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The pathophysiology of AHF
—New insights from recent studies of novel diuretics and vascular modulating therapies

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DOI: 10.4236/wjcd.2013.31A020    3,701 Downloads   6,630 Views   Citations

ABSTRACT

Treatment of chronic congestive heart failure (HF) has improved substantially during the past decades, with the introduction of modulators of the renin angiotensin aldosterone system (RAAS) such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and aldosterone antagonists and the introduction of the lifesaving beta-blockers as well as device therapy. Despite the dramatic improvement in the treatment of chronic HF, no such progress was achieved in the treatment of acute heart failure (AHF). Diuretics that were never rigorously examined in well controlled large prospective randomized studies remain the cornerstone and almost exclusively the only intravenous therapeutic option for AHF and no further effective therapy as introduced in more than 30 years. As a result, the short term morbidity and most importantly mortality of AHF remains extremely high with up to 20% of patients dying in the first months after admission for AHF and an additional 20% being readmitted to the hospital. In the current manuscript we will address the practical concerns regarding established and novel diuretic and vascular modulating therapies in patients with AHF, examine their recommended use and seek to determine a path to developing better and more effective therapies for AHF.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Cotter, G. , Milo, O. and Davison, B. (2013) The pathophysiology of AHF
—New insights from recent studies of novel diuretics and vascular modulating therapies
. World Journal of Cardiovascular Diseases, 3, 133-145. doi: 10.4236/wjcd.2013.31A020.

References

[1] Lloyd-Jones, D., Adams, R., Carnethon, M., et al. (2009) Heart disease and stroke statistics: 2009 update—A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 119, 480-486. doi:10.1161/CIRCULATIONAHA.108.191259
[2] Nieminen, M.S. and Harjola, V.P. (2005) Definition and epidemiology of acute heart failure syndromes. American Journal of Cardiology, 96, 5G-10G. doi:10.1016/j.amjcard.2005.07.015
[3] Jencks, S.F., Williams, M.V. and Coleman, E.A. (2009) Rehospitalizations among patients in the medicare fee-for-service program. The New England Journal of Medicine, 360, 1418-1428. doi:10.1056/NEJMsa0803563
[4] Gheorghiade, M., Abraham, W.T., Albert, N.M., et al. (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA, 296, 2217-2226. doi:10.1001/jama.296.18.2217
[5] Fonarow, G.C., Stough, W.G., Abraham, W.T., et al. (2007) Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: A report from the OPTIMIZE-HF Registry. Journal of the American College of Cardiology, 50, 768-777. doi:10.1016/j.jacc.2007.04.064
[6] Fonarow, G.C., Adams, K.F., Jr., Abraham, W.T., Yancy, C.W. and Boscardin, W.J. (2005) Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis. JAMA, 293, 572-580. doi:10.1001/jama.293.5.572
[7] Elkayam, U., Tasissa, G., Binanay, C., et al. (2007) Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. American Heart Journal, 153, 98-104. doi:10.1016/j.ahj.2006.09.005
[8] Thackray, S., Easthaugh, J., Freemantle, N. and Cleland, J.G. (2002) The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—A meta-regression analysis. European Journal of Heart Failure, 4, 515-529. doi:10.1016/S1388-9842(02)00041-7
[9] Lee, D.S., Austin, P.C., Rouleau, J.L., Liu, P.P., Naimark, D. and Tu, J.V. (2003) Predicting mortality among pa- tients hospitalized for heart failure: Derivation and validation of a clinical model. JAMA, 290, 2581-2587. doi:10.1001/jama.290.19.2581
[10] Filippatos, G., Rossi, J., Lloyd-Jones, D.M., et al. (2007) Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: Insights from the acute and chronic therapeutic impact of a vasopressin antagonist in chronic heart failure (ACTIV in CHF) study. Journal of Cardiac Failure, 13, 360-364. doi:10.1016/j.cardfail.2007.02.005
[11] Akhter, M.W., Aronson, D., Bitar, F., et al. (2004) Effect of elevated admission serum creatinine and its worsening on outcome in hospitalized patients with decompensated heart failure. American Journal of Cardiology, 94, 957- 960. doi:10.1016/j.amjcard.2004.06.041
