Targeting the renin-angiotensin-aldosterone system in heart failure

Nature Reviews Cardiology

Volumn 10, Issue 3, 2013, Pages 125-134

  Lang, Chim C ^a   Struthers, Allan D ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 (1 BIPHENYL 4 YLMETHYL 3 ETHOXYCARBONYL 1 BUTYLCARBAMOYL)PROPIONIC ACID; 3 (1 BIPHENYL 4 YLMETHYL 3 ETHOXYCARBONYL 1 BUTYLCARBAMOYL)PROPIONIC ACID PLUS VALSARTAN; ALISKIREN; ANGIOTENSIN RECEPTOR ANTAGONIST; CANDESARTAN; CANDOXATRIL; CANRENOIC ACID; CAPTOPRIL; CREATININE; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENALAPRIL; ENALKIREN; EPLERENONE; LISINOPRIL; LOSARTAN; MEMBRANE METALLOENDOPEPTIDASE; MINERALOCORTICOID ANTAGONIST; OMAPATRILAT; PLACEBO; RAMIPRIL; REMIKIREN; SPIRONOLACTONE; VALSARTAN; ZANKIREN; ANGIOTENSIN 1 RECEPTOR ANTAGONIST; CARDIOVASCULAR AGENT; RENIN;

ALBUMINURIA; ANGIONEUROTIC EDEMA; AORTA VALVE DISEASE; CARDIOVASCULAR RISK; CREATININE BLOOD LEVEL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDICATION; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; GYNECOMASTIA; HEART EJECTION FRACTION; HEART FAILURE; HEART LEFT VENTRICLE FAILURE; HEART PACING; HUMAN; HYPERKALEMIA; HYPERTENSION; HYPOTENSION; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); POTASSIUM BLOOD LEVEL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SIDE EFFECT; THERAPY DELAY; ANIMAL; DRUG ANTAGONISM; DRUG EFFECT; HEART LEFT VENTRICLE FUNCTION; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; TREATMENT OUTCOME;

ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANIMALS; CARDIOVASCULAR AGENTS; HEART FAILURE; HUMANS; MINERALOCORTICOID RECEPTOR ANTAGONISTS; MOLECULAR TARGETED THERAPY; NEPRILYSIN; RENIN; RENIN-ANGIOTENSIN SYSTEM; TREATMENT OUTCOME; VENTRICULAR FUNCTION, LEFT;

MLCS; MLOWN;

EID: 84880159174     PISSN: 17595002     EISSN: 17595010     Source Type: Journal    
DOI: 10.1038/nrcardio.2012.196     Document Type: Review

References (116)

