Heart Failure Reviews

, Volume 22, Issue 2, pp 141–148 | Cite as

Heart failure with preserved ejection fraction and skeletal muscle physiology

  • Stephen D. Farris
  • Farid Moussavi-Harami
  • April Stempien-Otero


Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure in the USA, increases in prevalence with aging, and has no effective therapies. Intriguingly, the pathophysiology of HFpEF has many commonalities with the aged cardiovascular system including reductions in diastolic compliance, chronotropic defects, increased resistance in the peripheral vasculature, and poor energy substrate utilization. Decreased exercise capacity is a cardinal symptom of HFpEF. However, its severity is often out of proportion to changes in cardiac output. This observation has led to studies of muscle function in HFpEF revealing structural, biomechanical, and metabolic changes. These data, while incomplete, support a hypothesis that similar to aging, HFPEF is a systemic process. Understanding the mechanisms leading to exercise intolerance in this condition may lead to strategies to improve morbidity in both HFpEF and aging.


Diastolic heart failure Skeletal muscle Left ventricular hypertrophy 


  1. 1.
    Mozaffarian D et al (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–322. doi: 10.1161/CIR.0000000000000152 CrossRefPubMedGoogle Scholar
  2. 2.
    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. doi: 10.1056/NEJMoa051530 CrossRefPubMedGoogle Scholar
  3. 3.
    Owan TE et al (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259. doi: 10.1056/NEJMoa052256 CrossRefPubMedGoogle Scholar
  4. 4.
    Yancy CW et al (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62:e147–e239. doi: 10.1016/j.jacc.2013.05.019 CrossRefPubMedGoogle Scholar
  5. 5.
    Pfuntner A, (Truven Health Analytics), W. L. T. H. A., Stocks C (AHRQ) (2013) Most frequent conditions in U.S. hospitals, 2011. HCUP Statistical Brief #162. Agency for Healthcare Research and Quality, Rockville, MDGoogle Scholar
  6. 6.
    Heidenreich PA et al (2013) Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circulation Heart failure 6:606–619. doi: 10.1161/HHF.0b013e318291329a CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Borlaug BA, Paulus WJ (2011) Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 32:670–679. doi: 10.1093/eurheartj/ehq426 CrossRefPubMedGoogle Scholar
  8. 8.
    Lee DS et al (2009) 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 119:3070–3077. doi: 10.1161/CIRCULATIONAHA.108.815944 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shah, S. J. et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation 131, 269–279, doi: 10.1161/CIRCULATIONAHA.114.010637 (2015).
  10. 10.
    Bishu K et al (2012) Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction. Am Heart J 164:763–770 e763. doi: 10.1016/j.ahj.2012.08.014 CrossRefPubMedGoogle Scholar
  11. 11.
    Adams JW, Brown JH (2001) G-proteins in growth and apoptosis: lessons from the heart. Oncogene 20:1626–1634. doi: 10.1038/sj.onc.1204275 CrossRefPubMedGoogle Scholar
  12. 12.
    Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15. doi: 10.1186/1755-1536-5-15 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Li AH, Liu PP, Villarreal FJ, Garcia RA (2014) Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. Circ Res 114:916–927. doi: 10.1161/CIRCRESAHA.114.302819 CrossRefPubMedGoogle Scholar
  14. 14.
    Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC (2013) Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 10:15–26. doi: 10.1038/nrcardio.2012.158 CrossRefPubMedGoogle Scholar
  15. 15.
    Borlaug BA (2014) The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11:507–515. doi: 10.1038/nrcardio.2014.83 CrossRefPubMedGoogle Scholar
  16. 16.
    Oh JK et al (1997) The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 10:246–270CrossRefPubMedGoogle Scholar
  17. 17.