[12] Dries, D.L., Exner, D.V., Domanski, M.J., Greenberg, B. and Stevenson, L.W. (2000) The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. Journal of the American College of Cardiology, 35, 681-689. doi:10.1016/S0735-1097(99)00608-7
[13] Gottlieb, S.S., Abraham, W., Butler, J., et al. (2002) The prognostic importance of different definitions of worsening renal function in congestive heart failure. Journal of Cardiac Failure, 8, 136-141. doi:10.1054/jcaf.2002.125289
[14] Aronson, D., Mittleman, M.A. and Burger, A.J. (2004) Elevated blood urea nitrogen level as a predictor of mortality in patients admitted for decompensated heart failure. American Journal of Medicine, 116, 466-473. doi:10.1016/j.amjmed.2003.11.014
[15] Felker, G.M., Leimberger, J.D., Califf, R.M., et al. (2004) Risk stratification after hospitalization for decompensated heart failure. Journal of Cardiac Failure, 10, 460-466. doi:10.1016/j.cardfail.2004.02.011
[16] Hillege, H.L., Girbes, A.R., de Kam, P.J., et al. (2000) Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation, 102, 203- 210. doi:10.1161/01.CIR.102.2.203
[17] Hillege, H.L., Nitsch, D., Pfeffer, M.A., et al. (2006) Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation, 113, 671-678. doi:10.1161/CIRCULATIONAHA.105.580506
[18] Smith, G.L., Lichtman, J.H., Bracken, M.B., et al. (2006) Renal impairment and outcomes in heart failure: Systematic review and meta-analysis. Journal of the American College of Cardiology, 47, 1987-1996. doi:10.1016/j.jacc.2005.11.084
[19] Krumholz, H.M., Chen, Y.T., Vaccarino, V., et al. (2000) Correlates and impact on outcomes of worsening renal function in patients ≥65 years of age with heart failure. American Journal of Cardiology, 85, 1110-1113. doi:10.1016/S0002-9149(00)00705-0
[20] Forman, D.E., Butler, J., Wang, Y., et al. (2004) Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. Journal of the American College of Cardiology, 43, 61-67. doi:10.1016/j.jacc.2003.07.031
[21] Cowie, M.R., Komajda, M., Murray-Thomas, T., Under-wood, J., Ticho, B. and POSH Investigators (2006) Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: Results of the prospective outcomes study in heart failure (POSH). European Heart Journal, 27, 1216-1222. doi:10.1093/eurheartj/ehi859
[22] Tavazzi, L., Maggioni, A.P., Lucci, D., et al. (2006) Nationwide survey on acute heart failure in cardiology ward services in italy. European Heart Journal, 27, 1207-1215. doi:10.1093/eurheartj/ehi845
[23] Scios Inc. (2003) ADHERE registry [database]. First quarter 2003 bench-mark report. Scios Inc., Sunnyvale.
[24] Nieminen, M.S., Brutsaert, D., Dickstein, K., Drexler, H., Follath, F., Harjola, V.P., et al. (2006) EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population. European Heart Journal, 27, 2725-2736. doi:10.1093/eurheartj/ehl193
[25] Lindenfeld, J., Albert, N.M., Boehmer, J.P., Collins, S.P., Ezekowitz, J.A., Givertz, M.M., Katz, S.D., Klapholz, M., Moser, D.K., Rogers, J.G., Starling, R.C., Stevenson, W.G., Tang, W.H., Teerlink, J.R. and Walsh, M.N. (2010) HFSA 2010 comprehensive heart failure practice guideline. Heart Failure Society of America, Journal of Cardiac Failure, 16, e1e2. doi:10.1016/j.cardfail.2010.04.004
[26] McMurray, J.J., Adamopoulos, S., Anker, S.D., Auricchio, A., Bohm, M., Dickstein, K., Falk, V., Filippatos, G., Fonseca, C., Gomez-Sanchez, M.A., Jaarsma, T., Kober, L., Lip, G.Y., Maggioni, A.P., Parkhomenko, A., Pieske, B.M., Popescu, B.A., Ronnevik, P.K., Rutten, F.H., Schwitter, J., Seferovic, P., Stepinska, J., Trindade, P.T., Voors, A.A., Zannad, F., Zeiher, A. Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology: Bax, J.J., Baumgartner, H., Ceconi, C., Dean, V., Deaton, C., Fagard, R., Funck-Brentano, C., Hasdai, D., Hoes, A., Kirchhof, P., Knuuti, J., Kolh, P., McDonagh, T., Moulin, C., Popescu, B.A., Reiner, Z., Sechtem, U., Sirnes, P.A., Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh, T., Sechtem, U., Bonet, L.A., Avraamides, P., Ben Lamin, H.A., Brignole, M., Coca, A., Cowburn, P., Dargie, H., Elliott, P., Flachskampf, F.A., Guida, G.F., Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen, O.W., Orn, S., Parissis, J.T., Ponikowski, P. and ESC Committee for Practice Guidelines (2012) 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. European Journal of Heart Failure, 14, 803-869. doi:10.1093/eurjhf/hfs105