1. McMurray, J. J. V. et al. 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. J. Heart Fail. 14, 803-869 (2012).
2. McMurray, J. J. V. Systolic heart failure. N. Engl. J. Med. 362, 228-238 (2010).
3. Bueno, H. et al. Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006. JAMA 303, 2141-2147 (2010).
4. Borlaug, B. A. & Paulus, W. J. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur. Heart J. 32, 670-679 (2011).
5. van Vark, L. C. et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158, 998 patients. Eur. Heart J. 33, 2088-2097 (2012).
6. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med. 325, 293-302 (1991)
7. The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N. Engl. J. Med. 316, 1429-1435 (1987).
8. Pfeffer, M. A. et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 327, 669-677 (1992)
9. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N. Engl. J. Med. 342, 145-153 (2000).
10. Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. for the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N. Engl. J. Med. 329, 1456-1462 (1993). (Pubitemid 23335891)
11. Koitabashi, N. & Kass, D. A. Reverse remodeling in heart failure-mechanisms and therapeutic opportunities. Nat. Rev. Cardiol. 9, 147-157 (2012).
12. Sun, Y. Myocardial repair/remodelling following infarction: roles of local factors. Cardiovasc. Res. 81, 482-490 (2009).
13. Cleutjens, J. P., Verluyten, M. J., Smiths, J. F. & Daemen, M. J. Collagen remodeling after myocardial infarction in the rat heart. Am. J. Pathol. 147, 325-338 (1995).
14. Weber, K. T. Extracellular matrix remodeling in heart failure. A role for de novo angiotensin II generation. Circulation 96, 4065-4082 (1997).
15. Konstam, M. A. et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation 86, 431-438 (1992).
16. Goussev, A. et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am. J. Physiol. Heart Circ. Physiol. 275, H626-H631 (1998). (Pubitemid 128734433)
17. Pahor, M. et al. Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats. Hypertension 18, 148-157 (1991).
18. Elder, D. H., McAlpine-Scott, J., Choy, A. M., Struthers, A. D. & Lang, C. C. Aortic valvular heart disease-is there a place for angiotensin-converting enzyme? Expert Rev. Cardiovasc. Ther. (in press).
19. Fielitz, J. et al. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J. Am. Coll. Cardiol. 37, 1443-1449 (2001).
20. Nadir, M. A. et al. Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. J. Am. Coll. Cardiol. 58, 570-576 (2011).
21. Elder, D. H. et al. The impact of renin-angiotensin-aldosterone system blockade on heart failure outcomes and mortality in patients identified to have aortic regurgitation: a large population cohort study. J. Am. Coll. Cardiol. 58, 2084-2091 (2011).
22. Elder, D. H., Lang, C. C. & Choy, A. M. Pacing-induced heart disease: understanding the pathophysiology and improving outcomes. Expert Rev. Cardiovasc. Ther. 9, 877-886 (2011).
23. Elder, D. H. et al. Renin-angiotensin system blockers are associated with reduced mortality and heart failure hospitalization in patients paced for complete atrioventricular block. Heart Rhythm 9, 505-510 (2012).
24. McMurray, J. J. V., Pfeffer, M. A., Swedberg, K. & Dzau, V. J. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation 110, 3281-3288 (2004). (Pubitemid 39525078)
25. Pitt, B. et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 355, 1582-1587 (2000). (Pubitemid 30240502)
26. Konstam, M. A. et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 374, 1840-1848 (2009).
27. Pfeffer, M. A. et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N. Engl. J. Med. 349, 1893-1906 (2003). (Pubitemid 37409706)
28. Dickstein, K. & Kjekshus, J. the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 360, 752-760 (2002). (Pubitemid 35247704)
29. Jessup, M. et al. 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 119, 1977-2016 (2009).
30. Granger, C. B. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362, 772-776 (2003). (Pubitemid 37093917)
31. McMurray, J. J. V. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 362, 767-771 (2003). (Pubitemid 37093916)
32. Cohn, J. N. & Tognoni, G. for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N. Engl. J. Med. 345, 1667-1675 (2001) (Pubitemid 33126822)
33. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547-1559 (2008).
34. Lakhdar, R., Al-Mallah, M. H. & Lanfear, D. E. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J. Card. Fail. 14, 181-188 (2008). (Pubitemid 351434594)
35. Swedberg, K. et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. J. Am. Coll. Cardiol. 59, 1598-1603 (2012).
36. Zannad, F. Angiotensin-converting enzyme inhibitor and spironolactone combination therapy: new objectives in congestive heart failure treatment. Am. J. Cardiol. 71, 34A-39A (1993). (Pubitemid 23046410)
37. Struthers, A. D. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J. Card. Fail. 2, 47-54 (1996). (Pubitemid 126666354)
38. MacFadyen, R. J., Lee, A. F., Morton, J. J., Pringle, S. D. & Struthers, A. D. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 82, 57-61 (1999). (Pubitemid 29309237)
39. Brilla, C. G. & Weber, K. T. Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc. Res. 26, 671-677 (1992).
