Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma

  • Taslima Bhuiyan
  • Mathew S. MaurerEmail author


Heart failure with preserved ejection fraction (HFPEF) is increasing in prevalence with the aging of the population, and morbidity and mortality rates are comparable to that of heart failure with reduced ejection fraction (HFREF). The diagnosis can be difficult to make, especially in older adults, stemming from the presence of multiple co-morbid illnesses with confounding symptoms. New diagnostic tools have resulted in guidelines proposed to define and diagnose HFPEF. Recent literature focusing on the pathophysiology underlying this disease suggests multiple mechanisms are involved in the generation of the phenotype, such as abnormal relaxation and ventricular-vascular coupling, chronotropic incompetence, volume overload, and redistribution and /or endothelial dysfunction. Currently, no clinically proven treatments are shown to decrease morbidity and mortality in this population; however, there may be a novel multidisciplinary and multistage treatment strategy that can be studied to address this complex disease which incorporates pharmacologic and non-pharmacologic therapeutics.


Heart failure Diastolic heart failure Heart failure preserved ejection fraction Heart failure normal ejection fraction Heart failure diagnosis Heart failure treatment 



Dr. Maurer is supported by grants from the NIH/NIA K24AG036778-01A1 and R01AG027518.


No conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    •• Lindenfeld J, Albert NM, Boehmer JP, HFSA, et al. Comprehensive heart failure practice guideline. J Card Fail. 2010;16:e1–194. This is a comprehensive document that discusses the epidemiology, pathophysiology, and diagnosis of heart failure in general, including a section on those with preserved EF. It also sets forth guidelines for the management of this complex disease by incorporating the most recent literature and evidence.PubMedCrossRefGoogle Scholar
  2. 2.
    Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med. 2002;137:631–9.PubMedGoogle Scholar
  3. 3.
    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;119:3070–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Tinetti ME, Baker DI, McAvay G, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med. 1994;331:821–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Redfield MM, Kitzman DW. Heart failure: a rose by any other name? Congest Heart Fail. 2006;12:166–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995;26:1565–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Owan TE, Redfield MM. Epidemiology of diastolic heart failure. Prog Cardiovasc Dis. 2005;47:320–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13:18–28.PubMedCrossRefGoogle Scholar
  10. 10.
    •• Kitzman DW, Rich MW. Age disparities in heart failure research. JAMA. 2010;304:1950–1. This commentary highlights the disparities in patient population selection in major clinical trials compared to population characteristics observed in registries who have heart failure with preserved EF. These differences may explain the negative clinical trial results in HFPEF and the poor outcomes observed in this group despite significant advancement of care in systolic heart failure. The authors call for strict criteria to include older subjects and subjects with multiple co-morbidities in large clinical trials because that is a more realistic study population and results are generalizable.PubMedCrossRefGoogle Scholar
  11. 11.
    Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective. Circ Heart Fail. 2008;1:91–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease. Circulation. 2003;107:346–54.PubMedCrossRefGoogle Scholar
  14. 14.
    Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107:490–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Miller MR. Structural and physiological age-associated changes in aging lungs. Semin Respir Crit Care Med. 2010;31:521–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Duarte D, Santos-Araujo C, Leite-Moreira AF. Hypertension and angiogenesis in the aging kidney: A review. Arch Gerontol Geriatr. 2010.Google Scholar
  17. 17.
    Hotta H, Uchida S. Aging of the autonomic nervous system and possible improvements in autonomic activity using somatic afferent stimulation. Geriatr Gerontol Int. 2010;10 Suppl 1:S127–36.PubMedCrossRefGoogle Scholar
  18. 18.
    Vanhecke TE, Kim R, Raheem SZ, McCullough PA. Myocardial ischemia in patients with diastolic dysfunction and heart failure. Curr Cardiol Rep. 2010;12:216–22.PubMedCrossRefGoogle Scholar
  19. 19.