[27] Cleland, J.G., Coletta, A. and Witte, K. (2006) Practical applications of intravenous diuretic therapy in decompensated heart failure. American Journal of Medicine, 119, S26-S36. doi:10.1016/j.amjmed.2006.09.014
[28] Hill, J.A., Yancy, C.W. and Abraham, W.T. (2006) Beyond diuretics: Management of volume overload in acute heart failure syndromes. American Journal of Medicine, 119, S37-S44. doi:10.1016/j.amjmed.2006.09.015
[29] Hasselblad, V., Gattis Stough, W., Shah, M.R., et al. (2007) Relation between dose of loop diuretics and outcomes in a heart failure population: Results of the ES- CAPE trial. European Journal of Heart Failure, 9, 1064- 1069. doi:10.1016/j.ejheart.2007.07.011
[30] Shah, R.V., McNulty, S., O’Connor, C.M., Felker, G.M., Braunwald, E. and Givertz, M.M. (2012) Effect of admission oral diuretic dose on response to continuous versus bolus intravenous diuretics in acute heart failure: An analysis from diuretic optimization strategies in acute heart failure. American Heart Journal, 164, 862-868. doi:10.1016/j.ahj.2012.08.019
[31] Voors, A.A., Dittrich, H.C., Massie, B.M., DeLucca, P., Mansoor, G.A., Metra, M., Cotter, G., Weatherley, B.D., Ponikowski, P., Teerlink, J.R., Cleland, J.G., O’Connor, C.M. and Givertz, M.M. (2011) Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: Results from PROTECT (placebo-controlled randomized study of the selective adenosine A1 receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function). Journal of the American College of Cardiology, 57, 1899-1907. doi:10.1016/j.jacc.2010.11.057
[32] Goldsmith, S.R. and Gheorghiade, M. (2005) Vasopressin antagonism in heart failure. Journal of the American College of Cardiology, 46, 1785-1791. doi:10.1016/j.jacc.2005.02.095
[33] Gheorghiade, M., Gattis, W.A., O’Connor, C.M., et al. (2004) Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA, 291, 1963-1971. doi:10.1001/jama.291.16.1963
[34] Gheorghiade, M., Niazi, I., Ouyang, J., et al. (2003) Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: Results from a double-blind, randomized trial. Circulation, 107, 2690-2696. doi:10.1161/01.CIR.0000070422.41439.04
[35] Gheorghiade, M., Orlandi, C., Burnett, J.C., et al. (2005) Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of vasopressin antagonism in heart failure: Outcome study with tolvaptan (EVEREST). Journal of Cardiac Failure, 11, 260-269. doi:10.1016/j.cardfail.2005.03.009
[36] Gheorghiade, M., Konstam, M.A., Burnett, J.C., Jr., et al. (2007) Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA, 297, 1332-1343. doi:10.1001/jama.297.12.1332
[37] Konstam, M.A., Gheorghiade, M., Burnett, J.C., Jr., et al. (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA, 297, 1319-1331. doi:10.1001/jama.297.12.1319
[38] Vaduganathan, M., Gheorghiade, M., Pang, P.S., Konstam, M.A., Zannad, F., Swedberg, K., Grinfeld, L., Burnett, J.C. Jr., Krasa, H.B., Zimmer, C., Blair, J., Ouyang, J., Maggioni, A.P. and EVEREST Investigators (2012) Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment. Journal of Cardiovascular Medicine (Hagerstown), 13, 415-422. doi:10.2459/JCM.0b013e328355a740
[39] Costanzo, M.R., Saltzberg, M.T. Jessup, M., Teerlink, J.R. and Sobotka, P.A. and Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) Investigators (2010) Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: Results from UNLOAD. Journal of Cardiac Failure, 16, 277-284. doi:10.1016/j.cardfail.2009.12.009
[40] Bart, B.A., Goldsmith, S.R., Lee, K.L., Redfield, M.M., Felker, G.M., O’Connor, C.M., Chen, H.H., Rouleau, J.L., Givertz, M.M., Semigran, M.J., Mann, D., Deswal, A., Bull, D.A., Lewinter, M.M. and Braunwald, E. (2012) Cardiorenal rescue study in acute decompensated heart failure: Rationale and design of CARRESS-HF, for the heart failure clinical research network. Journal of Cardiac Failure, 18, 176-182. doi:10.1016/j.cardfail.2011.12.009
[41] Bart, B.A., Goldsmith, S.R., Lee, K.L., Givertz, M.M., O’Connor, C.M., Bull, D.A., Redfield, M.M., Deswal, A., Rouleau, J.L., Lewinter, M.M., Ofili, E.O., Stevenson, L.W., Semigran, M.J., Felker, G.M., Chen, H.H., Hernandez, A.F., Anstrom, K.J., McNulty, S.E., Velazquez, E.J., Ibarra, J.C., Mascette, A.M., Braunwald, E. (2012) The heart failure clinical research network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. The New England Journal of Medicine, Epub ahead of print.
