Heart Failure Reviews

, Volume 24, Issue 5, pp 743–758 | Cite as

Pathogenesis and pathophysiology of heart failure with reduced ejection fraction: translation to human studies

  • Zijun Ge
  • Amy Li
  • James McNamara
  • Cris dos Remedios
  • Sean LalEmail author


Heart failure represents the end result of different pathophysiologic processes, which culminate in functional impairment. Regardless of its aetiology, the presentation of heart failure usually involves symptoms of pump failure and congestion, which forms the basis for clinical diagnosis. Pathophysiologic descriptions of heart failure with reduced ejection fraction (HFrEF) are being established. Most commonly, HFrEF is centred on a reactive model where a significant initial insult leads to reduced cardiac output, further triggering a cascade of maladaptive processes. Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias. The pathophysiologic processes behind remodelling in heart failure are complex and reflect systemic neurohormonal activation, peripheral vascular effects and localised changes affecting the cardiac substrate. These abnormalities have been the subject of intense research. Much of the translational successes in HFrEF have come from targeting neurohormonal responses to reduced cardiac output, with blockade of the renin-angiotensin-aldosterone system (RAAS) and beta-adrenergic blockade being particularly fruitful. However, mortality and morbidity associated with heart failure remains high. Although systemic neurohormonal blockade slows disease progression, localised ventricular remodelling still adversely affects contractile function. Novel therapy targeted at improving cardiac contractile mechanics in HFrEF hold the promise of alleviating heart failure at its source, yet so far none has found success. Nevertheless, there are increasing calls for a proximal, ‘cardiocentric’ approach to therapy. In this review, we examine HFrEF therapy aimed at improving cardiac function with a focus on recent trials and emerging targets.


Human Heart failure Basic sciences Translational 



For Figs. 1 and 2, the authors acknowledge the use of Motifolio© PowerPoint SmartArt Objects that were modified and re-edited to suite content.


  1. 1.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ et al (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail 18(8):891–975Google Scholar
  2. 2.
    van Heerebeek L, Paulus WJ (2016) Understanding heart failure with preserved ejection fraction: where are we today? Neth Hear J 24(4):227–236Google Scholar
  3. 3.
    Reed BN, Sueta CA (2015) A practical guide for the treatment of symptomatic heart failure with reduced ejection fraction (HFrEF). Curr Cardiol Rev 11(1):23–32Google Scholar
  4. 4.
    Kemp CD, Conte JV (2012) The pathophysiology of heart failure. Cardiovasc Pathol 21(5):365–371Google Scholar
  5. 5.
    MacIver DH, Dayer MJ (2012) An alternative approach to understanding the pathophysiological mechanisms of chronic heart failure. Int J Cardiol 154(2):102–110Google Scholar
  6. 6.
    Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Leiro MC, Drozdz J et al (2013) EURObservational research programme: regional differences and 1-year follow-up results of the heart failure pilot survey (ESC-HF pilot). Eur J Heart Fail 15(7):808–817Google Scholar
  7. 7.
    Yancy CW, Jessup M, Masoudi FA, McBride PE, Peterson PN, Stevenson LW et al (2016) 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol 68(13):1476–1488Google Scholar
  8. 8.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 37(27):2129–U130Google Scholar
  9. 9.
    Gheorghiade M, Larson CJ, Shah SJ, Greene SJ, Cleland JGF, Colucci WS et al (2016) Developing new treatments for heart failure focus on the heart. Circ Heart Fail 9(5):1–8Google Scholar
  10. 10.
    Vaduganathan M, Butler J, Pitt B, Gheorghiade M (2015) Contemporary drug development in heart failure: call for hemodynamically neutral therapies. Circ Heart Fail 8(4):826–831Google Scholar
  11. 11.
    Lipskaia L, Hulot JS, Lompre AM (2009) Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation. Pflügers Archiv: Eur J Physiol 457(3):673–685Google Scholar
  12. 12.
    Marks AR (2013) Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Investig 123(1):46–52Google Scholar
  13. 13.
    Lyon AR, MacLeod KT, Zhang YJ, Garcia E, Kanda GK, Lab MJ et al (2009) Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. Proc Natl Acad Sci U S A 106(16):6854–6859Google Scholar
  14. 14.
    Louch WE, Bito V, Heinzel FR, Macianskiene R, Vanhaecke J, Flameng W et al (2004) Reduced synchrony of Ca2+ release with loss of T-tubules—a comparison to Ca2+ release in human failing cardiomyocytes. Cardiovasc Res 62(1):63–73Google Scholar
  15. 15.