    Nishimura RA, Tajik AJ (1997) Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 30:8–18CrossRefPubMedGoogle Scholar
  18. 18.
    Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP (1983) Dynamics of left ventricular filling at rest and during exercise. Circulation 68:59–67CrossRefPubMedGoogle Scholar
  19. 19.
    Bryg RJ, Williams GA, Labovitz AJ (1987) Effect of aging on left ventricular diastolic filling in normal subjects. Am J Cardiol 59:971–974CrossRefPubMedGoogle Scholar
  20. 20.
    Andersen MJ, Borlaug BA (2014) Invasive hemodynamic characterization of heart failure with preserved ejection fraction. Heart Fail Clin 10:435–444. doi: 10.1016/j.hfc.2014.03.001 CrossRefPubMedGoogle Scholar
  21. 21.
    Sharma K, Kass DA (2014) Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115:79–96. doi: 10.1161/CIRCRESAHA.115.302922 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Little WC, Oh JK (2009) Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation 120:802–809. doi: 10.1161/CIRCULATIONAHA.109.869602 CrossRefPubMedGoogle Scholar
  23. 23.
    Tan YT et al (2009) The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol 54:36–46. doi: 10.1016/j.jacc.2009.03.037 CrossRefPubMedGoogle Scholar
  24. 24.
    Pitt B et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392. doi: 10.1056/NEJMoa1313731 CrossRefPubMedGoogle Scholar
  25. 25.
    Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM (2010) Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 3:588–595. doi: 10.1161/CIRCHEARTFAILURE.109.930701 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rosas PC et al (2015) Phosphorylation of cardiac myosin-binding protein-C is a critical mediator of diastolic function. Circ Heart Fail 8:582–594. doi: 10.1161/CIRCHEARTFAILURE.114.001550 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Borlaug BA (2014) Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J 78:20–32CrossRefPubMedGoogle Scholar
  28. 28.
    Abudiab MM et al (2013) Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 15:776–785. doi: 10.1093/eurjhf/hft026 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hamdani N et al (2013) Crucial role for Ca2(+)/calmodulin-dependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ Res 112:664–674. doi: 10.1161/CIRCRESAHA.111.300105 CrossRefPubMedGoogle Scholar
  30. 30.
    Hamdani N, Bishu KG, von Frieling-Salewsky M, Redfield MM, Linke WA (2013) Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc Res 97:464–471. doi: 10.1093/cvr/cvs353 CrossRefPubMedGoogle Scholar
  31. 31.
    Zile MR et al (2015) Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131:1247–1259. doi: 10.1161/CIRCULATIONAHA.114.013215 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kato S et al (2015) Prognostic significance of quantitative assessment of focal myocardial fibrosis in patients with heart failure with preserved ejection fraction. Int J Cardiol 191:314–319. doi: 10.1016/j.ijcard.2015.05.048 CrossRefPubMedGoogle Scholar
  33. 33.
    Su MY et al (2014) CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging 7:991–997. doi: 10.1016/j.jcmg.2014.04.022 CrossRefPubMedGoogle Scholar
  34. 34.
    Krum H et al (2011) Relation of peripheral collagen markers to death and hospitalization in patients with heart failure and preserved ejection fraction: results of the I-PRESERVE collagen substudy. Circ Heart Fail 4:561–568. doi: 10.1161/CIRCHEARTFAILURE.110.960716 CrossRefPubMedGoogle Scholar
  35. 35.
    Kurrelmeyer KM et al (2014) Effects of spironolactone treatment in elderly women with heart failure and preserved left ventricular ejection fraction. J Card Fail 20:560–568. doi: 10.1016/j.cardfail.2014.05.010 CrossRefPubMedGoogle Scholar
  36. 36.
    Sakata Y, Ohtani T, Takeda Y, Yamamoto K, Mano T (2013) Left ventricular stiffening as therapeutic target for heart failure with preserved ejection fraction. Circ J 77:886–892CrossRefPubMedGoogle Scholar
  37. 37.
    Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87:1285–1342. doi: 10.1152/physrev.00012.2007 CrossRefPubMedGoogle Scholar
  38. 38.
    Chiquet M, Gelman L, Lutz R, Maier S (2009) From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim Biophys Acta 1793:911–920. doi: 10.1016/j.bbamcr.2009.01.012 CrossRefPubMedGoogle Scholar
  39. 39.
    Loffredo FS, Nikolova AP, Pancoast JR, Lee RT (2014) Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 115:97–107. doi: 10.1161/CIRCRESAHA.115.302929 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Biernacka A, Frangogiannis NG (2011) Aging and cardiac fibrosis. Aging Dis 2:158–173PubMedPubMedCentralGoogle Scholar
  41. 41.
    Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R (2001) Age related changes of the collagen network of the human heart. Mech Ageing Dev 122:1049–1058CrossRefPubMedGoogle Scholar
  42. 42.
    Mays PK, Bishop JE, Laurent GJ (1988) Age-related changes in the proportion of types I and III collagen. Mech Ageing Dev 45:203–212CrossRefPubMedGoogle Scholar
  43. 43.
    Eghbali M, Eghbali M, Robinson TF, Seifter S, Blumenfeld OO (1989) Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res 23:723–729CrossRefPubMedGoogle Scholar
  44. 44.
    Gagliano N et al (2002) Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat. Mech Ageing Dev 123:413–425CrossRefPubMedGoogle Scholar
  45. 45.
    Fleg JL et al (2005) Accelerated longitudinal decline of aerobic capacity in healthy older adults. Circulation 112:674–682. doi: 10.1161/CIRCULATIONAHA.105.545459 CrossRefPubMedGoogle Scholar
  46. 46.
    Strait JB, Lakatta EG (2012) Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin 8:143–164. doi: 10.1016/j.hfc.2011.08.011 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Janczewski AM, Spurgeon HA, Lakatta EG (2002) Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca2+ regulation. J Mol Cell Cardiol 34:641–648. doi: 10.1006/jmcc.2002.2004 CrossRefPubMedGoogle Scholar
  48. 48.
    Shimiaie J et al (2015) Determinants of effort intolerance in patients with heart failure: combined echocardiography and cardiopulmonary stress protocol. JACC Heart Fail 3:803–814. doi: 10.1016/j.jchf.2015.05.010 CrossRefPubMedGoogle Scholar
  49. 49.
    Wood PW, Choy JB, Nanda NC, Becher H (2014) Left ventricular ejection fraction and volumes: it depends on the imaging method. Echocardiography 31:87–100. doi: 10.1111/echo.12331 CrossRefPubMedGoogle Scholar
  50. 50.
    Goto T et al (2013) Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women. Circ J 77:123–129CrossRefPubMedGoogle Scholar
  51. 51.
    Rivera-Brown AM, Frontera WR (2012) Principles of exercise physiology: responses to acute exercise and long-term adaptations to training. PM R 4:797–804. doi: 10.1016/j.pmrj.2012.10.007 CrossRefPubMedGoogle Scholar
  52. 52.
    LANDWEHR, R. A. R. A. R (2002) The surprising history of the “HRmax = 220-age” equation. J Exerc Physiol online 5Google Scholar
  53. 53.
    Tanaka H, Monahan KD, Seals DR (2001) Age-predicted maximal heart rate revisited. J Am Coll Cardiol 37:153–156CrossRefPubMedGoogle Scholar
  54. 54.
    Bhella PS et al (2011) Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail 13:1296–1304. doi: 10.1093/eurjhf/hfr133 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Brubaker PH et al (2006) Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardpulm Rehabil 26:86–89CrossRefGoogle Scholar
  56. 56.
    Phan TT et al (2010) Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail 3:29–34. doi: 10.1161/CIRCHEARTFAILURE.109.877720 CrossRefPubMedGoogle Scholar
  57. 57.
    Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS (2003) Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol 42:831–838CrossRefPubMedGoogle Scholar
  58. 58.
    Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS (2001) Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 104:1911–1916PubMedGoogle Scholar
