Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin

Circulation

Volumn 131, Issue 14, 2015, Pages 1247-1259

  Zile, Michael R ^a   Baicu, Catalin F ^a   Ikonomidis, John S ^a   Stroud, Robert E ^a   Nietert, Paul J ^a   Bradshaw, Amy D ^a   Slater, Rebecca ^b   Palmer, Bradley M ^c   Van Buren, Peter ^c   Meyer, Markus ^c   Redfield, Margaret M ^d   Bull, David A ^e   Granzier, Henk L ^b   LeWinter, Martin M ^c  

^a MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^b UNIVERSITY OF ARIZONA   (United States)

^c UNIVERSITY OF VERMONT   (United States)

^d MAYO CLINIC   (United States)

^e UNIVERSITY OF UTAH HEALTH SCIENCES CENTER   (United States)

Author keywords

Collagen; Diastole; Heart failure; Hypertension; Hypertrophy

Indexed keywords

AMINO TERMINAL PRO BRAIN NATRIURETIC PEPTIDE; ANGIOTENSIN RECEPTOR ANTAGONIST; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; C REACTIVE PROTEIN; CONNECTIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; FIBRILLAR COLLAGEN; PEPTIDES AND PROTEINS; PROTEIN ST2; TISSUE INHIBITOR OF METALLOPROTEINASE 1; UNCLASSIFIED DRUG; BIOLOGICAL MARKER; COLLAGEN; ISOPROTEIN; TTN PROTEIN, HUMAN;

ADULT; AGED; ARTICLE; CARDIOVASCULAR PARAMETERS; CONTROLLED STUDY; DIABETES MELLITUS; ECHOCARDIOGRAPHY; FEMALE; HEART FAILURE WITH PRESERVED EJECTION FRACTION; HEART LEFT VENTRICLE ENDDIASTOLIC PRESSURE; HEART MUSCLE BIOPSY; HUMAN; HUMAN TISSUE; HYPERTENSION; INFLAMMATION; MAJOR CLINICAL STUDY; MALE; MYOCARDIAL STIFFNESS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; BIOPSY; BLOOD; CARDIAC MUSCLE; COMPARATIVE STUDY; COMPLIANCE (PHYSICAL); COMPLICATION; DIASTOLE; ELASTICITY; HEART FAILURE; HEART STROKE VOLUME; HEART VENTRICLE; METABOLISM; MIDDLE AGED; PATHOLOGY; PHOSPHORYLATION; PHYSIOLOGY; PROTEIN PROCESSING;

AGED; BIOMARKERS; BIOPSY; COLLAGEN; COMPLIANCE; CONNECTIN; DIABETES COMPLICATIONS; DIASTOLE; ELASTICITY; FEMALE; HEART FAILURE; HEART VENTRICLES; HUMANS; HYPERTENSION; INFLAMMATION; MALE; MIDDLE AGED; MYOCARDIUM; PHOSPHORYLATION; PROTEIN ISOFORMS; PROTEIN PROCESSING, POST-TRANSLATIONAL; STROKE VOLUME;

EID: 84929376932     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.114.013215     Document Type: Article

References (76)