    Louch WE, Mork HK, Sexton J, Stromme TA, Laake P, Sjaastad I et al (2006) T-tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarction. J Physiol 574(2):519–533Google Scholar
  16. 16.
    Crossman DJ, Ruygrok PR, Soeller C, Cannell MB (2011) Changes in the organization of excitation-contraction coupling structures in failing human heart. PLoS One 6(3):1–10Google Scholar
  17. 17.
    Crossman DJ, Shen X, Jullig M, Munro M, Hou Y, Middleditch M et al (2017) Increased collagen within the transverse tubules in human heart failure. Cardiovasc Res 113(8):879–891Google Scholar
  18. 18.
    Shah SJ, Aistrup GL, Gupta DK, O'Toole MJ, Nahhas AF, Schuster D et al (2014) Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure. Am J Phys Heart Circ Phys 306(1):H88–H100Google Scholar
  19. 19.
    Song LS, Sobie EA, McCulle S, Lederer WJ, Balke CW, Cheng HP (2006) Orphaned ryanodine receptors in the failing heart. Proc Natl Acad Sci U S A 103(11):4305–4310Google Scholar
  20. 20.
    Crossman DJ, Young AA, Ruygrok PN, Nason GP, Baddelely D, Soeller C et al (2015) T-tubule disease: relationship between T-tubule organization and regional contractile performance in human dilated cardiomyopathy. J Mol Cell Cardiol 84:170–178Google Scholar
  21. 21.
    Crocini C, Coppini R, Ferrantini C, Yan P, Loew LM, Tesi C et al (2014) Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure. Proc Natl Acad Sci U S A 111(42):15196–15201Google Scholar
  22. 22.
    Wei S, Guo A, Chen BY, Kutschke W, Xie YP, Zimmerman K et al (2010) T-tubule remodeling during transition from hypertrophy to heart failure. Circ Res 107(4):520–U163Google Scholar
  23. 23.
    Frisk M, Ruud M, Espe EKS, Aronsen JM, Roe AT, Zhang LL et al (2016) Elevated ventricular wall stress disrupts cardiomyocyte T-tubule structure and calcium homeostasis. Cardiovasc Res 112(1):443–451Google Scholar
  24. 24.
    Zhang CM, Chen BY, Guo A, Zhu YQ, Miller JD, Gao S et al (2014) Microtubule-mediated defects in Junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation. 129(17):1742–1750Google Scholar
  25. 25.
    Beavers DL, Landstrom AP, Chiang DY, Wehrens XHT (2014) Emerging roles of junctophilin-2 in the heart and implications for cardiac diseases. Cardiovasc Res 103(2):198–205Google Scholar
  26. 26.
    van Oort RJ, Garbino A, Wang W, Dixit SS, Landstrom AP, Gaur N et al (2011) Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. Circulation. 123(9):979–988Google Scholar
  27. 27.
    Caldwell JL, Smith CER, Taylor RF, Kitmitto A, Eisner DA, Dibb KM et al (2014) Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ Res 115(12):986–U157Google Scholar
  28. 28.
    Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR et al (2007) Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol 42(6):1026–1035Google Scholar
  29. 29.
    Sachse FB, Torres NS, Savio-Galimberti E, Aiba T, Kass DA, Tomaselli GF et al (2012) Subcellular structures and function of myocytes impaired during heart failure are restored by cardiac resynchronization therapy. Circ Res 110(4):588–U197Google Scholar
  30. 30.
    Huang CK, Chen BY, Guo A, Chen R, Zhu YQ, Kutschke W et al (2016) Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model. Acta Pharmacol Sin 37(4):473–482Google Scholar
  31. 31.
    Chen B, Li Y, Jiang S, Xie YP, Guo A, Kutschke W et al (2012) Beta-adrenergic receptor antagonists ameliorate myocyte T-tubule remodeling following myocardial infarction. FASEB J 26(6):2531–2537Google Scholar
  32. 32.
    Reynolds JO, Quick AP, Wang QL, Beavers DL, Philippen LE, Showell J et al (2016) Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release. Int J Cardiol 225:371–380Google Scholar
  33. 33.
    Guo A, Wang Y, Chen B, Wang Y, Yuan J, Zhang L et al (2018) E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science 362(6421)Google Scholar
  34. 34.
