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Pathophysiology of heart failure with preserved ejection fraction

Author
Barry A Borlaug, MD
Section Editor
Wilson S Colucci, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC

INTRODUCTION

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 cardiac 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

While it is convenient to consider systolic and diastolic dysfunction as separate processes, the truth is that the two almost always coexist, as they are mechanistically intertwined with one another. The pathophysiology of HF with preserved ejection fraction (HFpEF) will be reviewed here. The clinical manifestations, diagnosis, treatment, and prognosis of HFpEF 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".)

TERMINOLOGY

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

                                    

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Literature review current through: Nov 2016. | This topic last updated: Wed Nov 09 00:00:00 GMT 2016.
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References
Top
  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. Yancy CW, Jessup M, Bozkurt B, et al. 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 2013; 62:e147.
  10. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37:2129.
  11. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016; 37:455.
  12. Borlaug BA. Defining HFpEF: where do we draw the line? Eur Heart J 2016; 37:463.
  13. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011; 123:2006.
  14. 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.
  15. Paulus WJ, van Ballegoij JJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth! J Am Coll Cardiol 2010; 55:526.
  16. 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.
  17. Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap. Circulation 2016; 134:73.
  18. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32:670.
  19. 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.
  20. 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.
  21. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63:2817.
  22. Zile MR, Baicu CF, Bonnema DD. Diastolic heart failure: definitions and terminology. Prog Cardiovasc Dis 2005; 47:307.
  23. Borlaug BA, Redfield MM, Melenovsky V, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6:944.
  24. Kuznetsova T, Herbots L, López B, et al. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2009; 2:105.
  25. Kane GC, Karon BL, Mahoney DW, et al. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA 2011; 306:856.
  26. Olson TP, Johnson BD, Borlaug BA. Impaired Pulmonary Diffusion in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail 2016; 4:490.
  27. Borlaug BA. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J 2014; 78:20.
  28. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11:507.
  29. Cheng CP, Igarashi Y, Little WC. Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992; 70:9.
  30. 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.
  31. 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.
  32. Little WC. Diastolic dysfunction beyond distensibility: adverse effects of ventricular dilatation. Circulation 2005; 112:2888.
  33. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 2016.
  34. Ohara T, Niebel CL, Stewart KC, et al. Loss of adrenergic augmentation of diastolic intra-LV pressure difference in patients with diastolic dysfunction: evaluation by color M-mode echocardiography. JACC Cardiovasc Imaging 2012; 5:861.
  35. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Dynamics of left ventricular filling at rest and during exercise. Circulation 1983; 68:59.
  36. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures. Circulation 1983; 67:521.
  37. Borlaug BA, Jaber WA, Ommen SR, et al. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97:964.
  38. Borlaug BA, Nishimura RA, Sorajja P, et al. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3:588.
  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. Zile MR, Baicu CF, Ikonomidis JS, et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 2015; 131:1247.
  45. Mohammed SF, Hussain S, Mirzoyev SA, et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015; 131:550.
  46. 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.
  47. 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.
  48. 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.
  49. Andersen MJ, Olson TP, Melenovsky V, et al. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure. Circ Heart Fail 2015; 8:41.
  50. Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17.
  51. 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.
  52. 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.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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.
  58. 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.
  59. 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.
  60. Zile MR. Treating diastolic heart failure with statins: "phat" chance for pleiotropic benefits. Circulation 2005; 112:300.
  61. Katz AM, Zile MR. New molecular mechanism in diastolic heart failure. Circulation 2006; 113:1922.
  62. Borlaug BA, Lam CS, Roger VL, et al. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 2009; 54:410.