1. 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. doi: 10.1161/CIRCHEARTFAILURE.113.000887.
2. Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu CF, Massie BM, Carson PE; I-PRESERVE Investigators. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011;124:2491-2501. doi: 10.1161/CIRCULATIONAHA.110.011031.
3. Zile MR, Bennett TD, St John Sutton M, Cho YK, Adamson PB, Aaron MF, Aranda JM Jr, Abraham WT, Smart FW, Stevenson LW, Kueffer FJ, Bourge RC. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation. 2008;118:1433-1441. doi: 10.1161/CIRCULATIONAHA.108.783910.
4. 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. doi: 10.1056/NEJMoa032566.
5. 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.
6. 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. doi: 10.1016/j.jacc.2010.10.024.
7. Aoki T, Fukumoto Y, Sugimura K, Oikawa M, Satoh K, Nakano M, Nakayama M, Shimokawa H. Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. Comparison between preserved and reduced ejection fraction heart failure. Circ J. 2011;75:2605-2613.
8. Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO, Tarasoutchi F, Grinberg M, Rochitte CE. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol. 2010;56:278-287. doi: 10.1016/j.jacc.2009.12.074.
9. Chung CS, Hutchinson KR, Methawasin M, Saripalli C, Smith JE 3rd, Hidalgo CG, Luo X, Labeit S, Guo C, Granzier HL. Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction. Circulation. 2013;128:19-28. doi: 10.1161/CIRCULATIONAHA.112.001268.
10. Chung CS, Granzier HL. Contribution of titin and extracellular matrix to passive pressure and measurement of sarcomere length in the mouse left ventricle. J Mol Cell Cardiol. 2011;50:731-739. doi: 10.1016/j.yjmcc.2011.01.005.
11. Wu Y, Peng J, Campbell KB, Labeit S, Granzier H. Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance. J Mol Cell Cardiol. 2007;42:186-195. doi: 10.1016/j.yjmcc.2006.09.017.
12. Wu Y, Cazorla O, Labeit D, Labeit S, Granzier H. Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol. 2000;32:2151-2162. doi: 10.1006/jmcc.2000.1281.
13. 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. doi: 10.1016/j.jacc.2013.02.092.
14. Hamdani N, Franssen C, Lourenço A, Falcão-Pires I, Fontoura D, Leite S, Plettig L, López B, Ottenheijm CA, Becher PM, González A, Tschöpe C, Díez J, Linke WA, Leite-Moreira AF, Paulus WJ. 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. doi: 10.1161/CIRCHEARTFAILURE.113.000539.
15. Hamdani N, Paulus WJ. Myocardial titin and collagen in cardiac diastolic dysfunction: partners in crime. Circulation. 2013;128:5-8. doi: 10.1161/CIRCULATIONAHA.113.003437.
16. Falcão-Pires I, Hamdani N, Borbély A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJ, Niessen HW, Leite-Moreira AF, Paulus WJ. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation. 2011;124:1151-1159. doi: 10.1161/CIRCULATIONAHA.111.025270.
17. Borbély A, Papp Z, Edes I, Paulus WJ. Molecular determinants of heart failure with normal left ventricular ejection fraction. Pharmacol Rep. 2009;61:139-145.
18. van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbély A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43-51. doi: 10.1161/CIRCULATIONAHA.107.728550.
19. 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. doi: 10.1161/CIRCULATIONAHA.105.587519.
20. 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. doi: 10.1161/01.CIR.0000155257.33485.6D.
21. Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA. Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res. 2004;95:708-716. doi: 10.1161/01.RES.0000143901.37063.2f.
22. LeWinter MM, Granzier HL. Titin is a major human disease gene. Circulation. 2013;127:938-944. doi: 10.1161/CIRCULATIONAHA.112.139717.
23. Hudson BD, Hidalgo CG, Gotthardt M, Granzier HL. Excision of titin's cardiac PEVK spring element abolishes PKCalpha-induced increases in myocardial stiffness. J Mol Cell Cardiol. 2010;48:972-978. doi: 10.1016/j.yjmcc.2009.12.006.
24. Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res. 2004;94:284-295. doi: 10.1161/01.RES.0000117769.88862.F8.
25. 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.
