Investigational and emerging therapies for heart failure
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
Treatment of heart failure (HF) is aimed at three goals: improvement in symptoms, slowing of disease progression, and prolongation of survival . (See "Overview of the therapy of heart failure with reduced ejection fraction".)
Investigational and emerging therapies for chronic and acute HF are reviewed here. While beneficial effects have been seen with some of these interventions in preliminary studies, the risk/benefit ratio and true efficacy remain to be proven.
Standard therapies for HF are discussed elsewhere. (See "Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
INVESTIGATIONAL THERAPIES FOR CHRONIC HEART FAILURE
Modulation of heart rate or autonomic tone
Parasympathetic stimulation — Decreased parasympathetic nervous system (PNS) activity may contribute to the pathophysiology of heart failure (HF) , but the role of PNS stimulation as a treatment of HF is unknown. Based on animal models showing improvement in HF with PNS stimulation, the potential role of increasing PNS activity in the treatment of HF with reduced ejection fraction (HFrEF) is being evaluated in humans. Several trials are underway to examine the effects of increasing PNS activity via vagus nerve stimulation on cardiac structure, function, and clinical outcomes .
Other — Use of beta blocker therapy and sinus node inhibition in patients with HF is discussed separately. (See "Use of beta blockers in heart failure with reduced ejection fraction".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:1810.
- Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008; 118:863.
- De Ferrari GM, Crijns HJ, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011; 32:847.
- Borlaug BA, Lewis GD, McNulty SE, et al. Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction. Circ Heart Fail 2015; 8:533.
- Zhuang XD, Long M, Li F, et al. PDE5 inhibitor sildenafil in the treatment of heart failure: a meta-analysis of randomized controlled trials. Int J Cardiol 2014; 172:581.
- Redfield MM, Chen HH, Borlaug BA, et al. 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.
- Crataegus oxyacantha (Hawthorn). Monograph. Altern Med Rev 2010; 15:164.
- Pittler MH, Guo R, Ernst E. Hawthorn extract for treating chronic heart failure. Cochrane Database Syst Rev 2008; :CD005312.
- Holubarsch CJ, Colucci WS, Meinertz T, et al. The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial. Eur J Heart Fail 2008; 10:1255.
- Zick SM, Vautaw BM, Gillespie B, Aaronson KD. Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) trial. Eur J Heart Fail 2009; 11:990.
- Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail 2012; 5:315.
- http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac40e05b-6e67-4ff9-a0e8-2e897e71b282 (Accessed on September 30, 2014).
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:2536.
- Le Corvoisier P, Hittinger L, Chanson P, et al. Cardiac effects of growth hormone treatment in chronic heart failure: A meta-analysis. J Clin Endocrinol Metab 2007; 92:180.
- Cittadini A, Saldamarco L, Marra AM, et al. Growth hormone deficiency in patients with chronic heart failure and beneficial effects of its correction. J Clin Endocrinol Metab 2009; 94:3329.
- Cittadini A, Marra AM, Arcopinto M, et al. Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC Heart Fail 2013; 1:325.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.
- Sanganalmath SK, Bolli R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013; 113:810.
- Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428:664.
- Nygren JM, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004; 10:494.
- Murry CE, Field LJ, Menasché P. Cell-based cardiac repair: reflections at the 10-year point. Circulation 2005; 112:3174.
- Reinecke H, Poppa V, Murry CE. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34:241.
- Murry CE. Cardiac aid to the injured but not the elderly? Nat Med 2007; 13:901.
- Fisher SA, Brunskill SJ, Doree C, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2014; :CD007888.
- Breitbach M, Bostani T, Roell W, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007; 110:1362.
- Endo J, Sano M, Fujita J, et al. Bone marrow derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload. Circulation 2007; 116:1176.
- Hill JM, Syed MA, Arai AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005; 46:1643.
- Zbinden S, Zbinden R, Meier P, et al. Safety and efficacy of subcutaneous-only granulocyte-macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 2005; 46:1636.
- Kawase Y, Ladage D, Hajjar RJ. Rescuing the failing heart by targeted gene transfer. J Am Coll Cardiol 2011; 57:1169.
- Pleger ST, Brinks H, Ritterhoff J, et al. Heart failure gene therapy: the path to clinical practice. Circ Res 2013; 113:792.
- Felix SB, Staudt A, Dörffel WV, et al. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study. J Am Coll Cardiol 2000; 35:1590.
- Müller J, Wallukat G, Dandel M, et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 2000; 101:385.
- Staudt A, Böhm M, Knebel F, et al. Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy. Circulation 2002; 106:2448.
- Staudt A, Schäper F, Stangl V, et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001; 103:2681.
