Heart failure with preserved ejection fraction: Mechanisms, clinical features, and therapies

Circulation Research

Volumn 115, Issue 1, 2014, Pages 79-96

  Sharma, Kavita ^a   Kass, David A ^a  

^a DEPARTMENT OF PATHOLOGY   (United States)

Author keywords

diastole; heart failure; hypertension; hypertrophy; therapy

Indexed keywords

3 (1 BIPHENYL 4 YLMETHYL 3 ETHOXYCARBONYL 1 BUTYLCARBAMOYL)PROPIONIC ACID PLUS VALSARTAN; BIOLOGICAL MARKER; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IVABRADINE;

CLINICAL FEATURE; CLINICAL RESEARCH; COMORBIDITY; DEMOGRAPHY; DIASTOLE; EPIDEMIC; HEART FAILURE WITH PRESERVED EJECTION FRACTION; HEART LEFT VENTRICLE EJECTION FRACTION; HUMAN; INFLAMMATION; KIDNEY DENERVATION; KIDNEY DYSFUNCTION; KINESIOTHERAPY; MORTALITY; MUSCLE METABOLISM; NERVE STIMULATION; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; SYSTOLE; TRANSLATIONAL RESEARCH; TREATMENT FAILURE;

DIASTOLE; HEART FAILURE; HYPERTENSION; HYPERTROPHY; THERAPY;

CYCLIC GMP-DEPENDENT PROTEIN KINASES; DIASTOLE; ENERGY METABOLISM; EXERCISE THERAPY; HEART FAILURE; HUMANS; HYPERTENSION, PULMONARY; INFLAMMATION; MUSCLE, SKELETAL; STROKE VOLUME; SYSTOLE; VENTRICULAR FUNCTION, LEFT;

EID: 84902975038     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.302922     Document Type: Review

References (171)