    van Heerebeek L, Borbely A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Borbely A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Bronzwaer JG, Paulus WJ. Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction? Prog Cardiovasc Dis. 2005;47:276–84.PubMedCrossRefGoogle Scholar
  22. 22.
    van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Lebeche D, Davidoff AJ, Hajjar RJ. Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5:715–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Zile MR, Richardson K, Cowles MK, et al. Constitutive properties of adult mammalian cardiac muscle cells. Circulation. 1998;98:567–79.PubMedGoogle Scholar
  25. 25.
    Granzier HL, Irving TC. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995;68:1027–44.PubMedCrossRefGoogle Scholar
  26. 26.
    LeWinter MM, Granzier H. Cardiac titin: a multifunctional giant. Circulation. 2010;121:2137–45.PubMedCrossRefGoogle Scholar
  27. 27.
    Borbely A, Falcao-Pires I, van Heerebeek L, et al. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Gonzalez A, Lopez B, Querejeta R, Zubillaga E, Echeverria T, Diez J. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension. 2010;55:1418–24.PubMedCrossRefGoogle Scholar
  29. 29.
    Bradshaw AD, Baicu CF, Rentz TJ, et al. Pressure overload-induced alterations in fibrillar collagen content and myocardial diastolic function: role of secreted protein acidic and rich in cysteine (SPARC) in post-synthetic procollagen processing. Circulation. 2009;119:269–80.PubMedCrossRefGoogle Scholar
  30. 30.
    Borbely A, Papp Z, Edes I, Paulus WJ. Molecular determinants of heart failure with normal left ventricular ejection fraction. Pharmacol Rep. 2009;61:139–45.PubMedGoogle Scholar
  31. 31.
    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;113:2089–96.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Bench T, Burkhoff D, O’Connell JB, et al. Heart failure with normal ejection fraction: consideration of mechanisms other than diastolic dysfunction. Curr Heart Fail Rep. 2009;6:57–64. This review article discusses the major mechanisms that play a role in heart failure with preserved EF. It discusses mechanisms that are unrelated to diastolic function, such as aging, presence o f co-morbidities, volume redistribution, and central and peripheral vascular disconnect, among others.PubMedCrossRefGoogle Scholar
  33. 33.
    Boyle A, Maurer MS, Sobotka PA. Myocellular and interstitial edema and circulating volume expansion as a cause of morbidity and mortality in heart failure. J Card Fail. 2007;13:133–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Maurer MS, King DL, El-Khoury Rumbarger L, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card Fail. 2005;11:177–87.PubMedCrossRefGoogle Scholar
  35. 35.
    Luchi RJ, Snow E, Luchi JM, Nelson CL, Pircher FJ. Left ventricular function in hospitalized geriatric patients. J Am Geriatr Soc. 1982;30:700–5.PubMedGoogle Scholar
  36. 36.
    Gardener J. Partial hospitalisation gives patients with mental health problems. Nurs Times. 1998;94:47.PubMedGoogle Scholar
  37. 37.
    Kitzman DW, Gardin JM, Gottdiener JS, et al. Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol. 2001;87:413–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation. 2000;101:2118–21.PubMedGoogle Scholar
  40. 40.
    Vasan RS, Levy D, Larson MG, Benjamin EJ. Interpretation of echocardiographic measurements: a call for standardization. Am Heart J. 2000;139:412–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med. 2001;344:17–22.PubMedCrossRefGoogle Scholar
  42. 42.
    Drazner MH, Rame JE, Marino EK, et al. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J Am Coll Cardiol. 2004;43:2207–15.PubMedCrossRefGoogle Scholar
  43. 43.
    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;104:779–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Maurer MS, Spevack D, Burkhoff D, Kronzon I. Diastolic dysfunction: can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol. 2004;44:1543–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:588–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Sanderson JE. Heart failure with a normal ejection fraction. Heart. 2007;93:155–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Petrie MC, Hogg K, Caruana L, McMurray JJ. Poor concordance of commonly used echocardiographic measures of left ventricular diastolic function in patients with suspected heart failure but preserved systolic function: is there a reliable echocardiographic measure of diastolic dysfunction? Heart. 2004;90:511–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Palmieri V, Innocenti F, Pini R, Celentano A. Reproducibility of Doppler echocardiographic assessment of left ventricular diastolic function in multicenter setting. J Am Soc Echocardiogr. 2005;18:99–106.PubMedCrossRefGoogle Scholar
  49. 49.