[42] Bart, B.A. (2012) Late-breaking clinical trials: Management of LV dysfunction: Devices and drugs. American Heart Association Scientific Sessions, Los Angeles.
[43] Metra, M., Cotter, G., Gheorghiade, M., Dei Cas, L. and Voors, A.A. (2012) The role of the kidney in heart failure. European Heart Journal, 33, 2135-2142. doi:10.1093/eurheartj/ehs205
[44] Pan, S., Chen, H.H., Dickey, D.M., Boerrigter, G., Lee, C., Kleppe, L.S., Hall, J.L., Lerman, A., Redfield, M.M., Potter, L.R., Burnett, J.C. and Simari, R.D. (2009) Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. Proceedings of the National Academy of Sciences of the USA, 106, 11282- 11287. doi:10.1073/pnas.0811851106
[45] Pan, S., Lee, C., Chen, H., Lerman, A., Burnett, J.C. and Simari, R. (2008) Abstract 1485: Tissue specific activation of cGMP by an alternatively spliced form of BNP. Circulation, 118, S_335.
[46] Costanzo, M.R., Heywood, J.T., Massie, B.M., Iwashita, J., Henderson, L., Mamatsashvili, M., Sisakian, H., Hayrapetyan, H., Sager, P., van Veldhuisen, D.J. and Albrecht, D. (2012) A double-blind, randomized, parallel, placebo-controlled study examining the effect of cross- linked polyelectrolyte in heart failure patients with chronic kidney disease. European Journal of Heart Failure, 14, 922-930. doi:10.1093/eurjhf/hfs074
[47] Pitt, B., Anker, S.D., Bushinsky, D.A., Kitzman, D.W., Zannad, F., Huang, I.Z. and PEARL-HF Investigators (2011) Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo- controlled study in patients with chronic heart failure (the PEARL-HF) trial. European Journal of Heart Failure, 32, 820-828. doi:10.1093/eurheartj/ehq502
[48] Van der Meer, P. and van Veldhuisen, D.J. (2011) To bind or not to bind: Potassium-lowering drugs in heart failure. European Journal of Heart Failure, 32, 791-792. doi:10.1093/eurheartj/ehr058
[49] Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF) (2002) Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA, 287, 1531-1540.
