no proven therapies for DHF. New epidemiologic and mechanistic data regarding DHF highlight the urgency with which the scientific community must address this important public health problem.

Key Points

  • Approximately half of all patients presenting with heart failure have near-normal systolic function and exhibit abnormalities predominantly in diastolic function

  • The prevalence of diastolic heart failure increases with age and is higher in women and in patients with a history of hypertension; mortality is equivalent to that associated with systolic heart failure

  • Determinants of diastolic function include myocardial relaxation and passive properties of the ventricular wall

  • Myocardial relaxation is mediated by calcium homeostasis, myofilament sensitivity to calcium and myocardial energetics

  • Myocardial stiffness is determined by changes in the extracellular matrix, cytoskeletal proteins and myofilaments

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diastolic and systolic heart failure as two distinct entities.
Figure 2: The 'single syndrome' hypothesis—the spectrum of heart failure from HFPEF to HFREF.
Figure 3: Kaplan–Meier survival curves for patients with diastolic and systolic heart failure.
Figure 4: Coordinate processes of active relaxation and abnormal stiffness for the cardiomyocyte and changes in diastolic heart failure.

References

  1. Fishberg AM (1937) Heart Failure. Philadelphia: Lea & Febiger

    Google Scholar 

  2. Aurigemma GP et al. (2006) Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation 113: 296–304

    Article  PubMed  Google Scholar 

  3. Borbély A et al. (2005) Cardiomyocyte stiffness in diastolic heart failure. Circulation 111: 774–781

    Article  PubMed  Google Scholar 

  4. van Heerebeek L et al. (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113: 1966–1973

    Article  PubMed  Google Scholar 

  5. Nagueh SF et al. (2004) Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110: 155–162

    Article  CAS  PubMed  Google Scholar 

  6. Neagoe C et al. (2002) Titin isoform switch in ischemic human heart disease. Circulation 106: 1333–1341

    Article  PubMed  Google Scholar 

  7. Heymans S et al. (2005) Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 112: 1136–1144

    Article  CAS  PubMed  Google Scholar 

  8. Ahmed SH et al. (2006) 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 113: 2089–2096

    Article  CAS  PubMed  Google Scholar 

  9. Carson P et al.; for the I-PRESERVE Investigators (2005) The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail 11: 576–585

    Article  CAS  PubMed  Google Scholar 

  10. Yusuf S et al.; CHARM Investigators and Committees (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362: 777–781

    Article  CAS  PubMed  Google Scholar 

  11. Paulus WJ et al. (2007) How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28: 2539–2550

    Article  PubMed  Google Scholar 

  12. Solomon SD et al.; Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators (2005) Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 112: 3738–3744

    Article  PubMed  Google Scholar 

  13. Skaluba SJ and Litwin SE (2004) Mechanisms of exercise intolerance: insights from tissue Doppler imaging. Circulation 109: 972–977

    Article  PubMed  Google Scholar 

  14. Yip G et al. (2002) Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 87: 121–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yu CM et al. (2002) Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 105: 1195–1201

    Article  PubMed  Google Scholar 

  16. Petrie MC et al. (2002) “Diastolic heart failure” or heart failure caused by subtle left ventricular systolic dysfunction? Heart 87: 29–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nikitin NP et al. (2002) Color tissue Doppler-derived long-axis left ventricular function in heart failure with preserved global systolic function. Am J Cardiol 90: 1174–1177

    Article  PubMed  Google Scholar 

  18. Wang J et al. (2007) Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol 49: 88–96

    Article  PubMed  Google Scholar 

  19. Yu CM et al. (2007) Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition. J Am Coll Cardiol 49: 97–105

    Article  PubMed  Google Scholar 

  20. Sliwa K et al. (2005) Epidemiology and etiology of cardiomyopathy in Africa. Circulation 112: 3577–3583

    Article  PubMed  Google Scholar 

  21. Rame JE et al. (2004) Development of a depressed left ventricular ejection fraction in patients with left ventricular hypertrophy and a normal ejection fraction. Am J Cardiol 93: 234–237

