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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
References
Fishberg AM (1937) Heart Failure. Philadelphia: Lea & Febiger
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
Borbély A et al. (2005) Cardiomyocyte stiffness in diastolic heart failure. Circulation 111: 774–781
van Heerebeek L et al. (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113: 1966–1973
Nagueh SF et al. (2004) Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110: 155–162
Neagoe C et al. (2002) Titin isoform switch in ischemic human heart disease. Circulation 106: 1333–1341
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
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
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
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
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
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
Skaluba SJ and Litwin SE (2004) Mechanisms of exercise intolerance: insights from tissue Doppler imaging. Circulation 109: 972–977
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
Yu CM et al. (2002) Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 105: 1195–1201
Petrie MC et al. (2002) “Diastolic heart failure” or heart failure caused by subtle left ventricular systolic dysfunction? Heart 87: 29–31
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
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
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
Sliwa K et al. (2005) Epidemiology and etiology of cardiomyopathy in Africa. Circulation 112: 3577–3583
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
Owan TE and Redfield MM (2005) Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 47: 320–332
Packer M (1990) Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 81: III78–III86
Lee DS and Vasan RS (2005) Novel markers for heart failure diagnosis and prognosis. Curr Opin Cardiol 20: 201–210
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
Vasan RS and Levy D (2000) Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 101: 2118–2121
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
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
Gandhi SK et al. (2001) The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344: 17–22
Cleland JG et al. (2007) Prognosis in heart failure with a normal ejection fraction. N Engl J Med 357: 829–830
Vasan RS et al. (1995) Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 26: 1565–1574
Owan TE et al. (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355: 251–259
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
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
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
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
Pritchett AM et al. (2005) Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol 45: 87–92
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
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
Muller OJ et al. (2003) Transgenic rat hearts overexpressing SERCA2a show improved contractility under baseline conditions and pressure overload. Cardiovasc Res 59: 380–389
MacLennan DH and Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4: 566–577
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
Chu G et al. (1997) Monomeric phospholamban overexpression in transgenic mouse hearts. Circ Res 81: 485–492
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
Cain BS et al. (1998) Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 32: 458–467
Piccini JP et al. (2004) New insights into diastolic heart failure: role of diabetes mellitus. Am J Med 116 (Suppl 5A): S64–S75
Flesch M et al. (1997) Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy. Hypertension 30: 383–391
Studeli R et al. (2006) Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression. Am J Transplant 6: 775–782
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
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
Vahebi S et al. (2005) Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Circ Res 96: 740–747
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
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
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
Wu Y et al. (2000) Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol 32: 2151–2162
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
Martos R et al. (2007) Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115: 888–895
Granzier H et al. (2005) Titin: physiological function and role in cardiomyopathy and failure. Heart Fail Rev 10: 211–223
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
van Heerebeek L et al. (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113: 1966–1973
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
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
Corral-Debrinski M et al. (1991) Hypoxemia is associated with mitochondrial DNA damage and gene induction: implications for cardiac disease. JAMA 266: 1812–1816
Olivetti G et al. (1991) Cardiomyopathy of the aging human heart: myocyte loss and reactive cellular hypertrophy. Circ Res 68: 1560–1568
Kai H et al. (2005) Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res 28: 483–490
Perticone F et al. (1999) Relationship between left ventricular mass and endothelium-dependent vasodilation in never-treated hypertensive patients. Circulation 99: 1991–1996
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
Lamb HJ et al. (1999) Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 99: 2261–2267
Leite-Moreira AF et al. (1999) Afterload induced changes in myocardial relaxation: a mechanism for diastolic dysfunction. Cardiovasc Res 43: 344–353
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
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
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
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
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
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
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
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
Takimoto E et al. (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11: 214–222
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
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
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
Huq F et al. (2004) Gene transfer of parvalbumin improves diastolic dysfunction in senescent myocytes. Circulation 109: 2780–2785
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncpcardio1245
This article is cited by
-
Myofilament dysfunction in diastolic heart failure
Heart Failure Reviews (2023)
-
Changes in left ventricular blood flow during diastole due to differences in chamber size in healthy dogs
Scientific Reports (2020)
-
Sex and Cardiovascular Involvement in Inflammatory Joint Diseases
Clinical Reviews in Allergy & Immunology (2019)
-
Creation of a restrictive atrial communication in heart failure with preserved and mid-range ejection fraction: effective palliation of left atrial hypertension and pulmonary congestion
Clinical Research in Cardiology (2018)
-
Role of tissue transglutaminase in age-associated ventricular stiffness
Amino Acids (2017)