[50] Elkayam, U., Bitar, F., Akhter, M.W., Khan, S., Patrus, S. and Derakhshani, M. (2004) Intravenous nitroglycerin in the treatment of decompensated heart failure: Potential benefits and limitations. Journal of Cardiovascular Pharmacology and Therapeutics, 9, 227-241. doi:10.1177/107424840400900403
[51] Mullens, W., Abrahams, Z., Francis, G.S., Skouri, H.N., Starling, R.C., Young, J.B., Taylor, D.O. and Tang, W.H. (2008) Sodium nitroprusside for advanced low-output heart failure. Journal of the American College of Cardiology, 52, 200-207. doi:10.1016/j.jacc.2008.02.083
[52] Sackner-Bernstein, J.D., Kowalski, M., Fox, M. and Aaronson, K. (2005) Short-term risk of death after treatment with nesiritide for decompensated heart failure: A pooled analysis of randomized controlled trials. JAMA, 293, 1900-1905. doi:10.1001/jama.293.15.1900
[53] Aaronson, K.D. and Sackner-Bernstein, J. (2006) Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA, 296, 1461-1466. doi:10.1001/jama.296.12.1465
[54] O’Connor, C.M., Starling, R.C., Hernandez, A.F., et al. (2011) Effect of nesiritide in patients with acute decompensated heart failure. The New England Journal of Medicine, 365, 32-43. doi:10.1056/NEJMoa1100171
[55] Mentz, R.J., Hernandez, A.F., Stebbins, A., Ezekowitz, J.A., Felker, G.M., Heizer, G.M., Atar, D., Teerlink, J.R., Califf, R.M., Massie, B.M., Hasselblad, V., Starling, R.C., O’Connor, C.M. and Ponikowski, P. (2012) Predictors of early dyspnoea relief in acute heart failure and the association with 30-day outcomes: Findings from ASCEND- HF. European Journal of Heart Failure, Epub ahead of print.
[56] Forssmann, W., Meyer, M. and Forssmann, K. (2001) The renal urodilatin system: Clinical implications. Cardiovascular Research, 51, 450-462. doi:10.1016/S0008-6363(01)00331-5
[57] Mitrovic, V., Luss, H., Nitsche, K., et al. (2005) Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: A double-blind, placebo-controlled, ascending-dose trial. American Heart Journal, 150, 1239.e1-1239.e8. doi:10.1016/j.ahj.2005.01.022
[58] Mitrovic, V., Seferovic, P.M., Simeunovic, D., et al. (2006) Haemodynamic and clinical effects of ularitide in decompensated heart failure. European Heart Journal, 27, 2823-2832. doi:10.1093/eurheartj/ehl337
[59] Lüss, H., Mitrovic, V., Seferovic, P.M., et al. (2008) Renal effects of ularitide in patients with decompensated heart failure. American Heart Journal, 155, 1012.e1-1012.e8.
[60] Teerlink, J.R. (2002) The role of endothelin in the pathogenesis of heart failure. Current Cardiology Reports, 4, 206-212. doi:10.1007/s11886-002-0052-2
[61] Aronson, D. and Burger A.J. (2003) Neurohormonal prediction of mortality following admission for decompensated heart failure. American Journal of Cardiology, 91, 245-248. doi:10.1016/S0002-9149(02)03119-3
[62] Teerlink, J.R., McMurray, J.J., Bourge, R.C., et al. (2005) Tezosentan in patients with acute heart failure: Design of the value of endothelin receptor inhibition with tezosentan in acute heart failure study (VERITAS). American Heart Journal, 150, 46-53. doi:10.1016/j.ahj.2005.04.035
[63] McMurray, J.J., Teerlink, J.R., Cotter, G., et al. (2007) Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: The VERITAS randomized controlled trials. JAMA, 298, 2009-2019. doi:10.1001/jama.298.17.2009
[64] Boerrigter, G., Costello-Boerrigter, L.C., Cataliotti, A, Lapp, H., Stasch, J.P. and Burnett, J.C. Jr., (2007) Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension, 49, 1128-1133. doi:10.1161/HYPERTENSIONAHA.106.083832
[65] Mitrovic, V., Lapp, H., Franz, N., et al. (2008) The soluble guanilate cyclase activator BAY 58-2667 has a favourable safety profile and improbe cardiopulmonary hemodynamics in acute decompensated heart failure. European Journal of Heart Failure, 7, 1. doi:10.1016/S1567-4215(08)60005-3
[66] Erdmann, E., Semigran, M.J., Nieminen, M.S., Gheorghiade, M., Agrawal, R., Mitrovic, V. and Mebazaa, A. (2013) Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. European Heart Journal, 34, 57-67. doi:10.1093/eurheartj/ehs196
[67] Boerrigter, G., Lark, M.W., Whalen, E.J., Soergel, D.G., Violin, J.D. and Burnett, J.C., Jr. (2011) Cardiorenal actions of TRV120027, a novel β-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: A novel therapeutic strategy for acute heart failure. Circulation: Heart Failure, 4, 770-778. doi:10.1161/CIRCHEARTFAILURE.111.962571
[68] Boerrigter, G., Soergel, D.G., Violin, J.D., Lark, M.W. and Burnett, J.C., Jr. (2012) TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure. Circulation: Heart Failure 5, 627-34. doi:10.1161/CIRCHEARTFAILURE.112.969220
[69] Cardioxyl Pharmaceuticals, Inc. (2012). http://www.cardioxyl.com/
[70] Teerlink, J.R., Cotter, G., Davison, B.A., Felker, G.M., Filippatos, G., Greenberg, B.H., Ponikowski, P., Unemori, E., Voors, A.A., Adams, K.F., Jr., Dorobantu, M.I., Grinfeld, L.R., Jondeau, G., Marmor, A., Masip, J., Pang, P.S., Werdan, K., Teichman, S.L., Trapani, A., Bush, C.A., Saini, R., Schumacher, C., Severin, T.M., Metra, M. and the Relaxin in Acute Heart Failure (RELAX-AHF) Investigators (2013) Serelaxin, recombinant human relaxin- 2, for treatment of acute heart failure (RELAX-AHF): A randomised, placebo-controlled trial. Lancet, 381, 29-39.