    Mercadier JJ, Lompré AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C et al (1990) Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Investig 85(1):305–309Google Scholar
  35. 35.
    Arai M, Alpert NR, Maclennan DH, Barton P, Periasamy M (1993) Alterations in sarcoplasmic-reticulum gene-expression in human heart failure—a possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res 72(2):463–469Google Scholar
  36. 36.
    Kiss E, Ball NA, Kranias EG, Walsh RA (1995) Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. Circ Res 77(4):759–764Google Scholar
  37. 37.
    Schwinger RHG, Bohm M, Schmidt U, Karczewski P, Bavendiek U, Flesch M et al (1995) Unchanged protein levels of SERCA-II and phospholamban but reduced Ca2+ uptake and Ca2+ ATPase activity of cardiac sarcoplasmic-reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation. 92(11):3220–3228Google Scholar
  38. 38.
    Sande JB, Sjaastad I, Hoen IB, Bokenes J, Tonnessen T, Holt E et al (2002) Reduced level of serine(16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity. Cardiovasc Res 53(2):382–391Google Scholar
  39. 39.
    Boardman NT, Aronsen JM, Louch WE, Sjaastad I, Willoch F, Christensen G et al (2014) Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of SERCA2. Am J Physiol-Heart Circ Physiol 306(7):H1018–H1024Google Scholar
  40. 40.
    Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y et al (2002) Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 8(8):864–871Google Scholar
  41. 41.
    del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ (2002) Targeting phospholamban by gene transfer in human heart failure. Circulation. 105(8):904Google Scholar
  42. 42.
    Kaye DM, Preovolos A, Marshall T, Byrne M, Hoshijima M, Hajjar R et al (2007) Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. J Am Coll Cardiol 50(3):253Google Scholar
  43. 43.
    Kaneko M, Hashikami K, Yamamoto S, Matsumoto H, Nishimoto T (2016) Phospholamban ablation using CRISPR/Cas9 system improves mortality in a murine heart failure model. PLoS One 11(12):1–16Google Scholar
  44. 44.
    Yamada M, Ikeda Y, Yano M, Yoshimura K, Nishino S, Aoyama H et al (2006) Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy. FASEB J 20(8):1197–1199Google Scholar
  45. 45.
    Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO et al (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Investig 111(6):869–876Google Scholar
  46. 46.
    van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC et al (2012) Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 14(11):1199–1207Google Scholar
  47. 47.
    Kranias EG, Hajjar RJ (2017) The phospholamban journey 4 decades after setting out for Ithaka. Circ Res 120(5):781–783Google Scholar
  48. 48.
    Huang CLH (2013) SERCA2a stimulation by istaroxime: a novel mechanism of action with translational implications. Br J Pharmacol 170(3):486–488Google Scholar
  49. 49.
    Micheletti R, Palazzo F, Barassi P, Glacalone G, Ferrandi M, Schiavone A et al (2007) Istaroxime, a stimulator of sarcoplasmic, reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure. Am J Cardiol 99(2A):24A–32AGoogle Scholar
  50. 50.
    Sabbah HN, Imai M, Cowart D, Amato A, Carminati P, Gheorghiade M (2007) Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure. Am J Cardiol 99(2A):41A–46AGoogle Scholar
  51. 51.
    Aditya S, Rattan A (2012) Istaroxime: a rising star in acute heart failure. J Pharmacol Pharmacother 3(4):353–355Google Scholar
  52. 52.
    Chen Y, Escoubet B, Prunier F, Amour J, Simonides WS, Vivien B et al (2004) Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation. 109(15):1898–1903Google Scholar
  53. 53.
    Federica del M, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW et al (1999) Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 100(23):2308Google Scholar
  54. 54.
    Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T et al (2000) Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A 97(2):793–798Google Scholar
  55. 55.
    Sakata S, Lebeche D, Sakata Y, Sakata N, Chemaly ER, Liang LF et al (2007) Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model. Am J Phys Heart Circ Phys 292(2):H1204–H12H7Google Scholar
  56. 56.
    Lyon AR, Bannister ML, Collins T, Pearce E, Sepehripour AH, Dubb SS et al (2011) SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ Arrhythm Electrophysiol 4(3):362–372Google Scholar
  57. 57.
    del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK et al (2001) Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure. Circulation. 104(12):1424–1429Google Scholar
  58. 58.
    Ishikawa K, Tilemann L, Ladage D, Aguero J, Leonardson L, Fish K et al (2012) Cardiac gene therapy in large animals: bridge from bench to bedside. Gene Ther 19(6):670–677Google Scholar
  59. 59.