    Article  PubMed  Google Scholar 

  22. Owan TE and Redfield MM (2005) Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 47: 320–332

    Article  PubMed  Google Scholar 

  23. Packer M (1990) Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 81: III78–III86

    Article  CAS  PubMed  Google Scholar 

  24. Lee DS and Vasan RS (2005) Novel markers for heart failure diagnosis and prognosis. Curr Opin Cardiol 20: 201–210

    Article  PubMed  Google Scholar 

  25. Hunt SA et al. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112: e154–e235

    Article  PubMed  Google Scholar 

  26. Vasan RS and Levy D (2000) Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 101: 2118–2121

    Article  CAS  PubMed  Google Scholar 

  27. Zile MR et al. (2001) Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure. Circulation 104: 779–782

    Article  CAS  PubMed  Google Scholar 

  28. Zile MR et al. (2004) Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 350: 1953–1959

    Article  CAS  PubMed  Google Scholar 

  29. Gandhi SK et al. (2001) The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344: 17–22

    Article  CAS  PubMed  Google Scholar 

  30. Cleland JG et al. (2007) Prognosis in heart failure with a normal ejection fraction. N Engl J Med 357: 829–830

    Article  CAS  PubMed  Google Scholar 

  31. Vasan RS et al. (1995) Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 26: 1565–1574

    Article  CAS  PubMed  Google Scholar 

  32. Owan TE et al. (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355: 251–259

    Article  CAS  PubMed  Google Scholar 

  33. Bhatia RS et al. (2006) Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 355: 260–269

    Article  CAS  PubMed  Google Scholar 

  34. Gilman G et al. (2007) Diastolic function: a sonographer's approach to the essential echocardiographic measurements of left ventricular diastolic function. J Am Soc Echocardiogr 20: 199–209

    Article  PubMed  Google Scholar 

  35. Dokainish H et al. (2004) Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 109: 2432–2439

    Article  PubMed  Google Scholar 

  36. Hillis GS et al. (2004) Noninvasive estimation of left ventricular filling pressure by E/e' is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 43: 360–367

    Article  PubMed  Google Scholar 

  37. Pritchett AM et al. (2005) Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol 45: 87–92

    Article  PubMed  Google Scholar 

  38. Tsang TS et al. (2003) Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value of echocardiography. J Am Coll Cardiol 42: 1199–1205

    Article  PubMed  Google Scholar 

  39. Periasamy M et al. (1999) Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 274: 2556–2562

    Article  CAS  PubMed  Google Scholar 

  40. Muller OJ et al. (2003) Transgenic rat hearts overexpressing SERCA2a show improved contractility under baseline conditions and pressure overload. Cardiovasc Res 59: 380–389

    Article  CAS  PubMed  Google Scholar 

  41. MacLennan DH and Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4: 566–577

    Article  CAS  PubMed  Google Scholar 

  42. Luo W et al. (1994) Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 75: 401–409

    Article  CAS  PubMed  Google Scholar 

  43. Chu G et al. (1997) Monomeric phospholamban overexpression in transgenic mouse hearts. Circ Res 81: 485–492

    Article  CAS  PubMed  Google Scholar 

  44. Periasamy M and Huke S (2001) SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility. J Mol Cell Cardiol 33: 1053–1063

    Article  CAS  PubMed  Google Scholar 

  45. Cain BS et al. (1998) Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 32: 458–467

    Article  CAS  PubMed  Google Scholar 

  46. Piccini JP et al. (2004) New insights into diastolic heart failure: role of diabetes mellitus. Am J Med 116 (Suppl 5A): S64–S75

    Article  Google Scholar 

  47. Flesch M et al. (1997) Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy. Hypertension 30: 383–391

    Article  CAS  PubMed  Google Scholar 

  48. Studeli R et al. (2006) Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression. Am J Transplant 6: 775–782

    Article  CAS  PubMed  Google Scholar 

  49. Wolska BM et al. (2001) Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions. J Physiol 536: 863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Takimoto E et al. (2004) Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res 94: 496–504

    Article  CAS  PubMed  Google Scholar 

  51. Vahebi S et al. (2005) Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Circ Res 96: 740–747

    Article  CAS  PubMed  Google Scholar 

  52. Tian R et al. (1997) Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart. J Clin Invest 99: 745–751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bronzwaer JG and Paulus WJ (2005) Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction? Prog Cardiovasc Dis 47: 276–284

    Article  PubMed  Google Scholar 

  54. Yamamoto K et al. (2002) Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 55: 76–82

    Article  CAS  PubMed  Google Scholar 

  55. Wu Y et al. (2000) Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol 32: 2151–2162

    Article  CAS  PubMed  Google Scholar 

  56. Aronson D (2003) Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 21: 3–12

    Article  CAS  PubMed  Google Scholar 

  57. Martos R et al. (2007) Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115: 888–895

    Article  PubMed  Google Scholar 

  58. Granzier H et al. (2005) Titin: physiological function and role in cardiomyopathy and failure. Heart Fail Rev 10: 211–223