[71] Teerlink, J.R., Metra, M., Felker, G.M., Ponikowski, P., Voors, A.A., Weatherley, B.D., Marmor, A., Katz, A., Grzybowski, J., Unemori, E., Teichman, S.L. and Cotter, G. (2009) Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): A multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet, 373, 1429-1439. doi:10.1016/S0140-6736(09)60622-X
[72] Davison, J.M. and Noble, M.C. (1981) Serial changes in 24 hour creatinine clearance during normal menstrual cycles and the first trimester of pregnancy. British Journal of Obstetrics and Gynaecology, 88, 10-17. doi:10.1111/j.1471-0528.1981.tb00930.x
[73] Metra, M., Cotter, G., Davison, B.A., Felker, G.M., Filippatos, G., Greenberg, B.H., Ponikowski, P., Unemori, E., Voors, A.A., Adams, K.F. Jr., Dorobantu, M.I., Grinfeld, L., Jondeau, G., Marmor, A., Masip, J., Pang, P.S., Werdan, K., Prescott, M.F., Edwards, C., Teichman, S.L., Trapani, A., Bush, C.A., Saini, R., Schumacher, C., Severin, T., Teerlink, J.R. and RELAX-AHF Investigators (2013) Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the relaxin in acute heart failure (RE- LAX-AHF) development program: Correlation with outcomes. Journal of the American College of Cardiology, 61, 196-206.
[74] Cuffe, M.S., Califf, R.M., Adams, K.F. Jr., Benza, R., Bourge, R., Colucci, W.S., Massie, B.M., O’Connor, C.M., Pina, I., Quigg, R., Silver, M.A. and Gheorghiade, M and Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators (2002) Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA, 287, 1541-1547. doi:10.1001/jama.287.12.1541
[75] Felker, G.M., Benza, R.L., Chandler, A.B., Leimberger, J.D., Cuffe, M.S., Califf, R.M., Gheorghiade, M., O’Connor, C.M. and OPTIME-CHF Investigators (2003) Heart failure etiology and response to milrinone in decompen- sated heart failure: Results from the OPTIME-CHF study. Journal of the American College of Cardiology, 41, 997- 1003. doi:10.1016/S0735-1097(02)02968-6
[76] Connor, C.M., Gattis, W.A., Uretsky, B.F., Adams, K.F. Jr., McNulty, S.E., Grossman, S.H., McKenna, W.J., Zannad, F., Swedberg, K., Gheorghiade, M. and Califf, R.M. (1999) Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: Insights from the flolan international randomized survival trial (FIRST). American Heart Journal, 138, 78-86. doi:10.1016/S0002-8703(99)70250-4
[77] Oliva, F., Latini, R., Politi, A., Staszewsky, L., Maggioni, A.P., Nicolis, E. and Mauri, F. (1999) Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. American Heart Journal J, 138, 247-253. doi:10.1016/S0002-8703(99)70108-0
[78] Cleland, J.G., Ghosh, J., Freemantle, N., Kaye, G.C., Nasir, M., Clark, A.L. and Coletta, A.P. (2004) Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO- Lipids and cardiac resynchronisation therapy in heart failure. European Journal of Heart Failure, 6, 501-508. doi:10.1016/j.ejheart.2004.04.014
[79] Follath, F., Cleland, J.G., Just, H., et al. and Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. Lancet, 360, 196-202. doi:10.1016/S0140-6736(02)09455-2
[80] Packer, M. (2005) REVIVE II: Multicenter placebo-controlled trial of levosimendan on clinical status in acutely decompensated heart failure. Program and abstracts from the American Heart Association Scientific Sessions. Late Breaking Clinical Trials II, Dallas, 13-16 November.