    Sakata S, Lebeche D, Sakata N, Sakata Y, Chemaly ER, Liang LF et al (2007) Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol 42(4):852–861Google Scholar
  60. 60.
    Kumarswamy R, Lyon AR, Volkmann I, Mills AM, Bretthauer J, Pahuja A et al (2012) SERCA2a gene therapy restores microRNA-1 expression in heart failure via an Akt/FoxO3A-dependent pathway. Eur Heart J 33(9):1067–1075Google Scholar
  61. 61.
    del Monte F, Hajjar RJ, Harding SE (2001) Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure. Circulation Research 88(11):E66-EGoogle Scholar
  62. 62.
    Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B et al (2011) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 124(3):304–313Google Scholar
  63. 63.
    Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M et al (2014) Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res 114(1):101–108Google Scholar
  64. 64.
    Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS et al (2016) Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 387(10024):1178–1186Google Scholar
  65. 65.
    Hulot JS, Salem JE, Redheuil A, Collet JP, Varnous S, Jourdain P et al (2017) Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial. Eur J Heart Fail 19(11):1534–1541Google Scholar
  66. 66.
    Penny WF, Hammond HK (2017) Randomized clinical trials of gene transfer for heart failure with reduced ejection fraction. Hum Gene Ther 28(5):378–384Google Scholar
  67. 67.
    Stammers AN, Susser SE, Hamm NC, Hlynsky MW, Kimber DE, Kehler DS et al (2015) The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA). Can J Physiol Pharmacol 93(10):843–854Google Scholar
  68. 68.
    Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M et al (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278(45):44230–44237Google Scholar
  69. 69.
    Lee A, Oh JG, Gorski PA, Hajjar RJ, Kho C (2016) Post-translational modifications in heart failure: small changes, big impact. Heart Lung Circ 25(4):319–324Google Scholar
  70. 70.
    Hay RT (2005) SUMO: a history of modification. Mol Cell 18(1):1–12Google Scholar
  71. 71.
    Kho C, Lee A, Jeong D, Oh JG, Chaanine AH, Kizana E et al (2011) SUMO1-dependent modulation of SERCA2a in heart failure. Nature. 477(7366):601–605Google Scholar
  72. 72.
    Tilemann L, Lee A, Ishikawa K, Aguero J, Rapti K, Santos-Gallego C et al (2013) SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Sci Transl Med 5(211):211ra159Google Scholar
  73. 73.
    Kho C, Lee A, Jeong D, Oh JG, Gorski PA, Fish K et al (2015) Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure. Nat Commun 6:7229Google Scholar
  74. 74.
    Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49Google Scholar
  75. 75.
    Withering W (1785) An account of the foxglove, and some of its medical uses: with practical remarks on dropsy, and other diseases. Birmingham, EnglandGoogle Scholar
  76. 76.
    Scholz H (1984) Inotropic drugs and their mechanisms of action. J Am Coll Cardiol 4(2):389–397Google Scholar
  77. 77.
    Pollesello P, Papp Z, Papp JG (2016) Calcium sensitizers: what have we learned over the last 25 years? Int J Cardiol 203:543–548Google Scholar
  78. 78.
    Bohm M, La Rosee K, Schwinger RH, Erdmann E (1995) Evidence for reduction of norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol 25(1):146–153Google Scholar
  79. 79.
    Unverferth DA, Blanford M, Kates RE, Leier CV (1980) Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med 69(2):262–266Google Scholar
  80. 80.
    Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K et al (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307(4):205–211Google Scholar
  81. 81.
    Packer M, Medina N, Yushak M (1984) Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation. 70(6):1038Google Scholar
  82. 82.
    Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM et al (1991) Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325(21):1468–1475Google Scholar
  83. 83.
    Krell MJ, Kline EM, Bates ER, Hodgson JM, Dilworth LR, Laufer N et al (1986) Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J 112(4):787–791Google Scholar
  84. 84.
    Francis GS, Bartos JA, Adatya S (2014) Inotropes. J Am Coll Cardiol 63(20):2069–2078Google Scholar
  85. 85.
    Packer M (1993) The development of positive inotropic agents for chronic heart failure: how have we gone astray. J Am Coll Cardiol 22(4 Suppl A):119A–126AGoogle Scholar
  86. 86.
    Perry G, Brown E, Thornton R, Shiva T, Hubbard J, Reddy KR et al (1997) The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336(8):525–533Google Scholar
  87. 87.
    Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM et al (2003) Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 41(6):997–1003Google Scholar
  88. 88.
    O'Connor CM, Gattis WA, Uretsky BF, Adams KF Jr, McNulty SE, Grossman SH et al (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). Am Heart J 138(1 Pt 1):78–86Google Scholar
  89. 89.
    Tacon CL, McCaffrey J, Delaney A (2012) Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med 38(3):359–367Google Scholar
  90. 90.
    Koster G, Bekema HJ, Wetterslev J, Gluud C, Keus F, van der Horst ICC (2016) Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med 42(9):1322–1335Google Scholar
  91. 91.
    Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GYH et al (2015) Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. Br Med J 351:1–9Google Scholar
  92. 92.
    Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT et al (2005) Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 149(2):209–216Google Scholar
  93. 93.
    Goto Y, Hata K (1997) Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessel 12(Suppl):103–105Google Scholar
  94. 94.
    Asanoi H, Ishizaka S, Kameyama T, Ishise H, Sasayama S (1994) Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure. J Cardiovasc Pharmacol 23(2):268–274Google Scholar
  95. 95.
    Boswood A (2010) Current use of pimobendan in canine patients with heart disease. Vet Clin N Am Small Anim Pract 40(4):571–580Google Scholar
  96. 96.
    Lubsen J, Just H, Hjalmarsson AC, La Framboise D, Remme WJ, Heinrich-Nols J et al (1996) Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Heart. 76(3):223–231Google Scholar
  97. 97.
    Kato K, Iizuka M, Yazaki Y, Sasayama S, Nakashima M, Ohashi Y et al (2002) Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure—the effects of pimobendan on chronic heart failure study (EPOCH study). Circulation 66(2):149–157Google Scholar
  98. 98.
    Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H et al (2012) Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 159(2):82–87Google Scholar
  99. 99.
    Robertson IM, Pineda-Sanabria SE, Yan Z, Kampourakis T, Sun YB, Sykes BD et al (2016) Reversible covalent binding to cardiac troponin C by the Ca2+-sensitizer Levosimendan. Biochemistry. 55(43):6032–6045Google Scholar
  100. 100.
    Facundo HTF, Fornazari M, Kowaltowski AJ (2006) Tissue protection mediated by mitochondrial K+ channels. Biochim Biophys Acta (BBA)-Mol Basis Dis 1762(2):202–212Google Scholar
  101. 101.
    Kaheinen P, Pollesello P, Levijoki J, Haikala H (2004) Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart. J Cardiovasc Pharmacol 43(4):555–561Google Scholar
  102. 102.
    Ukkonen H, Saraste M, Akkila J, Knuuti MJ, Lehikoinen P, Nagren K et al (1997) Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther 61(5):596–607Google Scholar
  103. 103.
    Tarkia M, Stark C, Haavisto M, Kentala R, Vähäsilta T, Savunen T et al (2016) Effect of levosimendan therapy on myocardial infarct size and left ventricular function after acute coronary occlusion. Heart. 102(6):465Google Scholar
  104. 104.
    Honisch A, Theuring N, Ebner B, Wagner C, Strasser RH, Weinbrenner C (2010) Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition. Basic Res Cardiol 105(2):155–167Google Scholar
  105. 105.
    Nieminen MS, Buerke M, Cohen-Solal A, Costa S, Edes I, Erlikh A et al (2016) The role of levosimendan in acute heart failure complicating acute coronary syndrome: a review and expert consensus opinion. Int J Cardiol 218:150–157Google Scholar
  106. 106.
    Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K et al (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(9328):196–202Google Scholar
  107. 107.
    Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB et al (2002) Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 23(18):1422–1432Google Scholar
  108. 108.
    Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ et al (2007) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. J Am Med Assoc 297(17):1883–1891Google Scholar
  109. 109.
    Landoni G, Biondi-Zoccai G, Greco M, Greco T, Bignami E, Morelli A et al (2012) Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med 40(2):634–646Google Scholar
  110. 110.
    Jüni P, Witschi A, Bloch R, Egger M (1999) The hazards of scoring the quality of clinical trials for meta-analysis. J Am Med Assoc 282(11):1054–1060Google Scholar
  111. 111.
    Nieminen MS, Fruhwald S, Heunks LMA, Suominen PK, Gordon AC, Kivikko M et al (2013) Levosimendan: current data, clinical use and future development. Heart Lung Vessels 5(4):227–245Google Scholar
  112. 112.