  59. 59.
    Parker BA, Ridout SJ, Proctor DN (2006) Age and flow-mediated dilation: a comparison of dilatory responsiveness in the brachial and popliteal arteries. Am J Physiol Heart Circ Physiol 291:H3043–H3049. doi: 10.1152/ajpheart.00190.2006 CrossRefPubMedGoogle Scholar
  60. 60.
    Haykowsky MJ, Kitzman DW (2014) Exercise physiology in heart failure and preserved ejection fraction. Heart Fail Clin 10:445–452. doi: 10.1016/j.hfc.2014.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Haykowsky MJ et al (2013) Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction. J Gerontol A Biol Sci Med Sci 68:161–167. doi: 10.1093/gerona/gls099 CrossRefPubMedGoogle Scholar
  62. 62.
    Hundley WG et al (2007) Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction. Am J Physiol Heart Circ Physiol 292:H1427–H1434. doi: 10.1152/ajpheart.00567.2006 CrossRefPubMedGoogle Scholar
  63. 63.
    Borlaug BA et al (2006) Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 114:2138–2147. doi: 10.1161/CIRCULATIONAHA.106.632745 CrossRefPubMedGoogle Scholar
  64. 64.
    Borlaug BA et al (2010) Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 56:845–854. doi: 10.1016/j.jacc.2010.03.077 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dhakal BP et al (2015) Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circulation. Heart failure 8:286–294. doi: 10.1161/CIRCHEARTFAILURE.114.001825 CrossRefPubMedGoogle Scholar
  66. 66.
    Haykowsky MJ et al (2011) Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol 58:265–274. doi: 10.1016/j.jacc.2011.02.055 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Haykowsky MJ et al (2013) Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass. J Gerontol A Biol Sci Med Sci 68:968–975. doi: 10.1093/gerona/glt011 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Haykowsky MJ et al (2014) Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol 113:1211–1216. doi: 10.1016/j.amjcard.2013.12.031 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Upadhya B, Haykowsky MJ, Eggebeen J, Kitzman DW (2015) Exercise intolerance in heart failure with preserved ejection fraction: more than a heart problem. J Geriatr Cardiol 12:294–304. doi: 10.11909/j.issn.1671-5411.2015.03.013 PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kitzman DW et al (2014) Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 306:H1364–H1370. doi: 10.1152/ajpheart.00004.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Bowen TS et al (2015) Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle. Eur J Heart Fail 17:263–272. doi: 10.1002/ejhf.239 CrossRefPubMedGoogle Scholar
  72. 72.
    Ryall JG, Schertzer JD, Lynch GS (2008) Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontology 9:213–228. doi: 10.1007/s10522-008-9131-0 CrossRefPubMedGoogle Scholar
  73. 73.
    Larsson L, Sjodin B, Karlsson J (1978) Histochemical and biochemical changes in human skeletal muscle with age in sedentary males, age 22–65 years. Acta Physiol Scand 103:31–39. doi: 10.1111/j.1748-1716.1978.tb06187.x CrossRefPubMedGoogle Scholar
  74. 74.
    Edelmann F et al (2011) Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 58:1780–1791. doi: 10.1016/j.jacc.2011.06.054 CrossRefPubMedGoogle Scholar
  75. 75.
    Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC (2010) Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circulation. Heart failure 3:659–667. doi: 10.1161/CIRCHEARTFAILURE.110.958785 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Haykowsky MJ et al (2012) Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol 60:120–128. doi: 10.1016/j.jacc.2012.02.055 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Stephen D. Farris
    • 1
  • Farid Moussavi-Harami
    • 1
  • April Stempien-Otero
    • 1
  1. 1.Department of Medicine, Division of CardiologyUniversity of Washington School of MedicineSeattleUSA

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