[81] Mebazaa, A. (2005) The SURVIVE-W Trial: Comparison of dobutamine and levosimendan on survival in acute decompensated heart failure. Program and abstracts from the American Heart Association Scientific Sessions 2005. Late Breaking Clinical Trials IV. Dallas, 13-16 November.
[82] Sabbah, H.N., Imai, M., Cowart, D., Amato, A., Carminati, P. and Gheorghiade, M. (2007) Hemodynamic properties of a new-generation positive lusoinotropic agent for the acute treatment of advanced heart failure. American Journal of Cardiology, 99, 41A-46A. doi:10.1016/j.amjcard.2006.09.005
[83] Khan, H., Metra, M., Blair, J.E., Vogel, M., Harinstein, M.E., Filippatos, G.S., Sabbah, H.N., Porchet, H., Valentini, G. and Gheorghiade, M. (2009) Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na-K-ATPase inhibition: A new promising treatment for acute heart failure syndromes? Heart Failure Reviews, Epub ahead of print, PubMed PMID: 19238540.
[84] Gheorghiade, M., Blair, J.E., Filippatos, G.S., Macarie, C., Ruzyllo, W., Korewicki, J., Bubenek-Turconi, S.I., Ceracchi, M., Bianchetti, M., Carminati, P., Kremastinos, D., Valentini, G., Sabbah, H.N. and HORIZON-HF Investigators (2008) Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure. Journal of the American College of Cardiology, 51, 2276-2285. doi:10.1016/j.jacc.2008.03.015
[85] Shah, S.J., Blair, J.E., Filippatos, G.S., Macarie, C., Ruzyllo, W., Korewicki, J., Bubenek-Turconi, S.I., Ceracchi, M., Bianchetti, M., Carminati, P., Kremastinos, D., Grzybowski, J., Valentini, G., Sabbah, H.N., Gheorghiade, M. and HORIZON-HF Investigators (2009) Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: Results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a novel intravenous inotropic and lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial. American Heart Journal, 157, 1035-1041. doi:10.1016/j.ahj.2009.03.007
[86] Teerlinkm, J.R. (2009) A novel approach to improve cardiac performance: Cardiac myosin activators. Heart Failure Reviews, 14, 289-298. doi:10.1007/s10741-009-9135-0
[87] Malik, F.I., Hartman, J.J., Elias, K.A., Morgan, B.P., Rodriguez, H., Brejc, K., Anderson, R.L., Sueoka, S.H., Lee, K.H., Finer, J.T., et al. (2011) Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science, 331, 1439-1443. doi:10.1126/science.1200113
[88] Teerlink, J.R., Clarke, C.P., Saikali, K.G., Lee, J.H., Chen, M.M., Escandon, R.D., Elliott, L., Bee, R., Habibzadeh, M.R., Goldman, J.H., et al. (2011) Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: A first-in-man study. Lancet, 378, 667-675. doi:10.1016/S0140-6736(11)61219-1
[89] Shen, Y.T., Malik, F.I., Zhao, X., Depre, C., Dhar, S.K., Abarzúa, P., Morgans, D.J. and Vatner, S.F. (2010) Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure. Circulation: Heart Failure, 3, 522-527. doi:10.1161/CIRCHEARTFAILURE.109.930321
[90] Cleland, J.G., Teerlink, J.R., Senior, R., Nifontov, E.M., Mc Murray, J.J., Lang, C.C., Tsyrlin, V.A., Greenberg, B.H., Mayet, J., Francis, D.P., et al. (2011) The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet, 378, 676-683. doi:10.1016/S0140-6736(11)61126-4
[91] Greenberg, B.H., Chou, W., Escandon, R., Lee, J.H., Saikali, K.G., Malik, F., Wolff, A.A. and Shaburishvili, T. (2009) Phase II safety study evaluating the novel cardiac myosin activator, CK-1827452, in patients with ischemic cardiomyopathy and angina. Journal of Cardiac Failure, 15, S67-S67. doi:10.1016/j.cardfail.2009.06.206

  
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