    Kindermann M, Reil JC, Pieske B, van Veldhuisen DJ, Bohm M. Heart failure with normal left ventricular ejection fraction: what is the evidence? Trends Cardiovasc Med. 2008;18:280–92.PubMedCrossRefGoogle Scholar
  50. 50.
    Miller VM, Redfield MM, McConnell JP. Use of BNP and CRP as biomarkers in assessing cardiovascular disease: diagnosis versus risk. Curr Vasc Pharmacol. 2007;5:15–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Romano S, di Mauro M, Fratini S, et al. Serial BNP assay in monitoring exercise tolerance in patients with diastolic dysfunction. Int J Cardiol. 2011;147:312–3.PubMedCrossRefGoogle Scholar
  52. 52.
    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;49:198–207.PubMedCrossRefGoogle Scholar
  53. 53.
    Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Heart Fail Clin. 2009;5:217–28.PubMedCrossRefGoogle Scholar
  54. 54.
    Hay I, Rich J, Ferber P, Burkhoff D, Maurer MS. Role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure. Am J Physiol Heart Circ Physiol. 2005;288:H1203–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med. 2010;362:590–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Dickstein K. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: application of natriuretic peptides. Reply. Eur Heart J 2008.Google Scholar
  57. 57.
    •• Hummel SL, DeFranco AC, Skorcz S, Montoye CK, Koelling TM. Am J Med. 2009;122:1029–36. This study revealed that a low-salt diet in patients with HFPEF is shown to decrease the risk of death and readmission to the hospital; however only a small percentage of patients with HFPEF are being counseled on a low-salt diet at time of discharge compared to patients with systolic heart failure. The authors concluded that if clinicians educate patients with HFPEF about the importance of a low-salt diet, there may be fewer deaths and readmissions to the hospital in this group of patients.PubMedCrossRefGoogle Scholar
  58. 58.
    Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail. 2010;3:659–67.PubMedCrossRefGoogle Scholar
  59. 59.
    The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997;336:525–33.Google Scholar
  60. 60.
    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;362:777–81.PubMedCrossRefGoogle Scholar
  61. 61.
    Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–25.PubMedCrossRefGoogle Scholar
  62. 62.
    Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.PubMedCrossRefGoogle Scholar
  63. 63.
    Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.PubMedCrossRefGoogle Scholar
  64. 64.
    Sweitzer NK, Lopatin M, Yancy CW, Mills RM, Stevenson LW. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions. Am J Cardiol. 2008;101:1151–6.PubMedCrossRefGoogle Scholar
  65. 65.
    He KL, Burkhoff D, Leng WX, et al. Comparison of ventricular structure and function in Chinese patients with heart failure and ejection fractions >55% versus 40% to 55% versus <40%. Am J Cardiol. 2009;103:845–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by treating comorbidities. JAMA. 2008;300:431–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Levitan EB, Wolk A, Mittleman MA. Consistency with the DASH diet and incidence of heart failure. Arch Intern Med. 2009;169:851–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Fung TT, Chiuve SE, McCullough ML, Rexrode KM, Logroscino G, Hu FB. Adherence to a DASH-style diet and risk of coronary heart disease and stroke in women. Arch Intern Med. 2008;168:713–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Meles E, Giannattasio C, Failla M, Gentile G, Capra A, Mancia G. Nonpharmacologic treatment of hypertension by respiratory exercise in the home setting. Am J Hypertens. 2004;17:370–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Coleman EA, Smith JD, Raha D, Min SJ. Posthospital medication discrepancies: prevalence and contributing factors. Arch Intern Med. 2005;165:1842–7.PubMedCrossRefGoogle Scholar
  71. 71.
    •• Hernandez AF, Greiner MA, Fonarow GC, et al. Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure. JAMA. 2010;303:1716–22. This study highlights one of the most important reasons for readmission in patients with HFPEF, which is poor follow-up care. In this study, the authors demonstrate that less than half of patients admitted with heart failure are seen within 7 days post-discharge, and less than 5% are seen by the same cardiologist in the hospital and within 7 days post-discharge in the office.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of CardiologyColumbia University Medical CenterNew YorkUSA
  2. 2.Clinical Cardiovascular Research Laboratory for the ElderlyAllen Hospital of New York Presbyterian HospitalNew YorkUSA

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