  63. 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.
  64. 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.
  65. 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.
  66. 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.
  67. Shah AM, Claggett B, Folsom AR, et al. Ideal Cardiovascular Health During Adult Life and Cardiovascular Structure and Function Among the Elderly. Circulation 2015; 132:1979.
  68. Borlaug BA, Olson TP, Lam CS, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56:845.
  69. Abudiab MM, Redfield MM, Melenovsky V, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 2013; 15:776.
  70. Lam CS, Roger VL, Rodeheffer RJ, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53:1119.
  71. Gorter TM, Hoendermis ES, van Veldhuisen DJ, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016.
  72. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011; 377:658.
  73. Adamson PB, Abraham WT, Bourge RC, et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014; 7:935.
  74. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013; 309:1268.
  75. Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015; 36:2565.
  76. Zile MR, Bourge RC, Redfield MM, et al. Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. JACC Heart Fail 2014; 2:123.
  77. Melenovsky V, Hwang SJ, Lin G, et al. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J 2014; 35:3452.
  78. Mohammed SF, Hussain I, AbouEzzeddine OF, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130:2310.
  79. Burke MA, Katz DH, Beussink L, et al. Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circ Heart Fail 2014; 7:288.
  80. 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.
  81. Akiyama E, Sugiyama S, Matsuzawa Y, et al. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol 2012; 60:1778.
  82. Weber T, Wassertheurer S, O'Rourke MF, et al. Pulsatile hemodynamics in patients with exertional dyspnea: potentially of value in the diagnostic evaluation of suspected heart failure with preserved ejection fraction. J Am Coll Cardiol 2013; 61:1874.
  83. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin 2011; 29:447.
  84. Schwartzenberg S, Redfield MM, From AM, et al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 2012; 59:442.
  85. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114:2138.
  86. Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation 2011; 123:1010.
  87. 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.
  88. 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.
  89. Haykowsky MJ, Brubaker PH, John JM, et al. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol 2011; 58:265.
  90. Dhakal BP, Malhotra R, Murphy RM, et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 2015; 8:286.
  91. Upadhya B, Haykowsky MJ, Eggebeen J, Kitzman DW. Exercise intolerance in heart failure with preserved ejection fraction: more than a heart problem. J Geriatr Cardiol 2015; 12:294.
  92. Kitzman DW, Upadhya B, Vasu S. What the dead can teach the living: systemic nature of heart failure with preserved ejection fraction. Circulation 2015; 131:522.
  93. Haykowsky MJ, Brubaker PH, Stewart KP, et al. 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 2012; 60:120.
  94. Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Circulation 2013; 128:1085.
  95. Zakeri R, Borlaug BA, McNulty SE, et al. Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail 2014; 7:123.
  96. Melenovsky V, Hwang SJ, Redfield MM, et al. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail 2015; 8:295.
  97. Santos AB, Roca GQ, Claggett B, et al. Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail 2016; 9:e002763.
  98. Freed BH, Daruwalla V, Cheng JY, et al. Prognostic Utility and Clinical Significance of Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction: Importance of Left Atrial Strain. Circ Cardiovasc Imaging 2016; 9.
  99. Wohlfahrt P, Redfield MM, Lopez-Jimenez F, et al. Impact of general and central adiposity on ventricular-arterial aging in women and men. JACC Heart Fail 2014; 2:489.
  100. Mohammed SF, Majure DT, Redfield MM. Zooming in on the Microvasculature in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail 2016; 9.
  101. van Empel VP, Mariani J, Borlaug BA, Kaye DM. Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction. J Am Heart Assoc 2014; 3:e001293.
  102. 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.
  103. Cave AC, Ingwall JS, Friedrich J, et al. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation 2000; 101:2090.
  104. 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.
  105. 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.
  106. Steine K, Stugaard M, Smiseth OA. Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation 1999; 99:2048.
  107. 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.
  108. 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.
  109. 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.
  110. Pepine CJ, Wiener L. Relationship of anginal symptoms to lung mechanics during myocardial ischemia. Circulation 1972; 46:863.
  111. 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.
  112. 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.
  113. Bolli R. Myocardial 'stunning' in man. Circulation 1992; 86:1671.
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