1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.
2. Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, Hernandez AF, Fonarow GC; Get With the Guidelines Scientific Advisory Committee and Investigators. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation. 2012;126:65-75.
3. 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;355:251-259.
4. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a populationbased study. N Engl J Med. 2006;355:260-269.
5. Liao L, Jollis JG, Anstrom KJ, Whellan DJ, Kitzman DW, Aurigemma GP, Mark DB, Schulman KA, Gottdiener JS. Costs for heart failure with normal vs reduced ejection fraction. Arch Intern Med. 2006;166: 112-118.
6. Loffredo FS, Nikolova AP, Pancoast JR, Lee RT. Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res. 2014;115:97-107.
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;350:1953-1959.
8. 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;3:588-595.
9. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschöpe C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008;117:2051-2060.
10. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, Ghali JK, Liebson PR. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?. Circulation. 2001;104:779-782.
11. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105:1387-1393.
12. Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function?. Circulation. 2003;107:656-658.
13. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA. 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.
14. Kitzman DW. Diastolic dysfunction in the elderly. Genesis and diagnostic and therapeutic implications. Cardiol Clin. 2000;18:597-617, x.
15. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003;107:714-720.
16. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, Redfield MM. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56:845-854.
17. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA. 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.
18. Quiñones MA, Zile MR, Massie BM, Kass DA; Writing Committee of the Dartmouth Diastolic Discourses. Chronic heart failure: a report from the Dartmouth Diastole Discourses. Congest Heart Fail. 2006;12:162-165.
19. Yip G, Wang M, Zhang Y, Fung JW, Ho PY, Sanderson JE. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition?. Heart. 2002;87:121-125.
20. Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SW. Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation. 2002;105:1195-1201.
21. Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006;113:296-304.
22. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:1977-2016.
23. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010;16:e1-194.
24. How to diagnose diastolic heart failure. European study group on diastolic heart failure. Eur Heart J. 1998;19:990-1003.
25. Yturralde RF, Gaasch WH. Diagnostic criteria for diastolic heart failure. Prog Cardiovasc Dis. 2005;47:314-319.
26. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 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-e239.
27. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847.
28. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 1999;33:1948-1955.
29. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, O'Connor CM, Sun JL, Yancy CW, Young JB; OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768-777.
30. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC; ADHERE Scientific Advisory Committee and Investigators. 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;47:76-84.
31. Klapholz M, Maurer M, Lowe AM, et al; New York Heart Failure Consortium. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol. 2004;43:1432-1438.
32. Shah S. Review: heart failure with preserved ejection fraction in African Americans. Ethn Dis. 2012;22:432-438.
33. Burke MA, Katz DH, Beussink L, Selvaraj S, Gupta DK, Fox J, Chakrabarti S, Sauer AJ, Rich JD, Freed BH, Shah SJ. Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2014;7:288-299.
34. Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-1392.
35. Redfield MM, Chen HH, Borlaug BA, et al; RELAX Trial. Effect of phosphodiesterase- 5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268-1277.
36. Edelmann F, Wachter R, Schmidt AG, et al; Aldo-DHF Investigators. Effect of Spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the ALDO-DHF randomized controlled trial. JAMA. 2013;309:781-791.
37. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XH, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998-1005.
38. Yip GW, Ho PP, Woo KS, Sanderson JE. Comparison of frequencies of left ventricular systolic and diastolic heart failure in Chinese living in Hong Kong. Am J Cardiol. 1999;84:563-567.
39. Tiller D, Russ M, Greiser KH, Nuding S, Ebelt H, Kluttig A, Kors JA, Thiery J, Bruegel M, Haerting J, Werdan K. Prevalence of symptomatic heart failure with reduced and with normal ejection fraction in an elderly general population-the CARLA study. PLoS One. 2013;8:e59225.
40. Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115:1982-1990.
41. Lee DS, Gona P, Vasan RS, Larson MG, Benjamin EJ, Wang TJ, Tu JV, Levy D. 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;119:3070-3077.
42. Lewis EF, Lamas GA, O'Meara E, et al; CHARM Investigators. Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J Heart Fail. 2007;9:83-91.
43. Hoekstra T, Lesman-Leegte I, van Veldhuisen DJ, Sanderman R, Jaarsma T. Quality of life is impaired similarly in heart failure patients with preserved and reduced ejection fraction. Eur J Heart Fail. 2011;13:1013-1018.
44. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.
45. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF Jr, Gheorghiade M. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114:397-403.
46. Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die?. Eur J Heart Fail. 2013;15:604-613.
47. Mangla A, Kane J, Beaty E, Richardson D, Powell LH, Calvin JE Jr. Comparison of predictors of heart failure-related hospitalization or death in patients with versus without preserved left ventricular ejection fraction. Am J Cardiol. 2013;112:1907-1912.
48. Wachter R, Schmidt-Schweda S, Westermann D, Post H, Edelmann F, Kasner M, Lüers C, Steendijk P, Hasenfuss G, Tschöpe C, Pieske B. Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure. Eur Heart J. 2009;30:3027-3036.
49. Lester SJ, Tajik AJ, Nishimura RA, Oh JK, Khandheria BK, Seward JB. Unlocking the mysteries of diastolic function: deciphering the Rosetta Stone 10 years later. J Am Coll Cardiol. 2008;51:679-689.
50. Yamamoto K, Redfield MM, Nishimura RA. Analysis of left ventricular diastolic function. Heart. 1996;75:27-35.
51. Kranias EG, Bers DM. Calcium and cardiomyopathies. Subcell Biochem. 2007;45:523-537.
52. Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med. 2013;63:338-349.
53. Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003;121:97-110.
54. Norman HS, Oujiri J, Larue SJ, Chapman CB, Margulies KB, Sweitzer NK. Decreased cardiac functional reserve in heart failure with preserved systolic function. J Card Fail. 2011;17:301-308.
55. Hamdani N, Paulus WJ, van Heerebeek L, Borbély A, Boontje NM, Zuidwijk MJ, Bronzwaer JG, Simonides WS, Niessen HW, Stienen GJ, van der Velden J. Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction. Eur Heart J. 2009;30:1863-1872.
56. Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM. Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res. 2000;87:235-240.
57. Penicka M, Bartunek J, Trakalova H, Hrabakova H, Maruskova M, Karasek J, Kocka V. Heart failure with preserved ejection fraction in outpatients with unexplained dyspnea: a pressure-volume loop analysis. J Am Coll Cardiol. 2010;55:1701-1710.
58. Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115:1982-1990.
59. Borbély A, van der Velden J, Papp Z, Bronzwaer JG, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774-781.
60. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kühl U, Schultheiss HP, Tschöpe C. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol. 2011;57:977-985.
61. van Heerebeek L, Borbély A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113:1966-1973.
62. González A, López B, Querejeta R, Zubillaga E, Echeverría T, Díez J. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension. 2010;55:1418-1424.
63. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschöpe C. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail. 2011;4:44-52.
64. 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.
65. Badenhorst D, Maseko M, Tsotetsi OJ, Naidoo A, Brooksbank R, Norton GR, Woodiwiss AJ. Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovasc Res. 2003;57:632-641.
66. Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target [published online ahead of print September 5, 2013]. Heart Fai Rev. http://link.springer.com/article/10.1007%2Fs10741-013-9405-8. DOI: 10.1007/s10741-013-9405-8.
67. 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;62:263-271.
68. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2:113-122.
69. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 2012;98:1546-1554.
70. van Heerebeek L, Hamdani N, Falcão-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126:830-839.
71. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114:1052-1068.
72. Lahmers S, Wu Y, Call DR, Labeit S, Granzier H. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res. 2004;94:505-513.
73. Borbély A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, Leite-Moreira AF, Bronzwaer JG, Papp Z, van der Velden J, Stienen GJ, Paulus WJ. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780-786.
74. Krüger M, Kötter S, Grützner A, Lang P, Andresen C, Redfield MM, Butt E, dos Remedios CG, Linke WA. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2009;104:87-94.
75. Hamdani N, Krysiak J, Kreusser MM, Neef S, Dos Remedios CG, Maier LS, Krüger M, Backs J, Linke WA. Crucial role for Ca2(+)/calmodulindependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ Res. 2013;112:664-674.
76. Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H. Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res. 2002;90:1181-1188.
77. Grützner A, Garcia-Manyes S, Kötter S, Badilla CL, Fernandez JM, Linke WA. Modulation of titin-based stiffness by disulfide bonding in the cardiac titin N2-B unique sequence. Biophys J. 2009;97:825-834.
78. Alegre-Cebollada J, Kosuri P, Giganti D, Eckels E, Rivas-Pardo JA, Hamdani N, Warren CM, Solaro RJ, Linke WA, Fernández JM. S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding. Cell. 2014;156:1235-1246.
79. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O, Brozovich FV, Burnett JC Jr, Linke WA, Redfield MM. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation. 2011;124:2882-2891.
80. Hamdani N, Franssen C, Lourenço A, et al. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ Heart Fail. 2013;6:1239-1249.
81. Tsai EJ, Liu Y, Koitabashi N, Bedja D, Danner T, Jasmin JF, Lisanti MP, Friebe A, Takimoto E, Kass DA. Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. Circ Res. 2012;110:295-303.
82. Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, Lazzarino G, Paolocci N, Gabrielson KL, Wang Y, Kass DA. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest. 2005;115:1221-1231.
83. Bruch C, Gradaus R, Gunia S, Breithardt G, Wichter T. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr. 2003;16:1031-1036.
84. Vinereanu D, Nicolaides E, Tweddel AC, Fraser AG. "Pure" diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure. Eur J Heart Fail. 2005;7:820-828.
85. Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJ, Solomon SD; PARAMOUNT Investigators. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63:447-456.
86. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation. 2005;111:2306-2312.
87. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin. 2011;29:447-459.
88. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, Kass DA. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86:513-521.
89. Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sullivan MJ. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol. 1991;17:1065-1072.
90. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, Kass DA. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114:2138-2147.
91. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil. 2006;26:86-89.
92. Phan TT, Shivu GN, Abozguia K, Davies C, Nassimizadeh M, Jimenez D, Weaver R, Ahmed I, Frenneaux M. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:29-34.
93. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 1999;341:1351-1357.
94. Puntawangkoon C, Kitzman DW, Kritchevsky SB, Hamilton CA, Nicklas B, Leng X, Brubaker PH, Hundley WG. Reduced peripheral arterial blood flow with preserved cardiac output during submaximal bicycle exercise in elderly heart failure. J Cardiovasc Magn Reson. 2009;11:48.
95. Liu CP, Ting CT, Lawrence W, Maughan WL, Chang MS, Kass DA. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants. Circulation. 1993;88:1893-1906.
96. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschöpe C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008;117:2051-2060.
97. Smith CS, Bottomley PA, Schulman SP, Gerstenblith G, Weiss RG. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation. 2006;114:1151-1158.
98. Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, Dwivedi G, Patel K, Steendijk P, Ashrafian H, Henning A, Frenneaux M. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54:402-409.
99. Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, Haykowsky M. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol. 2014;306:H1364-H1370.
100. Bhella PS, Prasad A, Heinicke K, Hastings JL, Arbab-Zadeh A, Adams- Huet B, Pacini EL, Shibata S, Palmer MD, Newcomer BR, Levine BD. Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13:1296-1304.
101. Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky S, Eggebeen J, Kitzman DW. 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. 2013;68:968-975.
102. Edelmann F, Stahrenberg R, Gelbrich G, Durstewitz K, Angermann CE, Düngen HD, Scheffold T, Zugck C, Maisch B, Regitz-Zagrosek V, Hasenfuss G, Pieske BM, Wachter R. Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction. Clin Res Cardiol. 2011;100:755-764.
103. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, Liu Y, Hoffmann U, Bauer DC, Newman AB, Kritchevsky SB, Harris TB, Butler J; Health ABC Study Investigators. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol. 2010;55:2129-2137.
104. Collier P, Watson CJ, Voon V, Phelan D, Jan A, Mak G, Martos R, Baugh JA, Ledwidge MT, McDonald KM. Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?. Eur J Heart Fail. 2011;13:1087-1095.
105. Shah KB, Kop WJ, Christenson RH, Diercks DB, Henderson S, Hanson K, Li SY, deFilippi CR. Prognostic utility of ST2 in patients with acute dyspnea and preserved left ventricular ejection fraction. Clin Chem. 2011;57:874-882.