    Altenberger J, Parissis JT, Costard-Jaeckle A, Winter A, Ebner C, Karavidas A et al (2014) Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial. Eur J Heart Fail 16(8):898–906Google Scholar
  113. 113.
    Nieminen MS, Altenberger J, Ben-Gal T, Bohmer A, Comin-Colet J, Dickstein K et al (2014) Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. Int J Cardiol 174(2):360–367Google Scholar
  114. 114.
    Orstavik O, Ata SH, Riise J, Dahl CP, Andersen GO, Levy FO et al (2014) Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart. Br J Pharmacol 171(23):5169–5181Google Scholar
  115. 115.
    Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H (1998) Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 98(20):2141–2147Google Scholar
  116. 116.
    Farmakis D, Alvarez J, Ben Gal T, Brito D, Fedele F, Fonseca C et al (2016) Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper. Int J Cardiol 222:303–312Google Scholar
  117. 117.
    Teerlink JR (2009) A novel approach to improve cardiac performance: cardiac myosin activators. Heart Fail Rev 14(4):289–298Google Scholar
  118. 118.
    Hwang PM, Sykes BD (2015) Targeting the sarcomere to correct muscle function. Nat Rev Drug Discov 14(5):313–328Google Scholar
  119. 119.
    Mamidi R, Gresham KS, Li A, dos Remedios CG, Stelzer JE (2015) Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C. J Mol Cell Cardiol 85:262–272Google Scholar
  120. 120.
    Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD 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(9792):667–675Google Scholar
  121. 121.
    Cleland JGF, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJV, Lang CC 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(9792):676–683Google Scholar
  122. 122.
    Teerlink JR, Felker GM, McMurray JJV, Ponikowski P, Metra M, Filippatos GS et al (2016) Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure the ATOMIC-AHF study. J Am Coll Cardiol 67(12):1444–1455Google Scholar
  123. 123.
    Teerlink JR, Felker GM, McMurray JJV, Solomon SD, Adams KF, Cleland JGF et al (2016) Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 388(10062):2895–2903Google Scholar
  124. 124.
    Greenberg BH, Chou W, Saikali KG, Escandón R, Lee JH, Chen MM et al (2015) Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina. JACC Heart Fail 3(1):22–29Google Scholar
  125. 125.
    Nagy L, Kovacs A, Bodi B, Pasztor ET, Fulop GA, Toth A et al (2015) The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat. Br J Pharmacol 172(18):4506–4518Google Scholar
  126. 126.
    Bakkehaug JP, Kildal AB, Engstad ET, Boardman N, Naesheim T, Ronning L et al (2015) Myosin activator omecamtiv mecarbil increases myocardial oxygen consumption and impairs cardiac efficiency mediated by resting myosin ATPase activity. Circ-Heart Fail 8(4):766–775Google Scholar
  127. 127.
    Oliva F, Latini R, Politi A, Staszewsky L, Maggioni AP, Nicolis E et al (1999) Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. Am Heart J 138(2 Pt 1):247–253Google Scholar
  128. 128.
    Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE et al (1998) A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 339(25):1810–1816Google Scholar
  129. 129.
    Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS et al (2002) Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 287(12):1541–1547Google Scholar
  130. 130.
    De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M (2006) Evidence-based use of levosimendan in different clinical settings. Eur Heart J 27(16):1908–1920Google Scholar
  131. 131.
    Packer M (2005) Revive II trial investigators: REVIVE II: multicenter placebo-controlled trial of levosimendan on clinical status in acutely decompensated heart failure. Circulation. 112:3363Google Scholar
  132. 132.
    Gheorghiade M, Blair JEA, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J et al (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. J Am Coll Cardiol 51(23):2276–2285Google Scholar
  133. 133.
    Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 113(6):709–724Google Scholar
  134. 134.
    Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR et al (2017) Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol 14(4):238–250Google Scholar
  135. 135.
    Depre C, Vanoverschelde J-LJ, Taegtmeyer H (1999) Glucose for the heart. Circulation. 99(4):578–588Google Scholar
  136. 136.
    Ingwall JS, Kramer MF, Fifer MA, Lorell BH, Shemin R, Grossman W et al (1985) The creatine kinase system in normal and diseased human myocardium. N Engl J Med 313(17):1050–1054Google Scholar
  137. 137.
    Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S et al (2003) Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J Am Coll Cardiol 42(9):1587–1593Google Scholar
  138. 138.