40. Brilla, C. G., Zhou, G., Matsubara, L. & Weber, K. T. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J. Mol. Cell. Cardiol. 26, 809-820 (1994). (Pubitemid 24223231)
41. Barr, C. S. et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am. J. Cardiol. 76, 1259-1265 (1995).
42. MacFadyen, R. J., Barr, C. S. & Struthers, A. D. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc. Res. 35, 30-34 (1997). (Pubitemid 27374737)
43. The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am. J. Cardiol. 78, 902-907 (1996).
44. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709-717 (1999). (Pubitemid 29407370)
45. Walsh, P. C. & Siiteri, P. K. Suppression of plasma androgens by spironolactone in castrated men with carcinoma of the prostrate. J. Urol. 114, 254-256 (1975).
46. Pitt, B. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309-1321 (2003). (Pubitemid 36384098)
47. 1c in patients with chronic heart failure. Am. Heart J. 160, 915-921 (2010).
48. Zannad, F. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364, 11-21 (2011).
49. Juurlink, D. N. et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N. Engl. J. Med. 351, 543-551 (2004). (Pubitemid 39025171)
50. Wei, L., Struthers, A. D., Fahey, T., Watson, A. D. & Macdonald, T. M. Spironolactone use and renal toxicity: population based longitudinal analysis. BMJ 340, c1768 (2010).
51. Pitt, B., Bakris, G., Ruilope, L. M., DiCarlo, L. & Mukherjee, R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 118, 1643-1650 (2008).
52. Farquharson, C. A. & Struthers, A. D. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 101, 594-597 (2000). (Pubitemid 30094728)
53. Macdonald, J. E., Kennedy, N. & Struthers, A. D. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart 90, 765-770 (2004). (Pubitemid 38813637)
54. Beygui, F. et al. Rationale for an early aldosterone blockade in acute myocardial infarction and design of the ALBATROSS trial. Am. Heart J. 160, 642-648 (2010).
55. US National Library of Medicine. ClinicalTrials.gov [online] http://clinicaltrials.gov/ct2/show/NCT01176968 (2012).
56. Ouvrard-Pascaud, A. et al. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 111, 3025-3033 (2005). (Pubitemid 40847778)
57. Beygui, F. et al. High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation 114, 2604-2610 (2006). (Pubitemid 44967343)
58. Shah, N. C., Pringle, S. D., Donnan, P. T. & Struthers, A. D. Spironolactone has antiarrhythmic activity in ischaemic cardiac patients without cardiac failure. J. Hypertens. 25, 2345-2351 (2007). (Pubitemid 47537930)
59. Assomull, R. G. et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J. Am. Coll. Cardiol. 48, 1977-1985 (2006). (Pubitemid 44738448)
60. Zannad, F., Alla, F., Dousset, B., Perez, A. & Pitt, B. on behalf of the RALES Investigators. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES). Circulation 102, 2700-2706 (2000).
61. Yee, K. M., Pringle, S. D. & Struthers, A. D. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J. Am. Coll. Cardiol. 37, 1800-1807 (2001). (Pubitemid 32499962)
62. Ram, R. & Van Wagoner, D. R. Aldosterone antagonism as an antiarrhythmic approach for atrial arrhythmias in heart failure. J. Cardiovasc. Electrophysiol. 17, 542-543 (2006).
63. Suzuki, G. et al. Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation 106, 2967-2972 (2002). (Pubitemid 35424750)
64. Hayashi, M. et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107, 2559-2565 (2003). (Pubitemid 36628936)
65. Udelson, J. E. et al. Randomized, double-blind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction. Circ. Heart Fail. 3, 347-353 (2010).
66. Borlaug, B. A. & Paulus, W. J. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur. Heart J. 32, 670-679 (2011).
67. Cleland, J. G. et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur. Heart J. 27, 2338-2345 (2006). (Pubitemid 44453578)
68. Yusuf, S. et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 362, 777-781 (2003). (Pubitemid 37093918)
69. Massie, B. M. et al. Irbesartan in patients with heart failure and preserved ejection fraction. N. Engl. J. Med. 359, 2456-2467 (2008).
70. Lund, L. H., Benson, L., Dahlström, U. & Edner, M. Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 308, 2108-2117 (2012).
71. Fang, J. C. Heart failure therapy: what should clinicians believe? JAMA 308, 2144-2146 (2012).
72. ESC Congress News. Spironolactone improves filling pressure in diastolic HF: Aldo-DHF [online], http://www.escardio.org/congresses/esc-2012/congress- news/Pages/Aldo-DHF.aspx (2012).
73. US National Library of Medicine. ClinicalTrials.gov [online] http://clinicaltrials.gov/ct2/show/NCT00094302 (2012).
74. Swaminathan, K. et al. Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles. Diabetologia 51, 762-768 (2008).
75. Wei, L., MacDonald, T. M. & Walker, B. R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann. Intern. Med. 141, 764-770 (2004).
76. Nguyen, G. Renin, (pro)renin and receptor: an update. Clin. Sci. (Lond.) 120, 169-178 (2011).
77. Nguyen, G. The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology. Curr. Opin. Nephrol. Hypertens. 16, 129-133 (2007).
78. Moilanen, A. M. et al (Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function. PLoS ONE 7, e41404 (2012).
79. Schroten, N. F. et al. New roles for renin and prorenin in heart failure and cardiorenal crosstalk. Heart Fail. Rev. 17, 191-201 (2012).