26. 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. doi: 10.1161/CIRCULATIONAHA.111.076075.
27. Borbély A, van Heerebeek L, Paulus WJ. Transcriptional and post-translational modifications of titin: implications for diastole. Circ Res. 2009;104:12-14. doi: 10.1161/CIRCRESAHA.108.191130.
28. 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. doi: 10.1161/CIRCRESAHA.108.193326.
29. Hamdani N, de Waard M, Messer AE, Boontje NM, Kooij V, van Dijk S, Versteilen A, Lamberts R, Merkus D, Dos Remedios C, Duncker DJ, Borbely A, Papp Z, Paulus W, Stienen GJ, Marston SB, van der Velden J. Myofilament dysfunction in cardiac disease from mice to men. J Muscle Res Cell Motil. 2008;29:189-201. doi: 10.1007/s10974-008-9160-y.
30. van der Velden J, Narolska NA, Lamberts RR, Boontje NM, Borbély A, Zaremba R, Bronzwaer JG, Papp Z, Jaquet K, Paulus WJ, Stienen GJ. Functional effects of protein kinase C-mediated myofilament phosphorylation in human myocardium. Cardiovasc Res. 2006;69:876-887. doi: 10.1016/j.cardiores.2005.11.021.
31. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114:1052-1068. doi: 10.1161/CIRCRESAHA.114.301286.
32. 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. doi: 10.1161/CIRCRESAHA.108.184408.
33. Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ, van Gilst WH. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34:1424-1431. doi: 10.1093/eurheartj/eht066.
34. Shah SJ, Heitner JF, Sweitzer NK, Anand IS, Kim HY, Harty B, Boineau R, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Lewis EF, Markov V, O'Meara E, Kobulia B, Shaburishvili T, Solomon SD, Pitt B, Pfeffer MA, Li R. 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. doi: 10.1161/CIRCHEARTFAILURE.112.972794.
35. Komajda M, Carson PE, Hetzel S, McKelvie R, McMurray J, Ptaszynska A, Zile MR, Demets D, Massie BM. Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). Circ Heart Fail. 2011;4:27-35. doi: 10.1161/CIRCHEARTFAILURE.109.932996.
36. McMurray JJ, Carson PE, Komajda M, McKelvie R, Zile MR, Ptaszynska A, Staiger C, Donovan JM, Massie BM. Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail. 2008;10:149-156. doi: 10.1016/j.ejheart.2007.12.010.
37. 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. doi: 10.1161/CIRCULATIONAHA.108.815944.
38. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63(25 pt A):2817-2827. doi: 10.1016/j.jacc.2014.03.034.
39. Donaldson C, Taatjes DJ, Zile M, Palmer B, VanBuren P, Spinale F, Maughan D, Von Turkovich M, Bishop N, LeWinter MM. Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium. Histochem Cell Biol. 2010;134:23-30. doi: 10.1007/s00418-010-0706-x.
40. Donaldson C, Palmer BM, Zile M, Maughan DW, Ikonomidis JS, Granzier H, Meyer M, VanBuren P, LeWinter MM. Myosin crossbridge dynamics in patients with hypertension and concentric left ventricular remodeling. Circ Heart Fail. 2012;5:803-811. doi: 10.1161/CIRCHEARTFAILURE.112.968925.
41. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539-2550. doi: 10.1093/eurheartj/ehm037.
42. Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN. HFSA 2010 Comprehensive heart failure practice guideline. J Card Fail. 2010;16:e1-e194.
43. Hamdani N, Bishu KG, von Frieling-Salewsky M, Redfield MM, Linke WA. Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc Res. 2013;97:464-471. doi: 10.1093/cvr/cvs353.
44. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440-1463. doi: 10.1016/j.echo.2005.10.005.
45. Baicu CF, Li J, Zhang Y, Kasiganesan H, Cooper G 4th, Zile MR, Bradshaw AD. Time course of right ventricular pressure-overload induced myocardial fibrosis: relationship to changes in fibroblast postsynthetic procollagen processing. Am J Physiol Heart Circ Physiol. 2012;303:H1128-H1134. doi: 10.1152/ajpheart.00482.2012.
46. Walsh BJ, Thornton SC, Penny R, Breit SN. Microplate reader-based quantitation of collagens. Anal Biochem. 1992;203:187-190.
47. Marotta M, Martino G. Sensitive spectrophotometric method for the quantitative estimation of collagen. Anal Biochem. 1985;150:86-90.
48. Warren CM, Krzesinski PR, Greaser ML. Vertical agarose gel electrophoresis and electroblotting of high-molecular-weight proteins. Electrophoresis. 2003;24:1695-1702. doi: 10.1002/elps.200305392.
49. McCulloch C, Searle SR. Generalized, Linear, and Mixed Models. New York, NY: John Wiley & Sons, Inc; 2001.
50. Akaike H. A new look at the statistical model identification' IEEE Trans Automatic Control. 1974;19:716-723.
51. Zile MR, Baicu CF, Stroud RE, Van Laer A, Arroyo J, Mukherjee R, Jones JA, Spinale FG. Pressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis. Am J Physiol Heart Circ Physiol. 2012;302:H1429-H1437. doi: 10.1152/ajpheart.00580.2011.
52. 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. doi: 10.1161/CIRCULATIONAHA.111.048520.
53. Lewinter MM, Popper J, McNabb M, Nyland L, Bell SB, Granzier H. Extensible behavior of titin in the miniswine left ventricle. Circulation. 2010;121:768-774. doi: 10.1161/CIRCULATIONAHA.109.918151.
54. Hamdani N, Krysiak J, Kreusser MM, Neef S, Dos Remedios CG, Maier LS, Krüger M, Backs J, Linke WA. Crucial role for Ca2(+)/calmodulin-dependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ Res. 2013;112:664-674. doi: 10.1161/CIRCRESAHA.111.300105.
55. Spinale FG, Zile MR. Integrating the myocardial matrix into heart failure recognition and management. Circ Res. 2013;113:725-738. doi: 10.1161/CIRCRESAHA.113.300309.
56. 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. doi: 10.1007/s12265-013-9472-1.
57. Granzier H, Wu Y, Siegfried L, LeWinter M. Titin: physiological function and role in cardiomyopathy and failure. Heart Fail Rev. 2005;10:211-223. doi: 10.1007/s10741-005-5251-7.
58. Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation. 2004;110:155-162. doi: 10.1161/01.CIR.0000135591.37759.AF.
59. Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP, Hajjar RJ, Linke WA. Titin isoform switch in ischemic human heart disease. Circulation. 2002;106:1333-1341.
60. Kötter S, Gout L, Von Frieling-Salewsky M, Müller AE, Helling S, Marcus K, Dos Remedios C, Linke WA, Krüger M. Differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts. Cardiovasc Res. 2013;99:648-656. doi: 10.1093/cvr/cvt144.
61. Hidalgo CG, Chung CS, Saripalli C, Methawasin M, Hutchinson KR, Tsaprailis G, Labeit S, Mattiazzi A, Granzier HL. The multifunctional Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIä) phosphorylates cardiac titin's spring elements. J Mol Cell Cardiol. 2013;54:90-97. doi: 10.1016/j.yjmcc.2012.11.012.
62. Gladden JD, Linke WA, Redfield MM. Heart failure with preserved ejection fraction. Pflugers Arch. 2014;466:1037-1053. doi: 10.1007/s00424-014-1480-8.
63. House C, Wettenhall RE, Kemp BE. The influence of basic residues on the substrate specificity of protein kinase C. J Biol Chem. 1987;262:772-777.
64. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med. 2004;10:248-254. doi: 10.1038/nm1000.
65. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557-1562.
66. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D; Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068-3072.
67. Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, Burnett JC Jr, Jacobsen SJ, Rodeheffer RJ. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA. 2011;306:856-863. doi: 10.1001/jama.2011.1201.
68. 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 population-based study. N Engl J Med. 2006;355:260-269. doi: 10.1056/NEJMoa051530.
69. 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. doi: 10.1056/NEJMoa052256.
70. 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. doi: 10.1016/S0140-6736(03)14285-7.
71. 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. doi: 10.1161/CIRCULATIONAHA.106.628347.
72. 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. doi: 10.1093/eurheartj/ehl250.
73. 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. doi: 10.1056/NEJMoa0805450.
74. van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD; SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53:2150-2158. doi: 10.1016/j.jacc.2009.02.046.
75. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-1392. doi: 10.1056/NEJMoa1313731.
76. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; 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. doi: 10.1001/jama.2013.2024.