106. Matsubara J, Sugiyama S, Nozaki T, Sugamura K, Konishi M, Ohba K, Matsuzawa Y, Akiyama E, Yamamoto E, Sakamoto K, Nagayoshi Y, Kaikita K, Sumida H, Kim-Mitsuyama S, Ogawa H. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. 2011;57:861-869.
107. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest. 2011;121:2301-2312.
108. Rainer PP, Hao S, Vanhoutte D, Lee DI, Koitabashi N, Molkentin JD, Kass DA. Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction. Circ Res. 2014;114:1246-1257.
109. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol. 2013;61:1498-1506.
110. Bishu K, Deswal A, Chen HH, LeWinter MM, Lewis GD, Semigran MJ, Borlaug BA, McNulty S, Hernandez AF, Braunwald E, Redfield MM. Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction. Am Heart J. 2012;164:763-770.e3.
111. Zile MR, Baicu CF. Biomarkers of diastolic dysfunction and myocardial fibrosis: application to heart failure with a preserved ejection fraction. J Cardiovasc Transl Res. 2013;6:501-515.
112. O'Meara E, de Denus S, Rouleau JL, Desai A. Circulating biomarkers in patients with heart failure and preserved ejection fraction. Curr Heart Fail Rep. 2013;10:350-358.
113. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009;53:1119-1126.
114. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD; TOPCAT Investigators. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail. 2014;7:104-115.
115. Robbins IM, Hemnes AR, Pugh ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman JH. High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ Heart Fail. 2014;7:116-122.
116. Borlaug BA. Invasive assessment of pulmonary hypertension: time for a more fluid approach?. Circ Heart Fail. 2014;7:2-4.
117. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125:289-297.
118. Shah SJ, Heitner JF, Sweitzer NK, et al. Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail. 2013;6:184-192.
119. Rusinaru D, Buiciuc O, Houpe D, Tribouilloy C. Renal function and long-term survival after hospital discharge in heart failure with preserved ejection fraction. Int J Cardiol. 2011;147:278-282.
120. Miura M, Shiba N, Nochioka K, Takada T, Takahashi J, Kohno H, Shimokawa H; CHART-2 Investigators. Urinary albumin excretion in heart failure with preserved ejection fraction: an interim analysis of the CHART 2 study. Eur J Heart Fail. 2012;14:367-376.
121. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51:1268-1274.
122. Dryer SE, Reiser J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol. 2010;299:F689-F701.
123. Eder P, Molkentin JD. TRPC channels as effectors of cardiac hypertrophy. Circ Res. 2011;108:265-272.
124. Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD. A TRPC6- dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell. 2012;23:705-715.
125. Verbrugge FH, Dupont M, Steels P, Grieten L, Malbrain M, Tang WH, Mullens W. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol. 2013;62:485-495.
126. Flather MD, Shibata MC, Coats AJ, et al; SENIORS Investigators. 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;26:215-225.
127. Yamamoto K, Origasa H, Hori M; J-DHF Investigators. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. 2013;15:110-118.
128. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Böhm M, Dei Cas L. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail. 2012;14:219-225.
129. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; PEP-CHF Investigators. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J. 2006;27:2338-2345.
130. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
131. Deswal A, Richardson P, Bozkurt B, Mann DL. Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J Card Fail. 2011;17:634-642.
132. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet. 2003;362:777-781.
133. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP
134. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005;111:1601-1610.
135. Pérez NG, Piaggio MR, Ennis IL, Garciarena CD, Morales C, Escudero EM, Cingolani OH, Chiappe de Cingolani G, Yang XP, Cingolani HE. Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction. Hypertension. 2007;49:1095-1103.
136. Salloum FN, Chau VQ, Hoke NN, Abbate A, Varma A, Ockaili RA, Toldo S, Kukreja RC. Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through proteinkinase g-dependent generation of hydrogen sulfide. Circulation. 2009;120:S31-S36.
137. Kass DA, Champion HC, Beavo JA. Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ Res. 2007;101:1084-1095.
138. Forfia PR, Lee M, Tunin RS, Mahmud M, Champion HC, Kass DA. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J Am Coll Cardiol. 2007;49:1079-1088.
139. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, Semigran MJ. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest. 2005;127:1647-1653.
140. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007;116:238-248.
141. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555-1562.
142. Guazzi M, Bandera F, Forfia P. Sildenafil and exercise capacity in heart failure. JAMA. 2013;310:432.
143. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition. J Mol Cell Cardiol. 2009;46:560-567.
144. Shah SJ. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. J Am Coll Cardiol. 2013;62:1339-1342.
145. Fukuta H, Little WC. Observational studies of statins in heart failure with preserved systolic function. Heart Fail Clin. 2008;4:209-216.
146. 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;112:357-363.
147. Reil JC, Reil GH, Böhm M. Heart rate reduction by I(f)-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction. Trends Cardiovasc Med. 2009;19:152-157.
148. Reil JC, Hohl M, Reil GH, Granzier HL, Kratz MT, Kazakov A, Fries P, Müller A, Lenski M, Custodis F, Gräber S, Fröhlig G, Steendijk P, Neuberger HR, Böhm M. Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J. 2013;34:2839-2849.
149. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH. Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol. 2013;62:1330-1338.
150. von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure [published online ahead of print May 14, 2014]. Pharmacol Ther. pii: S0163-7258(14)00097-7. doi: 10.1016/j.
151. Solomon SD, Zile M, Pieske B, Voors AA, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong JJ, Lefkowitz M, Packer M, McMurray JJV; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase II randomised-controlled trial. J Card Fail. 2012;18:883.
152. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50:401-414.
153. Edelmann F, Gelbrich G, Düngen HD, Fröhling S, Wachter R, Stahrenberg R, Binder L, Töpper A, Lashki DJ, Schwarz S, Herrmann-Lingen C, Löffler M, Hasenfuss G, Halle M, Pieske B. 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. 2011;58:1780-1791.
154. Powers SK, Smuder AJ, Kavazis AN, Quindry JC. Mechanisms of exercise-induced cardioprotection. Physiology (Bethesda). 2014;29: 27-38.
155. 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;3:659-667.
156. Kitzman DW, Brubaker PH, Herrington DM, Morgan TM, Stewart KP, Hundley WG, Abdelhamed A, Haykowsky MJ. Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. J Am Coll Cardiol. 2013;62: 584-592.
157. Böhm M, Ewen S, Linz D, Reil JC, Schirmer SH, Ukena C, Mahfoud F. Therapeutic potential of renal sympathetic denervation in patients with chronic heart failure. EuroIntervention. 2013;9(suppl R):R122-R126.
158. Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA; Symplicity HTN-2 Investigators. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126:2976-2982.
159. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401.
160. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the symplicity htn-2 trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.
161. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, Swedberg K, Schwartz PJ; CardioFit Multicenter Trial Investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011;32:847-855.
162. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. 2010;56:1254-1258.
163. Hauptman PJ, Schwartz PJ, Gold MR, Borggrefe M, Van Veldhuisen DJ, Starling RC, Mann DL. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J. 2012;163:954-962.e1.
164. Lopshire JC, Zipes DP. Spinal cord stimulation for heart failure: preclinical studies to determine optimal stimulation parameters for clinical efficacy. J Cardiovasc Transl Res. 2014;7:321-329.
165. Kobayashi M, Sakurai S, Takaseya T, Shiose A, Kim HI, Fujiki M, Karimov JH, Dessoffy R, Massiello A, Borowski AG, Van Wagoner DR, Jung E, Fukamachi K. Effects of percutaneous stimulation of both sympathetic and parasympathetic cardiac autonomic nerves on cardiac function in dogs. Innovations (Phila). 2012;7:282-289.
166. Pak PH, Maughan WL, Baughman KL, Kieval RS, Kass DA. Mechanism of acute mechanical benefit from VDD pacing in hypertrophied heart: similarity of responses in hypertrophic cardiomyopathy and hypertensive heart disease. Circulation. 1998;98:242-248.
167. Kass DA, Chen CH, Talbot MW, Rochitte CE, Lima JA, Berger RD, Calkins H. Ventricular pacing with premature excitation for treatment of hypertensive-cardiac hypertrophy with cavity-obliteration. Circulation. 1999;100:807-812.
168. Abraham WT. Disease management: remote monitoring in heart failure patients with implantable defibrillators, resynchronization devices, and haemodynamic monitors. Europace. 2013;15(suppl 1):i40-i46.
169. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner S, Shavelle D, Jeffries B, Yadav JS; CHAMPION Trial Study Group. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet. 2011;377:658-666.
170. Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda JM Jr, Magalski A, Zile MR, Smith AL, Smart FW, O'Shaughnessy MA, Jessup ML, Sparks B, Naftel DL, Stevenson LW; COMPASS-HF Study Group. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol. 2008;51:1073-1079.
171. Troughton RW, Ritzema J, Eigler NL, et al; HOMEOSTASIS Investigators. Direct left atrial pressure monitoring in severe heart failure: long-term sensor performance. J Cardiovasc Transl Res. 2011;4:3-13.