80. Feldman, D. L. et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 52, 130-136 (2008).
81. Fisher, N. D. & Hollenberg, N. K. Is there a future for renin inhibitors? Expert Opin. Investig. Drugs 10, 417-426 (2001). (Pubitemid 32186140)
82. Vaidyanathan, S., Jarugula, V., Dieterich, H. A., Howard, D. & Dole, W. P. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin. Pharmacokinet. 47, 515-531 (2008). (Pubitemid 351969826)
83. Seed, A. et al. Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur. J. Heart Fail. 9, 1120-1127 (2007). (Pubitemid 47633316)
84. van Esch, J. H. et al. Beneficial cardiac effects of the renin inhibitor aliskiren in spontaneously hypertensive rats. J. Hypertens. 28, 2145-2155 (2010).
85. McMurray, J. J. V. et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ. Heart Fail. 1, 17-24 (2008).
86. Solomon, S. D. et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur. Heart J. 32, 1227-1234 (2011).
87. Pitt, B. et al. Neurohumoral effects of aliskiren in patients with symptomatic heart failure receiving a mineralocorticoid receptor antagonist: the Aliskiren Observation of Heart Failure Treatment study. Eur. J. Heart Fail. 13, 755-764 (2011).
88. Novartis. Media releases: Novartis announces termination of ALTITUDE study with Rasilez®/Tekturna® in high-risk patients with diabetes and renal impairment [online] http://www.novartis.com/newsroom/media-releases/en/ 2011/1572562.shtml (2011).
89. Parving, H. H. et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol. Dial. Transplant. 24, 1663-1671 (2009).
90. Parving, H. H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204-2213 (2012).
91. Krum, H. et al. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study. Eur. J. Heart Fail. 13, 107-114 (2011).
92. Gheorghiade, M. et al. Rationale and design of the multicentre, randomized, double-blind, placebo-controlled Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT). Eur. J. Heart Fail. 13, 100-106 (2011).
93. McMurray, J. J. V. et al. Aliskiren, ALTITUDE, and the implications for ATMOSPHERE. Eur. J. Heart Fail. 14, 341-343 (2012).
94. de Boer, R. A. et al. Dual RAAS suppression: recent developments and implications in light of the ALTITUDE study. J. Renin Angiotensin Aldosterone Syst. 13, 409-412 (2012).
95. US National Library of Medicine. ClinicalTrials.gov [online] http://clinicaltrials.gov/ct2/show/NCT00894387 (2012).
96. Fisher, N. D., Jan Danser, A. H., Nussberger, J., Dole, W. P. & Hollenberg, N. K. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 117, 3199-3205 (2008).
97. US National Library of Medicine. ClinicalTrials.gov [online] http://clinicaltrials.gov/ct2/show/NCT00881439 (2009).
98. Forman, J. P., Williams, J. S. & Fisher, N. D. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 55, 1283-1288 (2010).
99. Freundlich, M. et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int. 74, 1394-1402 (2008).
100. US National Library of Medicine. ClinicalTrials.gov [online] http://clinicaltrials.gov/ct2/show/NCT01092130 (2010).
101. Mangiafico, S., Costello-Boerrigter, L., Andersen, I. A., Cataliotti, A. & Burnett, J. C. Jr. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehs262.
102. Bevan, E. G. et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J. Hypertens. 10, 607-614 (1992).
103. Lang, C. C., Motwani, J., Coutie, W. J. & Struthers, A. D. Influence of candoxatril on plasma brain natriuretic peptide in heart failure. Lancet 338, 255 (1991).
104. McDowell, G. et al. The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides. Br. J. Clin. Pharmacol. 43, 329-332 (1997). (Pubitemid 27116076)
105. Kentsch, M. et al. Neutral endopeptidase 24.11 inhibition may not exhibit beneficial haemodynamic effects in patients with congestive heart failure. Eur. J. Clin. Pharmacol. 51, 269-272 (1996). (Pubitemid 26422972)
106. Corti, R., Burnett, J. C. Jr, Rouleau, J. L., Ruschitzka, F. & Luscher, T. F. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation 104, 1856-1862 (2001). (Pubitemid 32963354)
107. Rouleau, J. L. et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 356, 615-620 (2000). (Pubitemid 30627587)
108. Packer, M. et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 106, 920-926 (2002). (Pubitemid 34925324)
109. Kostis, J. B. et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am. J. Hypertens. 17, 103-111 (2004). (Pubitemid 38125125)
110. Fryer, R. M. et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br. J. Pharmacol. 153, 947-955 (2008). (Pubitemid 351328937)
111. Gu, J. et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J. Clin. Pharmacol. 50, 401-414 (2010).
112. Ruilope, L. M. et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet 375, 1255-1266 (2010).
113. Kobalava, Z. et al. First experience with concomitant AT1 and neprilysin (NEP 24.11) inhibition with LCZ696 in patients with chronic heart failure [abstract]. Circulation 122, A19378 (2010).
114. Solomon, S. D. et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 380, 1387-1395 (2012).
115. Iwanaga, Y. et al. 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. 47, 742-748 (2006). (Pubitemid 43243094)
116. US National Library of Medicine. ClinicalTrial.gov [online] http://clinicaltrials.gov/ct2/show/NCT01035255 (2012).