    Weiss RG, Gerstenblith G, Bottomley PA (2005) ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A 102(3):808–813Google Scholar
  139. 139.
    Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W et al (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 96(7):2190–2196Google Scholar
  140. 140.
    Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD (2011) Targeting fatty acid and carbohydrate oxidation—a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 1813(7):1333–1350Google Scholar
  141. 141.
    Karbowska J, Kochan Z, Smolenski RT (2003) Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol Biol Lett 8(1):49–53Google Scholar
  142. 142.
    Sihag S, Cresci S, Li AY, Sucharov CC, Lehman JJ (2009) PGC-1 alpha and ERR alpha target gene downregulation is a signature of the failing human heart. J Mol Cell Cardiol 46(2):201–212Google Scholar
  143. 143.
    Kolwicz SC, Tian R (2011) Glucose metabolism and cardiac hypertrophy. Cardiovasc Res 90(2):194–201Google Scholar
  144. 144.
    Sorokina N, O’Donnell JM, McKinney RD, Pound KM, Woldegiorgis G, LaNoue KF et al (2007) Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation. 115(15):2033–2041Google Scholar
  145. 145.
    Lopatin YM, Rosano GM, Fragasso G, Lopaschuk GD, Seferovic PM, Gowdak LH et al (2016) Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol 203:909–915Google Scholar
  146. 146.
    Gao D, Ning N, Niu X, Hao G, Meng Z (2011) Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 97(4):278–286Google Scholar
  147. 147.
    Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L et al (2013) Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol 163(3):320–325Google Scholar
  148. 148.
    Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L et al (2005) Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 112(21):3280–3288Google Scholar
  149. 149.
    Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F et al (2015) Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. J American C C: Heart Fail 3(3):202–211Google Scholar
  150. 150.
    Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD (2005) Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J Cardiovasc Pharmacol 46(6):849–855Google Scholar
  151. 151.
    Chong CR, Sallustio B, Horowitz JD (2016) Drugs that affect cardiac metabolism: focus on Perhexiline. Cardiovasc Drugs Ther 30(4):399–405Google Scholar
  152. 152.
    Barclay ML, Sawyers SM, Begg EJ, Zhang M, Roberts RL, Kennedy MA et al (2003) Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics 13(10):627–632Google Scholar
  153. 153.
    Banerjee K, Ghosh RK, Kamatam S, Banerjee A, Gupta A (2017) Role of Ranolazine in cardiovascular disease and diabetes: exploring beyond angina. Int J Cardiol 227:556–564Google Scholar
  154. 154.
    Belardinelli L, Shryock JC, Fraser H (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 92(suppl 4):iv6Google Scholar
  155. 155.
    Bersin RM, Wolfe C, Kwasman M, Lau D, Klinski C, Tanaka K et al (1994) Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 23(7):1617–1624Google Scholar
  156. 156.
    Lewis JF, DaCosta M, Wargowich T, Stacpoole P (1998) Effects of dichloroacetate in patients with congestive heart failure. Clin Cardiol 21(12):888–892Google Scholar
  157. 157.
    Lopaschuk GD (2016) Metabolic modulators in heart disease: past, present, and future. Can J Cardiol 33(7):838–849Google Scholar
  158. 158.
    Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE et al (2006) Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 114(20):2130–2137Google Scholar
  159. 159.
    Schulze PC, Drosatos K, Goldberg IJ (2016) Lipid use and misuse by the heart. Circ Res 118(11):1736–1751Google Scholar
  160. 160.
    Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A et al (2002) The cardiac phenotype induced by PPAR-alpha overexpression mimics that caused by diabetes mellitus. J Clin Investig 109(1):121–130Google Scholar
  161. 161.
    Kaimoto S, Hoshino A, Ariyoshi M, Okawa Y, Tateishi S, Ono K et al (2017) Activation of PPAR-alpha in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am J Phys Heart Circ Phys 312(2):H305–HH13Google Scholar
  162. 162.
    Pol CJ, Lieu M, Drosatos K (2015) PPARs: protectors or opponents of myocardial function? PPAR Res 2015:1–19Google Scholar
  163. 163.
    Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P et al (1987) Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317(20):1237–1245Google Scholar
  164. 164.
    Sarma S, Ardehali H, Gheorghiade M (2012) Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure. Heart Fail Rev 17(1):35–43Google Scholar
  165. 165.
    Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258Google Scholar
  166. 166.
    Cleland JG, Hutchinson K, Pellicori P, Clark A (2014) Lipid-modifying treatments for heart failure: is their use justified? Heart Fail Clin 10(4):621–634Google Scholar
  167. 167.