    Article  PubMed  Google Scholar 

  59. Radke MH et al. (2007) Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy. Proc Natl Acad Sci USA 104: 3444–3449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. van Heerebeek L et al. (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113: 1966–1973

    Article  PubMed  Google Scholar 

  61. Yamasaki R et al. (2002) Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res 90: 1181–1188

    Article  CAS  PubMed  Google Scholar 

  62. Aronow WS (2003) Effects of aging on the heart. In Brocklehurst's Textbook of Geriatric Medicine and Gerontology, 341–348 (Eds Tallis RC and Fillit HM) Edinburgh: Churchill Livingstone

    Google Scholar 

  63. Corral-Debrinski M et al. (1991) Hypoxemia is associated with mitochondrial DNA damage and gene induction: implications for cardiac disease. JAMA 266: 1812–1816

    Article  CAS  PubMed  Google Scholar 

  64. Olivetti G et al. (1991) Cardiomyopathy of the aging human heart: myocyte loss and reactive cellular hypertrophy. Circ Res 68: 1560–1568

    Article  CAS  PubMed  Google Scholar 

  65. Kai H et al. (2005) Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res 28: 483–490

    Article  CAS  PubMed  Google Scholar 

  66. Perticone F et al. (1999) Relationship between left ventricular mass and endothelium-dependent vasodilation in never-treated hypertensive patients. Circulation 99: 1991–1996

    Article  CAS  PubMed  Google Scholar 

  67. Brush JE Jr. et al. (1988) Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 319: 1302–1307

    Article  PubMed  Google Scholar 

  68. Lamb HJ et al. (1999) Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 99: 2261–2267

    Article  CAS  PubMed  Google Scholar 

  69. Leite-Moreira AF et al. (1999) Afterload induced changes in myocardial relaxation: a mechanism for diastolic dysfunction. Cardiovasc Res 43: 344–353

    Article  CAS  PubMed  Google Scholar 

  70. Kawaguchi M et al. (2003) Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 107: 714–720

    Article  PubMed  Google Scholar 

  71. Lam CS et al. (2007) Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 115: 1982–1990

    Article  PubMed  PubMed Central  Google Scholar 

  72. Liu JE et al. (2001) The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study. J Am Coll Cardiol 37: 1943–1949

    Article  CAS  PubMed  Google Scholar 

  73. Liu JE et al. (2003) Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: the Strong Heart Study. J Am Coll Cardiol 41: 2022–2028

    Article  CAS  PubMed  Google Scholar 

  74. Paulus WJ et al. (1994) Different effects of “supply” and “demand” ischemia on left ventricular diastolic function in humans. In Left Ventricular Diastolic Dysfunction and Heart Failure, 286–305 (Eds Gaasch WH and LeWinter MM) Philadelphia: Lea & Febiger

    Google Scholar 

  75. Cleland JG et al.; PEP-CHF Investigators (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27: 2338–2345

    Article  CAS  PubMed  Google Scholar 

  76. Ahmed A et al. (2006) Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 114: 397–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Higashi M et al. (2003) Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res 93: 767–775

    Article  CAS  PubMed  Google Scholar 

  78. Takimoto E et al. (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11: 214–222

    Article  CAS  PubMed  Google Scholar 

  79. Kuwahara F et al. (2002) Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106: 130–135

    Article  CAS  PubMed  Google Scholar 

  80. Little WC et al. (2005) The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 11: 191–195

    Article  CAS  PubMed  Google Scholar 

  81. Hirsch JC et al. (2004) Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction. Am J Physiol Heart Circ Physiol 286: H2314–H2321

    Article  CAS  PubMed  Google Scholar 

  82. Huq F et al. (2004) Gene transfer of parvalbumin improves diastolic dysfunction in senescent myocytes. Circulation 109: 2780–2785

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported in part by grants from the Heart and Stroke Foundation (HSF) of Ontario, the Canadian Institutes of Health Research (CIHR) and CHFNET and TACTICS Partnership Programs of the HSF and CIHR. M Ouzounian is supported by a Research Fellowship Award from the Heart Failure Society of America and the TACTICS strategic training program of the CIHR.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter P Liu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ouzounian, M., Lee, D. & Liu, P. Diastolic heart failure: mechanisms and controversies. Nat Rev Cardiol 5, 375–386 (2008). https://doi.org/10.1038/ncpcardio1245

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1245

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing