PhosphdiesteRasE-5 inhibition to improve CLinical status and EXercise capacity in diastolic heart failure (RELAX) trial: Rationale and design

Circulation: Heart Failure

Volumn 5, Issue 5, 2012, Pages 653-659

  Redfield, Margaret M ^e   Borlaug, Barry A ^e   Lewis, Greg D ^d   Mohammed, Selma F ^e   Semigran, Marc J ^d   Lewinter, Martin M ^f   Deswal, Anita ^a   Hernandez, Adrian F ^b   Lee, Kerry L ^b   Braunwald, Eugene ^c  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b DUKE CLINICAL RESEARCH INSTITUTE   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d MASSACHUSETTS GENERAL HOSPITAL   (United States)

^e MAYO CLINIC   (United States)

^f UNIVERSITY OF VERMONT   (United States)

Author keywords

Diastolic heart failure; Heart failure; Phosphodiesterase inhibitor

Indexed keywords

BRAIN NATRIURETIC PEPTIDE; CYCLIC GMP; DIGOXIN; NATRIURETIC PEPTIDE RECEPTOR A; NEBIVOLOL; PHOSPHODIESTERASE V;

ARTERIAL STIFFNESS; ARTICLE; CARDIAC PATIENT; CARDIOVASCULAR FUNCTION; DIASTOLIC HEART FAILURE; DISEASE SEVERITY; ENZYME INHIBITION; EXERCISE; FUNCTIONAL STATUS; HEART ATRIUM FIBRILLATION; HEART LEFT VENTRICLE MASS; HEART RIGHT VENTRICLE DYSPLASIA; HUMAN; KIDNEY DYSFUNCTION; KIDNEY FUNCTION; LEFT VENTRICULAR SYSTOLIC DYSFUNCTION; LUNG EDEMA; MORTALITY; OXYGEN CONSUMPTION; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; SODIUM EXCRETION; TREATMENT RESPONSE;

CARDIOVASCULAR AGENTS; DOUBLE-BLIND METHOD; ECHOCARDIOGRAPHY, DOPPLER; EXERCISE TEST; EXERCISE TOLERANCE; HEART FAILURE, DIASTOLIC; HUMANS; MAGNETIC RESONANCE IMAGING; OXYGEN CONSUMPTION; PHOSPHODIESTERASE 5 INHIBITORS; PIPERAZINES; PURINES; QUESTIONNAIRES; RECOVERY OF FUNCTION; RESEARCH DESIGN; SULFONES; TIME FACTORS; TREATMENT OUTCOME; VENTRICULAR FUNCTION, LEFT;

EID: 84868651278     PISSN: 19413289     EISSN: 19413297     Source Type: Journal    
DOI: 10.1161/CIRCHEARTFAILURE.112.969071     Document Type: Article

References (71)

1. 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. (Pubitemid 44079340)
2. Shah RV, Desai AS, Givertz MM. The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and me-ta-analysis. J Card Fail. 2010;16:260-267.
3. 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.
4. 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. (Pubitemid 44264821)
5. 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.
6. 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. (Pubitemid 44747894)
7. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, Red-fibro MM. Global cardiovascular reserve dysfiunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56:845-854.
8. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol. 2011;58:265-274.
9. 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.
10. 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 stiffiness by phosphorylation of the titin springs. Circ Res. 2009;104:87-94.
11. Selby DE, Palmer BM, LeWinter MM, Meyer M. Tachycardia-induced diastolic dysfiunction and resting tone in myocardium from patients with a normal ejection fraction. J Am Coll Cardiol. 2011;58:147-154.
12. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart. 2011;97:964-969.
13. Wachter R, Schmidt-Schweda S, Westermann D, Post H, Edelmann F, Kas-ner 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.
14. 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.
15. Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM. 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;54:410-418.
16. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JE. 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. 2009;54:36-46.
17. 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.
18. Charoenpanichkit C, Little WC, Mandapaka S, Dall'Armellina E, Morgan TM, Hamilton CA, Hundley WG. Impaired left ventricular stroke volume reserve during clinical dobutamine stress predicts future episodes of pulmonary edema. J Am Coll Cardiol. 2011;57:839-848.
19. Hundley WG, Kitzman DW, Morgan TM, Hamilton CA, Darty SN, Stewart KP, Herrington DM, Link KM, Little WC. Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol. 2001;38:796-802. (Pubitemid 32835755)
20. 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. (Pubitemid 36222599)
21. Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. 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;59:442-451.
22. 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.
23. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol. 2007;50:2136-2144. (Pubitemid 350117342)
24. 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.
25. Di Salvo TG, Mathier M, Semigran MJ, Dec. GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol. 1995;25:1143-1153.
26. Lewis GD, Shah RV, Pappagianopolas PP, Systrom DM, Semigran MJ. Determinants of ventilatory efficiency in heart failure: the role of right ventricular performance and pulmonary vascular tone. Circ Heart Fail. 2008;1:227-233.
27. Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise he-modynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115:59-66. (Pubitemid 46058612)
28. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Silde-nafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555-1562. (Pubitemid 47511419)
29. Lee AP, Song JK, Yip GW, Zhang Q, Zhu TG, Li C, Chan A, Yu CM. Importance of dynamic dyssynchrony in the occurrence of hypertensive heart failure with normal ejection fraction. Eur Heart J. 2010;31:2642-2649.
30. Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47:742-748. (Pubitemid 43243094)
31. Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiol-ogy and therapeutics. Pharmacol Ther. 2009;122:216-238.
32. Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, Moens AL, Champion HC, Kass DA. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 2007;115:2159-2167. (Pubitemid 46659068)
33. Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P, Kass DA. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation. 2005;112:2642-2649. (Pubitemid 41532601)
34. 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 phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214-222. (Pubitemid 40321358)
35. 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, Michela-kis 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. (Pubitemid 47196559)
36. Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB. Differential expression of PDE5 in failing and nonfailing human myocardium. Circ Heart Fail. 2012;5:79-86.
37. Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van Lommel A, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP. Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myo-cardial infarction in mice. Circulation. 2009;119:408-416.
38. Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C, Pritzker M, Hall JL, Garry DJ, Chen Y. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation. 2010;121:1474-1483.
39. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864-1871.
40. Forfa PR, Lee M, Tunin RS, Mahmud M, Champion HC, Kass DA. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type na-triuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J Am Coll Cardiol. 2007;49:1079-1088. (Pubitemid 46349496)
41. Chen HH, Huntley BK, Schirger JA, Cataliotti A, Burnett JC Jr. Maximizing the renal cyclic 3'-5'-guanosine monophosphate system with type V phosphodiesterase inhibition and exogenous natriuretic peptide: a novel strategy to improve renal function in experimental overt heart failure. J Am Soc Nephrol. 2006;17:2742-2747. (Pubitemid 44484664)
42. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol. 2009;53:207-215.
43. Al-Hesayen A, Floras JS, Parker JD. The effects of intravenous sildenafil on hemodynamics and cardiac sympathetic activity in chronic human heart failure. Eur J Heart Fail. 2006;8:864-868. (Pubitemid 44794484)
44. Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res. 2003;92:595-597. (Pubitemid 36417692)
45. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with silde-nafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4:8-17.
46. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiester-ase-5 inhibition in a 1-year study. Circulation. 2011;124:164-174.
47. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O, Bro-zovich FV, Burnett JC Jr, Linke WA, Redfield MM. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic dis-tensibility in vivo. Circulation. 2011;124:2882-2891.
48. Yin J, Kukucka M, Hoffmann J, Sterner-Kock A, Burhenne J, Haefeli WE, Kuppe H, Kuebler WM. Sildenafil preserves lung endothelial function and prevents pulmonary vascular remodeling in a rat model of diastolic heart failure. Circ Heart Fail. 2011;4:198-206.
49. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary he-modynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339-2348. (Pubitemid 39647608)
50. Lepore JJ, Maroo A, Bigatello LM, Dec. GW, Zapol WM, Bloch KD, Se-migran 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. (Pubitemid 46218790)
51. Melenovsky V, Al-Hiti H, Kazdova L, Jabor A, Syrovatka P, Malek I, Kettner J, Kautzner J. Transpulmonary B-type natriuretic peptide uptake and cyclic guanosine monophosphate release in heart failure and pulmonary hypertension: the effects of sildenafil. J Am Coll Cardiol. 2009;54:595-600.
52. Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension. 2006;48:622-627. (Pubitemid 44843865)
53. Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens. 2001;15:707-713. (Pubitemid 32975870)
54. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediat-ed vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36:845-851.
55. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003;108:560-565. (Pubitemid 36961170)
56. Arena R, Myers J, Guazzi M. Cardiopulmonary exercise testing is a core assessment for patients with heart failure. Congest Heart Fail. 2011;17:115-119.
57. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Mar-burger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144-2150. (Pubitemid 35265382)
58. Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis. 1984;129(2 Pt 2):S49-S55. (Pubitemid 14190983)
59. Guazzi M, Dickstein K, Vicenzi M, Arena R. Six-minute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circ Heart Fail. 2009;2:549-555.
60. 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.
61. Lewis GD, Murphy RM, Shah RV, Pappagianopoulos PP, Malhotra R, Bloch KD, Systrom DM, Semigran MJ. Pulmonary vascular response patterns during exercise in left ventricular systolic dysfiunction predict exercise capacity and outcomes. Circ Heart Fail. 2011;4:276-285.
62. Guazzi M, Myers J, Peberdy MA, Bensimhon D, Chase P, Arena R. Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights. Eur Heart J. 2008;29:2751-2759.
63. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P, Guazzi M. Development of a ventilatory classification system in patients with heart failure. Circulation. 2007;115:2410-2417. (Pubitemid 46717963)
64. Murphy RM, Shah RV, Malhotra R, Pappagianopoulos PP, Hough SS, Systrom DM, Semigran MJ, Lewis GD. Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation. 2011;124:1442-1451.
65. Wessler BS, Kramer DG, Kelly JL, Trikalinos TA, Kent DM, Konstam MA, Udelson JE. Drug and device effects on peak oxygen consumption, 6-minute walk distance, and natriuretic peptides as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. Circ Heart Fail. 2011;4:578-588.
66. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K; Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003;289:2685-2694. (Pubitemid 37430139)
67. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhyth-mias. J Am Coll Cardiol. 2003;42:1454-1459. (Pubitemid 37267289)
68. Ziesche S, Cobb FR, Cohn JN, Johnson G, Tristani F. Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation. 1993;87(6 Suppl):VI56-VI64. (Pubitemid 23164223)
69. Levine TB, Bernink PJ, Caspi A, Elkayam U, Geltman EM, Greenberg B, McKenna WJ, Ghali JK, Giles TD, Marmor A, Reisin LH, Ammon S, Lindberg E. Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Circulation. 2000;101:758-764. (Pubitemid 30100082)
70. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;92:1499-1506.
71. Gullestad L, Manhenke C, Aarsland T, Skårdal R, Fagertun H, Wikstrand J, Kjekshus J. Effect of metoprolol CR/XL on exercise tolerance in chronic heart failure - a substudy to the MERIT-HF trial. Eur J Heart Fail. 2001;3:463-468. (Pubitemid 32776873)