- Schimke I, Müller J, Priem F, et al. Decreased oxidative stress in patients with idiopathic dilated cardiomyopathy one year after immunoglobulin adsorption. J Am Coll Cardiol 2001; 38:178.
- Felix SB, Staudt A, Landsberger M, et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol 2002; 39:646.
- Warraich RS, Dunn MJ, Yacoub MH. Subclass specificity of autoantibodies against myosin in patients with idiopathic dilated cardiomyopathy: pro-inflammatory antibodies in DCM patients. Biochem Biophys Res Commun 1999; 259:255.
- Warraich RS, Noutsias M, Kazak I, et al. Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: immunoglobulin G3 and clinical correlates. Am Heart J 2002; 143:1076.
- Blum A. Immunological mediated therapies for heart failure. Isr Med Assoc J 2009; 11:301.
- Gullestad L, Ueland T, Fjeld JG, et al. Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study. Circulation 2005; 112:3408.
- Shaw SM, Shah MK, Williams SG, Fildes JE. Immunological mechanisms of pentoxifylline in chronic heart failure. Eur J Heart Fail 2009; 11:113.
- Champion S, Lapidus N, Cherié G, et al. Pentoxifylline in heart failure: a meta-analysis of clinical trials. Cardiovasc Ther 2014; 32:159.
- Torre-Amione G, Sestier F, Radovancevic B, Young J. Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial. J Am Coll Cardiol 2004; 44:1181.
- Torre-Amione G, Anker SD, Bourge RC, et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet 2008; 371:228.
- Feldman AM, Silver MA, Francis GS, et al. Enhanced external counterpulsation improves exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2006; 48:1198.
- Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2014; 2:641.
- Madmani ME, Yusuf Solaiman A, Tamr Agha K, et al. Coenzyme Q10 for heart failure. Cochrane Database Syst Rev 2014; :CD008684.
- Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013; 381:29.
- Filippatos G, Teerlink JR, Farmakis D, et al. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J 2014; 35:1041.
- Teerlink JR, Voors AA, Ponikowski P, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail 2017; 19:800.
- RELAXin in Acute Heart Failure-2 - RELAX-AHF-2; Presentor/Author: Teerlink JR; Author/Summarized by Author: Kumbhani DJ; Original posted date: 05/05/2017 https://acc.org/latest-in-cardiology/clinical-trials/2017/05/07/16/09/relax-ahf-2?w_nav=LC (Accessed on May 23, 2017).
- Packer M, O'Connor C, McMurray JJV, et al. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med 2017; 376:1956.
- De Vecchis R, Esposito C, Ariano C, Cantatrione S. Hypertonic saline plus i.v. furosemide improve renal safety profile and clinical outcomes in acute decompensated heart failure: A meta-analysis of the literature. Herz 2015; 40:423.
- Gandhi S, Mosleh W, Myers RB. Hypertonic saline with furosemide for the treatment of acute congestive heart failure: a systematic review and meta-analysis. Int J Cardiol 2014; 173:139.
- Paterna S, Fasullo S, Parrinello G, et al. Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C) (SMAC-HF Study). Am J Med Sci 2011; 342:27.
- Licata G, Di Pasquale P, Parrinello G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J 2003; 145:459.
- Greenberg B, Czerska B, Delgado RM, et al. Effects of continuous aortic flow augmentation in patients with exacerbation of heart failure inadequately responsive to medical therapy: results of the Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy (MOMENTUM). Circulation 2008; 118:1241.
- Zile MR, Colombo PC, Mehra M, et al. Progressive improvement in cardiac performance with continuous aortic flow augmentation (aortic flow therapy) in patients hospitalized with severe heart failure: results of the Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy (MOMENTUM). J Heart Lung Transplant 2010; 29:86.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol 2017; 2:950.
- INVESTIGATIONAL THERAPIES FOR CHRONIC HEART FAILURE
- Modulation of heart rate or autonomic tone
- - Parasympathetic stimulation
- - Other
- - Sildenafil
- - Hawthorn extract
- - Testosterone
- - Growth hormone
- Cell therapy
- Gene therapy
- - Immunosuppressive therapy
- - Intravenous immune globulin
- - Immunoadsorption
- - Thalidomide
- - Pentoxifylline
- - Immunomodulation
- Antiviral therapy
- Mechanical therapies
- - Enhanced external counterpulsation
- Nutritional supplements
- - Coenzyme Q10
- INVESTIGATIONAL THERAPIES FOR ACUTE HEART FAILURE
- Investigational vasodilators
- - Serelaxin
- - Ularitide
- Hypertonic saline plus furosemide
- Continuous aortic flow augmentation
- High-dose mineralocorticoid receptor antagonist
- SUMMARY AND RECOMMENDATIONS