    Rosca MG, Tandler B, Hoppel CL (2013) Mitochondria in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 55:31–41Google Scholar
  168. 168.
    Schwarz K, Siddiqi N, Singh S, Neil CJ, Dawson DK, Frenneaux MP (2014) The breathing heart—mitochondrial respiratory chain dysfunction in cardiac disease. Int J Cardiol 171(2):134–143Google Scholar
  169. 169.
    Brunel-Guitton C, Levtova A, Sasarman F (2015) Mitochondrial diseases and cardiomyopathies. Can J Cardiol 31(11):1360–1376Google Scholar
  170. 170.
    Arcaro A, Pirozzi F, Angelini A, Chimenti C, Crotti L, Giordano C et al (2016) Novel perspectives in redox biology and pathophysiology of failing myocytes: modulation of the intramyocardial redox milieu for therapeutic interventions—a review article from the working group of cardiac cell biology, Italian Society of Cardiology. Oxidative Med Cell Longev 2016:6353469Google Scholar
  171. 171.
    Grois L, Hupf J, Reinders J, Schroder J, Dietl A, Schmid PM et al (2017) Combined inhibition of the renin-angiotensin system and neprilysin positively influences complex mitochondrial adaptations in progressive experimental heart failure. PLoS One 12(1):1–21Google Scholar
  172. 172.
    Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM (2016) Coenzyme Q10 and heart failure: a state-of-the-art review. Circ-Heart Fail 9(4):1–8Google Scholar
  173. 173.
    Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M et al (2008) Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol 52(18):1435–1441Google Scholar
  174. 174.
    Parihar P, Parihar MS (2017) Metabolic enzymes dysregulation in heart failure: the prospective therapy. Heart Fail Rev 22(1):109–121Google Scholar
  175. 175.
    Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48(4):297–310Google Scholar
  176. 176.
    Holzem KM, Vinnakota KC, Ravikumar VK, Madden EJ, Ewald GA, Dikranian K et al (2016) Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts. FASEB J 30(8):2698–2707Google Scholar
  177. 177.
    Cordero-Reyes AM, Gupte AA, Youker KA, Loebe M, Hsueh WA, Torre-Amione G et al (2014) Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function. J Mol Cell Cardiol 68:98–105Google Scholar
  178. 178.
    Hackam DG (2007) Translating animal research into clinical benefit—poor methodological standards in animal studies mean that positive results may not translate to the clinical domain. Br Med J 334(7586):163–164Google Scholar
  179. 179.
    Chandrasekera PC, Pippin JJ (2015) The human subject: an integrative animal model for 21(st) century heart failure research. Am J Transl Res 7(9):1636–1647Google Scholar
  180. 180.
    Wever-Pinzon O, Drakos SG, McKellar SH, Horne BD, Caine WT, Kfoury AG et al (2016) Cardiac recovery during long-term left ventricular assist device support. J Am Coll Cardiol 68(14):1540–1553Google Scholar
  181. 181.
    Dandel M, Hetzer R (2018) Recovery of failing hearts by mechanical unloading: pathophysiologic insights and clinical relevance. Am Heart J 206:30–50Google Scholar
  182. 182.
    Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S et al (2019) Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 393(10166):61–73Google Scholar
  183. 183.
    Uriel N, Kim G, Burkhoff D (2017) Myocardial recovery after LVAD implantation a vision or simply an illusion? J Am Coll Cardiol 70(3):355–357Google Scholar
  184. 184.
    Frigerio M, Roubina E (2005) Drugs for left ventricular remodeling in heart failure. Am J Cardiol 96(12A):10L–18LGoogle Scholar
  185. 185.
    Jweied E, de Tombe P, Buttrick PM (2007) The use of human cardiac tissue in biophysical research: the risks of translation. J Mol Cell Cardiol 42(4):722–726Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sydney Medical SchoolUniversity of SydneyCamperdownAustralia
  2. 2.Bosch Institute, School of Medical SciencesUniversity of SydneyCamperdownAustralia
  3. 3.Department of Pharmacy and Biomedical ScienceLa Trobe UniversityMelbourneAustralia
  4. 4.Department of CardiologyRoyal Prince Alfred HospitalSydneyAustralia
  5. 5.Cardiac Research Laboratory, Discipline of Anatomy and HistologyUniversity of SydneyCamperdownAustralia

Personalised recommendations